A Phase III Trial Evaluating the Efficacy and Safety of the House Dust Mite (HDM) Sublingual Immunotherapy (SLIT)-Tablet in Children and Adolescents (5-17 Years) With HDM Allergic Asthma
Phase: PHASE3
Conditions: Allergic Asthma Due to Dermatophagoides Farinae, Allergic Asthma Due to Dermatophagoides Pteronyssinus, Allergic Rhinitis Due to House Dust Mite
Sponsor: ALK-Abelló A/S

Coverpage 
Date: 
13-May-2023 
 
MT-11 
Status: 
Final 
HDM SLIT-tablet 
Version: 
1.0 
CONFIDENTIAL 
Page: 
1 of 1    
 
 
COVERPAGE MT-11 TRIAL PROTOCOL  
 
Official trial title 
A phase III trial evaluating the efficacy and safety of  
the house dust mite (HDM) sublingual immunotherapy  
(SLIT)-tablet in children and adolescents (5-17 years)  
with HDM allergic asthma 
NCT number  
NCT03654976 
Document date  
18-Feb-2021 
 
 
 

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EudraCT: 2016-004363-39 
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Clinical Trial Protocol for US 
Trial ID: MT-11 
Title of Trial 
A phase III trial evaluating the efficacy and safety of the house dust mite (HDM) 
sublingual immunotherapy (SLIT)-tablet in children and adolescents (5-17 years) with 
HDM allergic asthma 
 
 
 
Investigational Medicinal Product: HDM SLIT-tablet 
Phase: III 
EudraCT No.: 
IND No: 
2016-004363-39 
17691 
Sponsor: Global Clinical Development 
ALK-Abelló A/S 
DK-2970 Hørsholm 
Phone: +45 4574 7576 
Document Status: Final 
Date: 18-Feb-2021 
Version:  12.0  
 
 
 
Confidential 
Property of ALK 
May not be used, divulged, published or otherwise disclosed without the written consent of ALK 
 

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EudraCT: 2016-004363-39 
IND: 17691 
Version 12.0 
 
 
 
 
Table of contents 
Table of contents ........................................................................................................................ 2 
Table of figures........................................................................................................................... 5 
Table of tables ............................................................................................................................ 5 
List of appendices ...................................................................................................................... 6 
Table of abbreviations ................................................................................................................ 7 
Table of definitions ................................................................................................................... 10 
Table of revisions ..................................................................................................................... 12 
Protocol synopsis ..................................................................................................................... 13 
Flow chart ................................................................................................................................. 28 
1 
Introduction .............................................................................................................. 32 
1.1 
Disease background and current treatment modalities ............................................. 32 
1.2 
Stage of development .............................................................................................. 33 
1.3 
Trial rationale ........................................................................................................... 35 
1.4 
Benefit-risk assessments and ethical considerations................................................ 35 
2 
Objectives and endpoints ......................................................................................... 37 
2.1 
Primary objective ..................................................................................................... 37 
2.2 
Key secondary objective .......................................................................................... 38 
2.3 
Secondary objectives ............................................................................................... 38 
2.4 
Exploratory objectives .............................................................................................. 38 
2.5 
Primary endpoint ...................................................................................................... 38 
2.6 
Key secondary endpoints ......................................................................................... 39 
2.7 
Additional secondary endpoints ............................................................................... 39 
2.8 
Exploratory endpoints .............................................................................................. 40 
3 
Trial design .............................................................................................................. 41 
3.1 
Summary of trial design ........................................................................................... 41 
3.2 
Trial schedule........................................................................................................... 43 
3.3 
Discussion of design ................................................................................................ 43 
4 
Trial population ........................................................................................................ 46 
4.1 
Inclusion criteria ....................................................................................................... 46 
4.2 
Exclusion criteria ...................................................................................................... 48 
5 
Subject discontinuation ............................................................................................ 49 
5.1 
Discontinuation from IMP treatment ......................................................................... 49 
5.2 
Discontinuation from trial .......................................................................................... 50 
6 
Randomisation and treatment blinding/unblinding .................................................... 51 
6.1 
Subject ID number ................................................................................................... 51 

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6.2 
Randomisation ......................................................................................................... 51 
6.3 
Subject card ............................................................................................................. 51 
6.4 
Treatment blinding/unblinding .................................................................................. 51 
7 
Restricted and prohibited concomitant medication ................................................... 52 
8 
Trial products ........................................................................................................... 54 
8.1 
Investigational Medicinal Product ............................................................................. 54 
8.2 
Background treatment .............................................................................................. 55 
8.3 
Rescue medication .................................................................................................. 56 
8.4 
Packaging and labelling ........................................................................................... 58 
8.5 
Handling and storage ............................................................................................... 59 
8.6 
IMP and rescue medication accountability ............................................................... 59 
8.7 
Reporting of technical complaints............................................................................. 60 
9 
Treatment ................................................................................................................ 60 
9.1 
Posology and method of administration.................................................................... 60 
9.2 
Precautions in relation to first dosing ........................................................................ 60 
9.3 
Rescue medication for severe allergic reactions ...................................................... 60 
9.4 
Temporary interruption and discontinuation of treatment .......................................... 61 
9.5 
IMP compliance ....................................................................................................... 62 
9.6 
Post-trial treatment ................................................................................................... 62 
10 
Visit schedule ........................................................................................................... 62 
11 
Assessments............................................................................................................ 70 
11.1 
Informed consent ..................................................................................................... 71 
11.2 
Consent for biobank blood and urine samples.......................................................... 71 
11.3 
Consent for collection of blood samples for pharmacogenetic testing ...................... 72 
11.4 
Demographics .......................................................................................................... 72 
11.5 
Medical history ......................................................................................................... 72 
11.6 
Concomitant medication ........................................................................................... 72 
11.7 
Height and weight .................................................................................................... 73 
11.8 
Vital signs ................................................................................................................ 73 
11.9 
Lung function ........................................................................................................... 73 
11.10 
Physical examination ............................................................................................... 73 
11.11 
Pregnancy test ......................................................................................................... 74 
11.12 
Skin prick test........................................................................................................... 75 
11.13 
Blood and urine sampling ......................................................................................... 76 
11.14 
Laboratory assessments .......................................................................................... 77 
11.15 
Adverse event assessment ...................................................................................... 79 

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11.16 
Asthma exacerbation assessment............................................................................ 79 
11.17 
Assessment of symptoms ........................................................................................ 80 
11.18 
Medication assessment ............................................................................................ 81 
11.19 
Asthma Action Plan .................................................................................................. 82 
11.20 
Anaphylaxis Emergency Action Plan ........................................................................ 83 
11.21 
Solicited Adverse Events ......................................................................................... 84 
11.22 
Eosinophilic oesophagitis ......................................................................................... 85 
11.23 
Subject 
 reported outcomes ..................................................... 85 
12 
Adverse events ........................................................................................................ 89 
12.1 
Definitions ................................................................................................................ 89 
12.2 
Assessments............................................................................................................ 91 
12.3 
Collection, recording and reporting of adverse events .............................................. 91 
12.4 
Data monitoring committee ...................................................................................... 94 
12.5 
Pregnancy ................................................................................................................ 95 
13 
Early termination of trial ........................................................................................... 95 
14 
Data handling ........................................................................................................... 96 
14.1 
eCRF ....................................................................................................................... 96 
14.2 
eDiary ...................................................................................................................... 97 
14.3 
Query handling......................................................................................................... 97 
14.4 
Laboratory data ........................................................................................................ 97 
14.5 
Database lock .......................................................................................................... 98 
15 
Statistical methods ................................................................................................... 98 
15.1 
Sample size and power considerations .................................................................... 98 
15.2 
Sample size reassessment ...................................................................................... 99 
15.2.1 First blinded sample size reassessment with data cuf off point 1 Feb 2020 .............. 99 
15.2.2 Second blinded sample size reassessment due to the COVID-19 pandemic with cut 
off point the 1 Mar 2021 ...................................................................................................... 102 
15.3 
Analysis data sets .................................................................................................. 103 
15.4 
Subject disposition ................................................................................................. 104 
15.5 
Baseline characteristics ......................................................................................... 104 
15.6 
Extent of exposure ................................................................................................. 104 
15.7 
Concomitant therapy .............................................................................................. 104 
15.8 
Efficacy analyses ................................................................................................... 105 
15.9 
Safety analyses...................................................................................................... 108 
15.10 
Multiplicity .............................................................................................................. 108 
15.11 
Interim analyses ..................................................................................................... 109 
15.12 
Subgroup analyses ................................................................................................ 109 

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15.13 
Handling of missing data ........................................................................................ 109 
16 
Quality assurance and control ................................................................................ 110 
16.1 
Monitoring .............................................................................................................. 110 
16.2 
Source data and access to source documents ....................................................... 110 
16.3 
Investigator site file – and other trial documentation ............................................... 112 
16.4 
Protocol compliance ............................................................................................... 112 
16.5 
Audit ...................................................................................................................... 112 
17 
Ethics and regulatory procedures ........................................................................... 112 
17.1 
Statement of compliance ........................................................................................ 112 
17.2 
Disclosure and confidentiality ................................................................................. 113 
17.3 
Subject confidentiality ............................................................................................ 113 
17.4 
Data protection....................................................................................................... 113 
17.5 
IEC/IRB/regulatory authorities ................................................................................ 114 
17.6 
Inspections ............................................................................................................. 114 
17.7 
Protocol amendment and other changes in trial conduct ........................................ 114 
18 
Reporting and publication ...................................................................................... 115 
18.1 
Integrated clinical trial report .................................................................................. 115 
18.2 
Publication of results .............................................................................................. 115 
19 
Finance and insurance ........................................................................................... 116 
20 
Trial organisation ................................................................................................... 116 
21 
Reference list ......................................................................................................... 117 
Table of figures 
Figure 1 
Trial design ............................................................................................................. 42 
Figure 2 
Flow chart for SSR ................................................................................................ 102 
Table of tables 
Table 1 
Flow chart ................................................................................................................ 28 
Table 2 
Restricted and prohibited concomitant medications ................................................. 52 
Table 3 
Definition of low, medium and high dose ICS for subjects aged 5-11 years .............. 55 
Table 4 
Definition of low, medium and high dose ICS for subjects aged 12 years and above 56 
Table 5 
Schedule for rhinitis and conjunctivitis rescue medication ........................................ 58 
Table 6 
Visit schedule ........................................................................................................... 62 
Table 7 
Physical examination ............................................................................................... 74 
Table 8 
Skin prick test........................................................................................................... 75 
Table 9 
Medications with a possible interference with SPT ................................................... 76 
Table 10 
Subject’s symptom scoring ..................................................................................... 81 
Table 11 
Construction of symptom scores1 ............................................................................ 81 
Table 12 
Scoring of rhinoconjunctivitis rescue medication ..................................................... 82 
Table 13 
Power calculation .................................................................................................... 99 
 

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List of appendices 
Appendix 1: Rationale(s) for amendment(s) 
Appendix 2: Investigator agreement on clinical trial protocol 
Appendix 3: Protocol signature page 
Appendix 4: Trial organisation 
Appendix 5: Patient reported outcome questionnaires 
Appendix 6: COVID-19 Pandemic Measures for Trial Protocol MT-11 
Appendix 7: MT-11 Remote visit guidance during COVID-19 outbreak, applicable for visit 
4-10 remote visits  
Appendix 8: MT-11 Remote visit 11 guidance during COVID-19 pandemic 
Appendix 9: MT-11 site-to-patient shipment of trial medication 
 
 
 
 

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Table of abbreviations 
ACQ 
Asthma control questionnaire 
AE 
Adverse event  
AIT 
Allergy immunotherapy 
ALK 
ALK-Abelló A/S 
ALT 
Alanine aminotransferase 
AMP 
Auxiliary Medicinal Product 
AR 
Allergic rhinitis 
AST 
Aspartate aminotransferase 
BP 
Blood pressure 
CHMP 
The Committee for Medicinal Products for Human Use 
COVID-19 
Coronavirus disease 2019 
CRA 
Clinical research associate 
CRF 
Case report form 
CSMS 
Combined symptom and medication score (recommended by EAACI task 
force (Pfaar et al. 2014)) 
D. farinae  
Dermatophagoides farinae 
D. pteronyssinus Dermatophagoides pteronyssinus  
DMC 
Data monitoring committee 
DMS 
Daily medication score 
DSS 
Daily symptom score 
eCRF 
Electronic case report form 
eDiary 
Electronic diary 
EMA 
European Medicines Agency 
EMEA 
European Medicines Agency 
EudraCT 
European Union drug regulating authorities clinical trials database 
FAS 
Full analysis set 
FDA 
Food and Drug Administration 
FEV1 
Forced expiratory volume in 1 second 
FSFV 
First subject first visit 
FVC 
Forced vital capacity  
GCP 
Good clinical practice 
GINA 
Global initiative for asthma 
GLMM 
Generalised linear mixed model 
HDM 
House dust mite 
IB 
Investigator’s brochure 
ICH 
International conference on harmonisation of technical requirements for 
registration of pharmaceuticals for human use 
ICS 
Inhaled corticosteroid 
ICTR 
Integrated clinical trial report 
IEC 
Independent ethics committee 
IgE 
Immunoglobulin E 
IgE-BF 
Immunoglobulin E blocking factor 

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IgG4 
Immunoglobulin G4 
IMP 
Investigational medicinal product 
IND 
Investigational new drug  
IRB 
Institutional review board 
IUD 
Intrauterine device 
IUS 
Intrauterine system 
LABA 
Long-acting β2-agonist 
LDH 
Lactate dehydrogenase 
LR 
Likelihood ratio 
LSLV 
Last subject last visit 
LTRA 
Leukotriene receptor antagonist 
MAR 
Missing at random 
MCH 
Mean corpuscular haemoglobin 
MCV 
Mean corpuscular volume 
MedDRA 
Medical dictionary for regulatory activities 
MMRM 
Mixed-effect model repeated measurement 
NB 
Negative binominal 
NIH 
National Institutes of Health 
OCS 
Oral corticosteroid 
 
 
 
 
PDCO 
Paediatric Committee 
PEF 
Peak expiratory flow 
 
 
SABA 
Short-acting β2-agonist 
SAE 
Serious adverse event 
SAF 
Safety analysis set 
SAP 
Statistical analysis plan 
SCIT 
Subcutaneous immunotherapy 
 
 
SGOT 
Serum glutamic-oxaloacetic transaminase 
SGPT 
Serum glutamic pyruvic transaminase 
SLIT 
Sublingual immunotherapy 
SmPC 
Summary of product characteristics 
SOP 
Standard operating procedure 
SPT 
Skin prick test 
SSR 
Sample size reassessment  
TC  
Telephone call 
TCRS 
Total combined rhinitis score 
TCS 
Total combined score 
UN 
Unscheduled visit 
USPI 
United States Prescribing Information 
VAS 
Visual analogue scale 
WAO 
World Allergy Organisation 

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WHO 
World Health Organisation 
 
 

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Table of definitions 
Background 
treatment 
Standard of care treatment administered to all subjects in addition to the 
investigational medicinal product (IMP), in agreement with the European 
Medicines Agency (EMA) Definition of Investigational Medicinal products 
(IMPs) and use of Auxiliary Medicinal Products (AMPs) consultation 
document (EMA 2016a). The background treatment in this trial is low 
dose inhaled corticosteroid (ICS) plus long-acting β2-agonists (LABA) or 
medium/high dose ICS with or without LABA 
Clinically relevant 
asthma exacerbation 
• 
Doubling of ICS dose compared to background treatment, or 
• 
Systemic corticosteroids for treatment of asthma symptoms for at 
least 3 days, or 
• 
Emergency room visit due to asthma, requiring systemic 
corticosteroids, or  
• 
Hospitalisation for more than 12 hours due to asthma, requiring 
treatment with systemic corticosteroids 
 
Completed subject 
A randomised subject is considered as completed if he/she has not 
discontinued the trial 
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, e.g. montelukast 
End of trial 
The end of trial is defined as the date of the last subject last visit 
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 
Life-threatening 
asthma 
Asthma worsening that requires intubation and/or is associated with 
hypercapnia requiring non-invasive ventilator support 
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 HDM allergy symptoms in 
agreement with the EMA Definition of IMPs and use of AMPs 
consultation document (EMA 2016a).  
The asthma rescue medication in this trial is  
• 
Oral corticosteroid (OCS)  
• 
Short-acting β2-agonist (SABA)  
• 
Additional ICS for treatment of asthma exacerbations (optional) 

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The rhinoconjunctivitis rescue medication in this trial is 
• 
Antihistamine tablets/solution 
• 
Antihistamine eye drops  
• 
Corticosteroid nasal spray  
 
Rescue medication for severe allergic reaction in countries where this is 
a regulatory requirement: 
• 
Adrenaline/epinephrine auto-injector 
 
Severe asthma 
exacerbation 
• 
Systemic corticosteroids for treatment of asthma symptoms for at 
least 3 days, or  
• 
Emergency room visit due to asthma, requiring systemic 
corticosteroids, or  
• 
Hospitalisation for more than 12 hours due to asthma, requiring 
treatment with systemic corticosteroids 
 
Solicited AE 
 
 
 
Source documents 
 
An AE recorded by the investigator at visit 4 based on the symptoms 
reported in the subject’s eDiary during the first 28 days after 
randomisation 
 
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 
Trial completion 
 
 
 
 
 
 
 
 
 
 
 
 
The trial is completed once the integrated clinical trial report (ICTR) is 
signed 
 
 
 
 
 
 
 
 
 
 
 

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Table of revisions 
Date 
Version 
Description of document 
12-Jul-2017 
1.0 
Final protocol 
07-Aug-2017 
2.0 
Final protocol 
31-Aug-2017 
3.0 
Final protocol 
25-Jan-2018 
4.0 
UK – Amendment due to request from HRA REC.  
Amendment only applicable in the UK 
02-Feb-2018 
5.0 
German amendment due to request from the Paul Erhlich 
Institute, Germany. Amendment only applicable in Germany 
21-Sep-2018  
6.0 
US specific amendment due to request from the Food and 
Drug Administration and incorporating the UK and Germany 
country-specific amendment 
21-Sep-2018  
7.0 
Europe specific amendment due to request from the Food and 
Drug Administration and incorporating the UK and Germany 
country-specific amendment 
13-May-2019 
8.0 
Europe specific amendment to expand the period of 
randomisation and to accommodate the upcoming change of 
the European Union trial regulation, No 536/2014 
15-May-2019 
9.0 
US specific amendment to expand the period of randomisation 
and to accommodate the upcoming change of the European 
Union trial regulation, No 536/2014 
11-Nov-2020 
10.0 
Europe specific amendment to include COVID-19 measures, 
extend the recruitment period, add an additional SSR due to 
COVID-19 impact and to align the new SSR with previous SSR 
updates in the statistical analysis plan. 
11-Nov-2020 
11.0 
US specific amendment to include COVID-19 measures, 
extend the recruitment period, add a second SSR due to 
COVID-19 potential impact on power and to align the new SSR 
with previous SSR updates in the statistical analysis plan. 
18-Feb-2021 
12.0 
US specific amendment to include updated versions of “MT-11 
remote visit 11 guidance during the COVID-19 pandemic”, 
“MT-11 remote visit 4-10 guidance during the COVID-19 
pandemic” and “MT-11 site-to-patient shipments of trial 
medication” (appendices 7-9) in order to implement home 
pregnancy testing during remote visits caused by COVID-19. 
 
 
 
 
 
 

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Protocol synopsis 
Title of trial: 
A phase III trial evaluating the efficacy and safety of the house 
dust mite (HDM) sublingual immunotherapy (SLIT)-tablet in 
children and adolescents (5-17 years) with HDM allergic asthma 
Trial ID: 
MT-11 
Development phase: 
Paediatric phase III 
Regulatory trial identifier: EudraCT No: 2016-004363-39  
IND No: 17691 
Objectives: 
 
The primary objective is to demonstrate efficacy of the HDM SLIT-
tablet versus placebo as add-on treatment in children and 
adolescents (5-17 years) with HDM allergic asthma based on 
clinically relevant asthma exacerbations after at least 4 months of 
treatment. 
For this trial, clinically relevant asthma exacerbations are defined 
by at least one of the following criteria: 
• 
Doubling of ICS dose compared to background treatment 
• 
Systemic corticosteroids for treatment of asthma symptoms 
for at least 3 days 
• 
Emergency room visit due to asthma, requiring systemic 
corticosteroids  
• 
Hospitalisation for more than 12 hours due to asthma, 
requiring treatment with systemic corticosteroids  
The key secondary objectives are to demonstrate efficacy of the 
HDM SLIT-tablet versus placebo after at least 4 months as add-on 
treatment in children and adolescents with HDM allergic asthma 
with respect to: 
• 
Nocturnal awakening due to asthma which require SABA 
rescue medication 
• 
Rescue medication use (SABA) 
• 
Lung function (FEV1) 
Additional secondary objectives, based on endpoints measured at 
different timepoints throughout the trial, are to evaluate the HDM 
SLIT-tablet versus placebo for treatment of HDM allergic asthma 
with respect to: 
• 
Asthma symptoms 
• 
Asthma control 

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symptoms and medication use in an electronic diary (eDiary). 
Subjects will continue with their regular asthma background 
treatment. With the exception of additional sponsor provided ICS, 
which is optional, the subjects’ regular asthma rescue medication 
and rhinoconjunctivitis rescue medication must be replaced with 
the rescue medication provided by ALK at visit 2. 
 
