2.1 Protocol v1.0 Final Signed

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Clinical Trial Protocol
Title: A multicenter randomized double-blind adaptive placebo-controlled clinical trial

for evaluation of efficacy and safety of specific immunotherapy with an
aluminium hydroxide-adsorbed allergoid preparation of house dust mite
(Dermatophagoides pteronyssinus) in patients with allergic bronchial asthma
and with allergic rhinitis or rhinoconjunctivitis
Short Title: Phase III trial of specific immunotherapy with allergoid preparation of house
dust mite in patients with allergic bronchial asthma and with allergic rhinitis or
rhinoconjunctivitis
Trial ID: AL1402ac
Trial Phase: Phase III, therapeutic confirmatory pivotal trial
Sponsor: Allergopharma GmbH & Co. KG

Hermann-Krner-Strae 52,
21465 Reinbek, Germany
Tel: + 49 40 727 65 - 0
Fax: + 49 40 727 65 600
Date of Final Protocol: 3rd August 2016

Version No. Final 1.0
The trial will be conducted in compliance with this protocol, Good Clinical Practice and the
applicable regulatory requirements.
This document is the property of Allergopharma GmbH & Co. KG. No unpublished
information contained herein may be disclosed without prior written approval from
Allergopharma GmbH & Co. KG.
Clinical Trial Protocol AL1402ac

Version Date: Final 1.0, 3rd August 2016 Page 1 of 91
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II Statement of Investigator
I have thoroughly read this trial protocol. Having understood the requirements and conditions
of this clinical trial protocol, I agree to:
perform the clinical trial according to this protocol, international good clinical practice
principles and competent authority requirements;
provide direct access to source data/documents (source document verification);
permit trial-related monitoring, audits, IRB/IEC reviews, and regulatory inspections;
use the trial material, including medication, only as specified in this protocol;
adhere to the time schedule of this protocol;
report to the responsible drug safety officer, within 24 hours after awareness, any adverse
event that is serious, whether considered treatment-related or not;
sign this trial protocol before the trial formally starts:
the fact that the documents and other data pertinent to this trial are the exclusive property of
the sponsor
I understand that:
changes to the protocol must be made in the form of an amendment which has the written
approval of Allergopharma GmbH & Co. KG;
the content of this protocol is confidential and copying is not allowed;
any violation of the protocol and any protocol amendment may lead to early closure of the
trial site.
Investigator:
_____________________ __________________________ ______________________

(Date (Name, printed) (Signature)
DD-MMM-YYYY)
Address/stamp of trial site:

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III List of Abbreviations and Definition of Terms

AE adverse event
AIT allergen immunotherapy
ACQ Asthma Control Questionnaire
ACT Asthma Control Test
ADR adverse drug reaction
ALAT alanine aminotransferase
APS All-Patients Set
ASAT aspartate aminotransferase
AUC area under the curve
BDP beclomethasone dipropionate
BDRM blind data review meeting
-HCG beta-human chorionic gonadotropin
BPT bronchial provocation test
CA competent authority
cdf cumulative distribution function
CHMP Committee for Medicinal Products of Human Use
CI confidence interval
CPMP Committee for Proprietary Medicinal Products
CRA clinical research associate
CRF Case Report Form
CRO Contract Research Organisation
CV curriculum vitae
DMP data management plan
Df Dermatophagoides farinae
Dp Dermatophagoides pteronyssinus
DSMB Data Safety Monitoring Board
EC Ethics Committee
ECSC European Community for Steel and Coal
eDiary electronic diary
EDTA ethylen-diamin-tetra-acetat
EMA European Medicines Agency
FAS Full Analysis Set
FDA Food and Drug Administration
FEV1 forced expiratory volume in 1 second
FV final visit
-GT gamma-glutamyl transferase
GCP Good Clinical Practice
GINA Global Initiative for Asthma
GMP Good Manufacturing Practice
HDM house dust mite
IB Investigators Brochure
ICH International Conference on Harmonisation
ICS inhaled corticosteroid
ID identification
IEC Independent Ethics Committee
Ig immunoglobulin
IMP Investigational Medicinal Product
IRB Institutional Review Board

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ITT intention to treat

LOCF last observation carried forward
MedDRA Medical Dictionary for Regulatory Activities
N number
PEF peak expiratory flow
PIC Patient Informed Consent
PNU protein nitrogen unit
PPS Per-Protocol Set
p.r.n. pro re nata (as needed)
S screening visit
SABA short-acting inhaled beta 2-agonists
SAF Safety Set
SAE serious adverse event
SAP statistical analysis plan
SDV source data verification
SOP Standard Operating Procedure
SPC Summary of Product Characteristics
SPT skin prick test
SUSAR Suspected Unexpected Serious Adverse Reaction
T treatment
TMF trial master file
V visit
VRS Visual Rating Scale
WAO Word Allergy Organization
WHO World Health Organization

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IV Table of contents
I Signature Page................................................................................................................2
II Statement of Investigator .................................................................................................3
III List of Abbreviations and Definition of Terms.................................................................4
IV Table of contents .............................................................................................................6
List of tables.................................................................................................................. 10
List of figures ................................................................................................................ 10
Background Information....................................................................................................... 11
1.1 Scientific Background ........................................................................................ 11
1.2 Rationale for the Trial ........................................................................................ 11
1.3 Selection of Dosages .......................................................................................... 12
1.4 Trial Population ................................................................................................. 12
1.5 Risk Benefit Assessment .................................................................................... 13
2 Trial Objectives and Purpose ......................................................................................... 13
3 Trial Design................................................................................................................... 13
3.1 Overall Trial Design........................................................................................... 13
3.2 Trial Schedule .................................................................................................... 14
3.3 Discussion of Trial Design ................................................................................. 21
3.4 Endpoints ........................................................................................................... 21
3.4.1 Primary Endpoint ............................................................................................... 21
3.4.2 Secondary Endpoints.......................................................................................... 21
3.5 Selection of Patients........................................................................................... 23
3.5.1 Patient Inclusion Criteria.................................................................................... 23
3.5.2 Patient Exclusion Criteria................................................................................... 23
3.5.3 Restrictions during the Trial ............................................................................... 25
3.6 Method for Assigning Patients to Treatment Groups .......................................... 25
3.6.1 Patient Allocation............................................................................................... 25
3.6.2 Randomization ................................................................................................... 25
3.6.3 Stratification ...................................................................................................... 26
3.6.4 Randomization Codes and Decoding of Envelopes ............................................. 26
3.6.5 Unblinding ......................................................................................................... 26
3.7 Treatment of Patients ......................................................................................... 28
3.7.1 Schedule of Assessments.................................................................................... 28
3.8 Methods of Performing Trial-related Tests ......................................................... 31
3.8.1 Skin Prick Test................................................................................................... 31
3.8.2 Immunological Profile........................................................................................ 32

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3.8.3 Lung Function Test ............................................................................................ 32

3.8.4 Reversibility Test ............................................................................................... 33
3.9 Discontinuation Criteria ..................................................................................... 33
3.9.1 Discontinuation of Patients................................................................................. 33
3.9.2 Discontinuation of Trial Sites ............................................................................. 34
3.9.3 Discontinuation or Premature Suspension of the Trial ........................................ 34
3.10 Patient Compliance ............................................................................................ 35
4 Trial Medication............................................................................................................ 35
4.1 Investigational Medicinal Product (IMP)............................................................ 35
4.1.1 Trial Preparation ................................................................................................ 35
4.1.2 Placebo .............................................................................................................. 35
4.1.3 Packaging and Labelling .................................................................................... 36
4.1.4 Storage, Accountability and Destruction............................................................. 36
4.2 Administration of IMP ....................................................................................... 36
4.3 Dosage of IMP ................................................................................................... 38
4.3.1 Dose Escalation.................................................................................................. 39
4.3.2 Maintenance Treatment ...................................................................................... 39
4.3.3 Dosage Modification and Adjustment................................................................. 39
4.3.4 Precautions and Overdose .................................................................................. 41
4.3.5 Actions in Case of Emergency............................................................................ 41
4.4 Concomitant Medications................................................................................... 41
4.4.1 Permitted Asthma Medication ............................................................................ 41
4.4.2 Restricted Medication ........................................................................................ 42
4.4.3 Non-permitted Medication ................................................................................. 42
4.5 Diagnostics ........................................................................................................ 43
5 Assessment of Efficacy.................................................................................................. 43
5.1 Asthma control assessment................................................................................. 43
5.2 Additional Efficacy Variables ............................................................................ 46
5.2.1 Asthma Exacerbation ......................................................................................... 46
5.2.2 Rating of Rhinitis Symptoms.............................................................................. 47
5.3 Immunological Parameters ................................................................................. 48
5.4 Optional Exploratory Immunological Parameters ............................................... 48
5.5 Appropriateness of Measurements...................................................................... 48
6 Assessment of Safety..................................................................................................... 49
6.1 Adverse Events and Adverse Reactions.............................................................. 49
6.1.1 Definitions ......................................................................................................... 49

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6.1.2 Classifications .................................................................................................... 51

6.1.3 Adverse Event (AE) Recording .......................................................................... 52
6.1.4 Reporting of Serious Adverse Events (SAE)....................................................... 53
6.1.5 Follow-Up of AEs and SAEs.............................................................................. 53
6.2 Safety Parameters............................................................................................... 54
6.2.1 Clinical Laboratory Variables............................................................................. 54
6.2.2 Other Safety Variables ....................................................................................... 55
6.2.3 Parameters Relevant for the Assessment of Safety Issues ................................... 56
6.2.4 Likert Scale of Overall Tolerability .................................................................... 57
6.3 Data and Safety Monitoring Board ..................................................................... 58
6.3.1 Members of the DSMB ...................................................................................... 58
6.3.2 Procedure of the DSMB ..................................................................................... 58
6.3.3 DSMB Responsibilities ...................................................................................... 58
7 Trial Administrative Structure ....................................................................................... 59
7.1 Investigators....................................................................................................... 60
7.2 Sponsor Personnel.............................................................................................. 60
7.3 Contract Research Organization(s) ..................................................................... 60
7.4 Laboratories ....................................................................................................... 60
7.5 Supply Management........................................................................................... 60
7.6 Essential Documents .......................................................................................... 60
8 Statistics ........................................................................................................................ 61
8.1 Analysis Datasets ............................................................................................... 61
8.2 Analysis of Primary and Secondary Efficacy Variables ...................................... 61
8.2.1 Primary Efficacy Variable .................................................................................. 61
8.2.2 Secondary Efficacy Variables............................................................................. 61
8.3 Design and Hypothesis....................................................................................... 61
8.4 Confirmatory Analysis ....................................................................................... 63
8.5 Determination of Sample Size ............................................................................ 64
8.5.1 Sample Size until Interim Analysis (1st Part of the Trial) .................................... 64
8.5.2 Sample Size for 2nd Part of the Trial after Interim Analysis ................................ 66
8.6 Evaluation of Secondary Endpoints .................................................................... 67
8.7 Analysis of Safety and Tolerability Variables..................................................... 67
8.8 Comparability of Treatment Groups ................................................................... 68
8.9 Subgroup Analysis ............................................................................................. 68
8.10 Handling of Missing Data .................................................................................. 68
8.11 Drop-outs........................................................................................................... 69

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9 Changes and Deviations to Plan..................................................................................... 69

9.1 Protocol Amendment(s) ..................................................................................... 69
9.2 Protocol Deviations ............................................................................................ 69
10 Direct Access to Source Data and Source Documents .................................................... 71
11 Quality Control and Quality Assurance.......................................................................... 71
12 Ethics ............................................................................................................................ 71
12.1 Ethical Conduct of the Trial ............................................................................... 71
12.2 Ethics Committee............................................................................................... 71
12.3 Patient (Parent) Informed Consent...................................................................... 72
13 Data Handling and Record Keeping............................................................................... 72
13.1 Data Handling .................................................................................................... 72
13.1.1 Monitoring ......................................................................................................... 72
13.1.2 Source Data Verification .................................................................................... 72
13.2 Data Management .............................................................................................. 73
13.2.1 Source Data........................................................................................................ 73
13.2.2 Patient eDiary .................................................................................................... 74
13.2.3 eCRF.................................................................................................................. 74
13.2.4 Completion of eCRFs......................................................................................... 74
13.2.5 Corrections of eCRFs ......................................................................................... 75
13.2.6 Coding ............................................................................................................... 75
13.2.7 Confidentiality of Personal Data......................................................................... 75
13.3 Record Keeping ................................................................................................. 75
13.3.1 Patient file.......................................................................................................... 75
13.3.2 Investigator Site File .......................................................................................... 75
13.3.3 Retention of Clinical Trial Documentation ......................................................... 76
14 Financing and Insurance ................................................................................................ 76
14.1 Financing ........................................................................................................... 76
14.2 Insurance............................................................................................................ 76
15 Publication Policy.......................................................................................................... 77
15.1 Confidentiality ................................................................................................... 77
15.2 Data Ownership ................................................................................................. 77
15.3 Reports............................................................................................................... 77
15.4 Publications........................................................................................................ 77
16 Indemnity Statement...................................................................................................... 78
17 References..................................................................................................................... 78
17.1 Reference List .................................................................................................... 78

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18 Appendices.................................................................................................................... 82
18.1 FDA Guidance for Industry: Toxicity grading Scale for Healthy Adult and
Adolescent Volunteers Enrolled in Preventive Vaccine Clinical Trials (2007) .... 82
18.2 Instructions for Skin Prick Test .......................................................................... 84
18.3 Lung function test FEV1 (Forced expiratory volume in 1 second) .................... 87
18.4 PEF measurements ............................................................................................. 88
18.5 Reversibility test ................................................................................................ 89
18.6 GINA stepwise approach to asthma treatment .................................................... 90
18.7 Systemic Reactions, Classification/Grading according to WAO Classification ... 91
List of tables
Table 1 Schedule of Assessment Screening and Baseline Phase ........................................28
Table 2 Schedule of Assessments Treatment Phase ...........................................................29
Table 3 Explanations and Limitations ...............................................................................30
Table 4 Trial Preparation ..................................................................................................35
Table 5 Content of components.........................................................................................35
Table 6 Schedule for Dose Escalation and Maintenance for 3000 PNU and 5400 PNU .....38
Table 7 Equivalent ICS daily doses (g) to Budesonide according to GINA 2014.............44
Table 8 Daily questions for assessment of moderate asthma exacerbations........................45
Table 9 Results from trial AL1009ac ................................................................................64
Table 10 Sample Size .........................................................................................................64
Table 11 Tables for laboratory abnormalities ......................................................................82
Table 12 Potential Interference of Medications with the Skin Test Reaction .......................86
Table 13 A stepwise approach adapted from GINA 2015....................................................90
Table 14 Modified Systemic Reactions Classification.........................................................91
List of figures
Figure 1 Trial Flow Chart Part 1.........................................................................................16
Figure 2 Trial Flow Chart Part 2.........................................................................................17
Figure 3 Flow chart for minimal ICS control dose determination........................................18
Figure 4 Flow Chart Baseline Phase Examples ................................................................19
Figure 5 Correct form of administration .............................................................................37
Figure 6 Wrong form of administration ..............................................................................37

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Background Information
1.1 Scientific Background
Type I allergy is a chronic disorder characterized by the formation of IgE antibodies to proteins
and glycoproteins from plants, insects, animals, and fungi which are nontoxic for healthy
individuals. However, in allergic patients the crosslinking of specific IgE-antibodies on
effector cells by allergens activates an immunological cascade leading to acute symptoms of
Type I allergy including rhinitis, conjunctivitis, asthma, and sometimes even anaphylactic
shock [1].
House dust mites have a proven causal role in patients with allergic respiratory diseases, such
as allergic asthma and allergic rhinitis [2]. Both atopic diseases lead to increased burden of
disease and health care costs, exceedingly in patients with uncontrolled diseases [3-5].
Use of native allergens for allergy immunotherapy (AIT) started a century ago. Meanwhile the
modification of allergens is believed to improve the safety profile of AIT. The preparation
under investigation in this trial is an allergoid prepared by chemical modification of partially
purified native aqueous allergen extracts. The methods of production and properties of the
house dust mite allergoid preparations have been described previously [6;7] and are
summarized in the investigators brochure.
For orientation, a brief description of the production will be given in the following. Native
allergen extracts are depleted of components with a molecular mass of less than 5000 Dalton
by diafiltration before chemical modification with aldehydes. The principles and methodology
established in the development of pollen allergoids have been adopted and extended in creating
house dust mite allergoids in a depot formulation with aluminium hydroxide which is serving
as a potent adjuvant at the same time. Formaldehyde and glutaraldehyde have been used in
combination to chemically modify an aqueous extract of purified house dust mite bodies of
Dermatophagoides pteronyssinus (D p) and thereby constantly producing allergoid with
similar immunological properties as pollen allergoids. The modification causes a substantial
reduction in the allergenicity of the extract and can be judged by skin prick testing, provocation
testing, histamine release from sensitized leukocytes and measurement of IgE-binding activity
by radio allergo sorbent test (RAST)-inhibition [7-10]. However, the important immunogenic
activity and T-cell reactivity are retained [10]. These properties enable the allergoids to be used
as a basis for AIT with a reduced risk of inducing IgE-mediated side reactions and the
possibility of administering higher doses of immunogens over a shorter time course than with
native allergens; leading to a better efficacy.
1.2 Rationale for the Trial

With this clinical trial the sponsor is planning to investigate the effect of AIT in patients with
asthma caused by house dust mites. So far there is only little knowledge of allergoids on
asthma. But there have been some promising results. In a corticosteroid reduction trial
AL0104av (EudraCT-No.: 2004-003892-35) asthma patients were treated with a maintenance
dose of 1800 PNU for the mite allergoid preparation of D p allergen. This preparation was safe
and effective in the investigated children population with controlled allergic asthma induced by
house dust mites. The minimum corticosteroid dose required for asthma control could be
reduced significantly by more steps in the immunotherapy group compared to the standard care
control group [11]. For the investigated adult population a statistical significant difference to
placebo could not be shown. But the restriction to medium doses of corticosteroid requirement
at baseline yielded marked allergoid effects vs standardized symptomatic treatment comparator
in pooled analysis of children and adults.
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It remained unclear, if the used maintenance dose of 1800 PNU in that trial had the optimal
benefit/risk ratio for the indication of asthma. Therefore higher and lower doses have been
investigated in the dose range finding trial (DRF) AL1009ac (EudraCT-No.: 2011-002248-29)
in a small number of asthmatic patients. The aim of that trial was to evaluate safety and
efficacy of 4 different maintenance doses of 600, 1800, 3000 and 5400 PNU in a placebo
controlled trial in patients suffering from allergic asthma. The absolute change of the swelling
area of the late phase reaction before and after treatment period of an intracutaneous test has
been chosen as primary endpoint and the change of the minimum corticosteroid dose required
for asthma control assessed by the ACT as a secondary endpoint. For both endpoints statistical
significant efficacy compared to placebo could be shown for one or more of the investigated
doses.
Therefor the planned pivotal clinical trial will be carried out to confirm the results of the dose
finding trial in a large number of patients according to the current guidelines of the European
Medicines Agency {European Medicines Agency CHMP/EWP/18504/2006, 2008 23024
/id}{European Medicines Agency, 2012 27262 /id}[ as well as of the requirements of the
International Conference on Harmonisation (ICH) - Good Clinical Practice (GCP). The trial is
intended for submission to German and other European authorities to generate evidence data
needed to receive marketing authorizations for this product and is requested by the Therapy
Allergen Ordinance (Therapieallergene-Verordung) of the Paul-Ehrlich-Institute [15].
1.3 Selection of Dosages

Based on the results of the dose finding study regarding the efficacy endpoints and the safety
profile the optimal dose was considered to be either 3000 PNU or 5400 PNU. Therefore, these
two doses will be investigated in this phase III trial in a higher number of patients with allergic
asthma to assess the efficacy and safety. Thus the planned trial will serve to confirm the
optimal risk benefit ratio for the future marketed dose of Acaroid.
The investigational product will be applied in subcutaneous injections. Subcutaneous
immunotherapy leads to a good immunological response which is the basis for optimal clinical
efficacy. A detailed description of administration, dosages etc. is given in chapters 4.2 and 4.3.
1.4 Trial Population

Adult and adolescent patients will be informed about this trial by the investigators during the
routine visit at the trial site. Furthermore patients may be adverted to the trial e.g. in local
newspapers or by using leaflets to be posted at the trial site.
For the first part of the trial until the interim analysis, approximately 1300 male and female
outpatients (aged 12 to 65 years of age) will be screened competitively and 444 patients will be
randomized into the trial to provide 148 patients in each of the two active groups and 148
patients in the placebo group. It is assumed, that this number of patients will yield a total of at
least 354 evaluable patients in the FAS for the interim analysis. If the study has to be continued
after the interim analysis, a sample size calculation for the second period of the study will be
performed based on the results of the interim analysis.
A proportion of 30% - 50% adolescents is expected to be enrolled in the trial.
For determination of sample size see Section 8.5.
In this multicenter trial it is anticipated that 8 to 24 patients per trial site will be recruited until
the interim analysis. Generally, there will be no replacement strategy employed for patients
dropping out prematurely in this trial.

