A Randomized, Double-blind, Placebo-controlled, Dose Escalation Study to Evaluate the Safety and Tolerability of Subcutaneous Immunotherapy With DM-101 in Adults With Birch Pollen Allergy
Phase: PHASE1
Conditions: Birch Pollen Allergy
Sponsor: Desentum Oy

 
Study number DM-101-C-001 
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CONFIDENTIAL PROPERTY OF DESENTUM 
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CLINICAL STUDY PROTOCOL 
 
A randomized, double-blind, placebo-controlled, dose escalation 
study to evaluate the safety and tolerability of subcutaneous 
immunotherapy with DM-101 in adults with birch pollen allergy 
 
 
 
 
 
 
 
Study Code: 
 
DM-101-C-001 
 
EudraCT No: 
 
2019-001936-67 
 
Phase: 
 
I 
 
Sponsor: 
 
Desentum Oy 
 
Principal Investigator: 
 
 
Protocol Version: 
 
3.1 Final  
 
Protocol Date: 
 
25 Jan 2021 
 
 
 
 
 
 
 
 
 
Confidentiality Statement 
This protocol is the confidential property of Desentum Oy and is intended solely for 
the guidance of this clinical study. The protocol may not be disclosed to parties not 
associated with the clinical study or used for other purposes without prior written 
consent from Desentum Oy.

 
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SIGNATURES 
 
 
 
 
Principal Investigator: ________________________ 
Date: _____/_____/______ 
 
 
 
Clinical Research Services Turku - CRST Oy 
 
 
 
 
 
 
Biostatistician: 
_________________________ 
Date: _____/_____/_______ 
 
 
 
Oy 4Pharma Ltd. 
 
 
 
 
 
Representative 
of the Sponsor: 
_________________________ 
Date: _____/_____/_______ 
 
 
 
Desentum Oy  
 
 
 
 
 
Medical Monitor 
of the Sponsor: 
__________________________ 
Date: _____/_____/_______ 
 
 
 
 
 
 
 

 
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CONFIDENTIAL PROPERTY OF DESENTUM 
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CONTACT INFORMATION 
 
Principal Investigator  
 
 
Sponsor’s Medical Monitor 
 
Sponsor’s contact person 
 
 
Data Management & Biostatistics 
 
Pharmacovigilance 
 
SAE reporting:  
 
Safety Laboratory 
 
Allergen specific IgE screening laboratory 

 
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CONFIDENTIAL PROPERTY OF DESENTUM 
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TABLE OF CONTENTS 
 
SIGNATURES 
2 
CONTACT INFORMATION 
3 
SYNOPSIS 
8 
ABBREVIATIONS AND DEFINITION OF TERMS 
12 
1. 
INTRODUCTION 
14 
1.1. 
Background 
14 
1.2. 
Rationale 
15 
1.2.1. Study Rationale 
17 
1.2.2. Original Dose Selection Rationale (Protocol version 1.1) 
18 
1.3. 
Original Risk Benefit Assessment – Protocol version 1.1 
29 
1.4. 
Revised Risk Benefit Assessment for Cohorts 3 and 4 – Protocol version 
2.0 
31 
2.    STUDY OBJECTIVES AND ENDPOINTS 
33 
2.1.  
Objectives 
33 
2.1.1.  Primary Objective 
33 
2.1.2.  Secondary Objective 
33 
2.1.3.  Exploratory Objective 
33 
2.2. 
Endpoints 
33 
2.2.1. Primary Endpoint 
33 
2.2.2. Secondary Endpoints 
33 
2.2.3. Exploratory Endpoints 
33 
3. 
STUDY DESIGN 
34 
3.1. 
Overview 
34 
3.2. 
Study Periods 
36 
3.3. 
Safety Review Committee 
39 
4. 
STUDY SUBJECTS 
40 
4.1. 
Number of Subjects 
40 
4.2. 
Eligibility Criteria 
40 
4.2.1.   Inclusion Criteria 
40 
4.2.2. Exclusion Criteria 
41 
4.3. 
Lifestyle and Dietary Restrictions 
43 
4.3.1. Contraception Requirements 
43 
4.3.2. Meals and Dietary Restrictions 
43 
4.3.3. Caffeine, Alcohol, Recreational Drugs and Tobacco Use 
43 
4.3.4. Exercise, blood donation and vaccinations 
43 
4.4. 
Subject Withdrawal and Procedures 
44 
4.5. 
Screening and Baseline Failures 
45 
4.6. 
Subject Completion 
45 
4.7. 
Study Extension - Optional Sub-Study 
45 
5. 
STUDY MEDICATIONS 
45 
5.1. 
Investigational Medicinal Products 
45 
5.1.1.  Route of Administration 
45 
5.1.2.  Labelling and Packaging 
46 
5.1.3. Manufacturing 
46 
5.1.4. Storage and Handling Procedures 
46 
5.1.5. Accountability 
46 
5.1.6. Dosage and Administration 
46 
5.2. 
Treatment Assignment 
48 
5.3. 
Randomization and Blinding 
48 
5.4. 
Breaking of the Blinded Codes 
49 
5.5.    Procedures for Monitoring Subject Compliance 
49 
5.6.  
Concomitant Treatments 
50 

 
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5.7.  
Permitted Medications 
50 
5.8.  
Prohibited Medications 
50 
5.9. 
Non-Drug Therapies 
50 
5.10. Treatment of Study Treatment Overdose 
51 
6. 
STUDY CONDUCT FOR COHORTS 3 AND 4 
51 
6.1. 
Recruitment 
51 
6.1.1. Study Subject Screening Log and Identification Log 
52 
6.2. 
Screening 
52 
6.3. 
Treatment Period 
53 
6.4. 
Follow-up 
55 
6.5. 
Schedule of Activity Tables for Study Visits 
55 
7. 
STUDY ASSESSMENTS AND PROCEDURES 
60 
7.1.  
Demographic and Baseline Information 
60 
7.2. 
Assessment of Safety 
60 
7.2.1. Clinical Safety Assessments 
60 
7.2.2.  Laboratory Safety Assessments 
62 
7.3. 
Assessment of Allergic Sensitisation 
63 
7.3.1. Skin Prick Testing 
63 
7.3.2. Allergen-Specific IgE 
63 
7.4. 
Assessment of Efficacy 
64 
7.5. 
Assessment of Exploratory Immunological Biomarkers 
64 
7.6. 
Assessment of Pharmacokinetics 
64 
7.7. 
Optional Sub-study: Assessments 
64 
8. 
ADVERSE EVENTS 
65 
8.1. 
Definition of Adverse Events 
65 
8.2. 
Definition of Serious Adverse Events 
66 
8.3. 
Definition of Suspected Unexpected Serious Adverse Reactions 
66 
8.4. 
Definition of Adverse Events of Special Interest 
67 
8.4.1. Systemic Allergic Reactions 
67 
8.4.2. Injection Site Reactions 
68 
8.5. 
Recording of Adverse Events 
69 
8.6. 
Evaluation of Adverse Events and Serious Adverse Events 
69 
8.6.1. Assessment of Intensity 
69 
8.6.2. Assessment of Causality 
70 
8.7. 
Follow-up of Adverse Events / Serious Adverse Events 
70 
8.8. 
Reporting of Adverse Events and Serious Adverse Events 
70 
8.9. 
Reporting of Pregnancy 
71 
9. 
PREMATURE STUDY AND TREATMENT STOPPING CRITERIA FOR 
COHORTS 3 AND 4 
71 
9.1. 
Study Stopping Criteria 
71 
9.2. 
Treatment Stopping Criteria 
72 
9.3. 
Dose Adjustment Criteria 
72 
10. 
STATISTICS AND DATA MANAGEMENT 
73 
10.1. Estimation of Sample Size 
73 
10.2. Statistical Methods 
73 
10.3. Statistical Analysis Plan 
73 
10.4.   Statistical Hypotheses 
73 
10.5.   Data sets to Be Analysed 
73 
10.6. General Statistical Considerations 
73 
10.7. Demographic and Baseline Characteristics 
74 
10.8. Analysis of Efficacy Variables 
74 
10.9. Analysis of Safety Variables 
74 

 
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10.10. Analysis of Other Variables 
74 
10.11. Analysis of Exploratory Variables 
74 
10.12. Data Management 
74 
10.13. Database Design 
75 
10.14. Data Entry 
75 
10.15. The Query Process 
75 
10.16. Medical Encoding 
75 
10.17. Database Lock 
75 
10.18. Software 
75 
11. 
STUDY MANAGEMENT 
76 
11.1.  Study Monitoring 
76 
11.2.  Quality Control and Quality Assurance 
76 
11.3.  Deviations 
76 
11.4. Amendments 
76 
12. 
REGULATORY AND ETHICAL CONSIDERATIONS 
77 
13. 
DATA HANDLING AND RECORD KEEPING 
79 
13.1. Case Report Forms 
79 
13.2.  Source Data 
79 
14. 
STUDY SCHEDULE 
80 
15. 
FINANCING AND INSURANCE 
80 
16. 
STUDY REPORT AND PUBLICATION POLICY 
80 
17. 
ARCHIVING 
80 
18. 
REFERENCES 
81 
 
 
 
 
 
APPENDICES 
 
Appendix 1. World Allergy Organisation Subcutaneous Immunotherapy Systemic 
                      Reaction Grading System 
 
Appendix 2. Action Plan for Severe Allergic Reactions 
 
 
 
 
 
 
 

 
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CONFIDENTIAL PROPERTY OF DESENTUM 
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SYNOPSIS 
 
Name of the Sponsor/Company: 
 
Desentum Oy
Name of the finished product: 
 
DM-101 Drug Product
Name of the active ingredient: 
 
DM-101
Study code: 
 
DM-101-C-001, EudraCT No: 2019-001936-67 
Study title: 
 
A randomized, double-blinded, placebo-controlled, dose escalation study to evaluate the safety 
and tolerability of subcutaneous immunotherapy with DM-101 in adults with birch pollen allergy
Investigators and study centres: 
 
Principal Investigator, 
Clinical Research Services Turku - CRST Oy, Finland 
Development phase: 
 
I
Objectives: 
 
Primary Objective:  
To evaluate the safety and tolerability of s.c. administration of DM-101 in adult subjects with 
birch pollen allergy. 
 
Secondary Objective:  
To determine the proportion of adult subjects who reach the pre-defined maximum admissible 
s.c. DM-101 dose in each dosing group.  
 
Exploratory Objective:  
To evaluate the possible effects of repeated s.c. DM-101 dosing on immunological biomarkers 
in adult subjects with birch pollen allergy. 
Methodology: 
 
The study is a randomized, double-blind, placebo-controlled, parallel group study to evaluate 
the safety and tolerability of DM-101 s.c. administration in subjects with birch pollen allergic 
rhino-conjunctivitis. The study is planned to be conducted outside of the birch pollen season in 
Finland.  
 
The study will include up to 4 cohorts of participants. In each cohort, subjects are randomly 
allocated to receive s.c. doses of DM-101 or placebo. Cohort 1 includes a single dose 
administration. Cohorts 2 to 4 include escalating, repeat dose administration.  
 
The study starts with cohort 1 and sequentially proceeds to cohorts 2, 3 and 4. Dose 
escalation will be initiated only upon satisfactory review of all available safety data from 
previous dose levels and favourable recommendation from the study’s Safety Review 
Committee. 

 
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Cohort 1 was completed and dosing in cohort 2 was initiated in the first quarter of 2020. The 
study was temporarily halted on the 17th of March, 2020, during the conduct of cohort 2 due to 
the COVID-19 pandemic. An interim analysis of the obtained results from cohorts 1 and 2 was 
performed, and based on the findings, a substantial amendment to the study protocol was 
prepared (protocol version 2.0). The amended protocol version 2.0 includes adjustment of the 
study design and dosing regimens for cohorts 3 and 4. 
 
The study includes a screening, a treatment and a follow-up period.  
 
For cohort 1 (single dose) the study consists of 3 visits: Visit 1 screening; Visit 2 baseline and 
dosing; Visit 3 follow-up 28 days after the dosing.  
 
For cohort 2 the study was to consist of 7 visits: Visit 1 screening; Visit 2 (Day 1 and Day 2) 
baseline and dosing on Day 1 (6 ascending doses) and on Day 2 (3 ascending doses); bi-
weekly Visits 3-6 with single dosing (dose equaling to the highest safe and well-tolerated single 
dose of Day 2); Visit 7: follow-up 28 days after the last dosing. 
  
Cohort 2 was halted after partial completion of Visit 2 of 5 of the planned 8 participants. Cohort 
2 procedures will not be re-started according to protocol version 2.0. 
 
For cohort 3 the study consists of 7 visits: Visit 1 screening; Visit 2 baseline and dosing of a 
single injection; bi-weekly Visits 3-6 with dosing of single injections; Visit 7: follow-up 28 days 
after the last dosing.   
 
For cohort 4 the study consists of 7 visits: Visit 1 screening; Visit 2 baseline and dosing of a 
single injection; bi-weekly Visits 3-4 with dosing of single injections; Visits 5-6 dosing of 2 and 
3 injections in each, respectively; Visit 7: follow-up 28 days after the last dosing.   
 
Dosing and follow-up on Visits 2-6 is planned to take place within the premises of Turku 
University Hospital, in its Emergency Care Unit. A qualified physician will be present at the site 
throughout the confinement periods of the study subjects.  
 
In every cohort a sentinel group of 2 subjects, 1 receiving DM-101 and 1 receiving placebo, is 
planned to be dosed first in a double-blind fashion. Treatment of the remaining subjects in the 
cohort can be initiated no sooner than 22 hours after the sentinel subjects have completed 
their dosing without safety findings. The rest of the subjects in the cohort are also planned to 
receive their doses in a staggered fashion. 
 
Dose levels and dosing schedules are provided in Table 2 and 8 for all cohorts and a 
schematic of the study design is presented in Figure 1. 
Number of Subjects: 
 
Approximately 27 subjects are planned to be randomised into the study. 
 
Cohort 1: 6 subjects were randomized in a ratio of 2:1 to receive single doses of DM-101 or 
placebo.  
 
Cohort 2: 8 subjects were to be randomized in a ratio of 3:1 to receive repeated doses of DM-
101 or placebo, but only 5 of the planned 8 subjects were included before the study was 
temporarily halted. Due to the protocol amendment (version 2.0), no more subjects are 
planned to be randomized into cohort 2. 
 
Cohorts 3 and 4: 8 subjects per cohort will be randomized in a ratio of 3:1 to receive repeated 
doses of DM-101 or placebo. 

 
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Main eligibility criteria: 
 
Inclusion Criteria 
1. 
Males or females, aged 18 to 65 years inclusive. 
2. 
Good general health, as determined by the Investigator, based on medical evaluation, 
including medical history, physical examination, laboratory tests and electrocardiogram 
(ECG). 
3. 
A documented clinical history of birch pollen-induced allergic rhinitis or rhino-
conjunctivitis with symptoms that interfere with daily activities or sleep and remain 
bothersome despite the use of relevant symptomatic medication, and have been 
present over, at least, 2 allergy seasons.  
4. 
Bet v 1 specific serum IgE ≥ 0.7 kU/L (class 2), measured by ImmunoCAP®. 
5. 
Positive SPT to birch pollen allergen, with a wheal diameter ≥ 5 mm (average of 
longest and orthogonal) greater than that produced by the negative control. 
6. 
Body weight ≥50 kg and body mass index (BMI) within the range 18–35 kg/m2. 
7. 
Females are eligible to participate only if they are of: 
 
non-childbearing potential, defined as pre-menopausal females with documented 
tubal ligation or hysterectomy, or postmenopausal, defined as 12 months of 
spontaneous amenorrhea (in questionable cases a blood sample with levels of 
follicle stimulating hormone (FSH) > 40 MlU/ml and estradiol < 40 pg/ml (<147 
pmol/L) is confirmatory). Females on hormone replacement therapy (HRT) and 
whose menopausal status is in doubt will be required to use one of the 
contraception methods in Section 4.3.1.1. if they wish to continue their HRT during 
the study. Otherwise, they must discontinue HRT to allow confirmation of post-
menopausal status prior to study enrollment. For most forms of HRT, at least 2-4 
weeks should elapse between the cessation of therapy and the blood draw; this 
interval depends on the type and dosage of HRT. Following confirmation of their 
post-menopausal status, they can resume the use of HRT during the study without 
the need to use a contraceptive method. 
 
child-bearing potential and have a negative serum pregnancy test result at 
Screening and a negative serum pregnancy test result within 10 days prior to the 
first dosing visit, a negative urine pregnancy test before each subsequent dosing 
and agree: 
 
to use one of the contraception methods listed in Section 4.3.1.1. starting at least 
2 weeks prior to the start of dosing to sufficiently minimize the risk of pregnancy 
during the treatment period of the study. Female subjects must agree to use 
contraception until 30 days after the last treatment administration. 
 
or abstains from sexual intercourse or has only same-sex partner(s), when this is 
her preferred and usual lifestyle. 
8. 
Males who are sexually active with a female partner of childbearing potential must 
agree to use one of the contraception methods listed in Section 4.3.1.2. 
9. 
Willing and able to provide written informed consent. 
10. 
Willing and able to comply with the study requirements. 
 
Exclusion Criteria 
1. 
History or findings on physical examination of any significant disease or disorder (e.g. 
cardiovascular, pulmonary, gastrointestinal, hepatic, renal, neurological, 
immunological, musculoskeletal, endocrine, metabolic, major psychiatric, major 
physical impairment, cancer) which, in the opinion of the Investigator, may put the 
subject at risk because of participation in the study, influence the results of the study 
or the subject’s ability to participate in the study. 
2. 
Current diagnosis of asthma (other than seasonal during the birch pollen allergy 
season), requiring Global Initiative for Asthma (GINA) Step 2 or higher treatment, or 

 
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asthma partially controlled or uncontrolled according to GINA classification in the 6 
months before Screening. 
3. 
History of asthma deterioration that resulted in emergency treatment or hospitalisation 
in the 12 months before screening, or a life-threatening asthma attack (e.g. one 
requiring intubation and mechanical ventilation) at any time in the past. 
4. 
Forced Expiratory Volume in one second (FEV1) < 70% of predicted, regardless of 
asthma status at screening or baseline assessment at the first dosing visit. 
5. 
History of severe drug allergy, severe angioedema or systemic allergic reaction of 
Grade 3 or greater, according to the World Allergy Organization (WAO) scale, due to 
any cause.  
6. 
Use of systemic glucocorticoid medication within 30 days prior to Screening.  
7. 
Use of anti-IgE medication within 3 months prior to Screening. 
8. 
Use of mast cell stabilisers, anti-leukotriene agents or anti-histaminics less than 1 
week prior to dosing initiation. 
9. 
A course of short-duration allergen-specific immunotherapy or more than 3 months’ 
treatment with long-duration allergen immunotherapy, within five years prior to 
Screening. 
10. 
History of intolerance to the study drug, rescue medications (i.e. adrenaline, 
antihistaminics, glucocorticoids), or their excipients. 
11. 
Regular use of angiotensin-converting enzyme inhibitors, beta-adrenergic blockers or 
monoamine oxidase inhibitors. 
12. 
Ongoing treatment with substances interfering with the immune system. 
13. 
Treatment with an investigational drug within 30 days prior to Screening or concurrent 
participation in another clinical trial. 
14. 
Contraindication for the administration of adrenaline (e.g. subjects with acute or 
chronic symptomatic coronary heart disease or severe hypertension). 
15. 
Significant history of alcohol or drug abuse in the past 5 years, or a positive Screening 
or pre-dose drug/alcohol test result. A positive screening result for benzodiazepines or 
opioids may be accepted at the discretion of the investigator, if the finding can be 
satisfactorily explained by the subject’s medical history and concomitant medication 
information. 
16. 
Females who are pregnant, lactating or planning to become pregnant, or plan to 
donate oocytes for in vitro fertilisation during the study treatment period or within 
30 days following the treatment period. Subjects unwilling to employ appropriate 
contraceptive measures to ensure that pregnancy will not occur either during or for 
30 days following the completion of the treatment period. 
Investigational drug, dose and mode of administration: 
 
DM-101 Drug Product is a sterile solution for s.c. injection 
.  
 
Mode of administration: s.c. injection 
Reference drug(s)/placebo, dose and mode of administration: 
Placebo: Diluent for DM-101  
 
 
Route of administration: s.c. injection 

 
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Duration of treatment:  
 
Cohort 1: 1 day, single dose administration.  
Cohorts 2, 3 and 4: 8 weeks, including 5 bi-weekly administrations 
Assessments:  
 
Safety:  
Treatment Emergent Adverse Events (AE), including systemic allergic reactions and local 
injection site reactions 
Other safety variables: results of physical examination, vital signs, clinical laboratory values 
and spirometry 
Immunological Biomarkers 
Bet v 1 specific serum levels of IgE 
Other explorative biomarkers 
 
 
 

 
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ABBREVIATIONS AND DEFINITION OF TERMS 
 
AE 
 
Adverse Event 
AESI  
Adverse Event of Special Interest 
AIT 
 
Allergen Immunotherapy 
CA 
 
Competent Authority 
CRF 
 
Case Report Form 
CRO  
Contract Research Organisation  
CRST  
Clinical Research Services Turku 
DM 
 
Data Management  
DMP  
Data Management Plan 
EAACI  
European Academy of Allergy and Clinical Immunology 
EC 
 
Ethics Committee 
ECG 
 
Electrocardiogram 
eCRF  
Electronic Case Report Form 
EDC 
 
Electronic Data Capture 
EMA 
 
European Medicines Agency 
EU 
 
European Union 
FSH   
Follicle stimulating hormone 
FIH 
 
First In Human 
GCP 
 
Good Clinical Practice  
GINA  
Global Initiative for Asthma 
GMP  
Good Manufacturing Practice 
HRT      
Hormone Replacement Therapy 
IB 
 
Investigator’s Brochure 
IC 
 
Informed Consent 
ICF 
 
Informed Consent Form 
ICH 
 
International Conference of Harmonisation 
ICMJE  
International Council of Medical Journal Editors 
ICU 
 
Intensive Care Unit 
IMP 
 
Investigational Medicinal Product 
ISF 
 
Investigator study file 
IgA 
 
Immunoglobulin A 
IgE 
 
Immunoglobulin E 
IgG 
 
Immunoglobulin G 
ISF 
 
Investigator Site File 
NOAEL 
No-Observed Adverse Effect Level 
NtF 
 
Note to File 
PI 
 
Principal Investigator 
PV 
 
Pharmacovigilance 
SAE 
 
Serious adverse events  
SAP 
 
Statistical Analysis Plan 
SPT 
 
Skin Prick Test 
SRC 
 
Safety Review Committee 
S.C. 
 