Period 3 is the treatment initiation and maintenance period to allow 
the treatment with the HDM SLIT-tablet to take effect. It starts at 
randomisation and lasts for at least 4 months. The period ends on 
1 September 2018 for cohort 1, on 1 September 2019 for cohort 2, 
on 1 September 2020 for cohort 3, and on the 1 September 2022 
for cohort 4. 
During the first 28 days of period 3, pre-specified symptoms  
occurring after IMP intake will be recorded by the 
subject/parent/caregiver in the eDiary. The reported symptoms will 
be evaluated by investigator and reported in the eCRF as solicited 
AEs. 
 
Period 4 is the efficacy assessment period. Period 4 lasts until the 
end of trial or discontinuation from IMP and during this period, the 
rate of clinically relevant asthma exacerbations will be evaluated 
from 1 September 2018 to 30 April 2020 (cohort 1), 1 September 
2019 to 30 April 2021 (cohort 2), 1 September 2020 to 30 April 
2022 (cohort 3), and 1 September 2022 to 30 April 2024 (Cohort 
4). 
Subjects will be treated for 24-30 months in total since subjects 
can commence treatment in a predefined period lasting from 1 
November until 10 April. The efficacy period starts on 1 September 
for all subjects resulting in a pretreatment period of 4 to 10 months. 
The efficacy period ends 30 April for all subjects. As a result, some 
subjects may have 5-6 months between visit 10 and 11 while 
others may have their last visit 11 on the same day as visit 10. 
Subjects with less than 1 month between visit 10 and 11 will only 
have one visit to the clinic where all the procedures of 11 are 
performed. 
Approximately every 4 months after randomisation, subjects or 
their parent/caregiver will be asked to complete the eDiary for a 
period of 14 days 3 weeks prior to V5 (at 4 months), V6 (at 8 
months), V7 (at 12 months), V8 (at 16 months), V9 (at 20 months), 
V10 (at 24 months) and V11 (25-30 months).  
Subject safety precautions: 
All subjects will be provided with an Asthma Action Plan to provide 
guidance to effectively manage the subject's symptoms, and 
asthma rescue medication (OCS, SABA and a separate inhaler 
with ICS).  
Subjects experiencing 2 severe asthma exacerbations within 12 
consecutive months or 1 hospitalisation due to asthma requiring 

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treatment with systemic corticosteroids must be discontinued from 
the IMP treatment and should continue in the trial. 
Subjects will be provided with a Local and Systemic Allergic 
Reaction Emergency Plan . In countries where it is a regulatory 
requirement, subjects will also be provided with an 
adrenaline/epinephrine auto-injector. 
 
Trial safety precautions:   
A sponsor independent data monitoring committee (DMC) will 
monitor the subjects’ safety data in an unblinded fashion. The 
DMC Charter will specify the frequency of the DMC meetings. 
Early trial termination may be the result of the criteria specified 
below: 
1. Treatment-related death of an individual; 
2. Treatment-related anaphylactic shock in at least 2 
subjects2  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 blood pressure (BP) with associated symptoms of 
end-organ dysfunction (e.g., hypotonia [collapse], syncope, 
incontinence). Low systolic BP for children is defined as 
less than 70 mmHg plus (2 x age) from 1 to 10 years, and 
less than 90 mmHg for 11 to 17 years of age. 
3. A substantial increase in the rate of clinically relevant 
asthma exacerbations during period 3 defined by the 
following two criteria: 
a. the rate of clinically relevant asthma exacerbations 
in the active treatment arm is at least 3 times higher 
than the expected background rate (≥3*1.4 = ≥4.2 
exacerbations/subject/year) AND 
b. the rate of clinically relevant asthma exacerbations 
in the active treatment arm is at least 3 times higher 
than the rate observed in the placebo arm 
The DMC will monitor the rate of clinically relevant asthma 
exacerbations during period 3 to be able to pause the trial 
for safety review should a substantial increase in the active 
treatment arm compared to placebo occur. 
IMP intake may only be resumed after the information has been 
presented to health authorities, and health authorities concur with 
continued IMP intake. In case of complete premature IMP 
discontinuation, participating investigators, subjects, caregivers, 
 
2 The criterion for 2 events is based on prior trial experience where it has been observed that events of severe anaphylactic 
reactions unrelated to IMP may occur in allergic subjects even with a temporal relationship to tablet administration. 
 

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the IRB/IEC, and the relevant health authorities will be promptly 
informed. 
 
Trial schedule: 
 
 
Cohort 1 
Cohort 2 
Cohort 3 
Cohort 4 
First subject first visit (FSFV) 
Q1 2018 
Q3 2018 
Q3 2019 
Q3 2021 
Last subject randomised 
Q2 2018 
Q2 2019 
Q2 2020 
Q2 2022 
Last subject last visit (LSLV) 
Q2 2020 
Q2 2021 
Q2 2022 
Q2 2024 
 
 
 
Duration of treatment per subject: 24-30 months 
End of trial is defined as LSLV for the last cohort initiated 
Trial population: 
 
Subjects randomised in this trial will be children and adolescents 
5-17 years of age, with HDM allergic asthma who are at risk of 
asthma exacerbations despite being on treatment with low dose 
ICS plus LABA or medium/high dose ICS with or without LABA and 
who have HDM allergic rhinitis (AR). 
45% of the subjects will be 5-11 years of age in accordance with 
the recommendation of EMA Paediatric Committee (PDCO 
Standard Paediatric Investigation Plan for Allergen Products for 
Specific Immunotherapy. 
Subjects meeting all of the inclusion criteria and none of the 
exclusion criteria will be considered eligible for the trial. 
Inclusion criteria: 
 
I1. 
Written informed consent obtained from parents/caregivers 
before any trial related procedures are performed3. Consent 
or assent from the subject must be obtained according to 
national requirements. 
I2. 
Male or female of any race/ethnicity aged ≥4 to ≤17 years  
on the day informed consent is obtained from the 
parent/caregiver. The subject must be ≥5 to ≤17 years old at 
the randomisation visit  
I3. 
A female subject of childbearing potential4 must have a 
negative pregnancy test and be willing to practise 
appropriate5 contraceptive methods until the follow-up 
telephone call (TC) 
 
3 At least one parent/caregiver must be able to read. 
4 Females, after the first menstrual period.  
5 For the purpose of this protocol the following contraceptive methods are considered appropriate: oral contraceptives, trans dermal 
patches or depot injection of a progestogen drug (starting at least 4 weeks prior to IMP administration); double barrier method: 
condom or occlusive cap (diaphragm or cervical/vault caps) plus spermicidal agent; intrauterine device (IUD), intrauterine system 
(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. 
 

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I4. 
A clinical history of HDM allergic asthma of at least 1 year 
duration diagnosed by a physician6  
I5. 
Use of low daily dose of ICS plus LABA or medium/high daily 
dose of ICS with or without LABA for the control of asthma 
symptoms within the past year prior to randomisation. For 
definition of ICS doses please see Table 3 and Table 4 
I6. 
≥3 clinically relevant asthma exacerbations7 in the past two 
years or ≥2 clinically relevant asthma exacerbations in the 
past year or ≥1 severe asthma exacerbation8 in the past year 
prior to randomisation while being on asthma controller 
medication (low dose ICS plus LABA or medium/high dose 
ICS with or without LABA)9. The asthma controller 
medication at the screening visit must be at a dose 
equivalent to or below the dose the subject received before 
the last asthma exacerbation occurred 
I7. 
One or more of the following within the past 4 weeks prior to 
randomisation: 
a. Daytime asthma symptoms more than twice/week 
b. Any nocturnal awakening due to asthma which 
require use of SABA rescue medication 
c. SABA rescue medication needed for treatment of 
asthma symptoms more than twice/week 
d. Any activity limitation due to asthma  
I8. 
Lung function measured by FEV1 ≥ 70% of predicted value10 
or according to local requirements while on background 
treatment following at least a 6-hour washout of SABA at 
screening and randomisation 
I9. 
Clinical history of HDM AR within the last year prior to 
randomisation11 
I10. An average total combined rhinitis score (TCRS) > 0 during 
the baseline period (period 2) 
 
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. 
6 If medical records are not available, verbal history from subject/parent/caregiver can be used to fulfill this criterion and this must be 
documented in the medical records by the investigator. 
7 A clinically relevant asthma exacerbation is defined as at least one of the following criteria: a) Doubling of ICS dose compared to 
background treatment, b) Systemic corticosteroids for treatment of asthma symptoms for at least 3 days, c) Emergency room visit 
due to asthma, requiring systemic corticosteroids or d) Hospitalisation  for more than 12 hours due to asthma, requiring treatment 
with systemic corticosteroids.  
8 A severe asthma exacerbation is defined as at least one of the following: a) Systemic corticosteroids for treatment of asthma 
symptoms for at least 3 days, b) Emergency room visit due to asthma, requiring systemic corticosteroids or c) Hospitalisation for 
more than 12 hours due to asthma, requiring treatment with systemic corticosteroids. 
9 One asthma exacerbation within the last year must be documented including asthma medication and dosage immediately prior to 
this exacerbation. 
10 Interpretation of normal range for spirometric test should be based on the Quanjer reference equations (Quanjer et al. 1995). 
11 If medical records are not available, verbal history from subject/parent/caregiver can be used to fulfill this criterion and this must 
be documented in the medical records by the investigator. 

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I11. Positive specific immunoglobulin E (IgE) (defined as ≥class 
2, ≥0.70 kU/l) against Dermatophagoides pteronyssinus (D. 
pteronyssinus) and/or Dermatophagoides farinae (D. farinae) 
at screening 
I12. Positive skin prick test (SPT)12 to D. pteronyssinus and/or D. 
farinae at screening 
I13. Subject willing and able to comply with trial protocol  
  
Exclusion criteria: 
 
E1. Has a clinically relevant history and is sensitised, 
symptomatic, and regularly exposed to animal dander, 
molds, and/or cockroach (e.g., present in the home, job, 
school, etc.) or other perennial allergen  
E2. Has experienced a life-threatening asthma attack defined for 
this protocol as an asthma episode that required intubation 
and/or was associated with hypercapnia requiring non-
invasive ventilator support  
E3. Within the last month before the randomisation visit (visit 3), 
has had an occurrence of any clinical deterioration of asthma 
that resulted in emergency treatment, hospitalisation, or 
treatment with systemic corticosteroids 
E4. Within the last 3 months before the randomisation visit (visit 
3) while on high dose ICS treatment, has had an occurrence 
of any clinical deterioration of asthma that resulted in 
emergency treatment, hospitalisation, or treatment with 
systemic corticosteroids  
E5. SLIT treatment with D. pteronyssinus or D. farinae for more 
than 1 month within the last 5 years. In addition, any SLIT 
treatment with D. pteronyssinus or D. farinae within the 
previous 12 months 
E6. Subcutaneous immunotherapy (SCIT) treatment with D. 
pteronyssinus or D. farinae reaching the maintenance dose 
within the last 5 years. In addition, any SCIT treatment with 
D. pteronyssinus or D. farinae within the previous 12 months 
E7. Ongoing treatment with any allergy immunotherapy product 
E8. Severe chronic oral inflammation 
E9. 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)13 
 
12 A positive SPT is defined in the SPT Guideline. Briefly, for subjects in North America, a positive SPT is defined as a wheal size ≥5 
mm larger than the negative control. For subjects in Europe, a positive SPT is defined as a wheal size ≥3 mm. 
13 If in doubt, nasal endoscopy is recommended 

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E10. 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 
E11. Has a diagnosis or history of eosinophilic oesophagitis 
E12. 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 
E13. Active or poorly controlled autoimmune diseases, immune 
defects, immunodeficiencies, immunosuppression or 
malignant neoplastic diseases with current disease 
relevance 
E14. Ongoing treatment with OCS 
E15. Treatment with restricted and prohibited concomitant 
medication listed in Table 2 
E16. Treatment with an investigational drug within 30 days/5 half-
lives of the drug (which ever longest) prior to screening 
E17. A history of allergy, hypersensitivity or intolerance to any of 
the excipients or active substance of the IMP (except D. 
pteronyssinus and D. farinae) or to any excipient of the 
rescue medication provided in this trial 
E18. A business or personal relationship with trial staff or sponsor 
who is directly involved with the conduct of the trial 
E19. A history of alcohol or drug abuse 
E20. Has previously been randomised into this trial, is 
participating in this trial at another investigational site or is 
participating or planning to participate in any other clinical 
trial during the duration of this trial 
E21. Has a history or current evidence of any condition, treatment, 
laboratory values out of range or other circumstance that in 
the opinion of the investigator are clinically relevant and 
might expose the subject to risk by participating in the trial, 
confound the results of the trial, or interfere with the subject’s 
participation for the full duration of the trial 
E22. Has a condition or treatment that increase the risk of the 
subject developing severe adverse reactions after 
adrenaline/epinephrine administration 
E23. Is unable to or will not comply with the use of 
adrenaline/epinephrine auto-injectors for countries where this 
is a regulatory requirement 
 
Assessments: 
 
The following data will be collected: 
• 
Demographics 

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• 
Medical history 
• 
Concomitant medication 
• 
Asthma history, including, but not limited to the history of 
asthma symptoms and exacerbations 
• 
Rhinitis, conjunctivitis, atopic dermatitis and food allergy 
medical history 
• 
Adverse events (AEs) 
• 
Vital signs 
• 
Height and weight 
• 
Physical examination 
• 
Pregnancy test results (only applicable for female subjects 
of childbearing potential) 
• 
Clinical safety laboratory (blood chemistry, hematology, 
urinalysis)14 
• 
SPT 
 
Biomarker assessments: 
• 
Immunological and serological parameters such as IgE, 
IgG4 and IgE-blocking factor (IgE-BF) and other antibody 
isotypes against relevant allergens as well as other 
serological components 
• 
Pharmacogenetics 
 
 
14 Haematology: Erythrocytes, haemoglobin, haematocrit, mean corpuscular volume (MCV), mean corpuscular haemoglobin (MCH), 
platelets, leukocytes, neutrophils, eosinophils, basophils, lymphocytes, and monocytes. Blood chemistry: Creatinine, urea, sodium, 
potassium, chloride, calcium, glucose, albumin,  total bilirubin, alkaline phosphatase, aspartate aminotransferase (AST)/ serum 
glutamic-oxaloacetic transaminase (SGOT), alanine aminotransferase (ALT)/ serum glutamic pyruvic transaminase (SGPT) and 
lactate dehydrogenase (LDH). Urinalysis: pH, protein, glucose, ketone, leukocytes, urobilinogen, bilirubin, blood, nitrite and specific 
gravity. 

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• 
Systemic corticosteroids for treatment of asthma symptoms 
for at least 3 days 
• 
Emergency room visit due to asthma, requiring systemic 
corticosteroids 
• 
Hospitalisation for more than 12 hours due to asthma, 
requiring treatment with systemic corticosteroids 
 
The key secondary endpoints are:  
• 
Proportion of days with nocturnal awakenings due to 
asthma requiring SABA rescue medication during the 14 
days eDiary recording every 4 months after randomisation 
• 
The average daily dose of SABA during the 14 days eDiary 
recording every 4 months after randomisation 
• 
Percentage predicted FEV1 assessed every 4 months after 
randomisation  
 
Additional secondary efficacy endpoints are: 
• 
Time to first clinically relevant asthma exacerbation 
• 
Time to recurrent clinically relevant asthma exacerbation 
• 
Rate of severe asthma exacerbation during the efficacy 
period (period 4), defined as asthma worsening leading to 
at least one of the following criteria: 
o Systemic corticosteroids for treatment of asthma 
symptoms for at least 3 days 
o Emergency room visit due to asthma, requiring 
systemic corticosteroids  
o Hospitalisation for more than 12 hours due to 
asthma, requiring treatment with systemic 
corticosteroids  
• 
Time to first severe asthma exacerbation 
• 
Time to recurrent severe asthma exacerbations 
• 
ACQ or ACQ-IA 
Endpoints derived from the two week daily diary collected every 4 
months after treatment initiation include: 
• 
The average TCRS (TCRS is the sum of the rhinitis daily 
symptom score (DSS) and the rhinitis daily medication 
score (DMS)). 
• 
Average rhinitis DSS 
• 
Average rhinitis DMS 

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background treatment are not allowed to double the dose of ICS. 
Please note that local regulations and Summary of product 
characteristics (SmPCs) / United States Prescribing Information 
(USPI) must be followed.   
In case of an asthma exacerbation requiring systemic 
corticosteroids, the subjects should be treated with OCS in the 
form of Prednisolone/Prednisone tablets. Dosing regimen should 
follow recommendations by GINA guideline (GINA Executive 
Committee 2017), NIH guidelines (National Heart Lung and 
Blood Institute 2007) or national guidelines (Reddel et al. 2009). 
See Section 8.3. 
Asthma rescue medication: 
• 
Salbutamol, inhaler 100 µg/dose 
• 
Prednisolone or Prednisone tablets, 5 mg  
• 
Budesonide, inhaler 100 µg/dose and/or 200 µg/dose 
• 
Fluticasone propionate inhaler 50 µg/dose 
Rhinoconjunctivitis rescue medication: 
• 
Desloratadine tablets, 5 mg  
• 
Desloratadine, oral solution, 0.5 mg/ml  
• 
Azelastine eye drops, 0.5 mg/ml 
• 
Mometasone furoate nasal spray, 50 µg/dose 
The above generic names of rescue medication are the 
International Nonproprietary Names. Synonymous generic names 
may be used in local labelling. 
For the inhalers, the strength and dosage may be stated differently 
in local labelling; nominal dosage or the dosage as being delivered 
by the device. For example, the nominal strength for Fluticasone 
propionate, 50 µg/dose, may be labelled as 44 µg delivered per 
actuation. 
Rescue medication for severe allergic reaction in countries where 
this is a regulatory requirement: 
• 
Adrenaline/epinephrine auto-injector, dose selection should 
follow SmPC/USPI for product, i. e. for 
o Epipen:  
 
 
For children <25 kg; 0.15 mg  
 
For children ≥25 kg; 0.3 mg 
o Adrenaclick (Anapen): 
 
For children <30 kg; 0.15 mg  
 
For children ≥30 kg; 0.3 mg   

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The use of leukotriene receptor antagonists (LTRA) is permitted as 
concomitant medication for continued use on same dose only but 
will not be provided. 
 

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Flow chart 
Table 1 
Flow chart15 
Visit ID: 
V1 
TC1 
V2 
TC2 
V3 
V4 
TC3, 4 V5 
TC5, 
6, 7 
V6 
TC8, 
9, 10 
V7 
TC11, 
12, 13 
V8 
TC14, 
15, 16 
V9 
TC17, 
18, 19 
V1016 TC20
17 
V1118 TC21 
UN 
Visit: 
Screen
ing 
Reten-
tion 
Base-
line 
Mid 
base-
line 
call 
Ran-
domi-
sation 
Visit 4 
 
Visit 5 
 
Visit 6 
 
Visit 7 
 
Visit 8 
 
Visit 9 
 
Visit 
10 
 
Final 
visit 
Follow
-up 
Un-
sche-
duled 
visit 
Time19 from 
randomisation (IMP 
initiation) for all visits and 
TCs, except for visit 11 
(actual date of visit) 
Max 
12 wk 
before 
V3 
 
- 3 wk 
- 7 d 
- 2 wk 
± 2 d 
- 
+ 4 
 wk + 
7 d 
+ 2m 
±2d 
+ 3m 
±2d 
+ 4m ± 
7 d  
+ 5m 
±2d 
+ 6m 
±2d 
+ 7m 
±2d 
+ 8m ± 
7 d  
+9m 
±2d 
+10m 
±2d 
+11m 
±2d 
+ 12m 
± 7 d  
+13m 
±2d 
+14m 
±2d 
+15m 
±2d 
+ 16m 
± 7 d 
+17m 
±2d 
+18m 
±2d 
+19m 
±2d 
+ 20m 
± 7 d 
+21m 
±2d 
+22m 
±2d 
+23m 
±2d 
+ 24m 
± 7 d 
2 wk 
prior to 
V11 ± 
2 d  
30 Apr 
± 7 d 
+ 2 wk 
from 
V11 + 
7 d 
 
Informed consent and 
assent20 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Demography 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Medical history incl.  
evaluate previous asthma 
exacerbations 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
SPT21 
X 
 
(X) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Review of in-/exclusion 
criteria 
X 
 
X 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
15 To the extent possible, all examinations scheduled for the final visit must be performed on subjects who receive the IMP but do not complete the trial according to the protocol. If 
poss ble, the TC follow-up (TC21) should be performed and the corresponding eCRF pages should be filled in. 
16 Visit 10 is not applicable for subjects randomised in cohort 1 after 31-Mar-2018; for subjects randomised in cohort 2 after 31-Mar-2019, for subjects randomised in cohort 3 after 
31-Mar-2020 and for subejcts randomised in cohort 4 after 31-Mar-2022, if applicable. 
17 TC20 performed 2 weeks prior to final visit. 
18 Visit 11 will take place on 30-Apr-2020 ± 7 days for cohort 1, 30-Apr-2021 ± 7 days for cohort 2, 30-Apr-2022 ± 7 days for cohort 3 and 30-Apr-2024 ± 7 days for cohort 4. 
19 One month (m) is considered 30 days. 
20 Obtain written informed consent for the trial, storage of serum samples in the ALK Research Biobank, and for pharmacogenetics testing, before any other trial procedures are 
performed. 
21 If medication that could interfere with the SPT, according to Table 9, has not been washed out and the positive control is <3 mm for subjects in Europe or < 5 mm for subjects in 
North America, the SPT must be repeated after the interfering medication has been washed out. 