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1.5 Risk Benefit Assessment

In a dose range finding trial (AL1009ac) doses from 600 to 5400 PNU have been investigated
to determine the optimal dose with the best benefit/risk ratio in an adult population of allergic
asthma patients. Two potential doses, 3000 PNU and 5400 PNU, have been identified for
further evaluation of safety and efficacy in a higher number of patients.
The use of a placebo control group in this trial is justified to obtain reliable scientific evidence
on efficacy as well as safety and is recommended by European guidelines. The nature of this
trial is clearly explained to the patient and implemented in the trial to ensure ethical standards.
The trial concept is in the interest of public health needs and beneficial to the patient group. A
tight safety network has been established and helps to optimize the risk/benefit ratio: e.g.
implementation of a safety board, scheduled trial events and visits during treatment phase,
application of the investigational product only by especially trained investigators (or by
especially trained study nurses according to national practice and law under supervision of the
investigator), supervision of at least 30 minutes after injection of the investigational product.
The procedures outlined in this trial protocol (lung function assessments, skin prick test [SPT]
and blood sampling) are routine procedures in medical practice. They do not have risks beyond
those known for these procedures and therefore do not change the positive risk conclusion for
this specific trial. Further procedures like the reduction of the inhaled corticosteroid dose and
collection of diary data are more specific test procedures to determine the disease status of an
individual asthmatic patient. They are routinely used by the selected investigational trial sites
participating in this trial. The information gained from such investigations may also have
benefits for other patients. The risk of possible unexpected events is carefully supervised by the
Data Safety Monitoring Board (DSMB), and the sites are well trained to handle any unpleasant
events like anaphylactic reactions. The trial is intended to generate evidence data needed to
receive marketing authorizations for this investigational medicinal product (IMP) and will help
to optimize the treatment of patients with allergic asthma and allergic rhinitis or
rhinoconjunctivitis caused by house dust mites. Hence, the overall benefit/risk conclusion for
these additional investigations and this trial is positive.
2 Trial Objectives and Purpose

The aim of this clinical trial is to demonstrate efficacy and to evaluate safety of AIT with an
aluminium hydroxide adsorbed allergoid preparation of major allergens of D p in patients with
allergic bronchial asthma (acc. to GINA 2015) and allergic rhinitis or rhinoconjunctivitis
caused by house dust mites.
3 Trial Design
3.1 Overall Trial Design
This clinical trial will be performed as a multicenter, multinational, parallel group, adaptive,
randomized (1:1:1), double-blind, placebo-controlled phase III study in adolescent and adult
patients. The whole trial is divided into two parts with an unblinded interim analysis.
Depending on the results of the interim analysis, the trial can be stopped or can be continued in
a second part. Both parts of the trial consist of a baseline period to determine the necessity to
use inhalative corticosteroids (ICS) for treating asthma and to assess the minimal dose of ICS
required to achieve asthma control. The latter will be assessed during the autumn/winter period
which represents the time of the highest exposure to house dust mite allergens and will be

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determined using the ACQ6. During this period, patients will have to complete eDiaries up to
16 weeks to assess allergic asthmatic, nasal, and conjunctival symptoms.
After the baseline period the patients will receive double-blind treatment for approx. 8 months
followed by a 2nd period of 16 weeks to assess the minimal ICS dose and further 2 months of
observation for the assessment of asthma exacerbation (Figure 1). Altogether patients have to
complete eDiaries for approximately 18 months from the start of the baseline period until the
end of the trial.
The primary endpoint of this study is the change in dose steps of the minimum daily inhaled
corticosteroid dose required to ensure asthma control assessed by the ACQ6 (according to
GINA) after approx. 8 months of AIT.
Only patients requiring inhaled corticosteroid treatment up to 800 g Budesonide per day will
be eligible to enter the baseline phase of the study. All patients will start with switching their
currently used ICS- or ICS combination product to Budesonide at the equivalent dose, which
will be adjusted stepwise in pre-defined steps until the minimal inhaled asthma control dose is
achieved.
The trial will be performed in 2 parts with an adaptive design with 1 interim analysis. If the
efficacy turns out to be nearly as high as observed in the study AL1009ac for the 5400 PNU
dose, the trial can be stopped after the interim analysis of part 1. If the study is continued, a
sample size recalculation can be performed with the option of stopping the investigation of 1 of
the 2 verum treatments groups for part 2 of the trial.
After the last trial specific individual patient visit, all patients will be treated individually at the
investigators discretion.
3.2 Trial Schedule

The planned trial schedule (part 1) includes:
Duration of the trial: March 2017 May 2019
Screening period: March 2017 September 2017
Diary phase before treatment: October 2017 January 2018
Start of treatment: February 2018
Planned end of double-
blind treatment phase: September 2018
Diary phase after treatment: October 2018 March 2019
Last patient visit: April 2019
Interim database lock May 2019
Interim Analysis June 2019
If the interim analysis leads to stop of the trial:
End of trial: July 2019
Unblinding: July 2019
Final trial report: December 2019

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Depending on the outcome of the interim analysis there will be the option of a 2nd part with
additional patients:
Duration of the 2nd part: June 2019 May 2021
Screening period: June 2019 September 2019
Diary phase before treatment: October 2019 January 2020
Start of treatment: February 2020
Planned end of double-
blind treatment phase: September 2020
Diary phase after treatment: October 2020 March 2021
Last patient visit: April 2021
End of trial (database lock): July 2021
Unblinding: July 2021
Final trial report: December 2021
The end of the trial is defined as the date of last database lock in order to permit data cleaning
after the last patient visit.
Allergopharma GmbH & Co. KG ensures that an end of trial notification will be submitted to
the concerned competent authorities (CA) and ethics committees (EC) according to regulatory
requirements.

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Figure 1 Trial Flow Chart Part 1

S= Screening Visit, B= Baseline Visit, T= Treatment Visit, D= Diary Visit after Treatment, FV= Final Visit

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Figure 2 Trial Flow Chart Part 2 (Only if a second part with additional patients will be necessary after interim analysis!)

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Figure 3 Flow chart for minimal ICS control dose determination during the screening phase Examples
Controlled asthma
Controlled asthma Dose reduction with 200g DROP
(200g Budesonide) Budesonide OUT
Dose reduction
Controlled asthma (400 or 200g
Budesonide)
Controlled asthma with Dose reduction
1200, 800 or 400g (800, 400 or 200g
Budesonide Budesonide)
Uncontrolled asthma
Switch from inhalative Continue Baseline

corticosteroids to 400, Phase with controlled
ACQ6 (Paper version)
800 or 1200g dose of Budesonide
Budesonide (400, 800 or 1200g)
Controlled asthma
Uncontrolled asthma with Dose increase

800 or 400g Budesonide (1200 or 800g
Budesonide)
Uncontrolled asthma Dose increase

(1200g Budesonide)
Uncontrolled asthma
with 1200g DROP
Budesonide OUT
+28 days after S1 +28 days after S2

S1 S2 S3 B1
To confirm an ICS dose need between 1200 to 400 g/day before start of the baseline period a pre-assessment should be performed during the
screening phase. Therefore all patients will start with switching their currently used ICS- or ICS combination product to Budesonide at the
equivalent dose. After that, Budesonide will be increased or decreased in predefined steps until the minimal inhaled Budesonide dose required for
asthma control is achieved. For patients fulfilling the asthma control criteria already with the initial (prior to study start) ICS dose, the ICS dose
will be reduced until asthma control is not achieved anymore to indicate the medical need. The assessment for asthma control will be performed in
intervals of 4 weeks by a paper version of the ACQ6 at the site. Patients included at the end of the screening phase can switch from visit S2
directly to visit B1 and proceed with the tapering in the baseline phase even if a minimal ICS dose has not been determined during the screening
phase.
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Figure 4 Flow Chart Baseline Phase Examples

Example 1:
Oct Nov Dec Jan
START of DIARY PHASE Dose increase Dose increase

(400g Budesonide) (800g Budesonide) (1200g Budesonide)
Uncontrolled Uncontrolled
Controlled asthma
asthma asthma STOP
Visit B1 Visit B2 Visit B3 Visit B4 Visit B5

Example 2:
Oct Nov Dec Jan
START of DIARY PHASE Return to last dose with

(800g Budesonide) Dose reduction controlled asthma
(400g Budesonide) (800g Budesonide)
Controlled asthma Uncontrolled

Controlled asthma
asthma STOP
Example 3:
Oct Nov Dec Jan
Visit S5
START of DIARY PHASE
(1200g Budesonide) Dose reduction Dose reduction
(800g Budesonide) (400g Budesonide)
Controlled asthma Controlled asthma Drop out

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In the baseline phase the patient will start with the pre-assessed ICS dose. To measure the minimum ICS dose required to achieve asthma control, patients will
have to complete eDiaries carefully over periods of up to approximately 16 weeks during the time of highest annual house dust mite allergen exposure (approx.
October to January) and during the same period after treatment (approx. October to January), (Figure 4). If patients reach the minimum ICS dose to achieve
controlled asthma, they can be randomized and treatment can start. Patients uncontrolled with 1200g Budesonide and patients controlled with 200g
Budesonide have to be excluded as well as patients still controlled after the second step of reduction.

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3.3 Discussion of Trial Design

This clinical trial will be performed as a multicenter, multinational, parallel group, adaptive,
randomized, double-blind, placebo-controlled phase III study in adolescents and adults
patients.
The Guideline on the clinical development of products for specific immunotherapy for the
treatment of allergic diseases[14] recommends the use of a placebo group to show superiority
of immunotherapy. The guideline also proposes to include a baseline period. Thus, patients
will undergo a baseline period, followed by 1 additional assessment period after treatment.
Data from patient diaries of the baseline phase build the basis of an individual patient status
prior to the start of treatment.
To assess clinical efficacy of AIT, the primary parameter should reflect the patients relevant
clinical outcome. Therefore, the primary endpoint of this study is the change in dose steps of
the minimum daily inhaled corticosteroid dose required to ensure asthma control based on the
asthma control questionnaire (ACQ6) [13;16]) prior to treatment and after approximately 8
months of AIT.
3.4 Endpoints
3.4.1 Primary Endpoint

This is a confirmatory phase III pivotal study. The primary endpoint is the change in dose steps
of the minimum daily ICS dose required to ensure asthma control according to the ACQ6
(ACQ6 score 1.0) between baseline and after AIT. The ICS dose will be determined by
means of diary entries as described in Section 5.1.
3.4.2 Secondary Endpoints

The following secondary endpoints will be assessed:
Efficacy
Change refers to the change between the baseline value and the value after AIT.
Response status in terms of improvement by at least one dose step of the minimum
daily ICS dose required to ensure asthma control between baseline and after AIT
Response status in terms of no need for ICS after AIT
Change of the minimum daily ICS dose (Budesonide) in g required to ensure asthma
control.
Change in ACQ6 score under the highest daily ICS dose the patient was not controlled
at baseline according to the ACQ6.
Change in severity of asthma symptoms with the highest daily ICS dose the patient was
not controlled at baseline
Change in use of bronchodilator rescue medication (Salbutamol) with the daily ICS
highest dose the patient was not controlled at baseline
Change in pre-bronchodilator morning peak flow with the highest daily ICS dose the
patient was not controlled at baseline
Change in the number of night time awakening with the highest daily ICS dose the
patient was not controlled at baseline
Change in limitation of daily activities with the highest daily ICS dose the patient was
not controlled at baseline
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Change in the number of symptom free days with the highest daily ICS dose the patient
was not controlled at baseline
Change in the outcome of the Quality of Life Questionnaire (Mini-AQLQ) with the
highest daily ICS dose the patient was not controlled at baseline
Change in patients FEV1 value with the highest daily dose ICS the patient was not
controlled at baseline
Change of the Combined Symptom (rhinitis symptoms) and Medication Score (CSMS)
under the lowest daily ICS dose required to ensure asthma control at baseline
Change of the Combined Symptom (rhinitis- and conjunctivitis symptoms) and
Medication Score (CSMS) under the lowest daily ICS dose required to ensure asthma
control at baseline
Change of rhinitis symptoms of the CSMS under the lowest daily ICS dose required to
ensure asthma control at baseline
Change of the rhinitis medication score of the CSMS under the lowest daily ICS dose
required to ensure asthma control at baseline
Change of IgG4
Change of eosinophils
The time until the first moderate or severe asthma exacerbation during the diary phase
after AIT
The time until the first moderate or severe asthma exacerbation from the time of first
injection until the end of trial.
The number of asthma exacerbations (moderate or severe) during the diary phase after
AIT.
The number of asthma exacerbations (moderate or severe) from the time of first
injection until the end of trial.
Number of severe asthma exacerbations during the diary phase after AIT
The number of severe asthma exacerbations from the time of first injection until the end
of trial.
Number of moderate asthma exacerbations during the diary phase after AIT
The number of moderate asthma exacerbations from the time of first injection until the
end of trial.
Safety
In addition to the efficacy endpoints, the safety of the treatment during the entire trial period
will be assessed by
Adverse events
Clinical laboratory tests (hematology, clinical chemistry, and urinalysis)
Vital signs (resting blood pressure, pulse rate, and respiratory rate)
An assessment of the overall tolerability by the investigator and the patient using a
5-point Likert scale (Likert, 1932)

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3.5 Selection of Patients
3.5.1 Patient Inclusion Criteria

1. Written informed consent and assent according to local requirements before any trial-
related activities started (a trial-related activity is any procedure that would not have been
performed during the routine management of the patient.)
2. Male or female outpatient between 12 and 65 years (both inclusive)
3. IgE-mediated allergic bronchial asthma treated according GINA step 2-4 with rhinitis or
rhinoconjunctivitis induced by house dust mite documented by
SPT wheal for D p 3 mm in diameter
histamine (0.1% histamine) wheal 3 mm
a negative control reaction (NaCl) wheal < 2 mm
Immunoassay result specific IgE > 1.5 kU/L to D p
symptoms of asthma and rhinitis or rhinoconjunctivitis e.g. during the months
September to February or over the entire year
4. confirmed diagnosis of asthma (section 6.2.3.3.)
treatment according to GINA 2015 during the last year as documented by requirement
of ICS and requirement of a bronchodilator
FEV1 increase of 12% and 200 mL of the baseline FEV1 after inhalation of 400g of
Salbutamol or other short acting bronchodilator equivalent (historical data not older
than 2 years are acceptable)
Achievement of asthma control criteria (ACQ6 1.0 scores in 2 consecutive weeks at
the end of the assessment period) during the baseline diary phase within a required ICS
dose between 400 to 1200 g Budesonide per day
3.5.2 Patient Exclusion Criteria

The presence of any of the following criteria will exclude a patient from randomization and
treatment with IMP.
General criteria:
1. Unable to understand and comply with the requirements of the trial, as judged by the
investigator
2. Currently participating in any other trial or in participating in any other trial within 30 days
before inclusion in this trial
3. Low compliance, persistent incorrect inhaler technique as assessed by the investigator or
inability to understand instructions or trial documents
4. Involved in the planning and conduct of the trial
5. Employee of Allergopharma GmbH & Co. KG or of one of the trial sites
6. Any relationship of dependence with the sponsor or with the investigator
7. Previously enrolled or randomized to treatment in the present trial
8. Mentally disabled
9. Institutionalized due to an official or judicial order
For females with childbearing potential (i.e. females who are not chemically or surgically
sterilized or females who are not post-menopausal):
10. Positive pregnancy test
11. Use of an unacceptable or unreliable contraceptive method during the trial, as judged by the
investigator (reliable and highly effective methods of birth control defined as failure rate
less than 1% per year)

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12. Pregnant, breast feeding or wishes to breast feed

13. Seeking to become pregnant during the course of the trial
Immunotherapy criteria:
14. Any AIT with house dust mites
15. Current treatment with any kind of immunotherapy
16. Any AIT with unknown allergen
17. Clinically relevant symptoms to other regional specific allergens which interfere with the
assessment period of October to January. Exceptions are symptoms to allergens of cat and
dog, if the patient has no direct contact to these animals.
18. Sensitization in the immunoassay 0.7 kU/L against region specific allergens which
interfere with the assessment period of October to January. Exceptions are sensitizations to
storage mites if the sensitization assessed by immunoassay is lower than the sensitization
to at least one of the house dust mites (D p or D f). Exceptions are sensitizations assessed
by immunoassay to cat and dog, if the patient has no direct contact to these animals.
Diseases and health status:

19. Clinically relevant rhinitis or respiratory symptoms related to other reasons (e.g. chronic
sinusitis, COPD)
20. FEV1 < 70% of predicted normal (ECSC)[17]
21. Asthma or rhinitis symptoms for 20 years or longer
22. Laboratory values greater than Grade 1 according to the FDA Guidance for Industry
(Toxicity Grading Scale for Healthy Adult and Adolescent Volunteers Enrolled in
Preventive Vaccine Clinical Trials). For assessment the normal ranges of the central
laboratory will be applied.
23. Severe acute or chronic diseases (e.g. Diabetes mellitus type I, malignant neoplasia, chronic
renal failure, gastro-esophageal reflux disease, BMI > 30, aspirin induced asthma), severe
inflammatory diseases (liver, kidneys)
24. Autoimmune diseases, immune-defects including immune-suppression, immune-complex-
induced immunopathies (e.g. HIV, post-transplant patients, lupus erythematodes (SLE),
Graves disease)
25. Severe psychiatric and psychological disorders including impairment of cooperation (e.g.
alcohol or drug abuse)
26. Current Smoker
27. Ex-smoker with 10 pack years or more (A pack year is defined as twenty cigarettes smoked
every day for one year)
28. Recurrent seizures
29. Irreversible secondary alterations of the reactive organ (e.g. emphysema, bronchiectasis
etc.)
Medications:
30. Treatment with beta-blockers (local or systemic)
31. Contraindication for use of adrenalin (e.g. acute or chronic symptomatic coronary heart
disease, severe hypertension)
32. Completed or ongoing treatment with anti-IgE-antibody
33. Completed or ongoing long-term treatment with tranquilizer or other psychoactive drugs
34. Controlled asthma at baseline after 2 steps of ICS reduction

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3.5.3 Restrictions during the Trial

Before performing the SPT, use of any medication that could interfere with the skin reaction
have to be stopped. These drugs have to be stopped for a period of time equivalent to the
manufacturer-specified duration of action. Use of any short acting antihistamines (e.g.
diphenhydramine) should be stopped within 2 days, or long-acting antihistamines (e.g.
fexofenadine, cetirizine, loratadine or desloratadine) within 7 days prior to skin testing
(Appendix 18.2).
Asthma medication received prior to trial enrollment will be switched to salbutamol and
budesonide during the trial. Exacerbation treatment will have to be done with a short course of
oral corticosteroids.
3.6 Method for Assigning Patients to Treatment Groups
3.6.1 Patient Allocation

With start of screening visit, patients will be assigned to a 7-digit screening number wherein
the first 2 digits indicates the country, the 2 subsequent digits indicate a certain trial site within
each country starting with 01 and the last 3 digits number the patient within each site in a
numerical ascending order of inclusion into screening starting with number 001. The
combination of country and trial site number will be fixed in a separate document and
communicated to the trial sites before start of screening. The screening number will identify
the patient during the trial. At the randomization visit (visit T1), eligible patients will be
assigned additionally via electronic Case Report Form (eCRF) a random number in ascending
order for adults and a random number in ascending order for adolescents within each trial site.
This random number will also identify the randomized patient during the whole treatment
phase until the end of the trial.
For example: 0101-001 is the screening number assigned to the 1st patient at site 1 in Germany.
3.6.2 Randomization
To ensure that patients are assigned to each treatment group according to the foreseen
randomization ratio of 1:1:1 during the first part of the trial within each site, the randomization
will be performed block-wise, whereby the size of the blocks will be unknown by the trial
sites. The randomization ratio might be 1:1 in the second part of the trial after the interim
analysis.
The randomization will be performed stratified by age group (adults and adolescents). If the
random allocation of treatments to medication numbers is the responsibility of the
randomization manager at Allergopharma GmbH & Co. KG or an authorized designee,
according to the corresponding Standard Operating Procedure (SOP). The random schedules
and relevant forms will be kept in the department of Process and Formulation / Clinical
Supplies sealed and locked. They will not be accessible to the trial team prior to unblinding of
the trial after database lock. If the trial is not be stopped after the interim analysis the trial team
would kept unblended until the end of the second part of the trial.
The investigator requests a randomization number for a patient via eCRF. A randomization
number must not be requested before proof is given that the randomization code envelopes is
available at the trial site.
The random list will not be accessible to the trial team prior to termination of the trial, solution
of all queries, determination of the analysis sets, specification of the analysis, and hard lock of
the database.

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The iDMC or an independet designated statistician will have access to original randomization
schedule. The details will be fixed in the iDMC charter.
3.6.3 Stratification
It is anticipated to include 30% - 50% adolescents. Therefore, it is required to stratify patients
according to age groups to ensure a balanced representation in the treatment arms. Adolescents
are defined as 12 years and < 18 years of age at the randomization visit.
Blinding
The used placebo will be identical in appearance to the active investigational medicinal product
and also the vials of all treatment arms are identical in their outer appearance. The trial sites
will receive trial medication in a blinded fashion. The randomization module of the e-CRF will
assign the appropriate medication number to each patient as soon as the investigator has
provided the relevant information on the age stratum and requests the assignment. Each
number will only be assigned once, even if a patient is not treated after randomization.
3.6.4 Randomization Codes and Decoding of Envelopes

Three sets of randomization code emergency envelopes will be available. One set will be
stored under lock and key at the Drug Safety Department of Allergopharma GmbH & Co. KG.
The second set of sealed randomization code emergency envelopes will be sent to the
investigators along with the initial shipment of trial medication. The third set of sealed
randomization code emergency envelopes will be sent to the chairman of the DSMB.
The investigators will receive sealed randomization code emergency envelopes corresponding
to the randomization numbers on the trial medication labels for each patient in that trial site.
Each investigator is responsible for the safe keeping of the emergency envelopes. Before a
patient will be randomized the investigator or designee must check the availability of the
randomization code emergency envelopes.
3.6.5 Unblinding
Unblinding in case of emergency
The emergency envelopes may only be opened in the case of an emergency, if knowledge of
trial treatment will influence the further emergency procedures of the patient.
Date and time, reason for opening, as well as name and initials of the investigator have to be
documented on the opened emergency envelope. Unblinding must be reported immediately to
the Drug Safety Department of Allergopharma GmbH & Co. KG by using a provided
Unblinding Report Form. This form has to be filed, together with the code envelope, in the
Investigators Site File. Unblinding has to be documented on the source data sheets and the
eCRF of the patient. The responsible CRA has to be informed as soon as possible after
unblinding.
If the random code for a patient has been broken, the trial treatment must be stopped. The IMP
must be held in quarantine under the given IMP storage condition until further instructions by
the sponsor are received.
Unblinding by the Drug Safety Department
The Drug Safety Department of Allergopharma GmbH & Co. KG may break the code for a
patient only if a serious adverse event (SAE) was considered to be a suspected unexpected
serious adverse reaction (SUSAR). The blinding status will be maintained for persons

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responsible for the conduct of the trial and those responsible for data analysis and interpretation
of trial results.
Unblinding by the DSMB

The members of the DSMB are blinded and will maintain the blinding as far as possible. In
special cases, the DSMB member may decide to unblind patients according to the DSMB
charter.
In special situations, the members of the DSMB may become unblinded either for a single
patient, one treatment group, or the entire trial. The chairman of the DSMB receives the sealed
randomization code emergency envelopes in order to be able to unblind a single patient, if
necessary, due to medical reasons. Additionally, the chairman of the DSMB will receive
randomization lists on the allocation of the patients to the treatment group (active group I,
active group II or placebo) to enable the separate unblinding of a treatment group. The
chairman of the DSMB is responsible for the correct storing of the sealed randomization code
emergency envelopes and the randomization lists.
Regular unblinding during interim analysis
Only the iDMC and an independent designated statistician will have access to original
randomization schedule until the interim analysis. If the trial could not be stopped the blinding
will be kept to all other persons (patient, investigator and sponsor) until the end of the second
part of the trial. The details will be fixed in the iDMC charter.
Regular unblinding at end of trial
The investigator will remain blinded throughout the trial and will only be made aware of the
treatment allocation at the end of the trial when the database has been closed, and the data
analysis has been performed.
At the end of the trial, all emergency envelopes must be returned to the sponsor/medical
department and checked for intactness before closure of the database.

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3.7 Treatment of Patients
3.7.1 Schedule of Assessments

Table 1 Schedule of Assessment Screening and Baseline Phase
(The same assessments will be performed in part II if necessary but according to the timelines in
Figure 2)
Screening Phasee Baseline Phase
Assessment of Asthma Control by eDiary
Task Mar. 2017 Sep. 2017 Oct. 2017 Jan. 2018
S1 S2 S3 b,d B1 B2 B3 B4 B5
+4 +4Weeks +4 +4 +4 +4
Visit Weeks Weeks Weeks Weeks Weeks
Adverse Events X X X X X X X X
Allergic Symptoms X
Allocation of Screening Number X
Check and Hand-out of Paper ACQ6 X X X X
Check Inclusion/Exclusion Criteria X X X
Check of eDiary for ACQ, daily X X X X
Questions for Rhinoconjunctivitis and
Asthma
Check of Paper MiniAQLQ X X X X
Concomitant Medication X X X X X X X X
Confirmation of Next Visit X X X X X X X X
Confirmed Diagnosis of Asthma X
Demographic Data X
Evaluation of Paper ACQ6 Score X X X X
Hand-out and Training eDiary X
Hand-out of Asthma Control and X X X X X X X X
Reliever Medication
Lung Function Test FEV1 X X X X X X X X
Medical History/ Concomitant X
Diseases
Informed Consent/ Assent X
Pregnancy Test X
Physical Examination X
Reversibility Test a) X
Safety Laboratory /Urine X
Serum Sample Collection for X
Immunoassay
Skin Prick Test X
Switch of Asthma Medication to X
Budesonide equivalent
2-month Telephone Contact Xb
Vital Signs X
a
Historical data not older than 2 years will be accepted
b
If baseline phase is not directly connected to the screening phase, a 2-month telephone contact with patients must take place
c
Additional screening visits may be needed in the tapering process
d
Patients included at the end of the screening phase can switch from visit S2 directly to visit B1 and proceed with the tapering in the baseline
phase even if the minimal ICS dose has not been determined during the screening phase
e
Screening visit 1 can be spitted in two visits (e.g. due to wash-out period).

