Clinical trial NCT04881461
Conditions: Allergy
Keywords: Allergic rhinoconjunctivitis Adults Grass
Sponsor: ALK-Abelló A/S
Start date: 2021-05-10; Completion date: 2023-09-26
Enrollment: 445 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
This is a 2 year clinical study to compare 5-grass mix SLIT-drops with placebo in relieving grass pollen-induced rhinoconjunctivitis symptoms and in use of symptom-relieving medication during the second grass pollen season (peak grass pollen season, PGPS)

The study will collect health-related quality of life data in the groups treated with 5-grass mix SLIT-drops or with placebo during the first and second PGPS.

The trial medication used is already approved to treat allergic rhinitis caused by grass pollen in adults in several countries.

Detailed description:
This trial is a 2 year, parallel-group, double-blind, placebo-controlled phase III trial to evaluate efficacy and safety of the 5-grass mix SLIT-drops in adults with grass pollen-induced rhinoconjunctivitis with or without asthma. Approximately 440 adults will be enrolled in the trial and will receive the 5-grass mix SLIT-drops or placebo. The trial is conducted in several European countries.

Arms: arm 1: Glycerol, carbonate, sodium chloride One single-dose container (0.5 ml) once daily arm 2: Grass mix sublingual allergy immunotherapy drops One single-dose container (0.5 ml) once daily. 50 SRU/day for five consecutive days followed by 150 SRU/day for five additional consecutive days. Maintenance: 300 SRU/day from day 11.
Interventions: intervention 1: 5-grass mix SLIT-drops intervention 2: Placebo
Intervention descriptions: intervention 1: Sublingual allergy immunotherapy drops, for daily administration intervention 2: Placebo

Protocol documents:
Prot_000.pdf: 
Cover page 
SU-G-01 
Grass SLIT-drops 
COVER PAGE SU-G-01 TRIAL PROTOCOL 
Official trial title 
A randomised, parallel-group, double-blind, placebo-controlled phase III trial assessing 
the efficacy and safety of 5-grass mix SLIT-drops in adults with grass pollen-induced 
rhinoconjunctivitis 
NCT number 
NCT04881461 
Document date 
12-Nov-2021


Clinical trial protocol 
Date: 
12-Nov-2021
Trial ID: SU-G-01 
Version: 
4.0 
EudraCT No. 2020-000455-12 
Status: 
Final 
CONFIDENTIAL 
Page: 
1 of 77 
Clinical trial protocol 
Trial ID: SU-G-01 
A randomised, parallel-group, double-blind, placebo-controlled phase III trial 
assessing the efficacy and safety of 5-grass mix SLIT-drops in adults with  
grass pollen-induced rhinoconjunctivitis 
Sponsor: 
ALK-Abelló A/S 
Bøge Alle 6-8 
DK-2970 Hørsholm 
Investigational medicinal product: 5-grass mix SLIT-drops 
Phase: III  
Regulatory trial identifier number(s):  
EudraCT No: 2020-000455-12  
Document status: Final 
Date: 12-Nov-2021 
Version number: 4.0 
Property of ALK  
May not be used, divulged, published or otherwise disclosed without the written consent of ALK 


Clinical trial protocol 
Date: 
12-Nov-2021
Trial ID: SU-G-01 
Version: 
4.0 
EudraCT No. 2020-000455-12 
Status: 
Final 
CONFIDENTIAL 
Page: 
2 of 77 
Protocol synopsis
Trial ID 
EudraCT no. 
SU-G-01 
2020-000455-12 
Title of trial 
A randomised, parallel-group, double-blind, placebo-controlled phase III 
trial assessing the efficacy and safety of 5-grass mix SLIT-drops in adults 
with grass pollen-induced rhinoconjunctivitis 
Main objectives 
Primary objective: 
•
To compare the efficacy of 5-grass mix SLIT-drops to placebo in
relieving grass rhinoconjunctivitis symptoms and in use of
symptom-relief medication during the 2nd Peak Grass Pollen
Season (PGPS)
Key secondary objectives: 
•
To measure the impact of treatment with 5-grass mix SLIT-drops
compared to placebo on health-related quality of life as a result of
grass pollen-induced rhinoconjunctivitis during the 2nd PGPS
•
To compare the efficacy of 5-grass mix SLIT-drops to placebo in
relieving grass rhinoconjunctivitis symptoms and in use of
symptom-relief medication during the 1st PGPS
•
To measure the impact of treatment with 5-grass mix SLIT-drops
compared with placebo on health-related quality of life as a result
of their grass pollen-induced rhinoconjunctivitis during the 1st
PGPS
Primary estimand 
The primary estimand is the absolute difference between the 
5-grass SLIT-drops and placebo treatment policies based on the average
total combined score (TCS) during the 2nd PGPS in the population is
defined by the trial inclusion and exclusion criteria, in the hypothetical
situation that all subjects complete treatment for the planned duration.
Secondary 
estimand 
The 
secondary 
estimand 
is 
the 
absolute 
difference 
between 
5-grass SLIT-drops and placebo treatment policies based on the average
TCS during the 2nd PGPS, in a population defined by the trial inclusion and
exclusion criteria, regardless of whether subjects complete treatment for the
planned duration.
Primary endpoint 
The primary efficacy endpoint is the average daily allergic rhinoconjunctivitis 
TCS during the 2nd PGPS 
Secondary 
endpoints 
•
The average weekly overall rhinitis quality of life questionnaire (RQLQ)
score during the 2nd PGPS
•
The average daily allergic rhinoconjunctivitis TCS during the 1st PGPS


Clinical trial protocol 
Date: 
12-Nov-2021
Trial ID: SU-G-01 
Version: 
4.0 
EudraCT No. 2020-000455-12 
Status: 
Final 
CONFIDENTIAL 
Page: 
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•
The average weekly overall RQLQ score during the 1st PGPS
Trial design 
A phase III randomised, parallel-group, double-blind, placebo-controlled trial 
of 5-grass mix SLIT-drops in adults with grass pollen-induced moderate to 
severe allergic rhinoconjunctivitis, with or without asthma, conducted over 
two grass pollen seasons 
All randomised subjects should receive daily treatment continuously from at 
least 16 weeks before the anticipated start of the 1st entire grass pollen 
season (EGPS) through the 2nd EGPS, corresponding to approximately 26 
months of treatment 
At least 9 in-clinic visits and up to 3 phone contacts are planned for each 
subject 
Main assessments 
Efficacy assessments: 
Rhinoconjunctivitis symptoms assessment (Nose symptoms; runny nose, 
blocked nose, sneezing, itchy nose; Eye symptoms; gritty feeling of the 
eyes, red/ itchy eyes and watery eyes) 
Rhinoconjunctivitis rescue medication 
Safety assessments: 
Adverse events 
Clinical laboratory tests 
Vital and clinical signs 
Main criteria for 
inclusion 
•
Male or female aged ≥18 years on the day informed consent is
obtained
•
A clinical history of grass pollen-induced allergic rhinoconjunctivitis for
two years or more with or without asthma
•
A clinical history of severe allergic rhinoconjunctivitis symptoms
(interfering with usual daily activities or sleep) induced by grass pollen,
which remain troublesome despite symptomatic treatment with
antihistamines, nasal steroids or eye drops during the previous grass
pollen season
•
Positive specific immunoglobulin E (IgE) (defined as ≥class 2, ≥0.70
kU/l) against grass: Phleum pratense
•
Positive skin prick test to Phleum pratense at screening
Main criteria for 
exclusion 
•
Has a clinically relevant history of symptomatic seasonal and/or
perennial allergic rhinoconjunctivitis and/or asthma caused by an
allergen other than grass pollen, to which the subject is exposed,
which could potentially overlap with the efficacy assessment periods


Clinical trial protocol 
Date: 
12-Nov-2021
Trial ID: SU-G-01 
Version: 
4.0 
EudraCT No. 2020-000455-12 
Status: 
Final 
CONFIDENTIAL 
Page: 
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•
Within the last 3 months before the randomisation visit, has had an
occurrence of any clinical deterioration of asthma that resulted in
emergency treatment, hospitalisation, or treatment with systemic
corticosteroids
•
SLIT treatment with any grass pollen AIT for more than 1 month within
the last 5 years. In addition, any SLIT treatment with grass pollen AIT
within the previous 12 months
•
SCIT treatment with any grass AIT reaching the maintenance dose
within the last 5 years. In addition, any SCIT treatment with grass AIT
within the previous 12 months
•
Ongoing treatment with any allergy immunotherapy product
•
Uncontrolled or severe asthma requiring daily use of more than 800
mcg budesonide or equivalent at screening
Investigational 
medicinal products 
ALK 5-grass mix SLIT-drops 
The 5-grass mix SLIT-drops contains 5 different grass species: Dactylis 
glomerata L (cat grass / cock’s foot / orchard grass), Phleum pratense L. 
(timothy), Lolium perenne L. (ryegrass), Anthoxanthum odoratum L (sweet 
vernal / vernal grass), Poa pratensis L. (Kentucky bluegrass) 
The treatment schedule for the allergens included in this trial will be as 
follows: 
•
Initiation: 50 SRU/day for five consecutive days followed by 150
SRU/day for five additional consecutive days
•
Maintenance: 300 SRU/day (once a day) from day 11
The investigational treatment must be taken continuously during the trial 
Duration of 
treatment 
Treatment will be initiated after the end of the entire 2021 grass pollen 
season and will continue until the end of the 2023 entire grass pollen 
season corresponding to approximately 26 months of treatment 
Number of subjects 
to be enrolled 
440 subjects to be randomised 
Number and 
distribution of trial 
sites 
Estimated 50-65 
Statistical methods 
Statistical analyses will be performed using SAS software, version 9.4 or 
later (Cary, North Carolina, SAS Institute Inc.). All efficacy analyses will be 
performed based on the full analysis set employing hierarchically testing to 
control the family-wise error rate at 5% level. All endpoints will be tested 
on a 5% significance level, and all tests and confidence intervals will be 2-
sided. 


Clinical trial protocol 
Date: 
12-Nov-2021
Trial ID: SU-G-01 
Version: 
4.0 
EudraCT No. 2020-000455-12 
Status: 
Final 
CONFIDENTIAL 
Page: 
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Using the framework proposed in the ICH E9(R1) addendum, two 
estimands are defined: primary estimand - trial product estimand and 
secondary estimand - treatment policy estimand. The main estimator and 
sensitivity estimator(s) 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 IEs and missing data.  
The absolute treatment difference between two treatments will be 
estimated based on the full analysis set by using model of Mixed Model of 
Repeated Measurements with relevant endpoint in 1st year and in 2nd 
year as the response variables, treatment, visit number, interaction of 
treatment and visit number and asthma indicator as fixed variables and 
trial site as a random class effect. The estimated difference in adjusted 
means between the two groups will be presented together with the 
associated 2-sided 95%-confidence interval and the p-value for the test of 
no difference.  
Missing data will be imputed using method of unrestricted random 
sampling with replacement. The average score will be imputed, but not the 
daily/weekly values. Rubin’s multiple imputation strategy with 1000 
imputations will be used. Seed used for imputation will be 12345. 
Safety evaluation will include description of AEs, and descriptive data 
analysis of laboratory assessments, and vital signs. The safety evaluation 
will be based on the safety analysis set (all randomised subjects who 
received at least one dose of IMP). 
International 
coordinating 
investigator 
Sponsor’s 
name/address 
ALK Abelló A/S,  
Bøge Allé 1,  
DK-2970 Hørsholm 
Denmark 


Clinical trial protocol 
Date: 
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Trial ID: SU-G-01 
Version: 
4.0 
EudraCT No. 2020-000455-12 
Status: 
Final 
CONFIDENTIAL 
Page: 
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Table of contents   
Page 
Protocol synopsis ................................................................................................................. 2
Table of contents ................................................................................................................... 6
Table of figures...................................................................................................................... 9
Table of tables ....................................................................................................................... 9
List of appendices ............................................................................................................... 10
Table of abbreviations ........................................................................................................ 11
Table of definitions ............................................................................................................. 13
Protocol versions ................................................................................................................ 15
Flow chart ............................................................................................................................ 16
1 
Introduction ................................................................................................................... 19
1.1
Disease background and current treatment modalities ........................................ 19
1.2
Stage of development ......................................................................................... 20
1.3
Trial rationale ...................................................................................................... 20
1.4
Benefit-risk assessments .................................................................................... 20
1.4.1
Considerations regarding COVID-19 ................................................... 21
1.5
Ethical considerations ......................................................................................... 22
2 
Objectives, Estimands and endpoints ......................................................................... 22
2.1
Primary objective ................................................................................................. 22
2.2
Secondary objectives .......................................................................................... 22
2.2.1
Key secondary objectives .................................................................... 22
2.2.2
Supportive secondary objectives ......................................................... 22
2.3
Exploratory objectives ......................................................................................... 23
2.4
Primary estimand ................................................................................................ 23
2.5
Secondary estimand ........................................................................................... 23
2.6
Estimands for key secondary and supportive secondary objectives .................... 24
2.7
Primary endpoint ................................................................................................. 24
2.8
Secondary endpoints........................................................................................... 24
2.8.1
Key secondary endpoints .................................................................... 24
2.8.2
Supportive secondary endpoints ......................................................... 24
2.9
Exploratory endpoints.......................................................................................... 24
3 
Trial design .................................................................................................................... 25
3.1
Summary of trial design ....................................................................................... 25
3.1.1
Definition of pollen seasons ................................................................. 25
3.2
Discussion of design ........................................................................................... 26
3.3
Justification of dose ............................................................................................. 27
3.4
End of trial definition ............................................................................................ 27
4 
Trial population ............................................................................................................. 28
4.1
Inclusion criteria .................................................................................................. 28
4.2
Exclusion criteria ................................................................................................. 29
4.3
Screen failures .................................................................................................... 30


Clinical trial protocol 
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Trial ID: SU-G-01 
Version: 
4.0 
EudraCT No. 2020-000455-12  
Status: 
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CONFIDENTIAL 
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4.3.1 
Rescreening ........................................................................................ 30 
5 
Subject discontinuation ............................................................................................... 30 
5.1 
Discontinuation from IMP treatment .................................................................... 30 
5.2 
Discontinuation from trial ..................................................................................... 30 
5.3 
Lost to follow-up .................................................................................................. 31 
5.4 
Replacement of subjects ..................................................................................... 31 
6 
Randomisation and treatment blinding/unblinding .................................................... 31 
6.1 
Subject ID number .............................................................................................. 31 
6.2 
Randomisation .................................................................................................... 32 
6.3 
Treatment blinding/unblinding ............................................................................. 32 
6.4 
Subject card ........................................................................................................ 32 
7 
Restricted and prohibited concomitant medication ................................................... 32 
8 
Trial products ................................................................................................................ 35 
8.1 
IMP ..................................................................................................................... 35 
8.2 
Rescue medication .............................................................................................. 35 
8.3 
Packaging and labelling ...................................................................................... 36 
8.4 
Handling and storage .......................................................................................... 36 
8.5 
IMP and rescue medication accountability ........................................................... 37 
8.6 
Reporting of technical complaints ........................................................................ 37 
9 
Treatment ...................................................................................................................... 37 
9.1 
Treatment administration ..................................................................................... 37 
9.2 
Precautions in relation to first dosing ................................................................... 38 
9.3 
Treatment of severe allergic reactions/anaphylaxis ............................................. 38 
9.4 
Temporary interruption and discontinuation of treatment ..................................... 38 
9.5 
Post-trial treatment .............................................................................................. 39 
10 Visit schedule ................................................................................................................ 40 
11 Trial procedures ............................................................................................................ 40 
11.1 
Informed consent ................................................................................................ 40 
11.2 
Consent to collection of blood samples for storage in biobank ............................ 41 
11.3 
Demographics and body measurements ............................................................. 41 
11.4 
Medical history .................................................................................................... 41 
11.5 
Smoking habits.................................................................................................... 41 
11.6 
Concomitant and previous medication ................................................................. 41 
11.7 
Lung function ...................................................................................................... 42 
11.8 
Physical examination........................................................................................... 42 
11.9 
Eosinophilic Oesophagitis ................................................................................... 43 
11.10 Pregnancy test .................................................................................................... 43 
11.11 Skin prick test ...................................................................................................... 43 
11.12 Vital signs ............................................................................................................ 44 
11.13 Blood and urine sampling .................................................................................... 45 
11.14 Laboratory assessments ..................................................................................... 45 
11.15 Long-term storage of samples ............................................................................. 46 
11.16 Electronic diary and patient reported outcome questionnaires ............................. 47 
11.16.1 
Symptom assessment: Rhinitis and conjunctivitis symptoms ............... 47 
11.16.2 
Medication assessment ....................................................................... 47 


Clinical trial protocol 
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Version: 
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Status: 
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CONFIDENTIAL 
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 ............................................................................................. 48
11.16.4 
Rhinoconjunctivitis quality of life questionnaire .................................... 48
 ................................................................................ 48
11.17 Paper questionnaire ............................................................................................ 48
12 Safety procedures ......................................................................................................... 48
12.1 
Definitions ........................................................................................................... 49
12.2 
AE assessments ................................................................................................. 50
12.2.1
Severity ............................................................................................... 50
12.2.2
Causal relationship to IMP ................................................................... 50
12.2.3
Outcome ............................................................................................. 50
12.3 
Collection, recording and reporting of AEs .......................................................... 50
12.3.1
Reporting of SAEs ............................................................................... 51
12.3.2
Follow-up on AEs and SAEs ............................................................... 51
12.3.3
Reporting of medication errors, including overdose, abuse and misuse
 ............................................................................................................ 52
12.3.4
Reporting of significant laboratory events ............................................ 52
12.3.5
Reporting of pregnancies .................................................................... 52
12.3.6
Reporting of SAE and pregnancies after end of trial ............................ 52
12.4
Safety surveillance .............................................................................................. 53
12.5
DMC .................................................................................................................... 53
12.6
Pregnancy ........................................................................................................... 53
13 Early termination of trial ............................................................................................... 53
14 Data handling ................................................................................................................ 53
14.1
eCRF .................................................................................................................. 54
14.2
eDiary ................................................................................................................. 54
14.3
Query handling .................................................................................................... 55
14.4
Laboratory data ................................................................................................... 55
14.5
Database lock ..................................................................................................... 55
15 Statistical methods ....................................................................................................... 56
15.1
Estimands ........................................................................................................... 56
15.1.1
Intercurrent events .............................................................................. 56
15.1.2
Primary estimand ................................................................................ 57
15.1.3
Secondary estimand ............................................................................ 57
15.1.4
Estimands for key secondary and supportive secondary endpoints ..... 57
15.2
Sample size and power considerations ............................................................... 58
15.3
Analysis data sets ............................................................................................... 59
15.4
Subject disposition .............................................................................................. 60
15.5
Baseline characteristics ....................................................................................... 60
15.6
Extent of exposure .............................................................................................. 60
15.7
Medical history .................................................................................................... 60
15.8
Concomitant therapy ........................................................................................... 60
15.9
Derivation of endpoints ........................................................................................ 60
15.10 Multiplicity ........................................................................................................... 61
15.11 Efficacy analyses ................................................................................................ 61
15.11.1 
Estimator ............................................................................................. 61
15.11.2 
Handling of intercurrent events and missing data for the trial product 
estimand ............................................................................................. 63


Clinical trial protocol 
Date: 
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Trial ID: SU-G-01 
Version: 
4.0 
EudraCT No. 2020-000455-12  
Status: 
Final 
CONFIDENTIAL 
Page: 
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15.11.3 
Handling of intercurrent events and missing data for the treatment policy 
estimand ............................................................................................. 63 
15.11.4 
Estimators for estimands defined for key secondary efficacy objectives
 ............................................................................................................ 64 
15.11.5 
Exploratory analysis ............................................................................ 64 
15.12 Safety analyses ................................................................................................... 65 
15.12.1 
Evaluation of AEs ................................................................................ 65 
15.12.2 
Evaluation of other safety parameters ................................................. 65 
15.13 Interim analyses .................................................................................................. 65 
15.14 Handling of missing data ..................................................................................... 65 
16 Quality assurance and control ..................................................................................... 65 
16.1 
Monitoring ........................................................................................................... 65 
16.2 
Source data and access to source documents .................................................... 66 
16.3 
Investigator site file – and other trial documentation ............................................ 67 
16.4 
Protocol compliance ............................................................................................ 67 
16.5 
Audit .................................................................................................................... 67 
17 Ethics and regulatory procedures ............................................................................... 68 
17.1 
Statement of compliance ..................................................................................... 68 
17.2 
Disclosure and confidentiality .............................................................................. 68 
17.3 
Subject confidentiality.......................................................................................... 68 
17.4 
Data protection .................................................................................................... 68 
17.5 
IEC/IRB/regulatory authorities ............................................................................. 70 
17.6 
Inspections .......................................................................................................... 70 
17.7 
Protocol amendment and other changes in trial conduct ..................................... 70 
18 Reporting and publication ............................................................................................ 70 
18.1 
Integrated clinical trial report ............................................................................... 70 
18.2 
Publication of results ........................................................................................... 71 
19 Finance and insurance ................................................................................................. 72 
20 Trial organisation .......................................................................................................... 72 
21 Reference list ................................................................................................................ 73 
 
Table of figures    
 
Page 
Figure 1 
Trial design ......................................................................................................... 25 
 
Table of tables    
 
Page 
Table 1  
Grass pollen season definitions ........................................................................... 26 


Clinical trial protocol 
Date: 
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Trial ID: SU-G-01 
Version: 
4.0 
EudraCT No. 2020-000455-12 
Status: 
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CONFIDENTIAL 
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Table 2
Restricted concomitant medications .................................................................... 33
Table 3
IMP details .......................................................................................................... 35
Table 4
Schedule for rhinoconjunctivitis pharmacotherapy ............................................... 36
Table 5
Physical examination........................................................................................... 42
Table 6
Skin prick test ...................................................................................................... 43
Table 7
Medications with a possible interference with SPT .............................................. 44
Table 8
Mean and standard deviation of TCS during the peak of a season. ..................... 58
Table 9
Mean and standard deviation of RQLQ during the peak of a season. .................. 58
Table 10
Symptom relieving medication for rhinitis with/without conjunctivitis .................... 61
Table 11
Summary of MMRM response variables. ............................................................. 62
List of appendices 
Appendix 1: Protocol signature page  
Appendix 2: Investigator agreement on clinical trial protocol 
Appendix 3: Trial Organisation 
Appendix 4: Patient reported outcome questionnaires on health-related quality of life 
Appendix 5: Expected grass pollen season 
Appendix 6: COVID-19 pandemic measures  


Clinical trial protocol 
Date: 
12-Nov-2021
Trial ID: SU-G-01 
Version: 
4.0 
EudraCT No. 2020-000455-12 
Status: 
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CONFIDENTIAL 
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Table of abbreviations
AE 
Adverse event 
AIT 
Allergy immunotherapy 
ALT 
Alanine aminotransferase 
ARC 
Allergic rhinoconjunctivitis 
AST 
Aspartate aminotransferase 
BP 
Blood pressure 
CRA 
Clinical research associate 
CRO 
Clinical research organisation 
DMS 
Daily medication score 
DSS 
Daily symptoms score 
eCRF 
Electronic case report form 
EGPS 
Entire grass pollen season 
EMA 
European medicines agency 
ESI 
Events of special interest 
EudraCT 
European Union drug regulating authorities clinical trials database 
FAS 
Full analysis set 
FEV1 
Forced expiratory volume in 1 second 
FVC 
Forced vital capacity 
GCP 
Good clinical practice 
HAS 
Haute Autorité de Santé 
IB 
Investigators brochure 
ICH 
International conference on harmonisation of technical requirements for registration of 
pharmaceuticals for human use 
IEC 
Independent ethics committee 
IgE 
Immunoglobulin E 
IMP 
Investigational medicinal product 
IRB 
Institutional review board 
IRT 
Interactive response technology 
LABA 
Long-acting B-agonist 
LSLV 
Last subject last visit 
MAA 
Marketing authorisation application 


