Phase 2a Trial to Assess the Efficacy and Safety of LEO 152020 in Adult Patients With Cholinergic Urticaria
Phase: PHASE2
Conditions: Cholinergic Urticaria
Sponsor: JW Pharmaceutical

CONFIDENTIAL 
THIS DOCUMENT CONTAINS CONFIDENTIAL INFORMATION AND MUST NOT BE COPIED OR MADE AVAILABLE TO ANY THIRD PARTY WITHOUT 
THE PRIOR WRITTEN CONSENT OF THE LEO GROUP 
 
 
Clinical Trial Protocol 
 
EXP-2177 
 
Phase 2a trial to assess the efficacy and safety of LEO 152020 in adult patients with 
cholinergic urticaria 
 
A randomised, double-blind, placebo-controlled, multi-site, cross-over trial 
 
This clinical trial will be conducted in compliance with the clinical trial protocol, ICH GCP, 
and the applicable regulatory requirement(s). 
LEO Pharma A/S 
Trial ID: 
EXP-2177 
 
Date: 
08-Apr-2022 
 
EudraCT no: 
2020-004961-38 
 
Version: 
7.0 
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Clinical trial protocol statements 
Approval statement LEO Pharma A/S 
Electronic signatures made within eTMF LEO are considered to be a legally binding 
equivalent of traditional handwritten signatures. The following persons have approved this 
clinical trial protocol by using electronic signatures as presented on the last page of this 
document: 
, MMath, PhD 
 
Biostatistics lead, Medical Sciences 
 
 
 
, MD, DMSc. 
 
Medical lead, Translational Medicine, Research & 
Early Development 
 
 
 
, MD 
 
Senior Director, Medical Department 
 
 
 
, MSc. Pharm. 
 
Clinical operations lead, Global Clinical Operations 
 
 
 
, MD 
 
Signatory investigator 
 
  
Acknowledgement statement investigator(s) 
Each participating investigator must agree to the approved clinical trial protocol by signing a 
clinical trial protocol acknowledgement form or similar document.
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Protocol amendment summary of changes table 
Document history 
Document 
Date 
Type of protocol amendment 
Amendment 6 
(substantial) 
08-Apr-2022 
global 
Amendment 5 
(substantial) 
09-Mar-2022 
global 
Amendment 4 
(non-substantial) 
06-Dec-2021 
global 
Amendment 3 
(substantial) 
15-Jun-2021 
global 
Amendment 2 (non-
substantial) 
16-Apr-2021 
global 
Amendment 1 
(substantial) 
09-Mar-2021 
global 
Original protocol 
12-Jan-2021 
NA 
Protocol amendment summary of changes tables for previous amendments (Amendment 1, 
dated 09-Mar-2021, Amendment 2, dated 16-Apr-2021, Amendment 3, 15-Jun-2021, 
Amendment 4, dated 06-Dec-2021, and Amendment 5, dated 09-Mar-2022) are provided in 
Appendix 7. 
 
 
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Amendment 6 (08-Apr-2022) 
This amendment is considered substantial based on the criteria set forth in Article 10(a) of 
Directive 2001/20/EC of the European Parliament and the Council of the European Union or 
subsequent regulation. 
Overall rationale for the amendment: 
With the introduction of COVID-19 vaccines, COVID-19 may now be considered more like 
other influenza-like diseases – and COVID-19 (confirmed by a positive SARS-CoV-2 test 
result) is no longer deemed a major health risk as disease symptoms are commonly only mild 
and patients rapidly recover from COVID-19. This amendment is intended to take account for 
the changed status of the COVID-19 pandemic. 
Section no.  
and name 
Description of change 
Brief rationale 
8.3 Exclusion 
Criteria & 
Appendix 5 
Short version 
of eligibility 
criteria 
Exclusion criterion 13 has been 
modified: 
Formerly: 
13. Subjects with confirmed 
active infection with SARS-
CoV-2 and related disease 
(COVID-19). 
New: 
13. Subjects with confirmed 
active infection with SARS-
CoV-2 AND related COVID-19 
symptoms, which at the 
discretion of the investigator 
will jeopardize the safety of 
the subject or the integrity of 
the data collected. 
Additionally, any local 
requirements must be 
followed. 
The amendment reflects the changed 
status of COVID-19. It is important to 
note the investigational drug is not 
presumed to interfere with the 
immune response against COVID-19.  
With this amendment we will allow 
patients with a positive COVID-19 
test and with no or mild symptoms to 
be enrolled or to remain in this clinical 
trial. The decision to be enrolled or to 
remain in the trial despite a positive 
COVID-19 test will be at 
investigator’s discretion to safeguard 
patient safety and as long as in line 
with local regulations. 
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Section no.  
and name 
Description of change 
Brief rationale 
10.2.1 Reasons 
for permanent 
discontinuation 
of IMP 
Rewording of the reason for 
permanent discontinuation of 
IMP due to SARS-CoV-2 
infection 
Formerly: 
Subjects will permanently 
discontinue IMP in any of the 
treatment periods in the event 
of: 
• 
…. 
• 
Infection with COVID -19 
• 
…. 
 
New: 
Subjects will permanently 
discontinue IMP in any of the 
treatment periods in the event 
of: 
• 
…. 
• 
Symptomatic infection with 
SARS-CoV-2 that is likely 
to have an impact on 
efficacy or safety data (i.e., 
patients with a SARS-CoV-
2 infection without or very 
mild symptoms only (e.g., 
rhinitis or sore throat) might 
continue with the study at 
investigator’s discretion and 
in accordance with the 
applicable local 
regulations). 
• 
…. 
The adjustment was again made in the 
light of the changing course of disease 
in case of infection with SARS-CoV-
2, which currently tends to show 
milder courses and shorter durations 
due to the vaccination status but also 
the dominant viral variant. 
The infection situation will continue 
to be monitored and necessary 
adjustments will be implemented as 
needed. 
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Section no.  
and name 
Description of change 
Brief rationale 
11.4.5 Test for 
SARS-CoV-2 
infection 
Rewording of the section on 
procedure for patients with 
confirmed SARS-CoV-2 
infection. 
Formerly: 
Subjects with active and 
confirmed SARS-CoV-2 
infection will be managed in 
accordance with institutional 
guidelines with regards to trial 
site visits. In case of confirmed 
SARS-CoV-2 infection the 
subject will be withdrawn from 
trial. 
New: 
Subjects with active and 
confirmed SARS-CoV-2 
infection will be managed in 
accordance with institutional 
guidelines with regards to trial 
site visits. In case of 
confirmed SARS-CoV-2 
infection the subject will be 
withdrawn from trial. 
To align with section 10.2.1 “Reasons 
for permanent discontinuation of 
IMP”. 
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Section no.  
and name 
Description of change 
Brief rationale 
Clinical trial 
protocol 
statements 
 has been replaced 
by 
 
 as Senior Director, 
Medical Department at LEO 
Pharma A/S 
Due to personnel changes and changes 
in project responsibility at LEO 
Pharma A/S, it is necessary to adapt 
the Approval Statement accordingly 
 
 
 
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Table of contents 
Table of contents ....................................................................................................................... 8 
List of panels ........................................................................................................................... 13 
List of abbreviations ............................................................................................................... 14 
1 Protocol synopsis ................................................................................................................ 17 
2 Trial identification ............................................................................................................. 22 
3 Schematic of trial design ................................................................................................... 22 
4 Schedule of trial procedures ............................................................................................. 23 
5 Introduction and trial rationale ....................................................................................... 29 
5.1 Cholinergic urticaria ................................................................................................... 29 
5.2 Experience with investigational medicinal product .................................................... 29 
5.3 Trial rationale .............................................................................................................. 31 
5.4 Ethical considerations ................................................................................................. 32 
5.5 Benefit/risk assessment ............................................................................................... 32 
6 Trial objectives and endpoints .......................................................................................... 35 
7 Trial design ......................................................................................................................... 38 
7.1 Overall trial design ..................................................................................................... 38 
7.1.1 
Screening phase (Days -21 (-7) to -1) ........................................................... 39 
7.1.2 
Treatment phase (Visit 2 (Day 1) to Visit 5) ................................................. 39 
7.1.2.1 
Visit 2 (Day 1, Randomisation) = Baseline for treatment 
period A ................................................................................. 39 
7.1.2.2 
Visit 3 (Day 8, -1 to +3) ........................................................ 40 
7.1.2.3 
Visit 4 (Day 15 ± 1)/ Visit 4a (Day 22 ±1) = Baseline for 
treatment period B ................................................................. 40 
7.1.2.4 
Visit 5 (Baseline for treatment period B + 7 Days, -1 to +3) 40 
7.1.3 
Visit 6 - Safety Follow-up (Visit 5 +3 (+4) Days) / End of Trial .................. 41 
7.2 Number of subjects needed ......................................................................................... 41 
7.3 End of trial definition.................................................................................................. 41 
8 Trial population ................................................................................................................. 41 
8.1 Subject eligibility ........................................................................................................ 41 
8.2 Inclusion criteria ......................................................................................................... 42 
8.3 Exclusion criteria ........................................................................................................ 43 
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8.4 Screening and screening failures ................................................................................ 46 
9 Treatments .......................................................................................................................... 48 
9.1 Trial product description ............................................................................................. 48 
9.2 Administration of investigational medicinal product ................................................. 48 
9.3 Treatment assignment ................................................................................................. 51 
9.3.1 
Blinding ......................................................................................................... 52 
9.3.2 
Emergency unblinding of individual subject treatment ................................ 52 
9.4 Background treatment ................................................................................................. 53 
9.5 Rescue treatment ......................................................................................................... 53 
9.6 Concomitant medication and concurrent procedures ................................................. 53 
9.7 Prohibited medication(s) and procedures ................................................................... 55 
9.7.1 
Other restrictions ........................................................................................... 56 
9.8 Treatment logistics and accountability ....................................................................... 56 
9.8.1 
Labelling and packaging of trial products ..................................................... 56 
9.8.2 
Storage of trial products ................................................................................ 57 
9.8.3 
Drug accountability ....................................................................................... 57 
9.8.4 
Treatment compliance ................................................................................... 58 
9.8.5 
Trial product destruction ............................................................................... 58 
9.9 Provision for subject care following trial completion ................................................ 58 
9.10 Reporting product complaints..................................................................................... 58 
10 Discontinuation and withdrawal ...................................................................................... 60 
10.1 General principles ....................................................................................................... 60 
10.2 Reasons for permanent discontinuation of IMP ......................................................... 60 
10.2.1 Reasons for permanent discontinuation of IMP ............................................ 60 
10.3 Early termination assessments .................................................................................... 62 
10.4 Lost to follow-up ........................................................................................................ 62 
10.5 Criteria for the termination of the trial ....................................................................... 63 
10.5.1 Termination of the whole trial ....................................................................... 63 
10.5.2 Termination of the trial at an individual trial site .......................................... 64 
11 Trial assessments and procedures .................................................................................... 65 
11.1 Overview..................................................................................................................... 65 
11.2 Assessments performed only at screening/baseline .................................................... 67 
11.2.1 Demographics................................................................................................ 67 
11.2.2 Medical history .............................................................................................. 67 
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11.2.3 Height and weight ......................................................................................... 67 
11.3 Efficacy assessments .................................................................................................. 68 
11.3.1 Urticaria Activity Score post-provocation (UASprovo) ................................ 68 
11.3.2 Physician’s Global Assessment of Disease Severity by VAS ....................... 69 
11.3.3 Histamine Skin Prick Testing ........................................................................ 69 
11.3.4 Patient-reported outcomes ............................................................................. 70 
11.3.4.1 Patient’s Global Assessment of Severity by VAS ................. 70 
11.3.4.2 Urticaria Control Test ............................................................ 70 
11.3.4.3 Cholinergic Urticaria Activity Score 7 .................................. 71 
11.4 Safety assessments ...................................................................................................... 73 
11.4.1 Vital signs ...................................................................................................... 73 
11.4.2 Physical examination..................................................................................... 73 
11.4.3 ECG ............................................................................................................... 74 
11.4.4 Laboratory testing ......................................................................................... 75 
11.4.4.1 Overview ............................................................................... 75 
11.4.4.2 Investigator evaluation of laboratory samples ....................... 77 
11.4.5 Test for SARS-CoV-2 infection..................................................................... 78 
11.5 Pharmacokinetic assessments ..................................................................................... 78 
11.5.1 Blood sampling for analysis of drug ............................................................. 78 
11.6 Pharmacodynamics assessments ................................................................................. 79 
11.6.1 Blood biomarkers .......................................................................................... 79 
11.6.2 Skin biopsies ................................................................................................. 79 
11.7 Other assessments ....................................................................................................... 80 
11.7.1 Patient-reported outcomes ............................................................................. 80 
11.7.1.1 Diary ...................................................................................... 80 
11.7.1.2 Dermatology Life Quality Index ........................................... 80 
11.7.1.3 Cholinergic Urticaria Quality of Life Questionnaire............. 81 
11.7.2 Photography .................................................................................................. 81 
11.8 End of trial .................................................................................................................. 82 
11.9 Estimate of total blood volume collected ................................................................... 83 
11.10 Storage of biological samples ..................................................................................... 83 
12 Scientific rationale for trial design and appropriateness of assessments ..................... 84 
12.1 Scientific rationale for trial design ............................................................................. 84 
12.2 Appropriateness of assessments ................................................................................. 85 
13 Adverse events ................................................................................................................... 86 
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13.1 Definition and classification of adverse events .......................................................... 86 
13.2 Collection of adverse event reports ............................................................................ 86 
13.3 Reporting of adverse events........................................................................................ 86 
13.4 Reporting of serious adverse events ........................................................................... 87 
13.4.1 Investigator reporting responsibilities ........................................................... 87 
13.4.2 LEO reporting responsibilities ...................................................................... 88 
13.5 Other events that require expedited reporting ............................................................ 88 
13.5.1 Pregnancy ...................................................................................................... 88 
13.5.2 Adverse events of special interest ................................................................. 89 
13.6 Reporting of other events............................................................................................ 89 
13.6.1 Adverse events of special interest ................................................................. 89 
13.6.2 Medication error ............................................................................................ 90 
13.6.3 Misuse or Abuse ............................................................................................ 90 
13.6.4 Aggravation of condition .............................................................................. 91 
13.7 Follow-up for final outcome of adverse events .......................................................... 91 
13.8 Handling of an urgent safety measure ........................................................................ 91 
14 Statistical methods ............................................................................................................. 93 
14.1 Sample size ................................................................................................................. 93 
14.2 Trial analysis sets ........................................................................................................ 93 
14.3 Statistical analysis ....................................................................................................... 94 
14.3.1 Disposition of subjects .................................................................................. 95 
14.3.2 Demographics and other baseline characteristics.......................................... 95 
14.3.3 Exposure and treatment compliance ............................................................. 95 
14.3.4 Testing strategy ............................................................................................. 95 
14.3.5 Analysis of primary efficacy endpoint .......................................................... 96 
14.3.6 Analysis of secondary efficacy endpoints ..................................................... 97 
14.3.7 Analysis of patient-reported outcomes .......................................................... 98 
14.3.8 Analysis of pharmacodynamics and pharmacogenomics.............................. 99 
14.3.9 Analysis of safety .......................................................................................... 99 
14.3.9.1 Adverse events ...................................................................... 99 
14.3.9.2 Vital signs ............................................................................ 100 
14.3.9.3 Physical examination ........................................................... 101 
14.3.9.4 ECG ..................................................................................... 101 
14.3.9.5 Clinical laboratory evaluation ............................................. 101 
14.3.10 Pharmacokinetic analysis ............................................................................ 102 
14.3.11 Interim analysis ........................................................................................... 102 
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14.3.12 General principles ....................................................................................... 102 
14.3.13 Handling of missing values ......................................................................... 103 
15 References ......................................................................................................................... 104 
Appendix 1: Definitions of adverse events and serious adverse events ........................... 107 
Appendix 2: Classification of adverse events ..................................................................... 109 
Appendix 3: Trial governance considerations ................................................................... 112 
Appendix 3A: Regulatory and ethical considerations .............................................. 112 
Appendix 3B: Informed consent process ................................................................. 113 
Appendix 3C: Subject and data confidentiality ....................................................... 113 
Appendix 3D: Record keeping, quality control, and data handling ......................... 115 
Appendix 3E: Registration, reporting and publication policy ................................. 118 
Appendix 3F: Insurance ........................................................................................... 119 
Appendix 3G: Financial disclosure .......................................................................... 119 
Appendix 3H: Trial and trial site closure ................................................................. 120 
Appendix 3I: Responsibilities .................................................................................. 121 
Appendix 4: Examples of prohibited medication .............................................................. 122 
Appendix 5: Short version of eligibility criteria ................................................................ 124 
Appendix 6: Contact list ...................................................................................................... 127 
Appendix 7: Protocol amendment history ......................................................................... 128 
Amendment 5 (09-Mar-2022) .................................................................................. 128 
Amendment 4 (06-Dec-2021) .................................................................................. 130 
Amendment 3 (15-Jun-2021) ................................................................................... 131 
Amendment 2 (16-Apr-2021) .................................................................................. 134 
Amendment 1 (09-Mar-2021) .................................................................................. 138 
 