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3.7.1.1 Double-Blind Phase: Treatment Phase

Table 2 Schedule of Assessments Treatment Phase (The same assessments will be
performed in part II if necessary but according to the timelines in Figure 2)
Treatment phase eDiary Phase after Treatment

Assessment of Asthma Control and Exacerbation by eDiary
Feb. 2018 Sep. Oct. 2018 Jan. 2019
April 2019
Task 2018
Final Visit/
Premature
D1 D2 D3 D4 Termination
a
Visit T1 T2 -T15+ +4 weeks +4 weeks +4 weeks +4 weeks +4 weeks
Adverse Events X X X X X X X
Advise Patient to assess T9 only
symptoms of
Rhinoconjunctivitis and
intake of Medication for 2
weeks
Check Inclusion/Exclusion X
Criteria
Check of eDiary for ACQ X X X X
Check of eDiary for daily X X X X X X
Questions of Asthma
Check eDiary for daily T10 X X X X
Questions of
Rhinoconjunctivitis
Check of Paper MiniAQLQ X X X X
Concomitant Medication X X X X X X X
Confirmation of Next Visit X X X X X X
Hand-out of Asthma X X X X X X
Control and Reliever
Medication
Injection of IMP X X
Likert Scale of Overall X
Tolerability
Lung Function Test FEV1 X X
before and after each
Injection
Physical Examination X X
Pregnancy Test X X
Randomization X
Safety Laboratory/Urine X X
Serum Sample Collection Last T-
for Immunoassay VISIT
only
Vital Signs X X
a
Last injection and hand-out of diary should be no later than 19. September 2018.
T= Treatment Visit
T15+=
In case of dose modification more than 15 Treatment Visits are necessary. Treatment visits should be performed until the diary phase
starts. In some cases more than 15 injections are possible as well as less than 15 injections.

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3.7.1.2 Explanations and Limitations

Table 3 Explanations and Limitations
Measures and Tasks Explanations
Adverse Events The investigator has to evaluate, record, and report all new and ongoing
AEs according to section 6.1.3.
Allergic Symptoms The investigator will evaluate and record the allergic symptoms of the
patient (eyes, nose and lung) (section 6.2.3.4).
Allocation of Screening
The trial site will assign a screening number to each patient.
Number / Patient Allocation
Check Inclusion/Exclusion The investigator will check all inclusion and exclusion criteria as
Criteria described in section 3.5.
Check and Hand Out of Paper The investigator (or designee) will evaluate and check the paper ACQ6
ACQ6 during each screening visit for accuracy and completeness. (chapter 5.1).
Check of eDiary for ACQ, daily The investigator (or designee) will evaluate and check eDiary entries at
Questions of Asthma and daily each visit for accuracy and completeness (Chapter 5.1). According to the
Questions of score of the ACQ6, patients asthma can be evaluated as controlled or not
Rhinoconjunctivitis controlled. Asthma medication has to be adjusted accordingly. For the
evaluation of the ACQ6 (paper and electronic refer to chapter 5.1).
Concomitant Medication The investigator will evaluate and record relevant past and current
medication at first visit and all changes in subsequent visits (inclusive
controller and reliever medication) (chapter 4.4).
Confirmation of Next Visit At the end of each visit the next visit of the patient shall be scheduled
according to protocol and the tables 1 and 2,
Asthma Diagnosis Diagnosis of asthma according to section 6.2.3
Demographic Data Year of birth, sex, height, weight, ethnic group, smoking status, and pet
contact will be assessed (section 6.2.3.1).
Hand-out and Training eDiary The investigator (or designee) will hand out eDiary devices and instruct
and train patients on the correct completion of it at scheduled time points
during the 2 assessment periods. See tables 1 and 2, Schedule of
assessment. (chapter 3.2.). For further details of the diary and the
assessment of the ACQ6 electronically with the diary (chapter 5.1 and
section 13.2.2).
Hand-out of Asthma Control Investigators hand out asthma control and reliever medication and explain
and Reliever Medication usage of both medication to the patient (section 4.4.1).
Injection of IMP The investigator will review the individual administration schedule prior to
each patient visit to ensure adherence to the injection schedule. Relevant
instructions required to be followed are specified in chapter 4.3.
Likert Scale of Overall Tolerability assessment performed by the patient and the investigator
Tolerability (Likert scale) (section 6.2.4.).
Lung Function Test (PEF and Lung function FEV1 will be measured during each visit and before and
FEV1) after each injection. PEF measurement will be done by the patient using
the built in PEF meter of the eDiary device. For details on peak flow
measurement or lung function test, see section 3.8.3 and appendix
documents 18.3 and 18.4.
Medical History/ The investigator will record relevant past and ongoing diseases during the
Concomitant Diseases screening visit (section 6.2.3.2).
Patient (Parent) Informed Before any trial-related activities and in agreement with applicable
Consent /Assent regulatory requirements, the investigator must provide fully verbal and
written information to the patient and both parents or legal guardian
(adolescents).
Consent for optional blood sampling may be given and must be
documented in writing (section 12.3).
Physical Examination The investigator will perform a complete physical examination. (section

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3.7.1 and 6.2.2.2).

Pregnancy Test For women with childbearing potential only (section 6.2.1 and 6.2.3.5).
Randomization & Allocation of The investigator will allocate a random number to the patient by the eCRF
Random Number. as described in Section 3.6.2.
Reversibility Test Historical data not older than 2 years are acceptable. See Appendix
document 18.5 and section 3.8.4).
Safety Laboratory/Urine For details refer to the laboratory manual and section 6.2.1.
Serum For details refer to the laboratory manual and section 3.8.2.
Sample Collection for
Immunoassay
Skin Prick Test (SPT) For details, see section 3.8.1 and 18.1.
Switch of Asthma Medication At screening visit 1 the patient switch their asthma medication to
to Budesonide equivalent. Budesonide equivalent. For details, see section 5.1 Table 7.
2-month telephone contact If baseline phase is not directly connected to the screening phase, at a 2-
months interval a telephone contact with patients must take place. Changes
of inclusion/exclusion criteria (e.g. pregnancy) and adverse events or
concomitant medication has to be documented in the eCRF (see section
3.7.1 Schedule of Assessments).
Vital Signs After at least 5 minutes in sitting position measurement of heart rate,
respiratory rate and blood pressure (section 6.2.2.1).
3.8 Methods of Performing Trial-related Tests

For the selection of patients and safety reasons, clinical tests and blood analyses have to be
performed.
3.8.1 Skin Prick Test

At visit S1 a routine SPT will be carried out to allow an assessment of the sensitization of the
patients. This test must be performed even if a current positive SPT is available since inclusion
criteria will be checked by this test.
Concomitant medication has to be checked for interference with SPT and discontinued prior to
its conduct. (Appendix 18.2, Table 12).
The tests are performed on the volar sides of both forearms with the following substances and
test solutions:
Negative control: NaCl
Positive control: histamine dihydrochlorid 1.7 mg/mL
Df
Dp
For the documentation of SPT results, the following rules should be considered:
a) positive control is rated positive with a wheal size 3 mm
b) negative control is rated negative with a wheal size < 2 mm.
SPT results are documented 15 (+5) minutes after application of the SPT solutions. The wheal
contours will be encircled with a pen and transferred to a raw data sheet with adhesive tape.
The longest diameter must be entered into the CRF.
A late cutaneous response should be monitored. (EMA/414476/2011, Dreborg S & Frew A.,
1993). Further instructions are described in the Appendix 18.1.

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3.8.2 Immunological Profile

The assessment of the immunological profile includes the following parameters:
Total IgE at visit S1
Specific IgE for all allergens listed below at visit S1
Specific IgG4 for D p and D f at visits: S1, and T15+ (last treatment visit)
For evaluation of inclusion/exclusion criteria, IgE-sensitization will be determined for the
following allergens:
Specific IgE for all allergens which need to be evaluated to check adherence to in/exclusion
criteria and characterize the patients:
For all patients:
Grass (Grass mix earlybloom)
Birch (Betula verrucosa)
Cat epithelia
Dog epithelia
Alternaria (Alternaria alternate)
Cladosporium (Cladosporium herbarum)
House dust mite D f
House dust mite D p
Aspergillus (Aspergillus fumigatus)
Penicillium (Penicillium notatum)
Blattela (Blattela germanica)
Storage mites Acarus siro, Lepidoglyphus destructor, and Tyrophagus putrescentiae
Depending on region (details will be described in the lab manual):
Cypress (Cupressus sempervirens)
Parietaria (Parietaria judacia)
Ragweed (Ambrosia artemisiifolia)
Mugwort (Artemisia vulgaris)
Alder (Alnus)
Hazelnut (Corylus)
Ash (Fraxinus)
Specific IgE antibodies will be analyzed in order to comply with CHMP Guideline
EWP/18504/2006 (European Medicines Agency, 2008).
A written and detailed instruction for the standardized conduct of taking blood samples (blood
taking, storage and shipment, centrifugation etc.) is specified in the laboratory manual.
3.8.3 Lung Function Test

Determination of the forced expiratory volume in 1 second (FEV1) will be measured during
each visit by the trial site before and 30 minutes after each injection of trial medication
(Chapter 3.7.1).
Daily PEF will be measured every morning (6 am 10 am) before inhalation of SABA by the
patient during the diary phases.

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Test results are mainly related to the patients compliance and cooperation. Thus the initial
PEF measurement has to be assisted by the investigator or an experienced study nurse.
Allergopharma GmbH & Co. KG will provide manual mechanical peak flow meter and
electronic diaries (eDiaries) with integrated PEF meter so that the patients are able to measure
the lung function every day. Data measured with the integrated PEF meter will be recorded
automatically. The measurement has to be performed 3 times with considering the highest
value as valid. For a written and detailed instruction for the standardized conduct of performing
the lung function test see Appendix document 18.4.
3.8.4 Reversibility Test

At entry also a positive test result for full reversibility must have been obtained. If there is not
any historical test within the last 2 years available, a test has to be performed according to the
appendix document 18.5.
Historical test performed within the last 2 years will be accepted for:
FEV1 increase of 12% and 200 mL after inhalation of 400 g of Salbutamol or
other short-acting inhaled bronchodilator equivalent
3.9 Discontinuation Criteria
3.9.1 Discontinuation of Patients

A patient may discontinue his/her participation in the trial at any time without giving a reason.
In addition, an investigator may decide, for reasons of medical prudence, to prematurely
discontinue a patients participation. In either event, the investigator must notify the monitor
within 24 hours. Even though a patient withdrew his/her consent, the investigator should
arrange a final visit for safety reasons. If the date of consent withdrawal is before the final visit,
the voluntary participation of the patient must be guaranteed.
The patient must be withdrawn from the trial if one of the following general conditions apply:
The patient withdraws consent.
A female patient has a positive pregnancy test, irrespective of a planned abortion.
The patients treatment has been unblinded (randomization code broken).
The patient was included into the trial although violating an exclusion criterion or not
fulfilling all inclusion criteria if the patient is at an increased risk due to this violation.
The patient must be withdrawn from the trial if one of the following medical conditions
apply:
In case of a severe systemic adverse reaction ( grade 3 according to WAO classification,
Appendix 18.7) within 24 hours after an IMP injection. No further injection should be
administered to this patient before consultation with the sponsor. The patient will be
withdrawn from the trial after consultation with the sponsor and confirmation of the WAO
classification by the DSMB.
If a patient experiences an intense local reaction (see section 4.3.3) following the first
injection that would require a dose adjustment.
If a patient experiences an allergic systemic reaction (WAO grade 1 and higher) following
the first injection.
Hypotension requiring medical intervention with epinephrine or intravenous fluids.

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Any life-threatening event assessed by the investigator to be related to trial procedure or

administration of IMP.
The patient may be withdrawn from the trial if:

A serious adverse event (SAE) occurs.
In the investigators opinion it is in the patients interest to discontinue the trial for safety
reasons.
A patient that prematurely discontinues participation must be called in for the final visit (except
screening failure). The termination form in the eCRF must be completed even for screening
failures and the drug accountability form must be filled in if applicable. The patient must return
all IMP(s) and all non-IMP (if applicable). Re-screening of patients after discontinuation is not
allowed.
3.9.2 Discontinuation of Trial Sites

Each study site should contribute between 8 and 24 randomized patients during the first part of
the trial until the interim analysis. Allergopharma GmbH & Co. KG reserves the right to
terminate this trial prematurely at a specific trial site in case of:
Serious or persistent noncompliance to GCP or misconduct of the trial by the
investigator/institution.
Insufficient patient recruitment (less than 4 patients available for randomization).
3.9.3 Discontinuation or Premature Suspension of the Trial

Allergopharma GmbH & Co. KG reserves the right to terminate this trial prematurely if, in the
opinion of the DSMB, investigator or the sponsor, an excessive risk exists or if continuation of
the trial does not appear to be reasonably justified (i.e. the trial is not qualified to show efficacy
or harmlessness of the investigational medicinal product).
If the trial is prematurely terminated or suspended for any reason, the investigator must follow
the instructions of the sponsor to stop the trial. The investigator should promptly inform all
affected patients and should assure appropriate therapy and follow-up. Furthermore, the
investigator should promptly inform the institution where applicable.
If the investigator/institution terminates or suspends a trial without prior agreement of the
sponsor, the investigator/institution should promptly inform the sponsor and should provide the
sponsor with a detailed written explanation of the termination or suspension. Depending on
these communication the sponsor initiates all further EC and CA regulatory consequences.
In both cases, Allergopharma GmbH & Co. KG will promptly inform the CA and EC and
provide them with a detailed written explanation of the termination or suspension.
If the CA or EC terminates or suspends its approval/favorable opinion of a trial, the sponsor
will inform the investigators and institutions and provide them with a detailed written
explanation of the termination or suspension.
Suspended trials can only be restarted after reapproval or positive opinion from CA and EC.
The ending of the trial according to the predefined rules after the interim analysis are described
in section 8.3.

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3.10 Patient Compliance

IMP will be administered directly by the trained investigator. Each administration of IMP is
documented in the respective patient file. Due to the application form, the patients compliance
can be easily observed and documented by the investigator and the study nurse in the eCRF
and the patient file. No compliance diaries are necessary.
4 Trial Medication
4.1 Investigational Medicinal Product (IMP)
The trial preparations will be manufactured by Allergopharma GmbH & Co. KG according to
the revised Good Manufacturing Practice (GMP) Guidelines of the WHO. Manufacturing
procedures are described in detail to guarantee pharmaceutical quality. The production and
purification process of the investigational preparation used in this clinical trial are described in
the Investigators Brochure.
4.1.1 Trial Preparation

House dust mite allergens are extracted from purified mite bodies (D p with buffered saline,
partially purified by diafiltration, characterized, chemically modified by treatment with
aldehydes, and adsorbed onto aluminium hydroxide.
Table 4 Trial Preparation

Active treatment
Placebo 3000 PNU group 5400 PNU group
Strength A 0 500 900
TNU/mL
Strength B 0 5000 9000
PNU/mL
All needed strengths will be provided in 3 mL vials. They contain the following components:
Table 5 Content of components
Component Reference Function Concentration
Phenol Ph. Eur. Preservative 4.0 g/L
Adsorbate
Aluminium Ph. Eur. 1.0 g/L
(as Al(OH)3)
Sodium Osmolarity
Ph. Eur. 9.0 g/L
chloride adjustment
Volume
3.0 mL
filled/vial
4.1.2 Placebo
A placebo solution will be supplied as comparator. The placebo preparation used is identical to
the active solution but without any allergen substance in it. The vials containing the placebo
solution are identical to the trial preparation of the active product in their outer appearance.

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4.1.3 Packaging and Labelling

Labelling of the investigational product will be performed in accordance with GMP. The labels
used will be produced in accordance with the country specific regulations. All trial preparations
are supplied according to local regulations. Allergopharma GmbH & Co. KG or an authorized
CRO will supply all trial preparations. The packaging material is of uniform and neutral
design. Each package is marked as trial medication, stating the trial code as well as the name
and address of the manufacturer.
4.1.4 Storage, Accountability and Destruction

The IMP will only be shipped if all requirements have been fulfilled according to the sponsor
SOP. The sponsor or an authorized CRO will ship the trial medication directly to the trial sites
or the corresponding pharmacy. A detailed inventory of all shipments including shipment date,
number of vials per strength, batch numbers, expiry date, and allocated random numbers,
which will be used in this clinical trial, will be kept on file. The responsible department at
Allergopharma GmbH & Co. KG will coordinate all shipments.
Storage
IMP is to be handled and stored safely and properly according to GCP and in agreement
with the given storage instructions.
IMP has to be stored between +2C and +8C. The IMP must not be frozen!
IMP stored outside of these ranges must be put under quarantine by the trial team.
Sponsor/CRA must be informed in order to confirm if the IMP can further be administered
or if new IMP must be shipped to the site without delay.
IMP which was frozen once must not be administered to a patient under any
circumstance!
The investigator/designee is responsible for the appropriate storage at the trial site.
Under no circumstances the investigator or other trial personnel will allow that IMP is used
for purposes other than those directed by the protocol.
The expiry date is printed on the label of each vial and has to be strictly taken into
consideration. As soon as the expiry date of the IMP has been exceeded or a patient has
terminated the trial, the preparations have to be quarantined at the trial site and returned to
Allergopharma GmbH & Co. KG as outlined in section 4.1.4.
Accountability
It is the responsibility of the investigator to perform an adequate and complete accountability
check of the investigational product. Signed and completed confirmations of receipt must
always be sent to the sponsor to verify the proper receipt of IMP at the site.
The investigator must dispense IMP only to patients enrolled in the trial.
Destruction
At least at the end of each treatment period all vials (empty vials, used vials as well as unused
and expired IMP [including the covering boxes]) have to be returned to Allergopharma GmbH
& Co. KG. The shipment will be organized by the monitor after the drug accountability at the
site had been completed and verified.
4.2 Administration of IMP

Before each injection the investigator has to verify the identity of the patient (patient identifier,
randomization number) versus the information provided on the IMP label following the two-

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man rule. The investigator has to ensure that the patient receives the correct strength of IMP
and is free of symptoms of acute illness (e.g. common colds or allergy-related symptoms).
Before each injection the vial should be shaken to distribute the adsorbate.
Due to safety reasons, all patients have to undergo a FEV1 measurement before and 30 minutes
after each injection in order to recognize pulmonary reaction in time. If respiratory symptoms
have increased before the injection or the FEV1 value dropped to less than 80% of predicted
normal, then the injection must be postponed until the patient has reached a more stable
asthmatic condition. A trial medication application in a patient with less than 80% of predicted
normal value is a protocol deviation!
The investigator has to consider possible allergic local or systemic adverse events before
continuation of the administration of the trial preparations in order to be able to modify the
applied dose (see also 4.3.3).
The injections have to be performed by a qualified and trained investigator or by especially
trained study nurses according to national practice and law under supervision of the
investigator, according to the injection schedule and only within allowed time frames. An
administration of trial medication outside the allowed visit window is a protocol deviation.
At the beginning of treatment, injections must be administered at intervals of 7 days. The dose
will be increased progressively by one step at a time only, provided that the previous dose has
been tolerated well.
The injections have to be administered
slowly,
strictly deep subcutaneously,
under sterile precautionary measures,
on the extensor side of the upper arm, a hands breadth above the elbow,
using a short-ground cannula (provided by sponsor)
Figure 5 Correct form of administration
The following administrations are wrong and must be avoided:

Figure 6 Wrong form of administration

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To avoid an intravasal administration it is necessary to aspirate before injection.

Different batches of IMP must not be mixed up in one injection.
After each administration at the trial site, the patient has to be kept under close supervision for
at least 30 minutes. The investigator has to ensure appropriate emergency care during the
whole treatment phase.
If any systemic AE occurs, the observation period will have to be prolonged until the patient
has a stable condition. Before the patient leaves the trial site, an assessment of the patients
condition and the local reaction at the site of injection will take place. The patient will be
instructed to contact the investigator immediately if any signs of side effects occur during the
observation period or following the completion of the observation period.
All adverse events at the injection site and anaphylactic reactions observed, as well as
treatment with anti-allergic medication such as antihistamines, cortisone, -sympathomimetics,
and adrenaline given must be documented in the patient file and in the eCRF. Please refer to
section 6.1, if any dose modification is recommended.
It is necessary to instruct the patient to avoid physical efforts (strenuous physical work, sports)
during the days when injections are administered but also other interfering factors like alcohol,
for example.
4.3 Dosage of IMP

Table 6 Schedule for Dose Escalation and Maintenance for 3000 PNU and 5400 PNU
Dose of Injection
Injection 3000 5400
Number Treatment phase Interval Strength mL Placebo (PNU) (PNU)
1 A 0.1 0 50 90
2 7 days A 0.2 0 100 180
3 7 days A 0.4 0 200 360
Dose
4 escalation 7 days A 0.6 0 300 540
5 phase 7 days B 0.1 0 500 900
6 7 days B 0.2 0 1000 1800
7 7 days B 0.4 0 2000 3600
8 7 days B 0.6 0 3000 5400
9 2 weeks B 0.6 0 3000 5400
10 4 weeks B 0.6 0 3000 5400
Maintenance
11 phase 4 (+2) weekly B 0.6 0 3000 5400
et seqq. To be
continued

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4.3.1 Dose Escalation

The dosage schedule (Table 6) is the standard schedule but may be adjusted according to the
well-being of the individual patient. If the maximum dose is reached, this dose will be
administered during the course of the maintenance treatment.
In general, the time intervals during the escalation have to be adhered to. The injection interval
should not be less than 7 days. Deviations from the dose escalation scheme are only allowed in
case of AEs or prolonged injection intervals (Section 4.3.3 Dosage Modification and
Adjustment).
During dose escalation, injections will be administered at weekly intervals with increasing the
dose with each injection until a maximum dose of 0.6 mL of strength B has been reached.
No other doses than that defined above must be used.
4.3.2 Maintenance Treatment

After the maximum dose has been reached it will be administered again after 2 weeks.
Afterwards, the injection interval will be prolonged to 4 weeks. The maximum individually
tolerated dose will be given until the start of the diary phase.
4.3.3 Dosage Modification and Adjustment

No dose reduction is necessary when starting a new batch of IMP to continue the therapy. The
following intervals between injections must be kept (Table 6):
During dose escalation:
Injection interval should be 7 days. (A delay of 7 days is acceptable.)
During maintenance:
Injection interval should be 2 weeks at the first maintenance injection. (A deviation of 3
days is acceptable.)
Injection interval should be 4 weeks at the second and third maintenance injection and
thereafter. (deviations of -2 to +14 days are allowed.)
In special occasions, e.g. sick leave, it may not be possible to keep these intervals. In this case,
the following dose adaptation procedure must be applied.
Procedure for prolonged intervals during escalation

Interval since last injection > 2 weeks but 3 weeks: Escalation is still possible as
foreseen by the escalation scheme (Table 6).
Interval since last injection > 3 weeks but 4 weeks: Repetition of the last applied dose. If
well tolerated, escalation has to be continued as specified in the escalation scheme (Table
6 and Table 7).
Interval since last injection > 4 weeks but 5 weeks: Reduction by 1 dose step of the last
applied dose. If well tolerated, escalation has to be continued as specified in the escalation
scheme (Table 6 and Table 7).
Interval since last injection > 5 weeks: the therapy has to be restarted with strength A
applying a volume of 0.2 mL.
Interval since last injection > 5 weeks after first injection (0.1 mL): the therapy has to be
restarted with strength A applying a volume of 0.1 mL.
If well tolerated, escalation has to be continued as specified in the escalation scheme. This
applies to dose steps and injection interval length.
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Procedure for prolonged intervals during maintenance treatment

Interval since last injection > 5 but 10 weeks: Repetition of the last applied dose.
Interval since last injection > 10 but 12 weeks: Reduction by 1 dose step of the last
applied dose. If the first dose reduction is not tolerated a second dose reduction by 1 dose
step of the last applied dose should be administered.
Interval since last injection > 12 weeks: The therapy has to be restarted with strength A
applying a volume of 0.2 mL.
If well tolerated, the respective dose has to be selected as specified in the dosage schedule
(Table 6 and Table 7). This applies to dose steps and injection interval length.
Dosage modification after intense local reaction

Intense local reaction:
A reaction at the injection site that leads to distinct discomfort interfering with the patients
daily activities. E.g. an intense local reaction is also present, if the reaction after injection leads
to swelling of >10cm at the injection site.
Dosage modification after intense local reaction:
During escalation phase: Reduction by 1 dose step of the last applied dose. If well
tolerated, escalation has to be continued as specified in the escalation scheme in the dosage
schedule. If again not well tolerated, a second dose reduction by 1 dose step of the last
applied dose should be done.
During maintenance phase: Reduction by 1 dose step of the last applied dose. If well
tolerated, the maintenance dose (e.g. strength B 0.6 mL) has to be applied at the following
visit. Injection intervals should be kept at 4 weeks. If again not well tolerated a second dose
reduction by 1 dose step of the last applied dose should be performed.
If well tolerated, further doses have to be selected as specified in the dosage schedule.
Dosage modification after systemic anaphylactic reaction

A systemic anaphylactic reaction is graded based on organ systems involved and severity
according to the WAO Subcutaneous Immunotherapy Systemic Reaction Grading System
[18].
This grading system is used for dose modification in case of a systemic anaphylactic reaction
(see appendix 18.7):
Grade 1: Reduction by 1 dose step of the last applied dose
Grade 2: Reduction by 2 dose steps of the last applied dose
For grade 1 and grade 2: If the first dose reduction is not tolerated, a second dose reduction by
1 dose step of the last applied dose should be administered. If well tolerated, escalation has to
be performed as specified in the escalation scheme (Table 6 and Table 7). This applies to dose
steps and injection interval length.
Grade 3/ grade 4: The patient must be withdrawn from the trial after consultation with the
DSMB and sponsor.
In case of a systemic anaphylactic reaction (grade 3), this event has to be reported as SAE
and the respective procedures, especially reporting within 24 hours, have to be followed (see
section 6.1.4).