Clinical trial protocol 
Date: 
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Trial ID: SU-G-01 
Version: 
4.0 
EudraCT No. 2020-000455-12  
Status: 
Final 
CONFIDENTIAL 
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MAOIs 
Monoamine oxidase inhibitors 
MCID 
Minimal clinically important difference 
MedDRA 
Medical dictionary for regulatory activities 
MMRM 
Mixed Model of Repeated Measurements 
NPPs 
Named patient products  
PGPS 
Peak grass pollen season 
PP 
Per protocol 
QoL 
Quality of life 
QPPV 
Qualified person responsible for pharmacovigilance 
RCT 
Randomised controlled trial 
RQLQ  
Rhinitis quality of life questionnaire 
SABA 
Short-acting β2-agonist 
SAE 
Serious adverse event 
SAP 
Statistical analysis plan 
SAS 
Statistical analysis software; computer software for statistical programming 
SCIT 
Subcutaneous allergy immunotherapy 
SDTM 
Study Data Tabulation Model 
SLIT 
Sublingual allergy immunotherapy 
SLIT-drops 
Sublingual allergy immunotherapy drops 
SLIT-tablet 
Sublingual allergy immunotherapy tablet 
SmPC 
Summary of product characteristics 
SOP 
Standard operating procedure 
SPT 
Skin prick test 
SRU 
Standardized reactivity unit 
SUSAR 
Suspected unexpected serious adverse reactions  
TEAE 
Treatment emergent adverse events  
TCS 
Total combined score 
WHO 
World Health Organisation 


Clinical trial protocol 
Date: 
12-Nov-2021
Trial ID: SU-G-01 
Version: 
4.0 
EudraCT No. 2020-000455-12 
Status: 
Final 
CONFIDENTIAL 
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Table of definitions
Anaphylaxis 
The definition of anaphylaxis (Sampson H.A.et al. 2006) includes any 1 of the 
following 3 criteria: 
1.
Acute onset of an illness (minutes to several hours) with involvement of the skin,
mucosal tissue, or both (e.g. generalised hives, pruritus, or flushing, or swollen
lips, tongue, or uvula) AND either respiratory compromise (e.g. dyspnoea,
wheeze-bronchospasm, stridor, reduced Peak Expiratory Flow (PEF),
hypoxemia) or reduced BP* or associated symptoms of end-organ dysfunction
(e.g. hypotonia [collapse], syncope, incontinence)
2.
Two or more of the following that occur rapidly after exposure to a likely allergen
for the subject (minutes to several hours):
a)
Involvement of the skin-mucosal tissue (e.g. generalised hives, itch-flush,
swollen lips, tongue, or uvula)
b)
Respiratory compromise (e.g. dyspnoea, wheeze-bronchospasm, stridor,
reduced PEF, hypoxemia)
c)
Reduced BP* or associated symptoms (e.g. hypotonia [collapse], syncope,
incontinence)
d)
Persistent gastrointestinal symptoms (e.g. crampy abdominal pain, vomiting)
3.
Reduced BP after exposure to known allergen for the subject (minutes to several
hours): low systolic BP* or greater than 30% decrease in systolic BP
*Low systolic BP is defined as less than (70 mmHg + [2 x age]) from 1 to 10 years,
and less than 90 mmHg from 11 to 17 years
Completed 
subject 
A randomised subject is considered completed if he/she has not discontinued the trial 
before visit 9 
Completion date 
For each completed subject, the date of the last scheduled procedure/end of trial visit 
(visit 9) 
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 (TC 
follow-up) for the last subject in the trial  
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). 
Grass pollen 
season 
•
Start date: The first day of 3 consecutive days with (non-missing) pollen count
larger than or equal to 10 grains/m3
•
Stop date: The last day before 3 consecutive days with (non-missing) pollen
count less than 10 grains/m3
•
Peak: The 15 days period with the highest average pollen count during the entire
grass pollen season
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 


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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 to be used for managing randomisation, subject enrolment and 
trial supply management in this trial 
LSLV 
Last scheduled physical visit for any subject (visit 9) 
Life-threatening 
asthma 
Asthma worsening that requires intubation and/or is associated with hypercapnia 
requiring non-invasive ventilator support 
Primary 
completion date 
Date of the last data collection for the primary endpoint (ClinicalTrials.gov) is the last 
scheduled physical visit for any subject (visit 9) 
Rescue 
medication 
Medicinal products provided by ALK when the efficacy of the IMP is not sufficient or 
likely to cause an adverse event (AE) to the subject or to manage an emergency 
situation in relation to grass pollen allergy symptoms in agreement with the EMA 
Definition of IMPs and Use of AMPs Consultation Document (EMA 2016)  
The rhinoconjunctivitis rescue medication in this trial is: 
•
Antihistamine tablets
•
Antihistamine eye drops
•
Corticosteroid nasal spray
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 
TEAE 
TEAEs are defined as adverse events with start date and/or 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 
discontinuation date is defined as the date the investigator/sponsor decides to 
discontinue the subject 


Clinical trial protocol 
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CONFIDENTIAL 
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Protocol versions
Date 
Version 
Description of 
document 
Rationale for amendment 
29-Jan-2020
1.0 
Final Protocol 
N/A 
11-Mar-2020 2.0 
Final Protocol 
Version update to align with IB 
23-Oct-2020
3.0 
Final Protocol 
Key changes: 
•
To address EMA recommendations in the ‘Guidance on the
Management of Clinical Trials during the COVID-19
(Coronavirus) pandemic’ (EMA 2020)
•
FEV1 removed from screening visit 1 and from subsequent
visits after randomisation visit 2
•
Oropharyngeal exam removed from screening visit 1 and
from subsequent visits after randomisation visit 2
•
Addition of retention TC between visits V5 and V6
•
Removal of visit schedules/content from section 10. This
section is not mandatory, is repetitive to the flow chart and
assessments and creates a risk for error
•
Estimand has been added as per ICH E9 (R1) addendum
on estimands and sensitivity analysis in clinical trials to the
guideline on statistical principles for clinical trials (Step 5)
(ICH 2020)
12-Nov-2021 4.0 
Final Protocol 
Key changes 
•
List of appendices updates
•
Flowchart: Time window for V4 and V7 expanded to allow
up to 14 days prior to EGPS. Footnote 1 updated with
'optional' referring to TC1 and updated year of
randomisation to 2021.
•
3.4: End of trial definition updated to the date of the last
follow-up phone visit (TC follow-up) for the last subject in
the trial.
•
7.: Table 2 updated due to reassessment of criticality of
restricted and prohibited concomitant medication.
•
11.4: clarification on stratification added to medical history:
A subject should be stratified as asthmatic if they have been
diagnosed and/or treated for asthma in adulthood.
•
11.14: Assessments reordered to ease readability
•
12.1: Deletion of bullet stating that events defined as
efficacy endpoints should not be recorded as AEs.
•
12.1: Addition of bracket in sentence: Selected AEs (non-
serious or serious) will be considered ESIs
•
12.3 and 12.3.1 Specification of ESI forms and procedures
•
15.11.4 Correction of undefined reference
•
Appendix 3 updated due to change of central lab and CRO
legal entity and contact details


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Flow chart 
Visit ID: 
Protocol 
section 
V1 
V2 
TC1 
V3 
V4 
V5 
TC2 
V6 
V7 
V8 
V9 
TC   
Follow-
up 
Unsched-
uled visit 
Visit: 
V=Site Visit 
TC=Telephone Contact 
 
Screening 
Random-
isation 
Optional  
between 
V2 and 
V31 
1st off- 
season 
1st pre-
EGPS2  
1st on-
season  
Retention 
between 
V5 and 
V6 
2nd off-
season  
2nd pre-
EGPS2   
2nd on-
season  
End of 
trial  
Post-
treat-
ment 
 
Time Window  
 
At least 3 
days before 
V2  
 
At least 
16 
weeks 
before 
start of 
1st 
EGPS2 
November 
2021 
January 
2022  
14 to 0 
days 
before 
start of 
1st 
EGPS2 
7 to 0 
days 
before 
expected 
PGPS3 
4-12 
weeks 
before 
V6 
January 
2023 
 
14 to 0 
days 
before 
start of 
2nd 
EGPS2 
7 to 0 
days 
before 
expected 
PGPS3  
1 to 7 
days 
from 
end of 
2nd 
EGPS2  
4 to 10 
days 
after V9   
As 
necessary 
Informed consent 
11.1 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Demography and body measurements 
11.3 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Smoking habits 
11.5 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Medical history 
11.4 
X 
 
 
 
 
 
 
 
 
 
 
 
 
In-/exclusion criteria 
4.1/4.2 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
Randomisation 
6 
 
X 
 
 
 
 
 
 
 
 
 
 
 
Urine pregnancy test4 
11.10 
(X) 
(X) 
 
(X) 
(X) 
(X) 
 
(X) 
(X) 
(X) 
(X) 
 
(X) 
Physical examination 
11.8 
X 
 
 
 
 
 
 
 
 
 
X 
 
(X) 
 
1 An optional retention telephone contact for those subjects randomised between start of August and end of November 2021 
2 EGPS- entire grass pollen season (see Appendix 5) 
3 PGPS- peak grass pollen season (see Appendix 5) 
4 For females of child-bearing potential, urine pregnancy tests should be performed at each visit and if a menstrual period is missed.   


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Visit ID: 
Protocol 
section 
V1 
V2 
TC1 
V3 
V4 
V5 
TC2 
V6 
V7 
V8 
V9 
TC   
Follow-
up 
Unsched-
uled visit 
Visit: 
V=Site Visit 
TC=Telephone Contact 
 
Screening 
Random-
isation 
Optional  
between 
V2 and 
V31 
1st off- 
season 
1st pre-
EGPS2  
1st on-
season  
Retention 
between 
V5 and 
V6 
2nd off-
season  
2nd pre-
EGPS2   
2nd on-
season  
End of 
trial  
Post-
treat-
ment 
 
Oropharyngeal examination 
11.8 
 
X 
 
 
 
 
 
 
 
 
 
 
(X) 
Vital signs 
11.12 
X 
X 
 
X 
X 
X 
 
X 
X 
X 
X 
 
(X) 
Lung function test 
11.7 
 
X 
 
 
 
 
 
 
 
 
 
 
(X) 
Blood and urine samples for safety 
laboratory assessments 
11.13 
X 
 
 
 
 
 
 
 
 
 
X 
 
(X) 
Blood sample for specific IgE  
11.14 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
11.14 
X 
 
 
X 
X 
 
 
X 
 
 
X 
 
(X) 
Blood sample for biobanking5 
11.15 
(X) 
 
 
 
 
 
 
 
 
 
(X) 
 
 
SPT 
11.11 
X 
(X) 
 
 
 
 
 
 
 
 
 
 
(X) 
Intake of IMP at clinic 
9.1/9.2 
 
X 
 
 
 
 
 
 
 
 
 
 
 
Instruct the subject in use of IMP 
9.1/9.2 
 
X 
 
 
 
 
 
 
 
 
 
 
 
Record previous and concomitant 
medication 
11.6 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Assess and/or record AEs 
12.2 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Assess eosinophilic eosophagitis 
11.9 
X 
X 
 
X 
X 
X 
 
X 
X 
X 
X 
 
(X) 
Dispense IMP 
8.1 
 
X 
 
X 
X 
X 
 
X 
X 
X 
 
 
(X) 
 
5 Only if biobanking specific informed consent has been signed and according to country specific regulations. 


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Visit ID: 
Protocol 
section 
V1 
V2 
TC1 
V3 
V4 
V5 
TC2 
V6 
V7 
V8 
V9 
TC   
Follow-
up 
Unsched-
uled visit 
Visit: 
V=Site Visit 
TC=Telephone Contact 
 
Screening 
Random-
isation 
Optional  
between 
V2 and 
V31 
1st off- 
season 
1st pre-
EGPS2  
1st on-
season  
Retention 
between 
V5 and 
V6 
2nd off-
season  
2nd pre-
EGPS2   
2nd on-
season  
End of 
trial  
Post-
treat-
ment 
 
Dispense rescue medication 
8.2 
 
 
 
 
X 
(X) 
 
 
(X) 
(X) 
 
 
(X) 
Trial medication collection, compliance 
check compliance and drug 
accountability 
8.5 
 
 
 
X 
X 
X 
 
X 
X 
X 
X 
 
X 
 
11.17 
 
X 
 
 
 
 
 
 
 
 
X 
 
 
Issue and instruct in use of E- 
diary/LogPad 
11.16 
 
 
 
X 
 
 
 
 
 
 
 
 
 
Instruct in use of E- diary/LogPad 
11.16 
 
 
 
 
X 
(X) 
 
 
X 
(X) 
 
 
 
eDiary completion: 
• 
 
11.16.5 
 
 
 
 
 
X6 
 
 
 
 
 
 
 
eDiary completion: 
• 
RQLQ  
11.16.4 
 
 
 
X 
X……………….X7 
 
 
X……………….X7 
 
 
 
eDiary completion: 
• 
Symptoms 
• 
Medication 
11.16.1/ 
11.16.2 
 
 
 
 
X……………….X7 
 
 
X……………….X7 
 
 
 
eDiary completion:                  
• 
 
11.16.3 
 
 
 
 
X……………….X7 
 
 
X……………….X7 
 
 
 
Review eDiary recordings 
11.16 
 
 
 
 
 
X 
 
X 
X 
X 
X 
 
(X) 
Collect eDiary 
 
 
 
 
 
 
 
 
 
 
 
X 
 
 
 
6 The 
 will be performed at the defined end of the EGPS for each region (see Appendix 5) 
7 Rhinoconjunctivitis symptoms scores, use of rescue medication and 
 will be collected daily and RQLQ will be collected weekly during the EGPS until the defined end of the EGPS for 
each region (see Appendix 5) 


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1 
INTRODUCTION 
1.1 
Disease background and current treatment modalities 
Disease Background 
Allergic rhinoconjunctivitis (ARC) represents a global health problem, with grass pollen induced 
ARC being the most prevalent pollen allergy. An estimated 15 to 40% of the global population are 
affected (Brozek et al. 2017) and the number appears to be rising (Linneberg et al. 2007). 
Although the prevalence of seasonal ARC (hay fever) varies, studies including more than 100,000 
subjects have documented a high prevalence of ARC in Western European countries. If left 
untreated, ARC is considered to be one of the major risk factors for the development of asthma 
(Corren 2007). In 2013, data from the World Health Organization (WHO) showed the prevalence 
of asthma in the European Union to be 9.4% for children and 8.2 % for adults (Selroos et al. 
2015). Allergy immunotherapy (AIT) is a well-established therapy for improving ARC symptoms 
and limiting the progression of the disease by preventing the development of asthma and new 
allergen sensitisations (Jutel et al. 2016). 
Current Treatment Modalities 
The therapeutic management of allergy currently involves one or more of the following 
approaches: 
-
Allergen avoidance
-
Symptomatic medication
-
Specific immunotherapy
The strategy of allergen avoidance is difficult for an airborne allergen such as grass pollen, and 
while symptomatic medications may offer short-term relief of symptoms, they do not treat the 
underlying cause of allergy and hence cannot provide long-term remission. Furthermore, a 
significant number of people with allergic rhinitis continue to experience residual allergic symptoms 
despite use of symptomatic pharmacotherapy (Feliziani et al. 1995; Niggemann et al. 2006). 
Only specific immunotherapy targets the underlying allergic disease and, as such, has the potential 
to produce long-term remission as well as to prevent the development of new sensitisation and 
asthma. Traditionally, immunotherapy has been administered subcutaneously and due to the 
requirement for injectable delivery and the safety profile, its administration has been restricted to a 
clinical setting. The development of immunotherapy as sublingual drops and as tablets has 
provided a safer and more convenient alternative to the subcutaneous route (Durham & Penagos 
2016), allowing home administration by the patient.  
Sublingual immunotherapy (SLIT) administered as drops or tablets is an approved form of AIT 
shown to be effective in the treatment of severe grass pollen-induced ARC (Dretzke et al. 2013). 
The French National Authority for Health (Haute Autorité de Santé; HAS) have requested the 
demonstration of treatment benefit of allergen products specifically prepared for individuals (or 
named patient products (NPPs)) that are currently marketed in France. The SLIT NPP developed 
by ALK and currently registered under the French nominative authorisation APSI8 in France, is 
OSIRIS®. 
8 In France the NPP status is named allergènes préparés spécialement pour un individu (APSI [allergens 
specially prepared for individuals]) 


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1.2 
Stage of development 
OSIRIS® is a SLIT-drop product that has been available to patients in France since 1992. OSIRIS® 
has been available in selected European countries as SLIToneULTRA® since 2012.  
OSIRIS® and SLIToneULTRA® have the same composition of excipients (sodium chloride, sodium 
bicarbonate and glycerol), however they differ in their presentation: OSIRIS® is available in vials of 
3000 SRU/10 ml with a syringe to deliver the volume corresponding to 300 SRU each day, 
whereas SLIToneULTRA® is available as single-dose containers of 0.5 ml containing 50 SRU, 150 
SRU or 300 SRU per 0.5 ml. OSIRIS® and SLIToneULTRA® 5-grass mixes contain 20% each of 
the homologous grass species Dactylis glomerata, Lolium perenne, Phleum pratense, Poa 
pratensis and Anthoxanthum odoratum.  
In agreement with the HAS, SLIToneULTRA® five-grass mix has been selected as the 
investigational medicinal product in this trial because of the similarity of the formulations and due to 
the single-dose delivery in a clinical trial setting. SLIToneULTRA® five-grass mix will be referred to 
hereafter by the generic name 5-grass mix SLIT-drops. 
1.3 
Trial rationale 
The rationale for conducting this trial is to generate further clinical data on the efficacy and safety 
of 5-grass mix SLIT-drops based on a request from HAS requiring Marketing Authorisation 
Application (MAA) holders of NPPs available in France to provide more clinical evidence to support 
reimbursement in France. As well as assessing the sum of rhinoconjunctivitis symptom severity in 
combination with intake of rescue medication, this trial will also assess in a robust manner, the 
effect on quality of life of AIT in subjects suffering from grass pollen allergic rhinitis. 
ARC is the main driver for prescription of NPPs in France, even exceeding NPP prescriptions for 
allergic asthma, and as such, ARC has been selected as the target condition for this trial. ARC has 
been widely documented as having a strong impact on quality of life (QoL) of patients with this 
disease (Bousquet et al. 2008; Bousquet et al. 2001). It follows then, that demonstration of QoL 
improvement on this trial will bring additional, relevant data to support the benefit of clinical 
treatment.  
1.4 
Benefit-risk assessments 
SLIT has been shown to be effective for the treatment of severe grass pollen-induced AR (Dretzke 
et al. 2013) and is recommended by international guidelines for treatment of severe AR (Brozek et 
al. 2017; Canonica et al. 2009; GINA Executive Committee 2018). SLIT can be administered in 
the form of drops or tablets; sublingual drops represent a convenient treatment regimen for home 
use allowing for gradual up-dosing to the recommended maintenance dose. 
To date, no clinical trials have been conducted on SLIToneULTRA® 5-grass mix. However, two 
clinical trials (03-ITS-2001-Fr and OS-G-01) and two non-interventional studies (NI-SU-X-02 and 
NI-XX-01) have been conducted with closely related SLIToneULTRA® and OSIRIS® grass products 
(de Blay et al. 2007; Moral et al. 2016; Nittner-Marszalska et al. 2013; Paul-Ehrlich-Institut 
2019). These 4 trials support the efficacy and safety for SLIToneULTRA® 5-grass-mix, since all of 
the grass species used in these trial products are within the same homologous group. 
Of these four trials conducted with SLIToneULTRA® and OSIRIS® grass products, one investigated 
efficacy and all investigated safety. Further information can be found in the current edition of the 
IB. 


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In the efficacy trial, (de Blay et al. 2007) demonstrated a trend in favour of treatment with OSIRIS® 
3-grass mix compared with placebo based on the sum of rhinoconjunctivitis and asthma symptom 
and rescue medication scores. This difference was not statistically significant, however treatment 
was administered only three times a week and the active group contained significantly more 
subjects with asthma at inclusion than the placebo group. A post hoc analysis on subjects without 
asthma showed that subjects in the active treatment group had statistically significant better overall 
clinical scores compared with subjects in the placebo group.  
In all four SLIToneULTRA® and OSIRIS® trials, 389 subjects received grass treatment (de Blay et 
al. 2007; Moral et al. 2016; Nittner-Marszalska et al. 2013; Paul-Ehrlich-Institut 2019). In 
general, treatment was found to be well-tolerated: The majority of adverse events were mild or 
moderate local events and no treatment-related serious adverse events were reported.  
This safety profile is consistent with post-marketing data available in the ALK global safety 
database for 5-grass mix SLIT-drops where broad market exposure exists for SLIT-drops. For 
SLIToneULTRA® and OSIRIS® (all product/allergen variants) the registered cumulative patient 
exposure as of 31-Jan-2020 is approximately 1,570,000 treatment years and for grass products 
alone, the total exposure is approximately 316,000 treatment years. For 5-grass mix SLIT-drops, 
the cumulative patient exposure is approximately 1,800 treatment years. Systemic allergic 
reactions, including anaphylactic shock, have been identified as an important identified risk and 
eosinophilic oesophagitis as an important potential risk. Only 5 cases of anaphylactic shock (1 
concerning use of SLIToneULTRA® 5-grass-mix) and 2 potentially related cases of eosinophilic 
oesophagitis have been reported in the cumulative post-marketing experience of the SLIT drops, 
thus the safety concerns are considered of very low risk (for further details, please refer to the 
current edition of the IB). 
In addition, published literature commonly describes SLIT administration as safe and SLIT-related 
reactions as mild and sometimes as self-resolving (Ciprandi & Marseglia 2011) and no mortalities 
related to SLIT administration have been reported (Leatherman et al. 2015). 
The purpose of the present trial is to investigate the clinical efficacy of the 5-grass mix SLIT-drops 
compared with placebo based on the total combined rhinoconjunctivitis symptoms and medication 
intake, with daily treatment and stratified treatment allocation based on a pre-existing diagnosis of 
asthma. In addition, the treatment benefit in terms of improvement in quality of life will be 
investigated using the rhinitis quality of life questionnaire (RQLQ) tool (Juniper et al. 1999). Both 
treatment groups will be provided rescue medication to treat rhinoconjunctivitis symptoms during 
the trial. Subjects will be medically monitored and provided with appropriate treatment if warranted. 
In conclusion, subjects in the present trial may benefit from improvement in grass pollen allergic 
symptoms and medication use as well as from improvement in RQLQ. It is not considered that 
treatment with the trial product will expose subjects to any risks that unduly jeopardise their health. 
Thus, the benefits of trial participation outweigh the risks. 
1.4.1 
Considerations regarding COVID-19  
Regarding the pandemic of COVID-19, it is important to highlight that subjects' safety is always first 
priority. Participating in this trial, including receiving treatment with AIT, is not expected to increase 
subjects’ risk of contracting communicable diseases, including COVID-19. 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. If regional circumstances related to COVID-19 change, local guidance 
should be followed (see appendix 6). 


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1.5 
Ethical considerations 
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 
local independent ethics committees (IECs)/institutional review boards (IRBs) and health 
authorities before initiation. 
 