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List of panels 
Panel 1: Trial design ................................................................................................................. 22 
Panel 2: Schedule of trial procedures ....................................................................................... 23 
Panel 3: Objectives and endpoints ........................................................................................... 36 
Panel 4: Identification of investigational medicinal products .................................................. 48 
Panel 5: Prohibited medication(s) and/or procedure(s) ............................................................ 55 
Panel 6: Sequence of assessments ............................................................................................ 65 
Panel 7: (Modified) Urticaria Control Test .............................................................................. 71 
Panel 8: Hive severity score ..................................................................................................... 72 
Panel 9: Itch severity score ....................................................................................................... 72 
Panel 10: Clinical laboratory tests ............................................................................................ 76 
Panel 11: Adverse events of special interest ............................................................................ 89 
Panel 12: Severity specifications for adverse event of electrocardiogram QT corrected interval 
prolonged .......................................................................................................... 90 
Panel 13: Overview of statistical analyses for secondary efficacy endpoints .......................... 97 
 
 
 
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List of abbreviations 
AD 
Atopic dermatitis 
AE 
adverse event 
AESI 
adverse event of special interest 
AUC 
Area under the curve 
BCRP 
Breast cancer resistance protein 
 
 
BP 
blood pressure 
CDISC 
Clinical Data Interchange Standards Consortium 
CI 
confidence interval 
CMO 
contract manufacturing organisation 
CholU 
Cholinergic urticaria 
CholUAS7 
Cholinergic Urticaria Activity Score 7 
CholUQoL 
Cholinergic Urticaria Quality of Life questionnaire 
CONSORT 
Consolidated Standards of Reporting Trials 
COVID-19 
coronavirus disease 2019 
CRA 
clinical research associate 
CRO 
contract research organisation 
CRP 
C-reactive protein 
CTCAE 
Common Terminology Criteria for Adverse Events 
CTR 
clinical trial report 
DLQI 
Dermatology Life Quality Index 
DNA 
Deoxyribonucleic acid 
ECG 
Electrocardiogram 
eCRF 
electronic case report form 
EMA 
European Medicines Agency 
ET 
early termination visit 
FAS 
Full Analysis Set 
FcεRI 
high-affinity receptor for the Fc region of immunoglobulin E 
FU 
follow-up visit 
GCP 
Good Clinical Practice 
HBsAg 
Hepatitis B surface antigen 
anti-HBc 
Hepatitis B core antibody 
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H4R 
histamine H4 receptor 
hCG 
human chorionic gonadotropin 
HCP 
healthcare professional 
HDL 
High density lipoprotein 
HIV 
human immunodeficiency virus 
HSS(7) 
hive severity score; HSS7: weekly score 
ICF 
informed consent form 
ICH 
International Council for Harmonisation of Technical Requirements for 
Pharmaceuticals for Human Use 
ID 
identification number 
IEC 
independent ethics committee 
IGA 
Investigator’s Global Assessment 
IgE 
Immunoglobulin E  
IL 
Interleukin 
IMP 
investigational medicinal product 
ISF 
Investigator Site File 
ISS(7) 
Itch severity score; ISS7: weekly score 
IUD 
intrauterine device 
IUS 
intrauterine hormone-releasing system 
LDL 
Low density lipoprotein 
MAD 
Multiple-ascending dose 
MCID 
minimal clinically important difference 
MedDRA 
Medical Dictionary for Regulatory Activities 
NBUVB 
narrow band ultraviolet B] 
NOAEL 
No Observed Adverse Effect Level 
OAT3 
Organic anion transporter 3 
PD 
pharmacodynamics 
PhGA 
Physician’s Global Assessment 
PGI-S 
Patient’s Global Assessment of Severity   
P-gp 
permeability glycoprotein 
PK 
pharmacokinetics 
PO 
Per os (oral administration) 
PPS 
Per Protocol Analysis Set 
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PRO 
patient-reported outcome 
PT 
preferred term 
PUVA 
Psoralen + ultraviolet A 
QoL 
Quality of Life 
QTc(F) 
Q-T corrected interval (by Fredericia) 
SAD 
Single-ascending dose 
SAE 
serious adverse event 
SAF 
Safety Analysis Set 
SAP 
Statistical Analysis Plan 
SARS-CoV-2 
Severe acute respiratory syndrome coronavirus 2 
SD 
standard deviation 
SDTM 
Study Data Tabulation Model 
SOC 
system organ class 
SPT 
Skin Prick Testing 
SUSAR 
suspected, unexpected serious adverse reactions 
TEAE 
Treatment emergent adverse event 
Th1/Th2 
T helper cells type 1/type 2 
TSLP 
Thymic stromal lymphopoietin 
UASprovo 
Urticaria Activity Score post-provocation 
(m)UCT 
(modified) Urticaria Control Test 
UVA / UVB  
ultraviolet A and ultraviolet B 
VAS 
Visual Analogue Scale 
WHO 
World Health Organization 
WOCB 
Woman of childbearing potential 
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1 Protocol synopsis 
Trial ID 
EudraCT no. 
EXP-2177 
2020-004961-38 
Title of trial 
Phase 2a trial to assess the efficacy and safety of LEO 152020 in adult patients 
with cholinergic urticaria 
Short title of trial 
Phase 2a trial to assess the efficacy and safety of LEO 152020 in adult patients 
with cholinergic urticaria 
Main objective(s) 
and endpoint(s) 
 
Objectives 
Endpoints 
Primary objective 
 
To explore the efficacy of 
LEO 152020 compared with 
placebo in patients with 
CholU. 
 
Time frame: baseline of each treatment 
period to end of each treatment period 
Primary efficacy endpoint 
• 
Change from baseline in post-
provocation Urticaria Activity Score 
(UASprovo). 
Other/exploratory efficacy endpoint(s) 
 
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Secondary objective(s) 
 
To evaluate the safety of 
LEO 152020 compared with 
placebo in patients with 
CholU. 
Secondary endpoint 
• 
Number of treatment emergent 
adverse events (TEAE) per subject.  
 