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4.3.4 Precautions and Overdose

In case of an overdose or mix-up of treatments, side effects (e.g. generalized skin redness,
urticaria, mucosal reactions, drop of blood pressure, dyspnea) may be more intense. An
anaphylactic shock may occur.
The occurrence of side effects may require treatment with antihistamines, corticosteroids and
adrenaline. For treatment of an anaphylactic reaction see the Guidelines of WAO (40).
It is the responsibility of the investigator to check correct storage and use of the IMP, e.g. to
use the IMP in the correct dose order during escalation period, to use the IMP to the assigned
patient only and not to use expired IMP.
This is a placebo-controlled trial: Therefore, mix-up of IMP may be harmful to the patient.
4.3.5 Actions in Case of Emergency

In case of an anaphylactic reaction the investigator has to follow the recommendations of the
specific treatment which includes the application of adrenaline/epinephrine, corticosteroids, -
sympathomimetics, antihistamines as well as the substitution of volume. Anaphylaxis with
necessary therapeutic interventions has to be regarded as SAE and has to be documented and
reported as described in Section 6.1.4.
Treatment of emergencies due to anaphylactic reactions have to be treated according to
international Guidelines.
Drug Interaction
Concomitant treatment with symptomatic anti-allergic drugs (e.g. antihistamines,
corticosteroids, cromoglycates) may affect the tolerance level of the patient. In case of stopping
such treatment, it has to be considered to reduce the dose level of IMP in order to avoid allergic
reactions.
The use of betablockers is not allowed because of increased reactivity of the body in case of
allergic reactions. The use of ACE-inhibitors has to be deliberated and possible alternative
drugs have to be prescribed.
4.4 Concomitant Medications

Concomitant medication is any medication other than the trial product that is taken during the
entire clinical trial. Medication taken only before entering the clinical trial is considered as
previous medication.
As medication may have an influence on the outcome of this trial, it is absolutely important to
instruct the patients that they have to report their daily medication (dose and substance) and
any use of concomitant medication especially cyclooxygenase inhibitors like e.g. aspirin or
diclofenac at the trial visit.
The sponsor will provide the patients with symptomatic asthma medication (section 4.4.1). It is
the obligation of the investigator to instruct the patients how to take this medication.
4.4.1 Permitted Asthma Medication

The medication will be bought by the sponsor. It is the sponsors responsibility to organize
shipment of the asthma medication directly to the trial sites or pharmacies. A detailed
inventory of every shipment will be filed by the sponsor and the investigator.
The following medication will be permitted for symptomatic treatment of asthma during the
conduct of the trial:
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Budesonide up to 1200 g per day dry powder inhalation from a tube-shaped inhaler
Acute symptomatic treatment of lower airways symptoms will be treated with Salbutamol
MDI 100 g per dose used only as required (p.r.n.).
If further treatments (i.e. oral corticosteroids) are required for the treatment of asthma
exacerbations, these may be used.
Budesonide and Salbutamol will be provided by the sponsor to the investigator. The
investigator will dispense the medication according to requirements of the patient to achieve
asthma control. The investigator is responsible for maintaining accurate drug accountability on
a patient level. The investigator has to assure that medication dispensed to the patient must not
expire before the next scheduled individual patient visit and is available in sufficient amounts
for the patient. A possible delay of scheduled visits has to be taken into account.
Expired and unused asthma medication will be collected and returned to the sponsor after each
diary season.
4.4.2 Restricted Medication
Medication prescribed by the investigator

Should more severe upper or lower airways symptoms develop, a short course of oral
corticosteroids may be administered only on prescription by the investigator. Treatment of
exacerbations should follow the following dose schedule:
3 tablets of 5 mg Prednisolone, each, on the first day followed by
2 tablets on the second day and
1 tablet on the third day.
In cases of very severe exacerbations, where asthmatic symptoms dominate, patients should be
treated with higher doses of oral corticosteroids (Written asthma action plan, GINA, 2015).
Vaccination
If patients received vaccination against viral or bacterial pathogens there should be at least a 2
week period between vaccination and the start of the immunotherapy.
For patients receiving concurrent vaccination, there should be at least 1 week between the last
AIT injection and vaccination. AIT should be continued not earlier than 2 weeks after
vaccination with reduction of one dose step.. The requested timeframes might be extended if
requested by the manufacturer of the administered vaccine.
It should be noted that due to the given timeframes vaccination during the dose escalation
period is not possible.
4.4.3 Non-permitted Medication

Not allowed is any medication for treatment of asthma other than Budesonide and Salbutamol
(e.g. treatment with mast cell stabilizers or antileukotrienes).
The following medication have to be discontinued before performing a diagnostic test
according to their respective half-life:
Any medication (oral anti-histamines, oral corticosteroids, etc.) that could interfere with the
skin reaction has to be stopped before performing a SPT according their half-life (e.g. short
term high dose systemic corticosteroids approx. 1 week and local corticosteroids approx. 2
weeks prior to the test).

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Short acting antihistamines (e.g. Diphenhydramine) has to be stopped 2 days, long-acting

antihistamines (e.g. Fexofenadine, Ceterizine, Loratadine or Desloratadine) 7 days prior to
SPT.
Bronchodilator medication should be withheld 4 hours for SABA and 12 hours for
LABA before the conduct of the reversibility test.
4.5 Diagnostics
All diagnostics needed for this clinical trial will be provided by the sponsor (e.g. test solutions
for SPT, urine dip sticks, and pregnancy tests). The expiry date has to be strictly taken into
consideration.
It is the responsibility of the investigator to document the Confirmation of Receipt form and
return it to the sponsor. The investigator must use provided diagnostics only in purpose of the
trial.
At the end of the trial all diagnostics (used and unused) provided by the sponsor have to be
accounted by the monitor and collected and returned to Allergopharma GmbH & Co. KG
except for used urine dip sticks, pregnancy tests and used prick test lancets.
5 Assessment of Efficacy
5.1 Asthma control assessment
The Asthma Control Questionnaire (ACQ), in the original version with 7 items and in
shortened versions with 6 or 5 items, is able to assess adequately the patients asthma control
status. It has been shown to be a valid tool that allows an accurate and reproducible assessment
of asthma control compared to other commonly used instruments [19].
The shortened version ACQ6 is composed of 6 disease-related events experienced during the
previous week and scored by the patient:
night-time awakening due to asthma
symptoms on waking
limitations of activities
shortness of breath
wheezing
average number of daily puffs of short-acting inhaled beta-2 agonists bronchodilator used.
Each event is scored from 0 (no impairment) to 6 (maximum impairment). The overall score is
the average of the individual scores, ranging from 0 (totally controlled) to 6 (severely
uncontrolled).
In this trial, the cut-off score 1.0 will be used to distinguish between controlled (ACQ6 1.0)
and uncontrolled (ACQ6 > 1.0) asthma. The patients asthma is considered to be controlled if
the ACQ6 is 1.0 in 2 consecutive weeks at the end of the assessment period. If the ACQ6-
score is > 1.0 in either of the 2 weeks, the patients will be considered as uncontrolled and the
ICS dose has to be increased.
ACQ6 at screening
At screening, a paper version of the ACQ6 will be used to assess asthma control. At visit S1 all
patients will start with switching their currently used ICS to Budesonide at the equivalent dose
between 400-1200g per day (Table 7). After that, Budesonide will be increased/decreased

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step wise in pre-defined steps according to Figure 3 until the minimal inhaled Budesonide dose
required for asthma control will be achieved.
Table 7 Equivalent ICS daily doses (g) to Budesonide according to GINA 2014
Adults and adolescents 12 years and older

Inhaled corticosteroid Low Medium High
Budesonide (DPI) 200-400 >400-800 >800

Beclametasone dipropionate (CFC) 200-500 500-1000 >1000
Beclometasone dipropionate (HFA) 100-200 >200-400 >400
Ciclesonide (HFA) 80-160 >160-320 >320
Fluticasone propionate (DPI) 100-250 >250-500 >500
Fluticasone propionate (HFA) 100-250 >250-500 >500
Mometasone furoate 110-220 >220-440 >440
Triamcinolone acetonide 400-1000 >1000-2000 >2000
CFC: chlorfluorocarbon propellant; DPI: dry powder inhaler; HFA: hydrofluoroalkane
propellant.
ACQ6 at baseline and after treatment
At baseline and after treatment an electronic version of the ACQ6 will be used to assess asthma
control. At baseline the patient will start with his control dose assessed during the screening
phase. If the minimal control dose has not been achieved during the screening phase the patient
will start with the dose of the last increase/decrease step. ICS doses will be increased/decreased
step wise in pre-defined steps (200g, 400g, 800 g, 1200 g) according to Figure 4 until
the minimum asthma control dose will be achieved. Patients not controlled under 1200 g per
day Budesonide have to be excluded at baseline as well as patients controlled with 200 g or
still controlled after 2 reduction steps. After treatment the patient will repeat the tapering of the
ICS dose starting with the minimum dose for asthma control determined in the baseline phase.
In both phases the ACQ6 has to be completed weekly in 4-week intervals. In the first 2 weeks
the patient will be adapted to the change of the ICS dose and the last 2 weeks will apply for the
assessment of the asthma status of the patient. Only if the patient is controlled (ACQ6 1.0) in
both of the last 2 weeks, the ICS dose can be decreased, otherwise the dose has to be increased
(Figure 4). The interval has to be prolonged in case of bronchial infection/disease or other
events with influence on the patients asthma control status in week 3 or 4. In this case, the
diary entries of these respective week is not evaluable and have to be repeated after the end of
infection.
eDiary at baseline and after treatment

In addition to the ACQ6, the following daily information is required for the evaluation of
moderate exacerbations of the patients asthma:
measurement of daily peak expiratory flow
diary questions Q1-Q9 (Table 8)
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The definition of exacerbation is specified in section 5.2.1.
Table 8 Daily questions for assessment of moderate asthma exacerbations
Further there will be daily questions to symptoms and medications of rhinoconjunctivitis.

These questions are specified in section 5.2.2.
The electronic diaries in local language will be supplied by the sponsor. At each visit the
investigator checks the data entries in the diary together with the patient for possible
underlying AEs and concomitant medication and makes proper documentation in the eCRF, if
applicable.

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5.2 Additional Efficacy Variables
5.2.1 Asthma Exacerbation

Time to first exacerbation and number of exacerbations during and after treatment will be
assessed as a secondary endpoints. Moderate and severe asthma exacerbation are defined
according to the official American Thoracic Society/European Respiratory Society Statement:
Asthma control and exacerbations [20]:
Moderate asthma exacerbation

A moderate asthma exacerbation is an event that, when recognized, should result in a
temporary change in treatment, in an effort to prevent the exacerbation from becoming
severe.
One or more of the following criteria have to be fulfilled:
> 50% increase in SABA use and > 8 puffs on 2 of 3 consecutive days compared to
baseline
20% decrease in morning PEF from baseline on 2 of 3 consecutive days compared to
baseline
Night time awakenings requiring SABA use on at least 2 of 3 consecutive nights
The baseline value is considered to be the mean values assessed in week 3 and 4 with the
minimum ICS dose for asthma control during the baseline phase. Emergency room visits
because of the worsening of asthma not requiring systemic corticosteroids, will be classified as
moderate exacerbations.
For the assessment of a moderate exacerbation the following parameters will be documented
by daily entries in the eDiary in addition to the ACQ6:
daily asthma symptoms (cough, tightness, wheezing, shortness of breath).
intake of rescue medication (Salbutamol)
daily morning PEF
night time awakening requiring SABA
Severe asthma exacerbation

Severe asthma exacerbation are events that require urgent action on the part of the patient and
physician to prevent a serious outcome, such as hospitalization or death from asthma.
One or more of the following criteria have to be fulfilled:
use of systemic corticosteroids (tablets, suspension, or injection),
increase from a stable maintenance dose of systemic corticosteroids for at least 3 days
hospitalization or emergency room visit due to the requirement of systemic corticosteroids
for asthma treatment
For consistency, courses of relevant corticosteroids separated by 1 week or more should be
treated and documented as separate severe exacerbation.
Any moderate or severe asthma exacerbation will be documented in the eCRF, based on the
diary entries of the patient, the need for medication and the assessment of the investigator.

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5.2.2 Rating of Rhinitis Symptoms

Rhinitis and conjunctivitis symptoms and medication will be recorded by daily diary questions
at baseline, during and after treatment with IMP. The assessment will be performed by the
CSMS according to Pfaar et al. (2014).
1) Please record your nasal symptoms in the last 24 hours:

itchy nose
0 = did not occur
1 = mild symptoms
2 = moderate symptoms
3 = severe symptoms

sneezing
0 = did not occur
1 = mild symptoms
3 = severe symptoms

runny nose
0 = did not occur
1 = mild symptoms
3 = severe symptoms

blocked nose
0 = did not occur
1 = mild symptoms
3 = severe symptoms
5) Please record your conjunctival symptoms in the last 24 hours:

itchy/red eyes
0 = did not occur
1 = mild symptoms
2 = moderate symptoms3 = severe symptoms
6) Please record your conjunctival symptoms in the last 24 hours:

watery eyes
0 = did not occur
1 = mild symptoms
3 = severe symptoms

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Did you take any of the following medication within the last 24 hours?
Eye drops with antihistamine yes/no
Nasal drops or spray with antihistamine yes/no
Nasal spray with corticosteroid yes/no
Tablets with antihistamine yes/no
Tablets corticosteroid yes/no
Based on these items the CSMS according to Pfaar et al. (2014) will be calculated. Further
details will be defined in the SAP.
5.3 Immunological Parameters

The specific and unspecific immunological effects in each treatment group will be assessed by
analyzing the amount of specific IgG4 of D p and D f before and after therapy. Details on
sample collection and laboratory analysis can be found in Section 3.8.2.
5.4 Optional Exploratory Immunological Parameters

During the course of the investigation, anonymous samples of serum might be transferred to
external laboratories for highly specialized analyses. Further investigations are not planned
especially no genetic investigations. The blood samples itself will not be used commercially.
After termination of these external investigation the final evaluation will be performed by
Allergopharma. The remaining blood samples will be transferred back and destroyed after 5
years or earlier. The patient may consent to provide further blood samples taken at screening
(visit S1) and the last treatment visit. Per blood sample, 40 mL whole blood will be taken.
These samples will be sent to the central laboratory and then to the sponsor for storage up to 5
years after the end of the trial. Further analyses on exploratory immunological parameters will
be performed in the laboratory of the sponsor at Allergopharma GmbH & Co. KG or
anonymous samples of serum might be transferred to external laboratories for highly
specialized analyses. The aim is to study before and after specific immunotherapy the
inhibitory factor, that apparently emerges during successful treatment. Furthermore, allergen-
specific antibodies of different immunoglobulin classes and subclasses will be analyzed using
complex allergen preparations as well as single allergens as test allergens to determine the
patients sensitization profile. The patient must consent in writing. The results of these
exploratory immunological parameters are not part of this clinical trial and therefore will not be
included in the clinical trial report.
5.5 Appropriateness of Measurements

All efficacy and safety parameters measured in this trial are accepted standards and have been
used in clinical studies.
As primary endpoint the reduction of ICS has been chosen to investigate the efficacy of AIT in
patients with allergic asthma. The steroid sparing effect of AIT has been investigated in adults
in double-blind, placebo controlled trials [21-23] and in children in an open label trial
compared to a standard care control group receiving controller and reliever medication
according to GINA 2015 [11]. The reduction of corticosteroids while maintaining asthma
control as endpoint in AIT is based on the concept of disease control recommended by asthma
guidelines [20;24]). Also the Note for guidance on clinical investigation of medicinal products
for treatment of asthma (CHMP/EWP/2922/01; 22-Oct-2015)[13] recommends the
investigation of the steroid sparing effect as one possible primary endpoint for phase III studies
to evaluate AIT as add-on therapy for patients with allergic asthma.
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The ACQ was developed and validated as a composite diary to measure asthma control level
and change in asthma control which occurs either spontaneously or as a result of treatment. It
has been used in different versions: ACQ5, ACQ6 and ACQ7 (33, 34, 35). In all versions the
patient has to recall the health status of asthma from the previous 7 days. The ACQ is validated
for use by paper- and electronic version and will be applied for the assessment of the primary
endpoint and several secondary endpoints in this pivotal trial. Daily entries for symptoms,
nocturnal awakening, need for reliever/rescue treatment and lung function are the preferred
methods for assessing asthma exacerbation (GINA 2015) and will be applied by eDiary as well
in this study. A reasonable cut-off for the determination of controlled, /uncontrolled asthma in
this clinical trial as defined by GINA 2015 is to be considered the score of 1.0. According to
Olaguibel et al. (2012) the cut-off points of the ACQ questionnaire that best agree with the
levels of control proposed by GINA 2006 are: < 0.5 for controlled asthma; 0.5 0.99 for
partially controlled asthma, and 1 for uncontrolled asthma (36). Byrne et al. (2010) showed,
that Patients with GINA classification controlled, partly controlled and uncontrolled
asthma had mean ACQ5 scores of 0.43, 0.75 and 1.62, respectively and concluded that GINA
well controlled/partly controlled corresponds to ACQ5 <1.00(37). Juniper et al. (2010)
demonstrated that measurement properties of the ACQ5, ACQ6 and ACQ7 are comparable
(35).
Increases in allergen specific IgG antibody concentrations, in particular IgG4, provide valuable
evidence for the immunogenic activity of the active preparations.
6 Assessment of Safety
6.1 Adverse Events and Adverse Reactions
6.1.1 Definitions
Adverse Event
An AE can be any unfavorable and unintended sign (including an abnormal laboratory
finding), symptom, or disease temporally associated with the use of a medicinal product,
whether or not considered related to the medicinal product.
For this clinical trial it is mandatory to document AEs during the entire individual patients
trial participation.
Only investigators are allowed to capture and evaluate AEs.
The following should be recorded as an AE:
Any new medical condition detected after screening visit assessment.
Any worsening in intensity or frequency of a medical condition preexisting before
screening visit.
Any unfavorable and unintended sign or symptom resulting from any trial related
procedure.
Any abnormal value detected after screening visit assessment, rated as clinically significant
that is not explained by a concomitant disease documented in the medical history.
Any spontaneous or induced abort.
Any severe asthma exacerbation acc. to the definition of section 5.2.1 has to be recorded as
AE or SAE
The following should not be recorded as an AE:

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A medical condition existing prior to screening visit or detected with screening visit
assessment. This finding has to be documented in the medical history.
The disease which is under investigation in this clinical trial.
Pre-planned surgeries which are premeditated prior the first screening visit
Symptoms, and their intensity, of the primary disease which have already been captured in
the patients diary.
Expected and intended signs and symptoms of mild intensity resulting from diagnostic
procedures.
Pregnancies without any abnormality are not considered as an AE or SAE. They have to be
documented on the Pregnancy Reporting Form in Clinical Trials. Please note: a
pregnancy or a positive pregnancy test result leads to the immediate exclusion from the
trial.
Local reactions at injection sites 5 cm. All local reactions > 5cm should be documented
as an AE. However, all injections site reactions of 2.5 to 5 cm not causing any discomfort
for the patient should not be documented as AE but should be documented in the eCRF.
Symptoms of the investigated disease already captured in the patients diary.
SAE
A SAE is defined as any untoward medical occurrence or effect that
results in death,
is life-threatening,
requires inpatient hospitalization (at least an overnight admission) or prolongation of
existing hospitalization,
results in persistent or significant disability or incapacity,
is a congenital anomaly or birth defect,
is another medically important condition (e.g. anaphylaxis with necessary therapeutic
interventions with the use of epinephrine/ adrenaline, reaction with WAO grade 3, fetal
death, stillbirth).
The term life-threatening in the definition of serious refers to an event in which the patient was
at risk of death at the time of the event. It does not refer to an event which hypothetically might
have caused death if it was more severe.
Medical and scientific judgment should be exercised in deciding whether expedited reporting is
appropriate in other situations, such as important medical events that may not be immediately
life-threatening or result in death or hospitalization but may jeopardize the patient or may
require intervention to prevent one of the other outcomes listed in the definition above.
Adverse drug reaction

An adverse drug reaction (ADR) is any untoward and unintended response to an IMP. ADR
have a causal relationship with the treatment or a causal relationship cannot be ruled out.
6.1.1.1 ADRs of special interest in SCIT

Injection site reactions or systemic anaphylactic reactions are ADRs of special interest in SCIT.
For an injection site (local) reaction the main symptom should be documented to specify the
diagnosis (e.g. injection site swelling X cm right arm). Common symptoms of local reactions
are e.g. pain, tenderness, pruritus/itching, erythema/redness, induration/swelling. It is necessary

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to document the size for the symptoms erythema/redness and induration/swelling to adjust the
dose accordingly (Section 4.3.3).
For an anaphylactic reaction, all symptoms must be documented as 1 diagnosis. The narrative
describing the reaction including the onset and development of all symptoms must be available
in the raw data.
For anaphylactic reactions it is necessary to document the WAO grade to administer dose
modifications accordingly. See Section 6.1.3 for details.
For all anaphylactic ADRs which are not IgE mediated, anaphylactic, the WAO Grading
system should not be applied.
Suspected unexpected serious adverse reaction