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Visit ID: 
V1 
TC1 
V2 
TC2 
V3 
V4 
TC3, 4 V5 
TC5, 
6, 7 
V6 
TC8, 
9, 10 
V7 
TC11, 
12, 13 
V8 
TC14, 
15, 16 
V9 
TC17, 
18, 19 
V1016 TC20
17 
V1118 TC21 
UN 
Randomisation 
 
 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Physical examination22 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
(X) 
Oropharyngeal 
Examination 
 
 
X 
 
X23 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
 
 
(X) 
Height and weight24 
X 
 
X 
 
X 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
Vital signs 
X 
 
X 
 
X 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
(X) 
FEV1 25 
X 
 
X 
 
X 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
Urine pregnancy test, if 
applicable26 
X 
 
X 
 
X 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
(X) 
Blood and urine samples 
for safety laboratory 
assessments 
X 
 
 
 
 
 
 
 
 
 
 
X 
 
 
 
 
 
 
 
X 
 
(X) 
Blood sample for specific 
IgE27  
X 
(X)28 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
(X) 
Recording of asthma 
exacerbations 29 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Assess and record AEs 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X30 
X 
Assess eosinophilic 
oesophagitis 
X 
 
X 
 
X 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
(X) 
Record concomitant 
medication 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
22 Oropharyngeal examination is included in physical examination 
23 Oropharyngeal examinations will be done before and 60 mins after IMP administration at Visit 3, see section 9.2.  
24 If applicable, adjust the Asthma Action Plan and Local and Systemic Allergic Reaction Emergency Plan 
25 Measure FEV1 and calculate the % of predicted FEV1 after 6 hours of SABA. 
26 For female subjects of childbearing potential, additional urine pregnancy tests should be performed during the trial, if a menstrual period is missed. 
27 IgE against D pteronyssinus, D farinae, Cladosporium herbarum and Blattella germanica 
28 Inform subjects of continued participation in trial depending on the blood sample for specific IgE against D. pteronyssinus and D. farinae 
29 In case of an asthma exacerbation the subject should be called in for an unscheduled visit. 
30 If an AE was ongoing at the previous visit, if a new AE is identified at the telephone contact or if one of the safety laboratory parameters measured at the previous visit showed a 
clinically significant abnormality, the subject could be asked to return to the trial site. 

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Visit ID: 
V1 
TC1 
V2 
TC2 
V3 
V4 
TC3, 4 V5 
TC5, 
6, 7 
V6 
TC8, 
9, 10 
V7 
TC11, 
12, 13 
V8 
TC14, 
15, 16 
V9 
TC17, 
18, 19 
V1016 TC20
17 
V1118 TC21 
UN 
Dispense asthma and 
rhinoconjunctivitis rescue 
medication36 
 
 
X 
 
X  
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
 
 
(X) 
Evaluate inhalation 
technique 
 
 
X 
 
 
 
 
 
 
 
 
X 
 
 
 
 
 
 
 
 
 
 
Collect IMP, perform 
compliance check and 
drug accountability 
 
 
 
 
 
 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
 
Collect rescue medication 
as applicable and 
perform drug 
accountability 
 
 
 
 
X 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
 
Show and discuss Trial 
video 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Issue and instruct in the 
use of an eDiary 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Instruct in the recording 
of prespecified symptoms 
in eDiary 
 
 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Review eDiary and 
record solicited AEs in 
eCRF 
 
 
 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Activate eDiary for the 
next period 
 
 
X 
 
X 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
 
 
 
Daily eDiary recording 
 
 
 
 
-3 wk -4 wk 37 
 
-3 wk 
 
-3 wk 
 
-3 wk 
 
-3 wk 
 
-3 wk 
 
-3 wk 
 
-3 wk 
 
 
Check eDiary compliance 
 
 
 
 
X 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
 
Collect eDiary 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
 
 
 
35 Perform oropharyngeal examination before and 60 mins after IMP intake. 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 until the oral cavity has healed. 
36 Dispense rescue medication for severe allergic reaction (adrenaline/epinephrine) in countries where this is applicable. 
37 eDiary recording of prespecified symptoms 

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1 
Introduction 
1.1 
Disease background and current treatment modalities 
HDM allergy is an IgE-mediated hypersensitivity reaction to allergens contained in HDM 
fragments and faeces. These particles are airborne and are therefore inhaled reaching the 
human immune system primarily through the mucosal membrane of the airways, causing rhinitis 
and/or asthma (Arlian & Platts-Mills 2001). Thus, HDM respiratory allergic disease has two 
main clinical manifestations: allergic rhinitis/rhinoconjunctivitis and allergic asthma (Bousquet 
et al. 2001). 
HDM is an important allergen among children and adolescents. Among inhalant allergens, HDM 
sensitisation was found to be the most important risk factor for asthma development in children 
(Arshad et al. 2001; Lodge et al. 2011; Sears et al. 1989; Sporik et al. 1990; Terreehorst et 
al. 2002). In addition to HDM sensitisation being linked to the development of asthma in early 
childhood, it is also linked to chronic asthma, characterised by the impairment of lung function in 
school-aged children (Lau et al. 2000; Lodge et al. 2011) and persistence of asthma into 
adulthood (Illi et al. 2006). Patients sensitised to HDM have a significantly higher risk of 
recurrent asthma exacerbations (ten et al. 2005). 
Currently, treatment of allergic diseases is based on allergen avoidance, pharmacotherapy and 
allergy immunotherapy (AIT) (Bacharier et al. 2008; Bousquet et al. 2008; Bousquet et al. 
1998; GINA Executive Committee 2017; van Cauwenberge et al. 2000). However, evidence 
shows that allergen avoidance is not possible to an extent that relieves patients from their 
symptoms (Gotzsche & Johansen 2008; Valovirta et al. 2008), and international treatment 
guidelines question whether the effect justifies the cost and effort (Brozek et al. 2010; GINA 
Executive Committee 2017). 
Pharmacotherapy for HDM respiratory allergy most commonly includes antihistamines (oral or 
topical), local corticosteroids (nasal and/or inhaled) and inhaled β2-agonist, depending on the 
clinical manifestation and severity. None of the mentioned treatment options provide long-term, 
post-treatment benefits or alter the natural course of the allergic disease and most have effects 
in only one disease manifestation (i.e. AR or allergic asthma). 
The treatment algorithm in asthma is based on the concept of disease control, as described in 
the National Institutes of Health (NIH) guideline for the Diagnosis and Management of Asthma 
(National Heart Lung and Blood Institute 2007) and the Global Initiative for Asthma (GINA) 
guideline (GINA Executive Committee 2017) where SLIT is recommended as an option for the 
treatment of adult HDM-sensitive patients with asthma and allergic rhinitis who have 
exacerbations despite ICS treatment. The goals of asthma management are to achieve good 
symptom control and to minimise future risk of exacerbations, as based on an expectation that 
when asthma is controlled, patients will experience no more than occasional recurrence of 
symptoms and exacerbations will be rare. In paediatric asthma, a seasonal fluctuation in the 
occurrence of asthma exacerbations is well documented, with a rapid and substantial increase 
in asthma-related hospitalisations at the beginning of each school year (the ‘September 
epidemic’) (GINA Executive Committee 2017; Sears 2008). Evidence indicates that 
respiratory viral infections may play a causative role in this peak of asthma exacerbations 
(Sears 2008), and treatment to improve asthma control is central for reducing patients’ 
susceptibility towards virus-induced exacerbations (Busse et al. 2011). 

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Briefly, the asthma treatment algorithm defined by GINA and NIH recommends using one or a 
combination of daily controller medications, with ICS as the preferred option, in combination 
with LABA upon increasing severity. A stepwise approach is recommended, with an increase in 
dose or addition of other controller options if the patient is not well-controlled, and a 
corresponding step-down adjustment if the patient has been controlled for a while. At all steps, 
break-through symptoms are treated with reliever medication, typically a SABA. 
Thus, for patients with HDM allergic asthma, ICS either dispensed alone or in combination with 
LABA (combination products) are considered first-line treatment. While ICS constitute the most 
effective anti-inflammatory medications for treatment of asthma at the present time and provide 
disease control, ICS do not treat the underlying allergic disease and discontinuation is typically 
followed by a recurrence in inflammation and asthma symptoms. For children 6 years of age 
and above with moderate to severe persistent asthma who have a positive skin test or in vitro 
reactivity to a perennial aeroallergen and whose symptoms are inadequately controlled with 
inhaled corticosteroids, treatment with monoclonal antibodies, particularly Xolair, is increasingly 
being used. Xolair has been shown to decrease the incidence of asthma exacerbations in these 
patients. 
AIT treats the underlying immunological mechanisms responsible for allergic inflammation and 
represents a treatment option for HDM allergy that is complementary to pharmacotherapy. AIT 
is performed by repeated subcutaneous or sublingual administration of specific allergen to an 
allergic person in order to gradually induce immunological tolerance towards the allergen. 
Considerations for initiating AIT include disease severity, lack of efficacy of pharmacotherapy, 
side effects of pharmacotherapy, patient preference and the presence of more than one 
manifestation of the underlying allergic disease (Bousquet et al. 2008). 
1.2 
Stage of development 
The HDM SLIT-tablet is approved in the United States, Europe, Japan, and Australia as AIT for 
treatment of HDM respiratory allergic disease in the adult population. Additionally, it is approved 
in Europe and Japan for treatment of adolescents (12-17 years) with HDM AR. 
The HDM SLIT-tablet is formulated as a fast-dissolving pharmaceutical formulation (oral 
lyophilisate) containing standardised HDM allergen extract. Treatment involves once daily 
sublingual administration and targets the underlying HDM allergy to provide clinical benefit in 
both HDM AR and HDM allergic asthma. 
To date, the HDM SLIT-tablet has been investigated in 13 clinical trials and is currently being 
investigated in 1 ongoing trial in the paediatric population (5-17 years). The completed trials 
comprised 5 phase I trials, 2 phase II trials, and 6 phase III trials. This included 2 phase I trials 
conducted in children (5-14 years) and adolescents (12-17 years), respectively. In addition, 
adolescent subjects were included in 3 of the completed phase III efficacy trials. 
All trials were randomised, double-blind, placebo-controlled trials. Four efficacy trials had a 
primary endpoint related to HDM AR and 3 efficacy trials had a primary endpoint related to HDM 
allergic asthma. Safety was evaluated throughout the spectrum of the intended target 
population, i.e. subjects with persistent moderate-to-severe HDM AR despite the use of rhinitis 
pharmacotherapy and/or with HDM allergic asthma. 

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The MT-02 trial investigated the efficacy and safety of the HDM SLIT-tablet in adolescents and 
adults (14-74 years) with mild to moderate persistent HDM allergic asthma and mild to severe 
HDM AR (Mosbech et al. 2014). The results of the MT-02 trial demonstrated that adding the 
HDM SLIT-tablet to ICS treatment for 1 year allowed patients with mild to moderate HDM 
allergic asthma to reduce their ICS dose without affecting asthma control. 
The MT-04 trial investigated the efficacy and safety of the HDM SLIT-tablet in adults (18-65 
years) with HDM allergic asthma and AR, a baseline ACQ score of 1.0-1.5 and daily baseline 
ICS use corresponding to GINA steps 2-3 (Virchow et al. 2016). The primary efficacy analysis 
of the time to first asthma exacerbation showed a statistically significant reduced risk for 12 SQ-
HDM compared to placebo with a hazard ratio of 0.69 (p=0.027). Thus, the MT-04 trial 
demonstrated that for patients with HDM allergic asthma, adding the HDM SLIT-tablet to ICS 
treatment significantly reduced the risk of experiencing an asthma exacerbation. 
The TO-203-3-1 trial conducted in Japan evaluated the efficacy and safety of the HDM SLIT-
tablet in adults with HDM allergic asthma with or without HDM AR as assessed by a reduction in 
the risk of experiencing an asthma exacerbation. This trial was not able to verify efficacy of the 
HDM SLIT-tablet in HDM allergic asthma. The TO-203-3-1 trial design, endpoints, and 
population were modified from MT-04 to accommodate local requirements and treatment 
traditions. 
The approved adult dose of the HDM SLIT-tablet is 12 SQ-HDM. As pharmacodynamic effects 
of AIT products involve uptake by the immune system with limited absorption into the vascular 
system (Bagnasco et al. 2005), the doses of AIT used for adults and for children ≥5 years of 
age are identical (i.e. independent of age and body weight) (Alvarez-Cuesta et al. 2006). 
During clinical development of the HDM SLIT-tablet, a total of 810 paediatric subjects (<18 
years) have been included in the completed clinical trials, 283 of which were treated with the 12 
SQ-HDM dose. The majority of paediatric subjects were adolescents. 
The safety profile of the HDM SLIT-tablet in children and adolescents was investigated in two 
phase I safety trials MT-03 (children 5-14 years) and P008 (adolescents 12-17 years) (Corzo et 
al. 2014; Maloney et al. 2016). Results demonstrated safety profiles in children and 
adolescents that were similar to the safety profile observed for adult populations. Thus, in 
children (MT-03) and in adolescents (P008), the most frequently reported TEARs in active dose 
groups were mild to moderate local reactions in mouth and throat such as oral pruritus, throat 
irritation and mouth oedema. These events typically occurred within minutes the first 1-2 days 
after initial tablet intake and generally lasted from minutes to hours. There was a dose-response 
relationship in the observed AEs. In the completed clinical trials, no serious anaphylactic 
reactions or anaphylactic shock have been reported related to treatment with the HDM SLIT-
tablet. However, serious systemic allergic reactions and anaphylactic reactions have been 
reported post-marketing and are considered a class effect of AIT. 
In addition, adolescent subjects were included in the trial populations of the efficacy trials MT-
02, TO-203-3-2, and MK-8237-001. The available efficacy data provide no indication that the 
treatment effect of the HDM SLIT-tablet in paediatric subjects would differ from the treatment 
effect observed in adults. Also, across trials, data stratified for age showed similar safety 
profiles in adults (≥18 years) and adolescents (12-17 years). 
Please refer to the current Investigator’s Brochure (IB) for more details. 

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1.3 
Trial rationale 
The rationale behind the present trial is to investigate whether add-on treatment with the HDM 
SLIT-tablet has an acceptable safety profile and can provide a relevant treatment benefit in 
terms of a reduced number of asthma exacerbations for children and adolescent subjects with 
HDM allergic asthma on low dose ICS plus LABA or medium/high dose ICS with or without 
LABA and with HDM AR. Further, the trial will generate information on the 
 
 of the HDM SLIT-tablet. 
The trial population will include children and adolescents (5-17 years of age) with HDM allergic 
asthma on low dose ICS plus LABA or medium/high dose ICS with or without LABA who are at 
risk of asthma exacerbations and who have HDM AR. Eligible subjects have experienced 
asthma exacerbations in the last couple of years. This population is identified as patients with 
an unmet medical need. Despite being on asthma controller medication, these paediatric 
patients continue to experience asthma exacerbations which may involve hospitalisation and be 
a significant source of anxiety for patients as well as caregivers. In addition, a trial population 
with a history of frequent asthma exacerbations is in accordance with the EMA guideline (EMA 
2016b). Finally, the selected population experiences rhinitis symptoms and/or a need for rhinitis 
medication as a result of their HDM allergic disease and treating the underlying immunological 
mechanisms responsible for allergic inflammation would thus provide relief from both 
manifestations of HDM respiratory allergy in these patients. 
In this trial, subjects will be randomised (1:1) to treatment with the HDM SLIT-tablet (12 SQ-
HDM) or placebo in addition to their usual asthma background treatment and the asthma and 
rhinoconjunctivitis rescue medication for a treatment period of approximately 2 years. Primary 
efficacy will be assessed based on the rate of clinically relevant asthma exacerbations. This is 
in agreement with professional society guidelines and EMA guidelines, which specifies that a 
treatment effect on asthma exacerbations remains a relevant endpoint in paediatric patients 
(EMA 2016b; Reddel et al. 2009). In addition, data from the MT-04 trial demonstrated that in an 
adult trial population, the HDM SLIT-tablet was able to prevent asthma exacerbations when ICS 
was reduced (Virchow et al. 2016). Similarly, while the present trial design does not evaluate 
efficacy during a period of reduction in asthma controller medication, the trial rationale is that for 
a paediatric population, adding the HDM SLIT-tablet to asthma controller medication will provide 
therapeutic benefit in the form of improved asthma control and a reduced susceptibility towards 
asthma exacerbations. 
1.4 
Benefit-risk assessments and ethical considerations 
Despite substantial improvements in the treatment of asthma and the use of guideline-based 
therapy, approximately 50% of adult US asthma patients have inadequately controlled asthma 
(CDC 2015). Patients with unstable severe asthma suffer from limited control of symptoms, 
frequent exacerbations, and compromised quality of life. Exacerbations are particularly disabling 
for the patient and typically require treatment with high doses of systemic corticosteroids and 
may require hospital admission. A proportion of these patients with inadequately controlled 
asthma who require emergency room visits and hospitalisations due to exacerbations drive a 
substantial amount of the cost burden associated with asthma treatment. Treatments that can 
reduce the risk of future asthma exacerbations and improve measures of current impairment 
address a major unmet need in asthma management in North America and Europe today. 

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Among inhalant allergens, HDM sensitisation was found to be the most important risk factor for 
asthma development in children (Arshad et al. 2001; Lodge et al. 2011; Sears et al. 1989; 
Sporik et al. 1990; Terreehorst et al. 2002). Treatment with the HDM SLIT-tablet targets the 
underlying HDM allergy to provide clinical benefit in both HDM allergic asthma and HDM AR. 
Thus, in the present trial, subjects in the active treatment group may experience treatment 
benefits in terms of improved asthma symptom control and a reduced number of asthma 
exacerbations, as well as a reduced burden of symptoms related to HDM AR. 
When developing the HDM SLIT-tablet, the sublingual route was selected over subcutaneous 
injection to provide a product with a safety profile allowing for at-home administration. This 
results in improved convenience for patients and caregivers to those who have a fear of 
injections or who cannot set aside time off work or school for frequent doctor’s visits over a 
treatment period of several years. In addition, orodispersible dosage forms hold great promise 
for children as they are easy to administer, do not require additional water and, as long as 
dispersion is rapid, are difficult to spit out (EMEA 2006). 
The most prevalent AEs observed with the HDM SLIT-tablet include local reactions in the mouth 
and throat (e.g. oral pruritus, throat irritation, and mouth oedema) of mild to moderate severity. 
The risk of severe swelling is low and no AEs have involved local allergic swelling that 
compromised the airways in completed clinical trials. The risk of severe systemic allergic 
reactions is considered minimised for the HDM SLIT-tablet, as sublingual administration has not 
been found to result in relevant absorption into the systemic circulation. 
This clinical trial will follow the principles of the Helsinki Declaration 1964 and subsequent 
amendments and clarifications (World Medical Association 2013). The trial will be approved 
by the local independent ethics committee (IEC)/institutional review board (IRB) and health 
authorities before initiation. 
A placebo group will be used as a control-group in the trial. An active comparator is not included 
in the trial as there are no available authorised HDM SLIT-tablets. A placebo group is 
considered ethically justifiable since subjects in both treatment groups will be provided with 
background treatment and rescue medication to treat their asthma and rhinitis 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 or without giving reason. 
The population selected for this trial is characterised by a history of asthma exacerbations 
despite asthma treatment, which means the future risk of exacerbations in these subjects is 
considerable. In order to minimise the risk relating to severe asthma exacerbations, the trial 
protocol specifies that subjects who experience severe asthma exacerbations be treated 
appropriately, and a maximum number of severe asthma exacerbations allowed in any single 
subject has been defined, after which a subject must be discontinued from the IMP treatment. 
In order to minimise any risk related to the trial activities, the following tools have been 
incorporated in the protocol: 
- 
Each subject will be provided with self-monitoring tools in the form of a preprogrammed 
eDiary and a peak flow meter to increase awareness of asthma control 

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- 
Each subject will receive a supply of asthma and rhinoconjunctivitis rescue medication to 
be used as needed. In countries where it is a regulatory requirement, 
adrenaline/epinephrine auto-injectors will be dispensed 
- 
Each subject will receive a personal written Asthma Action Plan containing specific 
instructions on the actions required in case asthma symptoms increase or lung function 
decreases 
- 
Each subject will be provided with a pocket-size patient card containing investigator 
contact information 
- 
An independent DMC will be established for safety monitoring of the trial 
- 
Considerations regarding COVID-19 pandemic:  
o 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. If regional circumstances related 
to COVID-19 change, local guidelines should be followed, see appendix 6.  
o If an on-site visit is not possible due to COVID-19 pandemic, appendix 7-8 
enables the conduct of a remote visit at the discretion of the Investigator.  
o If an on-site visit is not possible due to COVID-19 pandemic, IMP and rescue 
medication can be shipped directly from site to patient at the discretion of the 
Investigator, see appendix 9.  
In summary, the benefits of add-on treatment with the HDM SLIT-tablet which are expected to 
include improved asthma control and a reduced risk of asthma exacerbations as well as 
reduced rhinitis symptoms are deemed to outweigh the risks and inconveniences associated 
with the treatment. The safety profile of the HDM SLIT-tablet in the paediatric population is 
expected to be favourable and to make the tablet suitable for at-home administration with a low 
risk of systemic adverse reactions and with mild to moderate local reactions in the oral cavity 
representing the most frequent adverse reactions. Additional details regarding specific benefits 
and risks for subjects participating in this clinical trial may be found in the accompanying IB and 
informed consent documents. 
In conclusion, the risks and benefits of trial participation are considered to be well balanced. 
2 
Objectives and endpoints 
2.1 
Primary objective 
The primary objective is to demonstrate efficacy of the HDM SLIT-tablet versus placebo as add-
on treatment in children and adolescents (5-17 years) with HDM allergic asthma based on 
clinically relevant asthma exacerbations38 after at least 4 months of treatment. 
 