A placebo group will be used as a control-group in the trial. A placebo group is considered ethically 
justifiable since subjects in both treatment groups will be provided with rescue medication to treat 
their rhinoconjunctivitis symptoms during the trial. Furthermore, subjects will be medically 
monitored during the trial and provided with appropriate treatment if warranted. Finally, subjects 
can withdraw from the trial at any time if they find the treatment intolerable and without giving 
reason. 
2 
OBJECTIVES, ESTIMANDS AND ENDPOINTS 
2.1 
Primary objective 
The primary objective is to compare the efficacy of 5-grass mix SLIT-drops to placebo in relieving 
grass rhinoconjunctivitis symptoms and in use of symptom-relief medication during the 2nd Peak 
Grass Pollen Season (PGPS).  
2.2 
Secondary objectives 
2.2.1 
Key secondary objectives 
• 
To measure the impact of treatment with 5-grass mix SLIT-drops compared to placebo on 
health-related quality of life as a result of grass pollen-induced rhinoconjunctivitis during the 
2nd PGPS. 
• 
To compare the efficacy of 5-grass mix SLIT-drops to placebo in relieving grass 
rhinoconjunctivitis symptoms and in use of symptom-relief medication during the 1st PGPS. 
• 
To measure the impact of treatment with 5-grass mix SLIT-drops compared to placebo on 
health-related quality of life as a result of their grass pollen-induced rhinoconjunctivitis during 
the 1st PGPS.  
2.2.2 
Supportive secondary objectives 
• 
To measure the impact of treatment with 5-grass mix SLIT-drops compared to placebo on 
health-related quality of life as a result of their grass pollen-induced rhinoconjunctivitis during 
the 1st Entire Grass Pollen season (EGPS) and during the 2nd EGPS. 
• 
To compare the efficacy of 5-grass mix SLIT-drops to placebo in relieving grass 
rhinoconjunctivitis symptoms and in use of symptom-relief medication during the 1st EGPS and 
during the 2nd EGPS. 
• 
To compare the efficacy of 5-grass mix SLIT-drops to placebo in relieving grass 
rhinoconjunctivitis symptoms during the 1st and during the 2nd PGPS, and during the 1st 
EGPS and during the 2nd EGPS. 


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• 
To compare the efficacy of 5-grass mix SLIT-drops to placebo in use of symptom-relief 
medication during the 1st and during the 2nd PGPS, and during the 1st and during the 2nd 
EGPS. 
2.3 
Exploratory objectives 
2.4 
Primary estimand 
The primary estimand is the absolute difference between the 5-grass SLIT-drops and placebo 
treatment policies based on the average TCS during the 2nd PGPS, 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 5-grass SLIT-drops 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 5-grass SLIT-drops 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.  
2.5 
Secondary estimand 
The secondary estimand is the absolute difference between 5-grass SLIT-drops and placebo 
treatment policies based on the average TCS during the 2nd PGPS, 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 the ‘intention to treat’ principle and provides a robust assessment of the 
efficacy of the 5-grass SLIT-drops.   


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2.6 
Estimands for key secondary and supportive secondary 
objectives 
The trial product estimand and treatment policy estimand, specified for the primary objective in 
Sections 2.4 and 2.5 respectively, are defined for each of the key secondary and supportive 
secondary objectives in a similar manner. 
2.7 
Primary endpoint 
The primary efficacy endpoint is the average daily allergic rhinoconjunctivitis total combined score 
(TCS) during the 2nd PGPS. 
2.8 
Secondary endpoints  
2.8.1 
Key secondary endpoints 
• 
The average weekly overall rhinitis quality of life questionnaire (RQLQ) score during the 2nd 
PGPS. 
• 
The average daily allergic rhinoconjunctivitis TCS during the 1st PGPS. 
• 
The average weekly overall RQLQ score during the 1st PGPS. 
2.8.2 Supportive secondary endpoints 
• 
The average weekly overall RQLQ score during the 1st EGPS. 
• 
The average weekly overall RQLQ score during the 2nd EGPS. 
• 
The average daily allergic rhinoconjunctivitis TCS during the 1st EGPS. 
• 
The average daily allergic rhinoconjunctivitis TCS during the 2nd EGPS. 
• 
The average daily allergic rhinoconjunctivitis DSS during the 1st PGPS. 
• 
The average daily allergic rhinoconjunctivitis DSS during the 2nd PGPS. 
• 
The average daily allergic rhinoconjunctivitis DSS during the 1st EGPS. 
• 
The average daily allergic rhinoconjunctivitis DSS during the 2nd EGPS. 
• 
The average daily allergic rhinoconjunctivitis DMS during the 1st PGPS. 
• 
The average daily allergic rhinoconjunctivitis DMS during the 2nd PGPS. 
• 
The average daily allergic rhinoconjunctivitis DMS during the 1st EGPS. 
• 
The average daily allergic rhinoconjunctivitis DMS during the 2nd EGPS. 
2.9 
Exploratory endpoints 


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3 
TRIAL DESIGN 
3.1 
Summary of trial design 
This is a phase III randomised, parallel-group, double-blind, placebo-controlled trial of 5-grass mix 
SLIT-drops in adults with grass pollen-induced moderate to severe allergic rhinoconjunctivitis, with 
or without asthma, to be conducted in conformance with Good Clinical Practices (GCP). The trial 
will be conducted over two grass pollen seasons. 
A total of 440 adults will be randomised (1:1) to receive either ALK sublingual solution of grass 
allergy extracts for immunotherapy (5-grass mix SLIT-drops) or placebo once daily.  
All subjects should receive daily treatment continuously from at least 16 weeks before the 
anticipated start of the 1st EGPS through the 2nd EGPS, corresponding to approximately 26 
months of treatment (see Figure 1). The subjects will be asked to complete a RQLQ diary one time 
in January 2022 during the off-season for grass and tree-pollen. Subjects will be asked to fill in a 
daily diary for the EGPS to capture information on rhinitis and/or conjunctivitis symptoms, use of 
symptom-relieving medications and impact of rhinitis and/or conjunctivitis on daily life and quality of 
life. Subjects will also be asked to fill in a weekly RQLQ diary during the EGPS.  
Data for the primary endpoint: the average daily allergic rhinoconjunctivitis TCS during the 2nd 
PGPS, will be collected by the subjects completing questions related to their daily symptoms and 
medication use in an electronic diary. No interim analysis is planned. 
Routine safety surveillance will be conducted throughout the trial. The follow-up visit will be 
conducted via a telephone call approximately one week after the End of Trial visit.   
Figure 1 
Trial design 
 
EGPS: Entire grass pollen season 
 
3.1.1 
Definition of pollen seasons 
The grass pollen seasons vary across regions both in intensity and duration although the seasonal 
pollen index start and stop dates of grass pollen is predictable (Sofiev 2017). The definitions of the 


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grass pollen season start, stop and grass pollen peak are provided in Table 1. The grass pollen 
expected start and stop dates for each region are specified in Appendix 5. 
Table 1  
Grass pollen season definitions 
Start date  
The first day of 3 consecutive days with (non-missing) pollen count larger 
than or equal to 10 grains/m3. 
Stop 
The last day before 3 consecutive days with (non-missing) pollen count 
less than 10 grains/m3. 
Peak  
The 15 days period with the highest average pollen count during the entire 
grass pollen season. 
The actual pollen plots of the grass pollen season will be reviewed in order to validate the pollen 
counts in the season described in the above criteria. The final pollen seasons will be defined prior 
to database lock and further specified in the statistical analysis plan (SAP). 
eDiary data will be collected during the expected EGPS season. The expected dates for each 
country are provided in Appendix 5. More precise dates for some regions are specified since larger 
countries can have different EGPS start and stop dates from north to south. If monitoring of the 
weather effecting the grass pollen season identifies a prolongation of the expected stop date of the 
EGPS for any country or region in Appendix 5, the effected site will be notified and the eDiary will 
be updated to allow for additional data collection. 
3.2 
Discussion of design 
The design for the present trial is based on the recommendation from the EMA guideline on the 
clinical development of products for AIT for the treatment of allergic diseases (EMEA 2008), as 
recommended in the WHO position paper on AIT for development of SLIT (Bousquet et al. 1998), 
and based on the experience from previous ALK trials with AIT. 
The primary endpoint TCS is the sum of the average rhinoconjunctivitis DSS and the average DMS 
during the 2nd PGPS. The primary endpoint analysis is from the peak grass pollen season in order 
to minimise the effect of natural variation that exists over the entire grass pollen season. 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.  
Scientific recommendations for ARC trials currently describe a primary outcome reflecting a 
combined symptom and medication score severity with secondary outcome measures including 
validated symptom scores and/or health related QoL questionnaires (Pfaar et al. 2014). However, 
in order to make additional claims on QoL, hierarchical testing will be employed on this trial with 
efficacy endpoints including symptom and medication scores and RQLQ QoL scores.  
The symptom score has been designed based on EMA guidance documentation (EMEA 2008) and 
on scoring from previous and ongoing ALK trials. The medication score proposed for this trial has 
been used in numerous clinical trials performed with the authorised products 
GRAZAX®/GRASTEK® and RAGWITEK® (Blaiss et al. 2011) (Nelson et al. 2011) (Creticos et al. 
2013) (Maloney et al. 2014) and was developed by the sponsor based on recognised guidelines 
(EMEA 2008) (Canonica et al. 2007), as well as on thorough discussions with key opinion leaders 
and specialists within the field of allergy.  
Clinical development experience with grass AIT has shown that the treatment effect during the first 
PGPS is strongly linked to the duration of the pre-seasonal exposure to AIT. Results from clinical 


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trials using the SLIT tablet GRAZAX® with grass pollen allergen (GT-02, GT-07 and GT-08), 
showed significant effect on improvement of symptom and medication scores following a pre-
seasonal treatment period of at least 8 weeks prior to the start of the PGPS. This improvement 
continued over time (Calderon et al. 2007). Furthermore, clear time-dependent increases in 
allergen-specific antibody responses have been observed during the first 8 weeks of daily dosing, 
with elevated levels sustained over a longer period (Malling et al. 2006). Based on this data and 
the cumulative clinical development experience with grass AIT, the GRAZAX® Summary of Product 
Characteristics (SmPC) recommends initiation of treatment of at least 16 weeks prior to expected 
initiation of the GPS. Following this, a pre-season exposure of at least 16 weeks has been included 
in this trial in order to see a treatment effect during the first EGPS.  
The trial is designed to be conducted over two grass pollen seasons in accordance with (EMEA 
2008) concerning sustained clinical effect. In order to demonstrate robust QoL data, subjects in this 
trial will be treated with investigational medicinal product (IMP) for up to 26 months and will be 
assessed over two extended grass pollen seasons. 
A double-blinded set-up has been chosen to minimise the potential bias resulting from differences 
in management, treatment or assessment of subjects and/or interpretation of results that could 
arise as a result of subject or investigator knowledge of the assigned treatment. 
A placebo arm has been introduced to establish the superiority of the IMP compared to placebo 
with respect to reducing the TCS. 
3.3 
Justification of dose 
Efficacy of SLIT-drops has been found to be dose-dependent in clinical trials where the dose was 
increased gradually from 50 to 150 SRU/day over 10 days to reach the minimum recommended 
maintenance dose of 300 SRU (see section 8.1) (Braun et al. 2010). This up-dosing titration 
schedule will be used for the current trial and was previously assessed with Phleum pratense 
OSIRIS® sublingual solution and found to be well-tolerated(Nittner-Marszalska et al. 2013) . 
Based on the results of immunological data, 300 SRU was established as the optimal tested dose 
for maintenance treatment. The 300 SRU dose is currently used in daily clinical practice (Didier et 
al. 2015) because it is considered safe and efficient (Canonica et al. 2009).  
3.4 
End of trial definition   
A subject is considered to have completed the trial if he/she has completed the last scheduled visit 
(V9). 
The end of the trial is defined as the date of the last follow-up phone visit (TC follow-up) for the last 
subject in the trial. 


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4 
TRIAL POPULATION 
Subjects randomised in this trial will be adults ≥18 years of age, with a clinical history of allergic 
rhinoconjunctivitis (with or without asthma) as diagnosed by a physician and having had symptoms 
despite treatment with antihistamines or nasal steroids during the two previous grass pollen 
seasons.  
Subjects meeting all the inclusion criteria and none of the exclusion criteria will be considered 
eligible for the trial. 
4.1 
Inclusion criteria 
Subjects are eligible to be included in the trial only if all the following criteria apply:  
I1. Written informed consent obtained before any trial related procedures are performed  
I2. Male or female aged ≥18 years on the day informed consent is obtained 
I3. For female subjects of childbearing potential,9 a negative pregnancy test and willingness to 
practice appropriate contraceptive methods10 until the follow-up visit must be confirmed 
I4. A clinical history of grass pollen-induced allergic rhinoconjunctivitis for two years or more with 
or without asthma11 
I5. A clinical history of severe allergic rhinoconjunctivitis symptoms (interfering with usual daily 
activities or sleep) induced by grass pollen, which remain troublesome despite symptomatic 
treatment with antihistamines, nasal steroids or eye drops during the previous grass pollen 
season 
I6. Positive specific immunoglobulin E (IgE) (defined as ≥class 2, ≥0.70 kU/l) against grass: 
Phleum pratense  
I7. Positive skin prick test (SPT)12 to Phleum pratense at screening 
I8. The subject must be willing and able to comply with the trial protocol 
 
 
9 Females, after the first menstrual period. Females who are post-menopausal are considered not to be of child-bearing potential. A 
postmenopausal state is defined as no menses for 12 months without an alternative medical cause.  
10 For the purpose of this protocol the following contraceptive methods are considered appropriate: oral contraceptives, transdermal 
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. 
11 If medical records are not available, verbal history from subject can be used to fulfill this criterion and this must be documented in the 
medical records by the investigator. 
12A positive Skin Prick Test (SPT) is defined in the SPT Guideline. For subjects in Europe, a positive SPT is defined as a wheal size ≥3 
mm. If medication that could interfere with the skin prick test, according to Table 7 has not been washed out and the positive control is 
<3 mm for subjects in Europe, the skin prick test can be repeated after the interfering medication has been washed out. 


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4.2 
Exclusion criteria 
Subjects are excluded from the trial if any of the following criteria apply:  
E1. Previous participation in this trial. Participation is defined as screening 
E2. Has a clinically relevant history of symptomatic seasonal and/or perennial allergic 
rhinoconjunctivitis and/or asthma caused by an allergen other than grass pollen, to which the 
subject is exposed, which could potentially overlap with the efficacy assessment periods 
E3. Within the last 3 months before the randomisation visit, has had an occurrence of any clinical 
deterioration of asthma that resulted in emergency treatment, hospitalisation, or treatment with 
systemic corticosteroids 
E4. Reduced lung function: FEV1 <70% of predicted value after adequate pharmacologic 
treatment13 
E5. SLIT treatment with any grass pollen AIT for more than 1 month within the last 5 years. In 
addition, any SLIT treatment with grass pollen AIT within the previous 12 months 
E6. SCIT treatment with any grass AIT reaching the maintenance dose within the last 5 years. In 
addition, any SCIT treatment with grass AIT within the previous 12 months 
E7. Ongoing treatment with any allergy immunotherapy product 
E8. Uncontrolled or severe asthma requiring daily use of more than 800 mcg budesonide or 
equivalent at screening 
E9. Severe chronic oral inflammation  
E10. 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)14  
E11. Has a diagnosis of eosinophilic oesophagitis 
E12. At randomisation, current symptoms of, or treatment for, upper respiratory tract infection, 
acute sinusitis, acute otitis media or other relevant infectious process (serous otitis media is 
not an exclusion criterion) 
E13. 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  
E14. 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 
E15. Active or poorly controlled autoimmune diseases, immune defects, immunodeficiencies, 
immunosuppression or malignant neoplastic diseases with current disease relevance  
E16. Immunosuppressive treatment (ATC code L04 or L01) ≤ 90 days prior to the screening visit 
 
13 Lung function will be measured according to the ATS/ERS spirometry recommendations (Reddel et al. 2009). The subjects will be 
included based on spirometry values measured at the site and reported by the site according to the site’s pre-programmed spirometric 
reference equations. The reference equations and values used should be documented on every pulmonary function report. 
14 If in doubt, nasal endoscopy is recommended 


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E17. Treatment with medications with potential impact on efficacy endpoints (e.g. treatment with 
anti-IgE drugs within 130 days/5 half-lives of the drug (which ever longest) or treatment with 
antidepressant or antipsychotic medications with antihistaminic effect) 
E18. 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 
E19. Female who is pregnant or breast-feeding  
E20. Has a business or personal relationship with trial staff or sponsor who is directly involved with 
the conduct of the trial 
4.3 
Screen 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/entered in the trial. A minimal set of screen failure information is required to 
ensure transparent reporting of screen failure participants in order to meet the Consolidated 
Standards of Reporting Trials (CONSORT) publishing requirements and to respond to queries from 
regulatory authorities. Minimal information includes demography, medical history, adverse events, 
eligibility criteria and screen failure details.  
4.3.1 
Rescreening 
Screen failures may not be rescreened.  
5 
SUBJECT DISCONTINUATION 
5.1 
Discontinuation from IMP treatment 
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 has a confirmed 
diagnosis of eosinophilic oesophagitis  
• 
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 
• 
If treatment is unblinded for the subject or investigator  
 
For all subjects discontinued from IMP, efforts must be made to have subjects attend and 
complete all scheduled visit procedures to collect the data for the primary and key secondary 
endpoints. Subjects must be educated about the scientific importance of their data, even if they 
discontinue trial product. 
5.2 
Discontinuation from trial 
The subject will be advised in the informed consent form that he/she has the right to discontinue 
from the trial at any time without prejudice.  
Subjects must be discontinued from the trial under the following circumstances: 


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• 
If, in the investigator’s opinion, continuation in the trial would be detrimental to the subject’s 
well-being 
• 
If informed consent is withdrawn 
If found required by ALK after discussion with the investigator, subjects may be discontinued from 
the trial under the following circumstances: 
• 
If subject is treated with prohibited medication as defined in Table 2 
• 
In case of protocol deviation, violation of eligibility criteria or deviation from the treatment 
plan specified in the protocol (e.g. incorrect administration of the IMP)  
• 
Simultaneous or previous participation (within 30 days of randomisation) in other clinical 
trials of an approved or non-approved investigational medicinal product   
 
In case a subject discontinues from the trial, the discontinuation page in the electronic case report 
form (eCRF) should be completed. On the discontinuation page the investigator should record the 
date of the discontinuation from the trial, the person initiating the discontinuation, and the primary 
reason for discontinuation. If an adverse event (AE) is involved in a discontinuation, this must be 
recorded as the primary reason. In all cases, the primary reason for discontinuation must be 
recorded in the eCRF and in the subject’s medical records. A follow-up visit on the subject is 
necessary to establish trial-related AEs that must be reported in accordance with the appropriate 
procedures. 
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. 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 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.  
Data obtained until discontinuation will be used for statistical analyses. 
5.4 
Replacement of subjects 
Subjects who discontinue IMP treatment or from the trial 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 into the eCRF at the 
screening visit. Only the investigator is able to reconcile the unique subject number with the identity 
of the data subject.  


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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 treatment allocation will be stratified based on pre-existing diagnosis of asthma in order to 
ensure equal treatment distribution of subjects with or without asthma. 
The randomisation codes will only be made available for the trial data manager and statistician 
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/site personnel 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 in a medical emergency 
situation 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. 
Unblinding may also be done by the Qualified Person Responsible for Pharmacovigilance (QPPV). 
The randomisation code breaking will be performed via interactive response technology (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. 
The IRT will notify the Clinical Research Assistant (CRA) and the sponsor’s safety department 
immediately after the randomisation code is broken. The subject must be discontinued from the 
trial after the randomisation code is broken. 
It may also be necessary to unblind an individual subject’s treatment by the sponsor/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 (SUSAR)). 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 will be given a subject card 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 the event of an 
emergency. 
7 
RESTRICTED AND PROHIBITED CONCOMITANT 
MEDICATION  
Restricted and prohibited concomitant medications are listed in Error! Reference source not found.. 
For medication that could possibly interfere with the SPT performed at screening please refer to 
Table 7. 


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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 of the 
subject. 
Table 2 
Restricted concomitant medications  
Product 
Time window 
Reason 
An investigational product other 
than the IMP 
≤ 30 days or 5 half-lives of the 
product (which ever longest) 
before visit 2 and until end of 
trial 
Possible interaction between 
IMPs.  
Interferes with efficacy and safety 
evaluations 
Antihistamine, routine use and 
preventive use to treat anticipated 
adverse events  
(rescue medication antihistamines 
provided by sponsor are permitted 
for treatment of acute allergic 
symptoms, see section 8.2) 
 
- Oral, intravenous, nasal or ocular 
 
 
 
 
 
 
 
 
 
 
From V4 until 01 Sep 2022  
and from V7 until 01 Sep 2023 
 
 
 
 
 
 
 
 
 
Interferes with rhinoconjunctivitis 
efficacy assessments. 
Antidepressant medications           
-Antidepressant medication with 
antihistaminic effect  
 
≤ 14 days before visit 2 and 
until end of trial 
 
Interferes with rhinoconjunctivitis 
efficacy assessments 
Interferes with safety evaluation 
Antipsychotic medications  
-Antipsychotic medication with 
antihistaminic effect 
≤ 7 days before visit 2 and until 
end of trial 
Interferes with rhinoconjunctivitis 
efficacy assessments due to 
antihistaminic effect. 
Interferes with safety evaluation 
Glucocorticosteroids  
-unless provided by the sponsor 
(see section 8.2) 
-does not include inhaled 
corticosteroids 
 
- topical (nasal or ocular) 
 
 
- with systemic effect:15   
- 
any oral tablets (OCS is 
allowed in cases of asthma 
exacerbation) 
 
 
 
 
 
 
 
From V4 until 01 Sep 2022  
and from V7 until 01 Sep 2023 
 
 
60 days before visit 4 and until 
end of trial 
 
 
 
 
 
 
Interferes with rhinoconjunctivitis 
efficacy assessment. 
 
Interferes with safety evaluation 
 
 
 
 
 
15 Treatment with systemic prednisolone with daily doses below 20 mg should not be discontinued. 
Estimated 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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- 
any parenteral formulations 
(intravenous, intra-articular 
or intramuscular) or depot 
formulations regardless of 
treatment days and dose 
≤ 90 days from visit 4 and until 
end of trial 
 
Systemic immunosuppressive 
treatment (ATC code L04, L01) 
*other than glucocorticosteroids 
 
≤ 90 days before visit 2 and 
until end of trial 
 
Interferes with rhinoconjunctivitis 
efficacy assessments. 
Biologic 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 or 5 half-lives of the 
product (which ever longest) 
prior to visit 2 and until end of 
trial 
Safety of subject. Interferes with 
rhinoconjunctivitis efficacy 
assessments. 
Immunotherapy with any other 
allergen(s) 
From screening visit 1 and until 
end of trial 
Interferes with rhinoconjunctivitis 
efficacy assessments. 
Interferes with safety evaluation 
Inhaled, topical (nasal or ocular) or 
oral nedocromil or cromolyn sodium 
≤ 14 days before visit 4 and 
until end of trial 
Interferes with rhinoconjunctivitis 
efficacy assessments 
Monotherapy of Long-acting B-
agonist (LABA) (LABA in 
combination with ICS is allowed) 
From visit 2 and until end of 
trial 
Interferes with safety evaluation 
Nasal or ocular decongestants 
≤ 3 days before visit 4 until 01 
Sep 2022 and ≤ 3 days before 
visit 7 until 01 Sep 2023 
Interferes with rhinitis efficacy 
assessments 


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8 
TRIAL PRODUCTS 
8.1 
IMP 
The IMP provided in this trial is 5-grass mix SLIT-drops or placebo. 
All IMPs are manufactured and provided by ALK. The placebo is similar to the active treatment with 
regards to appearance, smell and taste. 
Please refer to Table 3 and the Trial Supplies Catalogue provided by ALK for details regarding IMP 
and background treatment. 
Table 3 
IMP details 
IMP name: 
 
Active treatment 
5-grass mix SLIT-drops 
Placebo 
Active ingredients: 
Allergen extracts from the five grass 
species:  
Dactylis glomerata L (cat grass /cock’s 
foot/orchard grass),  
Phleum pratense L. (timothy grass), Lolium 
perenne L. (perennial rye-grass),  
Anthoxanthum odoratum L (sweet 
vernal/vernal grass),  
Poa pratensis L. (Kentucky 
bluegrass/meadow grass)   
None 
Dosage form: 
SLIT-drops 
Sublingual solution 
SLIT-drops 
Sublingual solution 
Excipients: 
Glycerol, carbonate, sodium chloride 
Glycerol, carbonate, sodium chloride 
Route of 
administration: 
Sublingual 
Sublingual 
Dose/strength: 
Initiation: 
50 SRU/day for five consecutive days 
followed by 150 SRU/day for five additional 
consecutive days. 
Maintenance: 
300 SRU/day from day 11.  
N/A 
Dosing instruction: 
One single-dose container (0.5 ml) once 
daily. 
First dose will be dispensed at site at visit 2 
(randomisation visit) 
One single-dose container (0.5 ml) 
once daily. 
First dose will be dispensed at site at 
visit 2 (randomisation visit) 
Each subject will be randomly assigned to receive active treatment or placebo. 
IMP dispensing 
The treatment will start at visit 2 (randomisation visit). Hereafter, IMP will be dispensed at visits 3-
8. The first dose will be administered under medical supervision for at least 30 minutes after intake.  
8.2 
Rescue medication 
During the trial, subjects may experience allergy symptoms that require additional treatment.  
Rhinoconjunctivitis pharmacotherapy for allergic rhinitis or conjunctivitis will be provided by the 


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sponsor to subjects as pre-defined, open-labelled rescue medication and may be used in addition 
to the IMP to which the subjects have been randomised if needed. 
For the rhinoconjunctivitis symptoms the subject will be provided with: 
• 
Oral antihistamine tablets (Desloratadine, 5 mg) 
• 
Nasal corticosteroid spray (Mometasone furoate, 50 µg/dose) 
• 
Antihistamine eye drops (Olopatadine eye drops, 1 mg/ml) 
The allergy pharmacotherapy provided to the subject should be used according to the product's 
labelling (e.g. SmPC). The dosage instructions are described in Table 4. 
Table 4 
Schedule for rhinoconjunctivitis pharmacotherapy 
Rhinoconjunctivitis 
pharmacotherapy 
Subject dosage instructions 
Rhinitis 
Oral antihistamine, tablets  
1 tablet once daily as needed for control of allergic rhinitis 
symptoms  
Nasal corticosteroids  
2 puffs in each nostril once daily as needed for control of allergic 
rhinitis symptoms. Dose can be reduced to 1 spray in each nostril 
when the treatment has become effective 
Conjunctivitis 
Antihistamine eye drops 
1 drop in the affected eye(s) twice daily, morning and evening as 
needed in case of persisting allergic conjunctivitis symptoms 
*Oral antihistamine has an effect on the conjunctivitis symptoms and will be counted in both the rhinitis 
and the conjunctivitis medication score 
Repeat supply of any rescue medication will be done at scheduled visits as needed. 
8.3 
Packaging and labelling 
The IMP will be supplied in foil bags containing five single-dose containers each. The foil bags will 
be packed in specific boxes containing a sufficient number of single-dose containers to cover the 
treatment periods 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. 
Rescue medication will be sourced as commercially available products in a member state of the 
EU or EEA. The products will be labelled with an additional label including trial specific information. 
Packaging and labelling will be outsourced. See Appendix 3 – List of Suppliers. 
8.4 
Handling and storage 
The trial products provided by ALK (IMP, rescue medication and SPT) 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. Trial products returned by the subject must be stored 
separate from other medication, e.g. unused IMP that has not yet been dispensed. 