Time frame: start treatment period to 3 days 
after end treatment period 
Other/exploratory objectives 
 
To explore the expression of 
biomarkers of LEO 152020 
compared with placebo in 
patients with CholU. 
Other/exploratory endpoint(s) 
To explore the 
pharmacokinetics of LEO 
152020 in patients with 
CholU. 
Other/exploratory endpoint(s) 
Final collection of 
data for the 
primary endpoint 
Visit 5 (7 days after baseline of treatment period B) 
Trial design 
EXP-2177 is a phase 2a, randomised, double-blind, placebo-controlled, multi-
centre, cross-over trial conducted in Germany. Subjects will be randomised, 
stratified by site to one of two treatment sequences. Each treatment period will 
last 7 days with a wash-out period of 7 days between treatments. Safety follow-
up visit will be performed 3 days after last IMP dose. 
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Main assessments 
Efficacy assessments: 
Urticaria Activity Score post-provocation (UASprovo): After Pulse-
controlled ergometry (PCE) provocation test subjects will be rated on their 
number of wheals and their itch severity, resulting in a sum score for the 
UASprovo ranging from 0 to 6 points: 
a) Numbers of wheals (0 wheals = 0; 1 to 20 wheals = 1; 20 to 50 wheals = 2;  
> 50 wheal = 3) 
b) Itching (none = 0, mild = 1, moderate = 2, severe = 3). 
Histamine Skin Prick Testing (SPT): Test for histamine sensitivity causing 
pruritus, skin flare and a skin wheal. The absolute wheal/flare size will be 
measured. A positive test is defined as a wheal and flare reaction (≥ 3mm in 
diameter relative to negative control). Pruritus during the SPT will be assessed 
by subjects every minute for 15 minutes in total using a 100mm VAS scale 
with 0 indicating ‘no itch’ and 10 indicating ‘worst itch imaginable’. 
Physician’s Global Assessment (PhGA): Instrument to rate the severity of the 
subject’s current disease severity using a Visual Analogue Scale (VAS) ranging 
from 0 (absence) to 10 (worst possible severity). 
Patient Reported Outcomes (PROs): 
Patient’s Global Assessment of Severity (PGA-S): Single item designed 
to capture the subject’s overall perception of their symptoms over the past 
week on a Visual Analogue Scale  ranging from 0 (absence) to 10 (worst 
possible severity). 
Urticaria Control Test (UCT): Disease-specific measure consisting of four 
questions that retrospectively assesses patients’ burden of disease over the 
previous 4 weeks and, in addition, over the past week (mUCT) to capture 
changes over a shorter recall period. Concepts covered include disease 
activity, QoL survey, disease control, and therapy. Each of the four 
questions are scored on a scale of 0 to 4. The UCT score is derived by 
adding up the scores from each of the four questions. A total score from 0 
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(no control) to 16 points (complete control) is derived, with a score of ≥ 12 
indicating well-controlled disease. 
Cholinergic Urticaria Activity Score 7 (CholUAS7): Validated tool to 
assess disease symptoms in CholU subjects. The weekly CholUAS7 is the 
sum of the daily Hive Severity Score (HSS) and the daily Itch Severity 
Score (ISS) for 7 consecutive days, each ranging between 0 and 3 per day. 
The possible range of the weekly CholUAS7 score is 0-42 with higher 
values indicating higher disease severity. 
Safety assessments: 
• Adverse Events, 
• Vital signs (resting blood pressure, pulse, and body temperature), 
• Physical examination 
• ECG (12-lead resting digital ECG; pre-dose at screening and 1 h post-dose 
at visit 2 to visit 5) 
• Central / Local laboratory testing (haematology, blood chemistry, serology, 
pregnancy test and SARS-CoV-2). 
Main criteria for 
inclusion 
• Subject with a history of CholU diagnosis for ≥ 6 months, 
• Subject has active and uncontrolled CholU disease at the time of screening 
and randomisation, as defined by the following: 
a. Urticaria control test (UCT) < 12 at screening 
b. UASprovo ≥ 3, 
• Age 18 or older, 
• Recent history (within 6 months of screening) with documented inadequate 
response to standard dose as to marketing authorization of H1 
antihistamines. 
Main criteria for 
exclusion 
• Other clearly dominating forms* of urticaria as aetiology for wheal and flare 
type reactions, 
*These diseases are allowed as comorbidities, if cholinergic urticaria is the 
dominating form of chronic urticaria, 
• Systemic immunosuppressive medications within 4 weeks prior to 
screening, 
• Systemic drugs (e.g. oral drug) with antihistamine properties including H1 
antihistamines and H2 antihistamines 1 week prior to randomisation. 
However, topical antihistamines in the form of nasal spray and eyedrops are 
allowed in the standard prescribed dose. 
Investigational 
medicinal 
product(s) 
Name of IMPs: 
LEO 152020 film-coated tablet 
• Active substance: LEO 152020  
• Dosage form: film-coated tablet 
• Concentration: 
 
• Dose: 
 
• Method of administration: oral 
 
Placebo film-coated tablet 
• Active substance: not applicable  
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• Dosage form: film-coated tablet 
• Concentration: not applicable 
• Dose: 
 
• Method of administration: oral 
Duration of trial 
participation 
Up to 8 weeks in total: 
• 
up to 3 weeks screening period 
• 
1 week: treatment period A 
• 
1 week: wash-out period – may be prolonged by 1 week if start of 
treatment period B needs to be postponed due to retest of UASprovo 
• 
1 week:  treatment period B 
• 
Up to 1 week follow-up period 
Number of 
subjects 
A total of 28 subjects will be randomised 1:1 to the treatment sequences in this 
cross-over trial 
Number and 
distribution of 
trial sites 
Approximately 3-6 sites in Germany 
Statistical 
methods 
The primary efficacy endpoint will be compared between treatments by means 
of a linear mixed model, containing treatment, period and carryover effects, the 
factor site, and UASprovo at treatment start within period as covariate. Null 
hypothesis is that the endpoints are equal for both treatments against the 
alternative that they are different. 
The primary analysis will be performed for the full analysis set. 
Signatory 
investigator 
, MD 
 
 
 Berlin, Germany 
Sponsor 
LEO Pharma A/S, Industriparken 55, 2750 Ballerup, Denmark 
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2 Trial identification 
EudraCT number: 2020-004961-38 
The clinical trial protocol will be registered in local registries if required by local legislation. 
3 Schematic of trial design 
Panel 1: Trial design 
 
 
*Similar to visit 2, at visit 4 the subject will be required to demonstrate a UASprovo ≥ 3 (with a minimum wheal 
score of ≥ 1 and minimum itch score of ≥ 1) in order to progress to treatment period B. If the subject does not 
demonstrate a UASprovo ≥ 3 they will be required to attend an additional study visit (visit 4a) 7±1 days later 
(see additional details in Panel 2).  
#Screening provocation test is optional if patients had a recent provocation test within 6 months of day 1 (visit 2)  
IMP(s): 
• 
Sequence 1) LEO 152020 
 during treatment period A and placebo tablets 
 during treatment 
period B,  
• 
Sequence 2) placebo 
 during treatment period A and LEO 152020 
 during treatment period 
B.  
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4 Schedule of trial procedures 
Panel 2: Schedule of trial procedures  
For sequence of assessments during the visits please refer to Section 11.1 
 
Screening 
Treatment period A 
Wash 
out 
Treatment period B 
Follow-
up 
ET1 
 
References 
(protocol 
section) 
Visit 
1 
2 
(Baseline A) 
3 
 
 
4* 
(Baseline B) 
4a** 
(Baseline B) 
5 
 
6 
 
 
 
Day 
-21 (-7)*** 
to -1 
1 
8 
 
15 
V4 + 7 
Baseline B + 7 
V5 + 3 
Visit window (days) 
N/A 
N/A 
-1 to + 3 
 
±1 
±1 
-1 to + 3 
+4 
Informed consent(s) 
X 
 
 
 
 
 
 
 
 
Appendix 
3B 
Subject eligibility 
X 
X 
 
 
 
 
 
 
 
8.2 and 8.3 
Demographics  
X 
 
 
 
 
 
 
 
11.2.1 
Medical history 
X 
 
 
 
 
 
 
 
 
11.2.2 
Height and weight 
X 
 
 
 
 
 
 
 
 
11.2.3 
Concomitant 
medications/and procedures 
X 
X 
X 
 
X 
X 
X 
X  
X 
9.6 
Diary handout 
X 
 
 
 
 
 
 
 
 
 
Diary review/collection of 
completed pages 
 
X 
X 
 
X 
X 
X 
X 
X 
 
Diary completion 
===================================================================➔ 
 
11.7.1.1 
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Screening 
Treatment period A 
Wash 
out 
Treatment period B 
Follow-
up 
ET1 
 
References 
(protocol 
section) 
Visit 
1 
2 
(Baseline A) 
3 
 
 
4* 
(Baseline B) 
4a** 
(Baseline B) 
5 
 
6 
 
 
 
Day 
-21 (-7)*** 
to -1 
1 
8 
 
15 
V4 + 7 
Baseline B + 7 
V5 + 3 
Visit window (days) 
N/A 
N/A 
-1 to + 3 
 
±1 
±1 
-1 to + 3 
+4 
Trial products and 
randomisation 
 
 
 
 
 
 
 
 
 
 
Randomisation 
 
X 
 
 
 
 
 
 
 
9.3 
IMP dispensation 
 
X 
 
 
X 
X 
 
 
 
9.8 
IMP usea 
 
X 
X 
 
X 
X 
X 
 
 
9.2 
IMP return 
 
 
X 
 
 
 
X 
 
 
9.8 
Compliance control 
 
 
X 
 
 
 
X 
 
 
9.8.4 
Investigator assessments 
of efficacy 
 
 
 
 
 
 
 
 
 
 
UASprovo (incl. Time until 
sweating/whealing) 
Xb 
X 
X 
 
X* 
X 
X 
 
X 
11.3.1 
Physician’s global 
assessment by VAS 
 
X 
X 
 
X 
X 
X 
 
 
11.3.2 
Histamine SPT (wheal size 
+ pruritus VAS) 
 
X 
X 
 
X* 
X 
X 
 
 
11.3.3 
Patient assessments 
 
 
 
 
 
 
 
 
 
 
CholUAS7 
 
X 
X 
 
X 
X 
X 
 
 
11.3.4.3 
UCT 
X 
Xc 
Xc 
 
Xc 
Xc 
Xc 
 
 
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Screening 
Treatment period A 
Wash 
out 
Treatment period B 
Follow-
up 
ET1 
 
References 
(protocol 
section) 
Visit 
1 
2 
(Baseline A) 
3 
 
 
4* 
(Baseline B) 
4a** 
(Baseline B) 
5 
 
6 
 
 
 
Day 
-21 (-7)*** 
to -1 
1 
8 
 
15 
V4 + 7 
Baseline B + 7 
V5 + 3 
Visit window (days) 
N/A 
N/A 
-1 to + 3 
 
±1 
±1 
-1 to + 3 
+4 
DLQI 
 
X 
X 
 
X 
X 
X 
 
 
11.7.1.2 
CholU-QoLd 
 
X 
X 
 
X 
X 
X 
 
 
11.7.1.3 
Patient’s global assessment 
by VAS 
 
X 
X 
 
X 
X 
X 
 
 
11.3.4.1 
Safety and lab 
measurements 
 
 
 
 
 
 
 
 
 
 
Physical examination 
X 
X 
X 
 
X* 
X 
X 
X 
 
11.4.2 
Vital signs 
X 
X 
X 
 
X* 
X 
X 
X 
 
11.4.1 
ECG  
Xe 
Xf 
Xf 
 
Xf 
Xf 
Xf 
Xg 
 
11.4.3 
SARS-CoV-2 screeningh 
X 
X 
X 
 
X 
X 
X 
X 
 
11.4.5 
Serum pregnancy test 
(WOCB only) 
X 
 
 
 
 
 
 
 
 
11.4.4.1 
Urine pregnancy test 
(WOCB  only) 
 
X 
 
 
X* 
X 
 
X 
 
11.4.4.1 
Hepatitis B, C, and HIV 
X 
 
 
 
 
 
 
 
 
11.4.4.1 
Serum chemistry and 
haematology 
X 
 
X 
 
 
 
X 
X 
X 
11.4.4.1 
Adverse events 
X 
X 
X 
 
X 
X 
X 
X 
X 
13.2 
Skin biopsyi 
 
X 
X 
 
 
 
 
 
 
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Screening 
Treatment period A 
Wash 
out 
Treatment period B 
Follow-
up 
ET1 
 
References 
(protocol 
section) 
Visit 
1 
2 
(Baseline A) 
3 
 
 
4* 
(Baseline B) 
4a** 
(Baseline B) 
5 
 
6 
 
 
 
Day 
-21 (-7)*** 
to -1 
1 
8 
 
15 
V4 + 7 
Baseline B + 7 
V5 + 3 
Visit window (days) 
N/A 
N/A 
-1 to + 3 
 
±1 
±1 
-1 to + 3 
+4 
Blood sampling biomarkersj 
 
X 
X 
 
X 
X 
X 
 
 
11.6.1 
PK blood samplingk 
 
X 
X 
 
X 
X 
X 
 
 
11.5.1 
Photography of biopsy sitel 
 
X 
X 
 
 
 
 
 
 
11.7.2 
End of trial 
 
 
 
 
 
 
 