38 A clinically relevant asthma exacerbation is defined as at least one of the following criteria: a) Doubling of ICS dose compared to 
background treatment, b) Systemic corticosteroids for treatment of asthma symptoms for at least 3 days, c) Emergency room visit 
 

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2.2 
Key secondary objective 
The key secondary objectives are to demonstrate efficacy of the HDM SLIT-tablet versus 
placebo after at least 4 months as add-on treatment in children and adolescents with HDM 
allergic asthma with respect to: 
• 
Nocturnal awakening due to asthma which require SABA rescue medication 
• 
Rescue medication use (SABA) 
• 
Lung function (FEV1) 
2.3 
Secondary objectives 
The additional secondary objectives, based on endpoints measured at different timepoints 
throughout the trial, are to evaluate the HDM SLIT-tablet versus placebo for treatment of HDM 
allergic asthma with respect to: 
• 
Asthma symptoms 
• 
Asthma control 
• 
Severe asthma exacerbations39 
• 
Treatment of HDM AR 
• 
Treatment of HDM allergic rhinoconjunctivitis 
• 
Changes in immunological parameters  
• 
Safety and tolerability  
2.4 
Exploratory objectives 
The exploratory objectives are to evaluate: 
• 
 
• 
 
• 
  
• 
  
2.5 
Primary endpoint 
The primary endpoint of the trial is the annualised rate of clinically relevant asthma 
exacerbations calculated as the number per year per subject during the efficacy evaluation 
period (period 4). 
A clinically relevant asthma exacerbation must be medically confirmed and is defined as asthma 
worsening leading to at least one of the following criteria: 
 
due to asthma, requiring systemic corticosteroids or d) Hospitalisation  for more than 12 hours due to asthma, requiring treatment 
with systemic corticosteroids. 
39 A severe asthma exacerbation is defined as at least one of the following: a) Systemic corticosteroids for treatment of asthma 
symptoms for at least 3 days, or b) Emergency room visit due to asthma, requiring systemic corticosteroids, or c) Hospitalisation for 
more than 12 hours due to asthma, requiring treatment with systemic corticosteroids. 

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• 
Doubling of ICS dose compared to background treatment 
• 
Systemic corticosteroids for treatment of asthma symptoms for at least 3 days 
• 
Emergency room visit due to asthma, requiring systemic corticosteroids  
• 
Hospitalisation for more than 12 hours due to asthma, requiring treatment with systemic 
corticosteroids  
2.6 
Key secondary endpoints 
The key secondary endpoints are:  
• 
Proportion of days with nocturnal awakenings due to asthma requiring SABA rescue 
medication during the 14 days eDiary recording every 4 months after randomisation 
• 
The average daily dose of SABA during the 14 days eDiary recording every 4 months 
after randomisation 
• 
Percentage predicted FEV1 assessed every 4 months after randomisation  
2.7 
Additional secondary endpoints 
• 
Asthma exacerbations 
o Time to first clinically relevant asthma exacerbation measured in days from start of 
the efficacy evaluation period 
o Time to recurrent clinically relevant asthma exacerbation measured in days from 
start of the efficacy evaluation period 
o The rate of severe asthma exacerbations during the efficacy assessment period 
(period 4). A severe asthma exacerbation meets at least one of the following criteria: 
 
Systemic corticosteroids for treatment of asthma symptoms for at least 3 
days 
 
Emergency room visit due to asthma, requiring systemic corticosteroids  
 
Hospitalisation for more than 12 hours because of asthma, requiring 
treatment with systemic corticosteroids 
o Time to first severe asthma exacerbations from start of the efficacy assessment 
period (period 4) 
o Time to recurrent severe asthma exacerbations from start of the efficacy assessment 
period (period 4) 
• 
Asthma symptoms  
o Average asthma DSS during the two week assessment period before V5, V6, V7, 
V8, V9, V10 and V11 
o Asthma VAS 
o Global evaluation for allergic asthma 
o Overall ACQ/ACQ-IA measured at V5, V6, V7, V8, V9, V10 and V11 
• 
Rhinitis symptoms and symptomatic medication 
o The average TCRS during the two week assessment period before V5, V6, V7, V8, 
V9, V10 and V11 
o The average rhinitis DSS during the two weeks assessment period before  V5, V6, 
V7, V8, V9, V10 and V11 
o The average rhinitis DMS during the two week assessment period before V5, V6, V7, 
V8, V9, V10 and V11 

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Figure 1 
Trial design 
 
 
Period 1 is the screening period. Subjects screened before 10 April 2018 will be included in 
cohort 1. Subjects screened between 10 April 2018 and 10 April 2019 will be included in cohort 
2. Subjects screened between 10 April 2019 and 10 April 2020 will be included in cohort 3. 
Subjects screened between 01 August 2021 and 10 April 2022 will be included in cohort 4. 
Period 2 is the baseline period of 3 weeks following screening. For cohort 1, the baseline period 
is during Q1 - Q2 2018. For cohort 2, the baseline period is during Q4 2018 - Q2 2019. For 
cohort 3, the baseline period is during Q4 2019 - Q2 2020. For cohort 4, the baseline period will 
occur during Q4 2021 – Q2 2022. During the baseline period, eligible subjects or their 
parent/caregiver will fill in their asthma and rhinoconjunctivitis symptoms and medication use in 
an eDiary. Subjects will continue with their regular asthma background treatment. The subjects’ 
regular asthma rescue mediation and rhinoconjunctivitis rescue medication must be replaced 
with the rescue medication provided by ALK at visit 2 with the exception of additional sponsor 
provided ICS, which is optional. 
 
Period 3 is the treatment initiation and maintenance period to allow the treatment with the HDM 
SLIT-tablet to take effect. It starts at randomisation and lasts for at least 4 months. The period 
ends on 1 September 2018 for cohort 1, on 1 September 2019 for cohort 2, on 1 September 
2020 for cohort 3 and on 1 September 2022 for cohort 4. 
During the first 28 days of period 3, prespecified symptoms40 occurring after IMP intake will be 
recorded by the subject/parent/caregiver in the eDiary. The reported symptoms will be 
evaluated by investigator and reported in the eCRF as solicited AEs. 
 
Period 4 is the efficacy assessment period. Period 4 lasts until the end of trial or discontinuation 
from the IMP41 and during this period the rate of clinically relevant asthma exacerbations will be 
 
40 AEs identified by the World Allergy Organization (WAO) as local side effects of SLIT (Passalacqua et al. 2013). 
41 Subjects will be discontinued from the IMP treatment after 2 severe asthma exacerbations in 12 consecutive months or 1 
hospitalisation due to asthma requiring treatment with systemic corticoteroids. 

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evaluated from 1 September 2018 to 30 April 2020 (cohort 1), 1 September 2019 to 30 April 
2021 (cohort 2), 1 September 2020 to 30 April 2022 (cohort 3) and 1 September 2022 to 30 
April 2024 (cohort 4). 
Subjects will be treated for 24-30 months in total since subjects can commence treatment in a 
predefined period lasting from 1 November until 10 April. The efficacy period starts on 1 
September for all subjects resulting in a pretreatment period of 4 to 10 months. The efficacy 
period ends 30 April for all subjects. As a result, some subjects may have 5-6 months between 
visit 10 and 11 while others may have their last visit 11 on the same day as visit 10. Subjects 
with less than 1 month between visit 10 and 11 will only have one visit to the clinic where all the 
procedures of 11 are performed.   
Approximately every 4 months after randomisation, subjects or their parent/caregiver will be 
asked to complete the eDiary for a period of 14 days 3 weeks prior to V5 (at 4 months), V6 (at 8 
months), V7 (at 12 months), V8 (at 16 months), V9 (at 20 months), V10 (at 24 months) and V11 
(25-30 months).  
3.2 
Trial schedule 
 
Cohort 1 
Cohort 2 
Cohort 3 
Cohort 4 
First subject first visit (FSFV): 
Q1 2018 
Q3 2018 
Q3 2019 
Q3 2021 
Last subject randomised 
Q2 2018 
Q2 2019 
Q2 2020 
Q2 2022 
Last subject last visit (LSLV): 
Q2 2020 
Q2 2021 
Q2 2022 
Q2 2024 
 
Duration of treatment per subject: 
24-30 months 
End of trial defined as LSLV for the last cohort initiated. 
3.3 
Discussion of design 
The selected design for the present trial is based on the EMA The Committee for Medicinal 
Products for Human Use (CHMP) guideline on the clinical investigation of medicinal products for 
the treatment of asthma (EMA 2016b) and incorporates the recommendations of the EMEA 
CHMP guideline on the clinical development of products for specific immunotherapy for the 
treatment of allergic diseases (EMA 2008), the needs stated in the World Health Organisation 
(WHO) position paper on allergen immunotherapy for development of sublingual 
immunotherapy (Bousquet et al. 1998), the EMA/PDCO Standard Paediatric Investigation Plan 
for Allergen Products for Specific Immunotherapy (EMA & PDCO 2015), and the Food and Drug 
Administration (FDA) guidance for industry on the content and format for paediatric use 
supplements (FDA 1996). 
The clinical efficacy endpoint has been chosen based on the guidelines referenced above as 
well as the joint statement on endpoints for clinical asthma trials and clinical practice from the 
American Thoracic Society and the European Respiratory Society (Reddel et al. 2009). The 
trial design is also based on the experience from previous ALK trials with allergy 
immunotherapy in general and with the HDM SLIT-tablet in particular for treatment of allergic 
asthma and rhinitis. 
The trial population comprises children (5-11 years) and adolescents (12-17 years) with a 
clinical history consistent with HDM allergic asthma who are at risk of asthma exacerbations 
despite being on treatment with low dose ICS plus LABA or medium/high dose ICS with or 

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without LABA and who have HDM AR. This trial population reflects a population that is suitable 
for treatment with specific allergy immunotherapy since the aim is to treat the underlying 
inflammation in asthma, thereby minimising the risk for exacerbations.  
The duration of treatment is approximately 2 years for all subjects. All subjects should be 
randomised before 1 May to ensure at least 4 months of treatment initiation and maintenance. 
The duration of the treatment initiation and maintenance period is based on the results from 
previous trials with the HDM SLIT-tablet for treatment of asthma and rhinitis symptoms (Demoly 
et al. 2016; Mosbech et al. 2014; Virchow et al. 2016) where onset of significant effect was 
seen after approximately 14 weeks of treatment.  
 
For the primary objective, efficacy measurements are to be performed during the autumn and 
winter where HDM allergic patients typically have more symptoms (Bousquet et al. 2008). 
Efficacy measurement duration will be approximately 20 months in order to capture two autumn 
and winter seasons. This means that the efficacy assessment period will start 1 September for 
all subjects.  
 
Safety endpoints include AEs, vital signs and laboratory values that are normally used in 
characterising the safety profile of an IMP. 
 
The active dosage chosen in the trial is 12 SQ-HDM, which is the approved dose for adults in 
the United States, Europe and Australia and for adolescents (12-17 years) in Europe. The dose 
is based on the appropriate dose established in adults as the dose providing the highest 
efficacy with the fastest onset of effect and with a safety profile that supports daily at-home 
administration (Demoly et al. 2016; Nolte et al. 2015; Virchow et al. 2016). This dose (12 SQ-
HDM) will constitute the relevant dose for all populations ≥5 years of age, in accordance with 
the general practice for AIT (Alvarez-Cuesta et al. 2006). 
 
Besides treatment with IMP, the subjects will use background treatment with low dose ICS plus 
LABA or medium/high dose ICS with or without LABA. Throughout the trial the ICS or ICS and 
LABA combination treatment will be at the same dose as when the subjects enter the trial. 
LABA treatment when not being used in combination with ICS is not allowed as it is no longer 
recommended as an option for add-on treatment at any step of therapy unless used in 
combination (GINA Executive Committee 2017). A separate inhaler with ICS alone will be 
allowed as asthma rescue medication in case of deterioration of symptoms or following a severe 
exacerbation. Alternatively, subjects can double the dose of their background ICS for an 
exacerbation rather than using sponsor provided ICS. SABA and OCS will also be provided as 
asthma rescue medication. Please note that the terms “background treatment” and “rescue 
medication” follows the EMA “Definition of IMPs and use of AMPs consultation document” from 
2016 (EMA 2016a) rather than the EMA “Guideline on the clinical development of products for 
specific immunotherapy for the treatment of allergic diseases” from 2008 (EMA 2008).  
Asthma exacerbations constitute the greatest unmet medical need for patients, are a cause of 
anxiety to patients and their families, resulting in the greatest stress on health care providers, 
and generate the greatest cost to the health care system (Lane et al. 2006). The exacerbation 
rate is a clinically relevant endpoint to assess treatment effect in patients with asthma (EMA 
2016b). Hence, the primary endpoint in this trial is the rate of exacerbations. 
The definition of a clinically relevant asthma exacerbation used in this trial is based on the 
recommendations given in the joint statement from the American Thoracic Society and the 

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European Respiratory Society 2009 (Reddel et al. 2009) and recommendations from GINA 
(GINA Executive Committee 2017). 
If the subject experiences one of the following events, this will be characterised as a clinically  
relevant asthma exacerbation: 
• 
Doubling of ICS dose compared to background treatment 
• 
Systemic corticosteroids for treatment of asthma symptoms for at least 3 days 
• 
Emergency room visit due to asthma, requiring systemic corticosteroids  
• 
Hospitalisation  for more than 12 hours due to asthma, requiring treatment with systemic 
corticosteroids 
The key secondary endpoints consist of:  
 
• 
Proportion of days with nocturnal awakenings due to asthma requiring SABA rescue 
medication during the 14 days eDiary recording every 4 months after randomisation 
• 
The average daily dose of SABA during the 14 days eDiary recording every 4 months 
after randomisation 
• 
Percentage predicted FEV1 assessed every 4 months after randomisation  
These endpoints has been chosen to underline the effect on asthma symptoms, asthma 
medication use and lung function. 
 
The expected rate of clinically relevant asthma exacerbations is 1.4 (Lanier et al. 2009) in this 
trial. A 20% reduction in the rate corresponds to an absolute reduction of 0.28 clinically relevant 
asthma exacerbations per subject per year. This can further be translated to saving 1 clinically 
relevant asthma exacerbation per year per 3.6 treated subjects. It has been proposed that any 
reduction in the rate of severe exacerbations (e.g., requiring treatment with systemic 
corticosteroids) is clinically relevant (Glacy et al. 2013). 
 
This trial is a randomised, parallel-group, double-blind, placebo-controlled multi-national trial. 
Randomisation introduces a deliberate element of chance into the assignment of treatments to 
subjects in a clinical trial. During subsequent analysis of the trial data, it provides a sound 
statistical basis for the quantitative evaluation of the evidence relating to treatment effects. It 
also tends to produce treatment groups in which the distributions of prognostic factors, known 
and unknown, are similar. In combination with blinding, randomisation helps to avoid possible 
bias in the selection and allocation of subjects arising from the predictability of treatment 
assignments (ICH Harmonised Tripartite Guideline 1998). It is desirable for statistical 
purposes to compare groups of equal size and therefore the randomisation procedure is 
planned as a 1:1 randomisation. 
 
A double-blinded set-up has been chosen to minimise the potential biases resulting from 
differences in management, treatment, or assessment of subject or interpretation of results that 
could arise as a result of subject or investigator knowledge of the assigned treatment. 
 
A placebo arm has been introduced to establish the superiority of the HDM SLIT-tablet 
compared to placebo and background treatment with respect to reducing the frequency of the 
severe asthma exacerbations. Placebo has been chosen as comparator since no well-
established comparator exist. 

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4 
Trial population 
Subjects randomised in this trial will be children and adolescents 5-17 years of age, with HDM 
allergic asthma who are at risk of asthma exacerbations despite being on treatment with low 
dose ICS plus LABA or medium/high dose ICS with or without LABA and who have HDM AR. 
The trial will include 45% subjects of 5-11 years of age in accordance with the recommendation 
of EMA/PDCO Standard Peadiatric Investigation Plan for Allergen Products for Specific 
Immunotherapy (EMA & PDCO 2015). The age groups follow the EMA/PDCO Standard 
Paediatric Investigation Plan for Allergen Products for Specific Immunotherapy (EMA & PDCO 
2015), and the FDA guidance for industry on the content and format for paediatric use 
supplements (FDA 1996) rather than the EMA Guideline on the clinical investigation of 
medicinal products for the treatment of asthma (EMA 2016b). 
 
Subjects meeting all of the inclusion criteria listed in Section 4.1 and none of the exclusion 
criteria listed in Section 4.2 will be considered eligible for the trial. Please also refer to the 
general dosing precautions in Section 9.2. 
 
4.1 
Inclusion criteria 
I1. 
Written informed consent obtained from parents/caregivers before any trial related 
procedures are performed42. Consent or assent from the subject must be obtained 
according to national requirements. 
I2. 
Male or female of any race/ethnicity aged ≥4 to ≤17 years  on the day informed consent is 
obtained from the parent/caregiver. The subject must be ≥5 to ≤17 years old at the 
randomisation visit  
I3. 
A female subject of childbearing potential43 must have a negative pregnancy test and be 
willing to practise appropriate44 contraceptive methods until the follow-up TC 
I4. 
A clinical history of HDM allergic asthma of at least 1 year duration diagnosed by a 
physician45  
I5. 
Use of low daily dose of ICS plus LABA or medium/high daily dose of ICS with or without 
LABA for the control of asthma symptoms within the past year prior to randomisation. For 
definition of ICS doses, please see Table 3 and Table 4 
 
42 At least one parent/caregiver must be able to read. 
43 Females, after the first menstrual period.  
44 For the purpose of this protocol the following contraceptive methods are considered appropriate: oral contraceptives, trans dermal 
patches or depot injection of a progestogen drug (starting at least 4 weeks prior to IMP administration); double barrier method: 
condom or occlusive cap (diaphragm or cervical/vault caps) plus spermicidal agent; IUD, IUS, implant, or vaginal ring (placed at 
least 4 weeks prior to IMP administration); or male partner sterilisation (vasectomy with documentation of azoospermia) prior to the 
female subject's entry into trial and is the sole sexual partner for that female subject. Sexual abstinence is acceptable as 
contraceptive if it is true abstinence and in line with the usual lifestyle of the subject. Periodic abstinence (e.g., calendar, ovulation, 
symptothermal, post-ovulation methods) and withdrawal are not acceptable methods of contraception. However, national 
requirements regarding contraception should always be followed. 
45 If medical records are not available, verbal history from subject/parent/caregiver can be used to fulfill this criterion and this must 
be documented in the medical records by the investigator. 

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I6. 
≥3 clinically relevant asthma exacerbations46 in the past two years or ≥2 clinically relevant 
asthma exacerbations in the past year or ≥1 severe asthma exacerbation47 in the past 
year prior to randomisation while being on asthma controller medication (low dose ICS 
plus LABA or medium/high dose ICS with or without LABA)48. The asthma controller 
medication at the screening visit must be at a dose equivalent to or below the dose the 
subject received before the last asthma exacerbation occurred 
I7. 
One or more of the following within the past 4 weeks prior to randomisation: 
a. Daytime asthma symptoms more than twice/week 
b. Any nocturnal awakening due to asthma which require use of SABA rescue 
medication 
c. SABA rescue medication needed for treatment of asthma symptoms more 
than twice/week 
d. Any activity limitation due to asthma  
I8. 
Lung function measured by FEV1 ≥ 70% of predicted value49 or according to local 
requirements while on background treatment following at least a 6-hour washout of SABA 
at screening and randomisation 
I9. 
Clinical history of HDM AR within the last year prior to randomisation50 
I10. An average TCRS>0 during the baseline period (period 2) 
I11. Positive specific IgE (defined as ≥class 2, ≥0.70 kU/l) against D. pteronyssinus and/or D. 
farinae at screening 
I12. Positive SPT51  to D. pteronyssinus and/or D. farinae at screening 
I13. Subject willing and able to comply with trial protocol  
 
46 A clinically relevant asthma exacerbation is defined as at least one of the following criteria: a) Doubling of ICS dose compared to 
background treatment, b) Systemic corticosteroids for treatment of asthma symptoms for at least 3 days, c) Emergency room visit 
due to asthma, requiring systemic corticosteroids or d) Hospitalisation  for more than 12 hours due to asthma, requiring treatment 
with systemic corticosteroids.  
47 A severe asthma exacerbation is defined as at least one of the following: a) Systemic corticosteroids for treatment of asthma 
symptoms for at least 3 days, b) Emergency room visit due to asthma, requiring systemic corticosteroids or c) Hospitalisation for 
more than 12 hours due to asthma, requiring treatment with systemic corticosteroids. 
48 One asthma exacerbation within the last year must be documented including asthma medication and dosage immediately prior to 
this exacerbation. 
49 Interpretation of normal range for spirometric test should be based on the Quanjer reference equations (Quanjer et al. 1995). 
50 If medical records are not available, verbal history from subject/parent/caregiver can be used to fulfill this criterion and this must 
be documented in the medical records by the investigator. 
51 A positive SPT is defined in the SPT Guideline. Briefly, for subjects in North America, a positive SPT is defined as a wheal size 
≥5 mm larger than the negative control. For subjects in Europe, a positive SPT is defined as a wheal size ≥3 mm. 