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Site storage conditions for IMP, rescue medication and SPT must be monitored by the site staff for 
adherence to label specifications and reviewed by the CRA during monitoring visits.  
Temperature 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 from ALK. The site must maintain records of: 
• 
Inventory at the site 
• 
Dispensing to each subject 
• 
Returns by each subject to site 
• 
Returns 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 
unused IMPs to the site at every drug accountability visit. Compliance will be assessed by foil bag 
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 protocol. 
Full drug accountability will not be performed on rescue medication. Subjects must be instructed to 
bring all unused rescue medication to the site at relevant visit. At the final visit, the investigator 
must return a copy of the completed drug accountability form to the ALK-appointed CRA or to the 
ALK 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. 
9 
TREATMENT 
9.1 
Treatment administration 
The solution from the single-dose containers should be administered once daily. Place the entire 
content of the single-dose container under the tongue (sublingual) and keep it there for 2 minutes 
before swallowing. 
Eating and drinking should be avoided for the next 5 minutes. 


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9.2 
Precautions in relation to first dosing 
The first intake of IMP should be at the clinic with a subsequent 30 minutes observation period. An 
oropharyngeal examination should be performed prior to the first IMP dosing and should be 
repeated after 30 minutes. 
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 
If, following exposure to an allergen, multiple organ systems are adversely affected, anaphylaxis is 
a likely event/diagnosis. Adrenaline auto-injectors are intended for immediate self-administration 
for an anaphylactic reaction, including symptoms/signs of upper airway obstruction. A list of 
symptoms that may be present during anaphylaxis include flushing, apprehension, syncope, 
tachycardia, thread or unobtainable pulse associated with a fall in blood pressure (BP), vomiting, 
diarrhoea and abdominal cramps, wheezing, dyspnoea due to laryngeal spasm, lower airway 
obstruction, pruritus, rashes (such as urticaria), or angioedema. Self-injectable adrenaline should 
be administered promptly when significant respiratory and/or cardiovascular symptoms accompany 
an allergic reaction. 
Subjects experiencing symptoms of an anaphylactic reaction without access to an adrenaline auto-
injector must immediately call their local emergency number.  
In the event of symptoms of anaphylaxis and regardless of use of self-injectable adrenaline, the 
subject must immediately call the local emergency number and the 24-hour investigational site 
emergency number indicated in the informed consent and 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 24 hours of first becoming aware of the use of self-injectable 
adrenaline. The symptoms and/or circumstances that triggered symptoms of anaphylaxis and/or 
the use of self-injectable adrenaline must be clearly recorded on the eCRF. 
9.4 
Temporary interruption and discontinuation of treatment 
Treatment may be discontinued for up to 7 days for the following reasons: 
• 
In case of oral surgery, including dental extraction and shedding of a tooth, to allow healing of 
the oral cavity 
• 
Inflammatory conditions in the oral cavity 
• 
Upper airway viral infection in an asthmatic subject 
• 
Other reasons if deemed necessary by the investigator 
Interruptions should be kept to a minimum, however 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 
based on the length of the IMP interruption and previous experienced AEs if the subject should 


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start up treatment again at the clinic or if it is ok that the subject starts up at home, or if IMP should 
be discontinued permanently. 
ALK should be notified in case of IMP discontinuation due to an AE. 
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 sponsor. 


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10 VISIT SCHEDULE 
Not applicable for this trial. 
11 TRIAL PROCEDURES 
This section outlines the trial procedures that will be performed during the trial.  
The tasks listed below must be performed by a physician: 
• 
Obtainment of informed consent 
• 
Evaluation of inclusion and exclusion criteria 
• 
Physical examination 
• 
Assessment of AEs/SAEs 
• 
Assessment of 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 asked to clarify, 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, including any period 
for wash-out of concomitant medication. 
It is the responsibility of the principal investigator or a sub-investigator to obtain the written 
informed consent from the subject. 
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 
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 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 subject must sign and date the informed consent form 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 subject must be informed in a timely manner about 
the updated subject information sheet and written informed consent must be obtained. 


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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 11.15). The subject 
should consent to long-term storage of the sample on a separate consent form prior to collection of 
the sample(s) as described in section 11.1. Participation in this part of the trial is optional. Subjects 
who do not wish to participate with biobanking can still participate in this trial. 
11.3 Demographics and body measurements 
The following data will be recorded: 
• 
year of birth16  
• 
Age 
• 
Race17 
• 
Sex 
• 
Height 
• 
Weight 
11.4 Medical history 
The relevant medical history 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.  
In addition, a detailed allergy history including recording of the subject’s history of rhinitis, 
conjunctivitis or rhinoconjunctivitis, atopic dermatitis and food allergy including start and stop date 
as well as cause of condition (if available). A subject should be stratified as asthmatic if they have 
been diagnosed and/or treated for asthma in adulthood.   
11.5 Smoking habits 
Information on exposure to cigarette smoke (active and passive) will be collected in the eCRF. 
11.6 Concomitant and previous medication 
The subjects’ use of concomitant medication including allergy and asthma medication must be 
recorded. Relevant previous medication should also be recorded. This includes previous allergy 
and asthma pharmacotherapy taken for the past 2 years. Other previous 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. See section 7 for 
restricted and prohibited concomitant medication on this trial. 
 
16 Collection of month if allowed according to local regulations 
17 Collection of race is required for calculation of FEV1 “The predicted FVC and FEV1 will based on the 
Quanjer equation (Quanjer et al. 1993). If the subject self-reports his/her race as Black, appropriate 
adjustments will automatically be made for race by programming the spirometer using the formula: FEV1 
predicted x 0.87 = FEV1 predicted adjusted for race” 


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At each 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. 
11.7 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 at randomisation visit 2 and as 
per investigator discretion during the trial. A 6-hour wash-out of SABA will be required before 
measurement of lung function. Lung function measurements will be performed with a spirometer 
available at the clinic. FVC and the derived FEV1 is measured as 3 valid measurements and the 
highest value will 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). The spirometry 
values will be reported by the site according to the site’s pre-programmed spirometric reference 
equations. The reference equations and values used should be documented on every pulmonary 
function report.  
11.8 Physical examination 
The physical examination should be performed by a physician and should be based on the body 
systems as described in Table 5.  
Table 5 
Physical examination 
Body system 
Minimum examinations to be completed 
General appearance 
As applicable 
Skin 
Inspection of skin  
 
Head (ears, eyes, nose 
and throat) 
Ears - Inspection of auricles and external canal (otoscopy is not required) 
Eyes - Inspection of conjunctivae and eyelids, examination of pupils including 
reaction to light 
Nose - Inspection of nasal mucosa  
Oral cavity - oropharyngeal inspection of lips, tongue, tonsils and uvula will be 
performed for signs of mouth irritation, oedema, and any other abnormalities.  
Oropharyngeal inspection is performed before and after administration of IMP at 
randomisation V2 and as per investigator discretion during the trial 
Respiratory 
Auscultation/stethoscopy of the lungs 
Heart 
Auscultation/stethoscopy of the heart 
Lymph nodes 
Examination of lymph nodes (cervical, axillary, and inguinal lymph nodes) 
Abdomen 
 
 
If applicable  
Urogenital 
Musculoskeletal and 
neurological 
Other abnormality 
Physical examination of optional body systems not performed should be marked as not done (ND) 
in the eCRF. 


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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. 
11.9 Eosinophilic Oesophagitis 
At each visit, subjects/caregivers will be asked whether any of the following has occurred since the 
last clinic visit: 
• 
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 present any of the above, the investigator should consider referring the subject to a 
gastroenterologist for evaluation. If there is a clinical suspicion of eosinophilic oesophagitis, 
subjects must be referred to a gastroenterologist. 
11.10 Pregnancy test 
For female subjects of childbearing potential, a urine pregnancy test will be performed at all regular 
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.  
11.11 Skin prick test 
Skin Prick tests (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 6. All allergens are 
supplied by ALK. 
SPT positive control is histamine hydrochloride 10 mg/ml. 
See the SPT guideline for further details on SPT. 
Table 6 
Skin prick test 
Country 
Allergen 
All Countries 
Positive control – Histamine 
Negative control – Saline 
HDM – Dermatophagoides pteronyssinus 
HDM – Dermatophagoides farinae 
Cat - Felis domesticus   


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Dog - Canis familiaris   
Mould - Alternaria alternata 
Grass – Phleum pratense 
Weed - Artemisia vulgaris 
Tree – Betula verrucosa 
Tree - Cupressus arizonica 
Some medications may affect the outcome of the SPT and should be washed out before 
performing the SPT (see Table 7). If medication that could interfere with the SPT has not been 
washed out and the positive control is <3 mm for subjects in Europe, the SPT must be repeated 
after the interfering medication has been washed out and before randomisation at V2.  
Table 7 
Medications with a possible interference with SPT 
Drug 
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 
 
Glucocorticosteroid18 
 
• 
Local application (on the 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 
11.12 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 the following visits, which meet the definition of an AE, must be 
recorded on an AE page in the eCRF. 
 
18 Treatment with systemic prednisolone with daily doses below 20 mg should not be discontinued. 
Estimated 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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11.13 Blood and urine sampling 
The following types of blood samples will be drawn during the trial, totalling an approximate blood 
volume of 39 ml (if the subject consents to the biomarker sample, the total blood volume will be 
approximately 49 ml): 
Purpose 
Volume  
Number of samples 
Safety / Haematology 
2 ml 
2 
Safety / Blood chemistry 
2.5 ml 
2 
Screening / IgE 
5 ml 
1 
 
 
 
Total volume 
39 ml 
 
The following urine samples will be drawn: 
Purpose  
Volume 
Samples during the trial. 
Safety/Urinalysis 
10 ml 
2 
Pregnancy tests 
NA 
at each visit, if applicable 
The following samples will only be drawn if specific consent has been obtained from the subject. 
Purpose 
Sample type 
Volume  
Number of samples during the trial 
Long term storage - 
biomarker sample  
Blood  
5 ml 
2 
Total volume 
 
10 ml 
 
11.14 Laboratory assessments 
All laboratory assessments will be performed centrally at one or more certified laboratories 
selected by ALK. 
The clinical laboratory values will be reported to the investigator by the laboratory and he/she must 
immediately review them for clinical significance.  
Laboratory assessments are described in a separate laboratory manual that also details blood 
sampling and shipment procedures. 
The following laboratory variables will be measured: 
Haematology - Automated differential 
Haemoglobin, erythrocytes, haematocrit, mean corpuscular haemoglobin (MCH), mean 
corpuscular volume (MCV), platelets, leucocytes, neutrophils, lymphocytes, monocytes, 
eosinophils and basophils 
Blood chemistry 
Alanine aminotransferase (ALT)/serum glutamic pyruvic transaminase (SGPT), albumin, alkaline 
phosphatase, aspartate aminotransferase (AST)/serum glutamic-oxaloacetic transaminase 
(SGOT), blood urea nitrogen (BUN), calcium, chloride, creatinine, glucose, lactate dehydrogenase 
(LDH), potassium, sodium and total bilirubin 


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Urinalysis 
bilirubin, glucose, haemoglobin, ketone, leukocytes, nitrite, pH, protein, specific gravity and 
urobilinogen 
IgE 
To assess the inclusion criteria in order to confirm the diagnosis of allergy against grass, blood 
samples will be drawn at the screening visit (visit 1) for determination of specific IgE against the 
following allergens: Phleum pratense 
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. 
 
 
 
 
 
11.15 Long-term storage of samples 
Blood sample for storage in Biobank 
This blood sample will only be drawn if the subject consents to long-term storage of a blood 
sample. 
If long-term sampling is accepted, a 5.0 ml blood sample will be drawn at visits 1 and 9 where 
blood sampling is already planned. The subject will consequently only donate an extra blood 
sample and no additional venipuncture 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, 
and which today is 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 subjects with allergies. The surrogate markers may be 
antibody levels, cytokine profiles, cell surface markers, specific set of proteins or metabolites or 
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. 


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11.16 Electronic diary and patient reported outcome questionnaires 
During the trial, the subject will complete an eDiary. The eDiary is a hand-held electronic device 
that will be issued to the subjects at visit 3. Subjects will be instructed by the investigator in how to 
fill in the eDiary. 
The following items will be provided in the eDiary at pre-specified intervals during EGPS (see the 
flow chart and Appendix 5): 
• 
Rhinoconjunctivitis quality of life questionnaire (RQLQ) 
• 
Rhinoconjunctivitis symptoms 
• 
Use of rhinoconjunctivitis rescue medication for treatment of rhinoconjunctivitis 
• 
 
 
 
11.16.1 
Symptom assessment: Rhinitis and conjunctivitis symptoms 
Subjects should be instructed by the investigator or delegated staff on how to complete symptom 
assessments and record the results in the diary on a daily basis – in the evening. 
A total of 6 allergic symptoms, 4 rhinitis and 2 conjunctivitis symptoms should be measured on a 
scale from no symptoms to severe symptoms. 
The subject should be instructed in the symptom score using the following definitions: 
0 - No symptoms - no sign/symptom evident 
1 - Mild symptoms - symptom clearly present, but minimal awareness; easily tolerated 
2 - Moderate symptoms - definite awareness of symptom that is bothersome but tolerable 
3 - Severe symptoms - symptom that is hard to tolerate; causes interference with activities of daily 
living and/or sleeping 
The 6 symptoms are classified in 2 groups as follows: 
Nose symptoms: 
• 
Runny nose 
• 
Blocked nose 
• 
Sneezing 
• 
Itchy nose 
Eye symptoms: 
• 
Gritty feeling/red/itchy eyes 
• 
Watery eyes 
11.16.2 
Medication assessment 
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. Subjects should be 
instructed to report their use of rhinoconjunctivitis rescue medication via the daily diary. As 
suggested in an European Academy of Allergy and Clinical Immunology (EAACI) position paper on 
standardisation of clinical outcomes (Pfaar et al. 2014) the subjects should be instructed to start 
with antihistamine tablets and/or eye-drops. Treatment with nasal steroids should only be initiated 
if antihistamines and/or eye drops do not alleviate the symptoms.  


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The medication use will be scored as shown in Table 10. 
 
 
 
 
 
11.16.4 
Rhinoconjunctivitis quality of life questionnaire 
The quality of life will be assessed by the standardised RQLQ(S) questionnaire (Juniper et al. 
1999) included in the electronic diary. RQLQ questionnaire contains 28 questions that are scored 
in 7-point scale (0 = not impaired at all; 6 = severely impaired). Questions are divided in 7 domains 
(activity limitations). The overall RQLQ score is derived by taking the average of 7 domain scores.  
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
11.17  Paper questionnaire 
 
Health-related quality of life assessment 
The health-related quality of life will be assessed using the 
 
 
 
. 
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 was 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.  


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12.1 Definitions 
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. 
 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)  
Events of medication error, overdose and abuse 
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 
Events of special interest (ESI) 
Selected (non-serious or serious) AEs 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. ESIs for this trial are: 
• 
Systemic allergic reactions including anaphylaxis 
• 
Events treated with adrenaline/epinephrine 
• 
Severe local swelling of the mouth and/or throat 
• 
Eosinophilic oesophagitis  


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Significant laboratory event 
A significant laboratory event should be recorded as an AE if one of the following is applicable:  
• 
It is 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 
12.2 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 
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 sequela qualifies as a SAE, the AE must be reported as such 
• 
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 
AEs must be recorded on the AE form in the eCRF with the initial eCRF report containing as much 
information as possible. One single AE form must be used per AE from start to resolution. For 
SAEs and ESIs, additional information will be collected. For each of the 4 pre-defined ESIs, the 


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investigator must fill out a specific eCRF ESI form with additional questions, in order to ensure that 
all relevant data is captured. 
If the same type of AE occurs 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 and the description. If the AE no longer reoccurs after IMP intake, 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 as the AE). 
12.3.1 
Reporting of SAEs 
The investigator must report all SAE (initial as well as follow-up) to ALK within 24 hours after 
obtaining knowledge of the information. 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 
(including relevant data e.g. demography, medical history, concomitant medication) must be 
reported by email or fax to ALK. For all ESIs, additional information specific to the ESI in question 
will be collected in the eCRF. 
Any specific eCRF ESI form 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 fax. Please state the trial ID 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.  
 
Email address: 
<
>  
Fax number: 
 
Emergency phone: 
 
The assessment of listedness is performed by ALK according to the reference safety information in 
the current version of the IB. 
ALK will inform the regulatory authorities and IECs/IRBs in accordance with local requirements in 
force and the ICH guidelines for GCP (ICH 1996). 
12.3.2 
Follow-up on AEs and SAEs 
SAEs must be followed up until resolution 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.  
For chronic diseases ongoing SAEs can be closed at the end of trial (visit 9) with the term "not 
recovered" (as evaluated upon medical evaluation by the investigator or the sponsor).  


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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 end of trial (visit 9).  
12.3.3 
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. 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. 
12.3.4 
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 CRF. Significant laboratory events found at the following visits, and which meet the 
definition of an AE, must be recorded on an AE form. 
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 
 
12.3.5 
Reporting of pregnancies 
The investigator must report information on pregnancy and pregnancy follow-up information 
including pregnancy complications, delivery and health of the infant until the age of one month 
within 14 calendar days of obtaining the information, using the pregnancy notification form and 
pregnancy follow-up form. 
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 two years of age) and suspected to be related to intra-
uterine exposure to the IMP should be reported to ALK. 
12.3.6 
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 phone 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 phone contact must be reported within 14 days by using the 
contact details listed in this section.  


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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, SAEs, and laboratory data.  
12.5 DMC 
A data monitoring committee (DMC) will not be established for this trial. 
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 has to be obtained.  
13 EARLY TERMINATION OF TRIAL 
ALK reserves the right to terminate the trial due to the following: 
• 
Safety concerns  
• 
Proven lack of efficacy from other completed trials with the same IMP 
 
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. 
Early trial termination may be the result of any single criterion specified below: 
• 
IMP-related death of an individual 
• 
IMP-related anaphylactic shock in at least 2 subjects defined as: 
Acute onset of an illness (minutes to several hours) with involvement of the skin, mucosal tissue, or 
both (e.g. generalised hives, pruritus, or flushing, swollen lips, tongue, or uvula) AND medically 
confirmed reduced BP with associated symptoms of end-organ dysfunction (e.g. hypotonia 
[collapse], syncope, incontinence).  
14 DATA HANDLING 
The diary in the trial will be an eDiary. The site will be trained in the use of eDiary by sponsor 
representatives. The sites will then train the subjects in how to fill in the eDiary.  


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An eCRF will be used for this trial. The data is entered by trained site investigator/staff into the 
eCRF according to guidelines. A completed eCRF is required for each subject who signs an 
informed consent. All eCRFs must be completed in English.  
The completed eCRFs and eDiaries are the property of the sponsor and must not be made 
available in any form to third parties (except for authorised representatives of appropriate 
governmental health or regulatory authorities) without written permission of the sponsor.  
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, September 1, 2019 or higher). 
Medical history and AEs will be coded using Medical Dictionary for Regulatory Activities (MedDRA) 
(version 22.1 or higher).  
14.2 eDiary  
Starting at visit 3, an eDiary will be dispensed and data will be entered by the subject. The subject 
will be trained in the eDiary by the investigator or designee. In addition, a training video with 
information on the eDiary will be available for the subjects. The data will be reviewed by the 
investigator. 
During the trial, data will be entered in an eDiary by the subject and transferred to the eDiary 
vendor database on a daily basis. 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 overall compliance for a subject in the 
trial not to be below 80%.  
There will be no other source documentation for these data other than the vendor database. 
After database lock, all access to the eDiary will be set as "read only". The sponsor will extract 
blinded data from the eDiary system. 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 periodic review by the sponsor. Findings during the review of the 
eDiary data will be evaluated by the investigator and updates/correction to the data can only be 
executed by the investigator or if raised by sponsor only executed after confirmation and approval 
by the investigator.  
Documentation of the data load from the eDiary vendor to ALK will be described in the data 
management report. 


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14.3 Query handling 
Query handling at the trial site will be performed according to the guidelines for the eCRF and 
eDiary systems. 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 
Laboratory samples will be processed at a central laboratory selected by ALK. When the samples 
have been analysed and the data released, a laboratory report will be sent to the investigator. The 
investigator must review and sign the laboratory reports. The lab data are also imported 
automatically in the eCRF for investigator evaluation of outliers. At the end of the trial the blinded 
laboratory data will be provided electronically to data management at ALK. 
 
 
 
The transfer of laboratory data to the eCRF will be described in a data transfer specification. 
Documentation of receipt and quality check of laboratory and immunological data will be provided 
in a data management report. 
14.5 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 at site.  
If changes to trial data become necessary after database lock this must be performed according to 
the current ALK Standard operating procedure (SOP). 
A data archive for the site subject data files (eCRF, eDiary and Laboratory data) are 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 computations will be performed using SAS® 
version 9.4 or later version. 
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. Before database lock, a separate SAP detailing 
the specifications given below will be prepared and agreed upon. This includes a detailed 
description of the total analysis set, full analysis set (FAS), safety analysis set, the per protocol 
(PP) analysis set and asthma analysis set (analysis sets are defined in Section 15.3. 
Numerical variables will be summarised in tables including mean, standard deviation, median, 
25%-quantile, 75%-quantile, minimum and maximum. 
Categorical variables will be summarised by tables displaying numbers and percentage of subjects 
in each category. 
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 marked. 
 