X 
X 
11.8 
 
1. In addition to the regular safety FU-visit (Visit 6) a shortened early termination visit (ET) should be performed as soon as possible after the last administration of 
the IMP, but not more than 3 days after the last use of the IMP for subjects prematurely withdrawn from trial for any reason. If no early termination visit can be 
performed within this time frame (i.e. within 3 days after the last use of the IMP), the safety follow-up visit should be performed as the last visit, only. 
* At visit 4, the subject will be required to demonstrate a UASprovo ≥ 3 (with a minimum wheal score of ≥ 1 and minimum itch score of ≥ 1) in order to progress to 
treatment period B. If the subject does not demonstrate a UASprovo ≥ 3, only assessment marked with * will be performed and an additional study visit will be 
scheduled (visit 4a) 7±1 days later.  
**Visit 4a is only performed if subject failed to demonstrate a UASprovo ≥ 3 at V4. If at visit 4a the subject demonstrates a UASprovo ≥ 3 then they will progress 
to treatment period B. If at visit 4a the subject does not demonstrate a UASprovo ≥ 3, then they will be terminated from the trial and an early termination visit will 
occur. 
*** The screening visit (visit 1) has to be conducted at least 7 days prior to the baseline visit (visit 2) to ensure a 7-day documentation of the ChloUAS (in the 
patient's diary) for calculation of the CholUAS7 at baseline visit (visit 2), and if applicable to respect a) a minimum interval of 7 days between two UAS 
provocation tests and/or ,b) a 1-week washout period for systemic antihistamines and/or medications with antihistamine properties. However, the use of topical 
antihistamines (e.g. with nasal sprays or eyedrops) for the treatment of concomitant allergies is allowed to be continued if applied in the standard prescribed dose. 
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a. First daily dose of IMP at visits under treatment (V2 to V5) will be administered on site, preferably in the 
 
b. Screening provocation test is optional if patients had a prior provocation test within 6 months of day 1 (visit 2). If subject fails to meet inclusion threshold during 
screening provocation test, then they are allowed one additional screening attempt. There should be at least 7 days between provocation tests, including between 
screening provocation test and visit 2 provocation test. 
c. UCT: Standard UCT has a recall period of 4 weeks. For screening, the standard UCT will be used. For visits 2-5, a modified UCT with a recall period of 7 days 
will be utilized.  
d. Chol-QoL: Standard Chol-QoL has a recall period of 2 weeks. For visits 2-5, a modified Chol-QoL with a recall period of 7 days will be utilized. 
e. At screening 3 consecutive ECGs will be measured and the average QTcF derived. 
f. One post-dose ECG will be performed 1h (±15 min) after the administration of the IMP on site to determine the theoretic maximum of QT-prolongation. For 
subjects who experienced a moderate or severe QT prolongation, the ECG should be repeated at respective visit(s) to confirm QT-prolongation. A subject may 
continue with the trial as long QT-prolongation does not exceed QTcF > 500 ms or a change in QTcF from baseline (pre-dose ECG) > 60 ms, 
g. For subjects who experienced a moderate QT prolongation (defined as 480 ms < QTcF ≤ 500 ms or 30 ms < change in QTcF from baseline (pre-dose 
ECG) ≤ 60 ms during the trial) an additional ECG should be made at safety follow-up (visit 6). 
h. SARS-CoV-2 test is required for all subjects at screening. At subsequent visits subjects will be monitored for SARS-CoV-2 infection signs and symptoms. If 
SARS-CoV-2 infection is suspected, a SARS-CoV-2 test should be performed. Subjects with confirmed SARS-CoV-2 infection will be managed in accordance 
with institutional guidelines and local requirements. 
i. Skin biopsies will be optional. Subject will sign an additional informed consent form. At visit 2, subjects will have a total of four 3 mm punch biopsies performed 
at 2 timepoints: 2 non-lesional skin biopsies (from an area, that usually develops wheal and flare upon provocation), taken prior to the provocation test and 2 
lesional skin biopsies taken after the provocation test. At visit 3, subjects will have two biopsies performed on non-lesional skin (from an area, that usually develops 
wheal and flare upon provocation) prior to the provocation test.  
j. Serum sampling for biomarker analysis at baseline visits (i.e. V2 and V4/4a) should be taken prior to the intake of the IMP and sampling at the end of treatment 
visits (i.e. V3 and V5) for each of the treatment periods should be done after the IMP intake. 
k. At visit 2 and visit 4/4a, PK blood samples should be taken approximately 
 after IMP intake at site. At V3 and V5, PK blood samples should be 
taken prior to administration of the IMP on site, and approximately 
 after administration of the IMP on site. 
l. Photography of the skin biopsy site will only be performed in patients who opt in for skin biopsies. 
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Abbreviations: ET – early termination visit; UASprovo – post-provocation Urticaria Activity Score, CholUAS7 - Cholinergic Urticaria Activity Score, UCT - 
urticaria control test, DLQI - dermatological quality of life index, CholU-QoL - cholinergic urticaria quality of life questionnaire, histamine SPT – histamine skin 
prick testing, VAS - visual analogue scale, WOCP – Woman of childbearing potential, HIV – human immunodeficiency virus, SARS-CoV-2 - Severe acute 
respiratory syndrome coronavirus 2, ECG – electrocardiogram, QTcF – Q-T corrected interval (by Fredericia), PK – pharmacokinetic IMP – investigational 
medicinal product. 
 
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5 Introduction and trial rationale 
5.1 Cholinergic urticaria  
Cholinergic urticaria (CholU) is a very frequent form of chronic inducible urticaria [1, 2]. 
CholU is defined by itching and whealing following the induction of sweating, either actively 
(e.g. exercise) or passively (e.g. hot bath, sauna). CholU is typically a disorder of young 
adults (~20 - 30 years old) with a high prevalence in the age group of 26 to 28 years (up to 
20%) [2]. CholU patients typically develop pruritic, pinpoint-sized, transient wheals with 
large flare reactions commonly localized to the limbs and the trunk a few minutes after the 
onset of sweating. The wheals in CholU patients are extremely itchy. In some patients, 
emotional stress, hot and spicy food, and hot beverages can also elicit symptoms. Usually, 
skin lesions last for 15 to 60 minutes. CholU is often associated with atopy [2, 3] and 
bronchial hyper-responsiveness [4]. 
CholU is a histamine-driven chronic inflammatory disease involving mast cells, basophils, 
and eosinophils. Several recent studies suggest that CholU may be an allergy to components 
of human sweat. First, CholU patients show immediate-type hypersensitivity reactions to their 
own diluted sweat after intradermal injections [5]. Second, basophils from CholU patients 
react to autologous sweat and release high amounts of histamine in vitro [6]. Finally, CholU 
patients, but not healthy controls, express immunoglobulin E (IgE) to sweat antigens [7]. 
5.2 Experience with investigational medicinal product 
LEO 152020 is a selective, oral histamine H4 receptor (H4R) antagonist with expected dual 
anti-pruritic and anti-inflammatory effects, and is being developed to be offered as an oral 
treatment option for atopic dermatitis (AD) [8]. 
LEO 152020 has been tested preclinically in various in vitro models and have shown 
 
 In functional assays, LEO 152020 has been 
characterized as a 
 of the H4R. 
As LEO 152020 is still at an early stage of development only non-clinical and limited clinical 
data are available. 
Non-clinical studies have demonstrated that LEO 152020 appears to be safe considering a 
 
 and adequate safety margins have been established. The 
important potential risks and the safety concerns included in the following sections are based 
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on the knowledge of the available nonclinical data and clinical single-ascending dose 
(SAD)/multiple-ascending dose (MAD) data, as well as events observed with other H4R 
antagonists [8]. 
One first-in-human clinical trial containing SAD and MAD parts with overall 88 subjects was 
completed. Emerging tolerability issues were observed in the 
 
cohort (highest dose tested), 
 and 
 
 cohort. These consisted of mild (grade 1) and transient gastrointestinal adverse 
events (primarily nausea, abdominal distention, and diarrhea) and nervous system disorders 
(dizziness - grade 1). All events mentioned above occurred rapidly after dosing and the 
majority of events resolved within 1 to 3 hours. These adverse events were not considered a 
safety concern. Of note, no tolerability issues were observed in 
 
cohort, in 
 cohort, in 
 cohort, or in 
any lower dose cohorts. The potential risk of QT prolongation (delay of cardiac 
repolarization) was identified based on nonclinical and clinical data. In the data from the SAD 
segment, the predicted mean and 90% CI ΔΔQTcF (Q-T corrected interval by Fredericia) 
obtained from concentration-QTcF analysis, at each dose Cmax geometric means, showed that 
the prolongation in QTcF was above the threshold of regulatory concern of 10 msec 
(Guideline ICH E14) from the doses of 
. At 
 the mean ΔΔQTcF 
was around 
 Therefore, it can be concluded that up to the dose of 
 
mg, the upper bound of the 90% CI for ΔΔQTcF was below the threshold of regulatory 
concern of 10 msec. However, for the doses 
 and 
 mg, both the mean ΔΔQTcF and the 
90% CI upper bound were 
. 
Safety precautions such as additional ECG monitoring and exclusion of subjects with known 
cardiac arrhythmia risk factors, exclusion of subjects with renal and hepatic impairment, 
exclusion of concomitant medication with known QT-prolongation effects as well as 
prohibition of concomitant medications that are inhibitors of the permeability glycoprotein (P-
gp) and Breast cancer resistance protein (BCRP) transporters and the strong OAT3 (organic 
anion transporter 3) inhibitor probenecid, which may increase systemic exposure of LEO 
152020 will be implemented for the clinical trials and therefore the dose of 
 is 
considered acceptable to be administered (for further information please refer to the 
investigator’s brochure (IB) [8]). 
 
 
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5.3 Trial rationale 
Histamine exerts its inflammatory effects by acting on its receptors. Both H1 receptors (H1R) 
and H4 receptors (H4R) have important roles in the progression and modulation of histamine-
mediated allergic and inflammatory diseases. The first line treatment options in CholU are 
avoidance of eliciting triggers and the daily use of non-sedating H1 antihistamines. However, 
many CholU patients do not achieve disease control with these measures [9]. Updosing of 
H1-antihistamines, the guideline-recommended treatment of choice in these patients, is only 
moderately effective. 
Antagonists that target H4R have shown promising effects in preclinical and clinical studies 
in the treatment of several allergic and inflammatory diseases [10]. 
H4R activation mobilizes intracellular calcium to prime mast cells for activation and 
degranulation [11]. H4R activation also upregulates the expression of high-affinity receptor 
for the Fc region of immunoglobulin E (FcεRI) on mast cells, further priming them for 
allergen-induced activation. In CholU, skin mast cells are activated to degranulate, at least in 
part, via FcεRI and IgE to autoallergens [5, 6].  
Eosinophils express H4R on their surface and histamine, acting via H4R, enhances the 
migration of eosinophils. Eosinophil shape change is a necessary process for chemotaxis to 
occur. Histamine and selective H4R agonists were shown to induce the shape change of 
eosinophils, an effect that is blocked by selective H4R antagonists [12, 13]. Skin biopsies of 
CholU lesions show histologic characteristics identical with those of other forms of urticaria 
including the presence of eosinophils in and around the walls of superficial subpapillary 
dermal vessels [14]. 
H4R may be involved in the pathogenesis of allergy and inflammation by activating Th2 (T 
helper cells) pathways. H4R is preferentially expressed in Th2 cells over naive T cells and 
Th1 cells [15]. Recent findings have shown that activation of H4R by histamine stimulates the 
synthesis of the Th2 cytokines IL-4 and IL-5 in mast cells [11]. Chronic urticaria is 
characterized by the emergence of Th2-type cytokines, including IL (interleukin)-4, IL-5, IL-
25, IL-33, and thymic stromal lymphopoietin (TSLP), which favour antibody isotype class 
switching to IgE, along with the presence of eosinophils and mast cells [16]. Patients with 
CholU exhibit increased levels of IgE [17] as well as increased numbers of skin mast cells and 
eosinophils [14].  
Results from a pilot study on the characterization of lesional and non-lesional skin of CholU 
for the expression levels of all four histamine receptors suggest that H4R is markedly 
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upregulated in the skin of CholU patients as compared to healthy controls (data from 
 