A suspected unexpected serious adverse reaction (SUSAR) is an ADR, that is serious and the
nature or severity is not consistent with the applicable product information (e.g. Investigator's
Brochure for an unapproved investigational product or summary of product characteristics for
an approved product).
6.1.2 Classifications
Intensity (severity)
Intensity is a clinical judgment of the investigator and describes the intensity of the event.
Mild: Transient symptoms, no interference with the patients daily activities.
Moderate: Marked symptoms, moderate interference with the patients daily activities.
Severe: Considerable interference with the patients daily activities.
Causality
When assessing the causality of an AE, the investigator has 3 options. The adverse event may be:
related to IMP or
not related to IMP or
related to study procedure.
The causality of an AE is suggested to be related to IMP, if:

the AE occurred in a causal temporal relationship to IMP administration
the localization of the AE implies a causal relationship to IMP administration
The causality of an AE is suggested to be not related, if:

the AE is obviously explained by the patients underlying disease(s)
the AE is in accordance with the effect or adverse effect of a concomitant medication
the AE has occurred already prior to 1st administration of IMP in comparable intensity
and/or frequency
the AE started prior to 1st administration of IMP
the AE does not occur in a causal temporal relationship to IMP administration
the AE is related to any trial procedure (procedure to be specified)
Outcome categories
Resolved: The patient has fully recovered or the condition has returned to the level
observed at baseline.
Resolved with sequelae: As a result of the AE or SAE, the patient suffered a persistent or
clinically significant sequelae (e.g. long term complications of AEs or its treatment).
Ongoing at final visit: The event is still present at the end of the observation period.
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Unknown/lost to follow-up: The outcome of the event is not known until the end of the
observation period or the subject did not report back to the site after attempts of the site to
contact the subject.
The patient died.
Clinical significance
Any medical assessment, investigation or examination should be judged by the investigator for
clinical significance. For example, abnormal laboratory values, vital signs or physical
examinations must be reviewed by the investigator and rated for clinical significance. The
following definition should support this judgment:
Clinically significant (CS) is any clinical abnormality or change that:

suggests a disease
suggests organ toxicity
is of an intensity that requires active management, i.e. change of dose, discontinuation of
drug, medical treatment, more frequent follow-up
implies further diagnostic investigation
The investigator has to check if this judgment may lead to an AE.
Not clinically significant (NCS): none of the above is applicable
This judgement should be explained and documented by the investigator.
6.1.3 Adverse Event (AE) Recording

All events that meet the definition of an AE and occur in the period from the first screening
visit including trial-related procedures until 30 days after the last IMP application or trial-
related procedure must be recorded.
At each contact between the trial site and the patient (visit or phone), the patient must be asked
non leading questions about his condition (e.g. How are you feeling?). Additionally, the CRA
has to ensure that the investigator takes all available documents into consideration (e.g. diary,
concomitant medication documentation) to assess the patients condition.
The investigator must record all requested information about an AE as source data and transfer
them to the AE form in the eCRF. The requested information is:
AE term: diagnosis or main symptom,
intensity,
onset of the AE,
causality assessment by the investigator and time of occurrence,
action taken,
final outcome of the AE and, if appropriate stop date of AE and
seriousness (serious AEs have to be reported within 24 hours to the sponsor using the
separate SAE form, see Chapter 6.1.4).
Only one AE per form has to be reported. The diagnosis rather than single symptoms must be
documented. In rare cases where no diagnosis is available, each sign and symptom has to be
recorded as individual AE. For medical procedures or examinations the underlying disease
instead of the procedure should be documented. The AE shall be evaluated and the causality of

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the AE has to be assessed by the investigator. For detailed information and instruction refer to
the Adverse Event Form Instruction in the eCRF.
Allergopharma GmbH & Co. KG Drug Safety Department will evaluate all SAEs with respect
to seriousness, causality and expectedness in accordance with Directive 2001/20/EC. The
expectedness of an AE will be determined according to the Investigator`s Brochure.
6.1.4 Reporting of Serious Adverse Events (SAE)

The investigator is responsible to enter all requested information about the SAE into the
patients file and to transfer the data into an AE and SAE form of the CRF. Additionally, the
date and time of awareness of the SAE have to be recorded in the source data.
The investigator is also responsible to report all SAEs within 24 hours after obtaining
knowledge of the event by automatic notification via the eCRF. When the eCRF is not
accessible, reporting has to be performed via telephone, fax or e-mail to:
Allergopharma GmbH & Co. KG
Safety Officer Department Drug Safety
Dr. Gabriele-Cornelia Fox
Hermann-Krner-Strae 52
21465 Reinbek
Germany
Tel.: +49 40 727 65 - 125
Fax: +49 40 727 65 - 252
E-Mail: drug.safety@allergopharma.com
If hospital or patient records are accompanying the SAE report all personal data that would
disclose the patient identity (patients birthday and month, name, initials, address or any other
identifier) must be masked by the investigator prior to forwarding information to the sponsor.
This can be done by e.g. deleting or cutting them out.
The initial report must be promptly followed by detailed, written reports.
Allergopharma GmbH & Co. KG complies with applicable regulatory requirements related to
the reporting of SAEs and especially SUSARs to the CAs and the ECs. In addition,
Allergopharma GmbH & Co. KG will prepare respective safety reports covering all aspects
according to requirements of respective competent authorities and ECs, respectively.
6.1.5 Follow-Up of AEs and SAEs

During and after participation of a patient in a clinical trial the investigator has to ensure that
adequate medical care is provided to the patient. The investigator has to inform the patient
when medical care is needed for inter current illnesses which the investigator becomes aware
of.
All AEs and SAEs shall be followed up at each visit by the investigator until an outcome can
be specified. If an AE/SAE is not resolved after the patients individual follow-up period (30
days after the last IMP application or trial-related procedure) the outcome ongoing at trial end
shall be documented.
At least 3 attempts (e.g. by fax, email, phone call or regular mail) should be made by the
investigator to receive information on the final outcome. All attempts should be documented in
the patient file.

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In case of missing, incomplete or inconsistent data, queries will be addressed to the

investigator. In case of any discrepancy of SAE data, the investigator shall clarify queries
addressed by the Data Management or Drug Safety Department as soon as possible but not
later than 7 days after the query was raised.
6.2 Safety Parameters

The investigator shall provide detailed source documentation about all listed topics in this
section. The investigator has to assure that the source documentation allows an evaluation of
the health status of the patient and especially if contraindications to AIT are given or if the
patient is not eligible for participating or further participating in the clinical trial according to
inclusion, exclusion, and withdrawal criteria.
6.2.1 Clinical Laboratory Variables

The safety laboratory includes the following parameters:
Clinical Chemistry and Hematology (material: whole blood or serum preparation):
Creatinine
Bilirubin, total
ASAT (Aspartate Aminotransferase)
ALAT (Alanine Aminotransferase)
-GT (Glutamyl Transferase)
Blood sugar:
Glucose (fasting or non-fasting; status only to be assessed for decision on in/exclusion of
patient)
Hematology:
Differential blood cell count
Hemoglobin
Leukocytes
Platelets
Eosinophils
Urine Analysis:
Protein
Blood (hemoglobin)
Leukocytes
Glucose
-HCG (pregnancy test)
Fertile female patients will be tested for pregnancy by urine pregnancy test according to local
requirements.

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Blood collection for safety laboratory test and urine sample collection for urine analysis and
pregnancy testing will be performed as described in the schedule of assessment (Chapter 3.7.1).
Urine analysis and the pregnancy test will be performed at the trial site with urine analyses
sticks and standardized pregnancy tests provided by the sponsor. All other values will be
measured in a central laboratory.
Valid normal ranges of laboratory parameters and the units of measurements are oriented to the
FDA Guidance for Industry (Toxicity Grading Scale for Healthy Adult and Adolescent
Volunteers Enrolled in Preventive Vaccine Clinical Trials) [25]. They will be obtained from
the central laboratory before start of this clinical trial and whenever normal ranges will be
changed.
If values are abnormal but judged as not clinically significant by the investigator, the reason
has to be documented (e.g. above normal due to physical exercise 24 hours prior to taking
blood sample).
Any abnormal result judged as clinically significant noticed at the screening visit, has to be
documented as concomitant disease in the medical history. An abnormal result with clinical
significance noticed in a subsequent visit has to be reported as an AE (Chapter 6.1.1). During
the monitoring visits, the lab reports will be rechecked by the CRA. The lab report, signed by
the investigator, will be filed in the patient file.
6.2.2 Other Safety Variables
6.2.2.1 Vital Signs

Arterial blood pressure, heart rate, and respiratory rate will be measured after at least 5 minutes
in a sitting position. Data will be recorded at the visits as mentioned in the schedule of
assessment (Chapter 3.7.1).
6.2.2.2 Physical Examination

The investigator will perform a complete physical examination including general appearance
(e.g. nutritional status, signs for dehydration, signs for jaundice, anemia, cyanosis, clubbing of
fingernails, edema of ankles etc.), examination of the head, throat and neck (e.g. eyes, nose,
goitre), examination of the cardiovascular system (e.g. heart auscultation, pulse etc.),
examination of the lung (e.g. auscultation, percussion etc.), abdominal examination (e.g.
stomach, liver, spleen, kidneys, urinary tract, reproductive organs etc.), examination of the
musculoskeletal system (e.g. spine, extremities, ankles etc.), skin inspection, examination of
lymph nodes of neck, armpits, groins, basic neurological exam, psychological appearance or
any other examination which might be important for the documentation of the patients health
status. Any finding has to be documented and check against relevant inclusion and exclusion
criteria.
If there are any findings during screening examination, the investigator has to make sure that
relevant entries are made in the Medical History section.
If there are any findings during following examinations, the investigator has to make sure that
relevant entries are made in the Concomitant Diseases/Adverse Event section.
Physical examination will be performed during screening (S1) before first injection (T1) and
final visit (FV).

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6.2.3 Parameters Relevant for the Assessment of Safety Issues
6.2.3.1 Demographic Data

During screening visit S1, the following demographic data will be documented:
Year of birth (also documented at visit T1)
Sex
Height
Weight
Ethnic group
Smoking status
Household pets, especially cats and dogs
6.2.3.2 Medical History

All relevant past and ongoing diseases which are known by the patient and all concomitant
conditions e.g. signs or symptoms detected during screening visit have to be documented.
Diseases are considered relevant if they require e.g. permanent treatment, or do impair the
quality of life of the patient. Reasonable judgment by the investigator has to be exercised in
reporting of medical history, e.g. childhood diseases will only be reported if the patient still
suffers from this disease. If the patient is unknown to the investigator, the patient has to be
asked to give consent that the general practitioner of the patient may be contacted to receive
information on medical history.
Conditions detected whenever during the clinical trial but confirmed to be started before
signing the patient informed consent should be added in the medical history as concomitant
disease. The start date of the condition should be documented as precise as possible, at least
with year of appearance.
6.2.3.3 Asthma diagnosis

For all patients, a confirmation of a positive or negative asthma diagnosis must be available.
This written confirmation can be obtained by an existing diagnosis from a specialist. If a
written confirmation is not available, the investigator has to decide if the patient has asthma
and has to document the symptoms leading to this diagnosis in the source data.
Questions to consider in the diagnosis of asthma, according to GINA guideline (GINA, 2015):
Has the patient had an attack or recurrent attacks of wheezing?
Does the patient have a troublesome cough at night?
Does the patient wheeze or cough after exercise?
Does the patient experience wheezing, chest tightness, or cough after exposure to airborne
allergens or pollutants?
Does the patient's colds go to the chest or take more than 10 days to clear up?
Do symptoms improve after appropriate asthma treatment?
For patients with confirmed asthma diagnosis the level of asthma control (well controlled,
partly controlled or uncontrolled according GINA 2015) must be documented and checked
against relevant inclusion and exclusion criteria.
A negative asthma diagnosis must also be documented.

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6.2.3.4 Allergic Symptoms

At screening visit S1 the allergy history (eyes, nose, and lung symptoms) of the patients will be
documented referring to the following items:
Time since patient has suffered from allergic symptoms
Occurrence of perennial symptoms
Months with relevant allergic symptoms
6.2.3.5 Pregnancy
Any pregnancy leads to the immediate exclusion from the trial. A premature unblinding of the
patient is not necessary unless the requirements for an SAE are fulfilled. Any reported
pregnancy has to be followed up and documented by the investigator until termination or
delivery:
An initial report within 1 week after the investigator obtains the information of pregnancy
from the patient. Female patients must be asked to inform the investigator immediately if
they become pregnant. The investigator, in return, has to inform the sponsor about the
pregnancy as soon as the information about the pregnancy is obtained, using the
Pregnancy Reporting Form which is available in the investigator site file.
A follow-up report upon request of Allergopharma GmbH & Co. KG. In case of required
follow-up information the investigator has to contact the patient and provide respective
information with a follow-up report.
A final report regarding the outcome of pregnancy.
After birth, the investigator shall contact the patient for obtaining further information.
At least 3 attempts (e.g. by fax, email, phone call or regular mail) should be made by the
investigator to receive follow-up information or information about the final outcome. All
attempts should be documented in the patient file. If fetal death or abortion is indicated or the
patient is lost to follow-up no further information is needed.
If abortion is indicated, an AE form has to be issued by the investigator, also for planned
abortion.
Pregnancies with adverse outcomes such as fetal death, stillbirth, and any congenital anomaly
are considered as SAE and must be reported as AE as well as SAE.
Allergopharma GmbH & Co. KG will record all information about pregnancies in its safety
data base.
6.2.4 Likert Scale of Overall Tolerability

Overall tolerability will be assessed by the investigator and the patient at trial termination (see
Chapter 3.7.1) using a 5-point Likert scale (Likert, 1932) as defined below.
Investigators assessment
I judge the overall tolerability of the treatment of this patient to be?
1 2 3 4 5
Very bad Bad Average Good Very good
Patients assessment
I judge the overall tolerability of my treatment to be?

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1 2 3 4 5
Very bad Bad Average Good Very good
6.3 Data and Safety Monitoring Board

A Data and Safety Monitoring Board (DSMB) will be established according to the DSMB
Charter to review safety data on a regular basis and, if applicable, to recommend whether to
continue, modify or discontinue the trial. Details on the function and procedures of the DSMB
are defined in the charter of the DSMB. The primary function of the DSMB is to ensure
patients safety.
6.3.1 Members of the DSMB

The DSMB will be defined and adequately trained before the start of the trial. The team
consists of 3 independent allergologically experienced physicians. All members must be
represented by a qualified deputy in case of unforeseeable absence or unattainability. There
will be 1 chairman of the DSMB who will be in close contact with the sponsor of the trial e.g.
the clinical project leader (CPL).
6.3.2 Procedure of the DSMB

The DSMB will start working when the 1st patient receives the 1st administration of IMP. After
each injection, the investigator will inform the responsible DSMB member about any serious
related adverse event with all necessary information required for immediate safety assessment.
This will be done by providing adverse event reports in the eCRF after occurrence of the event,
addressed to the attention of the DSMB chairman. A telephone call is not sufficient.
6.3.3 DSMB Responsibilities

The chairman of the DSMB has to check the (S)AE information available via (S)AE pages in
the eCRF as well as the relevant standard reports provided by eCRF on a daily basis. Special
attention has to be paid to the coding and review of the reported symptoms and AEs according
to WAO Subcutaneous Immunotherapy Systemic Reaction Grading System see Appendix
18.7. In case of any doubt, an intensive information exchange via telephone between all
members must take place to decide on the coding.
If no immediate action is required, the DSMB will meet at least twice a month by telephone
conference to assess all reported safety data.
In case that an anaphylactic reaction according to WAO has been reported, the chairman of the
DSMB has to evaluate the information and confirm the grading performed by the site.
In the event that 3patients of the same treatment group suffering from an anaphylactic reaction
according to WAO Grade 3 the DSMB has to decide on continuation or stopping. For
deciding if the treatment of all patients in that group may be stopped, all DSMB members have
to be involved.

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In such a case, the chairman of the DSMB provides a list of all patients who have to stop
treatment immediately. The CPL will inform the investigators and the eCRF providing CRO
accordingly. The treatment of patients included in parallel groups can be continued.
The sponsors CPL and sponsors medical advisor must be informed immediately under
blinded conditions, if possible at the same time the decision was made by all DSMB members.
To ensure blinded conditions of the trail, it is not allowed to transfer the results of the
unblinding to the medical advisor or CPL before the trial is analyzed.
7 Trial Administrative Structure

International
Coordinating Investigator: Prof. dr hab. med. Marek Jutel
ALL-MED Specjalistyczna Opieka Medyczna
ul. Al. Gen. Jzefa Hallera 95
53-201 Wrocaw, Poland
Phone: +48 (0)71 363 33 56
Clinical Project Manager: Viola Gdicke, MSc. Pharmaceutical Medicine
Phone: +49 (0)40 727 65 579
Clinical Project Manager: Michael Rudert, PhD
Phone: +49 (0)40 727 65 188
Medical Advisor: Martin Karjalainen, MD
Phone: +49 (0)40 727 65 308
Safety Officer: Gabriele-Cornelia Fox, PhD
Phone: +49 (0)40 727 65 - 125
Fax: +49 (0)40 727 65 - 252
Trial Statistician: Dorothea Wessiepe
Metronomia Clinical Research GmbH
Paul-Gerhardt-Allee
4281245 Mnchen, Germany
Phone: +49 (0)89 829265 100
Central Laboratory: Synlab Pharma Institute
a division of synlab Umweltinstitut GmbH
Bayernstr. 53
80335 Mnchen, Germany
Local Laboratory: Helga Kahlert, PhD
(analysis of optional blood samples) Allergopharma GmbH & Co. KG
Phone: +49 (0)40 727 65 109
External responsibilities may be delegated to a contract research organization (CRO).

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7.1 Investigators
The trial is planned to be conducted in approx. 100 sites in 10 European countries and 1 non-
European country. Allergopharma GmbH & Co. KG will keep a list of investigators and will
file all trial relevant documents according to GCP.
7.2 Sponsor Personnel

Allergopharma GmbH & Co. KG will keep a list of the sponsor trial personnel and their proofs
of qualification.
7.3 Contract Research Organization(s)

This trial will be monitored regularly by CRAs of the assigned CRO according to GCP and the
applicable SOPs of Allergopharma GmbH & Co. KG. Data management and the statistical
analysis will be performed by a CRO.
7.4 Laboratories
For laboratory assessments blood and serum samples will be sent to the contracted central
laboratory synlab pharma institute.
For additional exploratory immunological parameters samples will be sent from the trial sites
to the central laboratory first and then further to the sponsor for analysis (Chapter 5.4).
7.5 Supply Management

Allergopharma GmbH & Co. KG will manufacture the IMP according to GMP. Manufacturing
procedures are described in detail to guarantee pharmaceutical quality. The production and
purification process of the IMP used in this clinical trial is described in the IB. Allergopharma
GmbH & Co. KG or a assigned CRO will supply the IMP.
Allergopharma GmbH & Co. KG or an assigned CRO will supply non investigational
medicinal products, e.g. diagnostic agents and asthma medication necessary for the conduct of
this clinical trial.
7.6 Essential Documents

Before the trial is initiated at a trial site, the following documents from the site must be
available at Allergopharma GmbH & Co. KG or the responsible CRO:
Signed agreement between Allergopharma GmbH & Co. KG or an assigned CRO and the
investigator/site and if applicable the hospital
Signed and dated trial protocol
Signed and dated substantial amendment agreements, if any
Signed and dated IB
Written patient information and consent (PIC) form in local language (notified to/approved
by the ethics committee(s)
Current, signed and dated CV of the investigator and deputy
Written EC approval/vote according to local requirements
Competent authority (CA) approval according to local regulations
Insurance certificate
Further non site-specific essential documents must be available according to ICH E6 and
Allergopharma GmbH & Co. KG guidelines.

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8 Statistics
A detailed statistical analysis plan (SAP) will be finalized before unblinding the iDMC during
the interim analysis. Therefore, in this trial protocol only global and general items are
described in an extent that is necessary to understand the objectives of the trial and to assure
overall control of the type I error rate by the implemented decision rules for the interim
analysis as well as the defined multiple testing procedure.
8.1 Analysis Datasets

Patients will be assigned to the following patient sets before unblinding:
All-Patients Set (APS): This is the group of patients for whom informed consent was given.
The number of these patients equals the total number of screened patients. For this group,
demographic data, patients disposition, and reasons for premature study termination if
applicable will be described.
Safety Set (SAF): The group of all patients who received at least one dose of IMP. This is
the basic analysis set for all assessments of safety and tolerability. For this set, the exposure
to IMP will be analyzed.
Full Analysis Set (FAS) according to the intention-to-treat principle: This set is defined as
all patients who received at least one dose of IMP during the course of the trial and for
whom a valid ICS dose to ensure asthma control according to the ACQ6 is available at
baseline. In this set, the primary endpoint will be tested in a confirmatory sense.
Per-Protocol Set (PPS): This group is a subgroup of the FAS. Patients of the FAS without
major protocol violations will be included in the PPS. The final selection criteria will be
fixed and patients will be allocated to this set during the blind data review meeting prior to
the interim analysis. The same efficacy evaluations as in the FAS are planned. However,
the primary endpoint will only be evaluated in an exploratory sense. Relevant differences
between the FAS and PPS will be evaluated in the clinical trial report. PPS analyses will
only be performed if more than 10% of the patients included in the FAS have a major
protocol violation.
The reason(s) for exclusion of patients from one set will be documented in the SAP which will
be finalized and signed before breaking the blind for the interim analysis. It will be filed in the
trial master file (TMF). In a possible second part of the trial a second BDRM will be performed
and the same approach as for the interim analysis will be followed.
8.2 Analysis of Primary and Secondary Efficacy Variables
8.2.1 Primary Efficacy Variable

This is a confirmatory phase III pivotal study. The primary endpoint is the change in dose steps
of the minimum daily ICS dose required to ensure asthma control according to the ACQ6
(ACQ6 score 1.0) between baseline and after AIT. The ICS dose will be determined by
means of diary entries as described in Section 5.1.
8.2.2 Secondary Efficacy Variables

Secondary efficacy endpoints will be assessed acc. to Section 3.4.2.
8.3 Design and Hypothesis

This is a phase III clinical trial with one primary efficacy endpoint to confirm the efficacy of
Acaroid for at least one dose in the treatment of allergic asthma.