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4.2 
Exclusion criteria 
E1. Has a clinically relevant history and is sensitised, symptomatic, and regularly exposed to 
animal dander, molds, and/or cockroach (e.g., present in the home, job, school, etc.) or 
other perennial allergen  
E2. Has experienced a life-threatening asthma attack defined for this protocol as an asthma 
episode that required intubation and/or was associated with hypercapnia requiring non-
invasive ventilator support  
E3. Within the last month before the randomisation visit (visit 3), has had an occurrence of any 
clinical deterioration of asthma that resulted in emergency treatment, hospitalisation, or 
treatment with systemic corticosteroids 
E4. Within the last 3 months before the randomisation visit (visit 3) while on high dose ICS 
treatment, has had an occurrence of any clinical deterioration of asthma that resulted in 
emergency treatment, hospitalisation, or treatment with systemic corticosteroids  
E5. SLIT treatment with D. pteronyssinus or D. farinae for more than 1 month within the last 5 
years. In addition, any SLIT treatment with D. pteronyssinus or D. farinae within the 
previous 12 months 
E6. SCIT treatment with D. pteronyssinus or D. farinae reaching the maintenance dose within 
the last 5 years. In addition, any SCIT treatment with D. pteronyssinus or D. farinae within 
the previous 12 months 
E7. Ongoing treatment with any allergy immunotherapy product 
E8. Severe chronic oral inflammation 
E9. 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)52 
E10. 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 
E11. Has a diagnosis or history of eosinophilic oesophagitis 
E12. 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 
E13. Active or poorly controlled autoimmune diseases, immune defects, immunodeficiencies, 
immunosuppression or malignant neoplastic diseases with current disease relevance 
 
52 If in doubt, nasal endoscopy is recommended 

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E14. Ongoing treatment with OCS 
E15. Treatment with restricted and prohibited concomitant medication listed in Table 2 
E16. Treatment with an investigational drug within 30 days/5 half-lives of the drug (which ever 
longest) prior to screening 
E17. A history of allergy, hypersensitivity or intolerance to any of the excipients or active 
substance of the IMP (except D. pteronyssinus and D. farinae) or to any excipient of the 
rescue medication provided in this trial 
E18. A business or personal relationship with trial staff or sponsor who is directly involved with 
the conduct of the trial 
E19. A history of alcohol or drug abuse 
E20. Has previously been randomised into this trial, is participating in this trial at another 
investigational site or is participating or planning to participate in any other clinical trial 
during the duration of this trial 
E21. Has a history or current evidence of any condition, treatment, laboratory values out of 
range or other circumstance that in the opinion of the investigator are clinically relevant 
and might expose the subject to risk by participating in the trial, confound the results of the 
trial, or interfere with the subject’s participation for the full duration of the trial 
E22. Has a condition or treatment that increase the risk of the subject developing severe 
adverse reactions after adrenaline/epinephrine administration 
E23. Is unable to or will not comply with the use of adrenaline/epinephrine auto-injectors for 
countries where this is a regulatory requirement 
5 
Subject discontinuation 
5.1 
Discontinuation from IMP treatment 
Subjects must be discontinued from IMP treatment and should continue in the trial for safety 
assessments only under the following circumstances: 
• 
If the subject experiences 2 severe asthma exacerbations within a 12 consecutive 
months period 
• 
If the subject is hospitalised due to asthma requiring treatment with systemic 
corticosteroids  
• 
The subject experiences severe or persistent symptoms of oesophagitis  
• 
If the subject becomes pregnant 
• 
If, in the investigator’s opinion, continuation with IMP treatment would be detrimental to 
the subject’s well-being 

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5.2 
Discontinuation from trial 
The subject and/or subjects parent/caregiver will be advised in the informed consent form that 
he/she has the right to withdraw from the trial at any time without prejudice. Where 
discontinuation from the trial is initiated by the subject, the investigator is to ascertain the 
primary reason for discontinuation from the list below: 
• 
An AE for which the investigator did not consider discontinuation from the trial necessary 
• 
Perceived insufficient therapeutic effect 
• 
Co-existing disease 
• 
Withdrawal of consent 
• 
Other reasons 
Additionally, the subject may at any time be discontinued from the trial at the discretion of the 
investigator or ALK. 
Subjects must be discontinued from the trial under the following circumstances: 
• 
If, in the investigator’s opinion, continuation in the trial would be detrimental to the 
subject’s well-being 
• 
If subject is lost to follow-up 
• 
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) 
• 
If IMP is discontinued for several months  
In case a subject discontinues from the trial, the discontinuation page in the eCRF should be 
completed. On the discontinuation page the investigator should record the date of the 
discontinuation, the person initiating the discontinuation and the primary reason for 
discontinuation. If an 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. Follow-up on the subject is necessary to establish whether the 
reason was an AE. If so, this must be reported in accordance with the appropriate procedures. 
To the extent possible, all examinations scheduled for the final visit must be performed on 
subjects who receive IMP but did not complete the trial according to the protocol. If possible, the 
TC follow-up (TC21) should be performed and the corresponding eCRF pages should be filled 
in. 
Reasonable effort should be made to contact any subject lost to follow-up during the course of 
the trial in order to complete assessments and retrieve any outstanding data and 
medication/supplies. If the subject is lost to follow-up, 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. 

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6 
Randomisation and treatment blinding/unblinding 
6.1 
Subject ID number 
All subjects enrolled must be identifiable throughout the trial. Thus, at the screening visit all 
subjects will receive a unique subject number. The subject number will be generated when the 
subjects’ data are entered into the eCRF. 
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. 45% of the subjects will be 5-11 years of age at the time of randomisation in accordance 
with the recommendation of EMA/PDCO standard paediatric investigation plan for allergen 
products for specific immunotherapy (EMA & PDCO 2015). No other stratification will be used in 
this trial. 
When a subject is randomised a unique number is assigned for the first dispensing of IMP. 
6.3 
Subject card 
All randomised 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. 
6.4 
Treatment blinding/unblinding 
A double-blind set-up will be used. The HDM SLIT-tablet and the matching placebo will be 
similar in appearance and taste and will be packaged identically to maintain the treatment blind. 
Neither the sponsor, the subject, nor the trial site staff will know which treatment the subject is 
receiving. DMC members will be unblinded to treatment. 
The randomisation code for a particular subject can be broken in a medical emergency if 
knowledge of the IMP is necessary for the optimal treatment of the subject. If possible the trial 
site must contact ALK prior to unblinding the subject's treatment. However, in case of an 
emergency necessitating the knowledge of the IMP, unblinding and appropriate treatment 
should be the very first action by the site. 
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 associate (CRA) and the safety department at the 
sponsor immediately after the randomisation code is broken. 
The subject must be discontinued from the trial after randomisation code breaking. 
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 should be maintained during the trial. 

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2017, NIH guidelines (National Heart Lung and Blood Institute 2007) or national guidelines 
(Reddel et al. 2009). 
For children, the dosing of prednisolone/prednisone is typically 1-2 mg/kg body weight divided 
into 1-2 doses daily for 3-5 days. 
The doubling of ICS, either by using a Budesonide or Fluticasone propionate inhaler, based on 
equipotency of the corticosteroids, or by using the subject’s own background medication, should 
only be used under the supervision of the investigator or designee. Doubling of ICS is not 
permitted for subjects on high dose ICS. 
Rhinoconjunctivitis rescue medication  
 
During the trial, subjects may experience allergy symptoms that require additional treatment. 
Rescue medication for AR or conjunctivitis will be provided by ALK to subjects at visit 2 as pre-
defined, open-labelled rescue medication and must be used in addition to the IMP to which the 
subjects have been randomised. 
For the rhinitis symptoms the subject will be provided with: 
• 
Oral antihistamine tablets (Desloratadine tablets, 5 mg)  
• 
Oral antihistamine solution (Desloratadine, oral solution, 0.5 mg/ml)  
• 
Nasal corticosteroid spray (Mometasone furoate 50 µg/dose) 
For the conjunctivitis symptoms the subject will be provided with: 
• 
Antihistamine eye drops (Azelastine 0.5 mg/ml) 
The rhinitis and conjunctivitis rescue medication provided to the subject should be used 
according to the product's labelling (e.g. SmPC or USPI). The dosage instructions are described 
in Table 5. 

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investigational use”. For further details, please see the Rescue medication product 
information document. 
Products which are not commercially available in the same form in US as in EU (i.e. 
Prednisolone and Budesonide inhaler) will be sourced as commercially available in US to be 
used by US subjects only without additional labelling. 
Rescue medication supplied by ALK will be dispensed together with product information leaflets 
in local language. 
Packaging and labelling will be outsourced.  
8.5 
Handling and storage 
The trial products provided by ALK (IMP, asthma and rhinoconjunctivitis rescue medication and 
SPT) are to be used only for this trial and not for any other purpose. 
IMP, asthma and rhinoconjunctivitis rescue medication and SPT must be stored in a secure, 
limited-access location separately from normal clinic stocks and according to label 
specifications. IMP and rescue medication returned by the subject must be stored separately 
from other medication, e.g. unused IMP that has not yet been dispensed. 
Site storage conditions for IMP, asthma and rhinoconjunctivitis rescue medication and SPT 
must be monitored by the site staff for adherence to label specifications and reviewed by the 
CRA during monitoring visits. Any temperature deviation must be reported to ALK immediately 
according to the instruction. 
Monitoring must be done using a calibrated, stationary and continuously recording system. As a 
minimum a calibrated min/max thermometer is required. 
8.6 
IMP and rescue medication accountability 
The investigator or appropriate delegated staff must maintain records of the IMP and asthma 
and rhinoconjunctivitis rescue medication delivered to the trial site from ALK. The site must 
maintain records of: 
• 
Inventory at the site 
• 
Dispensing to each subject 
• 
Return by each subject to site (unused, partly used and used e.g. empty blister) 
• 
Return by site to ALK 
These records must include dates, quantities, batch/serial numbers, expiry dates and the IMP 
unique code numbers assigned to the trial 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 asthma and rhinoconjunctivitis rescue medication received from 
ALK. 
Full drug accountability will be performed for the IMP by tablet count. Full drug accountability 
will not be performed on asthma and rhinoconjunctivitis rescue medication. 
All IMP and asthma and rhinoconjunctivitis rescue medication accountability logs and records 
will be verified by the CRA during the monitoring visits in accordance with the monitoring plan. 

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At the final visit, the investigator should return all unused and partly used IMP and asthma and 
rhinoconjunctivitis rescue medication and 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 asthma and rhinoconjunctivitis rescue medication without written agreement with ALK. 
8.7 
Reporting of technical complaints 
Any technical complaint related to the trial products provided by ALK (IMP, asthma and 
rhinoconjunctivitis rescue medication and SPT) must be reported to ALK. The information must 
be accompanied by samples or a picture of the item. 
9 
Treatment 
9.1 
Posology and method of administration 
The IMP-tablet should be taken with dry fingers from the blister unit immediately after opening 
the blister and placed under the tongue, where it will disperse. Swallowing should be avoided 
for approximately 1 minute. 
Food and beverages should not be taken for 5 minutes after intake of IMP. The daily dose of 
IMP is 1 SLIT-tablet, which should preferably be taken in the morning. 
9.2 
 Precautions in relation to first dosing 
First intake of IMP should be at the clinic with a minimum of 30 minutes observation period after 
the intake. For the recording of onset and duration of solicited AEs that occur on Day 1 (visit 3), 
the subject should remain in the clinic for 60 minutes after IMP intake. 
Prior to IMP intake an oropharyngeal examination should be performed. This should be 
repeated 60 minutes after IMP intake.  
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 until the oral cavity has healed. 
 
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.  
For subjects with a severe asthma exacerbation within the last 30 days prior to randomisation 
treatment initiation should be postponed by minimum 30 days from the time of the severe 
asthma exacerbation (start of OCS treatment or first day of hospitalisation). The treatment 
initiation can be postponed maximum 3 times. 
Only subjects meeting all inclusion criteria listed in Section 4.1 and none of the exclusion criteria 
in Section 4.2 are considered eligible for randomisation and first dosing. 
9.3 
Rescue medication for severe allergic reactions   
In countries where it is a regulatory requirement, the subject/parent/caregiver will be provided 
with two adrenaline/epinephrine auto-injectors at the randomisation visit (visit 2). The 

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investigator will instruct the subject/parent/caregiver on how to use the adrenaline/epinephrine 
auto-injectors and to have it available when tablet is administered.  
Adrenaline/epinephrine auto-injectors are intended for immediate self-administration for an 
anaphylactic reaction, including symptoms/signs of upper airway obstruction. Anaphylaxis is 
likely when multiple organ systems are adversely affected following exposure to an allergen. A 
list of symptoms that may be present during anaphylaxis include flushing, apprehension, 
syncope, tachycardia, thread or unobtainable pulse associated with a fall in BP, vomiting, 
diarrhea and abdominal cramps, wheezing, dyspnea due to laryngeal spasm, lower airway 
obstruction, pruritus, rashes (such as urticaria), or angioedema. Self-injectable 
adrenaline/epinephrine 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/epinephrine auto-injector must immediately call the local emergency number. 
At visit 2, the subject/parent/caregiver will also be provided with educational information 
regarding symptoms of anaphylaxis and treatment, including a written Local and Systemic 
Allergic Reaction Emergency Plan  (Epstein et al. 2017). The investigator will provide written 
instructions and explain to the subject/parent/caregiver , when to administer the 
adrenaline/epinephrine auto-injectors. The investigator will complete a Local and Systemic 
Allergic Reaction Emergency Plan for each subject, provide a copy to the 
subject/parent/caregiver, and keep a copy for the site’s records (Section 11.20). 
In the event that the adrenaline/epinephrine auto-injector is used, the subject/parent/caregiver 
must immediately call the local emergency number. The subject must inform the investigator 
and an unscheduled visit should be arranged to further evaluate the subject. The investigator 
must report the event to the Sponsor within 24 hours of first becoming aware of the use of an 
adrenaline/epinephrine auto-injector. The symptoms and/or circumstances that triggered the 
use of the adrenaline/epinephrine auto-injector must be clearly recorded on the eCRF. 
At each visit following the dispensing, the investigator or designee will verify that the subject has 
adrenaline/epinephrine auto-injectors and will review instructions for use. Unused 
adrenaline/epinephrine auto-injectors will be collected at visit 11. 
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 deciduous tooth, to 
allow healing of the oral cavity 
• 
Inflammatory conditions in the oral cavity 
• 
Upper airway viral infection 
• 
Other reasons if deemed necessary by the investigator 
Interruptions should be kept to a minimum. If IMP is interrupted for more than 7 days in a row, 
the subject should contact the investigator before restarting the treatment. 
If IMP treatment is permanently discontinued, the subject may be discontinued from the trial. 
ALK should be notified in case of IMP discontinuation due to an AE. 

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• 
Obtainment of informed consent 
• 
Evaluation of in- and exclusion criteria 
• 
Physical examination 
• 
Assessment of AEs/serious adverse events (SAEs) 
• 
Assessment of FEV1 and laboratory results 
• 
Decision to break the randomisation code for individual subjects 
11.1 Informed consent 
All parents/caregivers 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. 
If the minor can understand the risks and benefits of the trial, he/she should also be informed 
and, if capable, provide written assent. Assent should be obtained according to national 
requirements. Subjects turning 18 years during the trial must sign the adult informed consent 
form. 
It is the responsibility of the principal investigator or a sub-investigator to obtain the written 
informed consent/assent from the parents/caregivers and subject, respectively. 
The investigator must explain the nature of the trial, its purpose, the procedures 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 the 
parent/caregiver and subject can be delegated to a nurse, but the investigator must be available 
for questions and both the nurse and the investigator must sign the consent form to document 
this. 
The parent/caregiver and subject must be given sufficient time to consider the trial before 
deciding whether to participate. Each subject must be informed that participation in the trial is 
voluntary, that he/she may withdraw from the trial at any time and that withdrawal of 
consent/assent will not affect his/her subsequent medical treatment or relationship with the 
treating physician. 
The informed consent/assent form must be signed and dated before the subject enters the trial 
(i.e. before any trial related activity). The investigator must give a copy of the signed informed 
consent/assent to the parent/caregiver and subject. The investigator should keep the original. 
If information becomes available that may be relevant to the subject’s willingness to continued 
participation in the trial the subject information sheet will be updated by ALK and approved by 
an IEC/IRB and the Competent authorities. The parent/caregiver and subject must be informed 
in a timely manner about the updated subject information sheet and written informed 
consent/assent must be obtained. 
11.2 Consent for biobank blood and urine samples 
When the subject/parent/caregiver is asked to consent to the participation in the trial, children 
with a body weight over 20 kg will be asked specifically if they will donate 3 blood samples of 5 
ml each and 3 urine samples of 5 ml each. All samples will be stored in the ALK Research 

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Biobank. The answer to this question will be recorded on the consent form for retention of blood 
and urine samples for future research, as well as in the eCRF. The samples will be taken at 
visits 3, 7 and 11. The subject/parent/caregiver cannot consent to sample donation after visit 3 
as the first sample has to be taken before first IMP intake. If sampling and storage of these 
blood and urine samples are not accepted by the subject/parent/caregiver, the samples must 
not be drawn. Subjects can participate in the trial without giving consent to donating biobank 
samples.  
11.3 Consent for collection of blood samples for pharmacogenetic testing 
When the subject/parent/caregiver is asked to consent/assent to the participation in the trial, 
children with a body weight over 20 kg will be asked specifically if they can accept sampling for 
pharmacogenetic tests and storage of a DNA and RNA sample. The answer to this question will 
be recorded on the consent form for retention of samples for future pharmacogenetic testing, as 
well as in the eCRF. The sample volume will be 2.5 ml and the samples will be taken at visit 3 
and 11. The subject/parent/caregiver cannot consent to sample donation after visit 3 as the first 
sample has to be taken before first IMP intake. Collection of pharmacogenetic samples is not 
necessary for participation in the trial. If pharmacogenetic sampling and storage is not accepted 
by the subject/parent/caregiver, the samples must not be drawn.  
11.4 Demographics 
The following data will be recorded: 
• 
Month and year of birth 
• 
Race and ethnic origin 
• 
Sex 
11.5 Medical history 
The relevant medical history, incl. diseases present at trial entry 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, atopic dermatitis and food allergy.  
Information on exposure to cigarette smoke will be collected. 
11.6 Concomitant medication 
The subjects’ use of all concomitant medication including rhinoconjunctivitis and asthma 
medication must be recorded. Standard information about the medication will be collected 
including name of medication, dose, administration route and treatment period. 
Medication not provided as a part of this trial should be kept to a minimum during the trial. 
However, if considered necessary for the subject’s well-being, concomitant medication may be 
given at the discretion of the investigator according to the local standard of care. 
At each visit 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. 

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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 Height and weight 
The subject’s body height and weight will be recorded as noted on the Flow chart. 
11.8 Vital signs 
Vital signs will include measurement of BP and heart rate in a seated position (after ≥ 5 minutes 
of seated inactivity). 
11.9 Lung function 
The assessment of the lung function will include measurements of forced vital capacity (FVC), 
and FVC percent predicted, FEV1 and FEV1 percent predicted, for all subjects. 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. 
The predicted FVC and FEV1 will be based on the Quanjer equation (Quanjer et al. 1995). 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 0.88 = FEV1 predicted adjusted for race. 
Spirometry should be performed in accordance with guidelines established by the American 
Thoracic Society/European Respiratory Society (Reddel et al. 2009). The % of predicted FEV1 
will be calculated in the eCRF. Lung function will be measured with subjects on background 
treatment, though following a 6-hour washout of SABA.  
11.10 Physical examination 
The physical examination should be performed by a physician and should be based on the 
following body systems see Table 7. 

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Urinalysis: 
Protein, pH, glucose, ketone, leukocytes, urobilinogen, bilirubin, haemoglobin nitrite and specific 
gravity. 
IgE: 
To confirm the diagnosis of allergy against HDM, blood samples will be drawn at the screening 
visit for determination of specific IgE against D. pteronyssinus and D. farinae. Additionally, the 
blood samples will be analysed for 
 and specific IgE against Blattella germanica 
(cochroach) and Cladosporium herbarum (mold). 
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. 
Immunology: 
To assess the immunological response of the treatment, blood samples will be drawn for 
determination of antigen-specific antibodies (e.g. IgE and IgG4), 
, and other 
immunological parameters. At each time point, 5 mL blood will be drawn in silicone-free serum 
gel tubes. The samples will be analysed by the Research Department at ALK. 
 