Subcutaneous 
SOP 
 
Standard Operating Procedure 
SUSAR  
Suspected unexpected serious adverse drug reaction 
TEAE   
Treatment Emergent Adverse Event 
TMF 
 
Trial Master File 
WAO    
World Allergy Organization 

 
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WOCBP 
Women of Childbearing Potential 
 
 
Abbreviations used for major birch pollen allergen Bet v 1 and its derivatives 
 
Bet v 1 
Naturally occurring major birch pollen allergen, native wild-type Bet v 1 
Bet v 1 d 
Naturally occurring hypoallergenic isoform of major birch pollen allergen  
Bet v1 
rBet v 1 
Recombinant Bet v 1  
rBet v 1 d  Recombinant hypoallergenic isoform Bet v 1 d  
rBet v 1 dm  Investigational Medicinal Product DM-101 
 

 
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1. INTRODUCTION 
1.1. 
Background 
Allergic diseases, including allergic rhinoconjunctivitis and allergic asthma, are common 
immunoglobulin E (IgE) hypersensitivity (type I) mediated immune disorders that affect a 
significant proportion of the population of all ages. Their prevalence is increasing world-
wide and they add considerably to the cost burden of health care (Bauchau, 2004; 
Calderón, 2012). Pollens are one of the most frequent triggers of allergic symptoms. It is 
estimated that about 40 % of allergic subjects are sensitised to pollen allergens and suffer 
from seasonal allergy symptoms during the pollination season (D’Amato, 2007). Among 
those individuals, approximately one quarter are allergic to birch (Betula verrucosa) 
pollen. Birch and a related group of deciduous trees, which includes alder, beech, hazel 
and oak, are the most common cause of tree pollen-triggered respiratory allergies in 
Northern and Central Europe and North America. It is estimated that around 15 million 
Europeans have birch pollen allergies of which about 10 % are believed to have 
symptoms that are not well controlled by conventional, symptom-relieving medications. 
The main allergen in birch pollen is "Bet v 1", and more than 95 % of tree pollen allergic 
patients possess IgE antibodies against it (Jarolim, 1989; Sekerková, 2011). Due to cross-
reactivity, approximately 70 % of subjects allergic to fruits and vegetables are also 
sensitised to Bet v 1. 
 
Allergic pathogenesis is caused by aberrant generation of allergen-specific Th2 cells with 
an effector phenotype. The Th2 cells, through the cytokines they secrete (i.e. IL-4, IL-5, 
IL-9, IL-13), drive the two critical elements responsible for the manifestation of allergic 
symptoms: a) increased synthesis of allergen-specific IgE, which mediates the type I 
hypersensitivity reactions, and b) differentiation, survival and chemotaxis of pro-
inflammatory cells, namely mast cells, basophils and eosinophils, that orchestrate the 
development of chronic inflammation (Broide, 2001; Kay , 2006). Therapeutic modulation 
of these immune cascades that underlie the disease pathology holds the key for 
successful “curative” treatment of allergic disorders. Currently, the management of pollen-
induced allergies relies primarily on allergen avoidance and use of pharmacotherapy 
which can offer symptom control and suppression of local inflammation. Topical 
glucocorticoids and anti-histaminics are the most common prescription medications 
(Meltzer, 2013). This approach is clearly beneficial, but it is not curative and requires 
continuous use of medication to maintain the clinical effect. The only therapeutic modality 
that prevents allergic symptoms through alteration of the dysfunctional immune 
mechanisms is specific Allergen Immunotherapy (AIT). Specific AIT can achieve effective 
symptom control, enhanced tolerance to allergen exposure, modulation of disease 
progress and potentially disease remission (Eifan, 2011; Calderón, 2012; Roberts, 2018). 
Extended meta-analyses of the results of all valid relevant clinical trials have confirmed 
the efficacy of AIT for pollen-driven allergic rhinoconjunctivitis (may be up to 60 - 90 % in 
fully compliant patients), as well as its cost-effectiveness compared to standard 
pharmacotherapy (Calderón, 2012; Nurmatov, 2017; Roberts, 2018). How AIT achieves 
its benefit is not entirely clear, but there is evidence that restriction of allergen-specific Th2 
and IgE activity takes place. This may be due to a number of treatment-induced changes, 
such as increased production of protective allergen-specific immunoglobulin G4 (IgG4) 
and immunoglobulin A (IgA) antibodies, decreased release of allergic mediators, up-
regulation of counter-balancing regulatory T cells and inhibition of tissue infiltration by 
allergy effector cells (Akdis, 2014; Penagos, 2018). 

 
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AIT involves repeated administration of the relevant allergen (via subcutaneous (s.c.) 
injection or orally/sublingually) for long periods of time, usually 3-5 years. Typically, AIT 
starts with a build-up phase, during which the allergen doses are progressively escalated, 
followed by a maintenance phase where a high, well tolerated, allergen dose is given 
regularly for a prolonged period. The better established and widely used forms of AIT 
include administration of natural allergen extracts. Despite its promising efficacy, AIT with 
natural allergens is associated with several limitations, including poor adherence due to 
the long duration of treatment, variable treatment responses because of the often-
questionable quality of allergen extracts and concerns for serious side effects, such as 
severe allergic reactions (Roberts, 2018). The magnitude and duration of the AIT benefit 
seems to be related to the total (cumulative) dose of the administered allergen. When 
natural allergens are used, the maximum cumulative dose that can be achieved is 
restricted and requires a long treatment period to be delivered in a safe manner 
(Calderón, 2011; Penagos, 2018; Worm, 2018). To reduce the duration of s.c. AIT, 
various rush and ultra-rush dose escalation protocols have been successfully developed 
and applied in clinical practice (Cox, 2006; Calabria, 2013). These protocols include fast 
increase of the allergen doses, over a very short build-up phase, in order to induce quick 
desensitization and to facilitate early initiation of the maintenance phase. Maintenance 
treatment for several years is, however, still required to achieve a high cumulative allergen 
dose and long-lasting benefit (Calderón, 2011).   
 
To address the existing challenges with current forms of AIT and to offer an alternative, 
highly safe, short-course approach with allergenic products manufactured through a 
standardized, reliable process, Desentum Oy has developed a novel type of hypoallergen 
with low IgE reactivity potential. This has been achieved with the use of recombinant DNA 
technology and substitution of the key amino acids in the allergenic molecule that 
determine its binding to IgE on the surface of allergy effector cells. Because of these 
alterations, the Desentum product has reduced capacity to trigger IgE-mediated 
hypersensitivity reactions. Therefore, if the product is used in AIT regimens, it may allow 
quick dose escalation to high dose levels, without induction of allergic Adverse Events 
(AE). 
 
1.2. 
Rationale  
DM-101 is Desentum’s modified, recombinant, hypoallergenic variant of Bet v 1, the major 
allergen responsible for the allergenicity of birch pollen. DM-101 is very similar to the 
native antigen, wild-type Bet v 1, with the exception of amino acid substitutions (DM-101 
Investigator’s Brochure (IB)). The preservation of the great majority of molecular 
sequence and the three-dimensional structure allows DM-101 to retain the capacity to 
bind effectively to Bet v 1-specific immunoglobulin G (IgG) antibodies, while the amino 
acid substitutions, result in reduced IgE binding capacity. Moreover, the introduction of 
these substitutions disrupts the ability for IgE monomer-monomer interaction and 
formation of dimers. This further reduces the allergenic potential, as effective IgE receptor 
cross-linking on the surface of mast cells and basophils and subsequent release of 
allergic mediators requires the presence of IgE dimers. 
 
The immunogenic profile of DM-101 has been assessed in a series of pre-clinical studies. 
In vitro histamine release experiments, using serum from birch pollen allergic patients, 
overall indicate that the release of histamine following stimulation of basophils with DM-
101 is reduced compared to the wild-type rBet v 1 allergen (DM-101 IB). Specifically, in 

 
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the initially (2010-2014) conducted histamine release assays, the EC50 values for the wild-
type rBet v 1 have been between 0.08 nM - 0.95 nM, while for DM-101 they have been 
between 1.66 nM - 59.0 nM (DM-101 IB). This corresponds to an EC50 ratio of DM-101 to 
wild-type rBet v 1 ranging from 7.1 to 117.8 (Table 1). 
 
Table 1 
 Results of histamine release assays with recombinant wild-type Bet 
v 1 (rBet v 1 wt), DM-101 and the recombinant hypoallergenic 
isoform Bet v 1 d (rBet v 1 d) 
 
 
Study 
timepoint
  
 
Serum 
sample 
 
rBet v 1 wt 
EC50 [nM] 
 
DM-101 
EC50 [nM] 
 
rBet v 1 d 
EC50 [nM] 
 
DM-101 / 
rBet v 1 wt
EC50 
 
rBet v 1 d / 
rBet v 1 wt 
EC50 
Jul 2010 
Subject 1 
0,95 
6,94 
  
7,3 
  
Jul 2010 
Serum pool 
0,48 
3,37 
  
7,1 
  
Feb2014 
Subject 1 
0,23 
1,66 
4,97 
7,2 
21,6 
Jul 2014 
Subject 1 
0,18 
2,40 
5,16 
13,3 
28,6 
Jul 2014 
Subject 2 
0,76 
15,00 
14,70 
19,7 
19,3 
Jul 2014 
Subject 3 
0,53 
8,30 
7,28 
15,7 
13,7 
Jul 2014 
Subject 4 
0,08 
3,40 
0,62 
40,5 
7,4 
July 2014 
Subject 5 
0,37 
4,40 
3,40 
11,9 
9,2 
July 2014 
Subject 6 
0,17 
3,70 
3,75 
21,8 
22,0 
Sep 2014 
Subject 1 
0,22 
14,00 
5,46 
65,2 
25,4 
Sep 2014 
Subject 2 
0,92 
59,00 
12,00 
64,1 
13,0 
Sep 2014 
Subject 3 
0,45 
53,00 
7,32 
117,8 
16,3 
Sep 2014 
Subject 4 
0,12 
6,10 
1,72 
49,2 
13,9 
EC50: Half maximal effective concentration 
 
Histamine release experiments performed some years later (in 2017), using the same 
serum samples, but freshly acquired basophils from different donors, showed a smaller 
overall difference in the allergenic potential of DM-101 compared to wild-type rBet v 1. In 
these later experiments the EC50 values for the wild-type rBet v 1 have been between 
0.036 nM - 0.261 nM, while for DM-101 they have been between 0.041 nM – 0.370 nM 
(DM-101 IB). It is likely that the unstandardized nature of the assay and the use of 
basophils from different donors over the years may account for the observed variations in 
test sensitivity. Please see the DM-101 IB for more information. 
 
In vivo studies support that the ability of DM-101 to activate generation of Bet v 1-specific 
blocking IgG antibodies, a key mechanism of the AIT-mediated development of allergen 
tolerance (Akdis, 2014; Penagos, 2018), remains intact (DM-101 IB). Studies in a birch 
pollen sensitized mouse model have demonstrated that repeated s.c. administration of 
DM-101 leads to induction of high Bet v 1-specific IgG levels and reduction of specific IgE 
levels, comparable to that achieved following s.c. administration of the wild-type allergen 
(DM-101 IB). This is a significant difference compared to some other forms of birch 

 
Study number DM-101-C-001 
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hypoallergens under development that do not appear to be associated with significant 
induction of specific IgG upon treatment (Lund, 2007). 
 
The non-clinical safety of DM-101 has been evaluated in birch pollen sensitized mice. No 
differences in safety parameters have been observed following a single, high dose (10µg) 
intravenous administration of DM-101 and analogous, control administration of wild-type 
rBet v 1 (DM-101 IB). Furthermore, no significant effects have been observed in the 
standard 10 weeks toxicity studies in rabbits, at s.c. DM-101 doses up to 500 µg / animal 
(approximately 125 µg /kg) administered every 2 weeks. Based on the completed non-
clinical program, the No-Observed Adverse Effect Level (NOAEL) is set at 500µg, the 
highest dose tested non-clinically for toxicity (DM-101 IB). This provides an approximately 
15-fold safety margin to the highest DM-101 dose level (500 µg, 8.3 µg/kg) originally 
planned to be administered in this First In Human (FIH) trial, had clinical safety 
observations allowed it (see protocol version 1.1). It also provides an approximately 
16,000-fold safety margin to the starting dose (30 ng) of this FIH study. 
 
1.2.1. Study Rationale 
Given the attractive characteristics of DM-101, Desentum aims to pursue its 
pharmacological development as a novel form of AIT for subjects with birch pollen-driven 
allergic disease and will now initiate a FIH evaluation. The proposed evaluation of the 
safety and tolerability of DM-101 is in accordance with the European Medicines Agency 
(EMA) guideline on the clinical development of products for specific immunotherapy for 
the treatment of allergic diseases (CHMP/EWP/18504/06). Successful completion of this 
study will provide the necessary supporting evidence to proceed to further evaluation of 
the safety and efficacy of a short course of DM-101 AIT in larger clinical trials. 
 
Classical phase I studies in healthy individuals are not appropriate for AIT products, since 
they do not provide helpful safety information, as non-allergic individuals do not react like 
allergic subjects and therefore they do not carry the risk of the targeted population. For 
this reason, the DM-101 FIH study will be conducted in subjects with a history of moderate 
to severe allergic rhinoconjunctivitis during the birch pollen season and confirmed 
sensitization to birch pollen allergen.  
 
Usually, FIH trials start with evaluation of single, ascending doses of the Investigational 
Medicinal Product (IMP), followed by multiple ascending dose evaluation until a safe and 
well tolerated dose range and dosing regimen are established. The targeted maximum 
dose is usually pre-defined in the study protocol, based on preceding non-clinical 
evidence. However, in the case of AIT products, assessment of the safety and tolerability 
of single doses does not necessarily provide appropriate information, as most AIT 
schedules include continuous dose escalation until a maximum tolerated or protocol-
defined target (maintenance) dose is reached. The continuous dose escalation induces 
immunological changes, associated with allergen desensitization, that reduce the risk of 
allergic reactivity following subsequent dose administration, compared to the risk carried 
by single administration of the allergenic product, without prior exposure to it. To permit, 
therefore, appropriate evaluation of the safety and tolerability of DM-101, a repeat dose 
escalation regimen, previously employed in AIT protocols for pollen-driven respiratory 
allergies (Calabria 2013; Winslow, 2016), was included in the FIH study plan (protocol 
version 1.1). The FIH study was initiated in February 2020, but temporarily halted because 
of the Covid-19 pandemic on 17th March 2020, during the conduct of cohort 2. 

 
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During the conduct of the rapid, repeat dose escalation phase regimen included in cohort 
2, safety findings were observed in all subjects dosed with DM-101. The findings did not 
meet the study’s stopping criteria but indicated that the maximum tolerated dose of DM-
101 is lower than initially anticipated. For this reason, the originally planned rapid dose 
escalation regimen has been amended (study protocol version 2.0). In the amended study 
protocol, a much slower and limited dose escalation is proposed, based on the findings 
from cohorts 1 and 2 of the study. This amended dosing regimen is expected to be well 
tolerated, but still capable of providing relevant information for further product 
development. 
 
1.2.2. Original Dose Selection Rationale (Protocol version 1.1)  
 
The doses of DM-101 to be tested in this FIH study (Table 2) have been selected based 
on the allergen doses commonly employed in various s.c. birch AIT protocols and the non-
clinical evidence derived from Desentum’s experiments, showing that the allergenic 
potency of DM-101 is lower than that of the native Bet v 1 allergen. 
 
Standard s.c. AIT with natural birch pollen extracts has being extensively used in clinical 
practice and has been found effective in reducing symptoms and medication needs during 
the pollen season, in subjects with moderate to severe birch pollen allergy (Moingeon, 
2016). The clinical benefit appears to be related to humoral immune changes, such as 
inhibition of IgE binding and IgE-facilitated allergen presentation, associated with 
decreased serum concentrations of Bet v 1-specific IgE and increased levels of Bet v 1-
specific IgG4 (Moingeon, 2016). Most regimens of s.c. AIT with standardized, 
commercially available birch pollen extracts (i.e. Betula Verrucosa Alutard SQ, ALK-
Abello) start with doses of 10-20 SQ-U which equals to 1.23-2.46 ng of allergen and 
progressively escalate to a maintenance dose of 100,000 SQ-U which equals to 12,300 
ng (Arvidsson, 2002; Bodtger, 2002; Larenas-Linnemann, 2008; Wurtzen, 2008).  
 
A recombinant form of the native, wild-type Bet v 1 (rBet v 1) has also been developed 
and used for AIT. Results from controlled clinical trials demonstrate that native rBet v 1 
AIT has an excellent safety profile and equivalent efficacy to s.c. AIT with natural birch 
pollen extracts (Pauli, 2008). Regimens of s.c. AIT with the native rBet v 1 usually start 
with 50 ng and following escalation reach a maximum dose of 15,000 ng per injection 
(Pauli, 2008). 
 
To improve the safety of birch pollen AIT, three types of hypoallergenic derivatives of the 
native rBet v 1, a mix of two fragments of rBet v 1, a trimer of rBet v 1 and a folding variant 
of rBet v 1 (rBet v 1-FV) obtained by alkaline denaturation, have been developed and 
assessed in the clinic (Moingeon, 2016). The s.c. AIT regimens using the mix of two rBet v 
1 fragments or the rBet v 1 trimer employ much higher starting doses (1,000 ng) and 
escalate progressively to a maintenance dose of 80,000 ng per injection (Niederberger, 
2004; Reisinger, 2005; Purohit, 2008). Regimens with analogous doses of rBet v 1-FV 
have also been tested, as well as a regimen with repeat administration of single s.c. doses 
of 20,000 ng, 80,000 ng, 160,000 ng or 320,000 ng of rBet v 1-FV once weekly for 10 
weeks (Meyer, 2013; Klimek, 2015). All three forms of hypoallergenic birch s.c. AIT have 
been found to be safe, despite the high doses of the rBet v 1 derivatives administered.  
 

 
Study number DM-101-C-001 
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The current study will initially evaluate the safety and tolerability of single administration of 
30 ng of DM-101 in cohort 1 (Table 2). This dose is below the starting doses employed in 
s.c. AIT protocols with wild-type rBet v 1 or other hypoallergenic rBet v 1 forms and is 
expected to be safe and well tolerated. Furthermore, the starting dose of this FIH study 
(30 ng) has a 16,000-fold safety margin compared to the NOAEL determined in a non-
clinical, repeated-dose toxicity study in rabbits, where no treatment-related adverse 
effects were observed at the highest dose level tested, 500 g (125 g/kg). In the unlikely 
case that the safety profile of this DM-101 dose is not as anticipated, the study will be 
halted because this will indicate that the tolerability of DM-101 in humans is not in 
agreement with what has been predicted from the non-clinical studies carried out by 
Desentum. 
 
Once the safety of the single 30 ng DM-101 dose is confirmed, initiation of cohorts that 
include an escalating dosing regimen, according to an established rush s.c. AIT protocol 
will commence (cohorts 2 to 6). This is the regimen Desentum intends to pursue for 
pharmaceutical development. The proposed rush, “build-up”, dose escalation over 2 
consecutive days has been shown to facilitate the quick desensitization of allergic patients 
and to allow the safe administration of high allergen doses at an early phase of treatment 
(Winslow, 2016). Evaluation of single, high DM-101 doses is not proposed in the study 
and is not considered constructive, because the safety profiles of high doses delivered by 
single administration versus rush dose escalation are expected to differ. Rush s.c. AIT 
regimens, for various aeroallergens, have been used in clinical practice for years and their 
safety and tolerability, compared to the prolonged dose escalation AIT protocols, has 
been established and found appropriate (Cox, 2006; Calabria 2013; Morais-Almeida, 
2016; Winslow, 2016).  
 
In cohort 2, the first of the dose escalation study cohorts, the starting dose will be 100 ng; 
this will be followed by sequential 2- or 2,5-fold dose escalation (i.e. 250 ng, 500 ng, 1,000 
ng, 2,500 ng etc.) within the cohort, over 2 consecutive days. The starting DM-101 dose of 
100 ng is still within the range of the starting doses employed in s.c. AIT protocols with 
wild-type rBet v 1 or hypoallergenic rBet v 1 products. Should the dose of 100 ng DM-101 
not be found to be safe and well tolerated, as is anticipated, the study will be halted 
because this will indicate that the tolerability of DM-101 in humans is not as expected. The 
starting dose in each subsequent cohort of participants, after cohort 2 (cohorts 3 to 6), will 
be sequentially 2- or 2,5-fold higher than the starting dose of the preceding cohort (i.e. 
250 ng, 500 ng, 1,000 ng and 2,500 ng). With this dosing scheme, the starting dose in 
each of the cohorts 3 to 6 will have been previously tested as the second escalation dose 
in the preceding cohort (Table 2).  
 
Within each of the cohorts 2 to 6, sequential 2- or 2,5-fold dose increases are proposed to 
take place over 2 consecutive days (Table 2). In each of these cohorts, the maximum DM-
101 dose found to be safe and well tolerated after completion of the 2 days’ dose 
escalation will be considered a “maintenance” dose and will be repeated on subsequent 
treatment visits, until the end of the treatment phase of the study. The maximum DM-101 
dose proposed to be administered in the first escalation cohort (cohort 2) is 25,000 ng, 
which is less than the maximum dose given in s.c. AIT regimens with other Bet v 1 
hypoallergens and approximately 1.6-fold higher than the maintenance dose used in s.c. 
AIT protocols with wild-type rBet v 1. The maximum DM-101 dose scheduled to be given 
in the last cohort in this FIH study (cohort 6), if safety allows it, is 500,000 ng. This dose 

 
Study number DM-101-C-001 
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level is approximately 33-fold higher than the maintenance dose used in s.c. AIT with wild-
type rBet v 1. 
 