). Several independent lines of evidence support 
the notion that the use of an H4R antagonist is an effective treatment option for patients with 
CholU. 
5.4 Ethical considerations  
This clinical trial will be conducted in accordance with the ethical principles originating from 
the Declaration of Helsinki [18] and ICH GCP [19] and in compliance with the approved 
protocol and applicable regulatory requirements. 
The trial design is considered scientifically justified and adheres to ethical standards ensuring 
the rights, safety, and well-being of the subject. The efficacy and safety of LEO 152020 will 
be evaluated in adults with CholU who may benefit from treatment with LEO 152020. 
For this very early phase evaluation of clinical efficacy an intra-individual comparison has 
been chosen requiring much fewer participants to potentially detect a statistically significant 
difference between treatments than a trial with inter-individual comparison of treatments. 
Only adult subjects aged at least 18 years will be included in the trial. Pregnant or 
breastfeeding women and women trying to become pregnant will not be enrolled in this 
clinical trial. Men and women of child-bearing potential have to agree to use a double method 
of contraception to prevent pregnancy during the clinical trial and until at least 3 days after 
discontinuation of treatment with the IMP. In addition, all females will have a pregnancy test 
performed before, during and at the End of Trial to ensure that no fetuses are exposed to the 
IMP. In accordance with the current version of ICH and GCP guidelines, qualified medical 
personnel will readily be available to advise on trial related medical questions. Medical 
monitoring will be conducted throughout the trial. Safety data will be reviewed by qualified 
personnel to ensure that prompt action is taken, if needed to protect the subject. 
5.5 Benefit/risk assessment 
The first line treatment for chronic urticarias, such as CholU, is standard dose as to marketing 
authorization second generation H1 antihistamines, however the majority of patients fail to 
achieve disease control. Even with increased doses up to four times standard dose H1 
antihistamines (second line treatment), a large portion of chronic urticaria patients will not 
control symptoms, and therefore there is a clear unmet need for a safe, efficacious treatment 
option for subjects with CholU. As a novel oral H4R antagonist, LEO 152020 is expected to 
be efficacious against both wheal formation and pruritus caused by CholU. 
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Other treatment options especially for patients unresponsive to 2nd generation H1 
antihistamines include omalizumab (recommended as third line treatment) and 
immunosuppressives (e.g. Ciclosporin A, recommended as fourth-line treatment only, due to 
the higher incidence of adverse effects of Ciclosporin A, when compared to 2nd generation H1 
antihistamines). As both of these treatment options are not considered as a standard of care for 
different reasons, and due to the short duration of the treatment with LEO 152020, the use of 
LEO 152020 is considered justified in light of a possible future treatment option for subjects 
with CholU. This is especially true given that H4R antagonists have already shown promising 
effects in the treatment of various allergic and inflammatory diseases in preclinical and 
clinical studies. Therefore, it seems to be also reasonable to assume that patients will have a 
potential benefit from their participation in the study, even if they have no other treatment 
option for the duration of the trial. 
Risks to subjects in the trial will be minimized by inclusion of subjects fulfilling all eligibility 
criteria (Sections 8.2 and 8.3) and by close clinical monitoring. Discontinuation and 
withdrawal criteria are also in place (Section 10.2). All subjects will receive both active and 
placebo during this cross-over trial. Active treatment with LEO 152020 at the proposed dose 
regimen is expected to have a therapeutic effect (based on biomarker analysis in the first in 
human trial with LEO 152020 [8] and modelling of data from a clinical trial with Adriforant 
[20]). 
Blood sampling presents the same low risk as normally associated with this procedure (i.e. 
infection, bleeding into the surrounding tissue, and, very rarely, inflammation of the vein or 
formation of blood clots). Blood sampling will only be conducted by qualified medical 
personnel. 
Subjects who consented to skin biopsies may experience discomfort associated with the 
collection of the samples. To minimize discomfort, the subject will receive an injection of a 
local anesthetic to numb the area where the biopsy will be taken. Subjects who have 
previously had reactions to an aesthetic medication will not be included in this component of 
the trial. Complications of skin biopsies may include bleeding, infection, bruising and/or pain 
at the biopsy site. Pressure dressings and ice may be used to help alleviate these symptoms. 
Wound healing at the biopsy site will be checked at a subsequent visit and sutures removed as 
needed. The subject will be informed that they may retain small scars after the procedure. 
Due to the important potential risk of QT prolongation, the choice of dose regimen explored 
in this trial was guided by modelling exposure vs. QTcF observed in the first in human trial 
with LEO 152020. Based on this modelling, the mean increase in QTcF as a result of 
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treatment with LEO 152020 
 is expected to be below regulatory and safety 
concern. To further ensure subject safety, subjects at cardiac arrhythmia risk and subjects with 
renal and hepatic impairment will be excluded from participation in the trial (Section 8.3). 
Moreover, medications for which QT prolongation is a known side effect and medications 
known to inhibit the BCRP and/or P-gp transporters and the strong OAT3 inhibitor probenecid 
will be prohibited during the trial. Subjects undergoing treatment with these and not able to 
replace them by safe alternative medication(s) will be excluded from participation in the trial. 
Finally, frequent ECG monitoring will be conducted with pre- and/or post-dose ECGs 
measured at the sites and evaluated centrally (Section 11.4.3). ECG measurements will be 
combined with measurements of LEO 152020 plasma concentration at Cmax to further 
evaluate the relation between exposure to LEO 152020 and potential QT prolongation at 
therapeutic doses in subjects with CholU. With the above provisions in place, the risks 
associated with participating in the trial are considered low and outweighed by the benefit of a 
potential future oral treatment option for CholU. The current risk profile is therefore deemed 
in favor of continued development of LEO 152020, however the investigators will always 
have the opportunity to contact the responsible CRA in case of any medical questions or 
concerns. If deemed necessary, the CRA will immediately reach out to the appropriate persons 
at LEO Pharma for medical support and further clarification. 
Participation in clinical trials may currently be associated with increased risks and challenges 
due to the COVID-19 pandemic caused by SARS-CoV-2. Based on non-clinical studies, 
LEO 152020 is considered a mild immunomodulatory compound and its mechanism of action 
is not believed to present a risk of a decreased antiviral immunity in subjects infected by 
COVID-19. In addition, LEO 152020 is not believed to increase the susceptibility of the 
subject to contract COVID-19 or other infections. However, a risk of exposure to infected 
people cannot be excluded as the subject may enter public areas (e.g. commute to the trial 
site) and have human contacts (e.g. with the site staff). Therefore, risks must appropriately be 
assessed, and mitigation measures taken to protect the subject and site staff and to ensure the 
integrity of the trial data. 
Both EMA and FDA as well as national health authorities in Europe have issued new 
guidelines aiming at providing recommendations for conduct of clinical trials during the 
COVID-19 pandemic [21-23] . Given the potential for the pandemic situation to relapse in 
relation to spread of COVID-19 in the future, special attention will be paid to protecting 
subjects and site staff involved in the trial against infection with SARS-CoV-2. 
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During the trial, the investigators will be trusted to take appropriate action to ensure 
individual subject safety according to the recommendations and preventive measures issued 
by their local authorities.  
Mitigation measures that are currently planned to be implemented in this clinical trial in case 
of an escalation of pandemic situation are detailed in a separate document (“Mitigation 
Measures due to COVID-19 Pandemic”), that will be part of the submission package send to 
the relevant Ethics Committee and the Competent Regulatory Authority for approval. 
As a result of the ongoing risk evaluation, further mitigation measures may come into force, 
resulting in an update of the above-mentioned document. If additional mitigation measures 
require approval, a substantial amendment will be submitted to the relevant Ethics Committee 
and the Competent Regulatory Authority and will not be implemented until approved. 
Exceptions to this are amendments made to eliminate immediate hazards to the patients 
(“urgent safety measures”). In this case the relevant Ethics Committee and the Competent 
Regulatory Authority will be notified about changes as soon as possible considering national 
and local circumstances. 
6 Trial objectives and endpoints 
The primary objective of EXP-2177 will be to evaluate the efficacy of LEO 152020 compared 
with placebo in patients with CholU. The choice of efficacy as the primary objective is 
supported by the completion of a first in man Phase 1 study demonstrating the safety of 
LEO 152020 at the proposed dosage. The secondary objective of this trial will be to evaluate 
the safety and tolerability of LEO 152020 compared with placebo in patients with CholU. 
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Panel 3: Objectives and endpoints 
Objectives 
Endpoints 
Primary objective 
 
To explore the efficacy of 
LEO 152020 compared with placebo 
in patients with CholU. 
 
Time frame: baseline of each treatment period to end of 
each treatment period 
Primary efficacy endpoint 
• 
Change from baseline in post-provocation Urticaria 
Activity Score (UASprovo) 
Other/exploratory efficacy endpoint(s) 
Secondary objective(s) 
 
To evaluate the safety of LEO 152020 
compared with placebo in patients 
with CholU. 
Secondary endpoint 
• 
Number of treatment emergent adverse events 
(TEAE) per subject.  
 
Time frame: start treatment period to 3 days after end 
treatment period 
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Objectives 
Endpoints 
Other/exploratory objectives 
 
To explore the expression of 
biomarkers of LEO 152020 compared 
with placebo in patients with CholU. 
Other/exploratory endpoint(s) 
To explore the pharmacokinetics of 
LEO 152020 in patients with CholU. 
Other/exploratory endpoint(s) 
 Abbreviations: CholU - cholinerge urticaria, UASprovo – post-provocation Urticaria Activity Score, CholUAS7 
- Cholinergic Urticaria Activity Score, UCT - urticaria control test, DLQI - dermatological quality of life index, 
CholU-QoL - cholinergic urticaria quality of life questionnaire, histamine SPT – histamine skin prick testing, 
VAS - visual analogue scale 
 
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7 Trial design 
7.1 Overall trial design  
EXP-2177 is a phase 2a, randomised, double-blind, placebo-controlled, multi-centre, cross-
over trial conducted in Germany. The cross-over trial design is considered optimal to ensure 
clear evaluation of the drug effects, including safety and efficacy. Subjects will be 
randomised, stratified by site to one of two treatment sequences:  
• Sequence 1) LEO 152020 
 during treatment period A and placebo 
 during treatment period B,  
• Sequence 2) Placebo 
 during treatment period A and LEO 152020 
 
 during treatment period B.  
Each treatment period will last 7 days. The placebo will serve as reference in evaluating 
efficacy and safety of LEO 152020. The cross-over trial design minimizes the sample size 
needed for the primary endpoint.  
The trial will consist of three distinct parts as outlined below: 
• Screening phase, day -21 to day -1: Duration of up to 3 weeks in which patients who have 
given informed consent are assessed for study eligibility. Subjects will have an initial wash-
out period from H1 histamines of 7 days (day -7 to -1). 
• Treatment phase: 
- 
Treatment period A: 
At visit 2 (randomisation; baseline of treatment period A) following confirmation of 
subject’s eligibility, baseline assessments will be conducted, and subjects will be 
randomised. Subjects will start the first treatment period (LEO 152020 
 or 
Placebo 
) of 7 days at visit 2, first dose on site, preferably in the 
 and last 
dose on 
 of visit 3 at the site. 
- 
Washout period of 7 ± 1 days 
- 
Treatment period B: 
After confirmation of eligibility, subjects will start the second treatment period (Placebo 
 or LEO 152020 
) of 7 days at visit 4/4a (baseline of treatment period 
B), first dose on site at visit 4/4a, preferably in the 
 and last dose on 
 
of visit 5 at the site. 
• Safety follow-up: Safety assessments will be performed 3 days after last IMP dose. 
Each part is associated with evaluations and procedures that must be performed at specific time 
points as described in the following sections and Panel 2. 
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If necessary, an unscheduled visit can be performed at any time and for any reason at the 
discretion of the investigator. Assessments to be performed during an unscheduled visit will 
depend on the reason why this visit is performed. 
7.1.1 Screening phase (Days -21 (-7) to -1) 
During the screening phase, the subjects’ eligibility to enter the clinical trial will be 
confirmed. At visit 1 (screening) laboratory samples will be collected and electrocardiogram 
(ECG) measurements will be performed. A standardized physical exercise provocation (pulse-
controlled ergometry [PCE]) for UASprovo assessment will be performed if the subjects had 
not a prior provocation test within the last 6 months. In case the subject fails to meet the 
inclusion threshold of the UASprovo, they are allowed one additional attempt after at least 7 
days. In general, there should be at least 7 days between provocation tests including between 
screening provocation test and visit 2 provocation test. 
At the latest, subjects will be provided with a diary 7 days prior to the baseline visit (Visit 2) 
and will be instructed to complete assessments for the CholUAS7 on a daily basis. Subjects 
will have to stop treatment with systemic H1 antihistamines and/or systemic drugs with 
antihistamine properties (if applicable) at the start of the initial washout period (day -7 to -1). 
Application of topical antihistamines for the treatment of concomitant allergies is allowed to 
be continued, if applied in the standard prescribed dose. All procedures will be performed as 
specified in Panel 2. 
7.1.2 Treatment phase (Visit 2 (Day 1) to Visit 5) 
The treatment phase comprises the randomisation visit, and two subsequent treatment periods 
separated by a 7-day wash-out period. At the start of the treatment phase, subjects will be 
randomised at visit 2 (day 1, baseline treatment period A) to either LEO 152020 
 