Biobank blood sample 
This blood sample will only be drawn if the subject has a body weight of more than 20 kg and 
consents to long term storage of an immunology sample. If blood sampling for the biobank is 
accepted, three 5 mL blood samples will be drawn. The blood sample will be drawn at visits 3, 7 
and 11 where blood sampling already is planned. The subject will consequently only donate  
extra blood, no additional venepuncture is required. 
The purpose of the biobank blood samples is to continue the research into the immunological 
processes involved in the observed clinical effects in subjects treated with allergy 
immunotherapy, 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 to ensure optimal treatment for future subjects with allergy. The 
surrogate markers may be antibody levels, cytokine profiles, cell surface markers, specific set of 
proteins or metabolites, combinations hereof, etc. Although the exploratory biomarker analyses 
will help to increase our understanding, the efforts described in this protocol are strictly research 
based. Thus, as the complex interactions between allergy immunotherapy, rhinoconjunctivitis 
and asthma are currently not characterised to a level that translates to a meaningful clinical 
advantage, individual results from the exploratory biomarker analyses will not be given to the 
subjects. For the same reasons, individual results will not be added to the subjects’ medical 
records. 
The subjects will have no direct benefit from the exploratory biomarker analyses. 
Blood sample for pharmacogenetics 
This blood sample will only be drawn if the subject has a body weight of more than 20 kg and 
consents to long term storage of a DNA sample.  
DNA and RNA material will be extracted from the blood sample at a central laboratory selected 
by ALK. If pharmacogenetic sampling is accepted, two 2.5 mL blood samples will be drawn. The 
blood sample will be drawn at visits 3 and 11 where blood sampling already is planned. The 

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subject will consequently only donate an extra blood sample, no additional venepuncture is 
required. 
The DNA and RNA samples collected in the current trial will be used to investigate various 
genetic causes for how subjects may respond to the treatment as well as the impact the 
treatment may have on the epigenetic profile of the subjects. The DNA and RNA samples will 
be stored to provide a resource for future studies conducted by ALK focused on the 
investigation of how genes can affect drug absorption, distribution and removal from the body, 
and drug action in the body or vice versa, how drugs can affect gene expression profiles. 
Studies may include analyses for identifying for instance genomic markers of atopic diseases, 
efficacy of allergy treatment, AEs, or other genomic markers relevant for the atopic disease and 
treatment of allergy. Pharmacogenetic results may be compared to pharmacodynamic results or 
clinical outcomes. Any significant pharmacogenetic relationships to outcome will require 
validation in future clinical trials. 
Since the complex interactions between allergy immunotherapy, rhinoconjunctivitis and asthma 
are currently not characterised to a level that translates to a meaningful clinical advantage, 
individual results from the pharmacogenetic analyses will not be given to the subjects. For the 
same reasons, individual results will not be added to the subjects’ medical records. 
The subjects will have no direct benefit from the exploratory biomarker analyses. 
If ALK publishes results obtained from genotyping or biomarker studies based on 
pharmacogenetic samples obtained in the trial, the results will be published in such a way that it 
cannot be tied to an individual subject. 
11.15 Adverse event assessment  
The investigator will question the subject about AEs since the last visit (as applicable), and will 
record the information on the eCRF (see Section 12 for instructions on assessment and 
reporting of (S)AEs and pregnancies to the sponsor). 
The eDiary will be used to capture information on 15 specific symptoms identified as local 
effects of sublingual immunotherapy (Section 11.21) on a daily basis from the subject for the 
first 28 days of treatment (Passalacqua et al. 2013). The eDiary is to be completed by the 
subject/parent/caregiver. Subjects and/or their parent/caregiver will be trained by the 
investigator or designee at visit 3 on the proper method to complete the eDiary. The reported 
symptoms will be evaluated by investigator and reported in the eCRF as solicited AEs. 
The solicited AEs that occur on Day 1 (visit 3) within 60 minutes of IMP intake, including the 
time of AE start and AE stop, will be monitored by site personnel, recorded in source 
documents, and entered into the eCRF. 
11.16 Asthma exacerbation assessment 
An Asthma Action Plan (Section 11.19) will be given to the subjects and parents/caregivers to 
provide guidance to effectively manage the subject's symptoms, as recommended by clinical 
practice guidelines. Subjects will be trained in their Asthma Action Plan by the investigator or 
designee. 
According to the Asthma Action Plan subjects must contact the investigator when asthma 
symptoms increase or in cases with reduction in lung function. The investigator or designee will 
fill in the appropriate treatment for the subjects in the Asthma Action Plan. 

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Subjects will continue with a constant dose of low dose ICS plus LABA or medium/high dose 
ICS with or without LABA throughout the trial.  
If a subject presents with worsening of asthma symptoms, investigator or designee should 
always evaluate if the subject requires treatment at emergency room. If emergency room visit is 
not required initial treatment can be either: 
• Doubling of ICS dose compared to background treatment for 2 weeks, or 
• Systemic corticosteroids for treatment of asthma symptoms for at least 3 days  
For the doubling of ICS dose a separate inhaler with ICS will be provided by ALK as part of the 
asthma rescue medication. Subjects may also double their ICS dose by using their background 
medication. Subjects that receive high dose ICS as background treatment are not allowed to 
double the dose of ICS. Please note that local regulations and SmPCs or USPI must be 
followed. In case of an asthma exacerbation requiring systemic corticosteroids, the subjects 
should be treated with OCS in the form of Prednisolone/Prednisone tablets. Dosing regimen 
should follow recommendations by GINA guideline (GINA Executive Committee 2017), NIH 
guidelines (National Heart Lung and Blood Institute 2007) or national guidelines (Reddel et 
al. 2009). See Section 8.3. 
The use of LTRA is permitted for continued use only but will not be provided by ALK. 
If a subject has 2 severe asthma exacerbations within 12 consecutive months or is hospitalised 
due to asthma requiring treatment with systemic corticosteroids the subject must be 
discontinued from the IMP treatment. 
Each severe asthma exacerbation must be separated by >7 days from the discontinuation of 
OCS to be considered an individual event (Lanier et al. 2009).  
Each clinically relevant asthma exacerbation must be separated by >7 days from the 
discontinuation of additional ICS or OCS to be considered an individual event. 
All clinically relevant asthma exacerbations and severe asthma exacerbations (as defined in 
Table of definitions on page 10) must be reported in the eCRF within 24 hours.          
11.17 Assessment of symptoms 
Rhinoconjunctivitis and asthma symptoms will be recorded in the eDiary by the subject with 
assistance from his/her caregiver at specified periods during the trial. A video with information 
on the rating will be available for the subjects. 
A total of 10 symptoms; 6 rhinitis and/or conjunctivitis symptoms and 4 asthma symptoms will 
be measured on a scale from no symptoms to severe symptoms (for details, please see Table 
10 and Table 11). 
 
The subject should be instructed in the symptom score using the following definitions: 
 

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• 
Cough, wheeze, chest tightness or shortness of breath, or 
• 
Waking at night due to asthma, or 
• 
Can do some, but not all, usual activities, or 
• 
Increased need for reliever medication, or 
• 
Peak flow 50-79% of personal best 
The investigator or designee will fill in the appropriate treatment for the subjects in the Asthma 
Action Plan.  
The subject is instructed to call an ambulance while taking reliever medication at regular 
intervals as pre-specified by the investigator for serious situations when the subjects experience 
that: 
• 
Symptoms worsens very quickly 
• 
Wheeze, chest tightness or shortness of breath continue after taking reliever medication, 
or 
• 
There is severe shortness of breath, inability to speak comfortably, blueness of lips, or 
• 
Peak flow is below 50% of personal best 
11.20 Anaphylaxis Emergency Action Plan 
The subject/parent/caregiver will be provided with educational information regarding symptoms 
of anaphylaxis and treatment, including a written Local and Systemic Allergic Reaction 
Emergency Plan (Epstein et al. 2017). The Local and Systemic Allergic Reaction Emergency 
Plan will detail the mild to moderate local reactions that include: 
• 
Mouth: bothersome itching, and/or mild swelling of lips and/or tongue 
• 
Throat: bothersome itching, irritation, and/or mild tightness 
• 
Ear: bothersome itching 
• 
Gastrointestinal: mild abdominal pain, nausea, and/or cramps 
The Local and Systemic Allergic Reaction Emergency Plan specifies that these symptoms may 
be treated with an anti-histamine, if treatment is required, where the dose is pre-specified by the 
investigator on the plan. 
Severe reactions are defined as: 
• 
Local reaction with swelling in the mouth/throat causing hoarseness and/or throat closing 
• 
Systemic reactions such as  
o Skin: hives all over body and/or redness all over body 
o Lung: shortness of breath, cough, and/or wheezing 
o Heart: weak pulse, dizziness, and/or passing out 
o Gastrointestinal: severe abdominal pain, vomiting, diarrhea, and/or cramping 
Severe reactions should be treated in accordance with the Local and Systemic Allergic Reaction 
Emergency Plan as instructed by the investigator. 

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11.21 Solicited Adverse Events 
The eDiary will be used to capture 15 specific symptoms, identified as local side effects of 
sublingual immunotherapy (Passalacqua et al. 2013): 
• 
Food tastes different 
• 
Mouth ulcer 
• 
Swelling in the back of the mouth 
• 
Itching in the mouth 
• 
Itching in the ear 
• 
Swelling of the lips 
• 
Swelling of the tongue 
• 
Tongue pain 
• 
Tongue ulcer 
• 
Throat irritation/tickle 
• 
Throat swelling 
• 
Stomach pain 
• 
Nausea (feel like throwing up) 
• 
Diarrhea 
• 
Vomiting 
If the subject answers “yes” to any of the symptoms, the subject will be asked if any medication 
was used to treat the symptom. 
These local side effects will be collected by a daily eDiary during the first 28 days of treatment. 
The eDiary is to be completed by the subject/parent/caregiver. Subjects will be trained by the 
investigator or designee at visit 3 in the proper way to complete the eDiary. The reported 
symptoms will be evaluated and reported in the eCRF as solicited AEs at the discretion of the 
investigator. 
The duration in minutes of the solicited AEs occurring on Day 1 will also be assessed. The AE 
start and stop time of solicited AEs that occur on Day 1 within 60 minutes of IMP intake, will be 
monitored by site personnel, recorded in source documents, and entered into the eCRF. After 
Day 1, standard AE reporting conventions will be utilised. 
Summary statistics for adverse event severity of the solicited AEs will be performed using the 
World Allergy Organization (WAO) grading system for SLIT local adverse events.  
A review of the severity grading by the WAO criteria and severity grading as determined by the 
investigator’s review of prespecified symptoms with their subjects will be conducted. For the 
purpose of the analysis, a modified WAO severity grading will be applied as follows: 
• 
Mild (Grade 1) - No symptomatic treatment required and no discontinuation of SLIT 
because of local side effects 
• 
Moderate (Grade 2) - Requires symptomatic treatment and no discontinuation of SLIT 
because of local side effects 

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• 
Severe (Grade 3) - Grade 2 and SLIT discontinued because of local side effects 
 
11.22 Eosinophilic oesophagitis 
At each visit, subjects/parents/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 GI symptoms 
If a subject presents with any of the above, the investigator should consider referring the subject 
to a gastroenterologist for evaluation. 
11.23 Subject 
 reported outcomes 
A number of outcomes will be reported by the subjects during the trial. To minimise the burden 
to the subjects, the subject reported outcomes have been distributed to alternating visits 
whenever possible. The following questionnaires will be completed by the subject, by the 
caregiver or via an interview by the trial staff during the visits at the site: 
• 
eDiary assessments  
• 
ACQ 
o ACQ-IA (subjects aged 5 to 10 years) Interviewer administered 
o ACQ (subjects aged 11 years and above) Self-completed by the subjects 
• 
 
o 
 
o 
 
• 
 
o 
 
• 
 
o 
 
• 
 
 
o 
 

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• 
Global evaluation of allergic asthma  
o Interviewer administered 
• 
Global evaluation of AR  
o Interviewer administered 
 
11.23.1 eDiary assessments 
During the trial, the subjects and/or their parent/caregiver will complete an eDiary. The eDiary is 
a hand-held electronic device that will be issued to the subjects before the start of the baseline 
period (period 2). 
The following items will be outlined in the eDiary at pre-specified intervals during the trial: 
• 
Asthma symptoms and VAS  
o Nocturnal awakenings due to asthma requiring SABA 
• 
Use of asthma rescue medication  
• 
Rhinoconjunctivitis symptoms and VAS 
• 
Use of rhinoconjunctivitis medication 
• 
Specific symptoms identified as local effect of sublingual immunotherapy, see Section 
12.3, for capturing solicited AEs 
The eDiary is to be completed by the subject/parent/caregiver for 21 days between baseline 
(V2) and randomisation visit (V3). After randomisation, the eDiary is to be completed for 2 
weeks before visit 5, 6, 7, 8, 9, 10 and 11. Finally, the eDiary is to be completed for 4 weeks 
following randomisation for capturing specific symptoms identified as local effect of sublingual 
immunotherapy. 
 
11.23.2 Asthma quality of life questionnaire 
The ACQ will be completed by all subjects during the trial at most regular visits and at all 
unscheduled visits. Subjects aged ≥11 years will self-complete the questionnaire when possible. 
An interviewer administered version will be used to subjects aged 5-10 years. The ACQ-IA will 
be used for all subjects aged 5 to 10 years of age although it is only validated for children from 6 
years of age. However, since this is a two year trial, all 5 year old children will be 7 years of age 
at the end of the trial. 
 
ACQ-IA 
The ACQ-IA questionnaire will be completed by subjects aged 5 to 10 years during the trial. 
Questions will be administered by a trained interviewer. The questionnaire contains five scoring 
symptoms, one question about SABA medication use and another about FEV1, the latter being 
completed by the clinic staff. Subjects are asked to recall their experiences during the previous 
7 days and respond to each question using a 7-point scale. The items are equally weighted and 
the ACQ-IA score is the mean of the 7 items and therefore between 0 (well controlled) and 6 
(extremely poorly controlled). 
Derivation of answers and the scales used has been provided in Appendix 5. 

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12 Adverse events 
Information about AEs, whether reported by the subject, identified 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 an 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 procedures and conduct of the trial. 
12.1 Definitions 
Adverse event 
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), symptom, or disease, whether or not considered related to the trial product. 
 
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 event 
A 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 inpatient hospitalisation, regardless of duration, or prolongation of existing 
hospitalisation 
• 
Results in persistent or significant disability or incapacity 
• 
Is a congenital anomaly or birth defect 
• 
Is judged to be medically important (this refers to an event that may not be immediately 
life-threatening or result in death or hospitalisation, but may jeopardise the subject or 
may require intervention to prevent one of the other outcomes listed above) 

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Events of special interest 
Selected AEs (non-serious or serious) will be considered events of special interest (ESI). ESIs 
are events that are considered critical for the evaluation of the product’s safety profile and/or for 
which additional data will be collected. Events of special interest for this trial are: 
• 
Severe asthma exacerbations and clinically relevant asthma exacerbations (as defined 
in Table of definitions) 
• 
Anaphylactic reactions, anaphylaxis60 and/or systemic allergic reactions 
• 
Events treated with adrenaline/epinephrine 
• 
Severe local swelling or oedema of the mouth and/or throat 
• 
Eosinophilic oesophagitis 
Severe and clinically relevant asthma exacerbations reported during the trial are expected as a 
result of subjects’ background disease and will be collected in the eCRF as ESIs throughout the 
trial in order to get detailed information related to the primary efficacy endpoint. Severe and 
clinically relevant asthma exacerbations will not be considered a safety endpoint unless an 
exacerbation fulfils the criteria for an SAE. Severe and clinically relevant asthma exacerbations 
reported during periods 3 and 4 will be summarised as part of the efficacy results in the 
integrated clinical trial report (ICTR). 
Medication errors, including overdose, abuse and misuse of the IMP 
The definition of an AE also covers medication errors and use of the IMP outside what is 
foreseen in the protocol, including misuse and abuse of the product. If doses higher than the 
recommended dose are taken, whether intentionally or unintentionally, the risk of AEs may 
increase. This includes the risk of systemic allergic reactions or severe local reactions. 
• 
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 
 
60 The definition of anaphylaxis (Sampson 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, togue, or uvula) AND either 
respiratory compromise (e.g., dyspnoea, wheeze-bronchospasm, stridor, reduced 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. 

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• 
Abuse: Persistent or sporadic, intentional excessive use which is accompanied by 
harmful physical or psychological effects 
• 
Misuse: Intentional and inappropriate use 
12.2 Assessments 
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 
Causal relationship to IMP 
The causal relationship between an (S)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 related to IMP, the most likely alternative aetiology should be 
provided. 
Outcome 
The outcome of an (S)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 adverse events 
At each contact with the trial site, the subject must be asked about AEs in an objective manner 
such as “Have you experienced any problems since the last contact?"  

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AEs must be recorded on the AE form in the eCRF. One single AE form must be used per AE 
from start to resolution. For SAEs and ESIs, specific SAE and ESI data fields in the eCRF must 
also be filled in. 
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. Once the AE no longer reccurs 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). 
Solicited Adverse Events 
The eDiary will be used to capture 15 specific symptoms, identified as local side effects of 
sublingual immunotherapy (Passalacqua et al. 2013). These local side effects will be collected 
on a daily basis by the subject during the first 28 days of treatment (Section 11.21). The eDiary 
is to be completed by the subject/parent/caregiver. Subjects or their parent/caregiver will be 
trained by the investigator or designee at visit 3 on the proper method to complete the eDiary. 
The reported symptoms will be evaluated by investigator and reported in the eCRF as AEs on 
the AE form in the eCRF. 
The duration in minutes of the solicited AEs occurring on Day 1 (visit 3) will be collected. The 
AE start and stop time of solicited AEs that occur on Day 1 within 60 minutes of IMP intake, will 
be monitored by site personnel, recorded in source documents, and entered into the eCRF. 
After Day 1, standard AE reporting conventions will be utilised, as described above. For more 
details on solicited AEs, please see Section 11.21. 
Eosinophilic Oesophagitis 
During the trial, subjects will be monitored for emerging symptoms of eosinophilic oesophagitis 
at the scheduled visits. Subjects will be referred to a gastroenterologist based on a clinical 
suspicion of 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 GI symptoms 

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Reporting of adverse events 
The investigator must report all SAE and ESI information (initial as well as follow-up) to ALK 
within 24 hours after obtaining knowledge of the information. Non-serious AEs should be 
reported as soon as possible. 
Adverse events must be recorded in the eCRF. The initial eCRF report must contain as much 
information as possible. SAEs and ESIs will automatically be sent to ALK via the eCRF system. 
In case the eCRF system is unavailable during the 24 hour reporting timeline, SAEs and ESIs 
(including relevant eCRF pages e.g. demography, medical history, concomitant medication) 
must be reported by email or fax to ALK. 
In case of additional supporting documents (e.g. discharge letter, laboratory pages, 
electrocardiogram), these must be sent to ALK via fax (please state trial ID, subject ID and site 
ID on the documents). All subject personal identifiers must be redacted on the supporting 
documents. 
Email address: 
  
Fax number: 
 
Emergency phone: 
 
 
The assessment of listedness is performed by ALK according to the current version of the 
reference safety information (i.e. Investigator’s Brochure). 
ALK will inform the regulatory authorities and IECs/IRBs in accordance with local requirements 
in force and the ICH guidelines for Good Clinical Practice (GCP) (ICH 1996). 
Follow-up on adverse events 
SAEs must be followed up until the outcome of the event is “recovered”, “recovered with 
sequelae” or “fatal” and until all queries have been resolved.  
Ongoing SAEs can be closed with the term “not recovered” for chronic diseases (as evaluated 
upon medical evaluation by the investigator or the sponsor). 
The investigator must respond to SAE follow-up requests from ALK without delay and no later 
than 14 days after receiving the request. 
The investigator must ensure that the worst case severity and seriousness of an event is kept 
throughout the trial. 
Non-serious AEs must be followed up until resolution or until the last follow-up phone contact. 
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 on the medical history 
page. Significant laboratory events found at the following visits, and which meet the definition of 
an AE, must be recorded on an AE page in the eCRF. 
A significant laboratory event should be recorded as an AE if one of the following is applicable: 

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• 
It is abnormal and clinically significant (medical judgement by investigator) 
• 
It leads to a change or discontinuation of treatment 
• 
It fulfils a seriousness criteria 
It indicates a potential safety risk to the subject 
The following constellation of laboratory values should by definition be considered an AE and 
reported accordingly: 
• 
An elevated AST or ALT lab value that is greater than or equal to 3 times the upper limit 
of normal and an elevated total bilirubin lab value that is greater than or equal to 2 times 
the upper limit of normal and, at the same time an alkaline phosphatase lab value that is 
less than 2 times the upper limit of normal, as determined by way of protocol-specified 
laboratory testing or unscheduled laboratory testing. 
The purpose of the criteria is to specify a threshold of abnormal hepatic tests that may 
require an additional evaluation for an underlying etiology.  
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 should be 
based on actual IMP exposure and not on e.g. drug accountability procedures. For overdose 
cases, the descriptive terms accidental or intentional overdose should be used. If an event is 
classified as an SAE, it must be reported as such. 
Reporting of pregnancies 
The investigator must report information on pregnancy and pregnancy follow-up information 
within 14 calendar days of obtaining the information, using the pregnancy form. For further 
information see Section 12.5. 
Reporting of SAE and pregnancies after last follow-up phone contact 
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. 
12.4 Data monitoring committee  
To supplement the routine trial monitoring performed by the sponsor, an independent DMC will 
be established. The DMC is an independent, external committee composed of members whose 
expertise covers relevant specialities. The members of the DMC must not be involved with the 
trial in any other way (e.g., they cannot be trial investigators) and must have no competing 
interests that could affect their roles with respect to the trial. 
Specific details regarding composition, responsibilities, and governance, including the roles and 
responsibilities of the various members and the sponsor; meeting facilitation; the trial 
governance structure; and requirements for and proper documentation of DMC reports, 

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minutes, and recommendations will be described in a separate charter that is reviewed and 
approved by the DMC. The DMC will monitor trial data at an appropriate frequency, as 
described in the detailed DMC charter. The DMC will make recommendations to the sponsor 
regarding appropriate actions to ensure both subject safety and the continued ethical integrity of 
the trial. 
12.5 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. 
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. 
13 Early termination of trial 
ALK reserves the right to terminate the trial under the following conditions: 
- 
Safety concerns 
- 
Recommendation by the DMC 
- 
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 independent ethics committee/institutional review boards 
(IEC/IRBs) and provide a detailed written explanation. The regulatory authorities should be 
informed according to national regulations. 
Early trial termination may be the result of any single criteria specified below: 
1. IMP-related death of an individual 
2. IMP-related anaphylactic shock in at least 2 subjects61 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).  
 