Progression from cohort 1 forward, to the subsequent cohorts, will take place only if the 
review of the collected safety and tolerability data from each preceding cohort is favorable 
(see Section 3). Dose escalation within each cohort will also take place only if safety 
allows it and the study’s dosing discontinuation or adjustment criteria (see Section 9) have 
not been met. 
 
Table 2. 
Originally planned Study cohorts - DM-101 Doses (ng) and Dosing 
Schedules* (Protocol version 1.1)  
 
 
 
Cohorts 
1 
2 
3 
4 
5 
6 
Visit 2 
Day 1 
1st injection 
30 
100 
250 
500 
1,000 
2,500 
2nd injection 
- 
250 
500 
1,000 
2,500 
5,000 
3rd injection 
- 
500 
1,000 
2,500 
5,000 
10,000 
4th injection 
- 
1,000 
2,500 
5,000 
10,000 
25,000 
5th injection 
- 
2,500 
5,000 
10,000 
25,000 
50,000 
6th injection 
- 
5,000 
10,000 
25,000 
50,000 
100,000 
Day 2 
1st injection 
- 
5,000 
10,000 
25,000 
50,000 
100,000 
2nd injection  
- 
10,000 
25,000 
50,000 
100,000 
250,000 
3rd injection 
- 
25,000 
50,000 
100,000 
250,000 
500,000 
 
 
Day 1 & Day 2 
Cumulative dose
30 
49,350 
104,250 
219,000 
493,500 
1,042,500 
Visit 3 
Day 14 
1 injection 
- 
25,000 
50,000 
100,000 
250,000 
500,000 
Visit 4 
Day 28  
1 injection 
- 
25,000 
50,000 
100,000 
250,000 
500,000 
Visit 5 
Day 42  
1 injection 
- 
25,000 
50,000 
100,000 
250,000 
500,000 
Visit 6 
Day 56  
1 injection 
- 
25,000 
50,000 
100,000 
250,000 
500,000 
 
 
Total Cumulative 
dose
30 
149,350 
304,250 
669,000 
1,493,500 
3,042,500 
 
 
*Acceptable Visit Windows:  ±1 day for Visit 3, and ±2 days for Visits 4, 5 and 6.  
 
 
 
 

 
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1.2.3 Revised Dose Selection Rationale for Cohorts 3 and 4 (Protocol version 2.0) 
 
 
Temporary halt of the study in March 2020 and interim analysis results  
 
This study was temporarily halted because of the Covid-19 pandemic on 17th March 2020 
based on PI’s decision in anticipation of visit restrictions to the dosing site located at Turku 
University Hospital and because of the perceived Covid-19-related risks to the study 
subjects and study personnel. No administrations of IMP took place after that, but the 
follow-up of all subjects already dosed by that date was continued according to the study 
protocol. 
 
By the 17th March 2020, cohort 1 dosing had been completed for all scheduled 6 subjects, 
and in accordance with the study protocol, the Safety Review Committee (SRC) had its first 
scheduled meeting and recommended the initiation of dosing in cohort 2. Dosing in cohort 
2 (Visit 2) was initiated and by the time the decision to halt the study was made, 5 out of the 
8 planned subjects had their scheduled Visit 2 dosing initiated. From these 5 subjects of 
cohort 2, only 1 subject who had received placebo completed Visit 2, Day 1 and Day 2 
administration. None of the other 4 subjects who had all received DM-101 was able to 
complete the Visit 2 Day 1 and Day 2 administration as planned in the study protocol 
because of treatment-related TEAEs (Table 6 and 7).  An SRC meeting took place on the 
20th March 2020 to review the collected safety data at the request of the PI. The SRC 
recognized that although none of the pre-defined study stopping criteria were met, there 
were safety signals related to the rapid dose escalation regimen and recommended the 
discontinuation of further dosing in cohort 2 and in subsequent cohorts according to the 
regimen included in study protocol version 1.1. Following this recommendation, and as the 
study was temporarily halted, the Sponsor decided to perform an interim analysis of all 
available data and to open the treatment code for the subjects included in the study up to 
that time, in order to make an informed decision on how to amend the dosing regimen and 
continue the study in due time. 
 
 

 
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Table 3. Extent of exposure by subject in cohorts 1 and 2 and reasons for dose 
reduction and/or treatment withdrawal  
Subject 
number 
Cohort 
Injection 
no 
Dose ng 
(Intended*/actual) 
Actual cumu-
lative dose 
Reason for dose reduction and/or withdrawal 
1001 
1 
1 
0 (Placebo) 
0 
1002 
1 
1 
30/30 
30 
1003 
1 
1 
30/30 
30 
1004 
1 
1 
30/30 
30 
1005 
1 
1 
0 (Placebo) 
0 
1006 
1 
1 
30/30 
30 
2001 
2 
1-9 
0 (Placebo)** 
0 
2002 
2 
1 
100 / 100 
100 
Withdrawn from the treatment after Day 1, 4th 
injection, due to a Grade 3 systemic allergic 
reaction. According to the protocol-specific 
dose adjustment criteria, a Grade 3 systemic 
reaction would have led to a dose reduction to 
the previous well-tolerated level, but it was 
considered to be in the best interest of the 
subject to discontinue treatment. 
2 
250 / 250 
350 
3 
500 / 500 
850 
4 
1000 / 1000 
1850 
2003 
2 
1 
100 / 100 
100 
The subject withdrew her consent after the 6th 
injection of Day 1. Moreover, due to 2 grade 3 
local injection site reactions following 2 
injections (5th and 6th injections) the treatment 
would also have been stopped according to the 
protocol-specific treatment stopping criteria. 
The subject developed a Grade 2 local injection 
site reaction after the 5th injection that 
progressed to Grade 3 after the administration 
of the 6th injection.  
2 
250 / 250 
350 
3 
500 / 500 
850 
4 
1000 / 1000 
1850 
5 
2500 / 2500 
4350 
6 
5000 / 5000 
9350 
2004 
2 
1 
100 / 100 
100 
Due to a Grade 3 local reaction after the 2nd 
injection of Day 1, the dose was reduced to the 
previous well-tolerated level (100 ng) according 
to the protocol-specific treatment adjustment 
criteria. The dosing would have continued on 
Day 2 with 100 ng injections, but the study was 
temporarily halted due to the Covid-19 
pandemic and no further dosing took place. 
2 
250 / 250 
350 
3 
500 / 100 
450 
4 
1000 / 100 
550 
5 
2500 / 100 
650 
6 
5000 / 100 
750 
2005 
2  
1 
100 / 100 
100 
Due to a Grade 2 systemic reaction after the 2nd 
injection of Day 1, , dosing was interrupted at 
the PI’s discretion with the intention to 
continue dosing on Day 2 with the previous 
well-tolerated dose (100 ng), but the study was 
temporarily halted due to the Covid-19 
pandemic and no further dosing took place. 
2 
250 / 250 
350 
* Planned doses of Cohort 2 included 6 injections on Day 1 and 3 injections on Day 2 of Visit 2. Only doses of 
administered injections are shown. 
**Subject 2001 received all planned 6 injections on Day 1 of Visit 2 and 3 injections on Day 2 of Visit 2. 

 
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The interim analysis of the safety data Tables 3-7 from of the subjects included in cohorts 
1 and 2 of the study (DM-101-C-001 Interim Clinical Study Report) revealed the following:  
 
- 
In cohort 1, single injection of 30 ng of DM-101 was found to be safe and well-
tolerated. All 4 subjects who received DM-101, but none of those 2 who received 
placebo, developed transient, mild, grade I local injection site reactions (mostly 
erythema) that disappeared within 16 h post-injection. No treatment-related 
systemic allergic reactions were reported. 
- 
In cohort 2, all 4 subjects who received dosing with DM-101 on Day 1 developed 
treatment-related injection site reactions and 3 of them also developed systemic 
allergic reactions Table 4, Table 5). Specifically, the following DM-101-related 
systemic allergic reactions were reported during Day 1 dosing:  
a) 1 subject developed a transient Grade 2 reaction with symptoms of redness of 
the neck, itching of the eyes and throat, throat pain, nasal congestion, heaviness 
of breathing and FEV1 decrease (treated with inhaled salbutamol) after the 5th 
(2500 ng) and 6th (5000 ng) DM-101 injections,  
b) 1 subject developed a transient Grade 2 reaction with symptoms of generalized 
pruritus, urticaria with papules, angioedema of the eyelids and numbness of the 
lips after the 2nd (250 ng) DM-101 injection, and  
c) 1 subject developed a Grade 3 reaction with symptoms of dysphagia, 
angioedema, pruritus, urticaria and hypotension that peaked after the 4th DM-
101 injection (1000 ng).  
 
Most of the observed local injection site reactions were of Grade 1 or 2. Grade 3 local 
reactions were reported by 2 subjects. One subject developed a Grade 3 reaction 
(erythema) after the 2nd DM-101 injection (250 ng) and another subject developed two 
Grade 3 reactions (erythema and induration/swelling) after the 5th (2500 ng) and 6th (5000 
ng) DM-101 injections. The reaction after the 5th injection evolved from a Grade 2 reaction 
to a Grade 3 reaction after the 6th injection. Overall, the starting dose of 100 ng in cohort 2 
was associated with local injection site reactions that were more prominent than those seen 
with 30 ng in cohort 1. 
 
None of the 4 subjects who receive dosing with DM-101 on Day 1 had Day 2 dosing initiated. 
In contrast, the 1 subject who received placebo completed Day 1 and 2 dosing with no 
TEAEs of special interest reported. 
 
 

 
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Table 4. Local injection site reactions of subjects receiving DM-101 in cohort 2  
Subject Number 
Injection with 
local reaction
Dose ng 
Total dose ng 
Local reaction 
grade
2002 
1st injection
100
1850
1
2nd injection
250
2
3rd injection
500
2
4th injection
1000
2
2003
1st injection
100
9350
1
2nd injection
250
2
3rd injection
500
2
4th injection
1000
2
5th injection
2500
3*
6th injection
5000
3
2004
1st injection
100
750
2
2nd injection
250
3
3rd injection
100
2
4th injection
100
1
5th injection
100
2
6th injection
100
2
2005 
1st injection
100
350
2
2nd injection
250
2
 
 
 
 
*This reaction progressed from Grade 2 to Grade 3 after the 6th injection had already been given 
 

 
Study number DM-101-C-001 
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Table 5. Systemic allergic reactions of subjects receiving DM-101 in cohort 2  
Subject 
number
Day 1 Visit 2 Actual 
Dose (ng)
Symptoms of systemic allergic reaction (SAR) 
SAR 
grading
2002
1st injection: 100 ng
No
2nd injection: 250 ng 
No 
3rd injection 500 ng 
No 
4th injection: 1000 ng 
 
Generalized pruritus, urticaria, angioedema in both 
eyelids, difficulty in swallowing, syncope, hypotension
3 
2003
1st injection: 100 ng 
No
2nd injection: 250 ng 
No 
3rd injection 500 ng 
No 
4th injection: 1000 ng 
No 
5th injection: 2500 ng 
Redness of the neck, itching of eyelids 
6th injection: 5000 ng 
Itchy throat, throat pain, itching, nasal congestion, 
heaviness in breathing, angioedema of the eyelids, 
flushing, generalised pruritus, numbness, sneezing, 
feeling of swelling in the mouth, conjunctival 
erythema
2 
2004 
1st injection: 100 ng  
No 
2nd injection: 250 ng 
No 
3rd injection 100 ng 
No 
4th injection: 100 ng
No
5th injection: 100 ng
No
2005 
1st injection: 100 ng  
No 
2nd injection: 250 ng 
 
Generalised pruritus, urticaria, angioedema of eyelids, 
numbness of the lower jaw and lips, increased need to 
swallow, conjunctival erythema
2 
 
 
Total numbers of TEAES are presented in Tables 6 and 7. 
 
Table 6. Summary of treatment-emergent adverse events in cohort 1  
Category 
DM-101 
(N=4) 
f   n  (%) 
Placebo 
(N=2) 
f   n  (%) 
Total 
(N=6) 
f   n  (%) 
Any TEAE 
   13  4  (100.0) 
3  2  (100.0) 
16  6  (100.0) 
IMP-related TEAE  
    5  4  (100.0) 
0  0  (0.0) 
 5  4  (66.7) 
Severe TEAE 
0  0  (0.0) 
0  0  (0.0) 
0  0  (0.0) 
Serious TEAE 
0  0  (0.0) 
0  0  (0.0) 
0  0  (0.0) 
TEAE leading to discontinuation 
0  0  (0.0) 
0  0  (0.0) 
0  0  (0.0) 
Abbreviations: TEAE = Treatment-emergent adverse event; n = the number of subjects with at least one TEAE; 
f = the number of TEAEs 
 

 
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Table 7. Summary of treatment-emergent adverse events  in cohort 2  
 Category 
DM-101 
(N=4) 
f   n  (%) 
Placebo 
(N=1) 
f   n  (%) 
Total 
(N=5) 
f   n  (%) 
Any TEAE 
56  4  (100.0) 
2  1  (100.0) 
58  5  (100.0) 
IMP-related TEAEs 
     50  4  (100.0) 
0  0  (0.0) 
 50  4  (80.0) 
Severe TEAEs 
  0  0  (0.0) 
0  0  (0.0) 
 0  0  (0.0) 
Serious TEAEs 
  0  0  (0.0) 
0  0  (0.0) 
  0  0  (0.0) 
TEAE leading to discontinuation* 
    2  2  (50.0) 
0  0  (0.0) 
    2  2  (40.0) 
Abbreviations: TEAE = Treatment-emergent adverse event; n = the number of subjects with at least one 
TEAE; f = the number of TEAEs 
*One of the discontinued subjects had 2 reasons for discontinuation, both withdrawal of consent and 2 
Grade 3 local injection site reactions after 2 injections of IMP. 
 
Based on the findings of the interim analysis and in order to ensure the safety of the study 
subjects, the dose and dose escalation scheme for further cohorts were decided to be 
revised.  
 
 
Justification for a revision of the original dose selection rationale  
 
The dose selection for the original protocol version 1.1 was based on starting allergen 
doses used in other birch pollen AIT products and the available non-clinical evidence on 
the allergenic potency and overall safety of DM-101. 
However, direct comparison of the amounts of allergens contained in different AIT 
products is complicated. In addition, the quality and potency of allergen preparations 
depend on the particular allergen composition and purity, as well as on the formulation 
and stability of the product. Moreover, the fact that the potency of allergen products in 
Europe is expressed in manufacturer-specific units, relative to a product-specific in-house 
reference, further complicates any comparisons of products from different manufacturers 
with respect to strength and efficacy (Larenas-Linnemann 2008, Kleine-Tebbe 2019). 
Prompted by the results of the interim analysis, Desentum undertook further laboratory 
work during the temporary halt of the clinical trial to understand the comparability of DM-
101 with other marketed birch pollen products used for AIT. This work (Report DM-101-R-
002) indicated that the formulation of each product may have more pronounced effects on 
allergen potency than originally anticipated. In all birch pollen AIT preparations used as 
reference materials for the initial selection of DM-101 doses for the FIH study the 
allergens were adsorbed on aluminium adjuvants. Aluminium adjuvants are used in 
vaccines to boost the immune response to the antigen, but they also provide a depot that 
adsorbs the antigen and prolong its release from the injection site, resulting in reduced 
systemic peak of allergen concentrations (Jensen-Jarolim 2015). Aluminium adjuvants 
may also change the conformation or even unfold the allergen (Bøgh et al. 2020). This 
diminishes the biological activity of the allergen, including decreased binding to IgE 
antibodies leading to reduced potency and hence induction of an allergic reaction. The 
limited comparability of adjuvanted and non-adjuvanted allergen formulations is now 
acknowledged. Unfortunately, no published information is available for non-adjuvanted 

 
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birch pollen allergens (or any other allergens) used for s.c. AIT that could serve as a 
better reference for DM-101 than the available adjuvanted products.  
To investigate the effects of the aluminium adjuvant on the properties of the major birch 
pollen allergen Bet v 1, Desentum carried out a series of experiments (Report DM-101-R-
002) where the identity, integrity and concentration of Bet v 1 in a commercially available 
s.c. birch pollen AIT product Alutard SQ® and DM-101 were compared. Alutard SQ is a 
birch pollen allergen extract adsorbed in aluminium hydroxide. Another birch pollen 
allergen extract product, Aquagen SQ®, which is mainly used for diagnostic purposes and 
does not contain aluminium hydroxide, was also included in the experiments to ascertain 
that the employed methods can identify the Bet v 1 protein of the comparator products 
correctly. Bet v 1 concentrations were measured with a commercial immunoassay and the 
protein integrity was analysed with SDS-PAGE and further with mass spectroscopy.  
The strength of the Alutard SQ product is expressed in SQ units defined by the 
manufacturer. Based on the literature, 100 000 SQ-U/ml of Alutard SQ correspond to 12.3 
ug/ml of Bet v 1 protein (Bødtger et al. 2002). However, the measured allergen 
concentration of Alutard SQ in Desentum’s experiments was much lower than the 
expected 12.3 ug/ml, and the Bet v 1 protein or other proteins in the extract were not 
visible when analysed on a silver stained SDS-PAGE gel. Mass spectroscopy analyses of 
Alutard SQ indicate that the protein is strongly adsorbed to aluminium hydroxide, and also 
suggest at least partial degradation. In contrast to Alutard SQ, the concentration and 
integrity of both Aquagen SQ and DM-101 in Desentum’s experiments were as expected. 
According to the literature, it is apparent that the amount of Bet v 1 present in allergen 
preparations has been measured before adding the aluminium adjuvant (Kaul, 2016). 
Thus, a likely explanation for the observed differences in the final preparations containing 
aluminium hydroxide is that the allergen protein is strongly adsorbed to the adjuvant 
and/or fragmented.  
The results of Desentum’s experiments suggest that in AIT preparations containing 
aluminium hydroxide the amount of soluble, biologically active Bet v 1 is much lower than 
the nominal content of Bet v 1. In contrast, the DM-101 product does not contain 
aluminium hydroxide and the entire antigen (rBet v 1 dm) content is soluble, intact and 
biologically active. Consequently, the DM-101 dose selection regimen in the original 
protocol version 1.1 included rapid administration of higher amounts of the antigen in 
active form than those used in the reference aluminium adjuvanted AIT products, a fact 
that may explain the unexpected occurrence of AEs indicative of allergic reactions early in 
the FIH clinical trial. 
 
Revised dose selection rationale for Cohorts 3 and 4 
 
Based on the safety findings from the initially conducted cohorts of this FIH trial and 
Desentum’s latest laboratory data on the amount of biologically active Bet v 1 in 
commercially available birch pollen s.c. AIT products, it is considered important to 
continue this study with a DM-101 dosing scheme that carries low risk of induction of 
serious allergic reactions. To this end, the study design has been amended to include only 
2 additional cohorts (cohorts 3 and 4) where DM-101 will be administered following a very 
slowly escalating repeat dose regimen, with doses starting from 30 ng, up to a maximum 

 
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of 300 ng. The rapid dose escalation over 2 consecutive days (Visit 2, Day 1 and 2) 
included in the original study protocol (version 1.1) has been omitted. Instead, a slow dose 
escalation that will take place over 5 bi-weekly dosing visits is proposed. 
 
Dosing in both cohorts, 3 and 4, will start with administration of a single s.c. injection of 
placebo or 30 ng of DM-101 on Visit 2, followed by a single s.c. injection of placebo or 50 
ng of DM-101 2 weeks later (Visit 3). Subsequently, in cohort 3 dosing will continue with 
single administration of placebo or 100 ng DM-101 on each of the Visits 4 to 6. In cohort 
4, Visits 4 to 6 will include s.c. injections of placebo or increasing doses of DM-101 
corresponding respectively to 100, 200 and 300 ng (Table 8). The doses of 200 ng and 
300 ng will be administered as 2 and 3 s.c. injections of 100 ng respectively, with at least 
30 min intervals between injections. 
  
The starting dose of 30 ng has been selected because it was found to be safe and well-
tolerated by the subjects who completed cohort 1 of this study. The subsequent 2nd dose 
of 50 ng and 3rd dose of 100 ng have been selected as modest steps of dose escalation in 
order to maximise safety. The 100 ng dose level has already been tested as the starting 
dose of the 4 subjects who received cohort 2 active treatment in this study; in these 
subjects, 100 ng DM-101 was not associated with the development of significant TEAEs 
or systemic allergic reactions. In cohort 3, 100 ng is the maximal planned dose that will be 
administered on subsequent visits until the end of the treatment phase. If this dosing 
scheme is well tolerated by the cohort 3 subjects, further dose escalation above 100 ng 
will be attempted in cohort 4 at Visit 4 (200 ng) and at Visit 5 (300 ng).  
 
Two-week intervals between doses are considered to be long enough for the intended 
immunological adaptation to develop, to allow dose escalation during the treatment 
period. This dosing interval was also used in the nonclinical toxicology evaluation of DM-
101. 
 
Cohort 4 will not be initiated until cohort 3 Visit 2 has been completed. Dose escalation to 
doses above 100 ng in cohort 4 will only take place if the review of the collected safety 
and tolerability data from Visit 5 of cohort 3 is favourable (see Section 3). Repeated 
dosing and dose escalation within these cohorts will also take place only if safety allows it 
and the study’s dosing discontinuation or adjustment criteria (see Section 9) have not 
been met. 