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To formalize the statistical approach, the following notation will be used:

G5400(z): Cumulative distribution function (cdf) of the change in dose steps of the
minimum daily ICS dose needed to achieve asthma control according to ACQ6
between baseline and after AIT in the 5400 PNU active treatment group.
G3000(z): cdf of the change in dose steps of the minimum daily ICS dose needed achieve
asthma control according to ACQ6 between baseline and after AIT in the 3000
PNU active treatment group.
Gplacebo(z): cdf of the change in dose steps of the minimum daily ICS dose needed to achieve
asthma control according to ACQ6 between baseline and after AIT in the placebo
group.
The following test problems are defined to test for superiority of the active treatment groups to
placebo with regard to the location parameter of the respective cdf:
Test for superiority of the 5400 PNU active treatment group in comparison to placebo:
global
H05400 : Gplacebo(z) = G5400(z) vs. H1 : Gplacebo(z) = G5400(z-), > 0
Test for superiority of the 3000 PNU active treatment group in comparison to placebo:
global
H03000 : Gplacebo(z) = G3000(z) vs. H1 : Gplacebo(z) = G3000(z-), > 0
Global null-hypothesis of no difference between placebo and both active treatment groups:
H5400/3000
0 = H5400
0 H3000
0
Interim Analysis
An adaptive interim analysis (Bauer and Khne, 1994) will be performed after completion of
the treatment phase by about 444 randomized patients. The following type I error rates and
decision boundaries for the interim and the final analysis are specified:
Global one-sided type I error rate: = 0.025
Boundary for the one-sided p-value for accepting the null-hypotheses within the interim
analysis: 0 = 0.50
One-sided local type I error rate for testing the null-hypotheses within the interim analysis:
1 = 0.0102.
Boundary for the product of one-sided p-values for the rejection of null-hypotheses in the final
analysis: c = 0.0038.
If none of the null-hypotheses can be rejected at the interim analysis a second stage of the trial
will be considered. The trial will not be continued, if both p-values resulting from testing the
hypotheses H05400 and H03000 are 0.5, i.e. greater than or equal to 0, the boundary for
accepting the null-hypotheses within the interim analysis.
If the trial can be continued with a second stage after the interim analysis (for at least one null-
hypothesis that is aspired to be rejected, the one-sided p-value ]0.0102, 0.50[) , the results of
the interim analysis will be used for the further planning of the second stage of the trial.
The evaluation of the interim results and the recommendations for continuation of the trial will
be made by an independent iDMC. No employee of the sponsor will be a member of this board
and no employee of the sponsor will have insight into details of the interim analysis and
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unblinded results. The charter of the iDMC with rules and responsibilities and the possible
options for stopping or continuing the clinical trial as well as for choosing the sample size for
the 2nd stage in case the trial is continued will be fixed before performing the interim analysis.
8.4 Confirmatory Analysis

To control the multiple one-sided type-I error rate of 1=0.0102 within the interim analysis, a
closed testing procedure will be applied. In the first step, the global null-hypothesis H5400/3000
0
of no difference between the treatment groups will be tested using the Simes test. According to
this testing procedure, H5400/30000 can be rejected at the level 1, if

P( ) , for at least one = 1,2 and where P( ) P( ) are the ordered one-sided p-values
from the single hypotheses H05400 and H03000 . According to the closed testing principle, after
having rejected the global null hypothesis H5400/3000
0 , both single hypotheses H05400 and
H03000 can be tested at 1=0.0102. If the global hypothesis cannot be rejected, the procedure
stops and the single hypotheses cannot be tested. The single hypotheses will be tested with the
stratified Mann-Whitney U-test (see detailed description below).
The above described testing procedure is equivalent to applying the Hochberg procedure to the
single hypotheses H05400 and H03000 (Hochberg 1988).
Huque has shown that non-negatively correlated test statistics based on the Z-statistic or t-
statistic fulfill a condition, that ensures control of the family wise type I error rate when the
Hochberg procedure is applied (Huque 2016). The distribution of the test statistic of the Mann-
Whitney U-test can be approximated by a Z-statistic .Furthermore, the test statistics are
positively correlated because they refer to comparisons to the same treatment group (placebo).
Therefore, control of the family wise type I error rate is assurec with the implemented testing
procedure.
To derive the p-values for the single hypotheses, the stratified Mann-Whitney U-tests will be
performed with the stratification variables country and age group (adolescents, adults). The
possible need to combine countries with only few randomized patients for the analysis will be
described in the SAP, which will be finalized prior to database lock and unblinding when being
aware about the distribution of patients within the countries and centers. Due to the high
number of involved centers and the related small number of patients per center, the variable
center will not be included as stratification variable. However, by taking into account the
geographical position of the countries, the combination algorithm will involve this aspect.
The primary analysis will be based on the FAS that will be built according to the intention-to-
treat principle as described above. A sensitivity analysis will be performed in patients for the
patients in the PPS that comprises all patients who adhere to the trial protocol with respect to
all major criteria, if at least 10% of the patients of the FAS were excluded from the PPS.
The following sensitivity analyses based on the FAS will be performed to evaluate further the
robustness of the primary analysis:
analyses with only one of the covariates included as stratification factor
non-stratified analysis
subgroup analyses with subgroups defined for each of the covariates (see Section 8.9)
exploratory analysis including the covariate center instead of country with regional
pooling of small centers. The combination algorithm for pooling of centers will also be
determined in the SAP, prior to unblinding the database.

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Additional sensitivity analyses may be defined in the SAP if needed.
8.5 Determination of Sample Size
8.5.1 Sample Size until Interim Analysis (1st Part of the Trial)
An improvement of one dose step of the daily ICS dose required to achieve asthma control is
considered to be clinically relevant for a patient. The active treatment groups will be compared
to the placebo group confirmatorily with regard to a difference in the change in dose steps
between the treatment groups. Further, the number of patients with an improvement of at least
one dose step will be analyzed as secondary endpoint.
The sample size calculation is based on a previous dose finding trial. In that trial improvements
of 2 steps were possible. In the planned phase III study improvements of 4 steps will
theoretically be possible but no more than 2 steps are expected. In the dose finding trial with
Acaroid (AL1009ac), changes in dose steps of the daily ICS dose were observed as shown in
Table 9 below.
Table 9: Results from trial AL1009ac

Results from trial AL1009ac (FAS) and further hypothetical scenarios for the active treatment
groups: number of patients (percentage of patients)
AL1009ac AL1009ac AL1009ac Hypothetical scenario no.
Placebo 3000 PNU 5400 PNU
1 2 3
(n=15) (n=8) (n=13)
Reduction by 2 steps 3 (20.0 %) 2 (25.0 %) 9 (69.2 %) (50 %) (50 %) (40 %)
Reduction by 1 step 6 (40.0 %) 4 (50.0 %) 2 (15.4 %) (25 %) (20 %) (30 %)
No change 3 (20.0 %) 1 (12.5 %) 2 (15.4 %) (25 %) (20 %) (25 %)
Increase by 1 step 3 (20.0 %) 1 (12.5 %) 0 (0.0 %) (0 %) (10 %) (5 %)
Table 10: Sample Size

Sample size per treatment group until interim analysis, based on the one-sided Mann-Whitney
U-test for the single hypotheses H05400 and H03000 at the significance level 0.0051 [= 1/2]
(without addition of drop-outs)
Sample size per group (1:1) for comparison of
Method Power 3000 PNU 5400 PNU 1 vs. 2 vs. 3 vs.
vs. placebo vs. placebo placebo placebo placebo
80% 304 22 55 88 120
SAS proc power
90% 388 29 70 113 154
80% 350 29 66 104 141
Zhao et al.
90% 439 36 83 130 177
Zhao et al., 2008
The sample size was determined for the pair-wise comparison of one active treatment group vs.
placebo at a significance level of 1/2 at the given power. If the scenario is met for at least one
of the active treatment groups, then the indicated power for rejecting the related null-
hypothesis is assured within the Hochberg procedure.
The calculated sample sizes based on the results of the dose finding study AL1009ac (Table 10,
column 3000 PNU vs. placebo and 5000 PNU vs. placebo) show a big difference and the
number of patients that served as basis for these calculations is low. It is reasonable to assume
that the observed results from the 3000 PNU group underestimate the treatment effect due to
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differences in baseline ICS doses between this treatment group and the placebo group observed
in the trial AL1009ac. On the other hand, the results for the 5400 PNU group may overestimate
the treatment effect. Due to these uncertainties and the need for an adequate number of treated
patients for safety evaluation, the sample size until the interim analysis is planned according to
the hypothetical scenario number 2 in Table 9 above, with 90% power. According to the more
conservative formula of Zhao et al. (2008), 130 patients per treatment group would be needed.
To account for a drop-out rate of approximately 12%, it is planned for the first part of the trial
to randomize 148 patients per treatment group in a 1:1:1 allocation ratio, i.e. 444 patients in
total.
Patients that discontinue the trial prematurely will not be replaced. The reasons and numbers of
drop-outs will be listed and tabulated by treatment group to evaluate differences between the
treatment groups.
In order to gain a more comprehensive insight in the robustness of the power characteristics
under alternative scenarios, simulations were performed. 72 different distributions of the
primary endpoint in the 3 treatment groups similar to the hypothetical scenarios in Table 10
were used to sample 10.000 different trials each. For each trial the outcome at the interim
analysis was determined using the Mann-Whitney U-test for the single hypotheses H05400 and
H03000 , yielding the two related p-values that were used to perform the multiple testing
procedure. The percentage of trials that could be stopped early for efficacy was determined
from these p-values according to the test procedure explained above. This percentage is
equivalent to the overall power of the first part of the study alone, and will be called interim
power hereafter. In contrast to Table 10, the interim power refers to the whole multiple testing
procedure at the interim analysis and not only to the test of one single null-hypothesis.
In all simulated scenarios, the rate of patients in the placebo group who showed at least one
dose step of reduction in daily ICS dose was fixed at 60%, with either 30% and 30% or 20%
and 40% in the groups of patients with 2 or 1 dose steps, respectively.
A summary of the results is given here: In none of the scenarios the trial had to be stopped at
the interim analysis due to futility, i.e. in no case both p-values from testing H05400 and H03000
fell above 0.
In 29 of the 72 hypothetical scenarios, the interim power was at least 90%, including the
hypothetical scenario 2 from Table 9 that was selected to determine the sample size for the first
part of the trial. Further 14 scenarios had an interim power between 80% and 90% and 29
scenarios an interim power of < 80%.
Whenever the difference between one active treatment group and the placebo group in the
percentage of patients with a reduction of 2 dose steps was 30%, the interim power was at least
90%. When the difference between one active treatment group and the placebo group in the
percentage of patients with 2 dose steps was 20%, the interim power ranged between 70% and
97% for all these scenarios. 14 of these scenarios had an interim power of at least 90%, 13
scenarios between 80% and 90%, and 6 scenarios between 70% and 80%. If the difference
between one active treatment group and the placebo group in the percentage of patients with 2
dose steps was only10%, the interim power was always lower than 80%, except for scenario
24, where both active treatment groups were assumed to show this difference to placebo and
one active dose group had 80% of patients with at least 1 stop step in ICS dose.
The simulations thus supported the power calculations from Table 10.

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8.5.2 Sample Size for 2nd Part of the Trial after Interim Analysis
The final sample size for the 2nd part of the trial will be determined during the interim analysis.
The possible scenarios and decision rules taking into account efficacy and safety aspects will
be documented in the iDMC charter, which will be finalized prior to database lock and
unblinding for the interim analysis.
The above-described simulations and power calculations were extended to the 2nd part of the
trial. It was assumed that in those cases, where a continuation of the trial would be considered,
i.e. one active treatment arm would be selected for the 2nd part. Furthermore, 2 different upper
boundaries of either 130 or 240 evaluable patients per treatment group were implemented as
possible maximal sample size for the 2nd part of the trial.
In the 2nd part, patients were thus allocated to one active treatment arm or to placebo in a 1:1
allocation ratio. The decision, which treatment arm should be selected was based on the
conditional power at interim analysis, which was calculated based on the observed results at
the interim analysis and on the fixed upper boundary of sample size using the formula by Zhao
et al (2008). After selecting the treatment arm with the higher conditional power, 10.000 trials
were drawn from the observed results at interim, i.e. assuming that the observed results at
interim represent the true distribution of the primary endpoint in the treatment arms. For each
trial it was determined whether the hypothesis H0selected treatment arm could be rejected, i.e.
whether the product of the one-sided p-values from the 1st and the 2nd part of the trial for the
same null hypothesis were lower than c /2= 0.0019 or not.
The simulation did not take into account that the iDMC might recommend stopping the trial at
the interim analysis due to low conditional power (based on observed results at interim and an
upper boundary for the sample size).
As explained above, 29 scenarios had an interim power of < 80% to stop the trial for efficacy at
the interim analysis. When drawing 10.000 samples out of the observed results of these trials,
the mean total samples size of evaluable patients to achieve 90% conditional power for the 2nd
part of the trial were at least 1112 patients (scenario 39) and at most 22660 patients (scenario
41). The median total samples sizes ranged between 473 patients (scenario 5) and 1688
(scenario 72) patients. The mean and median conditional power calculated according to Zhao
et al. for these scenarios based on a total of 260 (=2x130) evaluable patients for the 2nd part of
ranged between about 30% (median: 20%) (scenarios 72 and 42) and 63% (median: 71%)
(scenario 5). Based on a total of 480 (=2x240) evaluable patients in the 2nd part of the trial, the
mean conditional power ranged between about 42% (median 35%) for scenario 72 and about
77% (medians about 89%) for scenarios 5, 57, and 69.
29 scenarios had an interim power of more than 90%. If the trial would be continued in all
cases, the simulations showed mean total sample sizes of evaluable patients to achieve 90%
conditional power for the 2nd part of the trial of at least 274 patients (scenario 25) and at most
894 patients (scenario 9). The median total sample sizes ranged between 252 patients
(scenarios 25 and 31) and 392 patients (scenarios 15 and 22). The mean and median
conditional power for these scenarios based on 260 (=2x130) evaluable patients in total during
the 2nd part of the trial ranged between about 70% (median about 78%) (scenarios 22, 33, and
62) and 89 % (median 91%) (scenario 25). Based on 480 (=2x240) new evaluable patients in
the 2nd part of the trial, the mean conditional power ranged between 84% (median 94% ) of
scenarios 55 and 62 and 97% (median 98%) of scenarios 25 and 26.
Finally, looking at the 14 scenarios with an interim power between 80% and 90%, the mean
total sample sizes of evaluable patients to achieve 90% conditional power for the 2nd part of
the trial were at least 596 patients (scenario 68) and at most 1220 patients (scenario 24). The

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median total sample sizes ranged between 387 patients (scenario 68) and 457 patients (scenario
24). The mean and median conditional power for these scenarios based on 260 (=2x130)
evaluable patients in total during the 2nd part of the trial ranged between 64% (median: 72%)
(scenario 24) and 71% (median 79%) (scenario 68). Based on 480 (=2x240) new evaluable
patients in the 2nd part of the trial, the mean conditional power ranged between 79% (median
91%) for scenario 24 and about 86% (median 95%) for scenario 68.
The simulations for the 2nd part of the trial indicate that there are a reasonable number of
scenarios where an early stop of the trial with demonstration of efficacy is not possible at the
interim analysis but will still have a high probability of rejecting one null hypothesis after the
2nd part of the trial with a reasonable sample size. The rules for deciding whether the trial
should be continued and which sample size should be chosen for the 2nd part will be detailed in
the iDMC charter.
8.6 Evaluation of Secondary Endpoints

All secondary endpoints will be analyzed descriptively in the FAS. If at least 10% of the
patients of the FAS were excluded from the PPS, the analyses will also be performed for the
PPS.
Secondary endpoints including a response criterion (e.g. patients achieving at least one dose
step of the ICS dose needed to ensure asthma control) will be analyzed using a logistic
regression model including the same covariables of (pooled) country and age group as for the
primary endpoint. Odds ratios for the comparisons of the 3000 PNU and the 5400 PNU
treatment groups to the placebo group will be estimated.
Time-to-event endpoint (e.g. the time to the first moderate or severe asthma exacerbation) will
be analyzed using Kaplan-Meier methods and the log-rank test for a pair-wise comparison of
the 3000 PNU and the 5400 PNU treatment groups to placebo.
In general, the following statistical measures will be presented.
Continuous variables: number of observations, mean, standard deviation, median, minimum,
maximum, 2-sided 95% confidence interval for the mean, and the 25% and 75% quantiles.
Categorical variables: number of observations, number and percentage of each value according
to the total number of non-missing values in the respective treatment group and analysis set.
Descriptive p-values of adequate statistical tests comparing the baseline value with the post-
baseline value within each treatment group and comparing the 3000 PNU and the 5400 PNU
treatment groups to the placebo group will be given.
8.7 Analysis of Safety and Tolerability Variables

Safety of treatment during the entire trial period will be assessed by
AEs,
clinical laboratory tests (hematology, clinical chemistry, and urinalysis) and
vital signs (resting blood pressure, pulse rate, and respiratory rate).
An assessment of the overall tolerability by the investigator and the patient using a 5-point
Likert scale (Likert, 1932) will be performed.
AEs will be presented by MedDRA Preferred Term and System Organ Class in different
categories.

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Incidence rates of AEs, SAEs and anaphylactic systemic reactions (according to WAO
Subcutaneous Immunotherapy Systemic Reaction Grading System) related to investigational
product will be reported.
If adequate, laboratory values and vital signs will be presented with mean standard deviation,
95% CI, median, minimum, maximum for visit S1 and final visit (FV) and for the difference
between these visits. Pre- and post-treatment values will also be compared with adequate
exploratory statistical tests.
The results of the assessment of overall tolerability will be presented by the number and
percentage of responses and with mean standard deviation, 95% CI, median, minimum,
maximum for the investigators assessment as well as for the patients assessment.
8.8 Comparability of Treatment Groups

Demographic and background information will be summarized per treatment group using
frequency (number and percentage) for categorical variables and descriptive statistics (median,
minimum, maximum, mean, and standard deviation) for continuous variables. Exploratory p-
values to evaluate the comparability of the treatment groups from adequate statistical tests will
be given.
8.9 Subgroup Analysis

Analyses of subgroups with respect to the following variables will be performed:
sex
age group (adolescents and adults)
ICS dose at baseline
well controlled/partly controlled according to GINA (2015) at baseline
sensibility according to sIgE HDM at baseline by immunoassay
severity of rhinitis at baseline
requirement of salbutamol
country
BMI
Further subgroup analyses may be defined in the SAP before unblinding.
8.10 Handling of Missing Data

During the diary period of 4 weeks per ICS dose, the last 2 weeks are foreseen for the
assessment of asthma control. If the ACQ6 assessment of one or both of these weeks is missing
or not evaluable, the patient has to complete the diary for additional 1 or 2 weeks while
keeping the ICS dose constant if the available week shows controlled asthma. If one week is
missing and the asthma was uncontrolled in the non-missing week, asthma is considered to be
uncontrolled under the current dose.
If asthma control cannot be determined after AIT with all possible ICS doses, the last available
complete assessment will used to determine the minimum daily ICS dose that is required to
ensure asthma control. If no asthma control assessment is available after AIT from the eDiary
ACQ6, it will be considered to replace this information by information from the eCRF and/or
daily eDiary entries during treatment For those patients where no further assessment on the
minimum daily ICS dose which is required to ensure asthma control according to the ACQ6 is
available, multiple imputation methods for replacement of missing values will be used.

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Before unblinding, the SAP will be finalized. Further details of the handling missing values
will be described in the SAP. Depending on the amount of missing data, sensitivity analyses
with different replacement methods will be defined in the SAP.
8.11 Drop-outs
Drop-outs will not be replaced. For withdrawn patients, all data as stipulated in the trial
protocol will be collected until their final visit.
The reasons and numbers of drop-outs will be listed by treatment group to evaluate differences
between the treatment groups.
9 Changes and Deviations to Plan

9.1 Protocol Amendment(s)
Amendments to the protocol will be classified as substantial or non-substantial. A substantial
amendment is defined to have a significant impact on the safety or physical or mental integrity
of the patient, the scientific value of the trial, the conduct or management of the trial, or the
quality or safety of any IMP used in the trial.
Allergopharma GmbH & Co. KG initiates a protocol amendment and makes sure that the
amendment is properly signed and dated by all parties and is sent to the ECs and CAs
according to local laws. If applicable, ECs and/or CAs must give a favourable opinion or
approval to the amendment before its implementation.
In case of a substantial amendment, an updated protocol must be prepared with all text changes
including changes of all previous amendments (substantial and non-substantial).
In case of a non-substantial amendment, i.e. if only technical aspects of the trial are changed
without any consequence for the risk-benefit-ratio or the patients safety, it is not necessary to
wait for a favorable opinion or approval before implementation of the changes in the trial.
9.2 Protocol Deviations

Protocol deviations are defined as actions or procedures not performed according to the
protocol. Protocol deviations can be deviations from GCP, like wrong informed consent
procedure or not reported SAEs, deviations in IMP handling, wrong performed procedures or
missing or insufficient source data. Major deviations of a trial site will be reported within 1
working day by the CRA to the clinical project manager of the sponsor.
Examples of major deviations are:
Patient Informed Consent (PIC) Form
PIC form not available
PIC form not signed or not dated by patient or by investigator before any trial-specific
procedure
General practitioner informed by investigator despite patients consent was not given
PIC form not signed by patients parent(s)/legal guardian(s)
Inclusion and Exclusion Criteria
Violation of an inclusion or an exclusion criterion, but patient not discontinued as per
protocol
Patient not discontinued as per protocol
Discontinuation criterion met but not withdrawn from trial

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Investigational Medicinal Product (IMP) / Treatment

Wrong treatment schedule
Incorrect dose of IMP
Administration of expired IMP
IMP administered after temperature excursion(s) without sponsors approval
IMP mixed-up (e.g. between patients/vials/clinical trials)
Required peak flow measurement not performed
IMP injection administered even though PEF value was lower than [enter value] %
IMP administration by non-physician or not authorized site personnel on the Signature
Responsibility Log
Concomitant Medication (CM)
Use of non-permitted CM as per protocol
Diagnostic Procedures
Diagnostic procedure(s), e.g. SPT, laboratory, pregnancy test not performed as required
Diagnostic procedure performed even though patient is a screening failure
Serious Adverse Event (SAE)
SAE not reported to sponsor
SAE reporting not done within 24 hours after awareness of investigator
Source Data (SD) / Patient Data
Repeated absence of SD (if requested and not available on next MV)
eCRF documentation repeatedly not done within the defined timeframe
Incorrect completion of questionnaire (completion date not as per protocol, missing
questionnaire)
Trial Conduct
Trial specific procedures (other than 4.8 IMP administration) performed by not authorized
site staff
Any further trial assessment (other than 4. IMP / Treatment) not performed as per protocol
Patient visits (except 4.1 Wrong treatment schedule) out of trial protocol visit schedule
Unblinding of a patient without notification to sponsor
The investigator should not deviate from the protocol without agreement by the sponsor and
prior review and documented approval or favorable opinion of an amendment from the
IRB/IEC, except it is necessary to eliminate an immediate hazard to trial patients.
Under working conditions, deviations from the protocol may occur. The investigator must
document all such events with reason(s) on the CRF Deviation Form.
In case a protocol deviation may have an influence on trial results, it is classified as a protocol
violation. The rating below is further elaborated in the SAP of the trial.
Definitions
A major protocol violation is a serious nonadherence to the study protocol that has an
impact on the efficacy of the IMP and therefore leads to exclusion of a patient from
analyses in the PPS.

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A minor protocol violation is a less serious nonadherence to the study protocol or does not
have an impact on the efficacy of the IMP and does not lead to the exclusion of the patient
from the PPS.
10 Direct Access to Source Data and Source Documents

The investigator will permit trial-related monitoring, audits, IRB/IEC review, and regulatory
inspection(s), providing direct access to source data and -documents.
Regular monitoring visits by scientific representatives of the sponsors Medical Department and
of the CRO at the investigators site prior to the start and during the course of the trial will help
to follow up the progress of the clinical trial, to assure accuracy of the data and to detect
possible errors at an early time point.
In order to accomplish these aims, the investigators are asked to hand over the source data to
the CRA in regular intervals.
For quality assurance, the authorities require a direct comparison between the data recorded in
the eCRF and the source data compiled by the investigator, if existent. For this purpose, the
investigators will allow the CRA direct access to the source data compiled in connection with
this trial.
According to legal requirements, it is possible that CA may inspect the logistic procedures as
well as scrutinizes the trial data (audit). The investigator has to inform the sponsor about an
announced inspection and will allow the persons being responsible for the audit or the
inspection to have access to the source data and -documents and to answer any questions
arising. All involved parties will keep the patient data strictly confidential.
11 Quality Control and Quality Assurance

Quality Assurance of the sponsor or a contracted third party may audit the trial to ensure that
trial procedures and data collected comply with the protocol and the sponsors SOPs, and that
data is correct and complete.
12 Ethics
12.1 Ethical Conduct of the Trial
The trial will be conducted in accordance with the ethical principles that have their origin in the
Declaration of Helsinki [27] and that are consistent with GCP [28;29], and the applicable
regulatory requirements. The patients will be covered by Allergopharma GmbH & Co. KG's
insurance according to applicable regulatory requirements.
12.2 Ethics Committee

The sponsor or a designee will obtain favorable opinion from or notify the relevant EC of the
protocol, any amendments, the Patient Informed Consent (PIC) Form and any advertisements.
The sponsor will also send applicable safety reports to the EC and will keep an updated list of
submission and approval dates of all submitted documents.