15.1 Estimands 
A primary and secondary estimand is defined for each of the primary, key secondary and 
supportive secondary objectives (see Sections 2.4 - 2.6 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 defined in Section 15.11.1. Approaches for handling 
intercurrent events and missing data are given in Section 15.11.2, 15.11.3 and 15.14.  
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 IEs that have been identified as relevant is discontinuation of trial treatment due to adverse 
event or lack of efficacy. Prior to unblinding, potential unforeseen IEs will be specified in SAP to 
make sure an unbiased definition of IEs. 
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 (ICH 2020), the trial product estimand 
can be described by: 
A. Treatment: 5-grass mix SLIT-drops, where rescue medication is taken as required. 
B. Population: Subjects randomised in this trial will be adults ≥18 years of age, with a clinical 
history of allergic rhinoconjunctivitis (with or without asthma) as diagnosed by a physician 
and having had symptoms despite treatment with antihistamines or nasal steroids during 
the two previous grass pollen seasons 
C. Variable: Average total combined score (TCS) during the 2nd PGPS 
D. How to account for intercurrent events: under the hypothetical situation where all 
subjects had completed treatment for the planned duration (hypothetical strategy) 
E. Population summary: Absolute difference in means between treatment conditions. 
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 15.11.2. 
15.1.3 
Secondary estimand  
Using the framework proposed in the ICH E9(R1) addendum (ICH 2020), the treatment policy 
estimand can be described by: 
A. Treatment: 5-grass mix SLIT-drops, where rescue medication is taken as required. 
B. Population: Subjects randomised in this trial will be adults ≥18 years of age, with a clinical 
history of allergic rhinoconjunctivitis (with or without asthma) as diagnosed by a physician 
and having had symptoms despite treatment with antihistamines or nasal steroids during 
the two previous grass pollen seasons 
C. Variable: Average total combined score (TCS) during the 2nd PGPS 
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 in means between treatment conditions 
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 15.11.3. 
 
15.1.4 
Estimands for key secondary and supportive secondary endpoints 
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 and 
supportive secondary objectives, where the relevant key secondary and supportive secondary 
endpoints of interest is specified in attribute C. 


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15.2 Sample size and power considerations 
General considerations: 
In this trial, primary and secondary endpoints are tested hierarchically to control the family-wise 
error rate at 5% level. Individual endpoint analyses are based on treatment comparisons using a 2-
sided t-test on a 5% level of significance.  
The power calculations were done in two steps. The initial sample size calculation was done for 
observed cases only. This sample size is then evaluated using the estimand framework. The 
power is calculated for both the primary endpoint (TCS) and the key secondary endpoint (RQLQ). 
It is expected that the treatment difference in RQLQ is greater than the minimal clinically important 
difference (MCID) (0.16). 
TCS power calculation: 
The estimated TCS mean, standard deviation and treatment differences during the peak season 
from three trials is presented in Table 8. The power calculation is based on a TCS treatment 
difference of 21% (1.64 in absolute value) and a common standard deviation of 5.5. Under these 
assumptions, the trial has a power of 80% with the sample size of 180 evaluable subjects. The 
power will be 86% for the primary estimand and 80% for the secondary estimand with the 
assumption that 10% out of 220 subjects will discontinue the trial, with 4.5% of subjects 
discontinuing due to adverse events and 1% due to lack of efficacy each year.  
Table 8 
Mean and standard deviation of TCS during the peak of a season. 
 
RQLQ power evaluation: 
The estimated RQLQ mean, standard deviation and treatment differences during the peak season 
from 3 trials raw data is presented in Table 9. 
Table 9 
Mean and standard deviation of RQLQ during the peak of a season. 
Trial 
Placebo 
𝝁 (𝝈 ) 
Active 
𝝁 (𝝈 ) 
Difference 
Absolute (relative) 
GT-08 2006 
8.44 (5.48) 
5.14 (4.06) 
3.3 (39%) 
P05238 
7.74 (6.50) 
6.10 (5.09) 
1.64 (21%) 
P08067 
5.73 (5.03) 
4.56 (4.60) 
1.17 (20%) 
Average 
2.04  
Trial 
Placebo 
𝝁 (𝝈 ) 
Active 
𝝁 (𝝈 ) 
Difference 
Absolute (relative) 
GT-08 2005 
1.82 (1.11) 
1.37 (0.97) 
0.45 (25%) 


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A common standard deviation of 1.15 has been assumed in the power evaluation. An expected 
placebo mean is 1.60 and an expected treatment difference is 0.34. With 180 evaluable subjects 
per treatment arm, the power of 93% is reached for testing if RQLQ treatment difference is greater 
than proposed MCID of 0.16. The power will be 95% for the primary and 92% secondary 
estimands for the sample size of 220 subjects with the same discontinuation assumptions as for 
TCS. 
Conclusion:  
The suggested sample size is 180 evaluable subjects per treatment arm. 220 subjects should be 
randomised in each arm, assuming a 10% discontinuation of subjects per year, where 1% 
discontinued due to lack of efficacy and 4.5% due to adverse events. In such case, the trial will 
have a power of at least 80% in order to detect a statistically significant difference of at least 21% 
with common standard deviation no larger than 5.5 for primary endpoint in observed case scenario. 
The trial will have a power of 86% and 80% for primary endpoint for primary and secondary 
estimands respectively. The trial will have a power of at least 93% to detect treatment difference 
greater than 0.16 in RQLQ for observed case. Similarly, 95% and 92 % for the primary and 
secondary estimand respectively.   
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 failures and 
AEs before randomisation. 
The FAS is 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 analysis tables, and 
corresponding subject listings. 
The PP analysis set is all subjects in the FAS with no major protocol violations which will affect the 
primary endpoint. Details will be described in the SAP. The PP analysis set will be used for primary 
and key secondary analyses.  
The safety analysis set is all randomised subject who received at least one dose of IMP. The 
safety analysis set will be used for all safety tables and corresponding subject listings. 
Asthma analysis set includes subjects from FAS that have medical history of asthma. Asthma 
analysis set will be used for selected summary tables and analysis. If less than 20% of FAS will 
have medical history of asthma, then this analysis set will not be used. 
GT-08 2006 
1.48 (1.05) 
1.05 (0.91) 
0.43 (29%) 
P05238 
1.73 (1.34) 
1.41 (1.12) 
0.33 (18%) 
P08067 
1.32 (1.11) 
1.18 (1.08) 
0.15 (11%) 
Average 
0.34 


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15.4 Subject disposition 
A table of subject disposition by treatment group displaying number and percentage of subjects 
screened, included in the FAS, included in the PP analysis set discontinued and the primary 
reason for discontinuation 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. 
15.6 Extent of exposure 
Extent of IMP exposure and IMP accountability will be summarised by treatment group by means 
of descriptive statistics. 
15.7 Medical history 
Medical history will be coded using the Medical Dictionary for Regulatory Activities (MedDRA) in 
the analysis and summarised by treatment group, system organ class (SOC) and preferred term 
(PT). In addition, rhinitis, conjunctivitis or rhinoconjunctivitis, atopic dermatitis and allergies 
(including food allergies), will be summarised separately by treatment groups. 
15.8 Concomitant therapy 
Prior and concomitant medication will be coded according to the World Health Organization (WHO) 
drug dictionary in the analysis and summarised by treatment group. 
15.9 Derivation of endpoints 
Average daily rhinoconjunctivitis TCS during the PGPS/EGPS is an average of available daily TCS 
scores during corresponding periods. Similarly, average weekly overall RQLQ score during the 
PGPS/EGPS is an average of available weekly RQLQ scores during corresponding periods. 
The daily allergic rhinoconjunctivitis TCS is the sum of the allergic rhinoconjunctivitis DSS and the 
allergic rhinoconjunctivitis DMS.  
The allergic rhinoconjunctivitis DSS, corresponds to a sum of 6 individual symptom scores: runny 
nose, nasal congestion (blocked nose), sneezing, itchy nose, itchy eyes (gritty feeling, red eyes), 
and watery eyes. Each symptom will be scored with the following values: no symptoms (0 points), 
mild symptoms (1 point), moderate symptoms (2 points), or severe symptoms (3 points). Thus, the 
maximum daily symptom score will be 18. 
The rhinoconjunctivitis DMS will be based on use according to the need of the medications outlines 
in Table 10. 


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Table 10 
Symptom relieving medication for rhinitis with/without conjunctivitis 
Symptom-relieving medication 
Score/Dose unit 
Maximum Daily Score 
Desloratadine tablets, 5 mg 
6 
6 
Olopatadine eye drops, 1 mg/ml 
1,5 pr. eye 
6 
Mometasone nasal spray, 50 µg/dose 
2 
8 
Maximum daily rhinitis and/or conjunctivitis medication score 
 
20 
15.10 Multiplicity 
The trial product estimand is the primary estimand for all endpoints. The analyses for the main 
estimators will be controlled for multiplicity to ensure a family wise type I error rate is no lager than 
5%. The multiplicity will be controlled by employing hierarchical testing: pre-specifying the order of 
the hypothesis to be tested. For all 4 endpoints the null hypothesis tested is the hypothesis of 
equality of placebo and 5-grass mix SLIT-drops treatment group. 
The order of hypothesis to be tested is: 
1. The primary endpoint is the average daily allergic rhinoconjunctivitis total combined score 
(TCS) during 2nd PGPS.  
2. The overall RQLQ score during the 2nd PGPS 
3. The average daily allergic rhinoconjunctivitis TCS during the 1st PGPS 
4. The overall RQLQ score during the 1st PGPS 
The primary endpoint is the first hypothesis in the hierarchy and will be tested on a 5% significance 
level. The endpoints from 2nd to 4th in hypothesis tests will be only carried out if all previously 
tested hypotheses are statistically significant at the 5% level.  
Additional endpoints and analyses are supportive in nature and will not be controlled for 
multiplicity. 
15.11 Efficacy analyses  
The main estimator  as well as sensitivity estimators will be defined in Sections 15.11.1 and 
15.11.4, handling of missing data will be defined in Sections 15.11.2 and 15.11.3. Exploratory 
analyses defined in Section 15.11.5. 
15.11.1 
Estimator  
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 15.11.2 ,15.11.3 and 
15.14. 
Missing data will be imputed using the method of unrestricted random sampling with replacement. 
The average score will be imputed, but not the daily/weekly values. Missing data for 1st year will 
be imputed from observed data in 1st year and missing data for 2nd year will be imputed from the 
observed data in 2nd year. Thus, PGPS data will be imputed from observed PGPS data and EGPS 
from EGPS. Missing data for subjects with asthma will be imputed from patients with asthma 


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according the rules defined below and missing data for subjects without asthma will be imputed 
from subjects without asthma also following the rules defined below. Rubin’s multiple imputation 
strategy with 1000 imputations will be used (Rubin D.B 1987). Seed used for imputation will be 
12345.  
The endpoints will be analysed using Mixed Model of Repeated Measurements (MMRM) assuming 
unequal variances in the two treatment groups. Each endpoint (TCS, RQLQ, DMS, DSS) is 
modelled over two seasons (2022 and 2023) for PGPS. Similarly, each endpoint is modelled over 
two seasons for EGPS. The summary of response variables analysis using MMRM is presented in 
Table 11.   
 
Table 11 
Summary of MMRM response variables. 
Analysis number 
Endpoint in 1st year 
Endpoint in 2nd year 
1 
2nd key secondary endpoint: 
TCS during 1st PGPS 
Primary endpoint: TCS during 
2nd PGPS 
2 
3rd key secondary endpoint: 
average weekly overall RQLQ 
1st PGPS 
1st key secondary endpoint: 
average weekly overall RQLQ 
2nd PGPS 
3 
Supportive secondary 
endpoint: average weekly 
overall RQLQ 1st EGPS 
Supportive secondary 
endpoint: average weekly 
overall RQLQ 2nd EGPS 
4 
Supportive secondary 
endpoint: TCS 1st EGPS 
Supportive secondary 
endpoint: TCS 2nd EGPS 
5  
Supportive secondary 
endpoint: DSS 1st PGPS 
Supportive secondary 
endpoint: DSS 2nd PGPS 
6 
Supportive secondary 
endpoint: DSS 1st EGPS 
Supportive secondary 
endpoint: DSS 2nd EGPS 
7 
Supportive secondary 
endpoint: DMS 1st PGPS 
Supportive secondary 
endpoint: DMS 2nd PGPS 
8 
Supportive secondary 
endpoint: DMS 1st EGPS 
Supportive secondary 
endpoint: DMS 2nd EGPS 
 
The relevant endpoints in 1st and 2nd years are set to be the response variables and treatment, 
visit, treatment/visit interaction as well as asthma indication (yes/no) are fixed effect and trial site 
as a random class effect. If less than 20% of subjects will have asthma indication positive, then the 
asthma indication will be removed from the model. The compound symmetry covariance matrix is 
considered. In case there will be issues with convergence, first-order autoregressive covariance 
matrix will be considered.  Depending on the number and size of trial sites, pooling of trial sites 
may be considered, or trial sites may be replaced by regions or countries. This will be specified in 
the SAP. The summary of the results will contain p-value for the treatment effect, and both the 
absolute difference with 95% CI and the relative difference with 95% CI will be presented. If the 
assumptions underlying the MMRM are not fulfilled an appropriate transformation (e.g. the square 
root) of the response variables will be carried out. Results will be back-transformed and shown on 


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the original scale. Further details of the primary analysis, test of assumptions, and sensitivity 
analysis will be detailed in the SAP. 
15.11.2 
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 15.1.2). 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 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. 
15.11.3 
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 15.1.3). 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. 


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• 
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 
discontinuation. Further sensitivity estimator(s) for the treatment policy estimand may also be 
considered and will be detailed in the SAP. 
15.11.4 
Estimators for estimands defined for key secondary efficacy objectives 
The key secondary and supportive secondary endpoints will be analysed identically to the primary 
endpoint using the definitions of the trial product estimand and treatment policy estimand (see 
Sections 2.4 and 2.5) and the main and sensitivity estimators described in Section 15.11.1.  
15.11.5 
Exploratory analysis 


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15.12 Safety analyses 
15.12.1 
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, outcome and 
seriousness. 
The analyses will be described further in the SAP. 
15.12.2 
Evaluation of other safety parameters 
Laboratory assessments, vital signs, physical examination and FEV1 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. 
The analyses will be described further in the SAP. 
15.13 Interim analyses 
No interim analysis is planned. 
15.14 Handling of missing data  
Efficacy endpoints which are an average of daily diary entries over a defined pollen season period 
will be derived provided there is at least one relevant diary entry for that endpoint in the given 
pollen season period. Subjects with missing data for an endpoint will be included in the analysis of 
that endpoint through multiple imputation (see Sections 15.11.2, 15.11.3 and 15.11.4). 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 


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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.  
As a minimum requirement, the following data must be source data-verifiable in source 
documentation other than the CRF: 
• 
Subject’s date of birth 
• 
Confirmation of participation in the trial (trial ID, subject number/randomisation number, 
diagnosis) 
• 
Date of informed consents 
• 
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 lab 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 on 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 CRF 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 


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• 
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.  
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.  
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 CRF 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/CRO within 24-hours.   
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) 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)  
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, CRFs 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 CRF and any electronic database owned by ALK. All 
documents will be stored securely and only accessible by trial staff and authorised personnel. 
17.4 Data protection 
All data will be handled and stored according to GDPR (The European parliament 2016). 
Investigator 


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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. In these cases, ALK will take 
appropriate measures to protect data and ensure that the transfer of data will have an adequate 
level of data protection. ALK will rely on valid standard contract clauses signed with third parties.  
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. 
If this is a multi-site trial, 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 go 
through a pseudonymisation process, 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. 
Description of arrangements 
To ensure the safekeeping of clinical trial data ALK has Standard Operating Procedures that 
defines how data shall be managed including handling of security data breaches. When data is 


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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 amendment 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. 
18 REPORTING AND PUBLICATION 
18.1 Integrated clinical trial report 
Data will be reported in a clinical trial report 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 national coordinating investigator(s) will review and sign the clinical trial report. 


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18.2 Publication 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 CRF (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). Invitation to author publications will be at the discretion of 
ALK. All authors of publications need to fulfil all four criteria stated in the Vancouver 
guidelines/ICMJE criteria: 1) substantial contributions to the conception or design of the work; or 
the acquisition, analysis, or interpretation of data for the work; 2) drafting the work or revising it 
critically for important intellectual content; 3) final approval of the version to be published; and 4) 
agreement to be accountable for all aspects of the work in ensuring that questions related to the 
accuracy or integrity of any part of the work are appropriately investigated and resolved.  Failure to 
meet all 4 ICMJE criteria will result in removal as author. Other significant contributions to the 
publication will be acknowledged in accordance with journal or other relevant specific guidelines. 
If the number of authors is restricted, selection will be based on accountability 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. 
Furthermore, results of the trial will be posted in the EU Clinical Trials Registry no later than 12 
months after LSLV. No individual de-identified subject data will be shared. Results of the trial, 
together with the protocol and SAP, will be posted at ClinicalTrials.gov together with the final 
protocol and SAP no later than 12 months after the primary completion date. No individual de-
identified subject data will be shared. 


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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, it is 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 investigators and clinical research organisations 
(CROs) and e.g. subcontractors for project management, monitoring, central laboratory, etc. are 
listed in Appendix 3: Trial organisation. 


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21 REFERENCE LIST 
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SAP_001.pdf: 
Cover page 
SU-G-01 
Grass SLIT-drops  
COVER PAGE SU-G-01 STATISTICAL ANALYSIS PLAN 
Official trial title 
A randomised, parallel-group, double-blind, placebo-controlled phase III trial assessing 
the efficacy and safety of 5-grass mix SLIT-drops in adults with grass pollen-induced 
rhinoconjunctivitis 
NCT number 
NCT04881461 
Document date 
27-Oct-2023


Statistical analysis plan 
Date: 
27-Oct-2023
Trial ID: SU-G-01 
Version: 
1.0 
EudraCT No.: 2020-000455-12 
Status: 
Final 
CONFIDENTIAL 
Page: 
1 of 47 
Statistical Analysis Plan 
Trial ID: SU-G-01 
A randomized, parallel-group, double-blind, placebo-
controlled phase III trial assessing the efficacy and 
safety of 5-grass mix SLIT-drops in adults with grass 
pollen-induced rhinoconjunctivitis 
Sponsor: 
ALK A/S 
Bøge Alle 6-8 
DK-2970 Hørsholm 
Investigational medicinal product: 5-grass mix SLIT-drops 
Phase: III   
EudraCT No.: 2020-000455-12 
Document status: Final 
Date: 27-OCT-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: 
27-Oct-2023 
 
Trial ID: SU-G-01 
Version: 
1.0 
EudraCT No.: 2020-000455-12 
Status: 
Final 
CONFIDENTIAL 
Page: 
2 of 47 
 
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: 
27-Oct-2023
Trial ID: SU-G-01 
Version: 
1.0 
EudraCT No.: 2020-000455-12 
Status: 
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CONFIDENTIAL 
Page: 
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Table of contents  
Page 
ALK approval of statistical analysis plan ............................................................................... 2
Table of contents ...................................................................................................................... 3
Table of figures......................................................................................................................... 5
1 
List of abbreviations ......................................................................................................... 6
2 
Table of definitions ........................................................................................................... 8
3 
Introduction ....................................................................................................................... 9
3.1
Objectives and endpoints .......................................................................................... 9
3.1.1
Estimands ......................................................................................................... 12
3.1.1.1 
Intercurrent events ............................................................................................................. 12 
3.1.1.2 
Primary estimand ............................................................................................................... 12 
3.1.1.3 
Secondary estimand .......................................................................................................... 13 
3.2
Study design ........................................................................................................... 14
3.2.1
Flow chart ......................................................................................................... 15
3.2.2
Actual trial timelines .......................................................................................... 15
3.2.3
Randomisation .................................................................................................. 15
4 
Statistical hypotheses..................................................................................................... 15
4.1
Multiplicity adjustment ............................................................................................. 15
5 
Analysis sets ................................................................................................................... 16
5.1
Population sets ....................................................................................................... 16
5.2
Data point sets ........................................................................................................ 17
6 
Statistical analyses ......................................................................................................... 17
6.1
General considerations ........................................................................................... 17
6.1.1
Considerations regarding countries ................................................................... 19
6.1.2
IMP discontinuation ........................................................................................... 19
6.2
Analyses ................................................................................................................. 21
6.2.1
Handling of intercurrent events and missing data for the trial product estimand – 
main approach .................................................................................................................. 21
6.2.2
Handling of intercurrent events and missing data for the trial product estimand – 
sensitivity analysis ............................................................................................................. 23
6.2.3
Handling of intercurrent events and missing data for the treatment policy 
estimand – main approach ................................................................................................ 24
6.2.4
Handling of intercurrent events and missing data for the treatment policy 
estimand – sensitivity analysis........................................................................................... 26
6.2.5
Missing data examples ...................................................................................... 26
6.2.6
Exploratory endpoint analysis ............................................................................ 27
6.2.7
Supportive analyses .......................................................................................... 27


Statistical analysis plan 
Date: 
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Trial ID: SU-G-01 
Version: 
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EudraCT No.: 2020-000455-12 
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6.2.7.1 
Tipping point analysis under the primary and secondary estimand .................................. 27 
6.3 
Supplementary analyses ......................................................................................... 28 
6.3.1.1 
Asthma subgroup analysis ................................................................................................. 28 
6.3.1.2 
Subjects from the same household ................................................................................... 28 
6.3.1.3 
Symptoms-score tertiles analysis ...................................................................................... 28 
6.4 
Safety analyses ...................................................................................................... 29 
6.4.1 
Extent of exposure ............................................................................................ 29 
6.4.2 
Adverse events ................................................................................................. 29 
6.4.2.1 
Events of special interest ................................................................................................... 30 
6.4.2.2 
Reporting of adverse events .............................................................................................. 30 
6.4.3 
Additional safety assessments .......................................................................... 31 
6.5 
Changes and/or deviations to protocol-planned analyses ....................................... 31 
7 
Sample size determination ............................................................................................. 32 
8 
Demographics and baseline characteristics ................................................................. 33 
8.1 
Screening failures ................................................................................................... 33 
8.2 
Protocol deviations ................................................................................................. 33 
8.3 
Subject disposition .................................................................................................. 33 
8.4 
Baseline characteristics .......................................................................................... 33 
8.5 
Pollen counts .......................................................................................................... 34 
8.6 
Medical history ........................................................................................................ 34 
8.7 
Prior and concomitant therapy ................................................................................ 34 
9 
Supporting documentation ............................................................................................. 34 
9.1 
Definition of pollen seasons .................................................................................... 34 
9.2 
Derivation of endpoints ........................................................................................... 35 
9.2.1 
DSS .................................................................................................................. 35 
9.2.2 
DMS .................................................................................................................. 35 
9.2.3 
TCS ................................................................................................................... 36 
9.2.4 
RQLQ ................................................................................................................ 36 
 
....................................................................................................... 36 
 
.............................................................................................. 36 
 
 .......................................................................................... 36 
 
 .......................................................................................................... 36 
9.3 
Derivation of average endpoints ............................................................................. 37 
9.4 
Imputation of dates ................................................................................................. 37 
9.4.1 
Partial dates in AE reporting .............................................................................. 37 
9.4.2 
Incomplete date for last IMP dose ..................................................................... 37 
9.4.3 
Incomplete date for Previous/Concomitant medication ...................................... 37 
9.5 
Further details pertaining to statistical analyses ...................................................... 38 


Statistical analysis plan 
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9.5.1 
Transformations ................................................................................................ 38 
9.5.2 
Analyses with multiple imputation ...................................................................... 39 
9.5.3 
Model checking ................................................................................................. 40 
 
 .............................................................. 40 
 
 ......................................................... 40 
 
 ..................................................................... 40 
9.5.7 
Analysis of quality-of-life questioners ................................................................ 41 
9.5.8 
Convergence issues .......................................................................................... 41 
10 
References ..................................................................................................................... 42 
Appendix A: SAS codes ......................................................................................................... 43 
Appendix B: pollen seasons start and stop dates ............................................................... 44 
 