or placebo in treatment period A in a 1:1 manner. Subjects will then receive the opposite 
treatment (Placebo or LEO 152020 
) in treatment period B. 
Treatment period A 
7.1.2.1 Visit 2 (Day 1, Randomisation) = Baseline for treatment period A 
Inclusion/Exclusion criteria will need to be confirmed, in particular the UASprovo assessment 
and the check of subject’s diary to confirm compliance with trial instructions. After 
confirmation of the eligibility visit 2 assessments as specified in Panel 2 and Panel 6 
(sequence of assessments) will be performed. Subjects will be randomised and administer first 
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dose of IMP of day 1 at site, preferably in the 
 After 
 minutes ECG recording 
and PK sampling will be conducted. 
7.1.2.2 Visit 3 (Day 8, -1 to +3) 
Subjects will take the last dose of IMP in treatment period A in the 
 of visit 3 at site. 
Before IMP intake PK sampling will be performed. 
minutes after IMP administration 
ECG recordings and further PK sampling will be conducted. Other trial assessments will be 
performed as specified in Panel 2 and Panel 6. IMP will be returned, and the diary will be 
checked. 
Treatment period B 
7.1.2.3 Visit 4 (Day 15 ± 1)/ Visit 4a (Day 22 ±1) = Baseline for treatment 
period B 
After a wash out period of 7 ± 1 days, subjects will be tested for eligibility for start of 
treatment period B. Specific procedures will be performed as detailed in Panel 2 and Panel 6. 
The histamine SPT and UASprovo should be performed first before intake of first IMP for 
treatment period B. Subjects who fail to demonstrate a UASprovo ≥ 3 (with a minimum wheal 
score of ≥ 1 and minimum itch score of ≥ 1) will be required to attend an additional visit (visit 
4a) 7±1 day later. All further procedures planned for V4 will only be conducted if the subject 
is eligible for treatment period B. In case visit 4a has to be scheduled, some procedures of the 
visit 4 as specified in Panel 2 will be cancelled. At V4a the UASprovo will be assessed again. 
If subjects fail to demonstrate a UASprovo ≥ 3 (with a minimum wheal score of ≥ 1 and 
minimum itch score of ≥ 1), they will be terminated from the trial and an early termination 
visit will be performed. 
For eligible subjects all remaining procedures as specified in Panel 2 will conducted and IMP 
for treatment phase B will be distributed. Subjects will administer first dose of IMP on visit 4 
or visit 4a, respectively, at site, preferably in the 
 
7.1.2.4 Visit 5 (Baseline for treatment period B + 7 Days, -1 to +3) 
Subjects will take the last dose of IMP in treatment period B in the 
 of visit 5 at site. 
Before IMP intake, PK sampling will be performed. 
 minutes after IMP administration 
ECG recordings and further PK sampling will be performed. Other trial assessments will be 
performed as specified in Panel 2 and Panel 6. IMP will be returned, and the diary will be 
returned and checked. 
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7.1.3 Visit 6 - Safety Follow-up (Visit 5 +3 (+4) Days) / End of Trial 
A safety follow-up visit will be performed as end of study visit 3 days after last dose of IMP. 
Assessments will be conducted as detailed in Panel 2. Subjects who discontinue the study 
early should be requested to return for an early termination / end of treatment visit (see also 
Section 10.3) in addition at the time of the decision to withdraw from the study. 
Any serious adverse events (SAEs) will be followed up as specified in Section 13.7. 
7.2 Number of subjects needed 
A total of 28 subjects will be randomised in the trial. An expected screening failure of 10% 
and an expected attrition rate of 10% is assumed.  
This trial will be conducted at approximately 3-6 sites in Germany. 
The statistical power considerations for this sample size are described in Section 14.1. 
7.3 End of trial definition 
A subject is considered to have completed the trial if they have completed all periods of the 
trial including the safety follow-up visit (visit 6). 
The end of the trial is defined as the date of the last visit of the last subject in the trial. 
Final collection of data for the primary endpoint occurs at visit 5. 
8 Trial population  
8.1 Subject eligibility 
The investigator should only include subjects who meet all eligibility criteria, are not put at 
undue risk by participating in the trial and can be expected to comply with the protocol.  
The subject’s eligibility for the clinical trial must be verified according to the inclusion and 
exclusion criteria at visits specified in Panel 2. It will be recorded in the electronic case report 
form (eCRF) if the subject has met all the inclusion criteria and none of the exclusion criteria. 
Any implementation of national requirements/law for the subject’s participation in the clinical 
trial will be ensured and described in submission documentation to regulatory authorities and 
IECs, as applicable.  
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8.2 Inclusion criteria 
For inclusion into this trial, subjects must fulfil all of the following criteria: 
1. Signed and dated informed consent has been obtained prior to any protocol-related 
procedures. 
2. Subject with a history of CholU diagnosis for ≥ 6 months (based on medical records). 
3. Subject has active and uncontrolled CholU disease at the time of screening and 
randomisation, as defined by the following: 
a. Urticaria control test (UCT) < 12 at screening 
b. UASprovo ≥ 3 (with a minimum wheal score of ≥ 1 and minimum itch score of 
≥ 1) at screening* and randomisation 
i. *Screening provocation test is optional if patients had a prior 
provocation test that met threshold within 6 months of day 1 (visit 2) 
4. Age 18 or older 
5. Patients must not have more than one missing diary entry in the 7 days prior to 
randomisation. 
6. Recent history (within 6 months of screening) with documented inadequate response 
to standard dose as to marketing authorization of H1 antihistamines  
7. Female subjects of childbearing potential* must use a double contraception i.e. 
a highly effective** plus a barrier*** form of birth control throughout the trial from 
screening until follow-up visit. 
* A woman of childbearing potential (WOCBP) is defined as a female subject aged 
≥12 years old or a younger girl who, at the discretion of the investigator, is deemed to 
be of reproductive potential. A woman is defined as not being of childbearing potential 
if she is postmenopausal (at least 12 months with no menses without an alternative 
medical cause prior to screening), or surgically sterile (hysterectomy, bilateral 
salpingectomy, or bilateral oophorectomy). 
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**A highly effective method of birth control is defined as one which results in a low 
failure rate (less than 1% per year) such as bilateral tubal occlusion, intrauterine 
device (IUD), intrauterine hormone-releasing system (IUS), combined (estrogen and 
progestogen containing) hormonal contraception associated with inhibition of 
ovulation (oral, intravaginal, transdermal), progestogen-only hormonal contraception 
associated with inhibition of ovulation (oral, injectable, implantable), sexual 
abstinence (when this is in line with the preferred and usual life style of the subject 
and not just being without a current partner), vasectomised partner (given that the 
subject is monogamous and that the vasectomised partner has received medical 
assessment of the surgical success). 
*** barrier method such as male condom with spermicide, female condom with 
spermicide, over-the-counter sponge with spermicide, cervical cap with spermicide, 
diaphragm with spermicide. 
8. Male subjects with a female partner of childbearing potential must use adequate 
double contraceptive methods (barrier such as male condom with spermicide, female 
condom with spermicide, over-the-counter sponge with spermicide, cervical cap with 
spermicide, diaphragm with spermicide in conjunction with a highly effective form of 
female contraception for the partner), from randomisation to follow-up visit. 
8.3 Exclusion criteria 
Subjects must not enter the trial if they fulfil any of the following exclusion criteria:  
1. Other clearly dominating forms* of urticaria as aetiology for wheal and flare type 
reactions, including: 
a. Chronic spontaneous urticaria 
b. Inducible urticaria: urticaria factitia / symptomatic dermographism, cold-, heat-, 
solar-, pressure-, vibratory-, aquagenic-, or contact-urticaria 
*These diseases are allowed as comorbidities, if cholinergic urticaria is the dominating 
form of chronic urticaria 
2. Clinically significant infection within 4 weeks prior to randomisation that may 
compromise the safety of the subject  
3. History of lymphoproliferative disease or any known malignancy or history of 
malignancy (except for treated non-melanoma skin cancer or treated cervical 
carcinoma in situ) within the past 5 years 
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4. Risk factors for Torsades de Pointe including: 
a. Uncorrected hypokalemia, hypocalcemia or hypomagnesemia, history of cardiac 
failure, or history of clinically significant/symptomatic bradycardia 
b. (Congenital) long QT syndrome or family history of idiopathic sudden death  
c. Concomitant medication(s) with a known risk of Torsades de Pointe that cannot be 
discontinued or replaced by safe alternative medication 
d. Other cardiac arrhythmia risk factors at the discretion of the investigator 
5. Use of concomitant medication for which QT prolongation is a known side effect and 
which cannot be discontinued or replaced by (a) safe alternative medication(s) within 
5 half-lives prior to screening 
6. Resting QTcF (average of a triplicate measurement) < 300 msec or > 450 msec at 
screening  
7. Known history of ventricular arrhythmias 
8. Second- and third-degree atrioventricular block 
9. Subjects with signs of renal impairment as determined estimated glomerular filtration 
rate (eGFR) levels below 90 mL/min at screening. 
10. Subjects with signs of hepatic impairment as determined by abnormal liver function 
tests, defined as total bilirubin, aspartate aminotransferase or alanine aminotransferase 
>1.5 x the upper limit of normal (ULN) range, at screening. 
11. Infection with human immunodeficiency virus (HIV) 
12. Presence of hepatitis B or C infection, defined as: Positive hepatitis B surface antigen 
(HBsAg), or hepatitis B core antibody (anti-HBc), or hepatitis C virus antibody 
serology at screening. Subjects with positive anti-HBs are eligible provided that they 
have a negative HBsAg and negative HBc (blood pattern in vaccinated subjects). 
13. Subjects with confirmed active infection with SARS-CoV-2 AND related COVID-19 
symptoms, which at the discretion of the investigator will jeopardize the safety of the 
subject or the integrity of the data collected. Additionally, any local requirements must 
be followed. 
14. Any medication known to chronically alter drug absorption or elimination processes 
within 30 days prior to the first dose of IMP. 
15. Systemic immunosuppressive medications (e.g. Methotrexate, Cyclosporine, 
Azathioprine) within 4 weeks prior to screening and throughout the trial. 
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16. Systemic corticosteroids within 4 weeks prior to screening and throughout the trial 
(Note: Inhaled or intranasal steroids equivalent to doses up to 1 mg prednisone daily is 
allowed). 
17. Drugs which are known inhibitors of the P-gp and BCRP transporters as well as the 
strong OAT3 inhibitor probenecid within 1 weeks prior to randomisation or 5 half-
lives (whichever is longer) and throughout the trial. 
18. Systemic drugs (e.g. oral drug) with antihistamine properties including H1 
antihistamines and some antidepressants (e.g. tricyclic antidepressants) and H2 
antihistamines 1 week prior to randomisation and throughout the trial. However, 
topical antihistamines in the form of nasal spray and eyedrops are allowed in the 
standard prescribed dose. 
19. Use of tanning beds or phototherapy (narrow band ultraviolet B [NBUVB], ultraviolet 
B [UVB], ultraviolet A1 [UVA1], psoralen + ultraviolet A [PUVA]) within 4 weeks of 
screening and throughout the trial. 
20. Known or suspected hypersensitivity to any component(s) of the IMP or to a drug of a 
similar chemical class. 
21. Known hypersensitivity to iodine 
22. Current participation in any other interventional clinical trial. 
23. Treatment with any non-marketed drug substance (that is, an agent which has not yet 
been made available for clinical use following registration) within 5 half-lives or last 3 
months, whichever is longer. 
24. Previously randomised in this clinical trial. 
25. History of chronic alcohol or drug abuse within 12 months prior to screening, or any 
condition associated with poor compliance as judged by the investigator. 
26. Employees of the trial site or any other individuals directly involved with the planning 
or conduct of the trial, or immediate family members of such individuals. 
27. Subjects who are legally institutionalised. 
28. Female subject who are pregnant or lactating. 
29. Any unstable medical, surgical, psychiatric, or additional physical disorder* at any 
time during the trial and which according to investigator’s opinion could: 
• Affect subject safety and well-being or put the subject at risk because of their 
participation in the trial.  
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• Influence the findings of the trial. 
• Impede the subject’s ability to complete the trial. 
*Examples include but are not limited to cardiovascular, gastrointestinal, hepatic, 
renal, neurological, musculoskeletal, infectious, endocrine, metabolic, haematological, 
immunological, and psychiatric disorders and major physical impairment. 
30. Any clinically significant abnormal finding at screening and/or baseline which according 
to investigator’s opinion may:  
• Affect subject safety and well-being or put the subject at risk because of their 
participation in the trial. 
• Influence the results of the trial.  
• Influence the subject’s ability to complete the trial. 
The abnormal finding must be clinically significant and observed during the screening 
period. Examples include abnormal findings in physical examination, vital signs, 
electrocardiogram (ECG) (based on the central ECG report provided by the ECG 
vendor), haematology, clinical chemistry, or urinalysis. 
8.4 Screening and screening failures 
Subject identification number 
Trial participation begins once written informed consent is obtained. Refer to Appendix 3B 
for details on the informed consent process. Once informed consent is obtained, subjects will 
be assigned to ascending subject identification numbers (subject ID) in the order of their 
appearance at Screening and the screening evaluations to assess eligibility criteria may begin. 
The subject ID will be automatically generated by the eCRF system. The generation and 
composition of the subject ID will be described in the Completion Guide for the eCRF. The 
date of first screening activity could be on the same day or a later date than the informed 
consent was signed. The subject ID will be used to identify the subject during the screening 
process and throughout trial participation, if applicable. Subjects who have given written 
informed consent to participate in the trial and who have been assigned a subject ID are 
considered ‘screened’ subjects. The investigator will maintain a log of all consented subjects 
at the trial site (subject identification list) including subjects who are not randomised in the 
trial/ treatment assigned. This log will include each subject’s identity, date of consent and 
corresponding subject ID so that any subject may be identified if required for any reason. The 
date of screening and the status (screening failure or randomised) should also be documented. 
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The log must not be copied or retained by LEO Pharma. All subjects who signed the informed 
consent form must be entered into the eCRF. 
In addition, the investigator will maintain a log of all subjects considered for screening, 
whether they have provided written informed consent or not (pre-screening log). This log will 
be anonymous and will include the reason(s) for not entering the trial, if applicable, or the 
allocated subject ID. 
Screening failures 
Screen failures are defined as subjects who consent to participate in the trial but are not 
subsequently [randomly] assigned to trial treatment. A minimal set of screen failure 
information is required to ensure transparent reporting of screen failure subjects to meet the 
Consolidated Standards of Reporting Trials (CONSORT) publishing requirements  and to 
respond to queries from regulatory authorities. As a minimum, the following data will be 
collected in the eCRF 
 for screen failures: 
• Date of informed consent(s). 
• Demographics (age [year of birth], sex, race). 
• Reason for screen failure. 
• Failure to meet eligibility criteria for randomisation 
• Date of screen failure. 
• Any adverse events (AEs) and serious AEs (SAEs). 
• End of trial form (including other reasons for non-participation, if applicable) 
 