 
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Table 8  
Revised Study Cohorts - DM-101 Doses (ng) and Dosing 
Schedules* - Protocol version 2.0 
 
 
 
Cohorts 
11
22
3 
4 
Visit 2 
Day 1 
1st injection 
30 
100 
30 
30  
2nd injection 
- 
250 
 
 
3rd injection 
- 
500 
 
 
4th injection 
- 
1,000 
 
 
5th injection 
- 
2,500 
 
 
6th injection 
- 
5,0003 
 
 
Day 2 
1st injection 
- 
(5,000)4 
 
 
2nd injection  
- 
(10,000)4 
 
 
3rd injection 
- 
(25,000)4 
 
 
 
 
Day 1 & Day 2 
Cumulative dose
30 
(49,350)4 
30    
30      
Visit 3 
Day 14 
1 injection 
- 
(25,000)4 
50    
50      
Visit 4 
Day 28  
1 injection 
- 
(25,000)4 
100    
100     
Visit 5 
Day 42  
1-2 injections ** 
- 
(25,000)4 
100    
200     
Visit 6 
Day 56  
1-3 injections** 
- 
(25,000)4 
100    
300    
 
 
Total Cumulative 
dose
30 
(149,350)4 
380 
680 
 
*Acceptable Visit Windows:  ±1 day for Visit 3, and ±2 days for Visits 4, 5 and 6. 
** In cohort 4, doses of Visits 5 and 6 are divided into 2 and 3 injections, respectively 
1Cohort 1 was completed according to the study protocol version 1.1  
2Cohort 2 was started according to the study protocol version 1.1 but dosing and 
recruitment were interrupted at Visit 2 
3Highest dose actually administered in cohort 2 before halt of study;  
4Never administered 
 
1.3. 
Original Risk Benefit Assessment – Protocol version 1.1 
 
Desentum has assessed this FIH study for any risks that may be posed to the subjects 
taking part. DM-101 has an acceptable non-clinical safety and toxicity profile that supports 
initiation of clinical evaluation. Furthermore, there is preliminary, non-clinical evidence of 
the product’s capacity to trigger lesser IgE-mediated allergic reactivity compared to rBet 1 
v (DM-101 IB). Major health risks are not anticipated. However, s.c. AIT is associated with 
a low risk of reversible, systemic allergic reactions, mostly occurring within an hour 
following treatment administration (Kannan, 2013; James, 2017; Nurmatov, 2017). The 
use of standardized allergen extract products and rigorous practices of surveillance have 
made the risk for life-threatening reactions extremely small (Makatsori, 2014; Caminati, 

 
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2015). Nevertheless, the study involves risks and the potential development of local and 
systemic allergic reactions after dosing with DM-101 will be thoroughly monitored.  
Specific risk management measures include the following:  
 
Only subjects in good general health and with no previous history of anaphylaxis, 
moderate to severe or uncontrolled asthma, or immunologic or other major 
disorders will participate in this study (see Inclusion/Exclusion Criteria, Section 
4.2).  
 
The treatment phase of the study will be conducted out of the local birch pollen 
allergy season to reduce any potential risk from additional natural allergen 
exposure. 
 
The study will be undertaken at a clinical research unit with previous experience in 
FIH clinical trials and good understanding of the associated safety risks. The unit 
has all required facilities and knowledge how to handle medical emergencies, 
including severe, systemic allergic reactions, and is located very close to Turku 
University Hospital and its Intensive Care Unit (ICU). Dosing and over-night follow-
up on Visits 2 (for all cohorts) and 3 (for cohorts 2-6) will take place within the 
premises of Turku University Hospital, in its Emergency Care Unit. A qualified 
physician will be present at the site throughout the confinement periods of the 
study subjects. 
 
The DM-101 doses proposed for evaluation have been selected based on careful 
consideration of the allergen doses used in various s.c. birch AIT protocols tested 
in the clinic (see Section 1.2.). 
 
Treatment administration in each dosing cohort will follow a carefully staggered 
schedule to assure minimal exposure to the IMP, until preliminary clinical safety 
data have been collected. The staggered dosing schedule for each cohort is 
described in detail in Section 3.2. In addition, cautious criteria have been set to 
stop further administration of the IMP, in case of significant AEs (see Section 9). 
 
The study will start with cohort 1, in which the lowest DM-101 dose will be 
evaluated. Subsequent progression to cohorts 2 to 6 will be sequential and will 
take place only after completion of the build-up phase in the preceding cohort and 
favorable recommendation from the study Safety Review Committee (SRC), after 
its review of all available safety data (see Section 3.2.). 
 
During the first and second dosing visits (Visits 2 and 3), all subjects will remain 
under close medical supervision, confined overnight in Turku University Hospital’s 
Emergency Care unit, until completion of the 22 h - 24 h assessments after the last 
dose of the preceding day (see Section 3.2). During this period, a series of clinical 
and laboratory safety assessments will be performed. Subjects will not be 
discharged until the Investigator has reviewed the available safety data and finds 
them satisfactory. On the subsequent dosing visits (Visits 4, 5 and 6) during which 
no further dose escalation will take place, all subjects will remain confined in the 
clinical research unit for at least 4 h post-dosing. Furthermore, all subjects will be 
provided with detailed written instructions, rescue medication (adrenaline 
autoinjector) and an action plan on what to do in case of a late-appearing systemic 
allergic reaction. 

 
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Based on the non-clinical evidence for the reduced allergenic potential of DM-101 
compared to other birch allergen products used in AIT practice, its pre-clinical safety 
profile and the high medical need for novel, safe, and effective forms of short-course AIT 
for pollen-driven allergic diseases, it is considered that the estimated risk-benefit ratio is 
currently appropriate for this FIH study. 
 
1.4. 
Revised Risk Benefit Assessment for Cohorts 3 and 4 – Protocol version 2.0 
 
Based on the outcomes of an interim analysis of the data collected from the subjects who 
participated in the first 2 cohorts of the study prior to the temporary halt due to the Covid-
19 pandemic, the dose levels and dosing schemes for the subsequent dose cohorts have 
been revised for version 2.0 of the protocol.  
Desentum has reassessed this FIH study for any risks that may be posed to the subjects. 
Only 2 new cohorts (cohorts 3 and 4), of similar size and composition as the originally 
planned 4 additional cohorts (cohorts 3-6), will be included with doses and dose 
escalation schemes substantially modified. The dose escalation schemes in cohorts 3 and 
4 will provide information about the safety of repeated dosing on a bi-weekly basis, as well 
as on the development of desired immunological responses, both regarded as essential 
information for planning of phase II dose finding studies where the preliminary efficacy of 
DM-101 will be studied.  
Based on the interim results from the cohort 1 and 2 subjects, transient, mild injection site 
reactions may occur with the doses selected for cohorts 3 and 4, but major safety risks 
are not anticipated. Systemic allergic reactions were reported in cohort 2, but none was 
reported following injection of the dose of 100 ng. Administration of doses above 100 ng 
per s.c. injection are not planned in the amended dosing regimen. It is acknowledged that 
s.c. AIT is associated with a low risk of reversible, systemic allergic reactions, mostly 
occurring within an hour following treatment administration (Kannan, 2013; James, 2017; 
Nurmatov, 2017). The use of standardized allergen extract products and rigorous 
practices of surveillance have made the risk for life-threatening reactions extremely small 
(Makatsori, 2014; Caminati, 2015). Nevertheless, the study involves risks and the 
potential development of local and systemic allergic reactions after dosing with DM-101 
will be thoroughly monitored.  
Specific risk management measures include the following:  
 
Only subjects in good general health and with no previous history of anaphylaxis, 
moderate to severe or uncontrolled asthma, or immunologic or other major 
disorders will participate in this study (see Inclusion/Exclusion Criteria, Section 
4.2).  
 
The treatment phase of the study will be conducted out of the local birch pollen 
allergy season to reduce any potential risk from additional natural allergen 
exposure. 
 
The study will be undertaken at a clinical research unit with previous experience in 
FIH clinical trials and good understanding of the associated safety risks. The study 
team has all required facilities and knowledge how to handle medical 
emergencies, including severe, systemic allergic reactions, and collaborates 
closely with Turku University Hospital and its Intensive Care Unit (ICU). All dosing 

 
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visits of cohorts 3 and 4 will take place within the premises of Turku University 
Hospital, in its Emergency Care Unit. The subjects will be confined in the Unit for 
at least 6 h after the dosing. A qualified physician will be present at the site 
throughout the confinement periods of the study subjects. 
 
The DM-101 doses proposed for evaluation in cohorts 3 and 4 have been selected 
based on careful analysis of the interim results of cohort 1 and 2 subjects of this 
study and additional in vitro research carried out after study initiation. 
 
Treatment administration in each dosing cohort will follow a carefully staggered 
schedule to assure minimal exposure to the IMP, until preliminary clinical safety 
data have been collected. The staggered dosing schedule for each cohort is 
described in detail in Section 3.2. In addition, cautious criteria have been set to 
stop further administration of the IMP, in case of significant AEs (see Section 9). 
 
The starting dose (30 ng) of cohorts 3 and 4 has been found to be safe in the first 
part of this study (cohort 1). The planned dose escalation with biweekly dosing 
involves only very modest dose escalation. In cohort 3, all doses to be 
administered (30-100 ng) have already been administered as starting doses in 
cohorts 1 and 2 of the study without systemic allergic reactions. Progression of 
dose escalation above 100 ng in cohort 4 will take place only after completion of 
the 4th dosing of cohort 3 and favorable recommendation from the study’s Safety 
Review Committee (SRC), after its review of all available safety data (see Section 
3.2). 
 
Daily doses greater than 100 ng will be divided into separate injections with a dose 
of 100 ng in each, using at least 30 min intervals between the injections to reduce 
the risk of systemic allergic reactions. 
 
During all dosing visits, the subjects will remain under close medical supervision, 
confined in Turku University Hospital’s Emergency Care Unit, until completion of 
the 6 h assessments after the last injection (see Section 3.2). During this 
confinement period, a series of clinical and laboratory safety assessments will be 
performed. Subjects will not be discharged until the Investigator has reviewed the 
available safety data and finds them satisfactory. The subjects’ state of health will 
be followed up via telephone at approximately 12 and 24 h after completion of the 
dosing. Furthermore, all subjects will be provided with detailed written instructions, 
rescue medication (adrenaline autoinjector) and an action plan on what to do in 
case of a late-appearing systemic allergic reaction. 
Based on the interim results of cohorts 1 and 2 of this study, it is considered that the 
estimated risk-benefit ratio is appropriate for the continuation of this FIH study according to 
the revised study protocol (version 2.0).  
 
 

 
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 2.    STUDY OBJECTIVES AND ENDPOINTS 
2.1.  
Objectives  
2.1.1.  
Primary Objective 
To evaluate the safety and tolerability of s.c. administration of DM-101 in adult subjects 
with birch pollen allergy. 
 
2.1.2.  
Secondary Objective 
 
To determine the proportion of adult subjects with birch pollen allergy who reach the pre-
defined, maximum admissible s.c. DM-101 dose in each dosing group. 
 
2.1.3.  
Exploratory Objective 
 
To evaluate the possible effects of repeated s.c. DM-101 dosing on immunological 
biomarkers in adult subjects with birch pollen allergy. 
 
2.2. 
Endpoints 
2.2.1. Primary Endpoint 
 
The number of all Treatment Emergent Adverse Events (TEAE) in subjects receiving s.c. 
DM-101, compared to placebo.  
 
2.2.2. Secondary Endpoints 
 
The number and severity of systemic allergic reactions in subjects receiving s.c. DM-101, 
compared to placebo. 
 
The number and severity of local injection site reactions in subjects receiving s.c. DM-101, 
compared to placebo. 
 
The proportion of subjects reaching the pre-defined, admissible dose in each DM-101 
dosing group. 
 
2.2.3. Exploratory Endpoints 
 
The effect of repeated s.c. DM-101 dosing on serum levels of birch allergen-specific 
immunoglobulins, compared to placebo. 
The effects of repeated s.c. DM-101 dosing on novel, exploratory immunological 
biomarkers, compared to placebo. 
 
 

 
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3. STUDY DESIGN 
3.1. 
Overview 
This will be a randomized, double blind, placebo-controlled, parallel group study to 
evaluate the safety and tolerability of s.c. administration of DM-101 in subjects with birch 
pollen-evoked allergic rhinoconjunctivitis. The study will be conducted outside of the birch 
pollen season in Finland.  
 
The study will include up to 4 cohorts of participants. In each cohort, subjects will be 
randomly allocated to receive s.c. doses of DM-101 or placebo. Subjects will be allowed to 
participate in only one cohort and will receive one type of treatment, with either DM-101 or 
placebo, throughout the study. Cohort 1 of the study included a single dose 
administration. Cohorts 2 to 4 include repeat dose administration.  
 
Table 2 and 8 describes the type of dosing with DM-101 scheduled to be administered in 
each cohort of study participants. 
 
The study was started with cohorts 1 and 2, and will now proceed to cohorts 3 and 4 after 
a substantial protocol amendment. The amended protocol version 2.0 will be followed for 
the conduct of cohorts 3 and 4. A previous protocol version (1.1) was followed for cohorts 
1 and 2. 
 
Dose escalation will be initiated only upon satisfactory review of all available safety data 
from the previous cohort(s) and favorable recommendation from the study’s SRC.  
 
An overall schematic of the study design is presented in Figure 1. 
 

 
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3.2. 
Study Periods 
Study participation includes a screening period, a treatment period and a follow-up period.  
 
Screening Period: 
Up to 2 months (60 days) prior to treatment randomization, adult subjects with a history of 
birch pollen-evoked allergic rhinoconjunctivitis will be invited for screening at the clinical 
research unit (Visit 1). Subjects will first provide informed consent for participation in the trial 
and may then undergo a preliminary eligibility assessment to confirm their medical history 
and allergic sensitisation to birch pollen, by skin prick testing (SPT). Subjects with a positive 
SPT response to birch pollen will then proceed to further medical assessments to determine 
their eligibility in relation to the study selection criteria. At the discretion of the Investigator, 
screening evaluations may take place over one or two visits (Visit 1a and Visit 1b). 
 
Treatment Period: 
Once eligibility has been confirmed, subjects will proceed to the treatment period and will be 
randomly allocated to receive treatment with DM-101 or placebo.  
 
Cohort 1 (completed in accordance with protocol version 1.1)  
Subjects allocated into cohort 1 (Table 2) will visit the clinical research unit (Visit 2) and after 
a brief medical review will receive a single s.c. injection of DM-101 or placebo. All subjects in 
this cohort will remain confined in Turku University Hospital’s Emergency Care unit until at 
least 24 h after dosing and will be closely monitored. 
 
Dosing will be staggered in such a way that a sentinel group of 2 subjects, 1 receiving DM-
101 and 1 receiving placebo, will be dosed first in a double-blind fashion. Treatment of the 
remaining subjects in the cohort will be initiated, at the earliest, 22 h after the sentinel 
subjects have completed their dosing, without safety findings that meet the study’s stopping 
or treatment discontinuation criteria (see Section 9). Subjects in the main treatment group will 
also receive their doses in a staggered fashion, with 2 subjects receiving their doses first and 
the remaining subjects being dosed no sooner than 4 h later.  
 
Cohort 2 (started in accordance with protocol version 1.1, discontinued, not to 
be re-started) 
Initiation of cohort 2 was to take place only after completion of all Visit 2, 24 h post-dosing 
assessments in all subjects of cohort 1, review of all safety and tolerability data and a 
favorable recommendation from the study’s SRC. There was to be an at least 2 days’ interval 
between completion of the post-dosing 24 h monitoring period in cohort 1 and initiation of 
dosing in cohort 2. 
 
The study was temporarily halted because of the Covid-19 pandemic after completion of Visit 
2 for 1 subject and partial completion of Visit 2 for 4 subjects. Because of the reporting of 
TEAE of local and systemic allergic reactions in 4 of the 5 participants, the SRC 
recommended that dosing in the study should not be re-started without a substantial protocol 
amendment.  
 
 
 

 
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VISIT 2 
 
According to version 1.1 of the study protocol, subjects allocated into cohort 2 (Table 2) were 
to enter Turku University Hospital’s Emergency Care unit and after a brief medical review 
receive a series of s.c. injections with escalating doses of DM-101 or placebo over 2 
consecutive days (Visit 2 Day 1 and Visit 2 Day 2). All subjects in cohort 2 were to remain 
confined overnight in the hospital and were to be closely monitored until at least 24 h 
following completion of dosing on Day 2.  
 
Dosing and dose escalation was to be staggered in such a way that 2 sentinel subjects, 1 
receiving DM-101 and 1 receiving placebo, were to be dosed first in a double-blind fashion. 
Dosing of the remaining subjects in the cohort was to be initiated, at the earliest, 22 h after 
sentinel subjects had completed their Day 2 dosing, without safety findings that would meet 
the study’s stopping or treatment discontinuation criteria (see Section 9). Subjects in the 
main treatment group were also to receive their doses in a staggered fashion, with 2 subjects 
starting first to receive doses and the remaining subjects starting to receive doses no sooner 
than approximately 22 h after the first two subjects of the main group had completed their 
Day 2 dosing.   
 
Treatment on Day 1 was to start with administration of 100 ng of DM-101 or placebo. This 
was to be followed by administration of progressively escalating doses of DM-101 or 
placebo, at approximately 30 min intervals, up to a total of 6 s.c. injections per subject/day. 
On Day 2, treatment was to start with a repeat of the top DM-101 dose administered on Day 
1 or placebo, followed by another 2 administrations of escalating DM-101 doses or placebo, 
approximately 30 min apart, up to a maximum of 3 s.c. injections per subject/day. Dose 
escalation, in each subject, was to be allowed only if the study’s stopping and treatment 
discontinuation-adjustment criteria were not met (see Section 9).  
 
VISITS 3-6 
Dosing on Visit 3 was to take place only if there was a favorable recommendation from the 
SRC, after reviewing of all safety data collected from Visit 2 (Day 1 and Day 2).  
 
The subjects were to return to the hospital 2 weeks (± 1 day) after completion of their Visit 2 
Day 2 treatment (Visit 3), and after a brief medical review were to receive a single s.c. 
injection of the last DM-101 dose they were administered on Visit 2 Day 2 (Day 2 injection 3) 
or placebo. The subjects were to remain confined overnight in Turku University Hospital’s 
Emergency Care unit and were to be discharged only after satisfactory medical review by the 
attending physician of the clinical research unit, no sooner than approximately 24 h after 
dosing. 
 
After Visit 3, dosing was to be allowed only if the study’s stopping and treatment 
discontinuation criteria had not been met on the previous dosing visit (see Section 9). 
 
The subjects were to return to the clinical research unit for another 3 visits (Visit 4, Visit 5 
and Visit 6). Visit 4 was to take place 2 weeks (± 2 days) after Visit 3, followed by Visit 5 and 
Visit 6, each after another 2 weeks’ (± 2 days) interval. On each of these visits, subjects were 
to receive, after a brief medical review, a single s.c. injection of DM-101 or placebo. The 
dose of DM-101 each subject was to receive was to be the same as that administered on 
Visit 3. On each of these visits, the subjects were to remain confined in the clinical research 

 
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unit for approximately 4 h after dosing and were to be discharged only after satisfactory 
medical review by the attending study physician. All subjects were to receive a phone call 
from the clinical research unit, approximately 24 h after discharge, for a brief medical update. 
 
On each of the visits 3 - 6, the sentinel subjects of each cohort were to receive dosing first. 
The remaining subjects were to receive dosing at least 22 h later. Subjects in the main group 
were also to receive dosing in a staggered fashion, in such a way that there was to be an at 
least 30 min interval between each injection.  
 
Cohorts 3 and 4  
 
The revised dosing scheme of protocol version 2.0 will be applied in these cohorts (cohorts 3 
and 4). There will be 6 subjects in each cohort allocated to receive s.c. injections of DM-101 
and 2 subjects allocated to receive corresponding placebo injections. The recruitment 
procedures and subject selection criteria have not been modified for version 2.0 of the study 
protocol. 
 
VISIT 2 
 
Subjects allocated into cohorts 3 and 4 (Table 8) will enter Turku University Hospital’s 
Emergency Care unit, and after a brief medical review and other eligibility assessments they 
will receive a single s.c. injection of 30 ng of DM-101 or placebo. The subjects will remain 
confined in the hospital for approximately 6 h following dosing. 
 
Dosing will be staggered in such a way that 2 sentinel subjects, 1 receiving DM-101 and 1 
receiving placebo, will be dosed first in a double-blind fashion. Dosing of the remaining 
subjects in the cohort will be initiated no sooner than 22 h after the sentinel subjects have 
completed their Visit 2 dosing, without safety findings that would meet the study’s stopping or 
treatment discontinuation criteria (see Section 9). Subjects in the main treatment group in 
each cohort will also receive treatment in a staggered way, with 2 subjects starting first to 
receive doses and the remaining subjects starting to receive doses no sooner than 
approximately 22 h after the first two subjects of the main group have received their Visit 2 
dosing. 
 
Visit 2 of cohort 4 subjects will take place after Visit 2 of cohort 3 has been completed.  
 
VISITS 3-6  
 
After Visit 2, dosing in each cohort will be allowed only if the study’s stopping and treatment 
discontinuation criteria have not been met on the previous dosing visit (see Section 9). 
 
All subjects will return to the hospital for another 4 visits (Visit 3, Visit 4, Visit 5 and Visit 6) on 
a biweekly basis for the subsequent dosings. In cohort 3, subjects will receive a single s.c. 
injection on each of these visits. In cohort 4, subjects will receive a single s.c. injection on 
Visits 3 and 4 and a series of 2 or 3 s.c. injections on Visits 5 and 6, respectively, with a 
minimum of 30 min interval between subsequent injections. Each injection will be given at a 
slightly different site of the exterior surface of the upper arm. The injections will alternate 
between the right and left arm. 
 

 
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Dose escalation to the 200 ng daily dose (Visit 5) in cohort 4 will only take place after a 
favourable recommendation from the SRC, once it has reviewed all available safety data so 
far collected in the study, including data from Visit 5 of cohort 3. 
 
 
On each of the Visits 3-6. dosing will be staggered in the same way as on Visit 2, ie. 2 
sentinel subjects, 1 receiving DM-101 and 1 receiving placebo, will be dosed first in a double-
blind fashion. Dosing of the remaining subjects in the cohort will be initiated no sooner than 
22 h after the sentinel subjects have completed their dosing, without safety findings that 
would meet the study’s stopping or treatment discontinuation criteria (see Section 9). 
Subjects in the main treatment group in each cohort will also receive treatment in a 
staggered way, with 2 subjects starting first to receive doses and the remaining subjects 
starting to receive doses no sooner than approximately 22 h after the first two subjects of the 
main group have received their dosing. 
 