61 The criterion for 2 events is based on prior trial experience where it has been observed that events of severe anaphylactic 
reactions unrelated to IMP may occur in allergic subjects even with a temporal relationship to tablet administration. 
 

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Low systolic BP for children is defined as less than 70 mmHg + (2 x age) from 1 to 10 
years, and less than 90 mmHg for 11 to 17 years of age. 
3. Recommendation by the DMC 
a. The DMC will monitor the rate of clinically relevant asthma exacerbations during 
period 3 to be able to pause the trial for safety review should a substantial 
increase in the active treatment arm compared to placebo occur. A substantial 
increase in the rate of clinically relevant asthma exacerbations during period 3 
defined by the following two criteria: 
i. the rate of clinically relevant asthma exacerbations in the active treatment 
arm is at least 3 times higher than the expected background rate (≥3*1.4 
= ≥4.2 exacerbations/subject/year) AND 
ii. the rate of clinically relevant asthma exacerbations in the active treatment 
arm is at least 3 times higher than the rate observed in the placebo arm 
The DMC will monitor the rate of clinically relevant asthma exacerbations during period 3 
to be able to pause the trial for safety review should a substantial increase in the active 
treatment arm compared to placebo occur. 
IMP intake may only be resumed after the information has been presented to health authorities, 
and health authorities concur with continued IMP intake. In case of complete premature IMP 
discontinuation, participating investigators/subjects/parent/caregiver, the IRB/IEC, and the 
relevant health authorities will be promptly informed. 
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 and/or their parent/caregiver in how to fill 
in the eDiary.  
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 

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into the database will be coded using the World Health Organisation Drug Reference List (WHO 
Drug, 2016Q1 or higher). 
Medical history and AEs will be coded using Medical Dictionary for Regulatory Activities 
(MedDRA 20.0 or higher). 
14.2 eDiary 
Starting with the baseline phase (i.e. V2) an eDiary will be dispensed and diary data will be 
entered by the subject. Subjects and/or their parent/caregiver will be trained in the eDiary by the 
investigator. In addition, a video with information on the eDiary will be available for the subjects 
and their parent/caregiver.The eDiary data will be reviewed by the investigator.  
During the trial, diary data will be entered in an eDiary by the subject and/or their 
parent/caregiver and transferred to the vendor database on a daily basis. The 
investigator/designee should check subject compliance on an ongoing basis (weekly within the 
baseline period). If the subject has missed more than 2 days in a row or the total compliance for 
a period is less than 80% the investigator should contact the subject. 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 than the vendor database. 
Once all eDiary data has been collected, the diary database will be closed and transferred from 
the vendor to ALK. The investigator will also 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. Documentation of the data load from the eDiary vendor to ALK will 
be described in the data handling report. 
14.3 Query handling 
Query handling at the trial site will be performed according to the guidelines for the eCRF 
system. Queries are created by programmed validation checks according to an edit check 
specification. Queries will also be created based on manual data checks. 
All data changes/query decisions are created with an audit trail capturing the old information, 
the new information, identification of the user making the correction, the date the correction was 
made, and the reason for change. 
14.4 Laboratory data 
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 by email 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 trial 
the laboratory data will be provided electronically to data management at ALK. 
Immunological samples will be processed at ALK Research Laboratory and data will be 
provided electronically after database lock to data management. 
Documentation of receipt and QC of laboratory and immunological data will be provided in a 
data management report. 

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14.5 Database lock 
When the database has been declared to be complete and accurate, the database will be 
locked, access for CRAs and non-sponsor staff/persons will be revoked and data may be 
unblinded. 
If changes to trial data become necessary after database lock this must be performed according 
to the current ALK standard operating procedures (SOP). 
A data archive for the site subject data files 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. 
15 Statistical methods 
Statistical analyses will be carried out by ALK Biometrics Department. 
If nothing else is mentioned, all the statistical tests described in this section use a significance 
level of 5% and all tests and confidence intervals are two-sided. The null hypothesis is the 
hypothesis of no difference and the alternative to the null hypothesis is the hypothesis of a 
difference. 
Descriptive statistics for numerical variables includes summary tables displaying mean, SD, 
median, 5%-quantile, 25%-quantile, 75%-quantile, 95%-quantile, minimum and maximum. 
Descriptive statistics for categorical variables includes frequencies tables that display numbers 
and percentage. 
Before database lock, a separate statistical analysis plan (SAP) detailing the specifications 
given below will be prepared and agreed upon. 
Any changes in the statistical methods compared to the final SAP will be documented in the 
ICTR. Post-hoc analyses, if any, will be clearly marked. 
15.1 Sample size and power considerations 
The primary endpoint is the annualised rate of clinically relevant asthma exacerbations during 
the efficacy evaluation period (period 4). The rate of clinically relevant asthma exacerbations will 
be analysed using a negative binomial regression model. 
From (Lanier et al. 2009) the rate of clinically relevant asthma exacerbations is expected to be 
approximately 1.4 exacerbations per subject per year. Over a period of 24 weeks the number of 
clinically relevant asthma exacerbation in the placebo group were 0.64 per subject (~0.64*52/24 
=1.4 per subject per year). 
Power calculation are both performed based on the negative binomial distribution assuming 
overdispersion and based on the poisson distribution when assuming no overdispersion. 
Overdispersion means that some subjects will tend to have more exacerbations than others. 
The dispersion parameter in the negative binominal distribution is assumed to be k=0.7 (Pavord 
et al. 2012). When there is no overdispersion (k->0) the negative binominal distribution will 
become a poisson distribution. 
Table 13 displays the sample size calculations for different values of the treatment effect 
expressed as the reduction in exacerbation rates for active treatment compared to placebo 
(100%*(PLB-ACT/PLB)). The power is set to 90% and sample size calculations are performed 
using a close formula for the negative binomial regression model (Keene et al. 2007): 

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𝑁𝑁= ൜𝑧𝑧1−𝛽𝛽+ 𝑧𝑧1−𝛼𝛼2
⁄
log (𝜇𝜇1 𝜇𝜇2
⁄
) ൠ
2
× ൜𝜇𝜇1 + 𝜇𝜇2
𝜇𝜇1𝜇𝜇2
+ 2𝑘𝑘ൠ 
where N is the number of subject per treatment arm, 𝜇𝜇1 is the rate per subject in the given 
timeinterval for the placebo group, 𝜇𝜇2 is the rate per subject in the given timeinterval for the 
active group, 1 −𝛽𝛽 is the power, alpha is the level of significance and k is the dispersion 
parameter. 
 
Table 13 
Power calculation 
Power Alpha 
Time 
for efficacy 
assessment 
(weeks) 
Rate 
PLB 
 
 
 
Reduction (%) 
100%*(PLB-
ACT)/PLB) 
𝝁𝝁𝟏𝟏  𝝁𝝁𝟐𝟐 
k 
N per 
arm 
(NB*) 
N per 
arm 
(POIS) 
 
 
 
 
 
0.9 
0.05 
34 
 
 
 
 
1.4 
 
30% 
0.91 0.63 
 
 
 
 
0.7 
334 
219 
0.05 
52 
1.39 0.97 
259 
143 
0.05 
86 
2.29 1.61 
202 
87 
0.05 
34 
 
25% 
0.91 0.68 
501 
324 
0.05 
52 
1.39 1.04 
389 
212 
0.05 
86 
2.29 1.72 
306 
128 
0.05 
34 
 
20% 
0.91 0.73 
814 
519 
0.05 
52 
1.39 1.11 
635 
339 
0.05 
86 
2.29 1.83 
500 
205 
PLB: placebo, ACT: active, NB: negative binominal, POIS: poisson distribution. 
If assuming a drop-out rate of 30%, a power of at least 90% and an efficacy assessment period 
of 20 month (86 weeks), a sample size of approximately 300 (~205/0.7=293) subjects per arm 
should be sufficient to detect a difference in exacerbation rates of 20% when no overdispersion 
is present as shown in Table 13. In case of overdispersion defined by a dispersion parameter of 
k=0.7, a sample size of 300 (>202/0.7=288) subjects per arm would be sufficient to detect a 
difference in the exacerbation rates of 30%. 
15.2 Sample size reassessment 
15.2.1 First blinded sample size reassessment with data cuf off point 1 Feb 2020 
A blinded sample size reassessment (SSR) will be performed. In case of a potentially 
insufficiently powered trial with respect to the primary efficacy analysis of clinically relevant 
asthma exacerbations, the sample size will be increased accordingly from the planned 600 
subjects (=300 per treatment arm) up to a total maximum of 900 randomised subjects (=450 per 
treatment arm). 
The blinded SSR will be performed based on data from the approximately first 17 months of 
efficacy assessment period for cohort 1 and data from the approximately first 5 months of 

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efficacy assessment for cohort 2. For each subject the data cut off point for SSR will be the visit 
(including TCs) closest to but not before the 1st of February 2020.  
Blinded data will be used for estimating the total annual clinically relevant asthma exacerbation 
rate (𝜇𝜇̂𝑡𝑡𝑡𝑡𝑡𝑡𝑡𝑡𝑡𝑡) for both treatment groups, an overall overdispersion parameter (𝑘𝑘෠𝑡𝑡𝑡𝑡𝑡𝑡𝑡𝑡𝑡𝑡) and the 
overall drop-out rate. 𝜇𝜇̂𝑡𝑡𝑡𝑡𝑡𝑡𝑡𝑡𝑡𝑡 and 𝑘𝑘෠𝑡𝑡𝑡𝑡𝑡𝑡𝑡𝑡𝑡𝑡 will be estimated using a negative binominal regression 
model. Each subject will be included in the analysis with the time in years from start of period 4 
and until the date for the cut off point and with the number of cumulated clinically relevant 
asthma exacerbation with a start date within this period. For a subject who discontinues IMP 
prior to the cut off point all available data in period 4 until IMP discontinuation will be used.    
The drop-out rate prior to period 4 will be calculated as the number of subjects that have 
discontinued prior to period 4 divided by the number of randomised subjects.  
Cohort 1 will be used to calculate the average time for efficacy assessment for subjects that 
continue into period 4 according to the expression: 
𝜏𝜏̂𝑝𝑝4 =
∑
𝑡𝑡𝑡𝑡𝑡𝑡𝑡𝑡𝑖𝑖+ ൫𝑁𝑁𝑝𝑝4 −𝑁𝑁𝑑𝑑𝑑𝑑𝑑𝑑𝑑𝑑൯
𝑁𝑁𝑑𝑑𝑑𝑑𝑑𝑑𝑑𝑑
𝑖𝑖=1
∗608
𝑁𝑁𝑝𝑝4
 
where 𝜏𝜏̂𝑝𝑝4 is the average time in days with efficacy assessment of the primary endpoint for 
subjects who continue into period 4, 𝑡𝑡𝑡𝑡𝑡𝑡𝑡𝑡𝑖𝑖 is the time in days in period 4 before IMP 
discontinuation for subject i, 𝑁𝑁𝑑𝑑𝑑𝑑𝑑𝑑𝑑𝑑 is the number of IMP discontinuations in period 4 and 𝑁𝑁𝑝𝑝4 is 
the number of subjects who continue into period 4, and 608 days corresponds to the 20 months 
of efficacy assessment for subjects who complete the trial. The expression does not account for 
IMP discontinuations after the cut off point of approximately 17 months of efficacy assessment 
due to lack of data beyond this time point for sample size reassessment. Thus, it is assumed 
that no subjects will discontinue after approximately 17 months of efficacy assessment. 
Power/sample size estimation can be reassessed using a rewriting of the closed formula 
presented in Section 15.1. 
𝑁𝑁= ൜𝑧𝑧1−𝛽𝛽+ 𝑧𝑧1−𝛼𝛼2
⁄
log(𝜇𝜇1 𝜇𝜇2
⁄
) ൠ
2
× ൜𝜇𝜇1 + 𝜇𝜇2
𝜇𝜇1𝜇𝜇2
+ 2𝑘𝑘ൠ⇔ 
 
 
𝑁𝑁= ൜𝑧𝑧1−𝛽𝛽+ 𝑧𝑧1−𝛼𝛼2
⁄
𝑙𝑙𝑙𝑙𝑙𝑙 (1 𝑅𝑅𝑅𝑅
⁄
) ൠ
2
× ൞
(1 + 𝑅𝑅𝑅𝑅)2
2 ∗𝜇𝜇̂𝑡𝑡𝑡𝑡𝑡𝑡𝑡𝑡𝑡𝑡∗( 𝜏𝜏̂𝑝𝑝4
365) ∗𝑅𝑅𝑅𝑅
+ 2𝑘𝑘෠𝑡𝑡𝑡𝑡𝑡𝑡𝑡𝑡𝑡𝑡ൢ
൫1 −𝐷𝐷𝐷𝐷
෢൯
൘
 
 
where  
• 
1 −𝛽𝛽 is the power, 
• 
𝛼𝛼 is the level of significance,  
• 
Z is the quantile in the standard normal distribution, 
• 
Ratio of rates (RR) is the assumed treatment effect expressed as the RR of active 
treatment relative to placebo (𝑅𝑅𝑅𝑅= 𝜇𝜇2 𝜇𝜇1
⁄
), 
• 
𝜇𝜇̂𝑡𝑡𝑡𝑡𝑡𝑡𝑡𝑡𝑡𝑡 is the estimated total annual clinically relevant asthma exacerbation rate based on 
blinded data, 
• 
𝑘𝑘෠𝑡𝑡𝑡𝑡𝑡𝑡𝑡𝑡𝑡𝑡 is the estimated overall overdispersion parameter based on blinded data, 

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• 
𝐷𝐷𝐷𝐷
෢ is the estimated total drop-out rate prior to period 4 based on blinded data, 
• 
𝜏𝜏̂𝑝𝑝4 is the average time in days with efficacy assesment of the primary endpoint for all 
subjects who continue into period 4. 
The flow chart for the SSR is illustrated in Figure 2 below. 
A relative decrease in the clinically significant asthma exacerbation rate of 30% (RR=0.7) of 
active compared to placebo is assumed in the SSR. 
The upper limit for power is set to 85%. If the reassessed power for the planned 600 subjects is 
equal to or above 85%, no additional subjects will be randomized.   
The lower limit for power is set to 70%. If the maximum sample size limit of 900 subjects does 
not result in a power of 70% or greater, no additional subjects will be randomized. That is, the 
trial will continue with the planned 600 subjects. 
If the reassessed power for the planned 600 subjects is below 85% and the reassessed power 
for the maximum of 900 subjects is above 70%, additional subjects will be randomised until a 
power of 85% is achieved or until the maximum limit of 900 subjects is reached, see Figure 2. 
The data and trial are blinded for the statistician responsible for conducting the sample size 
reassessment. 
 
 

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the COVID-19 pandemic is roughly anticipated to be mid-March 2020 were the pandemic 
situation escalated in many of the countries included in the MT-11 trial. 
Table 14 Overview of MT-11 trial data to be included in an additional sample size reassessment 
with a cut of point for each subject closest to but not before 1st of March 2021 
Cohort Subjects 
randomised 
Subjects in 
period 4 
Start of period 4 Duration in month of period 4 
Total Prior to Covid-19 During Covid-19 
1* 
76 
72 
01 SEP 2018 
20 
17.5 
2.5 
2 
249 
244 
01 SEP 2019 
18 
6.5 
10.5 
3 
199 
- 
01 SEP 2020 
6 
0 
6 
*The overall start of the COVID-19 pandemic is roughly anticipated to be mid-March 2020. Site 613 in cohort 1 is excluded from 
SSR  
In order to keep the second SSR as prespecified as possible the only change compared to the 
first SSR is the date for the data cut off point. Otherwise the principle for the second SSR will be 
similar to the first prespecified SSR using the same formulas presented in section 15.2.1.   
15.3 Analysis data sets 
The total analysis set 
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 full analysis set  
The full analysis set (FAS) comprises all randomised subjects who received at least 1 dose of 
IMP. This analysis set will be the primary set for all efficacy analyses. The FAS will be used for 
all baseline/demography tables and efficacy tables and subject listings. 
The per protocol analysis set 
The per protocol (PP) analysis set comprises subjects without protocol deviations that may 
substantially affect the primary endpoint.  
Before data base lock, a list will be made that defines which subjects are excluded from the PP 
analysis set and the reason for exclusion. The criterias for exclusion will be based on procotol 
deviations such as: 
1. Violation of the inclusion/exclusion criteria 
2. Use of prohibited medication close to or during the efficacy evaluation period (period 4) 
3. IMP compliance in the entire trial. Subjects with a compliance below 80% are excluded 
from the PP analysis set 
4. Diary compliance. Subjects with less than 6 months of efficacy assessment in period 4 
are excluded from the PP analysis set 

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The PP analysis set will be used for a supportive analysis of the primary endpoint. 
The safety analysis set 
The safety analysis set (SAF) will be used for safety analyses. The SAF will include all 
randomised subjects who received at least 1 dose of IMP. Subjects will be included in the 
treatment group corresponding to the IMP they actually received during the trial. SAF will be 
used for safety tables and listings. 
15.4 Subject disposition 
A table of subject disposition by treatment group displaying number and percentage of subjects 
screened, randomised, included in FAS, with observation of the primary endpoint, included in 
PP, included in safety set, discontinued IMP, discontinued trial, by primary reason for IMP and 
trial discontinuation and who completed the trial will be presented. 
The overall IMP discontinuation will be displayed by a Kaplan-meier plot. Cumulative incidence 
plot will be used to show cause specific IMP discontinuation distribution. 
15.5 Baseline characteristics 
Demographic (including age, sex, race, ethnic origin, country/region, weight, height, and body 
mass index) and baseline characteristics (including baseline asthma medication, predicted 
FEV1, duration of HDM AR and HDM allergic asthma, sensitisation type, medical history) will be 
summarised by treatment group. 
15.6 Extent of exposure 
IMP accountability (number of daily doses used) is the difference between the number of daily 
doses dispensed and the number of daily doses returned. IMP compliance is the number of 
daily doses used divided by the duration of the treatment period in days and multiplied with 100. 
A treatment year is the number of daily doses divided by 365. Duration of IMP treatment period 
in days, IMP accountability, IMP compliance and treatment years will be displayed in summary 
tables by treatment groups. 
15.7 Concomitant therapy 
Concomitant medication and illness will be summarised by means of descriptive statistics. 