Table of figures    
 
Page 
Figure 1 Trial design ............................................................................................................. 14 
Figure 2: TCS trajectory. ...................................................................................................... 26 
Figure 3 Fieller's method ...................................................................................................... 38 
Figure 4 Transformations ..................................................................................................... 39 
 
Table of tables    
 
Page 
Table 1 Trial timelines .......................................................................................................... 15 
Table 2 Population sets ........................................................................................................ 16 
Table 3 Data point sets and observation periods. ................................................................. 17 
Table 4 Summary of analyses .............................................................................................. 18 
Table 5: Sources of observed data used for imputation under the primary estimand. ........... 23 
Table 6: Sources of observed data used for imputation under the sensitivity analyses of the 
primary estimand. ............................................................................................... 24 
Table 7: Sources of observed data used for imputation under the secondary estimand........ 25 
Table 8: Mean and standard deviation of TCS during the peak of a season. ........................ 32 
Table 9: Mean and standard deviation of RQLQ during the peak of a season. ..................... 32 
Table 10 Grass pollen season definitions. ............................................................................ 34 
Table 11 Symptom relieving medication for rhinitis with/without conjunctivitis ...................... 35 


Statistical analysis plan 
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Version history 
This statistical analysis plan (SAP) for trial SU-G-01 is based on protocol version 4.0 dated 12-
Nov-2021. 
SAP Version 
Date 
Change 
Rationale 
1 
12-JUL-2023 
Not applicable 
Original version 
 
1 List of abbreviations 
 
AAS 
Asthma analysis set 
AE 
Adverse event 
AIT 
Allergy immunotherapy 
ALT 
Alanine aminotransferase 
ARC 
Allergic rhinoconjunctivitis 
AST 
Aspartate aminotransferase 
ATS 
American Thoracic Society 
BP 
Blood pressure 
BUN 
Blood urea nitrogen 
DBL 
Database lock 
DMS 
Daily medication score 
DPS 
Data points sets 
DSS 
Daily symptom score 
eCRF 
Electronic case report form 
EGPS 
Entire grass pollen season 
EMA 
European medicines agency 
 
 
ESI 
Events of special interest 
EudraCT 
European Union Drug Regulating Authorities Clinical Trials 
FAS 
Full analysis set 
FEV1 
Forced expiratory volume in 1 second 
FVC 
Forced vital capacity 
GCP 
Good clinical practice 
GLMM 
Generalised linear mixed model 
ICH 
International Conference on Harmonisation of Technical Requirements for Registration 
of Pharmaceuticals for Human Use 
ICS 
Inhaled corticosteroids 
IE 
Intercurrent event 
IgE 
Immunoglobulin E 


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IMP 
Investigational medicinal product 
ITT 
Intention-to-treat 
IRT 
Interactive response technology 
LABA 
Long-acting bronchodilator inhalers 
LDH 
Lactate dehydrogenase 
LSLV 
Last subject last visit 
MAR 
Data missing at random 
MCAR 
Missing completely at random 
MCH 
Mean corpuscular haemoglobin 
MCID 
Minimal clinically important difference 
MCV 
Mean corpuscular volume  
MedDRA 
Medical Dictionary for Regulatory Activities 
MMRM 
Mixed-effect model for repeated measurement 
MNAR 
Data missing at not random 
PGPS 
Peak grass pollen season 
pH 
Potential of hydrogen 
PRO 
Patient reported outcome 
PT 
Preferred term 
RQLQ 
Rhinitis quality of life questionnaire 
SABA 
Short-acting β2-agonist 
SAE 
Serious adverse event 
SAP 
Statistical analysis plan 
SAF 
Safety analysis set 
SAS® 
Computer software for statistical programming 
SD 
Standard deviation 
SGOT 
Serum glutamic-oxaloacetic transaminase 
SGPT 
Serum glutamic pyruvic transaminase 
SLIT 
Sublingual immunotherapy 
SOC 
System organ class 
SPT 
Skin prick test 
TCS 
Total combined score 
TEAE 
Treatment emergent adverse event 
TOS 
Total analysis set 
WHO 
World Health Organization 
 
 


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2 Table of definitions 
AE 
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. 
Completed treatment 
A subject is considered to have completed treatment if he/she has been 
randomized and has not discontinued treatment. 
Completed subject 
A randomised subject is considered completed if he/she has not discontinued 
the trial before V9. 
Completion date 
For each completed subject, the date of the last scheduled procedure/end of 
trial visit(V9). 
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 end of the trial is defined as the date of V9. 
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). 
Grass pollen season 
• 
Start date: The first day of 3 consecutive days with (non-missing) 
pollen count larger than or equal to 10 grains/m3. 
• 
Stop date: The last day before 3 consecutive days with (non-missing) 
pollen count less than 10 grains/m3. 
Peak grass pollen season 
The 15 days period with the highest average pollen count during the entire 
grass pollen season. 
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). 
LSLV  
Last scheduled physical visit for any subject (V9). 
Primary trial completion date  
Date of the last data collection for the primary endpoint (ClinicalTrials.gov) is 
the last scheduled physical visit for any subject (V9). 
Rescue medication 
Medicinal products provided by ALK when the efficacy of the IMP is not 
sufficient or likely to cause an AE to the subject or to manage an emergency 
situation in relation to grass pollen allergy symptoms in agreement with the 
EMA Definition of IMPs and Use of AMPs Consultation Document (EMA 2016)  
The rhinoconjunctivitis rescue medication in this trial is:  
• 
Antihistamine tablets  
• 
Antihistamine eye drops  
• 
Corticosteroid nasal spray. 
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 


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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. 
TEAE  
TEAEs are defined as AEs with start date and/or 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 CSR is signed. 
Withdrawal from trial date  
Date of subject withdrawal from trial. In case of subjects lost to follow-up, the 
withdrawal date is defined as the date the investigator/sponsor decides to 
withdrawal the subject. 
3 Introduction 
The SAP supplements the statistical section in the protocol and provides additional details 
regarding estimands, analysis sets, endpoints and statistical analyses. In Section 9.1 detailed 
descriptions of pollen seasons, derivation of endpoints, imputation of dates, and the statistical 
analyses are provided. In supplementary document to the SAP: Documentation of Trial Analysis 
Sets, the various subject related listings are provided.  
Changes to the analyses and changes that might (or can) impact the analyses described in the 
protocol are documented in Section 6.5. 
This SAP has been written and approved before database lock and unblinding. 
3.1 Objectives and endpoints 
Objectives 
Endpoints 
Primary 
The primary objective is to compare the 
efficacy of 5-grass mix SLIT-drops to placebo 
in relieving grass rhinoconjunctivitis symptoms 
and on the use of symptom-relief medication 
during the 2nd PGPS. 
The primary efficacy endpoint is the average 
daily allergic rhinoconjunctivitis TCS during the 
2nd PGPS 
Key secondary 
To measure the impact of treatment with 5-
grass mix SLIT-drops compared to placebo on 
health-related quality of life as a result of grass 
pollen-induced rhinoconjunctivitis during the 2nd 
PGPS.  
The average weekly overall RQLQ score 
during the 2nd PGPS. 
To compare the efficacy of 5-grass mix SLIT-
drops to placebo in relieving grass 
rhinoconjunctivitis symptoms and on the use of 
symptom-relief medication during the 1st 
PGPS. 
The average daily allergic rhinoconjunctivitis 
TCS during the 1st PGPS. 
To measure the impact of treatment with 5- The average weekly overall RQLQ score 


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grass mix SLIT-drops compared to placebo on 
health-related quality of life as a result of their 
grass pollen-induced rhinoconjunctivitis during 
the 1st PGPS. 
during the 1st PGPS. 
Supportive secondary 
To measure the impact of treatment with 5-
grass mix SLIT-drops compared to placebo on 
health-related quality of life as a result of their 
grass pollen-induced rhinoconjunctivitis during 
the 1st - EGPS and during the 2nd EGPS. 
• 
The average weekly overall RQLQ 
score during the 1st EGPS. 
• 
The average weekly overall RQLQ 
score during the 2nd EGPS.  
To compare the efficacy of 5-grass mix SLIT-
drops to placebo in relieving grass 
rhinoconjunctivitis symptoms and in use of 
symptom-relief medication during the 1st 
EGPS and during the 2nd EGPS. 
• 
The 
average 
daily 
allergic 
rhinoconjunctivitis TCS during the 1st 
EGPS.  
• 
The 
average 
daily 
allergic 
rhinoconjunctivitis TCS during the 2nd 
EGPS.  
To compare the efficacy of 5-grass mix SLIT-
drops to placebo in relieving grass 
rhinoconjunctivitis symptoms during the 1st 
and during the 2nd PGPS, and during the 1st 
EGPS and during the 2nd EGPS. 
• 
The 
average 
daily 
allergic 
rhinoconjunctivitis DSS during the 1st 
PGPS.  
• 
The 
average 
daily 
allergic 
rhinoconjunctivitis DSS during the 2nd 
PGPS.  
• 
The 
average 
daily 
allergic 
rhinoconjunctivitis DSS during the 1st 
EGPS.  
• 
The 
average 
daily 
allergic 
rhinoconjunctivitis DSS during the 2nd 
EGPS. 
To compare the efficacy of 5-grass mix SLIT-
drops to placebo in use of symptom-relief 
medication during the 1st and during the 2nd 
PGPS, and during the 1st and during the 2nd 
EGPS. 
• 
The 
average 
daily 
allergic 
rhinoconjunctivitis DMS during the 1st 
PGPS.  
• 
The 
average 
daily 
allergic 
rhinoconjunctivitis DMS during the 2nd 
PGPS.  
• 
The 
average 
daily 
allergic 
rhinoconjunctivitis DMS during the 1st 
EGPS.  
• 
The 
average 
daily 
allergic 
rhinoconjunctivitis DMS saduring the 2nd 
EGPS. 
To measure (or compare) the safety and 
tolerability of 5-grass mix SLIT-drops and (or 
to) placebo. To measure safety and treatment 
tolerability of patients who have grass pollen-
induced rhinoconjunctivitis and who receive 
• 
TEAEs 
• 
ESIs 
• 
IMP-related TEAEs 


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either 5-grass mix SLIT-drops or placebo at 
randomisation and at the end of trial. 
• 
Treatment-emergent SAEs 
• 
TEAEs leading to discontinuation of 
treatment (using definitions of reasons 
for discontinuing treatment as in 
estimand framework in section 6.1.2) 
• 
Time to discontinuation of treatment 
due to TEAEs (using definitions of 
reasons for discontinuing treatment as 
in estimand framework in section 6.1.2) 
• 
Vital signs during the trial 
• 
Physical examination at randomisation 
and end of trial 
• 
Lung function tests at randomisation  
• 
Clinical laboratory assessments at 
randomisation and end of trial 
Exploratory 


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3.1.1 Estimands 
The formal statistical analysis of primary, key secondary, and some supportive secondary 
endpoints consists of two strategies (hypothetical and treatment policy defined in Sections 
3.1.1.2 and 3.1.1.3, respectively), supporting and supplementary analysis. Each strategy aims 
to answer a different clinical question of interest by using different ways to address intercurrent 
events. Definitions of relevant intercurrent events for this trial are provided in Section 3.1.1.1. 
Each strategy consists of a main approach and sensitivity analysis estimands. Different 
assumptions are made in each estimand analysis to predict the behaviour of the missing data 
so that predictions are aligned with the interpretation of the estimand. Sections 6.2.1 and 6.2.2 
provide the handling of missing data for each estimand. Hypothetical strategy main analytical 
approach estimand is referred to as primary estimand, and treatment policy strategy main 
analytical estimand is referred to as secondary estimand. 
The supportive analysis investigates alternative approaches regarding missing data. One 
supportive analyses are planned for this trial: tipping-point analysis described in Section 6.2.7.1. 
Two supplementary analyses for hypotetical strategy's main approach estimand are planned: 
ongoing asthma subgroup analysis described in Section 6.3.1.1 and patients from the same 
household described in Section 6.3.1.2. 
3.1.1.1 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 to precisely define the treatment 
effect that is to be estimated. 
The IEs that have been identified as relevant is discontinuation of trial treatment. No additional 
IEs were identified during the conduct of the trial.  
Due to the long duration of allergy immunotherapy, 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. 
3.1.1.2 Primary estimand  
Primary estimand is referred to as the ‘trial product estimand’. The trial product estimand 
assesses the anticipated effect of the 5-grass SLIT-drops if it is taken as instructed. This 
estimand is considered to be of most relevance to the patient population, as it describes the 
potential benefit they could obtain from the 5-grass SLIT-drops 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. 
Using the framework proposed in the ICH 2020, the trial product estimand can be described by: 
A. Treatment: 5-grass mix SLIT-drops, where rescue medication is taken as required 
B. Population: adults with grass pollen-induced rhinoconjunctivitis 
C. Variables: average daily allergic rhinoconjunctivitis TCS during 2nd PGPS 
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 in means between treatment (see Section 
9.5). 


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A hypothetical strategy is 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 is included in the analysis. Any diary data recorded after the discontinuation of 
trial treatment will be excluded from the analysis. Details of the handling of IEs for primary 
estimand main estimator are provided in section 6.2.1. 
Put differently, the hypothetical assumption is that subjects remain on randomised treatment, 
but this does not necessarily imply that all subjects randomised to the same treatment 
experience similar benefits of that treatment. The determining factor is discontinuation of IMP 
due to following reasons (see section 6.1.2): 
• 
due to “lack of efficacy” 
• 
due to “IMP-related AEs” 
• 
due to “other reasons” 
Under the primary estimand, the assumption is that subjects who discontinue IMP due to “lack 
of efficacy” would not have experienced a treatment benefit other than that observed in the 
placebo arm. Contrary, subjects discontinuing for either of the two other reasons would have 
experienced a treatment benefit similar to the observed among subjects randomised to the 
same treatment arm.  
These considerations imply that under the primary estimand, the only observed data used for 
analysis are obtained before discontinuation of IMP, while data obtained after discontinuation 
will be treated as missing. It further follows that imputation of missing data or data treated as 
missing will condition on the reason for discontinuation as outlined above. Moreover, data can 
be missing even for subjects not discontinuing IMP (e.g. due to low compliance). The reasoning 
for this type of missingness is ignorable and, consequently, this missing data will be imputed 
under the assumption that subjects experience a treatment benefit similar to that observed 
among subjects randomised to the same treatment arm. For further details, see section 6.2.1. 
3.1.1.3 Secondary estimand 
This estimand is 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 expected population of patients. 
This estimand is in line with the ‘intention to treat’ principle and provides a robust assessment of 
the efficacy of the 5-grass SLIT-drops. 
The treatment policy estimand can similarly to the trial product estimand be described by: 
A. Treatment: 5-grass mix SLIT-drops, where rescue medication is taken as required. 
B. Population: Adults with grass pollen-induced rhinoconjunctivitis 
C. Variable: average daily allergic rhinoconjunctivitis TCS during 2nd PGPS 
D. How to account for intercurrent events: regardless of whether subjects have 
complete treatment for the planned duration (treatment policy strategy).  
E. Population summary: absolute difference in means between treatment (see Section 
9.5). 
A treatment policy strategy is 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 for 
secondary estimand main estimator are provided in section 6.2.2. 


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The secondary estimand’s main feature is that subjects complete the trial though not 
necessarily, while still exposed to IMP. Therefore, all observed data is used in the analysis of 
this estimand irrespective of adherence to IMP, and only truly missing data needs to be 
imputed. 
3.2 Study design 
This is a phase III, randomised, parallel-group, double-blind, placebo-controlled trial of 5-grass 
mix SLIT-drops in adults with grass pollen-induced moderate to severe allergic 
rhinoconjunctivitis, with or without asthma. The trial was conducted over two grass pollen 
seasons. 
A total of 440 adult subjects were planned to be randomised (1:1) to continuously receive either 
active treatment (grass SLIT-drops) or placebo treatment once daily  
All subjects should receive daily treatment continuously from at least 16 weeks before the 
anticipated start of the 1st EGPS through the 2nd EGPS (definitions are provided in Section 9.1), 
corresponding to approximately 26 months of treatment (see Figure 1 ). Open-label rescue 
medication for AR/C was provided during the GPS. The subjects were asked to complete a 
RQLQ diary at V3 during the off-season for grass and tree pollen and then weekly during the 
EGPSs. The subjects were furthermore asked to fill in an eDiary daily during the EGPSs to 
capture information on rhinitis and/or conjunctivitis symptoms, use of symptom-relieving 
medications, and impact of rhinitis and/or conjunctivitis quality of life. 
 
Figure 1 Trial design 
Data for the primary endpoint were collected by the subjects by completing questions related to 
their daily symptoms and medication use in an electronic diary (eDiary). 
No interim analysis was planned. 
Routine safety surveillance was conducted throughout the trial. The follow-up visit was 
conducted via a telephone call approximately one week after the end of trial visit.   
The first subject was randomised 15-Aug-2022 and subjects were planned to received 
treatment for 26 months. A total of 445 subjects were randomised and dosed. 


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3.2.1 Flow chart 
The flow chart can be found in protocol.  
3.2.2 Actual trial timelines 
The actual trial timelines are presented in Table 1. 
Table 1 Trial timelines 
First subject first visit (FSFV) 
02-May-2021 
Last subject randomised 
31-Dec-2021 
Last subject last visit (LSLV) 
22-Sep-2023 
3.2.3 Randomisation 
The randomisation list was 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 and all protocol deviations that have been identified, evaluated, classified, categorised 
and closed. 
The randomisation was administered centrally via IRT and treatment allocation was stratified 
based on pre-existing diagnosis of asthma to ensure equal distribution of subjects with or 
without asthma across the treatments. 
Randomisation errors 
During the conduct of the trial, one randomisation error has occurred. An overview of the error 
can be found in supplementary document to the SAP: Documentation of Trial Analysis Sets. 
The randomisation error was included in the FAS. If missing data have occurred, it will be 
handled using the estimand framework. 
4 Statistical hypotheses 
4.1 Multiplicity adjustment 
The trial product estimand is the primary estimand for all endpoints. The analyses for the 
primary and for the three key secondary endpoints will be controlled for multiplicity to ensure a 
family wise type I error rate is no larger than 5%.  
The multiplicity will be controlled by employing a hierarchical testing procedure by pre-
specifying the order of the hypothesis to be tested. For the primary and key secondary 
endpoints the null hypothesis tested, is the hypothesis no difference between placebo and 5-
grass mix SLIT-drops treatment group. 
The testing order of hypothesis is: 
1. The primary efficacy analysis of the average daily allergic rhinoconjunctivitis TCS during 
the 2nd PGPS.  
2. The key secondary efficacy analysis of average weekly overall RQLQ score during the 
2nd PGPS. 


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3. The key secondary efficacy analysis of average daily allergic rhinoconjunctivitis TCS 
during the 1st PGPS. 
4. The key secondary efficacy analysis of average weekly overall RQLQ score during the 
1st PGPS. 
The primary endpoint is the 1st hypothesis in the hierarchy and will be tested on a 5% 
significance level. The testing of endpoints from the 2nd to the 4th in the hypothesis hierarchy will 
only be is only carried out formally if all previously tested hypotheses are statistically significant 
at the 5% level.  
Additional endpoints and analyses are supportive in nature, thus they will not be controlled for 
multiplicity. 
5 Analysis sets 
5.1 Population sets 
For the purposes of analyses, the following subject analysis sets are defined: TOS, FAS, SAF 
and AAS. The definitions are provided in Table 2. 
Table 2 Population sets 
Subject analysis sets 
Description 
Total Analysis Set (TOS) 
All subjects who signed informed consent and thus 
includes screening failures. 
Full Analysis Set (FAS) 
FAS consists of all randomised subjects. Subjects are 
analysed as randomised i.e. according to their 
randomised assignment of treatment.   
Safety Analysis Set (SAF) 
SAF consists of all randomised subjects who received at 
least one dose of IMP. Subjects are analysed as treated 
i.e. according to treatment they actually received.  
Asthma Analysis Set (AAS) 
The AAS is a subgroup of the FAS and consists of 
subjects that have ongoing asthma at randomisation. 
Subjects are analysed as randomised i.e. according to 
their randomised assignment of treatment. 
The TOS will be used for subject disposition output. The FAS will be used for baseline tables, all 
efficacy endpoints reporting; SAF will be used for safety data reporting; and AAS will be used 
for selected summary tables. 
 
 


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5.2 Data point sets 
The following DPS are defined: 
Table 3 Data point sets and observation periods. 
DPS 
Description 
DPS1 (On-treatment observation period) 
This includes all assessments that are 
observed while a subject is on treatment and 
within grass pollen season. For subjects who 
completed the trial, all assessments will be 
included, and for a subject that discontinued 
trial treatment, all assessments will be used 
until the treatment discontinuation. 
For relevant endpoints, baseline observation 
will also be included (
). 
 
DPS2 (In-trial observation period) 
This includes all assessments that are 
observed while a subject is in trial and within 
grass pollen season.  
For relevant endpoints, baseline observation 
will also be included (
). 
 
FAS and DPS1 will be used to estimate the hypothetical strategy estimand, whereas FAS and 
DPS2 will be used to estimate the treatment policy estimand. Note that the on-treatment study 
period is only applicable for subjects exposed to randomised treatment. 
6 Statistical analyses 
Statistical analyses will be carried out by ALK, Biometrics, Hørsholm, Denmark. All computation 
will be performed using the statistical analysis system (SAS), SAS® version 9.4 or later. 
The analyses described in this section along with the supporting information supplied in Section 
9 specify the statistical analyses.  
6.1 General considerations 
The efficacy data will be analyzed using estimand framework. The primary and first key 
secondary endpoints will be analyzed based on on-treatment (DPS1) and in-trial (DPS2) data, 
while the rest of the endpoints will be analyzed based on on-treatment (DPS1) data. Different 
approaches of handling missing data will be applied. Overview of analysis methods and 
analysis sets to be used are summarized in Error! Reference source not found..  
 