 
Follow-up Period: 
All subjects will return to the research site for a Follow-up visit (Visit 3 for cohort 1 and Visit 7 
for cohorts 2-4), for medical assessment and collection of blood samples. The Follow-up visit 
will take place approximately 4 weeks (28 days ± 3 days) after the last dosing of each 
subject. 
 
 
3.3. 
Safety Review Committee 
For this study, a SRC has been assembled. After completion of cohort 1 and cohort 2 and 
the interim data analysis, the SRC is responsible for 1) providing recommendations on the 
dose escalation from 100 ng to 200 ng in cohort 4 based on the safety data collected up to 
and including cohort 3 Visit 5 and cohort 4 Visit 4, i.e. prior to cohort 4 Visit 5, where the 
administration of 200 ng dose is planned; 2) on continuation of dosing of cohort 3 to Visit 6; 
3) on continuation or termination of the study; 4) on possible suspension or modification of 
dosing based on the study’s stopping criteria (see Section 9); 5) on the appropriateness of 
the safety measures and the possible need for alterations. If needed, the study will be halted 
until appropriate measures have been taken to amend the study protocol and until all 
relevant approvals have been received to continue the study. 
 
Additional SRC meetings will be held, as needed; additional meetings will be triggered by 
safety observations as described in Section 9.  
 
The SRC includes members with experience in the conduct and risk 
assessment/management of clinical trials and ethical aspects. The SRC is comprised of the 
Principal Investigator, the Sponsor’s Medical Monitor, representative(s) of the Sponsor and a 
qualified biostatistician.  
 
Detailed instructions for SRC meetings and its decision-making process are described in a 
separate document called “SRC Instructions”. The study data will be reviewed blinded. 
However, if it is deemed necessary for ascertaining the safety of the study subjects, the 
review may also be unblinded. 
 

 
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4. STUDY SUBJECTS 
4.1. 
Number of Subjects 
An adequate number of subjects, with documented birch pollen allergy, will be enrolled in the 
study, such that up to 27 subjects will be randomized to receive treatment with IMP in the 
scheduled 4 cohorts of participants. In particular, in: 
 
Cohort 1: 6 subjects were randomized in a ratio of 2:1 to receive single doses of DM-101 or 
placebo.  
 
Cohort 2: 5 subjects were randomized to receive repeated doses of DM-101 or placebo 
before the temporary halt of the study. Because of systemic allergic reactions observed in 3 
of the 5 thus far included participants on Day 1 of Visit 2, the SRC did not recommend re-
start of dosing in cohort 2 without a substantial protocol amendment. Four of the 5 enrolled 
subjects had received DM-101 on Visit 2 and one subject had received placebo injections. 
 
 
Cohorts 3 and 4: 8 subjects per cohort to be randomized in a ratio of 3:1 to receive repeated 
doses of DM-101 or placebo. 
 
For replacement of cohort 3 and 4 subjects who prematurely discontinue the study for 
reasons other than TEAE, additional subjects may be enrolled at the discretion of the 
Investigator, following discussion and agreement with the Sponsor.  
 
4.2. 
Eligibility Criteria 
Subjects will be eligible for inclusion in this study only if all of the following criteria apply: 
 
4.2.1.   Inclusion Criteria 
1. 
Males or females, aged 18 to 65 years inclusive. 
 
2. 
Good general health, as determined by the Investigator, based on medical evaluation, 
including medical history, physical examination, laboratory tests and 
electrocardiogram (ECG). 
 
3. 
A documented clinical history of birch pollen-induced allergic rhinitis or rhino-
conjunctivitis with symptoms that interfere with daily activities or sleep and remain 
bothersome despite the use of relevant symptomatic medication, and have been 
present over, at least, 2 allergy seasons.  
 
4. 
Bet v 1 specific serum IgE ≥ 0.7 kU/L (class 2), measured by ImmunoCAP®. 
 
5. 
Positive SPT to birch pollen allergen, with a wheal diameter ≥ 5 mm (average of 
longest and orthogonal) greater than that produced by the negative control. 
 
6. 
Body weight ≥50 kg and body mass index (BMI) within the range 18–35 kg/m2. 
 
7. 
Females are eligible to participate only if they are of: 

 
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 
non-childbearing potential, defined as pre-menopausal females with documented 
tubal ligation or hysterectomy, or postmenopausal, defined as 12 months of 
spontaneous amenorrhea (in questionable cases a blood sample with levels of 
follicle stimulating hormone (FSH) > 40 MlU/ml and estradiol < 40 pg/ml (<147 
pmol/L) is confirmatory). Females on hormone replacement therapy (HRT) and 
whose menopausal status is in doubt will be required to use one of the 
contraception methods in Section 4.3.1.1. if they wish to continue their HRT 
during the study. Otherwise, they must discontinue HRT to allow confirmation of 
post-menopausal status prior to study enrollment. For most forms of HRT, at least 
2-4 weeks should elapse between the cessation of therapy and the blood draw; 
this interval depends on the type and dosage of HRT. Following confirmation of 
their post-menopausal status, they can resume the use of HRT during the study 
without the need to use a contraceptive method. 
 
child-bearing potential and have a negative serum pregnancy test result at 
Screening and a negative serum pregnancy test result within 10 days prior to the 
first dosing visit, a negative urine pregnancy test before each subsequent dosing 
and agree: 
 
to use one of the contraception methods listed in Section 4.3.1.1. starting at least 
2 weeks prior to the start of dosing to sufficiently minimize the risk of pregnancy 
during the treatment period of the study. Female subjects must agree to use 
contraception until 30 days after the last treatment administration. 
 
or abstains from sexual intercourse or has only same-sex partner(s), when this is 
her preferred and usual lifestyle. 
 
8. 
Males who are sexually active with a female partner of childbearing potential must 
agree to use one of the contraception methods listed in Section 4.3.1.2. 
 
9. 
Willing and able to provide written informed consent. 
 
10. 
Willing and able to comply with the study requirements. 
 
4.2.2. Exclusion Criteria 
1. 
History or findings on physical examination of any significant disease or disorder (e.g. 
cardiovascular, pulmonary, gastrointestinal, hepatic, renal, neurological, 
immunological, musculoskeletal, endocrine, metabolic, major psychiatric, major 
physical impairment, cancer) which, in the opinion of the Investigator, may put the 
subject at risk because of participation in the study, influence the results of the study 
or the subject’s ability to participate in the study. 
 
2. 
Current diagnosis of asthma (other than seasonal during the birch pollen allergy 
season), requiring Global Initiative for Asthma (GINA) Step 2 or higher treatment, or 
asthma partially controlled or uncontrolled according to GINA classification in the 6 
months before Screening. 
 
3. 
History of asthma deterioration that resulted in emergency treatment or hospitalisation 
in the 12 months before screening, or a life-threatening asthma attack (e.g. one 
requiring intubation and mechanical ventilation) at any time in the past. 
 

 
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4. 
Forced Expiratory Volume in one second (FEV1) < 70% of predicted, regardless of 
asthma status at screening or baseline assessment at the first dosing visit. 
 
5. 
History of severe drug allergy, severe angioedema or systemic allergic reaction of 
Grade 3 or greater, according to the World Allergy Organization (WAO) scale, due to 
any cause.  
 
6. 
Use of systemic glucocorticoid medication within 30 days prior to Screening.  
 
7. 
Use of anti-IgE medication within 3 months prior to Screening. 
 
8. 
Use of mast cell stabilisers, anti-leukotriene agents or anti-histaminics less than 1 
week prior to dosing initiation. 
 
9. 
A course of short-duration allergen-specific immunotherapy or more than 3 months’ 
treatment with long-duration allergen immunotherapy, within five years prior to 
Screening. 
 
10. 
History of intolerance to the study drug, rescue medications (i.e. adrenaline, 
antihistaminics, glucocorticoids), or their excipients. 
 
11. 
Regular use of angiotensin-converting enzyme inhibitors, beta-adrenergic blockers or 
monoamine oxidase inhibitors. 
 
12. 
Ongoing treatment with substances interfering with the immune system. 
 
13. 
Treatment with an investigational drug within 30 days prior to Screening or concurrent 
participation in another clinical trial. 
 
14. 
Contraindication for the administration of adrenaline (e.g. subjects with acute or 
chronic symptomatic coronary heart disease or severe hypertension). 
 
15. 
Significant history of alcohol or drug abuse in the past 5 years, or a positive 
Screening or pre-dose drug/alcohol test result. A positive screening result for 
benzodiazepines or opioids may be accepted at the discretion of the investigator, if 
the finding can be satisfactorily explained by the subject’s medical history and 
concomitant medication information. 
 
16. 
Females who are pregnant, lactating or planning to become pregnant, or plan to 
donate oocytes for in vitro fertilisation during the study treatment period or within 
30 days following the treatment period. Subjects unwilling to employ appropriate 
contraceptive measures to ensure that pregnancy will not occur either during or for 
30 days following the completion of the treatment period. 
 
 

 
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4.3. 
Lifestyle and Dietary Restrictions 
4.3.1. 
Contraception Requirements 
 
4.3.1.1.  Female Subjects 
Women of childbearing potential (WOCBP) and females on hormone replacement therapy 
(HRT) whose menopausal status is in doubt should use a contraceptive method with a failure 
rate of < 1 %. These may include oral, transdermal or injectable contraceptives, intrauterine 
devices or barrier methods (diaphragms, condoms, spermicides), practicing abstinence or a 
non-heterosexual lifestyle or having male partners who are sterile (e.g. vasectomised for at 
least 90 days).  
 
During the study, all WOCBP should be instructed to contact the Investigator immediately if 
they suspect they might be pregnant. 
 
4.3.1.2. Male Subjects 
Male subjects with WOCBP sexual partners must use an effective contraceptive method from 
the day of the first administration of study treatment until the Follow-up visit. Effective 
contraceptive methods include the use of a latex condom plus the use by the female partner 
of a highly effective contraceptive method (see Section 4.3.1.1.). Periodic abstinence (e.g. 
calendar, ovulation, symptom-thermal, post-ovulation methods) and withdrawal are not 
acceptable methods of contraception. 
 
4.3.2. 
Meals and Dietary Restrictions  
Subjects will be required to be fasting for 2 h pre- and post-treatment administration, for 
reasons of safety. Intake of small amounts (<2 dl) of water will be allowed.  
 
4.3.3. 
Caffeine, Alcohol, Recreational Drugs and Tobacco Use 
Subjects will have to abstain from ingesting excessive amounts (more than one cup) of 
caffeine- or xanthine-containing products (e.g. coffee, tea, cola drinks, chocolate) for 6 h prior 
to each treatment administration.  
 
Subjects will have to abstain from alcohol for 24 h prior to each visit to the clinical research 
unit and until collection of all assessments has been completed.  
 
Use of tobacco products is not allowed during the stay in the clinical research unit. 
 
Subjects should refrain from all recreational drugs from screening until the end of the Follow-
up period.  
 
4.3.4. 
Exercise, blood donation and vaccinations  
Subjects will have to abstain from strenuous physical exercise for 48 h prior to each blood 
collection for clinical laboratory tests.   
 

 
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Subjects will be asked to refrain from donating blood for purposes not related to this study or 
receiving any immunization from the Screening visit until the end-of-study visit.  
 
4.4. 
Subject Withdrawal and Procedures 
A subject may withdraw from the study at any time at his/her own request and for any 
reason. Possible withdrawal of consent will not have any negative effect on the subject’s 
medical care. 
 
When a subject chooses to withdraw from the study, the Investigator will record, where 
possible, a reason according to the following:  
 
Treatment related adverse effects  
 
Unpleasant study procedures  
 
Another disease or condition that intervenes and prevents continuation in the study  
 
External factors unrelated to the study 
A subject may also be withdrawn by the Investigator for the following reasons: 
 
Adverse events which in the opinion of the Investigator compromise the subject’s 
participation in the study 
 
Non-compliance with study procedures 
 
Lost to follow-up 
 
Withdrawal of consent 
 
Protocol violation 
 
Termination of the study 
 
Pregnancy prior to completion of planned dosing of the IMP 
 
The subject cannot comply with study requirements 
 
Use of any prohibited medication during the study 
For subjects who withdraw from the study, all safety assessments scheduled for the Follow-
up visit will be requested and observations will be recorded as far as possible. Reasons for 
omission of tests will be documented. The date and reason(s), if provided, for withdrawal 
from the study will also be recorded in the electronic Case Report Form (eCRF). 
 
If the subject withdraws due to an AE, all of the Follow-up assessments will be requested 
and the event followed until resolution or care is transferred to the subject’s general 
practitioner or primary care physician. 
 
It will be decided case-by-case whether a discontinued subject will be replaced or not. 
Discontinued study subjects are not allowed to re-enter the study. Replacement procedures 
are briefly described in section 4.1. 
 

 
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4.5. 
Screening and Baseline Failures 
From subjects screened but not included in the study, the following data will be collected on 
eCRFs: date of Informed Consent, demographic information, the inclusion/exclusion 
criterion/criteria causing the exclusion and the date of the decision of exclusion. 
  
4.6. 
Subject Completion 
A completed subject is one who has completed all phases of the study including the Follow-
up visit. 
 
The end of the study is defined as the last subject’s Follow-up visit (Visit 3 for cohort 1 or 
Visit 7 for cohorts 2 to 4).  
 
4.7. 
Study Extension - Optional Sub-Study 
An extension of the study to include an additional follow-up visit after the birch pollen allergy 
season of 2021, for information on allergic symptoms and blood sample collection for the 
assessment of immunological biomarkers, may be considered for the subjects participating in 
cohorts 2-4, if the results of the core study, conducted prior to the birch pollen allergy season 
of 2021, are satisfactory. Participation in this sub-study will be optional and based on 
separate consent. 
 
 
5. STUDY MEDICATIONS 
5.1. 
Investigational Medicinal Products 
The active Investigational Medicinal Product (IMP) of the study is DM-101.  
 
DM-101 is a s.c. AIT product presented as a solution for s.c. injection. The active substance 
is a genetically engineered, purified, recombinant protein derived from the major birch pollen 
allergen Bet v 1.  
 
The drug product of the IMP, DM-101 is a sterile solution.  
 
The placebo product in this study is the diluent for DM-101. 
 
The IMP DM-101 and placebo have identical appearance. The solution is colorless or slightly 
yellow, and clear or opalescent.  
 
5.1.1.  
Route of Administration 
Both IMPs, DM-101 and placebo, will be administered by s.c. injection.  
 

 
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5.1.2.  
Labelling and Packaging 
The DM-101 drug product is filled into 2R Ph.Eur. Type I clear glass vials in 2.2 ml volume. 
The vials are closed with Fluorotec stoppers and aluminium seals.  
 
The diluent for DM-101 is filled in 15 ml Ph.Eur. Type I glass vials in 10 ml volume. The vials 
are closed with bromobutyl stoppers and aluminium seals. 
 
Individual study medication vials and study packs will be labelled in accordance with 
applicable Good Manufacturing Practice (GMP) regulations. The vial label will record the 
study identifier, product name, batch number, sponsor’s name, as well as the subject and 
visit number/date, which will be filled in by the study site personnel before use. The DM-101 
vials will be packed in carton boxes of 10 vials and the diluent vials will be packed in carton 
boxes of 10 vials. The outer packaging of each box will contain the following information: 
study identifier, product name, strength, dosage form, route of administration, quantity of 
vials, investigator’s name, name and address of sponsor, batch number, period of use, 
storage conditions, “for clinical trial use only”. 
 
5.1.3. Manufacturing 
The DM-101 drug product and the diluent for DM-101 are manufactured by Biovian Oy, 
Turku, Finland, in accordance with current EU Good Manufacturing Practice, at appropriately 
licensed facilities.  
 
5.1.4. Storage and Handling Procedures  
IMPs will be stored refrigerated at + 2- +8 °C in a designated storage area at the clinical 
research unit, in a secure, temperature controlled, locked environment with restricted access.  
 
No preservative is used in the drug product. Therefore, each vial is for single use only.  
 
The Sponsor will be permitted, upon request, to audit the supplies, storage, dispensing 
procedures and records, provided that the blinding of the study is not compromised. 
 
5.1.5. Accountability 
In accordance with Good Clinical Practice (GCP), the clinical research unit will be 
accountable for all supplies of DM-101 and placebo. Details of receipt, storage, 
reconstitution, administration and return will be recorded.  
 
All unused supplies of DM-101 and placebo will either be destroyed at the clinical research 
unit or returned to the Sponsor at the end of the study, in accordance with instructions by the 
Sponsor.  
 
5.1.6. Dosage and Administration 
5.1.6.1. 
Reconstitution and Handling of Investigational Medicinal Product 

 
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The reconstitution process includes dilution of the DM-101 drug product with Diluent to DM-
101 and extraction of the required volume of the IMP into a sterile syringe for s.c. 
administration.  
 
All steps included in drug IMP reconstitution will be performed at the clinical research site 
under aseptic conditions (under a laminar flow hood), using sterile equipment, suitable for 
preparing sterile injection solutions for human use by clinical research unit personnel who are 
not otherwise involved in the study. 
 
3 serial dilution steps are required to reach the desired dose/concentration of DM-101 for 
cohorts 3 and 4 according to protocol version 2.0.  
 
All dilution vials used in the reconstitution will be labelled with the dilution level, subject 
identifier and preparation date.  
 
The reconstitution process will be performed according to a separate ”Instructions for 
Reconstitution and Handling of Study Products” manual. 
 
The personnel preparing the drug IMP doses must know the treatment code (active or 
placebo). Therefore, to protect the double-blind administration, according to the study design, 
this process will be performed by designated unblinded clinical research unit personnel who 
will not be otherwise involved in the study. The filling of the injection syringe will be done by 
the unblinded personnel preparing the dilutions. Study personnel administering the injections 
(blinded) to the subjects will receive the pre-filled injection syringes labelled with subject 
number and injection number and will adjust the volume in the syringe to the final dose 
volume right before the injection, thus they will be blinded to the actual treatment allocation. 
The administered volumes of the active product and placebo will be identical at each dose 
level, to allow double-blind administration. 
 
5.1.6.2. 
Administration for Cohorts 3 and 4 
On the Dosing Visits, the IMP will be administered after a brief medical review that includes 
the procedures described in Table 11, to confirm the eligibility of the subjects. Abnormal 
findings may require suspension of dosing (see Section 4.2). The Investigator should discuss 
any findings of concern with the Medical Monitor before dosing. 
 
The person administering the injection (blinded) will adjust the volume in the syringe to the 
final dose volume right before the injection. The injection will be administered s.c. by the 
Investigator or designee into the exterior surface of the upper arm. On Visits 5 and 6 in 
cohort 4 where several s.c. injections are scheduled, the injections will be administered in 
alternate arms (right - left - right). 
 
The doses will be administered using a 1 mL sterile syringe and an appropriately sized 
needle (25 G). The injection technique follows standard AIT practices, with aspiration to 
ensure extravascular needle placement and slow injections.  
 
The administered injection volume will vary from 0.03 to 0.1 ml (Table 9) depending on the 
dose. In each cohort of participants, for each IMP administration, the volume for injection of 
placebo will be equal to the active product volume for injection. 
 
 

 
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Table 9  
Cohort 3 and 4: DM-101 dilution level and concentration, injection 
volume and number of injections / dose 
* Dose 300 ng consists of 3 injections of 100 ul volume each 
** Dose 200 ng consists of 2 injections of 100 ul volume 
 
The subjects will be in a sitting/supine position during the injections. Subcutaneous dose 
volumes varying from 0.03 to 0.10 ml (Table 9) will be injected per injection. In cohort 4, the 
total dose volume of 2 and 3 injections at Visits 5 and 6 will be 0.2 and 0.3 ml, respectively.  
 
Subjects will be dosed using a sentinel strategy as described in Section 3.2. The doses of 
DM-101 scheduled to be administered in each cohort are presented in Table 8. 
 
5.2. 
Treatment Assignment  
At the Screening visit, after signing of the ICF (Informed Consent Form), potential study 
participants will be assigned unique, individual screening numbers starting from S001. After 
confirmation of eligibility, at admission, subjects will be assigned subject numbers in the 
order in which they will be enrolled in the study, as shown in Table 10. The subject number 
will determine the allocation of participants into the 4 study cohorts. 
 
Table 10 
  
Assignment of Subjects to Cohorts for Treatment Allocation 
 
Cohort 
Subject Numbers 
1 
1001-1006 
2 
2001-2008 
3 
3001-3008 
4 
4001-4008 
  
If applicable, replacement subjects in cohorts 3 and 4 will receive the same cohort and 
treatment allocation as the subjects they replace. Replacement subjects will be allocated the 
same subject number as the replaced subject with the addition of number 1 at the beginning 
(e.g. if subject number 3001 is replaced, the replacement subject’s number will be 13001).  
 
5.3. 
Randomization and Blinding 
This is a double-blind study. The site personnel and the study subjects will know the dose 
level(s) of DM-101 under investigation in each cohort of participants but will be blinded to the 
Dose (ng) 
Dilution level 
Concentration of the 
dilution 
Number of 
injections 
Volume/injection 
(ul) 
300 * 
1:1 000 
1000 ng/ml 
3 
100* 
 
200 ** 
1:1 000 
1000 ng/ml 
2 
100** 
100 
1:1 000 
1000 ng/ml 
1 
100 
50 
1:1000 
1000 ng/ml 
1 
50 
30 
1:1 000 
1000 ng/ml 
1 
30 

 
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type of treatment (active or placebo) allocated to an individual subject. The blinding of the 
IMP will be achieved by employing an unblinded member of the study team to prepare the 
injection syringes for dosing of placebo and active product at each DM-101 dose level of 
each cohort. 
 
Allocation to treatments will be according to a predetermined random order resulting from 
block randomization with randomly permuted blocks. Randomization will take place for each 
cohort separately. 4Pharma Ltd. will generate the randomization list using the statistical 
analysis system SAS® for Windows and its PROC/Plan procedure. 
 