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12.3 Patient (Parent) Informed Consent

Before any trial-related activities, the investigator must give the patient full verbal and written
information about the trial in a form that the patient can understand. The investigator must
ensure that the patient is fully informed about the aims, procedures, potential risks and
consequences, any discomforts and expected benefits of the trial. Before consenting, the patient
must be left with ample time to consider and to pose questions.
The investigator informs the patients about a voluntary participation regarding blood sampling
for assessment of exploratory immunological parameters. These additional blood samples will
be taken at screening and final visit. It must be emphasized that participation is voluntary and
that the patient has the right to deny blood sampling without consequences for the participation
in the study. As with the entire study participation, the patient can withdraw his consent on this
part any time without prejudice and consequences. Investigator (physician) must obtain the
patients voluntary participation on this optional assessment in writing on the signed and dated
PIC.
During the course of the trial the patient will be informed in a timely manner if information
becomes available that may be relevant to the patients willingness to continue participation in
the trial.
The patient must agree that his/her data will be processed and stored in a pseudonymous form
for evaluation of this trial and any later overviews. Data may also be transferred in anonymous
form to third parties, e.g. other companies or authorities that may be located in other countries
with potentially different regulations for data. Data will follow the development of the product
and will be used for documentation of the products efficacy and safety. Data will be
transferred to involved parties only within the authority given by official agencies. The PIC
states that any data obtained will be kept if consent is withdrawn.
It must be emphasized that participation is voluntary and that the patient has the right to
withdraw from the trial at any time without prejudice and consequences.
The investigator must obtain the patients voluntary, personally signed and dated PIC before
any trial-related procedure.
The original, signed PIC must be kept in the investigator site file.
13 Data Handling and Record Keeping

13.1 Data Handling
13.1.1 Monitoring
During the course of the trial, a CRA will visit the trial site before trial initiation and at
intervals defined in the monitoring manual set up for this trial depending on recruitment (risk-
adopted monitoring). The purpose of the monitoring visits is to ensure that the eCRFs are
completed correctly, the protocol is adhered to and drug accountability is obtained. The CRA
will also be available for discussions by phone.
13.1.2 Source Data Verification

For source data verification, the sponsors representative must have direct access to source
documents that support the data recorded, e.g. medical records, original laboratory records and
PICs. Refer to Section 13.2.1 for a complete list of source data to be verified. Electronic source
data must be printed, signed and dated by investigator and stored in the investigator site file.

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Essential documents including PICs must be filed and kept in the investigator site file on an
ongoing basis.
Source data as defined in Section 13.2.1 must be entered in official hospital records, laboratory
records or similar documents.
13.2 Data Management

Patients will be identified in the database by their screening number. A data management plan
will describe data handling in detail.
For all laboratory tests as described in Chapters 3.8.2 and 6.2.1, results should be provided in
standard units. If one or more laboratories deliver laboratory test results in nonstandard units,
data management must be informed and must have a complete list of conversion factors in
order to convert nonstandard test results to standard test results.
For all patient related data pseudonymization will be performed.
All clinical data collected in the eCRFs, diaries, patient questionnaires, and the results from
laboratory tests will be merged in the database. In parallel to the entry process, data will be
checked for plausibility. Questions that could not be answered by a computer algorithm will be
checked manually by a medically experienced person. Incompleteness or inconsistencies will
be queried. All resolved queries will be incorporated in the eCRF and the trial database. The
updating process will be tracked within the eCRF (audit trail) or database.
When no outstanding queries are left, the database will be locked and transferred to the
responsible trial statistician for analysis after finalization of the SAP.
All calculations as well as data handling and storing will be done with appropriate computer
systems. Hardware and software information will be provided in the SAP.
13.2.1 Source Data

The investigator must list during the site initiation visit the data that will be entered directly in
the eCRF. This list must be signed and dated by the investigator before the start of the
screening period.
The following data are source data:
Signed and dated PIC
Patient records
Printouts of electronic devices, e.g. spirometry printouts
Laboratory reports
Any data entered directly into the eCRF, e.g. SPT results, vital signs
Likert scale
ACQ6 assessments
Patients paper diaries and e-diaries
Patient questionnaires
IMP and asthma medication application logs
The scope of the Source Data Verification (SDV) is regulated in the Monitoring Manual set up
for this clinical trial.

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13.2.2 Patient eDiary

For the duration of the eDiary phases (baseline and after treatment) patients have to keep
electronic symptom/medication diaries. A paper version will not be provided in these phases.
At each visit the investigator reviews the data entries in the eDiary together with the patient to
confirm the following:
Entries are complete.

Use of asthma medication according to instructions and reasonable according to symptoms.
Deviations or missing values are discussed with and commented by the patient.
In case of use of other concomitant medication, type and dosage regimen will be
documented in the patient file and entered in the concomitant medication page of the eCRF.
The patient will be asked if he or she was absent of their residence during the diary period.
The investigator evaluates the influence of absence on the symptoms reported by the
patient. The investigator will document the evaluation in the eDiary database.
Days with infections of the upper bronchial airways are not evaluable for the week of
asthma control determination. This week has to be repeated thereafter.
Potential AEs are discussed.
Each AE must be documented in detail on the AE form, which is part of the eCRF. Asthma
exacerbations will also be documented in the eCRF.
The documentation period for the subject diary is outlined in Chapter 5.1.
13.2.3 eCRF
The sponsor will provide eCRF and support (e.g. training, second level hotline) necessary for a
smooth conduct of the trial.
All data collected in connection with this trial are recorded in the eCRF. The eCRF reflects the
procedures as described in the trial protocol in the order of the patients visits.
In the eCRF the patients are identified by their screening numbers. The eCRF must be signed
by the primary investigator (electronic signature procedure).
The CRFs are official documents; they must be suitable for submission to authorities on
request and serve as data base for the assessment of quality and validity of clinical results for
marketing authorizations. AEs are recorded on a special form in the eCRF. In case of SAEs the
sponsor has to be informed immediately and a SAE form has to be used for documentation.
Further general data handling of the eCRF data (e.g. data entry, data clarification and data
validation) will be defined in the data management plan.
13.2.4 Completion of eCRFs

Data required according to this protocol are to be recorded in the eCRFs as soon as possible but
at most within 2 working days. The investigator must document all visits and assessments in
the eCRF and must ensure that no empty data blocks exist. If a test or assessment was not
done, the investigator must indicate this. If a question does not apply, the investigator must
document this.
The investigator must sign the overall affirmation statement of each visit, AE, and patient to
confirm responsibility, accuracy, and completeness of data and for the trial being carried out
according to the protocol and any amendments.

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Entries in the eCRF can only be done by trained investigator or investigators staff. Single
entries, e.g. signatures on AE pages can only be done by investigators.
13.2.5 Corrections of eCRFs

The investigator or designee must correct data by adding the reason for the data change into the
eCRF. Changes and author will be saved in the audit trail. Changes on already signed eCRFs
must be signed again. Queries issued within the eCRF must be answered as soon as possible
but at most within 7 working days.
Direct entries into the eCRF are not foreseen unless those mentioned in the Section 13.2.1
13.2.6 Coding
The sponsors instruction for coding of AEs and concomitant diseases, and concomitant
medication must be followed. The versions of the coding dictionaries will be fixed in the Data
Handling Manual and kept constant during the trial.
13.2.7 Confidentiality of Personal Data

The clinical investigator as well as the sponsor adheres to the right of data protection for each
patient included in the trial. To monitor the correct conduct of the trial and to follow the ICH
Guideline for GCP the investigator has to cooperate with the sponsor with respect to quality
assurance of the clinical trial. It is the responsibility of the investigator to allow full patient data
access to responsible persons of the sponsor and representatives of the authorities as well as the
ECs. The investigator must ensure the availability of the patient file in connection with this
clinical trial. All data documented in the CRF and collected by the sponsor for data evaluation
are made anonymous (age and further demographic data are provided). Furthermore, all
employees of the sponsor involved in this clinical trial must comply with confidentiality.
Please note that no personal information of a patient (e.g. name, address etc.) is allowed to be
known by the sponsor. For any direct contacts to the sponsor such information has to be made
illegible (i.e. on patient files).
The patient agrees to the data protection procedures by signing the PIC.
13.3 Record Keeping
13.3.1 Patient file

The investigator must document at least the data required according to this protocol in the
patient file.
13.3.2 Investigator Site File

The sponsor or responsible CRO keeps a TMF and provides an investigator site file for each
trial site according to content of Essential Documents for the Conduct of a Clinical Trial of
the ICH/CPMP guideline for GCP. If a pharmacy is involved a separate pharmacy site file as
part of the investigator site file will be provided.
Essential documents must be filed in a trial master file and investigator site file on an ongoing
basis.
All essential documents must be safely retained by the sponsor and the investigator for the
periods specified in Section 13.3.3. Essential documents at the investigational site include:
Patient list containing screening and randomization number, name of the patient and date of
birth
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One signed copy of the final trial protocol and any amendment
Investigators copies of patient diaries, data clarification forms and any associated patient-
related source data or, where applicable, authorized copies of source data
Signed and dated PIC forms
One copy of site investigators and co-workers curricula vitae
Copies of all correspondence with the EC and any direct correspondence with the CA
Copies of relevant laboratory reference ranges and methods
Copies of trial supplies receipt, drug inventory form
Copies of all correspondence between the investigator and the CRA and between the
investigator and the sponsor
A complete list is given in the ICH GCP guideline. Prior to destruction the investigator needs
to have the permission in written from the sponsor.
13.3.3 Retention of Clinical Trial Documentation

The investigator must arrange archiving of the source data as well as investigator site file and
eCRF copies (electronically) in a secure place protected from water, fire and unauthorized
access.
These documents must be archived:
until at least 2 years after the last approval of a marketing application in an ICH region, i.e.
at least 2 years following the marketing approval date for the drug of the investigated
indication (if there is no other procedure that has been agreed between the sponsor and the
investigator),
until there are no pending or contemplated marketing applications in an ICH region, or
until at least 2 years have elapsed since the formal discontinuation of the clinical
development of the trial product.
The documents should, however, be archived for a longer period if required by the applicable
local regulatory requirements or if agreed with the sponsor. It is the responsibility of the
sponsor to inform the investigator/institution when these documents no longer need to be
archived.
The patient files and records of trial patients must be retained in accordance with national
legislation and in accordance with the maximum period of time defined by the hospital,
institution or private practice.
The sponsor will maintain the documentation pertaining to the trial as long as the trial product
is marketed and the clinical trial report 5 years hereafter.
14 Financing and Insurance

14.1 Financing
The financial aspects of the trial will be documented in an agreement between the sponsor and
the CRO as well as the sponsor and the investigator or any other involved party. The agreement
must be confirmed in writing before the trial commences.
14.2 Insurance
Insurance coverage is guaranteed according to legal requirements for the entire trial duration
for each patient. Each patient is insured against any health impairment occurring as a result of
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participation in the trial in accordance with the laws and regulations of the country in which the
trial is performed. The insurance conditions including a certificate can be found in the
sponsors trial master file and in each investigator site file.
The patients will be informed by the investigator about the existence of this insurance and the
resulting obligations. The insurance conditions will be handed out to the patient. Any deviation
from this trial protocol caused by patients fault can lead to the loose of insurance coverage.
15 Publication Policy
15.1 Confidentiality
Information of the IMP and patent applications, scientific data or other pertinent information
are confidential and remain the property of Allergopharma GmbH & Co. KG.
The investigator is not allowed to disclose or publish any information of patent applications,
manufacturing processes, or formulation information about the IMP to others without
permission from Allergopharma GmbH & Co. KG.
15.2 Data Ownership

The eCRF copies, associated documents, and reports from the trial are the property of
Allergopharma GmbH & Co. KG.
Trial results and any discoveries related to the trial, regardless whether they have technical or
medical character, are the exclusive properties of the sponsor. Any published information on
results of the trial have to be in accordance with the clinical trial research agreement.
15.3 Reports
It is the sponsors responsibility that a clinical trial report is finalized within 12 months after
the end of the trial as defined in Chapter 3.2.
The international coordinating investigator will sign the final version of the clinical trial report.
15.4 Publications
At least 60 days prior to submitting or presenting a manuscript or other materials relating to the
trial to a publisher, reviewer, or other outside persons, the trial site shall provide to
Allergopharma GmbH & Co. KG a copy of all such manuscripts and materials, and allow
Allergopharma GmbH & Co. KG 60 days to review and comment on them. If the
Allergopharma GmbH & Co. KG requests, the trial site shall remove any confidential
information (other than trial results) prior to submitting or presenting the materials. The trial
site agrees that if the trial is part of a multicenter trial; any publication by the trial site of the
results of the trial conducted at the trial site shall not be made before the first multicenter
publication; provided, however, that if no multicenter publication is made within one year from
database lock, the trial site may publish individually in accordance with these provisions.
For greater certainty, it is hereby recalled that in its capacity as sponsor of the trial,
Allergopharma GmbH & Co. KG is solely responsible to coordinate the publications of
multicenter clinical trials in order to ensure that the related results are reported in a coherent
and responsible manner so that results from clinical trial data subsets are not published in
advance of or without clear reference to the primary publication and/or do not repeat such
primary publication. Therefore, Allergopharma GmbH & Co. KG shall be duly informed of
any publication plans in order to review any proposed manuscript before submission for

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publication. Allergopharma GmbH & Co. KG shall not suppress or veto publications. However
no submission for publication(s) shall be made before Allergopharma GmbH & Co. KG has
first been able to ensure proper intellectual property rights.
16 Indemnity Statement
Allergopharma GmbH & Co. KG indemnifies and holds harmless the hospital and its
employees and agents against all claims and proceedings (to include any settlements or ex
gratia payments made with the consent of the parties hereto and reasonable legal and expert
costs and expenses) made or brought (whether successfully or otherwise):
By or on behalf of patients taking part in the trial (or their dependents) against the hospital
or any of its employees or agents for personal injury (including death) to patients arising
out of or relating to the administration of the product under investigation or any clinical
intervention or procedure provided for or required by the protocol to which the patients
would not have been exposed but for their participation in the trial
By the hospital, its employees or agents or by or on behalf of a patient for a declaration
concerning the treatment of a patient who has suffered such personal injury.
The above indemnity by Allergopharma GmbH & Co. KG shall not apply to any such claim or
proceeding:
To the extent that such personal injury (including death) is caused by the negligent or
wrongful acts or omissions or breach of the hospital, its employees or agents.
To the extent that such personal injury (including death) is caused by the failure of the
hospital, its employees, or agents to conduct the trial in accordance with the protocol.
Unless as soon as reasonably practicable following receipt of notice of such claim or
proceeding, the hospital shall have notified Allergopharma GmbH & Co. KG in writing of
it and shall, upon Allergopharma GmbH & Co. KGs request, and at Allergopharma GmbH
& Co. KGs expenses, have permitted Allergopharma GmbH & Co. KG to have full care
and control of the claim or proceeding using legal representation of its own choosing.
If the hospital, its employees, or agents shall have made any admission in respect of such
claim or proceeding or taken any action relating to such claim or proceeding prejudicial to
the defense of it without the written consent of Allergopharma GmbH & Co. KG such
consent not to be unreasonably withheld provided that this condition shall not be treated as
breached by any statement properly made by the hospital, its employees or agents in
connection with the operation of the hospitals internal complaint procedures, accident
reporting procedures, accident reporting procedures or disciplinary procedures or where
such statement is required by law.
17 References
17.1 Reference List
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pathophysiological considerations. Curr Opin Allergy Clin Immunol 2003; 3(1):51-55.
(2) Platts-Mills TA, Erwin EA, Heymann PW, Woodfolk JA: Pro: The evidence for a
causal role of dust mites in asthma. Am J Respir Crit Care Med 2009; 180(2):109-113.

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(3) Masoli M, Fabian D, Holt S, Beasley R: The global burden of asthma: executive
summary of the GINA dissemination Committee report. Allergy 2004; 59(5):469-478.
(4) GINA. Global Strategy for Asthma Management and Prevention. Revised 2015. 2015.
(5) Canonica GW, Bousquet J, Mullol J, Scadding GK, Virchow JC: A survey of the
burden of allergic rhinitis in Europe. Allergy 2007; 62(Suppl 85):17-25.
(6) Maasch HJ, Marsh DG: Standardized extracts: Modified allergens - Allergoids. Clin
Rev Allergy 1987; 5(1):89-106.
(7) Puttonen E, Maasch HJ, Pilstrm L: Studies on allergen and allergoid preparations from
purified Timothy (Phleum pratense) pollen extracts. I. Physicochemical characteristics
and binding to allergen-specific human IgE. Int Arch Allergy Appl Immunol 1982;
68:1-6.
(8) Puttonen E, Pilstrm L, Wahn U, Maasch HJ: Studies on allergen and allergoid
preparations from purified Timothy (Phleum pratense) pollen extracts. II. Anaphylaxis
studies in rats and histamine release from human leucocytes. Int Arch Allergy Appl
Immunol 1982; 68:7-12.
(9) Wihl JA, Pilstrm L, Maasch HJ: Studies on allergen and allergoid preparations from
purified Timothy (Phleum pratense) pollen extracts. III. Comparative investigations by
skin prick tests and nasal provocation tests. Int Arch Allergy Appl Immunol 1985;
76:162-167.
(10) Kahlert H, Grage-Griebenow E, Stwe HT, Cromwell O, Fiebig H: T Cell Reactivity

with Allergoids: Influence of the Type of APC. J Immunol 2000; 165:1807-1815.
(11) Zielen S, Kardos P, Madonini E: Steroid-sparing effects with allergen-specific

immunotherapy in children with asthma: A randomized controlled trial. J Allergy Clin
Immunol 2010; 126(6):942-949.
(12) European Medicines Agency. Guideline on the clinical development of products for
specific immunotherapy for the treatment of allergic diseases. Draft. 2007. European
Medicines Agency (EMEA). Committee for Medicinal Products of Human Use
(CHMP).
(13) European Medicines Agency. CHMP/EWP/2922/01 Rev.1. Note for guidance on
clinical investigation of medicinal products for treatment of asthma. 22-10-2015.
European Medicines Agency (EMEA). Committee for Medicinal Products of Human
Use (CHMP). London.
(14) European Medicines Agency CHMP/EWP/18504/2006. Guideline on the clinical
development of products for specific immunotherapy for the treatment of allergic
diseases. 2008. European Medicines Agency (EMEA). Committee for Medicinal
Products of Human Use (CHMP).
(15) Verordnung ber die Ausdehnung der Vorschriften ber die Zulassung der Arzneimittel
auf Therapieallergene, die fr einzelne Personen auf Grund einer Rezeptur hergestellt
werden, sowie ber Verfahrensregelungen der staatlichen Chargenprfung
(Therapieallergene-Verordnung): Bundesgesetzblatt 2008;2177-2178.

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(16) Juniper EF, Bousquet J, Abetz L, Bateman ED: Identifying 'well-controlled' and 'not
well-controlled' asthma using the Asthma Control Questionnaire. Respir Med 2006;
100(4):616-621.
(17) Quanjer PH, Tammeling GJ, Cotes JE, Pedersen OF, Peslin R, Yernault JC: Lung
volumes and forced ventilatory flows. Report Working Party Standardization of Lung
Function Tests, European Community for Steel and Coal. Official Statement of the
European Respiratory Society. Eur Resp J 1993; 16(Suppl.):5-40.
(18) Cox L, Larenas-Linnemann D, Lockey RF, Passalacqua G: Speaking the same

language: The World Allergy Organization Subcutaneous Immunotherapy Systemic
Reaction Grading System. J Allergy Clin Immunol 2010; 125(3):569-574.
(19) Barnes PJ, Casale TB, Dahl R, Pavord ID, Wechsler ME: The Asthma Control
Questionnaire as a clinical trial endpoint: past experience and recommendations for
future use. Allergy 2014; 69(9):1119-1140.
(20) Reddel HK, Taylor DR, Bateman ED, Boulet LP, Boushey HA, Busse WW, Casale TB,
Chanez P, Enright PL, Gibson PG, de Jongste JC, Kerstjens HA, Lazarus SC, Levy
ML, O'Byrne PM, Partridge MR, Pavord ID, Sears MR, Sterk PJ, Stoloff SW, Sullivan
SD, Szefler SJ, Thomas MD, Wenzel SE: An official American Thoracic
Society/european Respiratory Society statement: asthma control and exacerbations:
standardizing endpoints for clinical asthma trials and clinical practice. Amer J Respir
Crit Care Med 2009; 180(1):59-99.
(21) Blumberga G, Groes L, Haugaard L, Dahl R: Steroid-sparing effect of subcutaneous

SQ-standardised specific immunotherapy in moderate and severe house dust mite
allergic asthmatics. Allergy 2006; 61(7):843-848.
(22) Mosbech H, Korsgaard J, Seitzberg D, De Blay F. Asthma duration or number of

sensitisations do not influence the treatment effect of the house dust mite allergy
immunotherapy tablet. Allergy 65[S92], 575-576. 2010.
(23) Ai C, Zhang Q, Ding J, Ren C, Wang G, Liu X, Tian F, Zhao J, Zhang H, Chen YQ,
Chen W: Suppression of dust mite allergy by mucosal delivery of a hypoallergenic
derivative in a mouse model. Appl Microbiol Biotechnol. In press.
(24) GINA. Global Strategy for Asthma Management and Prevention. Revised. 2014.
(25) FDA. Guidance for Industry. Toxicity Grading Scale for Healthy Adult and Adolescent
Volunteers Enrolled in Preventive Vaccine Clinical Trials. 2007. U.S. Department of
Health and Human Services. Food and Drug Administration. Center for Biologics
Evaluation and Research.
(26) Mosbech H, Deckelmann R, De Blay F, Pastorello EA, Trebas-Pietras E, Andres LP,
Malcus I, Ljorring C, Canonica GW: Standardized quality (SQ) house dust mite
sublingual immunotherapy tablet (ALK) reduces inhaled corticosteroid use while
maintaining asthma control: A randomized, double-blind, placebo-controlled trial. J
Allergy Clin Immunol 2014; 134(3):568-575.
(27) Declaration of Helsinki. World Medical Association Declaration of Helsinki. Ethical

principles for Medical Research Involving Human Subjects, Helsinki 1964, amended in

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Tokyo 1975, Venice 1983, Hong Kong 1989, South Africa 1996 and Edinburgh 200,
clarified in Washington 2002 and To. 1975.
(28) ICH E6(R1). ICH Harmonised Tripartite Guideline for Good Clinical Practice. E6(R1).
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(29) Directive 2001/20/EC. Directive 2001/20/EC of the European Parliament and of the
Council of 4 April 2001 on the approximation of the laws, regulations and
administrative provisions of the Member States relating to the implementation of good
clinical practice in the conduct of clinical trials on medicinal products for human use.
2001. Official Journal of the European Communities.
(30) Heinzerling L, Mari A, Bergmann KC, Bresciani M, Burbach G, Darsow U, Durham S,
Fokkens W, Gjomarkaj M, Haahtela T, Bom AT, Whrl S, Maibach H, Lockey R: The
skin prick test - European standards. Clin Transl Allergy 2013; 3(1):3.
(31) Konstantinou GN, Bousquet PJ, Zuberbier T, Papadopoulos NG: The Longest Wheal
Diameter Is the Optimal Measurement for the Evaluation of Skin Prick Tests. Int Arch
Allergy Immunol 2010; 151(4):343-345.
(32) Miller MR, Hankinson J, Brusasco V, Burgos F, Casaburi R, Coates A, Crapo R,