In case of any SAEs, these must be followed-up as described in Section 13.7. 
Re-screening of screening failures is allowed once if deemed appropriate by the investigator 
e.g. in case of highly abnormal and obviously wrong laboratory values, due to logistical 
reasons or once due to missed UASprovo threshold. At re-screening a new subject ID will be 
assigned. 
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9 Treatments 
9.1 Trial product description 
Panel 4: Identification of investigational medicinal products 
Investigational 
medicinal product 
Dosage form 
Active ingredient 
and concentration 
Manufacturer responsible for 
batch release 
LEO 152020 
mg 
film-coated tablets 
Film coated 
tablet 
LEO 152020 
 
 
 
 
  
LEO Pharma A/S,  
Placebo film-coated 
tablet 
Film coated 
tablet 
Not applicable 
LEO Pharma A/S,  
 
9.2 Administration of investigational medicinal product 
LEO 152020 or placebo will be administered orally for 7 days each during treatment period 
A and B according to the following dosing regimens: 
• LEO 152020 
 
• Placebo 
 
The subject will be asked to take  tablets orally: 
 
 The IMP will be dispensed to the subject according to the schedule of trial 
procedures (Panel 2). During the respective treatment period, the subject will be asked to self-
administer the IMP. Doses of IMP will be taken at the site or at the subject’s home as 
explained below. 
First administration in each treatment period (A and B) will take place during patient’s visits 
at site, preferably in the 
 If visits are performed in the afternoon, the next following 
dose need to be at least 9 hours after the previous dose. If this is not possible on the same 
days, the next administration will be the 
 dose on the next day. On the days planned 
for the study visits (visit 3 and visit 5, respectively), the subject must not take the 
 
dose at home. The last administration in each treatment period (A and B) will be done on site 
during these visits.  
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As the administration of the IMP on site should be done under fasting conditions, subjects 
should already be instructed at their screening visit to avoid food intake 2 hours prior to the 
scheduled IMP administration on site (visit 2 to visit 5). 
The remaining doses will be administered by subjects themselves at home without regard to 
dietary intake (i.e. fasting or fed condition). 
Administration of the IMP at the site 
Visits should be scheduled at times to make the fasting requirements and minimum time of 9 
hours between consecutive doses of IMP feasible for the subject. At each visit, before the 
subject takes the IMP, the trial staff should clarify with the subject when they took their last 
dose of IMP before the visit and when they had their last food intake. 
•   If the subject took their last dose of IMP more than 6 hours prior to the visit, they may take 
the planned dose of IMP at the clinic. 
•   If the subject took what would be considered their 
 dose of IMP less than 6 hours 
prior to the visit the next 
 this should be documented as a medication error 
(Section 13.6.2). In this case, the subject may take the planned dose of IMP at the clinic, 
unless considered contraindicated by the investigator. 
•   If subjects have food intake less than 2 hours before the scheduled IMP administration on 
site, they have to wait a correspondingly long time before taking the IMP. The next following 
food intake should only be done at least 1 hour after the IMP administration. 
•   If the subject took a 
 dose of IMP in error before coming to the clinic for their 
visit, the visit should be rescheduled within 3 days (ensuring that the subject has sufficient 
IMP to continue with the treatment for this period). 
Administration of the IMP at the subject’s home 
When taking the IMP at their home, the subject is recommended to take the 
 dose of 
IMP just after waking up. In the 
 the subject is recommended to take the IMP just 
before going to bed. If this is inconvenient, the subject may take the IMP at other times during 
the day as long as the minimum time of 9 hours between 2 consecutive doses of IMP can be 
met. 
When taking the IMP at their home, subjects may take the IMP without regards to dietary 
intake (i.e. fasting or fed condition). 
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Subjects will be asked to record the date and time of each IMP intake. This will allow 
monitoring of treatment compliance (Section 9.8.4) and whether consecutive doses were 
taken at least  hours apart. 
In case the subject forgets to take a dose of IMP or misses a visit at the clinic, the subject 
should proceed as follows: 
•   If there is a minimum time of 9 hours to the next planned dose of IMP, the subject should 
take the forgotten dose of IMP as soon as the subject becomes aware. 
•   If there are less than 9 hours to the next planned dose of IMP, the subject should skip the 
forgotten dose of IMP and wait until the next planned dose of IMP. In such case, the subject 
should record the missed dose of IMP as forgotten.  
Subjects will receive the IMP for treatment period A at visit 2 and will return all unused 
tablets and the packaging at visit 3. For treatment period B the IMP will be dispensed at 
visit 4 (or visit 4a, if start of treatment period B was delayed by 7 days) and subjects have to 
return all unused tablets and the packaging at visit 5. For details about dispensing visits please 
refer also the schedule of trial procedures (Section 4). At each dispensing visit site staff will 
dispense IMP with the appropriate kit number for the subject (for details see also Section 9.3). 
The date of dispensation and the kit number of the IMP will be collected in the eCRF. 
Provisions for overdose 
The risk of accidental overdose of clinical consequence on QT prolongation is considered low 
as it would involve intake of an unlikely large dose of IMP at once: 
 mg in a single dose*, 
equivalent to  tablets of active IMP (*based on results of the first in human trial with LEO 
152020, reference IB [8]). In the unlikely event of an overdose, there is a small risk of QT 
prolongation (complication and no visible sign). To minimize the risk of accidental overdose, 
it will be explained to the subject at the clinic and in an instruction for use for the subject to 
take home how the subject should take the IMP. Date and time of IMP intake recorded by the 
trial staff in the eCRF (for doses of IMP taken at the clinic) and recorded by the subject in the 
diary (for doses of IMP taken at the subject’s home), as well as review of treatment 
compliance (Section 9.8.4) and IMP accountability (Section 9.8.3) may all be used to detect 
any medication error, including accidental overdose (Section 13.6.2). 
LEO Pharma does not recommend any specific treatment in relation to overdose. If needed, it 
will be at the discretion of the investigator to treat any accidental overdose appropriately  
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9.3 Treatment assignment  
Treatment assignment will be pre-planned according to a computer-generated randomisation 
schedule. This randomisation schedule randomly allocates subjects who have been found to 
comply with all the inclusion criteria and not to violate any of the exclusion criteria on day 1 
(visit 2) in a 1:1 ratio to one of the two treatment sequences. Treatment will start either with 
LEO 152020 
 or with Placebo in treatment period A and will continue with the 
opposite treatment (Placebo or LEO 152020 
) in treatment period B.  
The blinded products are labelled with product codes e.g. “W” or “Z” and a unique kit 
number. The randomisation number will assign the subject in each treatment period to one of 
the two products labelled with the product codes. For each site a complete randomisation 
schedule will be generated, such that each site could randomise 28 subjects. The 
randomisation number and the kit numbers have to be documented in the CRF. 
Visit 2 (Day 1) and Visit 4 (or 4a) 
At day 1 eligible subjects will receive the next available randomisation number at the trial 
site, which assigns the subject to one of the two treatment sequences. The study personnel 
responsible for dispensing of products will dispense for the first treatment period one IMP kit 
labelled with the product code as indicated on the randomisation list for this randomisation 
number. 
At the next dispensing visit delegated site staff will dispense an IMP kit with the product code 
for the next treatment period as indicated in the randomisation schedule for subject’s 
randomisation number. 
At visit 2 and visit 4 (or 4a, respectively), the unique kit number dispensed to the subject has 
to be documented in the eCRF and the subject’s record.  
Each trial site will be supplied with sufficient IMP for the clinical trial on an ongoing basis. 
The randomisation schedules will be generated by a non-blinded statistician. The non-blinded 
statistician will be used only for generating the randomisation list. He/she will be excluded 
from other study operations. The code lists will be inaccessible to staff involved with the 
conduct and administration of the clinical trial until the clinical trial is un-blinded. 
The randomisation code number will be a 3-digit code. 
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9.3.1 Blinding 
The trial is conducted as a double-blind trial. Subject, investigator, and staff involved in the 
data analysis and reporting of the results will be blinded to the planned and actual treatment 
from randomisation to the formal unblinding of the trial. Distribution of the products must be 
performed by site staff not involved in assessments of efficacy or safety parameters. Blinding 
will minimise ascertainment bias due to getting knowledge of the treatment. 
LEO 152020 film-coated tablet (
 mg) and placebo film-coated tablet have been designed to 
have the same size and colour so that active and placebo treatments look and feel identical. 
The packaging of LEO 152020 film-coated tablet (
 mg) and placebo film-coated tablet also 
contains no direct evidence of their identity. It is not considered possible to differentiate 
between the IMPs solely by sensory evaluation. The products are labelled with product codes 
at the contract manufacturing organisation (CMO) but it will not be disclosed which product 
code indicates LEO 152020 or placebo until the clinical trial is un-blinded. 
9.3.2  Emergency unblinding of individual subject treatment 
While the safety of a subject always comes first, it is still important to carefully consider if 
unblinding is necessary to ensure a subject’s safety. An emergency unblinding request can be 
made by the investigators, health care professionals (HCPs) who are not members of the trial 
staff, or authorised LEO Pharma personnel. 
Provisions are in place for 24-hour emergency unblinding of individual subject treatment. If 
emergency unblinding is required, the investigator or delegated site staff can directly contact 
the emergency unblinding CRO via a corresponding local emergency unblinding telephone 
number, that can be found in the Investigator Site File (ISF). 
The investigator or delegated site staff will need to provide the trial ID, the subject ID and the 
randomisation code number of the subject to the emergency unblinding CRO who will 
immediately reveal the individual treatment allocation. 
 