The randomization list will be provided to the designated person at the clinical research unit 
who will be responsible for the handling of the IMP. To keep the study double-blind, this 
person will not participate in any other study activities. The person who will prepare the IMP 
for injection to the study participants must be a qualified health care professional. 
 
The randomization according to the randomization list is implemented in the electronic data 
capture (EDC) system, and the subjects in each cohort will be randomly allocated to 
treatments by the Investigator. 
 
5.4. 
Breaking of the Blinded Codes 
For cases of emergency, the Investigator or the persons to whom emergency unblinding 
have been delegated are provided with an electronic unblinding function in the EDC system 
to break the randomization code for a single subject. In addition, sealed subject-specific 
emergency code envelopes containing the treatment allocation for each subject in separate 
envelopes are available to ensure that unblinding can be performed at any time needed.  
 
In case the emergency envelope is used for unblinding the study treatment for an individual 
subject, the reason for unblinding has to be written on the envelope. In addition, the person 
performing the unblinding has to date and sign the envelope. The code must not be broken 
for any other reason than a medical emergency. 
 
The randomization code of cohort 1 and 2 subjects was broken for an interim analysis after 
the study had been temporarily halted and the database for cohort 1 and 2 subjects had 
been locked. The blinded randomization code for all cohort 3 and 4 subjects will be broken 
only after all subject data have been recorded and verified, and the database has been 
locked. 
 
5.5.    Procedures for Monitoring Subject Compliance 
When each dose of IMP is prepared for a subject, the preparation of the dose will be 
confirmed by a second unblinded member of the clinical research unit staff. The study 
medication will be administered by s.c. injection by the Investigator or designee. There will be 
close medical supervision during and after treatment administration. 
 
The date and time of each administered dose will be recorded in the source documents. The 
dose of study treatment and study participant identification will be confirmed at the time of 
treatment administration by a member of the clinical research unit staff, other than the person 
administering the study treatment.  

 
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5.6.  
Concomitant Treatments 
The Investigator must record the use of all concomitant medications, both prescribed and 
over-the-counter, into the eCRF and the subject’s medical records. This includes medications 
used on both regular and as-needed basis.  
 
5.7.  
Permitted Medications  
Any concomitant medication will be considered on a case by case basis, by the Investigator 
and the Medical Monitor. Paracetamol up to 4 g/day will be permitted as required, at the 
discretion of the Investigator. Hormonal contraceptives may be used by WOCBP. No 
medication will be allowed during the confinement of the subject in the clinical research unit, 
without approval by the Investigator. In an emergency, the Investigator may administer any 
necessary medication, as considered appropriate. 
 
Two adrenaline autoinjectors will be provided by the clinical research unit at Visit 2 to all 
subjects participating in cohorts 3 and 4, for use at home in case of a delayed allergic 
reaction. Detailed written instructions and an action plan on what to do in case of a delayed, 
systemic allergic reaction will also be provided (Appendix 2). 
 
5.8.  
Prohibited Medications  
Subjects must abstain from taking prescription or non-prescription drugs within 7 days (or 14 
days if the drug is a potential enzyme inducer) or 5 half-lives (whichever is longer) prior to the 
first administration of study medication and until completion of the Follow-up visit, unless in 
the opinion of the Investigator (in consultation with the Medical Monitor, if needed) the 
medication will not interfere with the study. 
 
Oral antihistamines and local application of glucocorticoids on the skin should not be used for 
5 days prior to SPT, at Screening. 
 
Use of the following medications is not permitted during the study, prior to completion of 
dosing: 
 
Monoamine oxidase inhibitors (14 days minimum washout period prior to initiation of 
dosing) 
 
Beta-adrenergic blockers (7 days minimum washout period prior to initiation of 
dosing) 
 
Angiotensin-converting enzyme inhibitors (7 days minimum washout period prior to 
initiation of dosing) 
Subjects using any of the above medication during the study will be withdrawn from 
treatment administration.  
 
5.9. 
Non-Drug Therapies 
Subjects must abstain from taking any vitamins, herbal and dietary supplements within 7 
days (or 14 days if the drug is a potential enzyme inducer) prior to the first administration of 

 
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study medication until completion of the Follow-up visit, unless in the opinion of the 
Investigator the medication will not interfere with the study. 
 
5.10. Treatment of Study Treatment Overdose 
For this study, any dose of DM-101 exceeding the dose levels described for each cohort in 
Table 8, will be considered an overdose. 
 
The Sponsor does not recommend specific treatment for an overdose. The Investigator will 
use clinical judgment to treat any overdose, if and as needed. 
 
 
6. STUDY CONDUCT FOR COHORTS 3 AND 4 
6.1. 
Recruitment 
 
Adult subjects with a history of birch pollen-driven allergic rhino-conjunctivitis will be invited 
by the clinical research unit to participate in the study. 
 
The contract research organization (CRO) performing the study, CRST, has a data bank of 
potentially eligible subjects who may be invited for participation in the study.  
Subject recruitment may additionally be carried out by advertisements in public media. The 
texts to be used in recruitment advertisements and a description of other possible means of 
subject recruitment will be included in the clinical trial submission to the Ethics Committee 
(EC).  
 
Subjects potentially interested in participating in this study will contact the CRO staff (e.g., 
Study Nurse, Investigator) via the contact information included in the recruitment 
advertisements, i.e. phone, e-mail or other means. At the initial contact, a dedicated member 
of staff will brief all potential study participants, in layman’s language, about the overall study 
objectives, general time requirements for participation and eligibility criteria. All potential 
candidates will be told, at the beginning of the communication with the CRO staff, that the 
information gained in this initial contact will be collected on a study-specific interview form to 
be included in the study file. The name, date of birth and contact information of the subject 
will be recorded on the interview form. The collection of personal information is described in 
a Description of the Personal Data Register, which is kept in the Investigator Site File (ISF) 
and is made available to the subjects, if they wish. If a subject candidate does not decide to 
participate in the study, his/her personal information will be destroyed confidentially when the 
study file is archived. 
 
During this initial contact, a preliminary evaluation of the key inclusion and exclusion criteria 
of the trial will be performed and recorded in the interview form. If the main eligibility criteria 
are not fulfilled, the subject will be immediately told and the interview will be terminated with 
possible health-related instructions. If the subject is found to be a suitable candidate for 
participation in the study, the procedures for providing the written ICF will be discussed, and 
upon the subject’s wish, a screening visit may be booked.  
 

 
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Recruitment of subjects will start after approvals for the conduct of the clinical trial have been 
received from the EC and CA (Competent Authority). 
 
6.1.1. Study Subject Screening Log and Identification Log 
The investigator will keep a subject identification list in the ISF. The list includes information 
to link all study-related records to a subject, i.e. source data. Furthermore, a subject 
screening and enrolment log of all subjects screened for the study will be maintained. The 
identity of the subject (screening number, the subject’s first name, last name and personal 
identity number), date of ICF, date of entry into the study or date of exclusion and the reason 
for exclusion, if applicable for those recruited for screening but not fulfilling the eligibility 
criteria, will be recorded on the list.  
 
6.2. 
Screening 
 
Visit 1 (Visit 1a and 1b)  
Subject candidates interested in participating in the study and potentially eligible will undergo 
screening assessment to define their eligibility. Screening will be performed up to a 
maximum of 60 days before randomisation and may consist of 2 visits to the clinical research 
unit (Visit 1a and Visit 1b). 
At the first screening visit, prior to any study procedures taking place, information about the 
study will be given, both verbally and in writing, and written ICF must be obtained from each 
subject. The provided study information will explain the objectives of the study and its 
potential risks and benefits. All subjects must have adequate time to read the provided 
information and to ask the Investigator any questions they may have. The Investigator must 
be satisfied that each subject has understood the information provided, before written 
consent is obtained. If there is any doubt as to whether the subject has understood the 
written and verbal information, the subject must not enter the study. 
 
If a subject agrees to participate, he/she will be asked to sign and date an ICF. The original 
signed ICF will be kept in the ISF and must be made available for inspection by the Sponsor 
or representatives of a regulatory authority. A copy of the signed ICF will be given to the 
subject. A record must also be made in the medical records that the subject voluntarily 
agreed to participate in the study.  
 
After informed consent is obtained, the Visit 1 procedures described in Table 11 (for cohorts 
3 and 4) will take place (see Section 6.5.). 
 
During screening, the SPT will be performed before the collection of a blood sample for birch 
pollen-specific IgE measurement. Only subjects with a positive response to birch pollen 
allergen in the SPT, as defined by the study’s eligibility criteria (see Section 4.2), will proceed 
to blood sample collection for assessment of their birch pollen-specific IgE. The screening 
SPT may be rescheduled, if the subject has taken oral antihistaminics and/or applied 
glucocorticoids to the skin in the previous 5 days. 
 
Pregnancy testing from serum for WOCBP should be performed at screening and be 

 
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additionally arranged for 10 days prior to the first treatment visit (Visit 2) according to the 
eligibility criteria, if the interval between the 2 visits is longer. 
 
Subjects who failed screening should not be rescreened for participation in the study. 
 
6.3. 
Treatment Period 
 
The treatment period will start out of the birch pollen season of the region where the clinical 
research unit is located. 
 
At least 7 days after completion of screening, eligible subjects will enter into the study’s 
treatment period, where they will be allocated into cohorts 3 or 4 of participants. Upon 
confirmation of eligibility, study subjects will be given participant cards stating that they are 
participating in a clinical trial, their subject number and the Investigator’s 24-hour contact 
numbers. 
 
 
All WOCBP participating in the study must have a serum pregnancy test performed no earlier 
than 10 days prior to Visit 2, and a urine pregnancy test performed prior to dosing on each 
subsequent treatment visit. The pregnancy test must be negative for the subject to be dosed. 
Dosing will take place by s.c. injection of DM-101 or placebo on the exterior surface of the 
upper arm. 
 
All dosing visits of cohorts 3 and 4 will take place in Turku University Hospital’s Emergency 
Care Unit, with confinement until 6 h after completion of dosing. At all visits, emergency 
equipment, including a cardiac resuscitation trolley, equipment for airway insertion, oxygen 
cylinders, portable suction machines, defibrillator, circulation lines, and drugs must be 
available and immediately accessible for the treatment of suspected severe allergic reactions 
following the administration of study medication (See Section 8.3. and Appendix 1). A trained 
physician, capable to handle severe, systemic allergic reactions, will remain on-site during 
the confinement period on all dosing visits. The subjects will be equipped with an indwelling 
venous cannula for 4 hours after dosing. 
 
Blood samples for determination of tryptase will be taken in the event of a suspected Grade 3 
or higher systemic allergic reaction. An initial sample should be taken approximately 
one hour after the onset of the reaction, with another sample taken at approximately 
three hours and then repeated every three hours until the Investigator is satisfied that the 
subject may be discharged. Blood sampling for tryptase must not delay initial resuscitation. 
Any subject that experiences a suspected Grade 3 or higher systemic allergic reaction must 
also have a blood sample collected for measurement of his/her baseline tryptase levels at 
the Follow-up visit. 
 
Visit 2 
During the first treatment visit (Visit 2), a single dose of 30 ng of DM-101 or corresponding 
placebo s.c. injection will be administered as described in Section 3.2. Table 12 (see Section 
6.5) shows the procedures that will take place, before and after dosing. Dosing will be 
initiated only if the results of the pre-dosing brief medical review and other eligibility 

 
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assessments are satisfactory. The subjects will remain confined in Turku University 
Hospital’s Emergency Care Unit for approximately 6 h following their dosing. 
Treatment will be staggered in such a way that 2 sentinel subjects, 1 receiving DM-101 and 1 
receiving placebo, will be dosed first in a double-blind fashion. Dosing of the remaining 
subjects in the cohort will be initiated no sooner than 22 h after the sentinel subjects have 
completed their Visit 2 dosing, without safety findings that would meet the study’s stopping or 
treatment discontinuation criteria (see Section 9). Subjects in the main treatment group in 
each cohort will also receive treatment in a staggered way, with 2 subjects starting first to 
receive doses and the remaining subjects starting to receive doses no sooner than 
approximately 22 h after the first two subjects of the main group have completed their Visit 2 
dosing. 
Visit 2 of cohort 4 will not initiated until Visit 2 of cohort 3 has been completed. 
All subjects will be given at the end of Visit 2, before discharge from the site, an adrenaline 
autoinjector and written instructions with an action plan on what to do if they develop a 
delayed allergic reaction (see Appendix 2). 
Subjects will be contacted by telephone approximately 12 and 24 h after completion of 
dosing for a safety interview after each dosing visit. 
 
Visits 3, 4, 5 and 6 
After Visit 2, all subjects will return to the hospital on a biweekly basis for the subsequent 
dosings, to receive either a single s.c. injection or a series of 2 or 3 s.c. injections of the 
study medication. All dosings, except the 4th and 5th dosings of cohort 4, involve only single 
injections. In cohort 4, the administration of the study medication at Visits 5 and 6 involves 2 
and 3 s.c. injections, respectively. There will be a minimum of 30 min interval between 
subsequent injections. Each injection will be given at a slightly different site of the exterior 
surface of the upper arm. The injections will alternate between the right and left arm. 
On each of the Visits 3-6 dosing will be staggered in the same way as on Visit 2, ie. 2 
sentinel subjects, 1 receiving DM-101 and 1 receiving placebo, will be dosed first in a double-
blind fashion. Dosing of the remaining subjects in the cohort will be initiated no sooner than 
22 h after the sentinel subjects have completed their dosing, without safety findings that 
would meet the study’s stopping or treatment discontinuation criteria (see Section 9). 
Subjects in the main treatment group in each cohort will also receive treatment in a 
staggered way, with 2 subjects starting first to receive doses and the remaining subjects 
starting to receive doses no sooner than approximately 22 h after the first two subjects of the 
main group have received their dosing. 
 
Visit 5 dosing of cohort 4 will only take place after a favorable recommendation from the 
SRC, once it has reviewed all available safety data so far collected in the study, including 
data from Visit 5 of cohort 3.  
 
Dosing will only be allowed if the study’s stopping and treatment discontinuation criteria have 
not been met.  
 
Subjects will be contacted by telephone approximately 12 and 24 h after completion of 
dosing for a safety interview after each dosing visit. 
 

 
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Table 12 (for cohort 3) and Table 13 (for cohort 4) (see Section 6.5) show the procedures 
that will take place, before and after dosing, during the visits. All subjects will remain confined 
in Turku University Hospital’s Emergency Unit for approximately 6 h following their dosing, 
and may then be discharged if the medical review by the Investigator or a designee is 
satisfactory. 
 
 
6.4. 
Follow-up  
All subjects will return to the clinical research unit 4 weeks (± 3 days) following the day of 
their last dose for a Follow-up visit (Visit 7).  
 
Table 11 (see Section 6.5.) describes the procedures scheduled for the Follow-up visit for 
cohorts 3 and 4. 
 
6.5. 
Schedule of Activity Tables for Study Visits 
A general schedule of visits 2-7 activities is presented in Table 11. Tables 12 (for cohort 3) 
and 13 (for cohort 4) provide details of Visits 2-6. 
 
 

 
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Table 11. Cohorts 3 and 4 General schedule of activities (Protocol version 2.0) 
 
Protocol Activity 
Visit1 
Screening
Visit 2 
Visit 3 
Visit 4 
Visit 5 
Visit 6 
Visit 7 
Follow 
up 
Days in relation to Visit 2 
-60 
0 
14 
28 
42 
56 
84 
Visit window, days 
-60 - -7 
  
±1 
±2 
±2 
±2 
±3 
Informed consent 
X 
  
  
  
  
  
  
Demographics 
X 
  
  
  
  
  
  
IMP dosing 
  
X 
X 
X 
X 
X 
  
General medical history 
X 
  
  
  
  
  
  
Inclusion/Exclusion criteria 
X 
  
  
  
  
  
  
Complete physical examination 
X 
  
  
  
  
  
X 
Brief physical examination  
  
X 
X 
X 
X 
X 
  
Vital signs 
X 
X 
X 
X 
X 
X 
X 
Body temperature 
X 
X 
X 
X 
X 
X 
X 
Spirometry/FEV12 
X 
X 
X 
X 
X 
X 
X 
ECG 
X 
X 
X 
X 
X 
X 
X 
Skin prick test 
X 
  
  
  
  
  
  
Blood sample for specific IgE to Bet 
v components 
X 
X4 
X4 
  
X4 
  
X 
Blood sample for specific IgE to 
other than Birch common allergens 
X 
  
  
  
  
  
  
Blood sample for safety lab tests 
X 
X 
X 
X 
X 
X 
X 
Blood sample for screening serology
X 
  
  
  
  
  
  
Urine dipstick test 
X 
X 
X 
X 
X 
X 
X 
Breath alcohol & urine drug screen 
X 
X 
X 
X 
X 
X 
  
Pregnancy test3 
X 
X 
X 
X 
X 
X 
X 
Serum FSH/ estradiol for 
postmenopausal women 
X 
  
  
  
  
  
  
Blood sample for exploratory 
immunological biomarkers  
  
X4 
X4 
  
X4 
  
X 
Blood sample for tryptase 
  
X5 
X6  
Injection site examination7 
  
X 
X 
X 
X 
X 
X 
Provision of adrenaline autoinjector 
and action plan in case of severe 
delayed allergic reaction 
  
X 
  
  
  
  
  
Concomitant medication review 
X 
X 
X 
X 
X 
X 
X 
Adverse events 
  
X8 
Phone calls 
  
X 
X 
X 
X 
X 
  

 
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1Screening can be split over 2 visits: Visit 1a is to confirm preliminary eligibility based on medical 
history and birch pollen allergy sensitivity (SPT) and Visit 1b to perform full screening assessments 
after initial eligibility has been confirmed. 
 
2Spirometry assessments will be performed at screening. Measurement of FEV1 only will be 
performed at all other timepoints. Subjects with a history of asthma should not take short-acting beta 
agonists for a minimum of 4 h and long-acting beta agonists for 8 h prior to spirometry assessments. 
 
3Pregnancy testing from serum for WOCBP should be performed at screening and be additionally 
arranged for 10 days prior to the dosing visit (Visit 2) according to the eligibility criteria, if the interval 
between the 2 visits is longer. Urine pregnancy test should be performed prior to dosing at Visit 2, Visit 
3, Visit 4, Visit 5 and at Visit 6. 
 
4Blood samples will be collected prior to the dose administration. 
 
5Blood sample to be taken only in the event of a suspected Grade 3 or higher systemic allergic 
reaction, approximately 1 hour and 3 hours after the suspected reaction and then repeated every 3 
hours until discharge. 
 
6Blood sample for tryptase will be collected in any subject who has had a suspected anaphylactic 
response during the study treatment period (including subjects withdrawn from the study) to be used 
for baseline comparison. 
 
7Injection site reactions will be captured as adverse events, as well as AE of special interest. 
 
8Systemic allergic reactions will be captured as adverse events, as well as AE of special interest. 
 
 
 

 
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Table 12. Cohort 3 Visits 2-6. Detailed schedule of activities (Protocol version 
2.0) 
 
1 Pre-dose blood sample to be collected only on Visit 2, 3 and 5. 
2Blood sample to be taken only in the event of a suspected Grade 3 or higher systemic allergic 
reaction, approximately 1 h and 3 h after the suspected reaction and then repeated every 3 h until 
discharge. 
3Injection site reactions will be captured as AE, as well as AE of special interest. 
4Subjects will be contacted by telephone 12 h and 24 h after dosing for a safety review. 
5Systemic allergic reactions will be captured as AE, as well as AE of special interest. 
 
 
 
Protocol activity
Visit 2 / Visit 3 / Visit 4 / Visit 5 / Visit 6
  
Pre-
dose 
0 
30 min
1 h 
2 h 
4 h 
6 h 
12 & 
24 h 
IMP dosing 
  
X 
  
  
  
  
  
  
Brief physical examination 
X 
  
  
  
  
  
X  
  
Vital signs 
X 
X 
X 
X 
X 
X 
X 
  
Body temperature 
X 
  
  
X 
  
X 
X 
  
FEV1 
X 
  
  
X 
  
X 
X 
  
ECG 
  
  
  
  
X 
  
X  
  
Blood sample for safety lab tests 
X 
  
  
  
  
 X 
 X 
  
Urine dipstick test 
X 
  
  
  
  
  
 X 
  
Pregnancy test (urine) 
X 
  
  
  
  
  
  
  
Breath alcohol & urine drug screen 
X 
  
  
  
  
  
  
  
Blood sample for specific IgE to Bet 
v components 
X1 
  
  
  
  
  
  
  
Blood sample for explorative 
immunological biomarkers 
X1 
  
  
  
  
  
  
  
Blood sample for tryptase 
  
X2 
  
Injection site examination3 
  
X 
X 
X 
X 
X 
X 
  
Phone call 
  
  
  
  
  
  
  
X4 
Provision of adrenaline autoinjector 
and action plan in case of severe 
delayed allergic reaction 
  
  
  
  
  
 
X  
  
Concomitant medication review 
X 
Adverse events 
X5 

 
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Table 13. Cohort 4 Visits 2-6. Detailed schedule of activities (Protocol version 
2.0) 
Protocol activity
 
Visit 2 / Visit 3 / Visit 4 / Visit 5 / Visit 6
  
Pre-dose 
0 
30 min
1 h 
90 min8 
2 h 
4 h 
6 h9 12 & 24 h9
IMP dosing 
  
X 
X1 
X2 
 
  
  
  
  
Brief physical examination 
X 
  
  
  
 
  
  
X  
  
Vital signs 
X 
X 
X 
X 
X 
X 
X 
X 
  
Body temperature 
X 
  
  
X 
 
  
X 
X 
  
FEV1 
X 
  
  
X 
 
  
X 
X 
  
ECG 
  
  
  
  
 
X 
  
X  
  
Blood sample for safety lab tests 
X 
  
  
  
 
  
X 
 X 
  
Urine dipstick test 
X 
  
  
  
 
  
  
X 
  
Pregnancy test (urine) 
X 
  
  
  
 
  
  
  
  
Breath alcohol & urine drug screen 
X 
  
  
  
 
  
  
  
  
Blood sample for specific IgE to Bet v 
components 
X3 
  
  
  
 
  
  
  
  
Blood sample for explorative 
immunological biomarkers 
X3 
  
  
  
 
  
  
  
  
Blood sample for tryptase 
  
 
X4 
  
Injection site examination5 
  
X 
X 
X 
X 
X 
X 
X 
  
Phone call 
  
  
  
  
 
  
  
  
X6 
Provision of adrenaline autoinjector 
and action plan in case of severe 
delayed allergic reaction 
  
  
  
  
 
  
 
 X 
  
Concomitant medication review 
 
X 
Adverse events 
 
X7 
1Dosing at 30 min time point only on Visit 5 and Visit 6. 
2Dosing at 1 h time point only on Visit 6. 
3Pre-dose blood sample to be collected only on Visit 2, 3 and 5. 
4Blood sample to be taken only in the event of a suspected Grade 3 or higher systemic allergic 
reaction, approximately 1 h and 3 h after the suspected reaction and then repeated every 3 h until 
discharge. 
5Injection site reactions will be captured as AE, as well as AE of special interest. 
6Subjects will be contacted by telephone 12 h and 24 h after dosing for a safety review. 
7Systemic allergic reactions will be captured as AE, as well as AE of special interest. 
890 min time point only on Visit 6 of Cohort 4. 
9Calculated from the last injection 
 

 
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7. 
STUDY ASSESSMENTS AND PROCEDURES 
This section describes each planned study assessment. The timing of each assessment is 
listed in Tables 11-13 in Section 6.5.  
 