 


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Table 4 Summary of analyses 
Endpoint 
Analysis methods 
Analysis sets 
Data type 
Primary endpoint:TCS 
during 2nd PGPS 
Key secondary enpoind:  
RQLQ during 2nd PGPS 
Trial product estimand – 
main approach  
FAS 
Imputed, DPS1 
Trial product estimand – 
sensitivity analysis  
Treatment policy estimand – 
main approach   
Imputed, DPS2 
Treatment policy estimand – 
sensitivity analysis 
Supportive analysis: Tipping-
point analysis under the trial 
estimand – main approach  
Imputed, DPS1 
Supplementary analysis: 
Ongoing asthma subgroup 
analysis 
Supplementary analysis: 
Subjects from the same 
household 
Supplementary analysis: 
Symptoms-score tertiles 
analysis 
Observed, DPS1 
Descriptive analysis 
FAS/AAS 
Key secondary enpoind:  
TCS during 1st EGPS 
RQLQ during 1st  EGPS 
Trial product estimand – 
main approach  
FAS 
Imputed, DPS1 
Trial product estimand – 
sensitivity analysis  
Treatment policy estimand – 
main approach   
Imputed, DPS1 
Treatment policy estimand – 
sensitivity analysis 
Descriptive analysis 
Observed, DPS1 
Secondary endpoints: 
TCS, RQLQ, DMS and DSS 
Trial product estimand – 
main approach  
FAS 
Imputed, DPS1 
Descriptive analysis 
Observed, DPS1 
Secondary endpoints: 
safety and tolerability  
Descriptive analysis 
SAF 
Observed  


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Unless otherwise mentioned all the statistical tests described in this section will use a 
significance level of 5% and all tests and confidence intervals will be two-sided. All null 
hypotheses are “no differences in means between treatment arms” and the alternative 
hypotheses will always be “a (not specified) difference”. 
Descriptive statistics for efficacy endpoints will be based on observed on-treatment data. 
Descriptive statistics for numerical (continuous) variables include displaying treatment group 
mean, SD, median, minimum and maximum. Descriptive statistics for categorical variables will 
include frequency tables displaying the numbers and percentages. 
Adjusted or “estimated” treatment group means (least squares means) will be estimated using 
coefficients across classification effects and, where relevant, continuous covariates proportional 
to those found in the relevant analysis set at baseline.  
In addition to the inferential analyses, all efficacy endpoints will be presented in summary 
tables. 
Where appropriate, summaries for the endpoints will be provided for 1st and 2nd seasons (eDiary 
data) and PGPS/EGPS, or by visits (vital signs, clinical laboratory assessments, physical 
examinations, and lung-function tests). 
6.1.1 Considerations regarding countries 
Variation between different countries and sites are expected due to variation in geography and 
climate and thus grass exposure which may affect assessments. Further, variation in standard 
treatment procedures, and possible differences in the conduct of the trial are expected to vary 
between countries. Variation between sites (centres) is also expected but is assumed to be 
small compared to the variation between countries. The major source of variability is expected 
to be pollen exposure. Some sites can have very few subjects making it unreasonable to 
include sites as a covariate in the analysis model. In this trial, country is used as a covariate in 
the models. 
6.1.2 IMP discontinuation 
As pointed to previously, reasons for discontinuation of IMP will be categorised into three 
categories: 1) due to “IMP-related AE” 2) due to “lack of efficacy” and 3) due to “other reasons”. 
As the eCRF defined that trial- and treatment discontinuation reasons are not corresponding to 
this tripartite split the following mapping form the observed data in the eCRFs to the three 
categories will be performed: 
Treatment discontinuation reasons presented in the eCRF’s “Visit Status”-form are: 
• 
Severe or persistent symptoms of eosinophilic oesophagitis 


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• 
Pregnancy 
• 
Physician's decision 
• 
Adverse event(s) 
• 
Asthma difficult to control 
• 
Treatment is unblinded 
while withdrawal from trial reasons presented in eCRF’s “End of study”-form are: 
• 
Screening failure 
• 
Withdrawal of consent  
• 
Adverse event(s) 
• 
Lost to follow-up 
• 
Non-compliance with protocol 
• 
Pregnancy 
• 
Death 
• 
Lack of efficacy 
• 
Randomisation code broken  
• 
Other 
Before DBL, the discontinuation of treatment is re-defined and the subject specific list of 
discontinuations and their classifications to fit the estimand framework is in supplementary 
document to the SAP: Documentation of Trial Analysis Sets. 
Discontinuation due to AEs 
A subject is considered discontinued from the treatment due to IMP-related AE if the following 
conditions are met: 
1. If, in the “Visit status”-form or End of study”-form reported reason for treatment 
discontinuation or withdrawal from trial is: 
• 
Severe or persistent symptoms of eosinophilic oesophagitis 
• 
Adverse event(s) 
• 
Asthma difficult to control 
2. And AEs related to discontinuation are classified as possibly or probably related. 
Discontinuation due to lack of efficacy 
A subject is considered discontinued from the treatment due to lack of efficacy if the following 
conditions are fulfilled: 
1. If, in the “End of study”-form, it is noted that the subject withdrawal from trial due to “Lack 
of efficacy”. 
Discontinuation due to “other reasons” 
A subject is considered discontinued from the treatment due to other reasons if the subject 
discontinues treatment or withdrawal from trial due to other reasons than mentioned above. 


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6.2 Analyses 
The main estimator and sensitivity estimator for both estimands will be based on an identical 
method of statistical analysis .The estimator for all estimand will be based on MMRM with 
treatment, year, treatment and year interaction, and ongoing asthma status as fixed effects and 
country and year interaction as random class effect (more details specified Section 9.5.2). 
Exposure to pollen can vary yearly; thus, treatment effects may differ each year. Therefore, the 
model contains treatment and year interaction as a fixed effect. Pollen count depends on local 
geography and weather and can vary locally yearly. Thus, the model comprises country and 
year interaction as a random effect.  
The actual data used in each analysis may vary according to the different strategies taken for 
the handling of IEs and missing data. In the trial product estimand, data until treatment 
discontinuation will be included in the analysis and treatment policy estimand all observed data 
will be included.  
Imputations will be done on the average scores, but not daily/weekly values. To calculate an 
average score, only one observation is needed. 
Missing data will be imputed by sampling from an appropriate pool that matches the subject's 
characteristics. Missing data for 1st year will be imputed from observed data in 1st year, and 
missing data for 2nd year will be imputed from the observed data in 2nd year. Thus, PGPS data 
will be imputed from observed PGPS data and EGPS from observed EGPS. Missing data for 
subjects with ongoing asthma will be imputed from subjects with ongoing asthma, and missing 
data for subjects without ongoing asthma will be imputed from subjects without ongoing asthma 
following the rules defined below.  
If the IE occurred after 1st season, then the missing data imputation in the 1st year will be 
handled disregarding the IE and imputed under assumption MAR (data will be imputed from the 
subject’s own treatment arm for both estimands). The missing data of 2nd season will be 
handled based on IE. If IE occurred after 2nd, the missing data will be handled disregarding IE in 
both seasons. For more details, see Sections 6.2.1 and 6.2.2. 
The imputation pool of subjects will consist of subjects with all and partially observed data. In 
other words, if subject will be used in the analysis, they will also be used in the pool of the 
subjects to impute from.  
Rubin’s (Rubin 1987) multiple imputation strategy will be used to pool results of multiple 
analysis. 
6.2.1 Handling of intercurrent events and missing data for the trial product estimand – 
main approach 
The relevant endpoints will be compared between treatment groups using the trial product 
estimand with population FAS and data point DPS1. This means that subjects for whom the 
endpoint is missing (the exclusion of daily diary data due to discontinuation of trial treatment) 
will still be included in the analysis through multiple imputations under the hypothetical situation 
where subjects continued to take trial treatment as planned. The missing data imputation is 
done using the following rules:  
• 
For subjects that discontinue trial treatment due to lack of efficacy, multiple imputation of 
the missing endpoint will be taken 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 are assumed to be missing not at random (MNAR).  


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• 
For subjects that discontinue trial treatment due to IMP-related AEs, multiple imputation 
of the missing endpoint will be taken 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 irrespective to randomised treatment. Data is 
assumed to be missing at random (MAR).  
• 
For subjects that discontinue trial treatment due to any other non-IMP-related reason or 
subjects that have missing data but completed the trial, 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. 
In summary, missing data is imputed based on the following observed on-treatment data (Table 
5): 
 
 


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Table 5: Sources of observed data used for imputation under the primary estimand. 
Missing data or data treated as missing in 2022, 2023 
or in both years. 
Observed data as source for bootstrap: sampling from 
subjects with complete 1st and 2nd year data for the pollen-
period under consideration 
Randomised 
treatment 
Discontinuation 
reason 
Ongoing asthma 
status at 
screening 
Randomised treatment 
Ongoing asthma status at 
screening 
Active 
Lack of efficacyA 
Yes 
Placebo 
Yes 
Active 
IMP-related AEsA 
Yes 
Active 
Yes 
Active 
OtherA 
Yes 
Active 
Yes 
Active 
Data is missingB 
Yes 
Active 
Yes 
Active 
Lack of efficacyA 
No 
Placebo 
No 
Active 
IMP-related AEsA 
No 
Active 
No 
Active 
OtherA 
No 
Active 
No 
Active 
Data is missingB 
No 
Active 
No 
Placebo 
Lack of efficacyA 
Yes 
Placebo 
Yes 
Placebo 
IMP-related AEsA 
Yes 
Placebo 
Yes 
Placebo 
OtherA 
Yes 
Placebo 
Yes 
Placebo 
Data is missingB 
Yes 
Placebo 
Yes 
Placebo 
Lack of efficacyA 
No 
Placebo 
No 
Placebo 
IMP-related AEsA 
No 
Placebo 
No 
Placebo 
OtherA 
No 
Placebo 
No 
Placebo 
Data is missingB 
No 
Placebo 
No 
A: Data is either (actually) missing or treated as missing because of “earlier” treatment discontinuation 
B: Data is missing prior to any observed date of treatment discontinuation 
6.2.2 Handling of intercurrent events and missing data for the trial product estimand – 
sensitivity analysis 
The sensitivity analysis for the trial product estimand will use the multiple imputation policy 
described above for the main analysis except:  
• 
For subjects that discontinue the trial treatment due to IMP-related AEs, multiple 
imputation of the missing endpoint will be from the placebo group. This assumes 
subjects reporting IMP-related AEs would have 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. See Table 6. 


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Table 6: Sources of observed data used for imputation under the sensitivity analyses of the 
primary estimand. 
Missing data or data treated as missing in 2022, 2023 
or in both years. 
Observed data as source for bootstrap: sampling from 
subjects with complete 1st and/or 2nd year data for the 
pollen-period under consideration 
Randomised 
treatment 
Discontinuation 
reason 
Ongoing asthma 
status at 
screening 
Randomised treatment Ongoing asthma status at 
screening 
Active 
Lack of efficacy$ 
Yes 
Placebo 
Yes 
Active 
IMP-related AEsA 
Yes 
Placebo 
Yes 
Active 
OtherA 
Yes 
Active 
Yes 
Active 
Data is missingB 
Yes 
Active 
Yes 
Active 
Lack of efficacyA 
No 
Placebo 
No 
Active 
IMP-related AEsA 
No 
Placebo 
No 
Active 
OtherA 
No 
Active 
No 
Active 
Data is missingB 
No 
Active 
No 
Placebo 
Lack of efficacyA 
Yes 
Placebo 
Yes 
Placebo 
IMP-related AEsA 
Yes 
Placebo 
Yes 
Placebo 
OtherA 
Yes 
Placebo 
Yes 
Placebo 
Data is missingB 
Yes 
Placebo 
Yes 
Placebo 
Lack of efficacyA 
No 
Placebo 
No 
Placebo 
IMP-related AEsA 
No 
Placebo 
No 
Placebo 
OtherA 
No 
Placebo 
No 
Placebo 
Data is missingB 
No 
Placebo 
No 
A: Data is either (actually) missing or treated as missing because of “earlier” treatment discontinuation 
B: Data is missing prior to any observed date of treatment discontinuation 
Otherwise, the sensitivity analyses will be similar to the main analyses. 
6.2.3 Handling of intercurrent events and missing data for the treatment policy 
estimand – main approach 
The relevant endpoints will be compared between treatment groups using the treatment policy 
estimand using FAS and DPS2. For subjects discontinuing trial treatment, all diary data 
(including data collected after discontinuation of trial treatment) will be included in the derivation 
of the relevant endpoint. 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 IMP-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 


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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 other reasons than IMP-related AEs or 
lack of efficacy reasons or subject have missing data, multiple imputation of the missing 
endpoint will be taken from their own treatment group. This assumes that the missing 
data are MAR.  
Otherwise, the analyses of the secondary estimand are similar to the main analyses of the 
primary estimand. The summary of missing data imputation is provided in Table 7 
Table 7: Sources of observed data used for imputation under the secondary estimand. 
Missing data in 2022, 2023 or in both years 
Observed data as source for bootstrap: sampling 
from subjects with complete 1st and/or 2nd year data 
for the pollen-period under consideration 
Randomised 
treatment 
Discontinuation 
reason 
Ongoing 
asthma status 
at screening 
Randomised treatment Ongoing Asthma status at 
screening 
Active 
Lack of efficacy 
Yes 
Placebo 
Yes 
Active 
IMP-related AEs 
Yes 
Placebo 
Yes 
Active 
Other 
Yes 
Active 
Yes 
Active 
Data is missingA 
Yes 
Active 
Yes 
Active 
Lack of efficacy 
No 
Placebo 
No 
Active 
IMP-related AEs 
No 
Placebo 
No 
Active 
Other 
No 
Active 
No 
Active 
Data is missingA 
No 
Active 
No 
Placebo 
Lack of efficacy 
Yes 
Placebo 
Yes 
Placebo 
IMP-related AEs 
Yes 
Placebo 
Yes 
Placebo 
Other 
Yes 
Placebo 
Yes 
Placebo 
Data is missingA 
Yes 
Placebo 
Yes 
Placebo 
Lack of efficacy 
No 
Placebo 
No 
Placebo 
IMP-related AEs 
No 
Placebo 
No 
Placebo 
Other 
No 
Placebo 
No 
Placebo 
Data is missingA 
No 
Placebo 
No 
A: Data is missing prior to any observed date of treatment discontinuation 
The sensitivity analysis 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. 


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6.2.4 Handling of intercurrent events and missing data for the treatment policy 
estimand – sensitivity analysis 
The sensitivity analysis 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. For subject, that has missing data but completed the trial data is imputed from 
they own treatment arm. 
6.2.5 Missing data examples 
Several examples are provided to illustrate how missing data will be handled according to the 
rules defined above. Importantly “missing data” under the primary estimand does not 
necessarily mean that data were not observed but rather actually missing data and observed 
data that is considered missing due to treatment discontinuation. 
For each year (1st and 2nd season), calculating average TCS, DSS, DMS, and RQLQ is a simple 
average of the diaries' observed records (no imputation of daily data) for some specific period.  
 
 
Figure 2: TCS trajectory. 
The Figure 2 shows three imaginary subjects between the 20th of June, 2022 and the 1st of 
August, 2022, as an example of daily records of TCS. The hypotetical grass pollen season is 
from 20th of June to 1st of August, 2022. The three subjects have identical TCS trajectories but 
discontinue treatment at three different time points. Also, we consider the case for the PGPS 
(the case for the EGPS and the year 2023 are dealt with similarly).  


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For these subjects, the 2022-PGPS lies between 24th of June and 7th of July, 2022.  
• 
Subject (#1) discontinues IMP on 22nd.of June. Thus, the entire PGPS lies after IMP 
discontinuation; therefore, this subject has no observations. Consequently, all records 
pertaining to the PGPS in 2022 and 2023 must be imputed. The observed data until 22nd 
of June will be used for the estimation of average endpoints for EGPS for 2022. 
• 
Subject (#2) discontinues IMP on 1st of July. This subject has observations between 24th 
June and 1st of July from the PGPS, and only these observations will be used as the 
basis for the subject’s 2022 PGPS record. This subject is thus fully observed in 2022’s 
EGPS and PGPS. Consequently, only imputations for 2023 will be performed. 
• 
Subject (#3) discontinues IMP after the end of the PGPS 2022. All the subject’s records 
from the PGPS will be used to calculate the average TCS, and consequently, only 
imputations for 2023 will be performed. 
Consider one more subject, which is not illustrated in Figure 2: 
• 
Subject (#4) discontinued IMP before 20th of June, 2022. Though this subject might have 
some recordings before the actual start EGPS 2022, but all the average endpoints will 
have to be imputed for both years.  
There are several observations to be aware about from the example above:  
• 
The pattern of missingness (and consequently the pattern of imputation) may differ 
within the same subject for EGPS and PGPS. This pattern is (for each 
endpoint/pollen season) either: 
o Completely missing (both years 2022 and 2023 are missing) 
o Observed in 2022 but missing in 2023 (monotone missing pattern) 
o Missing in 2022 and observed in 2023 (this can happen if diary data is, in 
fact, missing during, the relatively short PGPS (2 weeks) in 2022 but the 
subject otherwise completed the trial and treatment) (not monotone missing 
pattern) 
• 
“Completer” is a subject that is observed during both years. 
• 
The number of observations upon which a subject’s observed (EGPS and PGPS) 
average data depend considerably among subjects. 
6.2.6 Exploratory endpoint analysis 
 
 
 
 
 
6.2.7 Supportive analyses 
6.2.7.1 Tipping point analysis under the primary and secondary estimand 
The objective of tipping point analysis is to investigate the feasibility of alternative assumptions 
regarding missing data, leading to a change in conclusions. In other words, it aims to determine 
the threshold at which the evidence of a treatment effect no longer remains.  


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The tipping point 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. The considered 
penalty step for TCS will be 0.5 and for RQLQ will be 0.05. The penalty is gradually increased 
until the point, the tipping point, where the null hypothesis is no longer rejected. If the value of 
the tipping-point is considered a clinical plausible this analysis does not support rejecting 
primary hypothesis. 
The tipping point analysis will be performed for primary and first key secondary endpoints using 
trial product estimand main approach. 
6.3 Supplementary analyses  
6.3.1.1  Asthma subgroup analysis 
The subgroup analysis will test if the effect of treatment differs between subjects with and 
without ongoing asthma at screening. The analysis will be performed on imputed data using 
primary and secondary estimand, main analysis approaches. To be specific, data will be 
analysed using a Mixed Model of Repeated Measurements (MMRM) with treatment, year; 
treatment and year interaction, and ongoing asthma status as fixed effects and country and year 
interaction as random class effect and allowing unequal R-matrices among the two treatment 
arms. 
Treatment contrasts corresponding to each level of ongoing asthma status will be output along 
with multivariate tests of year-specific subgroup effects: that is, for each year, the two treatment 
contrasts are statistically significant from one another. 
6.3.1.2 Subjects from the same household 
The subjective nature of PRO measure may influence the overall quality of the data Chang et al. 
2019. Multiple factors can impact the truthfulness of the data, but in this supportive analysis, the 
aim is to investigate whether subjects from the same household can influence each other's 
evaluation of symptoms. 
This evaluation will be done by removing all subjects from the same households from the 
analysis. The list of subjects will be provided in the supplementary document to the SAP: 
Documentation of Trial Analysis Sets before DBL. The evaluation will be done on the primary 
endpoint (TCS during PGPS) and the first key secondary endpoint (RQLQ during PGPS). The 
analysis is done using primary estimands, the main analysis approach. 
If there is no, or minimal influence, the results are expected to be similar to those using all 
subjects' data. This analysis will be done only if in total 10 subjects will be from the same 
household. 
6.3.1.3 Symptoms-score tertiles analysis 
Howarth et al. (2012) examined effects of allergen immunotherapy where study sites were 
grouped by the level of allergic rhinoconjunctivitis symptoms (low, medium, high) among 
placebo-treated subjects. The hypothesis was that sites where the symptoms scores were the 
highest under placebo, the seasonal disease activity was the highest and, presumably, 
therefore an effect of the allergen immunotherapy could potentially be greater here than at sites 
where the symptoms scores under placebo were lower. 
To address this, trial sites will be grouped into tertiles according to the trial sites’ placebo mean 
TCS in the PGPS based purely on observed TCS values (i.e. no imputation) for each of the two 
years (2022 and 2023), respectively. TCS and RQLQ will be analysed for the PGPS using the 


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DPS1/on-treatment observation period data. The model(s) will be ANCOVAs run for each year 
separately. The model will include treatment, seasonal-disease-activity-subgroup and asthma 
strata as fixed effects and allowing unequal residual variances among the two treatment arms. 
Treatment contrasts corresponding to each level of trial-site-subgroup will be output along with 
(multivariate) tests of (year-specific) subgroup effects: that is, for each year, whether the three 
treatment contrasts (corresponding to the three tertiles subgroups) are statistically significant 
from one another. 
6.4 Safety analyses 
All safety summary tables, figures and listings will be based on the SAS unless otherwise 
specified.  
6.4.1 Extent of exposure 
IMP exposure 
Exposure will be assessed by calculating difference between the number of doses dispensed 
and the number of doses returned. Returned doses were counted by counting unopen foil bags 
and multiplying by number of doses in a bag (5 doses in a foin bag) Accountability by an 
investigator is performed at V3 (1st off-season), V4 (1st pre-EGPS), V5 (1st on-seasons), V6 (2nd 
off-seasons), V7 (2nd pre-EGPS), V8 (2nd on-season) and V9 (end of trial). The number of doses 
taken will be summarised by treatment group.  
IMP duration 
The duration of treatment for each subject will be calculated from the date of randomisation up 
until and including the date of the last IMP intake. Treatment duration will be summarised by 
treatment group.  
IMP compliance  
IMP compliance (%) will be assessed as the number of doses taken divided by the treatment 
duration multiplied by 100. As IMP exposure will be counted without taken into account dosses 
lost, thus IMP compliance will be capped to 100%. IMP compliance will be summarised by 
treatment group. 
eDiary compliance 
eDiary compliance will be summarised by treatment group and year. Here, compliance is 
calculated separately for the daily entries (TCS) and the weekly entries (RQLQ). Compliance is 
calculated as the number of actual entries to the number of intended entries. For subjects 
withdrawing from the trial, their withdrawal date (if during the EPGS) will serve as the cut-off 
when calculating the number of intended entries. 
IMP interruption 
IMP interruption is defined as if IMP intake is interrupted for more than 7 days and not in relation 
to an AE. Number of subjects that have IMP interruptions, number of IMP interruptions will be 
summarised by treatment group and year. 
6.4.2 Adverse events  
MedDRA version 23.1 will be used for reporting of AEs. All summaries will be provided using 
SAF. 


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6.4.2.1  Events of special interest 
An AE is any untoward medical occurrence in a subject that does not necessarily have a causal 
relationship with the administered IMP. An AE is a TEAE if the time of onset is on or after the 
time of the first dose administration of IMP and, no later than seven days seven days after the 
last dose administration of IMP. Selected (non-serious or serious) AEs are considered ESIs. 
ESIs are events that are considered critical for the evaluation of the product’s safety profile and 
for which additional data was collected. ESIs for this trial are:  
• 
Systemic allergic reactions including anaphylaxis 
• 
Events treated with adrenaline 
• 
Severe local swelling of the mouth and/or throat 
• 
Eosinophilic oesophagitis. 
6.4.2.2  Reporting of adverse events 
All TEAEs will be summarised by treatment group according to causality (IMP related or not), 
severity (mild, moderate, severe), seriousness (yes/no), action taken, outcome (recovered or 
resolved / recovered or resolved with sequelae / not recovered or not / resolved / fatal / 
unknown), and whether the event led to IMP discontinuation and interruption. The number of 
subjects in treatment group, the frequency and proportion of 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 defined as those that 
are present in at least 2% 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 and presented by SOC and PT similar to how TEAEs are 
presented. The same follows for SAEs, TEAEs leading to IMP discontinuation, and IMP-related 
TEAEs leading to IMP interruption. 
For most frequent IMP-related TEAEs (present in at least 2% of subject in the active treatment 
group) onset and duration will be presented as follows:  time to onset and average duration both 
in days, will be presented by SOC and PT and treatment. In addition, for day 1 of treatment 
average time to onset in minutes will be presented by SOC PT and treatment. 
In addition, most frequent non-serious TEAEs reported in at least 5% of subjects in any 
treatment group by SOC and PT. 
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 PT and treatment. 
A table with the overall summary of the safety profile will be produced showing number of 
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 IMP discontinuation, IMP-related TEAEs 
leading to IMP interruption, individual ESIs, TEAEs, and all non-treatment-emergent AEs for the 
total analysis set will be listed. Medication errors will also be listed. Pregnancies will be listed if 
fewer than 10 cases have been reported; otherwise summarised.  


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6.4.3 Additional safety assessments  
Shift tables will be produced for clinical laboratory assessments (haematology, blood chemistry 
and urinalysis) assessments including the categories low, normal, high, and missing as 
relevant, where the shift table will include the categories normal, abnormal not clinically 
significant, and abnormal clinically significant. 
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. 
Findings of urine pregnancy test will be summarised in a listing. 
6.5 Changes and/or deviations to protocol-planned analyses 
Several changes were made to the statistical analysis described in the trial protocol. The list of 
changes is summarised in this section: 
• 
PP analysis set is removed from analysis sets used in this trial. This analysis set does 
not align with the estimand framework; therefore, it will not be used in this trial. 
• 
Safety and tolerability objectives and endpoints are added as supportive secondary 
endpoints. 
• 
As described in the estimand framework, the most important IE is the discontinuation of 
IMP. The IMP discontinuation was not collected in the relevant manner in eCRF. 
Discontinuation of IMP is then re-classified based on reported IMP discontinuation and 
trial withdrawal reason (see Section 6.1.2), and these re-classified reasons are used in 
the estimand framework. 
• 
In this trial, subjects were stratified based on their history of asthma in adulthood. During 
the trial, it was determined that it is most relevant for interpretation of the disease and 
treatment is ongoing asthma status at screening. Therefore, the asthma status at 
screening will be used in the analysis models instead of asthma strata. Twenty one 
subjects were stratified as asthmatics but did not have ongoing asthma at screening. 
Subjects with ongoing asthma are expected to be well-balanced between treatment 
arms.  
• 
In the protocol, the primary and key secondary endpoint estimator contains the trial 
site/country as a random effect. In SAP, county and year interaction is a random effect. 
The change accounts for the variability of pollen load yearly in each country. 
• 
 
 
. 
• 
In the protocol, the proposed MCID is 0,16. Since the protocol proposal, additional 
research was performed and based on published results presented new MCID for PGPS 
is 0,1 and EGPS 0,22 (Blaiss et al. 2022).  
• 
Pollen season end date and pollen peak definition a modified to add clarity. Pollen 
season end date is specified that it is the last day of the last occurrence of 3 consecutive 
days with pollen count larger or equal to 10 grains/m3. For the peak season it is specified the 
14 consecutive days period is used as a peak. 