Enright P, van der Grinten CP, Gustafsson P, Jensen R, Johnson DC, MacIntyre N,
McKay R, Navajas D, Pedersen OF, Pellegrino R, Viegi G, Wanger J: Standardisation
of spirometry. Eur Respir J 2005; 26(2):319-338.
(33) Juniper E, O'Byrne P, Guyatt G, Ferrie P, King D: Development and validation of a
questionnaire to measure asthma control. Eur Respir J 1999; 14: 902-907.
(34) Juniper F, Svensson K, Mork A, Stahl E: Measurement properties and interpretation of

three shortenerd vesions of the asthma control questionnaire. Respiratory Medicine
(2005) 99, 553558
(35) Juniper E et al.:Asthma Control Questionnaire in Children: validation, measurement
properties, interpretation. Eur Respir J 36. 1410-1416, 2010.
(36) Olaguibel et al.: Measurement of asthma control according to global initiative for
asthma guidelines: a comparison with the asthma control questionnaire. Respiratory
Research 2012, 13:50.
(37) OByrne et al.: Measuring asthma control: a comparison of three classification systems.
Eur Respir J 2010; 36: 269276.
(38) Hochberg: A sharper Bonferroni procedure for multiple tests of significance.
Biometrika 75(4):800-802), 1988
(39) Zaho YD, Rahardia D, Qu Y: Sample size calculation for the WilcoxonMann
Whitney test adjusting for ties. Statistics in Medicine 2008; 27:426468.
(40) Simons et al.:World Allergy Organization Guidelines for the Assessment and
Management of Anaphylaxis. WAO Journal ; February 2011

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18 Appendices
18.1 FDA Guidance for Industry: Toxicity grading Scale for Healthy Adult
and Adolescent Volunteers Enrolled in Preventive Vaccine Clinical Trials
(2007)
In accordance with the cited guidance.
Table 11 Tables for laboratory abnormalities

Serum * Mild (Grade 1) Moderate Severe Potentially Life
(Grade 2) (Grade 3) Threatening
(Grade 4)**
Sodium Hyponatremia mEq/L 132 134 130 131 125 129 < 125
Sodium Hypernatremia mEq/L 144 145 146 147 148 150 > 150
Potassium Hyperkalemia mEq/L 5.1 5.2 5.3 5.4 5.5 5.6 > 5.6
Potassium Hypokalemia mEq/L 3.5 3.6 3.3 3.4 3.1 3.2 < 3.1
Glucose Hypoglycemia mg/dL 65 69 55 64 45 54 < 45
Glucose Hyperglycemia Insulin
Fasting mg/dL 100 110 111 125 >125 requirements
Random mg/dL 110 125 126 200 >200 or
hyperosmolar
Blood Urea Nitrogen 23 26 27 31 > 31 coma
Requires
BUN mg/dL dialysis
Creatinine mg/dL 1.5 1.7 1.8 2.0 2.1 2.5 > 2.5 or requires
dialysis
Calcium hypocalcemia mg/dL 8.0 8.4 7.5 7.9 7.0 7.4 < 7.0
Calcium hypercalcemia mg/dL 10.5 11.0 11.1 11.5 11.6 12.0 > 12.0
Magnesium hypomagnesemia mg/dL 1.3 1.5 1.1 1.2 0.9 1.0 < 0.9
Phosphorous hypophosphatemia 2.3 2.5 2.0 2.2 1.6 1.9 < 1.6
mg/dL
CPK mg/dL 1.25 1.5 x 1.6 3.0 x ULN 3.1 10 x > 10 x ULN
ULN*** ULN
Albumin Hypoalbuminemia g/dL 2.8 3.1 2.5 2.7 < 2.5 --
Total Protein Hypoproteinemia g/dL 5.5 6.0 5.0 5.4 < 5.0 --
Alkaline phosphate 1.1 2.0 x ULN 2.1 3.0 x ULN 3.1 10 x > 10 x ULN
increase by factor ULN
Liver Function Tests ALT, AST 1.1 2.5 x ULN 2.6 5.0 x ULN 5.1 10 x > 10 x ULN
increase by factor ULN
Bilirubin when accompanied 1.1 1.25 x ULN 1.26 1.5 x ULN 1.51 1.75 x > 1.75 x ULN
by any increase in Liver Function Test ULN
increase by factor
Bilirubin when Liver Function Test 1.1 1.5 x ULN 1.6 2.0 x ULN 2.0 3.0 x > 3.0 x ULN
is normal; increase by factor ULN
Cholesterol 201 210 211 225 > 226 ---
Pancreatic enzymes amylase, lipase 1.1 1.5 x ULN 1.6 2.0 x ULN 2.1 5.0 x > 5.0 x ULN
ULNupon institutional normal
* The laboratory values provided in the tables serve as guidelines and are dependent
parameters. Institutional normal reference ranges should be provided to demonstrate that they are
appropriate.
** The clinical signs or symptoms associated with laboratory abnormalities might result in
characterization of the laboratory abnormalities as Potentially Life Threatening (Grade 4). For
example: a low sodium value that falls within a grade 3 parameter (125-129 mE/L) should be
recorded as a grade 4 hyponatremia event if the subject had a
new seizure associated with the low sodium value.
***ULN is the upper limit of the normal range.

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Hematology * Mild (Grade 1) Moderate Severe (Grade 3) Potentially Life

(Grade 2) Threatening
(Grade 4)
Hemoglobin (Female) - gm/dL 11.0 12.0 9.5 10.9 8.0 9.4 < 8.0
Hemoglobin (Female) Any decrease 1.5 1.6 2.0 2.1 5.0 > 5.0
change from baseline value - gm/dL
Hemoglobin (Male) - gm/dL 12.5 13.5 10.5 12.4 8.5 10.4 < 8.5
Hemoglobin (Male) Any decrease 1.5 1.6 2.0 2.1 5.0 > 5.0
change from baseline value gm/dL
WBC Increase - cell/mm3 10,800 15,000 15,001 20,000 20,001 25, 000 > 25,000
WBC Decrease - cell/mm3 2,500 3,500 1,500 2,499 1,000 1,499 < 1,000
Lymphocytes Decrease - cell/mm3 750 1,000 500 749 250 499 < 250
Neutrophils Decrease - cell/mm3 1,500 2,000 1,000 1,499 500 999 < 500
Eosinophils - cell/mm3 650 1500 1501 - 5000 > 5000 Hypereosinophil
Platelets Decreased - cell/mm3 125,000 140,000 100,000 124,000 25,000 99,000 ic
< 25,000
PT increase by factor 1.0 1.10 x 1.11 1.20 x ULN 1.21 1.25 x ULN > 1.25 ULN
(prothrombin time) ULN**
PTT increase by factor 1.0 1.2 x ULN 1.21 1.4 x ULN 1.41 1.5 x ULN > 1.5 x ULN
(partial thromboplastin time)
Fibrinogen increase - mg/dL 400 500 501 600 > 600 --
Fibrinogen decrease - mg/dL 150 200 125 149 100 124 < 100 or
associated
with gross
bleeding or
disseminated
intravascular
* The laboratory values provided in the tables serve as guidelines and are dependent upon institutional
normal parameters. Institutional normal reference ranges should be provided to demonstrate that they are
appropriate.
** ULN is the upper limit of the normal range.
Urine * Mild (Grade 1) Moderate Severe (Grade 3) Potentially

(Grade 2) Life
Threatenin
Protein Trace 1+ 2+ g (Grade 4)
Hospitalization
or
Glucose Trace 1+ 2+ dialysis
Hospitalization
for
Blood (microscopic) 1 - 10 11 50 > 50 and/or gross hyperglycemia
Hospitalization
red blood cells per blood or
high power field (rbc/hpf) packed red
blood cells
* The laboratory values provided in the tables serve as guidelines and are dependent upon institutional (PRBC)
normal parameters. Institutional normal reference ranges should be provided to demonstrate that they are
appropriate.

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18.2 Instructions for Skin Prick Test

Skin Prick Test in Clinical Trials
During the screening, a routine Skin Prick Test (SPT) will be carried out to allow an objective
assessment of the sensitization pattern of the patient. SPT is not practical in patients who have
extensive eczema, dermographism, urticaria, undergo UV-light treatment, or who are taking
medications which interfere with the proper interpretation of the test results.
Drug interactions
Antihistamines, corticosteroids, and other drugs may falsify SPT results. Therefore patients
should, where possible, discontinue on medications that interfere with test results, accentuate
systemic allergic reactions or render patients less responsive to treatment with epinephrine. In
general, medication potentially interfering with the SPT should be stopped 5 times the
respective half life prior to the SPT procedure. For details please see table from Heinzerling
2013 [30] below. Patients taking a beta blocker or angiotensin converting enzyme (ACE)-
inhibitor, may be at a higher risk because of less response to epinephrine that might be needed
to treat a systemic allergic reaction. Patients must be monitored for at least 30 minutes after
administration of the test solution and then be medically evaluated. Patients may experience
side effects as late as several hours after allergen administration. When in doubt and especially
in case of systemic reactions, patients should be instructed to promptly consult their doctor.
Precautions for use
Although the SPT is safe with only rare cases of systemic allergic reactions, a physician or
other health care professional and emergency equipment must be immediately available when
such tests are performed. Patients should be appropriately screened for asthma. A peak flow
(PEF) of less than 80% of the predicted normal acc. to ECSC prior to the SPT is a relative
contraindication. Asthma should be controlled or testing deferred until control is achieved.
Method of administration
Skin prick testing should be performed on the volar forearm, at least 2 3 cm from the wrist
and the antecubital fossae resting on a table in a comfortable position. While no specific skin
preparation is necessary, the skin should be acclimatized to room temperature in case of
extreme outdoor temperatures. If the test area is cleaned with water, alcohol, or similar
products, it should be waited at least 2 minutes for normal cutaneous blood flow to return. The
dropper pipet should be used to place a drop of the solution next to the skin area marked with
the identifiers beforehand by using a black ball pen. Drops should be spaced approximately
4 cm apart. A drop of each test solution should be placed on the skin in identical order for
each patient tested and immediately pricked. A single-head metal lancet is pressed through the
drop of allergen extract and held against the skin for at least 1 second, with equal pressure
applied for each test. The epithelial layer of the skin should be penetrated without inducing
bleeding. A new lancet must be utilized for each test solution. Excess solution from drops on
the skin can be blotted using a clean tissue. It is important to assure that there is no cross-
contamination between drops of different allergen extracts, i.e., that the drops do not run
together. A timer with an alarm should be utilized so that all tests, including the histamine and
negative control test results are read 15 (+ 5) minutes following application. In case of
exceeding the test has to be repeated.

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Documentation
The negative control (being negative if the wheal is < 2mm) excludes the presence of
dermographism which, when present, makes the tests difficult to interpret. The positive
histamine control should be positive ( 3mm ) to make sure that the test materials are applied
correctly and to exclude negative SPT results due to potentially interfering medications
administered by the patient. A test is positive with a wheal of 3mm. A positive test reaction
will show as a pale yellowish wheal (edema) and flare (erythema) reaction. Reproducibility is
greater when only the longest diameter of the wheal, and NOT the associated erythema, is
measured. In order to achieve a permanent record, the size of the wheal has to be outlined with
a black ball pen, blotted onto a transparent skin tape together with the identifiers, and
transcribed onto paper by carefully peeling the tape of the skin and sticking into the patient file.
The longest diameter (see [31]) of the wheal of each particular test is then measured. Please
check the in- and exclusion criteria according to the test results.
Undesirable effects
Extremely sensitive patients may develop more intense local reactions. If necessary, it may be
useful to apply a steroid cream topically for patients convenience. The border between
anticipated reaction of the SPT (e.g. itching, swelling, erythema) and SPT related AEs is fluent.
Therefore it is the responsibility of the investigator to document trial procedure related AEs,
especially in isolated instances, when skin prick testing may produce generalized side effects to
the point of severe systemic reactions (anaphylactic shock). Anaphylactic shock may occur in a
matter of minutes after allergen administration. Typical warning signs include itching and
sensation of heat on and under the tongue and in the throat and especially on the palms of the
hands and soles of the feet. For treatment of an anaphylactic reaction see the Guidelines of
WAO (40).
Special precautions for storage
Store in a refrigerator (2C 8C). Do not freeze!
Storage life after first use of a vial is 1 year.
For further information, please refer to SPT package leaflet.

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Table 12 Potential Interference of Medications with the Skin Test Reaction

adapted from Demoly (2003); Rueff (2010) and Position Paper: Allergen standardization and
skin tests: The European Academy of Allergy (1993)

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18.3 Lung function test FEV1 (Forced expiratory volume in 1 second)

FEV1 is the volume of air that has been exhaled at the end of the first second of forced
expiration, after full inspiration. Values of between 80% and 120% of the average value are
considered normal. Predicted normal values for FEV1 depend on age, sex, height, mass and
ethnicity as well as the research study that they are based on. Predicted normal values in this
study are based on European Community for Steel and Coal (ECSC 1993).
Following general rules have to be considered:
Spirometry will be performed according to recommendation of the American Thoracic Society-
European Respiratory Society consensus guidelines on pulmonary function testing [32].
Determination of the forced expiratory volume in one second (FEV1) will be performed using a
Spirometer or a Bodyplethysmograph.
Due to varieties of devices it is mandatory that one site use the same device for all
measurements and for all patients during the whole trial.
All printouts of the pulmonary function measurements have to be dated and signed and have to
be filed in the patient source data sheet.
The measurement has to be repeated for a minimum of 3 times (triplet) and the best FEV1
value has to be documented in the electronic CRF (eCRF).
The test repeatability has to be checked after the 3rd measurement and more tests have to be
performed if necessary (max. 8 times).
Calibration has to be done as specified by the Spirometer provider.
Conduct of testing:
The patient must rest in a sitting position for a minimum of 15 minutes prior to testing.
The patients must be seated in an upright position during all measurements.
A nose clip must be used during all measurements.
The mouthpiece of the device has to be placed in mouth with closed lips around the
mouthpiece
The patient has to be instructed to breathe normal (in and out) for three times.
The patient has to be instructed to blow out completely and rapidly
Then the patient has to be instructed to breathe in completely and rapidly.
Followed by an interruption of less than 1 second the patient has to be instructed to
blow out as fast as possible until unable to breathe out any longer.
To finish the test the patient has to breathe normally again and can remove the
mouthpiece.
Please note: The patient has to be encouraged and coached verbally, this is essential for the
patients continuation to exhale till the end of the measurement (e.g. "motivation")
Triplet test reproducibility:
If the difference between the 2 highest FEV1 measurements is greater than 10% an additional
measurement is required.

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18.4 PEF measurements

Lung function test for patients self control during the screening phase
Peak Expiratory Flow rate is the largest air flow through the respiratory tract that can be
achieved during forced expiration.
Predicted normal PEF values are based on European Community for Steel and Coal (ECSC
1993) and depend on age, sex, height and ethnicity.
PEF measurement will be performed according to recommendation of the American Thoracic
Society- European Respiratory Society consensus guidelines on pulmonary function testing
[32]
Determination of the Peak Expiratory Flow in L/min will be measured only by using a
portable Peak-Flow Meter that will be handed out to each patient within this trial.
Due to varieties of Peak-Flow Meter it is mandatory that a patient uses the same Peak-
Flow Meter for all measurements throughout the screening phase.
The measurement has to be repeated for a minimum of 3 times (triplet) and the best
PEF value represents the actual PEF of this day.
The patient has to be trained by the study team in conducting PEF measurements.
Conduct of testing with a manual Peak Flow Meter:
The same position (sitting or standing) has to be adopted for each measurement.
(Slide the needle down to the lower end of the measuring scale)
The Peak-Flow Meter has to be hold horizontally. (The patient has to make sure that
her fingers are not covering to pointer slit or the openings at the end of the device)
The patient has to inhale deeply.
The mouthpiece has to be surrounded by the mouth of the patient firmly.
The patient has to blow as hard as possible. He/she to be instructed to blow out as fast
as possible, at least 2 seconds as if he/she would blow out a candle.
To finish the test the patient has to breathe normally again and can remove the
mouthpiece.
Please note: The patient has to be encouraged and coached verbally, this is essential for the
patients continuation to exhale till the end of the measurement (e.g. "motivation").
Triplet test reproducibility:
If the difference between the highest and next highest PEF value is greater than 40L/min an additional
measurement should be performed. The best PEF value out of these four measurements represents the actual PEF
of this day. Documentation of daily PEF values is only required for patients personal use.
Calculation of present day PEF value at home:

(present highest PEF value / )
% =
( %)

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18.5 Reversibility test

The reversibility test has to be conducted to determine whether the patients lung function can
be improved with therapy in addition to their regular asthma treatment. The test consists of 3
parts: Measurement of pre-FEV1 intake of bronchodilator Measurement of post-FEV1.
Reversibility test will be performed according to recommendation of the American Thoracic
Society- European Respiratory Society consensus guidelines on pulmonary function testing
[32].

Prior to the measurement of lung function (FEV1) for the reversibility test following rescue
medications are not allowed to be used by the patient:
Within 4 hours prior to lung function test: Short-acting inhaled beta 2-agonists (SABA) e.g.
Salbutamol, Abuterol should not be used
For at least 12 hours prior to the lung function test: Long-Acting Beta2-Agonist (LABA) e.g.
Salmoterol or Formoterol
The test must be rescheduled if one of the rescue medications mentioned above have been
taken.
Conduct of testing:
Measurement of pre-FEV1 must be performed prior to inhalation of bronchodilator.
Intake of bronchodilator: 4 hubs of Salbutamol 100g (total dose 400 g) have to be inhaled
gently and completely. For adolescents a lower total dose (2 hubs of Salbutamol- total dose
200 g) can be used. During each hub the breath should to be held for at least 3-5 seconds
prior exhalation.
Measurement of post-FEV1 must be performed within 15-20 min
In case of exceeding the test has to be repeated.
Finally a minimum of 3 technical acceptable FEV1 measurements must be obtained and
documented in the patients file.
Patients best FEV1 value (of 3 assessments) must be defined as well and used for calculation
of reversibility.
Calculation of reversibility
A significant reversibility is defined as a FEV1 increase of 12%and 200mL.
(highest postFEV1 highest preFEV1)x 100
% =
highest preFEV1

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18.6 GINA stepwise approach to asthma treatment

Table 13 A stepwise approach adapted from GINA 2015, Global Strategy for Asthma
Management and Prevention, Box 7. Stepwise approach to asthma treatment, [4]
Step 1 Step 2 Step 3 Step 4 Step 5
PREFERRED
CONTROLLER Low dose Low dose Med/high Refer for
CHOICE ICS ICS/LABA
ICS/LABA* add-on
treatment e.g.
anti-IgE
Other controller Consider low Leukotriene Med/high dose ICS High dose Add low
options dose ICS receptor
antagonists Low dose ICS + ICS + LTRA Dose OCS
(LTRA) LTRA
(or + theoph)
Low dose (or + theoph)
theophylline
RELIEVER As-needed short-acting

As-needed SABA or low dose
inhaled beta 2-agonists
ICS/formoterol*
(SABA)
*
Low dose ICS/formoterol is the reliever medication for patients prescribed low dose budesonide/formoterol or
low dose beclometasone/formoterol

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18.7 Systemic Reactions, Classification/Grading according to WAO

Classification
Table 14 Modified Systemic Reactions Classification
Acc. to the World Allergy Organization Subcutaneous Immunotherapy Systemic Reaction Grading System (Cox et al., 2010)
Grade 1 Grade 2 Grade 3 Grade 4 Grade 5
Symptom(s)/sign(s) of Symptom(s)/sign(s) Lower Lower or upper Death

1 organ system of more than 1 respiratory respiratory
present* organ system Asthma: (e.g. 40 % Respiratory failure
Cutaneous present PEF or FEV1 drop with or without loss
Generalized pruritus, or NOT responding to of consciousness
urticaria, flushing, or Lower respiratory an inhaled or
sensation of heat or Asthma: cough, bronchodilator) Cardiovascular
warmth** wheezing, shortness or Hypotension with or
or of breath (e.g. less Upper without loss of
Angioedema (not than 40 % PEF or respiratory consciousness
laryngeal, tongue or FEV1 drop, Laryngeal, uvula,
uvular) responding to an or tongue edema
or inhaled with or without
bronchodilator) stridor
Upper respiratory
or
Rhinitis (e.g.
sneezing, rhinorrhea, Gastrointestinal
nasal pruritus and/ or Abdominal cramps,
nasal congestion) vomiting or diarrhea
or or
Throat-clearing (itchy Other
throat) Uterine cramps
or
Cough perceived to
originate in the upper
airway, not the lung,
larynx, or trachea
or
Conjunctival
Erythema, pruritus or
tearing
Other
Nausea, metallic taste,
or headache
*Each grade is based on organ system involved and severity. Organ systems are defined as cutaneous,
conjunctival, upper respiratory, lower respiratory, gastrointestinal, cardiovascular, and other. A reaction from a
single organ system such as cutaneous, conjunctival, or upper respiratory, but not asthma, gastrointestinal, or
cardiovascular is classified as a grade 1. Symptom(s)/sign(s) from more than one organ system or asthma,
gastrointestinal, or cardiovascular are classified as grades 2 or 3. Respiratory failure or hypotension with or
without loss of consciousness define grade 4 and death grade 5. The grade is determined by the physicians
clinical judgment. **This constellation of symptoms may rapidly progress to a more severe reaction.


2.1 Protocol v1.0 Final Signed

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AL1402ac

Clinical Trial Protocol

Title: A multicenter randomized double-blind adaptive placebo-controlled clinical trial

Trial ID: AL1402ac

Trial Phase: Phase III, therapeutic confirmatory pivotal trial

Sponsor: Allergopharma GmbH & Co. KG

Date of Final Protocol: 3rd August 2016

Clinical Trial Protocol AL1402ac

_____________________ __________________________ ______________________

Address/stamp of trial site:

Clinical Trial Protocol AL1402ac

III List of Abbreviations and Definition of Terms

Clinical Trial Protocol AL1402ac

ITT intention to treat

Clinical Trial Protocol AL1402ac

Clinical Trial Protocol AL1402ac

3.8.3 Lung Function Test ............................................................................................ 32

Clinical Trial Protocol AL1402ac

6.1.2 Classifications .................................................................................................... 51

Clinical Trial Protocol AL1402ac

9 Changes and Deviations to Plan..................................................................................... 69

Clinical Trial Protocol AL1402ac

Clinical Trial Protocol AL1402ac

1.2 Rationale for the Trial

1.3 Selection of Dosages

1.4 Trial Population

Clinical Trial Protocol AL1402ac

1.5 Risk Benefit Assessment

2 Trial Objectives and Purpose

Clinical Trial Protocol AL1402ac

3.2 Trial Schedule

Clinical Trial Protocol AL1402ac

Clinical Trial Protocol AL1402ac

Figure 1 Trial Flow Chart Part 1

Clinical Trial Protocol AL1402ac

Clinical Trial Protocol AL1402ac

Switch from inhalative Continue Baseline

Uncontrolled asthma with Dose increase

Uncontrolled asthma Dose increase

+28 days after S1 +28 days after S2

Figure 4 Flow Chart Baseline Phase Examples

Oct Nov Dec Jan

START of DIARY PHASE Dose increase Dose increase

Visit B1 Visit B2 Visit B3 Visit B4 Visit B5

START of DIARY PHASE Return to last dose with

Controlled asthma Uncontrolled

Visit B1 Visit B2 Visit B3 Visit B4 Visit B5

Controlled asthma Controlled asthma Drop out

Visit B1 Visit B2 Visit B3 Visit B4 Visit B5

Clinical Trial Protocol AL1402ac

Clinical Trial Protocol AL1402ac

3.3 Discussion of Trial Design

3.4.1 Primary Endpoint

3.4.2 Secondary Endpoints

Clinical Trial Protocol AL1402ac

3.5 Selection of Patients

3.5.1 Patient Inclusion Criteria

3.5.2 Patient Exclusion Criteria

Clinical Trial Protocol AL1402ac

12. Pregnant, breast feeding or wishes to breast feed

Diseases and health status:

Clinical Trial Protocol AL1402ac

3.5.3 Restrictions during the Trial

3.6 Method for Assigning Patients to Treatment Groups

_ ____