Whenever multiple assessments are scheduled to be performed at the same time, the clinical 
safety assessments should be made first. 
 
7.1.  
Demographic and Baseline Information 
The following demographic parameters will be recorded: date of birth, gender, race and 
ethnicity. 
 
The subject’s height (in centimeters) and body weight (in kilograms) will be measured. 
 
A complete medical history, with an emphasis on allergy history, including history of allergic 
rhinoconjunctivitis and asthma, will be recorded at Screening. In addition, the medication 
(including over the counter and dietary supplements), alcohol, smoking and recreational 
drugs history, as well as information on previous participation in clinical trials and blood 
donation will be recorded and assessed, as related to the eligibility criteria listed in Section 
4.2. With the subject’s permission expressed in the ICF, the Investigator may ask for other 
information relevant for the subject’s health and the purposes of the study from any health 
care provider who has possession of the subject’s medical records. 
 
7.2. 
Assessment of Safety 
Planned time points for all safety assessments are listed in Tables 11-13 included in Section 
6.5.  Additional time points for safety tests, including vital signs, body temperature, ECG, 
spirometry, physical examination and laboratory safety tests may be added during the course 
of the study, if deemed necessary by the Investigator based on newly available data, to 
ensure appropriate safety monitoring.  
 
7.2.1. Clinical Safety Assessments 
Physical Examination 
A complete physical examination will include assessments of the head, eyes, ears, throat, 
neck, skin, neurological, respiratory, cardiovascular, gastrointestinal, musculoskeletal system 
and lymph nodes.  
A brief physical examination will include assessments of the skin, throat, respiratory, 
cardiovascular system and abdomen (palpation of the liver and spleen). 
 
Vital Signs  
Vital signs measurements will include systolic and diastolic blood pressure, pulse rate and 
respiratory rate. Vital signs will be recorded with the subject in a sitting or semi-recumbent 
position and after at least five min rest. 
 

 
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Two measurements will be taken at screening and prior to dosing. The mean value recorded 
prior to the first dosing of each day will be considered as baseline for that day.  
 
Measurements that deviate substantially from previous readings will be repeated as soon as 
possible. All readings will be recorded in the subject’s notes. 
 
Body Temperature  
Body temperature will be measured with an automated auricular thermometer.  
 
Two measurements will be taken at screening and pre-treatment. The mean value recorded 
prior to the first treatment administration will be classed as baseline.   
 
Readings that deviate substantially from the subject’s baseline or are deemed not technically 
acceptable will be repeated as soon as possible. All readings will be recorded in the subject’s 
notes. 
 
Electrocardiogram 
12-lead ECG will be recorded during the study using an ECG machine that automatically 
calculates the heart rate and measures PR, QRS, QT, and QTc intervals and derives 
QTc(B).   
 
Duplicate recordings will be obtained at Screening. The mean value recorded at Screening 
will be recorded as baseline. Single recordings will be obtained at the other determined 
timepoints during the study, except if according to the opinion of the Investigator there are 
abnormal findings and therefore triplicate ECGs should be obtained. 
 
Spirometry  
Standard spirometry will be performed at screening. Measurement of FEV1 will be performed 
at all other scheduled timepoints during the study. The clinical research unit will use their 
local standard procedures. Triplicate assessments will be made at screening and prior to the 
first dose on each dosing day. The best FEV1 (and the corresponding FVC at Screening) will 
be recorded in the eCRF. On the other time points, only single assessments will be made, 
unless the FEV1 result is below 90 % of that day’s baseline result, in which case the FEV1 
assessment will be repeated two more times. The best FEV1 will be recorded in the eCRF.  
 
The best of three valid FEV1 readings recorded prior to the first dosing will be classed as 
baseline.   
 
Subjects with history of asthma should not use short-acting beta agonists for 4 h or long-
acting beta agonists for 8 h prior to the spirometry assessments. 
 
Injection Site Examination 
At each treatment visit, the injection sites will be examined immediately prior to and after 
treatment administration, as described in the Tables 11-13 in Section 6.5., for signs of 
reaction. Injection sites will also be examined during the Follow-up visit. 
 
Reactions should be graded on a five-point (0 to 4) scale for each of the following 
parameters: pain, tenderness, erythema/redness, induration/swelling (see Table 14). 

 
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Table 14 
Grading of Injection Site Reactions 
 
 
1The parameter should be evaluated using the grading scale, as well as an actual measurement of the 
reaction at the greatest single diameter. 
 
 
7.2.2.  Laboratory Safety Assessments 
Clinical Laboratory Assessments  
Hematology, clinical chemistry, urinalysis and additional parameters to be tested are listed 
below. Reference ranges for all laboratory parameters will be provided by the local 
laboratory. 
 
Haematology:  
Haematocrit, haemoglobin, red blood cells, white blood cells and 
differential WBC count (neutrophils, eosinophils, basophils, 
lymphocytes, monocytes), platelets. 
 
Biochemistry: 
Sodium, potassium, chloride, urea, creatinine, calcium, total protein, 
albumin, uric acid, total bilirubin, glucose, lactate dehydrogenase, 
creatine phosphokinase, alanine transaminase, aspartate 
transaminase, gamma glutamyltransferase, alkaline phosphatase, c-
reactive protein. 
 
 
Blood samples will be collected for assay of tryptase, in the case of a 
suspected severe allergic reaction (see Section 6.3.). 
. 
Urine dipstick: 
pH, protein, ketones, leukocytes, blood and glucose; abnormal results 
will be followed up with particle counting and bacterial culture, as 
needed. 
Parameter 
Grade 0 
Grade 1 
Grade 2 
Grade 3 
Grade 4 
Pain  
 None 
Does not 
interfere 
with activity  
Repeated use 
of non-
narcotic pain 
reliever > 24 
hours or 
interferes with 
activity  
Any use of 
narcotic pain 
reliever or 
prevents daily 
activity  
Emergency 
room visit or  
hospitalisation  
Tenderness  None 
Mild 
discomfort to 
touch  
Discomfort 
with 
movement  
Significant 
discomfort at 
rest  
Emergency 
room visit or 
hospitalisation  
Erythema / 
Redness1 
None 
2.5 to 5 cm  
> 5 to 10 cm  
> 10 cm  
Necrosis or 
exfoliative 
dermatitis  
Induration / 
Swelling1  
None 
2.5 to 5 cm 
and does not 
interfere with 
activity  
> 5 to 10 cm 
or interferes 
with activity  
> 10 cm or 
prevents daily 
activity  
Necrosis  

 
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All laboratory tests with values that are clinically significantly abnormal during participation in 
the study should be repeated until the values return to normal or baseline or an adequate 
explanation is established. 
 
Other Screening Tests 
Pregnancy tests from serum and urine samples should be performed to all WOCBP, as 
described in the eligibility criteria (see Section 4.2) and indicated in Tables 11-13 in Section 
6.5.  
 
FSH and estradiol should be tested, as needed, at Screening in women of non-child bearing 
potential only (see eligibility criteria Section 4.2).  
 
The subjects will also undergo screening serology tests for HIV (HIVAg/Ab), hepatitis B 
(HbsAg) and hepatitis C (HCVAb). 
 
Alcohol breath test and drug urine screen (to include at minimum: amphetamines, 
barbiturates, cocaine, opiates, cannabinoids and benzodiazepines) tests will be performed at 
Screening and at the start of each dosing day. 
 
7.3. 
Assessment of Allergic Sensitisation 
7.3.1. Skin Prick Testing 
At Screening, SPT (performed on the flexor aspect of the forearm) with birch pollen allergen 
will be performed at the clinical research unit. Positive and negative controls will be included 
in the assessment (histamine and diluent, respectively).  
 
Prior to the SPT, drugs that might interfere with this assessment (particularly oral 
antihistaminics and local skin application of glucocorticoids) must be avoided for 5 days. 
 
The response to SPT will be assessed by measuring the orthogonal diameter of the wheal, at 
the mid-point of the longest axis, and the average of the longest and the orthogonal diameter 
will be calculated. Pseudopodia will not be assessed.  
 
The mean wheal diameter of the negative control must be < 2 mm for the test to be 
considered valid. If the negative control wheal diameter is ≥ 2 mm, the test should be 
repeated on another day. The positive control should give a reaction with a wheal diameter ≥ 
3 mm greater than the negative control.  
 
7.3.2. Allergen-Specific IgE 
A blood sample (10 ml) will be collected for the measurement of Bet v allergenic components 
(Bet v 1, Bet v 2, Bet v 4, Bet v 6)-specific IgE levels in serum by ImmunoCAP® at the 
Screening  and other time points indicated in Tables 11-13 (see Section 6.5.). 
In addition, the following allergen-specific IgE levels in serum will be measured at Screening 
only to allow better understanding of the allergic sensitization profile of the study participants:  
 

 
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- 
Alder, hazel, peanut, hazelnut, kiwi, celery, apple, peach, soy (cross-reactive 
allergens, Profilin 10 protein). 
- 
Equine, cat, dog, mugwort, Timothy Grass, Dermatophagoides pteronyssinus, 
Dermatophagoides farinae and Cladosporium herbarum 
 
7.4. 
Assessment of Efficacy 
There are no efficacy assessments included in this study. 
 
7.5. 
Assessment of Exploratory Immunological Biomarkers 
Blood samples will be collected for potential analysis of immunological biomarkers that may 
be related to the effects of immunotherapy, including birch pollen-specific immunoglobulins 
(IgG sub-classes and IgA), blocking antibodies, B and T cell phenotyping, and cytokines. The 
samples will be analysed in a qualified laboratory. After completion of the analyses the 
remaining blood will be destroyed, unless the subject has given separate, optional consent 
for their further storage for additional potential biomarker analyses related to the purposes of 
the study. 
 
7.6. 
Assessment of Pharmacokinetics 
There are no pharmacokinetic assessments included in this study. 
 
7.7. 
Optional Sub-study: Assessments 
A separate optional sub-study may involve collection of medical history information and a 
blood sample collection for analysis of exploratory immunological biomarkers after the 2021 
birch pollen allergy season, i.e. in the autumn of 2021. Only participants in cohorts 2 - 4 will 
be invited to take part in this sub-study. This sub-study does not involve any other 
assessments or procedures except an interview and the blood sample collection. Separate 
consent will be asked for participation in this optional sub-study.  
 
 
 

 
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8. 
ADVERSE EVENTS 
The Investigator and his staff are responsible for detecting, documenting and reporting 
events that meet the definition of an AE. Adverse events will be reported, irrespective of 
whether they are volunteered, elicited, or noted on physical examination or medical review, 
throughout the study, from the signing of the ICF until the Follow-up visit. 
 
AEs occurring prior to the first treatment administration, but after obtaining informed consent 
will be reported separately from TEAEs, which will be of particular interest. 
 
Definitions of AEs and serious adverse events (SAE) and the documentation and reporting of 
them within this study will follow the GCP, EU and Finnish national guidance.  
 
8.1. 
Definition of Adverse Events 
An AE is any untoward medical occurrence experienced by a study subject, temporally 
associated with the use of a medicinal product, whether or not considered related to the 
medicinal product. For the current study, all AEs will be coded using the Medical Dictionary 
for Regulatory Activities (MedDRA, version 22.1) by 4Pharma in co-operation with CRST. 
 
An AE can therefore be any unfavorable and unintended signs (including clinically relevant 
changes in laboratory parameters), symptoms, diseases (new or exacerbated) or accidents 
temporally associated with the use of a medicinal product.   
 
AEs comprise all disturbances of general health status. Events meeting the definition of an 
AE include: 
 
Any abnormal laboratory test results (haematology, clinical chemistry, or urinalysis) or 
other safety assessments (e.g. ECG, spirometry, vital signs measurements), including 
those that worsen from baseline, and the Investigator considers them clinically 
significant. 
 
Exacerbation of a chronic or intermittent pre-existing condition, including either an 
increase in frequency and/or intensity of the condition. 
 
New conditions detected or diagnosed after study treatment administration even though 
it may have been present prior to the start of the study. 
 
Signs, symptoms, or the clinical sequelae of a suspected interaction with the study 
treatment. 
 
Signs, symptoms, or the clinical sequelae of a suspected overdose of either study 
treatment or a concomitant medication (overdose per se will not be reported as an 
AE/SAE unless this is an intentional overdose taken with possible suicidal/self-harming 
intent.  This should be reported regardless of sequelae). 

 
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Events that do not meet the definition of an AE include: 
 
Any clinically significant abnormal laboratory findings or other abnormal safety 
assessments that are associated with the underlying disease, unless judged by the 
Investigator to be more severe than expected for the subject’s condition. 
 
The disease/disorder being studied, or expected progression, signs, or symptoms of the 
disease/disorder being studied, unless more severe than expected for the subject’s 
condition. 
 
Medical or surgical procedure (e.g., endoscopy, appendectomy); the condition that leads 
to the procedure is an AE. 
 
Situations where an untoward medical occurrence did not occur (social and/or 
convenience admission to a hospital). 
 
Anticipated day-to-day fluctuations of pre-existing disease(s) or condition(s) present or 
detected at the start of the study that do not worsen. 
 
8.2. 
Definition of Serious Adverse Events 
A SAE is any AE occurring during the study that results in any of the following outcomes: 
 
Results in death 
 
Is life-threatening. The term 'life-threatening' in the definition of 'serious' refers to an event 
in which the subject was at risk of death at the time of the event.  It does not refer to an 
event, which hypothetically might have caused death, if it were more severe. 
 
Requires hospitalization or prolongation of existing hospitalization. This is defined as the 
subject being hospitalised overnight. Any pre-planned or anticipated in-hospital visits 
must be documented in advance at the screening visit and will be excluded from this 
category. 
 
Results in significant disability/incapacity. 
 
Is a congenital anomaly/birth defect. 
 
Is an important medical event that may require medical or surgical intervention to prevent 
one of the above outcomes. 
Medical and scientific judgement 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 hospitalisation but may jeopardise the 
subject and may require intervention to prevent one of the other outcomes listed in the 
definition above. These should also be considered to be SAEs. 
 
8.3. 
Definition of Suspected Unexpected Serious Adverse Reactions 
An unexpected adverse drug reaction is any adverse drug reaction (ADR), the specificity or 
severity of which is not consistent with the current IB of DM-101. In this FiH study, all adverse 
reactions to DM-101 will be considered unexpected. Suspected unexpected serious ADRs 
(SUSARs) are subject to expedited reporting to the CA by the pharmacovigilance provider (PV) 
of the study. The investigator reports all authority-reportable AEs to the Sponsor and the 

 
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pharmacovigilance provider, for reporting to the CA according to applicable legislation, and as 
agreed between the parties 
 
 
8.4. 
Definition of Adverse Events of Special Interest  
8.4.1. Systemic Allergic Reactions 
All allergic reactions that occur after the initiation of IMP dosing should be recorded in the 
subject’s medical records and also as an AE in the eCRF. If a systemic allergic reaction 
meets the definition of serious, then it should be classified as a SAE and will be recorded and 
reported in the same way as any other SAE. 
 
In addition, all systemic allergic reactions must be graded, as defined by the WAO 
Subcutaneous Immunotherapy Systemic Reaction Grading System (Appendix 1) and be 
considered AEs of Special Interest (AESI). All Grade 2 to 5 systemic allergic reactions must 
be reported in an expedited manner to the Sponsor within 24 h from their occurrence. 
 
Treatment of systemic allergic reactions 
Systemic allergic reactions may be life-threatening and any suspected severe allergic 
reaction must be treated immediately.  
 
All medications and medical equipment for the treatment of suspected, severe allergic 
(anaphylactic) reactions must be immediately available at the clinical research unit. 
 
Figure 2 presents an example of an algorithm for the management of suspected anaphylactic 
reactions, proposed by the European Academy of Allergy and Clinical Immunology 
(EAACI).The Investigator will follow CRST’s Standard Operating Procedure (SOP) for 
treating suspected anaphylactic reactions, and a copy of the Guideline and the SOP must be 
placed in the ISF. The subjects of cohorts 3 and 4 will be equipped with i.v. cannula until at 
least 4 h after the last injection of the day, and the i.v. route will therefore be available for 
fluid therapy and for administration of antihistaminics and glucocorticoids. 
 

 
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From Anaphylaxis: Guidelines from the European Academy of Allergy and Clinical Immunology Muraro A et al., 
2014 Allergy. 69:1026-1045. 
 
Figure 2 
Schematic illustration of the initial management of anaphylaxis proposed 
by the EAACI. 
 
 
If a delayed, systemic allergic reaction occurs following dosing, once a subject has left the 
clinical research unit, the subject should follow the action plan provided to him/her by the 
Investigator at Visit 2 (See Appendix 2). Subjects should also contact their health care 
provider or seek emergency medical attention, as indicated.  
 
Subjects who develop Grade 3 and 4 systemic allergic reactions should be hospitalised 
overnight or monitored for at least 12 hours. 
 
8.4.2. Injection Site Reactions 
All allergic reactions that occur after the initiation of IMP dosing should be recorded in the 
subject’s medical records and also as AESI in the eCRF. 
 
All Injection site reactions should be evaluated as AEs and also be graded on a five-point (0 
to 4) scale for each of the following parameters: pain, tenderness, erythema/redness, 
induration/swelling (Table 14). 
 

 
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8.5. 
Recording of Adverse Events 
When an AE or SAE occurs, it is the responsibility of the Investigator to review all 
documentation (e.g., hospital progress notes, laboratory, and diagnostics reports) relative to 
the event. The Investigator will then record all relevant information regarding the event in the 
subject’s medical record and transcribe it to the eCRF. 
 
When recording an AE / SAE, the following details must be given: 
 
Event observed (brief description using medical terminology) 
 
Start and stop dates and times 
 
Severity (Section 8.5.1.) 
 
Causality (Section 8.5.2.) 
 
Relationship to other events (e.g. study procedure or concomitant medication) 
 
Action taken (brief description) 
 
Outcome 
 
Serious (Yes/No) 
When an AE occurs, the Investigator will attempt to establish a diagnosis of the event based 
on signs, symptoms, and other clinical information. In such cases, the diagnosis will be 
documented as the AE/SAE and not the individual signs/symptoms. 
 
All AEs will be recorded as they are reported, whether spontaneously volunteered by a 
subject or in response to questioning about well-being at each study visit. The subject will be 
questioned in a general way and no specific symptoms will be suggested. The questioning 
about AEs will cover the current visit and the period of time between the previous and current 
visit although subjects may report AEs occurring at any other time during the study. Follow-
up of all AEs will continue until the overall clinical outcome is definitive.  
 
8.6. 
Evaluation of Adverse Events and Serious Adverse Events 
8.6.1. Assessment of Intensity 
The Investigator will assess the intensity for each AE and SAE reported during the study and 
will assign it to one of the following categories: 
 
Mild 
An event that is noticeable, but easily tolerated by the subject, 
causing minimal discomfort and not interfering with usual daily 
activities, compared to subject’s baseline. 
Moderate 
An event that is sufficiently discomforting to interfere with usual 
daily activities, compared to subject’s baseline. 
Severe 
An event that prevents usual daily activities, compared to 
subject’s baseline. 
 

 
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8.6.2. Assessment of Causality 
When an AE or SAE occurs, the Investigator should assess the relationship between the IMP 
and the occurrence of the event. The Investigator should use clinical judgment to determine 
the relationship and assign it to one of the following categories: 
Related 
Any event that has a reasonable temporal relationship with the 
administration of study medication or follows a response pattern 
known to be related with the study IMP.  
Unlikely to be 
related 
Any event that does not have a reasonable temporal relationship 
with the administration of study medication and does not follow a 
response pattern known to be related to the study IMP. 
Not related 
Any event that started before administration of study medication 
and/or for which there is a clear alternative explanation.
 
The same criteria will be used to assign causality to study procedures. 
 
8.7. 
Follow-up of Adverse Events / Serious Adverse Events 
After the initial AE or SAE report, the Investigator is required to proactively follow each 
subject at subsequent visits/contacts. All AEs and SAEs will be followed until resolution, until 
the condition stabilizes, until the event is otherwise explained, or until the subject is lost to 
follow-up. New or updated information will be recorded in the originally completed data 
collection tool.  
 
The Investigator is responsible for ensuring that follow-up includes any supplemental 
investigations that may be indicated, including (but not limited to) additional laboratory tests, 
histopathology or consultation with other health care professionals. If a subject dies during 
participation in the study or during a recognized follow-up period, the Investigator should 
provide a copy of any post-mortem findings, including histopathology.  
 