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15.8 Efficacy analyses 
Derivation of the primary efficacy endpoint 
Clinically relevant asthma exacerbation endpoint 
The source for deriving the clinically relevant asthma exacerbation endpoints is the AE form of 
the eCRF. On the AE form the clinically relevant asthma exacerbations are reported with an AE 
number, a start and a stop time/date and the criterion/criteria’s fulfilled for the event being 
categorised as a clinically relevant asthma exacerbation (section 2.5) .  
A clinically relevant asthma exacerbation must be separated by >7 days from a previous 
clinically relevant asthma exacerbation in order to be considered an individual event. I.e. the 
difference between the start date of an event (i) and the stop date for the previous event (i-1) 
must be more than 7 days: 
𝐴𝐴𝐴𝐴 𝑆𝑆𝑆𝑆𝑎𝑎𝑎𝑎𝑎𝑎 𝑑𝑑𝑑𝑑𝑑𝑑𝑑𝑑𝑒𝑒𝑒𝑒𝑒𝑒𝑒𝑒𝑒𝑒=𝑖𝑖−𝐴𝐴𝐴𝐴 𝑆𝑆𝑆𝑆𝑆𝑆𝑆𝑆 𝑑𝑑𝑑𝑑𝑑𝑑𝑑𝑑𝑒𝑒𝑒𝑒𝑒𝑒𝑒𝑒𝑒𝑒=𝑖𝑖−1 > 7 𝑑𝑑𝑑𝑑𝑑𝑑𝑑𝑑 
If there are 7 days or less between two or more successive clinically relevant asthma 
exacerbations the asthma exacerbations will be considered as one single event starting with the 
start date of the first asthma exacerbation and ending with the stop date of the last asthma 
exacerbation.  
Annualised rate of clinically relevant asthma exacerbations in period 4  
The efficacy assessment period (period 4) begins on the 1st of September for all subjects and 
lasts until the end of trial or discontinuation from IMP. The annualised rate of clinically relevant 
asthma exacerbations is calculated for each subject as the number of observed clinically 
relevant asthma exacerbations divided by the time in years in period 4. For the statistical 
analyses of clinically relevant asthma exacerbations based on a negative binomial regression 
model the number of clinically relevant asthma exacerbations will be the response variable and 
the log10 transformed time in years in period 4 will be the corresponding offset. 
For each subject the number of clinically relevant asthma exacerbations are the sum of all 
clinically relevant asthma exacerbations with a start date in period 4 while the subject is still on 
IMP. The time in period 4 is calculated as the time in years from start in period 4 until last day of 
IMP intake, i.e.: 
𝑇𝑇𝑇𝑇𝑇𝑇𝑇𝑇𝑌𝑌𝑌𝑌𝑌𝑌𝑌𝑌𝑌𝑌= 𝑌𝑌𝑌𝑌𝑌𝑌𝑌𝑌𝑌𝑌൫𝑑𝑑𝑑𝑑𝑑𝑑𝑑𝑑𝐿𝐿𝐿𝐿𝐿𝐿𝐿𝐿 𝐼𝐼𝐼𝐼𝐼𝐼−𝑑𝑑𝑑𝑑𝑑𝑑𝑑𝑑𝑆𝑆𝑆𝑆𝑆𝑆𝑆𝑆𝑆𝑆 𝑝𝑝𝑝𝑝𝑝𝑝𝑝𝑝𝑝𝑝𝑝𝑝 4൯  
A subject who discontinues IMP prior to period 4 will not have any observations of the clinically 
relevant asthma exacerbations in period 4 and is therefore not included in the primary analysis. 
For a subject who discontinues IMP prematurely in period 4, all available data in period 4 until 
IMP discontinuation will be used. The number of clinically relevant asthma exacerbations is the 
sum of all clinically relevant asthma exacerbations with a start date in period 4 before IMP 
discontinuation. The time with observations in period 4 is the time in years from start of period 4 
until the last point of contact for collecting asthma exacerbations or until the last day of IMP 
intake, depending on which date comes first, i.e.: 
𝑇𝑇𝑇𝑇𝑇𝑇𝑇𝑇𝑌𝑌𝑌𝑌𝑌𝑌𝑌𝑌= 𝑌𝑌𝑌𝑌𝑌𝑌𝑌𝑌𝑌𝑌൫min (𝑑𝑑𝑑𝑑𝑑𝑑𝑑𝑑𝐿𝐿𝐿𝐿𝐿𝐿𝐿𝐿 𝑝𝑝𝑝𝑝𝑝𝑝𝑝𝑝𝑝𝑝 𝑜𝑜𝑜𝑜 𝑐𝑐𝑐𝑐𝑐𝑐𝑐𝑐𝑐𝑐𝑐𝑐𝑡𝑡, 𝑑𝑑𝑑𝑑𝑑𝑑𝑑𝑑𝐿𝐿𝐿𝐿𝐿𝐿𝐿𝐿 𝐼𝐼𝐼𝐼𝐼𝐼 ) − 𝑑𝑑𝑑𝑑𝑑𝑑𝑑𝑑𝑆𝑆𝑆𝑆𝑆𝑆𝑆𝑆𝑆𝑆 𝑝𝑝𝑝𝑝𝑝𝑝𝑝𝑝𝑝𝑝𝑝𝑝 4൯ 
Example 1: A subject is lost to follow up in period 4 and the last point of contact for collecting 
asthma exacerbations data while the subject was still on IMP treatment was telephone contact 4 
(TC 4). The subject reported 1 clinically relevant asthma exacerbation with an event start date in 

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period 4 while the subject was still on IMP treatment, and the time from start of period 4 until 
TC4 is 93 days. This subject will contribute with 1 asthma exacerbation and a duration time of 
93/365=0.25 years in period 4. The annualised rate for this subject is 4 events per year. 
Example 2: A subject discontinues IMP due to AEs but continues in the trial. The date of last 
IMP intake corresponds to 250 days of treatment in period 4 and the subject did not experience 
any clinically relevant asthma exacerbations that started in period 4 while the subject was still 
on IMP. This subject will contribute with 0 asthma exacerbations and a duration time of 
250/365=0.68 years in period 4. The annualised rate for this subject is 0 events per year. 
Primary efficacy analysis 
The primary efficacy analysis will be based on all subjects in FAS with observations of the 
primary endpoint. The primary endpoint will be analysed by means of a negative binominal (NB) 
regression model with the number of asthma exacerbations as the response variable, treatment 
group, age group (<12 years/≥ 12 years) and country as fixed factors and the logarithm of the 
duration time in years in period 4 as an offset value. The between treatment group comparison 
will be performed using a Log Likelihood Ratio (LR) test derived from the NB regression 
analysis. The null hypothesis is that the rate of clinically relevant asthma exacerbations is equal 
for the active group and the placebo group. The alternative hypothesis is that the rate of 
clinically relevant asthma exacerbations is different for the active group and the placebo group. 
The primary outcome is the resulting p-value from the LR test reported together with the ratio of 
the rates and Wald 95% confidence intervals. The result of the primary efficacy analysis is 
considered successful when the p-value is below 0.05. 
 
SAS Code for primary efficacy analysis 
proc genmod data=a;  
  class treat  agegroup country; 
  model y = treat agegroup country/ link=log dist = nb offset=log_time type3; 
   lsmeans treat/ cl means exp diff; 
run; 
 
If the NB regression model fails to converge a poisson regression model with an overdispersion 
parameter will instead be applied for the primary efficacy analysis with the same covariates and 
offset as for the NB regression. If this model also fails to converge the poisson regression model 
without overdispersion will be used for the primary efficacy analysis.  
As a supportive analysis the primary efficacy endpoint will be analysed based on the PP 
analysis set using the same NB regression model as for the primary efficacy analysis. 
Sensitivity analyses with respect to missing data of the primary efficacy endpoint are described 
in section 15.13. 
Key secondary and secondary efficacy analysis 
The key secondary and secondary efficacy analyses will be based on all subjects in FAS with 
observations of the key secondary/secondary efficacy endpoints. 

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The proportion of days with nocturnal awakening which require SABA use over the two weeks 
diary assessment period (before V5, V6, V7, V8, V9, V10 and V11) will be analysed by means 
of a generalised linear mixed effect model (GLMM) with a logit link function. Treatment, visit, 
age group (<12 years/≥ 12 years) and country will be included as fixed factors. Baseline 
proportions of nocturnal awakenings requiring SABA will be included as a covariates and 
subject will be included as a random effect. Parameters in the model are estimated by applying 
pseudo-likelihood techniques as in Wolfinger and O’Connell (Wolfinger & O'connell 1993) and 
Breslow and Clayton (Breslow & Clayton 1993). From the GLMM model, the odds ratio for 
having a day with nocturnal awakening of active treatment relative to placebo will be presented 
together with the coherent p-values and 95% confidence limits. 
 
The average daily dose of SABA over the two weeks diary assessment period (before V5, V6, 
V7, V8, V9, V10 and V11) will be analysed by means of a mixed-effect model repeated 
measurement (MMRM). The model includes treatment, visit, age group (<12 years/≥ 12 years) 
and country as fixed factors, the baseline average daily SABA dose as a covariate and subject 
as a random effect. Different residual errors for each treatment group will be speficied and the 
within-subject correlated errors is modelled with a Toeplitz structure (TOEP). A between 
treatment comparison will be performed by means of a t-test with Kenward-Roger degrees of 
freedom approximation. The resulting p-value will be reported together with the difference in 
adjusted means. In addition the relative difference will be reported together with 95% 
confidence limits calculated based on Fieller’s theorem. 
 
Percentage predicted FEV1 assessed every 4 month after randomisation will be analysed by 
means of a MMRM. The model includes treatment, visit and age group (<12 years/≥ 12 years) 
and country as fixed factors, the baseline percentage predicted FEV1 as a covariate and subject 
as a random effect. Different residual errors for each treatment group will be speficied and the 
within-subject correlated errors is modelled as TOEP. A between treatment comparison will be 
performed by means of a t-test with Kenward-Roger degrees of freedom approximation. The 
resulting p-value will be reported together with the difference in adjusted means. In addition the 
relative difference will be reported together with 95% confidence limits calculated based on 
Fieller’s theorem. 
 
The average TCRS over the two week diary assessment (before V5, V6, V7, V8, V9, V10 and 
V11) will be analysed by means a MMRM.The analysis includes the square root transformed 
average TCRS as response variable; treatment, visit, and treatment-by-visit interaction, age 
group (<12 years/≥ 12 years) and country as fixed factors; the square root transformed baseline 
score as a covariate and subject as random effects. Different residual errors for each treatment 
group is specified. For each visit, the between treatment comparison will be performed by 
means of a t-test. The resulting p-value will be reported together with the difference in back-
transformed adjusted means. As additional information the relative difference of the back-
transformed adjusted means is reported together with 95% confidence limits. The latter is 
calculated based on Fieller's theorem. 
The average rhinitis DSS, the average rhinitis DMS, the average total combined 
rhinoconjunctivitis score, the average rhinoconjunctivitis DSS, the average rhinoconjunctivitis 
DMS will be analysed using a similar MMRM model as described for the average TCRS. 
The average asthma DSS score and ACQ/ACQ-IA will also be analysed by means of a MMRM 
model. 

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Time to first severe asthma exacerbation and time to first clinically relevant asthma 
exacerbation will be analysed by means of a Cox proportional hazards regression analysis. The 
model is stratified for country and includes treatment group as a factor. 
The severe asthma exacerbations will be analysed by means of a NB regression model with 
treatment group, agegroup (<12 years/≥ 12 years) and country as factors and the logarithm of 
the duration time in years in period 4 as an offset value. 
The global evaluation as binary outcomes “improved/not improved” will be analysed using a 
generalised linear mixed model (GLMM) model. 
In addition, all efficacy endpoints will be presented in summary tables. 
15.9 Safety analyses 
Analyses of AEs  
AEs are recorded from the subjects sign the informed consent and until the last follow-up visit. 
Unless otherwise specified, AE endpoints in this protocol refer to events occurring after the first 
IMP administration (treatment-emergent AEs). 
AEs will be summarised by treatment group, MedDRA system organ class (SOC) and preferred 
term (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. 
Additionally the following AEs will be summarised by treatment group 
• 
asthma exacerbations  
• 
asthma related hospitalisations  
• 
worsening of asthma requiring medication  
• 
discontinuations of treatment due to asthma related symptoms  
• 
solicited AEs  
• 
unsolicited adverse events 
The analyses will be described further in the SAP.  
Analyses of other safety parameters 
Physical examination assessments, laboratory assessments, vital signs and FEV1 will be 
summarised by means of descriptive statistics. 
15.10 Multiplicity 
The issue of multiple testing for the primary and 3 key secondary efficacy endpoints will be 
handled by using hierarchical testing. The order of the hierarchical tests is: 
1. Superiority testing of the HDM SLIT-tablet over placebo with respect to the rate of 
clinically relevant asthma exacerbations during the efficacy evaluation period 

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2. Superiority testing of the HDM SLIT-tablet over placebo with respect to proportions of 
days with nocturnal awakenings due to asthma which require SABA use during the 14 
days eDiary period recorded every 4 month after randomisation 
3. Superiority testing of the HDM SLIT-tablet over placebo with respect to the average daily 
dose of SABA use during the 14 days eDiary period recorded every 4 month after 
randomisation 
4. Superiority testing of the HDM SLIT-tablet over placebo with respect to the percentage 
predicted FEV1 assessed every 4 month after randomisation 
A lower test can only be evaluated when the null hypothesis in the former test has been 
rejected. 
15.11 Interim analyses 
No interim analysis is planned for efficacy. Subject safety will be monitored by a DMC, see 
Section 12.4. A sample size reassessment is planned based on blinded data , see section 15.2. 
15.12 Subgroup analyses 
Subgroup analyses of the rate of clinically relevant asthma exacerbations during the efficacy 
evaluation period (period 4) include age (5-11, 12-17 years), sex, race (caucasian, non-
caucasian), asthma treatment, allergen sensitivity (mite only, mite + others), geographic 
location. The trial is not powered to detect a treatment effect within a subgroup and the 
subgroup analyses will thus only be descriptive in nature.  
A forest plot will be provided by the above specified subgroups. The plot will display the 
estimated ratio of rates to placebo (and corresponding confidence interval) for each subgroup. 
The estimated ratio of rates is calculated using the NB regression model defined in section 15.8 
and based on all observed data in FAS. 
15.13 Handling of missing data 
For the primary endpoint, annualised rate of clinically relevant asthma exacerbations, missing 
data can occur in two ways.  
1) A subject who discontinues treatment or trial before period 4 will not have any 
observation of the primary endpoint. 
2) A subject who discontinues treatment or trial during period 4 before the planned end-of-
trial visit after approximately 20 months of efficacy assessment will have observations of 
the primary efficacy endpoint for less than 20 months. 
The efficacy assessment period (period 4) begins on the 1st of September for all subjects and 
lasts until the end of trial or discontinuation from IMP. For a subject who discontinues treatment 
prematurely in period 4, all available data in period 4 until IMP discontinuation will be used for 
the primary efficacy analysis. The negative binomial regression model applied for the primary 
efficacy analysis is a Generalized Linear Mixed Effect Model (GLMM) and under a missing at 
random (MAR) assumption, the method provides an unbiased estimate of the treatment effect 
that would have been observed if all subjects had continued on treatment for the full trial 
duration. 

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Subjects who discontinue IMP prior to period 4 will not contribute to the primary efficacy 
analysis. 
Data from 2 previous phase II/III trials (MT-02, MT-04) with the HDM SLIT-tablet in adult 
subjects with HDM allergic asthma suggest that up to 10% of all subjects are expected to 
discontinue treatment or trial prior to entering period 4. 
To evaluate the sensitivity of the results of the primary efficacy analysis with respect to missing 
data, including the MAR assumption, the following sensitivity analysis will be performed: 
1) Subjects who discontinue IMP treatment prior to the efficacy assessment period (period 
4) will be imputed by the rate of clinically relevant asthma exacerbations observed in the 
treatment initiation and maintenance period (period 3) until IMP/trial discontinuation, i.e., 
the number of asthma exacerbations in period 3 per time in years in period 3. This 
imputation conservatively assumes a treatment effect similar to the treatment effect 
obtained in period 3 had the subjects continued on IMP for the same length of time in 
period 4. This imputed dataset is based on all randomised subjects and will be analysed 
using the negative binomial regression model (GLMM) specified for the primary efficacy 
analysis. 
2) Missing data for subjects who discontinue IMP/trial prematurely in period 4 will be 
imputed using a conditional “jump to reference” approach. Subjects are assumed to be 
switched to the placebo arm after discontinuation in period 4 and for the rest of the 
planned duration of the trial. Multiple copies of the imputed dataset will be generated by 
imputing missing values based on estimated parameters for the placebo group. Each 
copy will then be analysed using the negative binomial regression model (GLMM) 
specified for the primary efficacy analysis. The resulting estimates and standard 
deviations for the multiple data sets are finally pooled to one single estimate and 
associated standard deviation using the method of Rubin (Rubin D.B 1987).  
 
16 Quality assurance and control 
16.1 Monitoring 
Regular monitoring visits will be performed according to International Conference on 
Harmonisation (ICH) GCP. Data will be evaluated for compliance with the protocol and accuracy 
in relation to source documents. In accordance with written SOP, 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 eCRF: 
 Date of informed consent 

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 Subject’s date of birth 
 Date of screening visit  
 Confirmation of participation in the trial (trial ID, subject number, diagnosis) 
 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 assessments made during the trial e.g. FEV1, SPT and laboratory results 
must be kept in the subject’s medical record – evaluated, signed and dated by an investigator at 
the trial site. Documentation on thermo-sensitive paper must be copied and signed by the 
investigator. The copy signed by the investigator should be kept together with the original in the 
subject’s medical record. 
The following data could be recorded directly in the eCRF and is then considered to be source 
data (if acceptable by national legislation and hospital routine): 
• 
Demography and body measurements 
• 
Vital signs 
• 
Physical examination 
The investigator must give the CRA direct access to examine, analyse and verify any medical 
records or reports to procedures, source documentation, data records and reports used, 
referenced or created as part of the conduct of this trial (e.g. relevant hospital or medical 
records), to confirm consistency with eCRF entries. 
The CRA will examine the electronic medical record system and decide one of the following 
options for source data verification: 
• 
Option 1 
If an audit trail is available, the CRA may choose either to perform source data verification 
through a direct comparison of the eCRF and the electronic medical record or may choose 
to work according to option 2 
• 
Option 2 
If no audit trail is available. Relevant source data from electronic medical records should be 
printed out by the investigator or delegate preferably at the day of the monitoring visit. The 
investigator or delegate must sign and date the print-out 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. 

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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 and at least for 25 years following the trial whichever is longest. 
The investigator must retain the subject identification log and subject information sheet and 
consent forms 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 eCRF data). In addition, deviations must be 
accompanied by a description of the deviation, the relevant dates (start and stop) and the action 
taken. Deviation reports and supporting documentation must be kept in the investigator’s file 
and in the ALK trial master file. 
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. 
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 World Medical Association Declaration of Helsinki - Ethical Principles for Medical 
Research Involving Human Subjects (World Medical Association 2013) 

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• 
International Conference on Harmonisation Harmonised Tripartite Guideline for Good 
Clinical Practice E6(R2) (ICH 2016) 
• 
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 GCP in the Conduct of Clinical Trials on 
Medicinal Products for Human Use. 2001 (2001) 
• 
European Commission. Commission Directive 2005/28/EC of 8 April 2005 laying down 
principles and detailed guidelines for GCP as regards IMPs for human use, as well as 
the requirements for authorisation of manufacturing or importation of such products. 
2005 (European Commission 2005) 
• 
FDA regulations relating to GCP and clinical trials, Protection of Human Subjects (21 
CFR Part 50) 
17.2 Disclosure and confidentiality 
By signing the protocol, the investigator agrees to keep all information, data and materials 
whether in oral, written, graphic, electronic or other form provided by ALK or a third party acting 
on behalf of or at the instruction of ALK in strict confidentiality. 
Trial documents provided by ALK (protocol, IB, eCRFs and other material) should be stored 
appropriately to ensure their confidentiality. The information provided by ALK to the investigator 
may not be disclosed to others except as expressly authorised by this protocol or the clinical 
trial agreement or with the prior written consent of ALK. 
The investigator may disclose confidential information to employees of the investigator, hospital 
authorities and IECs/IRBs on a need-to-know basis and only if the aforementioned parties are 
bound or obligated by provisions of confidentiality no less strict than imposed upon the 
investigator under this protocol or the clinical trial agreement. Further, the investigator may 
disclose confidential information set out in the protocol to the extent necessary to obtain 
informed consent from subjects who wish to participate in the trial. 
Any data, results, reports, findings, discoveries and any other information developed or 
collected during this trial shall be regarded as ALK's confidential information until published. 
Financial disclosure from the investigators will be obtained before the trial. 
17.3 Subject confidentiality 
The trial staff should ensure that the subjects' anonymity is maintained. The subjects will be 
identified only by a subject ID number on the eCRF 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 
By signing this protocol, the investigator recognises that certain personal identifying information 
with respect to the investigator and all subinvestigators 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 

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• 
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 the ALK, 
affiliates and ALK representative, in the investigators country and other countries, including 
countries that do not have laws protecting such information. 
Additionally, the investigator’s name and business contact information may be included when 
reporting certain SAEs to regulatory authorities or to other investigators. By signing this 
protocol, the investigator expressly consents to these uses and disclosures. 
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. 
17.5 IEC/IRB/regulatory authorities 
Before initiation of this trial, the protocol, the proposed subject 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 informed consent form have 
been approved by the IEC/IRB and the regulatory authority must be obtained by ALK 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. 

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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 an ICTR in compliance with the requirements of the current version of 
ICH E3: Structure and Content of Clinical Trial Report (ICH 1995), ICH GCP Guidelines (ICH 
2016), and ALK SOPs. 
The signatory investigator will review and sign the ICTR. The trial is completed once the 
integrated clinical trial report (ICTR) is signed. 
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 eCRF (or copies of these), or in the form of a report, with or without 
comments and with or without analysis, in order to submit them to the regulatory authorities of 
any country. 
By signing the investigator agreement, the investigator agrees that the results of this trial may 
be used for submission to national and/or international registration and supervising authorities. 
The authorities will be notified of the investigator's name, address, qualifications and extent of 
involvement. 
It is envisaged that the findings of this trial, including sub-analysis, and if relevant the 
epidemiology of the screened population and the selection process, will, in due time and by 
mutual agreement, be published in international journals, theses and/or presented at scientific 
meetings or symposia. All presentations and publications must be reviewed by ALK prior to 
public presentation or submission. For multi-site trials, it is mandatory that the primary 
publication is based on data from all trial sites, analysed as stipulated in the protocol and in the 
SAP. Authorship is based on the International Committee of the Medical Journal Editors’ 
Uniform Requirements (Vancouver Declaration). If the number of authors is restricted, selection 
will be based on fulfilment of 1) involvement in the development of the protocol and 2) being 
coordinating investigators. 
Investigators 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 publication 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 

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exclude or delete any confidential information, except trial results generated, from the proposed 
publication or presentation. 
ALK will review the presentations and publications for accuracy (thus avoiding potential 
discrepancies with submissions to regulatory authorities), verify that the confidential information 
is not being inadvertently divulged and provide any relevant supplementary information. Upon 
ALK's request, the investigator shall delay a publication or presentation for 6 months from ALK's 
receipt of the publication or presentation to permit ALK to file a patent application or take other 
steps as necessary to protect the confidential information (including trial results of ALK’s). 
19 Finance and insurance 
ALK subscribes to an insurance policy covering, in its terms and provisions, ALK’s legal liability 
for injuries caused to participating subjects and arising out of these trial procedures 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 telephone numbers and fax numbers of relevant ALK staff are listed in the investigator’s 
site file. 
The title, name, address and contact details of investigators and clinical research organisations  
e.g. subcontractors for project management, clinical trial packaging, monitoring, central 
laboratory etc. are listed in Appendix 4: Trial organisation. 
 
 

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21 Reference list 
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