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7 Sample size determination 
General considerations 
In this trial, primary and secondary endpoints will be tested hierarchically to control the family-
wise error rate at 5% level. Individual endpoint analyses will be based on treatment 
comparisons using a 2-sided t-distributed test on a 5% level of significance. 
The power calculations were done in two steps. This sample size wasthen evaluated using the 
estimand framework. The power was calculated for both the primary endpoint (TCS) and the 
key secondary endpoint (RQLQ). It is expected that the treatment difference in overall RQLQ 
during peak season is greater than the MCID of 0.10 and during entire season greater than 0.22 
(Blaiss et al. 2022). 
TCS power calculation 
The estimated TCS mean, standard deviation and treatment differences during the peak season 
from three trials is presented in Table 8. The power calculation is based on a TCS treatment 
difference of 21% (1.64 in absolute value) and a common standard deviation of 5.5. Under 
these assumptions, the trial has a power of 80% with the sample size of 180 evaluable subjects. 
The power is 86% for the primary estimand and 80% for the secondary estimand with the 
assumption that 10% out of 220 subjects will discontinue the trial, with 4.5% of subjects 
discontinuing due to AEs and 1% due to lack of efficacy each year. 
Table 8: Mean and standard deviation of TCS during the peak of a season. 
Trial 
Placebo 𝜇(𝜎) 
Active 𝜇(𝜎) 
Difference absolute 
(relative) 
GT-08 2006 
8.44 (5.48) 
5.14 (4.06) 
3.3 (39%) 
P05238 
7.74 (6.50) 
6.10 (5.09) 
1.64 (21%) 
P08067 
5.73 (5.03) 
4.56 (4.60) 
1.17 (20%) 
Average 
2.04 
RQLQ power evaluation 
The estimated RQLQ mean, standard deviation and treatment differences during the peak 
season from 3 trials raw data is presented in Table 9 below. 
Table 9: Mean and standard deviation of RQLQ during the peak of a season. 
Trial 
Placebo 𝜇(𝜎) 
Active 𝜇(𝜎) 
Difference Absolute 
(relative) 
GT-08 2005 
1.82 (1.11) 
1.37 (0.97) 
0.45 (25%) 
GT-08 2006 
1.48 (1.05) 
1.05 (0.91) 
0.43 (29%) 
P05238 
1.73 (1.34) 
1.41 (1.12) 
0.33 (18%) 
P08067 
1.73 (1.34) 
1.18 (1.08) 
0.15 (11%) 
Average 
0.34 
A common standard deviation of 1.15 has been assumed in the power evaluation. An expected 
placebo mean is 1.60 and an expected treatment difference is 0.34. With 180 evaluable 


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subjects per treatment arm, the power of 98% is reached for testing if RQLQ treatment 
difference is greater than proposed MCID of 0.1. The power is 95% for the primary and 92% 
secondary estimands for the sample size of 220 subjects with the same discontinuation 
assumptions as for TCS. 
Conclusion 
The suggested sample size is 180 evaluable subjects per treatment arm. 220 subjects should 
be randomised in each arm, assuming a 10% discontinuation of subjects per year, where 1% 
discontinued due to lack of efficacy and 4.5% due to AEs. In such case, the trial has a power of 
at least 80% in order to detect a statistically significant difference of at least 21% with common 
standard deviation no larger than 5.5 for primary endpoint in observed case scenario. The trial 
has a power of 86% and 80% for primary endpoint for primary and secondary estimands 
respectively. Similarly, 95% and 92 % power for RQLQ for the primary and secondary estimand 
respectively. The trial has a power of at least 98% to detect treatment difference greater than 
0.1 in RQLQ for observed case. 
8 Demographics and baseline characteristics 
Summaries for numerical variables tables will display the descriptive statistics such as: mean, 
SD, median, min and max. 
Summaries for categorical variables frequency tables will display counts and percentages. 
8.1 Screening failures 
A summary of reasons for screening failure will be presented for the TOS. 
8.2 Protocol deviations 
Overall important PDs will be summarized 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. 
8.3 Subject disposition 
Subject disposition will be summarised by number and percentage of subjects screened, 
randomised and not treated, randomised and treated, included in the analysis sets, completed 
trial, withdrawal from the trial, reason of withdrawal of trial, completed IMP, discontinued IMP, 
and reason for IMP discontinuation by treatment group and total. Some endpoints  will be also 
summarised by year. In addition, the reasons for discontinuation of IMP following the estimand 
framework will be summarised by treatment groups and total. 
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). 
8.4 Baseline characteristics 
Demographic variables (age, sex, race, country) will be summarised by treatment and total 
groups. 


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Baseline characteristics (including baseline asthma status, inhaled corticosteroid use, duration 
of grass pollen allergy and mono/poly sensitized) are summarised by treatment groups.  
In separate tables, SPT test results (including actual wheel size and results and whether 
subjects are mon/poly sensitised), FEV1, percentage of predicted FEV1 and IgE are summarised 
by treatment groups.  
8.5 Pollen counts 
Pollen season definitions are provided in Section 9.1. Pollen counts will be summarised by 
treatment group and total. Pollen counts will be weighted by the number of subjects in each 
pollen station and divided by the number of subjects in the trial. In addition, lengths of EGPS 
and for each year will be summarised. Lengths of EGPS will also be weighted as pollen counts.  
8.6 Medical history 
Medical history will be summarised by treatment groups. Medical history of allergic rhinitis, 
conjunctivitis, asthma, atopic dermatitis and food allergy are summarised by treatment groups. 
8.7 Prior and concomitant therapy 
Prior and concomitant medication will be summarised by treatment groups. 
9 Supporting documentation 
9.1 Definition of pollen seasons 
Each trial site was allocated to a pollen station. The start and stop dates of the grass pollen 
seasons will be based on the daily pollen counts as defined in Table 10. The pollen EGPS dates 
will be within a period of expected pollen season defined trial protocol (see Trial Protocol, 
Appendix 5: Expected grass pollen season). 
Table 10 Grass pollen season definitions. 
Start date of EGPS 
The first day of 3 consecutive days with (non-missing) pollen count larger than or equal to 
10 grains/m3. 
Stop date of EGPS 
The last day of the last occurrence of 3 consecutive days with (non-missing) pollen count 
lager or equal to 10 grains/m3. 
PGPS 
The 14 consecutive days period with the highest average pollen count during the entire 
grass pollen season. 
Based on the definition above, if the EGPS is shorter than 14 days, than PGPS will be equal to 
EGPS. In addition, a visual inspection of the pollen count (pollen grains/m3 versus time) will be 
made to validate the pollen counts in the season.  
In case of missing pollen counts for specific pollen regions the 3 following principals will be used 
prior to unblinding: 
• 
If pollen counts for maximum 2 days will be missing with at least 5 days with observed 
pollen counts days then the missing pollen counts (after first occurrence of pollen) will be 
replaced by applying the last observation carried forward method. 


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• 
If pollen counts will be completely missing or missing for extended period of time for a 
specific pollen station then a replacement pollen station will be manually assigned. 
• 
In all other cases of missing pollen counts start and stop dates will be defined by visual 
inspection of the pollen counts for the specific pollen station and neighbouring pollen 
stations to approximate the general approach specified above. 
Pollen seasons (i.e., actual start and end dates or start and end dates based on visual 
inspection) will be defined prior to database lock and further specified in Appendix B: pollen 
seasons start and stop dates. 
9.2 Derivation of endpoints 
Symptoms and medication use days was recorded daily by the subject in the eDiary. For each 
day it was only possible for the subject to either record both symptoms and medication use or 
neither. 
 
 
 
9.2.1 DSS 
The 6 symptoms of rhinoconjunctivitis consists of 4 rhinitis symptoms (runny nose, blocked 
nose, sneezing, itchy nose) and 2 conjunctivitis symptoms (gritty feeling/red/itchy eyes, watery 
eyes). Each symptom is scored from 0 to 3 by the subject daily: 0 = no symptoms,1 = mild 
symptoms, 2=moderate symptoms, and 3=severe symptoms.  
The DSS is the sum of the 6 individual DSS and ranges from 0 to 18. 
9.2.2 DMS 
The DMS is the sum of the total daily scores for each medication. The total DMS for each 
symptomatic medication is calculated as the unit score multiplied by the number of units entered 
in the daily diary by the subject (Table 11). Note that the score is capped so that for each 
medication the score of the recommended dose is also the maximum score, i.e. this score 
cannot be exceeded even though the recommended dose is exceeded. The DMS ranges from 0 
to 20. 
Table 11 Symptom relieving medication for rhinitis with/without conjunctivitis 
Symptom-relieving medication 
Score/dose 
unit 
Maximum daily score 
SUGGEST: 
MAX DAILY UNITS 
Desloratadine tablets, 5 mg 
6 
6 
1 (Tablets) 
Olopatadine eye drops, 1 mg/mL 
1.5 pr. eye 
6 
4 (Drops) 
Mometasone nasal spray, 50 μg/dose 
2 
8 
4 (Puffs) 
Maximum daily rhinitis and/or conjunctivitis 
medication score 
- 
20 
 


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9.2.3 TCS 
The daily TCS is the sum of the DSS and the DMS and ranges from 0 to 38. 
9.2.4 RQLQ 
The RQLQ has 28 questions in 7 domains (activity limitation, sleep problems, nose symptoms, 
eye symptoms, non-nose/eye symptoms, practical problems and emotional function) (Juniper 
et. al 1998). 
Subjects were asked how bothered they have been by their rhinoconjunctivitis during the 
previous week and to respond to each of the 28 questions on a 7-point scale (from 0 = not 
bothered/none of the time to 6 = extremely bothered/all of the time). The overall RQLQ score is 
the mean of all 28 responses and the individual domain scores are the means of the items in 
those domains. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
.  
 
 
 
 


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9.3 Derivation of average endpoints 
Average endpoints will be calculated for both EGPS and PGPS pollen seasons. Pollen seasons 
are defined above, and the average endpoints will be derived for the following endpoints: 
• 
TCS 
• 
RQLQ 
• 
DSS 
• 
DMS 
Average endpoints will be derived as the simple mean of all observations (i.e. non-missing 
daily/weekly values) within the relevant time frame and data point set. 
9.4 Imputation of dates 
9.4.1 Partial dates in AE reporting 
Partial dates and time for start of AEs will be imputed as follows:  
• 
Missing day will be imputed as maximum of first day of month and day of first IMP dose. 
• 
Missing month will be imputed as maximum of first day in January and date of first IMP. 
• 
Missing time is calculated as the first minute of the day (i.e. if the AE start date is 16-
AUG-2022 then the AE start datetime will be 16-AUG-2022 T:00:00) 
 
Partial dates and time for end of AEs will be imputed as follows:  
• 
Missing day will be imputed as minimum of last day in month and day of last contact. 
• 
Missing month will be imputed as minimum last day of December and date of last 
contact. 
• 
Missing time is calculated as the last minute of the day (i.e. if the AE end date is 16-
AUG-2022 then the AE start datetime will be 16-AUG-2022 T:23:59) 
 
With these imputation rules, AEs will be considered TE when dates are partial and the existing 
information does not exclude the possibility of the event being treatment-emergent.  
9.4.2 Incomplete date for last IMP dose 
Any partial date of last dose will be imputed as follows:  
• 
Missing day is imputed as minimum of last day in month and day of last visit.  
• 
Missing month is imputed as minimum of last day of December and date of last visit.  
• 
Missing last IMP dose date is imputed as the date of last known visit 
9.4.3 Incomplete date for Previous/Concomitant medication 
No date imputation will take place on previous/concomitant medication. However, medications 
with partial end dates will be considered to be previous medication. 


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9.5 Further details pertaining to statistical analyses 
Adjusted means for each treatment group, the absolute treatment difference with 95% CI and p-
value, and the relative treatment difference with 95% confidence interval will be presented. The 
95% confidence interval for the relative difference will be calculated using Fieller’s theorem 
(Fieller 1954) see Error! Reference source not found.  
 
Figure 3 Fieller's method 
9.5.1 Transformations 
Some endpoints will be square root transformed before (formal statistical) analysis. The square 
root transformation is generally applied, as this usually results in a good approximation to the 
normal distribution. In addition, a lot of subjects do not use rescue medication, so the average 
DMS score is often 0, and this will also be accounted for by using the square root 
transformation in contrast to the logarithmic transformation. The transformed endpoint is then 
included in the model as a response variable.  
The p-value for the absolute difference will be reported as the test result and no back-
transformation will be done. To enable reporting of relative difference on the original scale, 
transformed means will be back-transformed (see Error! Reference source not found.) and 
95% CI will be calculated using the methods described in Figure 3. For the absolute difference, 


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the SE is approximated using the first-order Delta method (first-order Taylor approximation), 
and the 95% CI is calculated from this. 
 
Figure 4 Transformations 
9.5.2 Analyses with multiple imputation 
The imputations will be carried out using the method of unrestricted random sampling with 
replacement (seed = 68686) and with 1,000 multiple imputed datasets created. It means that 
observed data is “bootstrapped” or sampled with replacement within the strata defined in the 
rows of Table 5, Table 6 and Table 7 and used to substitute (impute) missing data. If the actual 
significance level of the performed test will be between 4%-6%, then the number of imputations 
will be increased from 1,000 to 10,000. This will be done to ensure the precision of estimated 
standard error, and thus the right hypothesis testing conclusion will be made. 


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Missing data for each year will be imputed based on observed cases for the same year and 
using subjects as source for the imputations which happen to have data in the “current” year in 
question. 
Further, PGPS data will be imputed from observed PGPS data and EGPS from EGPS data from 
the corresponding year and ongoing asthma status. The ongoing asthma status might only be 
considered if there is enough unique permutation to impute from.  
The relevant endpoints in 1st and 2nd years will be analysed using a MMRM with treatment and 
year interaction, and ongoing asthma status as fixed effects and country and year interaction as 
random class effect and allowing unequal R-matrices among the two treatment arms. After the 
by-imputation MMRMs, results are summaries/combined using Rubin’s method (Rubin 1987). 
9.5.3 Model checking 
The assumption of normally distributed residuals will be evaluated by visual inspection of 
quantile-quantile plots for the primary and key secondary endpoints. If the square root 
transformation does not result in a good approximation to the normal distribution, no 
transformation will be applied if this improves the approximation to a normal distribution. 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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9.5.7 Analysis of quality-of-life questioners 
The overall RQLQ score during V3 (1st off-season) 
 at 
randomisation and at the end of trial will be analysed via descriptive statistics. Descriptive 
statistics by treatment include number of subjects, mean, standard deviation, median, minimum, 
and maximum. 
9.5.8 Convergence issues 
If any models defined above do not converge, several attempts will be made to reach 
convergence: 
• 
The first step will be set the same R-matrice among the two treatment arms. 
• 
The second step will be to change the unstructured covariance matrix to the compound 
symmetry matrix. 
• 
The third step we will be to remove ongoing asthma status from the model. 
• 
The fourth step we will be to be to pool countries into regions. 
• 
The fifth step will be to remove the random effect of region and year interaction from the 
model. 
 
 


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10 References 
ICH 2020: ICH E9 (R1) addendum on estimands and sensitivity analysis in clinical trials to the 
guideline on statistical principles for clinical trials EMA/CHMP/ICH/436221/2017. 
Chang et al. 2019: Chang, E. M., Gillespie, E. F., & Shaverdian, N. (2019). Truthfulness in 
patient-reported outcomes: factors affecting patients' responses and impact on data quality. 
Patient related outcome measures, 10, 171–186. https://doi.org/10.2147/PROM.S178344. 
Juniper et al. 1998: Juniper, E. F., Howland, W. C., Robertsa, N. B., Thompson, A. K., & King, 
D. R. (1998). Measuring quality of life in children with rhinoconjunctivitis. Journal of allergy and 
clinical immunology, 101(2), 163-170. 
Rubin 1987: Rubin, D.B. (1987) Multiple Imputation for Nonresponse in Surveys. John Wiley & 
Sons Inc., New York. http://dx.doi.org/10.1002/9780470316696. 
Blaiss et al. 2022: Blaiss, M. S., Gronskyte Juhl, R., Siew, L. Q., Hammerby, E., & Devillier, P. 
(2022). Determining the minimal important differences in the RQLQ score with grass and tree 
allergy immunotherapy versus placebo in adults with moderate‐to‐severe allergy. Allergy, 77(6), 
1843-1851. 
 
 


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Appendix A: SAS codes 
Primary efficacy analysis 
proc mixed data=analysis_MI method=reml; 
    by paramcd _imputation_; 
    class avisitn trt01pn aasfl country usubjid; 
    model aval = trt01pn avisitn trt01pn*avisitn aasfl / ddfm=KR  
                                                         solution; 
    random country(avisitn); 
    repeated avisitn / subject=usubjid type=UN group=trt01pn; 
    lsmeans trt01pn*avisitn / cl cov pdiff om; 
run; 
 
 
 
 


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Appendix B: pollen seasons start and stop dates 
Pollen 
station 
Sites 
Year 
Season 
Start date 
Stop date 
Comment 
CZBRNO 
207 
2022 
EGPS 
19MAY2022 04JUL2022  
PGPS 
31MAY2022 13JUN2022  
2023 
EGPS 
25MAY2023 20JUL2023  
PGPS 
20JUN2023 03JUL2023  
CZCEBU 
203, 212 
2022 
EGPS 
19MAY2022 18JUL2022  
PGPS 
02JUN2022 15JUN2022  
2023 
EGPS 
22MAY2023 25JUL2023 Missing data 
imputed with 
CZJIHL. 
PGPS 
29JUN2023 12JUL2023 
CZJIHL 
205 
2022 
EGPS 
18MAY2022 23JUL2022  
PGPS 
07JUN2022 20JUN2022  
2023 
EGPS 
22MAY2023 25JUL2023  
PGPS 
29JUN2023 12JUL2023  
CZLIBE 
209, 211, 
213 
2022 
EGPS 
24MAY2022 15JUL2022  
PGPS 
06JUN2022 19JUN2022  
2023 
EGPS 
28MAY2023 16JUL2023  
PGPS 
31MAY2023 13JUN2023  
CZUORL 
202, 210 
2022 
EGPS 
31MAY2022 19JUN2022  
PGPS 
03JUN2022 16JUN2022  
2023 
EGPS 
22MAY2023 25JUL2023 Missing data 
imputed with 
CZJIHL. 
PGPS 
29JUN2023 12JUL2023 
EETALL 
302 
2022 
EGPS 
15JUN2022 12AUG2022  
PGPS 
17JUN2022 30JUN2022  
2023 
EGPS 
15JUN2023 19JUL2023 Dates were 
adjusted after 
visual 
inspection. 
PGPS 
15JUN2023 28JUN2023  


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FRAMIE 
676 
2022 
EGPS 
09MAY2022 20JUL2022  
PGPS 
06JUN2022 19JUN2022  
2023 
EGPS 
18MAY2023 16JUL2023  
PGPS 
03JUN2023 16JUN2023  
FRBRUL 
635 
2022 
EGPS 
11APR2022 29JUL2022  
PGPS 
14MAY2022 27MAY2022  
2023 
EGPS 
02MAY2023 30JUL2023  
PGPS 
24MAY2023 06JUN2023  
FRCHOL 
601 
2022 
EGPS 
02MAY2022 14JUL2022  
PGPS 
14MAY2022 27MAY2022  
2023 
EGPS 
05APR2023 12JUL2023  
PGPS 
26MAY2023 08JUN2023  
FRNARB 
636 
2022 
EGPS 
13APR2022 18JUL2022  
PGPS 
17MAY2022 30MAY2022  
2023 
EGPS 
28APR2023 12JUL2023  
PGPS 
16MAY2023 29MAY2023  
FRORLE 
632 
2022 
EGPS 
20MAY2022 16JUL2022  
PGPS 
21MAY2022 03JUN2022  
2023 
EGPS 
03MAY2023 23JUL2023  
PGPS 
22MAY2023 04JUN2023  
FRSTRA 
670 
2022 
EGPS 
07MAY2022 07JUL2022  
PGPS 
20MAY2022 02JUN2022  
2023 
EGPS 
04MAY2023 20JUL2023  
PGPS 
23MAY2023 05JUN2023  
FRTOUL 
631 
2022 
EGPS 
04MAY2022 20JUN2022  
PGPS 
18MAY2022 31MAY2022  
2023 
EGPS 
02MAY2023 24JUL2023  
PGPS 
23MAY2023 05JUN2023  
FRTOUN 
633 
2022 
EGPS 
29APR2022 18JUN2022  


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PGPS 
18MAY2022 31MAY2022  
2023 
EGPS 
10MAY2023 03JUL2023  
PGPS 
15JUN2023 28JUN2023  
LTVILN 
501, 502, 
503, 504, 
506, 507, 
508 
2022 
EGPS 
10JUN2022 05JUL2022  
PGPS 
18JUN2022 01JUL2022  
2023 
EGPS 
09JUN2023 01JUL2023 Dates were 
adjusted after 
visual 
inspection. 
PGPS 
09JUN2023 22JUN2023  
LVRIGA 
401, 402, 
403, 404, 
405, 406 
2022 
EGPS 
05JUN2022 23JUL2022  
PGPS 
23JUN2022 06JUL2022  
2023 
EGPS 
10JUN2023 21JUL2023 Dates were 
adjusted after 
visual 
inspection. 
PGPS 
10JUN2023 23JUN2023  
PLBYDG 
105, 106, 
109,  
2022 
EGPS 
13MAY2022 11AUG2022  
PGPS 
24JUN2022 07JUL2022  
2023 
EGPS 
21MAY2023 26AUG2023  
PGPS 
25JUN2023 08JUL2023  
PLCRAC 
102, 108, 
110, 112, 
113, 114 
2022 
EGPS 
29MAY2022 11JUL2022  
PGPS 
24JUN2022 07JUL2022  
2023 
EGPS 
26MAY2023 25JUL2023  
PGPS 
29JUN2023 12JUL2023  
PLLUBL 
103 
2022 
EGPS 
31MAY2022 10JUL2022  
PGPS 
22JUN2022 05JUL2022  
2023 
EGPS 
25MAY2023 15AUG2023  
PGPS 
26JUN2023 09JUL2023  
PLPTRY 
104, 115 
2022 
EGPS 
10MAY2022 11AUG2022  
PGPS 
31MAY2022 13JUN2022  


Statistical analysis plan 
Date: 
27-Oct-2023 
 
Trial ID: SU-G-01 
Version: 
1.0 
EudraCT No.: 2020-000455-12 
Status: 
Final 
CONFIDENTIAL 
Page: 
47 of 47 
 
2023 
EGPS 
23MAY2023 14AUG2023  
PGPS 
25JUN2023 08JUL2023  
PLWROC 
101, 107, 
111 
2022 
EGPS 
13MAY2022 20JUL2022  
PGPS 
30MAY2022 12JUN2022  
2023 
EGPS 
23MAY2023 21JUL2023  
PGPS 
29MAY2023 11JUN2023  
 


Signature Page for VV-CLIN-004975 v1.0
Signature Page for VV-CLIN-004975 v1.0
Approval Task
27-Oct-2023 09:34:39 GMT+0000
Approval Task
27-Oct-2023 09:41:57 GMT+0000
Approval Task
27-Oct-2023 09:46:38 GMT+0000
Approval Task
27-Oct-2023 09:53:59 GMT+0000
Approval Task
27-Oct-2023 13:18:16 GMT+0000