8.8. 
Reporting of Adverse Events and Serious Adverse Events 
Once the Investigator determines that an event meets the definition of a SAE, the SAE 
should be reported to the pharmacovigilance provider (PV) and Sponsor within 24 h, 
regardless of the time that may have elapsed since the time the event occurred and 
regardless of the causal relationship of IMP to the event.  Any follow-up information on a 
previously reported SAE should also be reported to the PV and Sponsor later as needed. 
SAEs should be followed up until resolved or until the event is considered chronic and/or 
stable outcome. 
The PV provider in this study is A+ Science. Contact details and instructions for SAE reporting 
to PV provider and Sponsor’s Medical Monitor will be located in the ISF. The PV provider 
reports all authority reportable AEs to the CA. 
 

 
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8.9. 
Reporting of Pregnancy 
Subjects who become pregnant during the treatment period must receive no further study 
treatment and the pregnancy must be reported using the same procedure as for SAE 
(Section 8.7). Subjects who become pregnant once treatment administration has been 
completed may remain in the study and the pregnancy must be reported using the same 
procedure as for SAE. A Pregnancy Notification Form must be completed. The outcome of 
the pregnancy should be followed up until term or premature termination. A Pregnancy 
Outcome Form, to assess the health of the mother and any infants, should be completed and 
reported following the same procedure as the Notification Form. 
 
 
9. PREMATURE STUDY AND TREATMENT STOPPING CRITERIA FOR COHORTS 3 
AND 4 
The progress of the study will be monitored by the SRC (see Section 3.3.) The committee will 
review all safety data at timepoints defined in the study design (see Section 3) and will make 
recommendations regarding continuation, suspension or modification of dosing. 
 
9.1. 
Study Stopping Criteria 
The Sponsor reserves the right to prematurely terminate the study for valid scientific or 
administrative reasons. 
For reasons of safety, further dosing in the study will be suspended and all safety data will be 
reviewed by the SRC if any of the following happens: 
 
 
Death of a study participant possibly attributable to study treatment or procedure.  
 
One Grade 4 systemic allergic reaction according to the WAO classification, following 
injection of the study IMP.  
 
Two Grade 3 systemic allergic reactions according to the WAO classification, 
following injection of the study IMP in 2 participants in the same cohort.  
 
One Grade 4 injection site reaction in 3 participants in the same cohort. 
If a decision to suspend dosing in the study is reached, the SRC will review thoroughly all 
safety data and will determine whether:  
- Dosing (scheduled or adjusted) may be re-started in current or subsequent cohorts.  
- The study must be stopped and no additional subjects be dosed. 
The EC and the CA will be informed, if the study is terminated prematurely. The Investigator 
will proceed to appropriate actions concerning the study subjects in the case of premature 
termination of the study. 
 
 

 
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9.2. 
Treatment Stopping Criteria 
For an individual subject, dosing of study IMP will be discontinued if any of the following 
happens: 
 
One Grade 4 systemic allergic reaction according to the WAO classification, following 
injection of the study IMP. 
 
 
Two or more Grade 3 systemic allergic reactions according to the WAO classification, 
following injection of the study IMP. 
  
 
One Grade 4 injection site reaction. 
 
 
Two Grade 3 injection site reactions following two injections. 
 
 
An AE or need for medication not consistent with the protocol requirements that, in 
the judgment of the Investigator, presents an unacceptable consequence or risk to 
the subject. 
 
 
Inability or unwillingness to comply with the study protocol or protocol deviation that is 
considered sufficient to jeopardize the subject’s well-being or the integrity of the 
study. 
 
 
Pregnancy during study participation. 
 
 
Withdrawal of consent 
 
Discontinuation of dosing will not necessarily result in withdrawal of the subject from the 
study. For the subjects who discontinue treatment, all safety assessments scheduled for the 
Follow-up will be requested and observations will be recorded. 
 
9.3. 
Dose Adjustment Criteria 
For each individual subject, dose escalation will be halted and dosing will be adjusted 
according to the following:  
 
If a Grade 3 systemic allergic reaction, according to the WAO classification, or a 
Grade 3 injection site reaction occurs, following administration of a dose of the study 
IMP, the previous well-tolerated daily dose level should be repeated at the time the 
next dosing is scheduled. If this is found to be tolerated, the subject will continue to 
receive the same, tolerated dose level at each subsequent scheduled dosing. Further 
dose escalation according to the protocol’s pre-defined scheme should not be 
attempted. The number of doses scheduled for one dosing day should not be 
exceeded. 
 
 

 
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10. STATISTICS AND DATA MANAGEMENT 
10.1. Estimation of Sample Size 
A total of 27 subjects will be randomized into the study; additional subjects may be included 
to replace discontinued subjects in cohorts 3 and 4. Cohort 1 included 6 subjects, and 5 of 
the planned 8 subjects were included in cohort 2 before the study was temporarily halted. No 
new subjects will be included in cohort 2 after re-start of the study (Protocol version 2.0). 
Cohorts 3 and 4 will include 8 subjects each. The selected sample size is not based on any 
formal power calculations. 
 
10.2. 
Statistical Methods 
A summary of the statistical methods is given below.   
 
10.3. Statistical Analysis Plan 
Detailed statistical analysis information will be provided in a separate Statistical Analysis 
Plan (SAP) before the database lock. 
 
10.4.   Statistical Hypotheses 
No formal statistical hypotheses are stated in this study. The primary objective of the study is 
the evaluation of safety and tolerability of s.c. administration of DM-101 in adult subjects with 
birch pollen allergy. Safety and tolerability data will be analysed descriptively.  
 
10.5.   Data sets to Be Analysed 
A subject classification document including a list of protocol deviations with a clinical 
classification of the deviations and the definition of the analysis datasets will be prepared and 
approved after database lock before opening of the randomization code.  
  
Three main analysis data sets will be constructed. The intent-to-treat (ITT) data set will 
include all subjects having received study medication and providing at least a minimum 
amount of relevant measurements. The safety data set will consist of subjects having 
received at least one dose of study medication. The per protocol (PP) data set will exclude all 
subjects from the ITT data set who meet any of the predefined criteria in the subject 
classification document. 
 
10.6. General Statistical Considerations 
The data will primarily be analysed using summary statistics. Summary statistics will include 
at least the number of subjects, mean, standard deviation, median, minimum and maximum 
values for continuous variables, and frequencies and percentages for categorical variables. 
All data collected will be listed by subject and by cohort. In case inferential statistical 
analyses are conducted, a 2-sided p-value of less than 0.05 is considered statistically 
significant.    

 
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10.7. Demographic and Baseline Characteristics 
The demographic and baseline characteristics of the subjects will be presented using 
descriptive summary statistics by cohort and treatment. 
 
10.8. Analysis of Efficacy Variables 
Not applicable.  
 
10.9. Analysis of Safety Variables 
The primary endpoint of the study is the number of all TEAEs in subjects receiving treatment 
with DM-101, compared to placebo. TEAEs will be MedDRA coded and tabulated by System 
Organ Class and Preferred Term. Occurrence of single Preferred Terms will be presented by 
cohort and treatment. Also, separate tabulations by treatment will be provided. For each 
preferred term, the average number of events will be calculated. In addition, TEAEs will be 
reported by causality and severity.  
    
The number and severity of systemic allergic reactions in subjects receiving treatment with 
DM-101, compared to placebo, will be presented in a similar manner as the TEAEs.  
 
Local injection site reactions (pain, tenderness, erythema/redness, induration/swelling) will 
be graded on a five-point (0 to 4) scale. These will be presented and summarized by cohort 
and treatment.   
 
Other safety variables include results from physical examination, vital signs, clinical 
laboratory values and spirometry. The results will be presented using descriptive statistics by 
cohort and treatment.  
 
10.10. Analysis of Other Variables 
The proportion of subjects reaching the pre-defined, cumulative dose in each DM-101 
treatment group is one of the secondary endpoints. It will be summarised using descriptive 
statistics. 
 
10.11. Analysis of Exploratory Variables 
Descriptive statistics and visualizations will be provided for immunological biomarkers. Also 
exploratory statistical analyses will be conducted to provide preliminary information on the 
used doses as compared to placebo, if feasible. Details of these analyses will be given in the 
statistical analysis plan (SAP).  
 
10.12. Data Management 
Technical and detailed elaboration of the principal features of data management (DM) will be 
available in a separate Data Management Plan (DMP) specifically written for this study. 
 

 
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10.13. Database Design 
The study database and data entry screen design, as well as edit checks will be defined 
according to the corresponding eCRFs and the study protocol. 
 
10.14. Data Entry  
Data will be collected on eCRFs designed in accordance with the study protocol. The 
investigator or designated study site personnel will enter subject data into the eCRFs as 
soon as possible during or after the subject’s visit. All data entries in the eCRFs should be 
consistent with the source documents. The investigator will electronically sign the data to 
confirm that all the information is accurate and correct. 
 
10.15. The Query Process 
The Study Monitor will review the eCRFs and compare them with the relevant source 
documents to ensure the validity and accuracy of the study data. If corrections are needed, 
the Study Monitor will raise a query in the eCRF. The investigator or designated study site 
personnel will answer the queries and make the needed corrections or alterations. 
 
10.16. Medical Encoding 
AEs and medical history verbatim terms will be coded using MedDRA version 22.1. 
Concomitant Medications verbatim terms will be encoded using the Anatomical Therapeutic 
Chemical (ATC) classification system (ATC Index, WHO Collaborating Centre for Drug 
Statistics Methodology), most recent version held by 4Pharma. 
 
10.17. Database Lock 
When all data have been entered and discrepancies have been solved, the database can be 
locked. The locked database is used in the final statistical analyses for study reporting. 
 
10.18. Software 
Viedoc™ Clinic version 4.50 or newer will be used as an EDC system in this study. SAS® for 
Windows version 9.4 or newer will be used in randomization, statistical analysis and 
reporting of the study data. 
 
 
 

 
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11. 
STUDY MANAGEMENT 
11.1.  Study Monitoring 
 
The study will be monitored by a qualified Clinical Study Monitor appointed by Crown and 
approved by the Sponsor. The study monitor will not be otherwise involved in study conduct 
and will be allowed to monitor the study as frequently as necessary to ensure that data 
recording and protocol adherence are satisfactory. The eCRFs and related source data will 
be reviewed in detail and 100 % source data verification will be performed. A Clinical Study 
Monitoring Plan will be prepared by Crown and approved by the Sponsor before the study 
start. 
 
11.2.  Quality Control and Quality Assurance 
 
During the clinical execution of the trial, the SOPs of CRST are followed, unless otherwise 
agreed between the parties. For DM and statistics, the SOPs of 4Pharma are followed. For 
study monitoring, the SOPs of Crown are followed. The principles of GCP are followed 
throughout the study. The analyses of hematology and clinical chemistry will be performed at 
TYKSLAB, the accredited clinical laboratory of Turku University Hospital. The analyses of 
serum levels of allergen specific IgE will be performed at Yhtyneet-Medix Laboratoriot Oy. 
Laboratory quality certificates will be available. 
 
The quality assurance personnel of Crown and the Sponsor may conduct audits in any phase 
of the study. The study may also be inspected by CAs. 
 
A curriculum vitae in English will be obtained from all investigators who sign the protocol and 
from other relevant persons. 
 
11.3.  Deviations 
Non-subject specific protocol deviations will be documented in Deviation Log maintained by 
the study monitor. Deviations concerning a single subject will be described in the 
corresponding eCRF. Protocol deviations will be classified as major or minor by the Sponsor. 
 
11.4. Amendments 
Minor changes (e.g., concerning logistics or administration) to the clinical study protocol can 
be clarified in a NtF or in a non-substantial amendment, if the change has no effect on the 
safety of the subjects or on the scientific value of the study. The investigator will inform the 
Sponsor of such minor changes. All essential changes to the clinical study protocol are 
described in a substantial amendment, which is submitted for approval by the EC and CA 
before adopting the changes, except when necessary to eliminate immediate hazards to the 
study subjects. Amendments to the clinical study protocol are prepared as agreed by the 
parties involved in the study. 
 
 

 
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12. 
REGULATORY AND ETHICAL CONSIDERATIONS 
This study will follow the relevant regulations and guidance for biomedical research involving 
human subjects, such as the Declaration of Helsinki, ICH GCP, and national and EU 
legislation. Special emphasis will be put on the well-being of the subjects. 
 
Prior to initiation of the study, the study protocol, the subject information leaflet and the ICF 
and the texts of any advertisements used for the recruitment of study subjects will be 
submitted to and approved by an independent EC. The EC will also be notified of any other 
materials to be given to the subjects (e.g. study subject diary, participation card). The study 
will be authorized by the CA (the Finnish Medicines Agency, Fimea) before its 
commencement.  
 
The study subject candidates will be provided with both verbal and written information on the 
study, its risks and benefits. They are encouraged to ask questions on the study. After having 
had enough time to consider their participation, they may sign the ICF. No study procedure 
will be implemented prior to obtaining written IC that is signed by the subject at the time of 
consent. A copy of the signed ICF will be given to the subject. The investigator will keep each 
subject’s signed ICF on file for inspection by a regulatory authority at any time. 
 
The subjects are told what personal information will be collected of them and how. The 
collection of personal information is described in compliance with the EU General Data 
Protection Regulation; the description is kept in the ISF and is made available to the 
subjects, if they wish. The investigator assures that the privacy of the subjects, including their 
personal identity and all medical information, will be maintained at all times.  
 
No personal medical benefits can be expected from participating in the study. The 
participation will be compensated and the amount of payment will be approved by the EC. 
 
For an ethical evaluation of this trial with no direct benefits to the participants, a risk analysis 
has been carried out. This FIH trial is to be performed in otherwise healthy subjects who are 
allergic to birch pollen. The aim is to investigate the safety and tolerability of a novel, 
recombinant, modified birch pollen allergen (DM-101), in order to allow further clinical 
development of DM-101 as a novel treatment for birch pollen allergy. The main risk identified 
in this analysis is that of an allergic reaction evoked by exposure to DM-101. Based on 
available nonclinical evidence, DM-101 should be less prone to evoke acute allergic 
reactions compared to other products currently used in s.c. AIT of birch pollen allergy, but 
this cannot be considered certain at this stage as relevant evidence in humans is lacking, 
since this is the first clinical trial with DM-101. Specifically, the following precautions and risk 
mitigation measures have been employed in the planning of this study in order to minimize 
the risks to study participants: 
 
Subject selection criteria are such that unnecessary risks are avoided; subjects 
should be in good health, not having concomitant illnesses or using medications that 
might interfere with subject safety or study assessments; 
 
Sentinel dosing and staggered dosing will be employed; 
 
The starting single dose and the dose escalation protocol for repeated administration 
have been selected based on all available evidence, including observations made in 
cohort 1 and 2 subjects of this study;  

 
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 
Rescue medication (adrenaline, i.v. and oral antihistaminics, i.v. and oral 
glucocorticoids) will be available, there will be written procedures in place for their 
use, and subjects should not have contraindications to their use; venous cannulae will 
be in place on the dosing visits; adrenaline autoinjectors and written instructions on 
what to do in case of a late allergic reaction will be provided upon discharge on the 
first dosing visit; in case of late-appearing reactions, a study physician will be 
available 24/7 by phone. 
 
Subjects of cohorts 3 and 4 will remain confined at Turku University Hospital until 6 h 
after dosing. 
 
The trial will be carried out outside of the birch pollen season in Finland, to avoid co-
exposure to the natural birch allergen. 
 
Progression to subsequent dosing cohorts will take place only if the PI’s and SRC’s 
review of the collected safety and tolerability data from each preceding cohort is 
favorable; dose escalation within each cohort will also take place only if safety allows 
it and the study’s dosing discontinuation or adjustment criteria have not been met. 
 
Other possible risks and the measures taken for their mitigation are the following: 
 
Induction of birch pollen allergy by exposure to DM-101: subjects will be selected 
based on documented evidence of allergy to the major birch pollen allergen Bet 1 v; 
thus, exposure to DM-101 should not evoke allergy in a subject not previously 
sensitized. 
 
Unexpected findings in any of the evaluations carried out for the purposes of the 
study: any such incidental findings will be adequately communicated to the subject in 
question, with appropriate counseling on the need for medical care or follow-up; 
 
Unexpected AEs related to DM-101, other than allergic in nature: unexpected 
mechanisms for causation of AEs are always possible in early-phase clinical trials, 
but their likelihood is small as the employed doses of DM-101 are small (at most, 710 
ng), and as repeated dosing of 0.5 mg doses was well tolerated in the GLP toxicity 
study performed in rabbits. The team will monitor the subjects closely for any 
unexpected AEs and appropriate measures will be taken, if needed, for their 
treatment. The measures taken for mitigation of allergy risks are also applicable to 
other possible AEs. 
 
The subjects will be followed closely for possible AEs and specific dosing interruption criteria 
are included in the study protocol to ensure subject safety. A SRC will also monitor subject 
safety and will make recommendations on further dosing and possible modifications to the 
study.  
 
An invasive procedure included in this study is venous cannulation on the dosing visits. 
Venous cannulation may result in feelings of discomfort and pain, haematoma, 
thrombophlebitis and vasovagal reactions, but it is considered warranted for subject safety, 
facilitating administration of fluids and rescue medication (antihistaminics and 
glucocorticoids) in case of an anaphylactic reaction or other emergency. Apart from dosing, 
venous cannulation and venipuncture for collection of blood samples, all other study 
procedures are considered non-invasive. The volume of blood drawn from each subject will 
not exceed 200 ml in cohort 1 and 450 ml in cohorts 2-4. This blood loss should not produce 
any adverse effects. 
 

 
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The subjects are urged to report all AEs to the study personnel and they are given phone 
numbers of the investigator, the study nurses and CRST’s 24/7 on-call physician whom they 
are instructed to contact if they observe potentially significant AEs, or in other urgent study-
related issues. 
 
Substantial changes to the final approved protocol will be initiated only with the EC’s 
favorable opinion of a written amendment, except when necessary to eliminate immediate 
hazards to the study subjects. When a change involves only logistics or administration, it will 
be considered non-substantial, and needs not be submitted to the EC or the CA for approval. 
The CA will also be notified before adopting a substantial amendment. 
 
The trial has been registered in a publicly accessible database prior to study start. After the 
study has been completed and a Clinical Study Report prepared, the EC and CA will be 
notified of the study results, and a summary of the results will be posted in a publicly 
accessible database. The study results are also intended to be published in a peer-reviewed 
scientific journal, with authorship criteria and other publication-related issues in agreement 
with established ICMJE guidance.   
 
 
13. 
DATA HANDLING AND RECORD KEEPING 
13.1. Case Report Forms 
Generated subject data will be recorded on eCRFs provided for this study by 4Pharma. Only 
authorized persons, as agreed at the study initiation meeting, are allowed to make entries on 
eCRFs. Agreed study team members can make corrective entries on the eCRFs if the 
Investigator has not yet signed the eCRF page. After signing, only the Investigator is allowed 
to make corrections.  
 
eCRFs are required for each study subject. They will be completed in English by the 
Investigator or other authorized study personnel. The Investigator has to confirm the content 
of the eCRF by an electronic signature. 
 
Corrections to the eCRFs can be made by the Investigator or other authorized study 
personnel. An audit trail within the system will track all changes/corrections made. 
 
Instructions and training for completing the eCRFs will be provided. These instructions will 
cover the content and technical issues of the EDC system. 
 
13.2.  Source Data 
Study-specific source data forms will be prepared by CRST’s study personnel or provided by 
the Sponsor before study initiation. Access to the source data revealing the identity of the 
study subjects is only to study personnel. The generated source data are stored at CRST.  
 
The results of the laboratory blood and urine safety determinations are stored as print-outs 
within the ISF at CRST and in the patient records of TYKSLAB, Hospital District of Southwest 
Finland, the personnel of which is bound to professional secrecy. The coded 12-lead ECG 
and spirometry print-outs are stored at CRST.  
 

 
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The contact information of the subject’s next-of-kin will be destroyed before the ISF is 
archived. 
 
 
14. 
STUDY SCHEDULE 
The clinical study is planned to be performed during Q3/2019-Q2/2021. 
 
 
15. 
FINANCING AND INSURANCE 
Financial matters are covered by an agreement between CRST and the Sponsor, and in 
respective agreements with the other relevant parties of the study. The Sponsor has an 
insurance policy (Lääkevahinkovakuutus) covering damages caused by the investigational 
products administered during the study. The insurance statement will be provided in the ISF 
and TMF (Trial Master File). In case of any injury caused by an incident that is related to the 
study procedures but is not causally related to the investigational products, study subjects 
will be covered by the patient insurance of CRST.  
 
 
16. 
STUDY REPORT AND PUBLICATION POLICY 
A final study report will be prepared in accordance with relevant ICH guidance, as agreed 
between the parties, after the study has been completed or prematurely terminated. The 
Sponsor may submit the report to another party. The EC and CA will be notified about the 
study completion according to laws and regulations and as agreed between the parties. The 
study report will be approved by the Investigator and the Sponsor. The Sponsor remains the 
exclusive owner of the study data defined in the protocol. The eventual publication of the 
study results and the authorships of the eventual publications will be mutually agreed later. 
The planned publication will not be submitted for publication without prior approval of the 
Sponsor. 
 
 
17. 
ARCHIVING 
The ISF (including e.g. source data, subject screening and identification logs, original signed 
ICFs, copies of CRFs, and drug accountability records) will be archived by CRST to enable 
possible follow-up assessments or audits by the Sponsor, or inspections by regulatory 
authorities. The ISF is archived for at least 15 years after the end of the study, unless 
specified otherwise by a written agreement between the Sponsor and CRST.  
 
Information collected during the course of this study will be stored by the Sponsor and used 
in the development of DM-101 in its development as a treatment for birch pollen allergy, and 
thereafter for as long as the information is relevant to patient care. Its use includes the 
transfer of data to regulatory authorities of the EU or its member states, the USA or other 
countries for the purpose of obtaining, maintaining and processing of marketing 
authorizations. All information is handled confidentially and according to the current laws and 
regulations. 
 

 
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The Sponsor will archive the TMF according to current laws and regulations. 
 
 
18. 
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