For a requester who is not a member of the site staff (e.g. a physician in an emergency room), 
the local contact number for the emergency unblinding CRO will be provided on the subject 
card (Appendix 3B) to be used if the investigator or delegated site staff cannot be reached. 
Like the investigator or delegated site staff, the requester need to provide the trial ID, the 
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subject ID and the randomisation code number to the emergency unblinding CRO, that will 
immediately reveal the individual treatment allocation. 
The emergency unblinding CRO will clarify that the requester requires immediate unblinding 
without further medical consultation. 
 
Unblinding should only be done in case of an emergency and when it is essential for effective 
treatment of the subject. Most often, trial drug discontinuation and knowledge of the possible 
treatment assignments are sufficient to treat the subject. The Sponsor is to be informed 
immediately about any unblinding event. 
Documentation of any unblinding should include the name of the trial personnel performing 
the unblinding, the date of the unblinding and the reasons that led to unblinding. It has to be 
reported on the blind break form filed in the Investigators site file. In addition, AEs or SAEs 
related to the unblinding have to be reported appropriately. 
LEO Pharma Global Safety will receive a set of emergency envelopes, including the identity 
of the product codes for potential unblinding for regulatory purpose. 
9.4 Background treatment 
Not applicable 
9.5 Rescue treatment 
Not applicable 
9.6 Concomitant medication and concurrent procedures 
Any medication or vaccine that the subject receives from 28 days prior to screening through 
safety follow-up must be recorded in the subject’s medical record and the eCRF along with 
details such as: 
• Medication name or therapy (generic or brand name). 
• Whether the medication or therapy is a rescue medication for the indication. 
• Indication (e.g. concomitant diagnosis, prophylaxis). 
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• Start and stop date of administration (it will also be recorded if the medication is 
ongoing). 
• Dosage information, including dose per administration, unit, and frequency. 
• Route of administration ([oral, topical, subcutaneous, transdermal, intraocular, 
intramuscular, respiratory (inhalation), intralesional, intraperitoneal, nasal, vaginal, 
rectal, intravenous, or other (if other, a specification must be provided)). For topical 
treatments, the dosage form (cream, lotion, ointment, other) will also be recorded. 
For vaccines the following details should be recorded: 
• Type of vaccine (brand name) 
• Indication (e.g. COVID-19 vaccination) 
• Location of injection (e.g. left upper arm) 
• Specify dose (dose x of y) 
• Start and stop date (start date = stop date) 
Similarly, any concurrent procedure must also be recorded in the subject’s medical record and 
the eCRF. The following details will be recorded: procedure name (including anatomical area, 
if relevant), indication, and start and stop date (it will also be recorded if the procedure is 
ongoing).  
The investigator must collect the information from each subject (WOCBP and males with 
partners of childbearing potential) which contraception is used with their partners. This 
information should be collected from every subject at those visits when a pregnancy test is 
performed (but from ALL subjects as specified above). This information should only be 
documented in the source documents to confirm inclusion criterion 7 and 8. 
Investigators may prescribe concomitant medications or treatments to provide adequate 
supportive care as deemed necessary, except for medications listed in Section 9.7. The 
sponsor’s medical expert should be contacted if there are any questions regarding concomitant 
or prior therapy. 
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9.7 Prohibited medication(s) and procedures 
The medications and/or procedures listed in Panel 5 are prohibited during the trial as specified 
below.  
Panel 5: Prohibited medication(s) and/or procedure(s) 
Medication 
Prohibited from 
Prohibited to 
Systemic immunosuppressive medications 
(e.g. Methotrexate, Cyclosporine, 
Azathioprine) 
4 weeks prior to screening 
Safety follow-up 
Biologic medications (e.g. omalizumab, 
dupilumab) 
5 half-lives prior to screening 
Safety follow-up 
Systemic corticosteroids 
4 weeks prior to screening (Note: 
Inhaled or intranasal steroids 
equivalent to doses up to 1 mg 
prednisone daily is allowed) 
Safety follow-up 
Systemic H1 antihistamines with no risk 
for QT prolongation* 
1 week prior to randomisation 
Safety follow-up 
Systemic H1 antihistamines with risk for 
QT prolongation* 
1 week prior to randomisation or 
5 half-lives (whichever is longer) 
Safety follow-up 
H2 antihistamines 
1 week prior to randomisation 
Safety follow-up 
Drugs with antihistamine properties 
including some antidepressants (e.g. 
tricyclic antidepressants) 
1 week prior to randomisation 
Safety follow-up 
Drugs with a known effect on the QT 
interval  
1 week prior to randomisation or 
5 half-lives (whichever is longer) 
Safety follow-up 
Drugs which are known inhibitors of the P-
gp and BCRP transporters** 
1 week prior to randomisation or 
5 half-lives (whichever is longer) 
Safety follow-up 
Probenecid (strong OAT3 inhibitor) 
1 week prior to randomisation or 
5 half-lives (whichever is longer) 
Safety follow-up 
* The application of topical antihistamines (e.g. nasal sprays or eyedrops) for the treatment of concomitant 
allergies (e.g. allergic rhinitis or hay fever) in the standard prescribed dose is allowed to be continued during 
the entire trial, if applicable. 
**See Appendix 4 as examples of BCRP or P-gp transporters. 
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In case any prohibited treatments are used during the trial, they must be recorded as 
concomitant medication and reported as protocol deviation by the CRA. 
In case any prohibited medication with known effect on the QT interval or known inhibitors 
of the P-gp and BCRP transporters and the strong OAT3 (organic anion transporter 3) 
inhibitor probenecid were used, the medical monitor must be immediately notified and an 
early termination visit for the subject should be considered. 
9.7.1 Other restrictions 
The following restrictions must be adhered to during the trial and for the following time 
periods: 
Procedure 
Prohibited from 
Prohibited to 
Use of tanning beds or phototherapy 
(narrow band ultraviolet B [NBUVB], 
ultraviolet B [UVB], ultraviolet A1 
[UVA1], psoralen + ultraviolet A 
[PUVA])  
Within 4 weeks of screening 
Safety follow-up 
Practices 
Prohibited from 
Prohibited to 
Exposures likely to trigger a strong 
CholU flare (e.g. strenuous exercise, 
sauna) 
24 hours prior to UASprovo 
UASprovo 
 
Non- adherence to these restrictions will be reported as protocol deviations. 
9.8 Treatment logistics and accountability  
9.8.1 Labelling and packaging of trial products 
The IMP will be packaged in individually numbered kits. 
The labelling of IMPs will be in accordance with Annex 13, local regulations and trial 
requirements. Label text will be translated into local language, as required.  
For home-use, the subjects will receive instructions for use  which will be translated into local 
language. These will be part of the subject’s diary. 
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9.8.2 Storage of trial products  
All LEO Pharma supplied IMPs must be stored in a secure and restricted area under the 
conditions specified on the label and remain in the original container until dispensed. 
At the trial site and/or pharmacy at the trial site, the IMP must be stored below 25°C. The IMP 
must not be refrigerated nor frozen. 
The temperature during storage at the trial site should be monitored by a calibrated, stationary, 
and continuously monitoring system. Minimum requirement is a calibrated min/max 
thermometer.  
A temperature log must be kept documenting the storage within the right temperature interval. 
Storage facilities should be checked at least every working day. 
At the subject’s home, the IMP should be stored at room temperature below 25°C and should 
not be refrigerated or frozen. 
9.8.3 Drug accountability 
The investigator is fully responsible for the IMPs at the trial site and for maintaining adequate 
control of the IMPs and for documenting all transactions with them. 
Dispensing of IMPs may be delegated, e.g., to a hospital pharmacy, as locally applicable. 
Documentation of drug accountability must be kept of the IMPs dispensed to and returned by 
each individual subject randomised in the trial. This documentation must be available during 
monitoring visits and will be checked by the CRA to verify correct dispensing of the IMPs. 
Drug accountability information will be recorded for individual drug accountability per 
subjects as well as for the inventory status of all IMPs at the trial site on paper forms. 
The subject will return unused IMPs (including packaging material) at the visits specified in 
the schedule of trial procedures (Section 4). 
Returned trial product (unused IMPs (including packaging material)) can be stored at room 
temperature and must be stored separately from non-allocated trial product. 
All [unused] IMPs (including packaging material) supplied by the CMO on behalf of LEO 
Pharma will be returned to the CMO. Prior to their return, the IMPs must be fully accounted 
for by the CRA with the help of site staff responsible for dispensing the IMPs. Accountability 
must be documented on drug accountability forms.  
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IMPs will be returned from the trial site to the CMO directly. 
9.8.4 Treatment compliance 
At visit 3 (end of treatment period A) and visit 5 (end of treatment period B) the subjects will 
be asked if they have used the IMPs as instructed, and the diary will be reviewed by site 
personnel. If a subject is found to be non-compliant during treatment period A, the 
investigator should remind the subject of the importance of following the instructions given, 
including taking the IMP as prescribed during dispensation visit (visit 4 or 4a, respectively). 
Compliance/non-compliance and the reason for it must be recorded in the eCRF. 
Reporting in eCRF 
The following data will be recorded in the eCRF:  
• Did the subject comply with the IMP dosing schedule and instructions (yes, no); If 
no, the number of tablets not taken (including timepoints for missing intakes) and 
/or instructions which were not adhered to (e.g. dietary instructions, interval 
between doses) will be documented. 
• Primary reason for non-compliance - subject forgot, lack of time, adverse event, 
other (if other, a specification should be provided). 
• Total number of tablets taken per treatment period. 
9.8.5 Trial product destruction 
All unused and partly used wallets containing IMP must be returned to CMO for destruction. 
Completely empty wallets can be destroyed locally according to approved procedures and/or 
local requirements. 
9.9 Provision for subject care following trial completion 
In order to ensure appropriate treatment of the subjects after they have completed the trial, the 
subjects will be treated at the investigator’s discretion or referred to other physician(s) 
according to standard practice. 
9.10 Reporting product complaints 
Any defects or issues with the IMP including use errors and inadequate labelling must be 
reported to the Quality Department via Global Safety at LEO Pharma on the trial specific 
(paper) complaint form within 3 days of first knowledge.  
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Critical complaints (defined as any defect, issue, that has or potentially could have a serious 
impact on the subject [e.g. SAE]) must be reported to the Quality Department via Global 
Safety within 24 hours of knowledge.  
Complaint forms should contain a detailed description of the defect, issue, including whether 
it led to an AE. (S)AEs which occur due to a defect or issue with the IMP will be reported by 
the investigator as described in Sections 13.3 and 13.4.  
During the investigation of the product complaint, the IMP must be stored at labelled 
conditions unless otherwise instructed. The trial site will be notified whether the IMP needs to 
be returned for further investigation or may be destroyed.  
Global Safety, LEO Pharma contact information for reporting product complaints: 
E mail address: drug.safety@leo-pharma.com 
Fax number: +45 69102468 
 
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10 Discontinuation and withdrawal 
10.1 General principles 
A subject may withdraw from the trial (prior to first dose or during any treatment period) or 
permanently discontinue trial treatment at any time if the subject, the investigator, or LEO 
Pharma considers that it is not in the subject’s best interest to continue. 
A subject who permanently discontinues IMP is a subject who, although they stop treatment 
with the IMP, agree to their follow up as described in Section 10.3. A subject who withdraws 
from the trial is a subject who stops treatment with the IMP and all further protocol defined 
trial activities. Early termination assessments to be conducted for both events are described in 
Section 10.3. 
Subjects who withdraw from the trial after first dose and subjects who permanently 
discontinue IMP will not be replaced. 
If a subject withdraws from the trial, they may request destruction of any samples taken and 
not tested, and the investigator must document this in the subject’s medical record. 
10.2 Reasons for permanent discontinuation of IMP 
10.2.1 Reasons for permanent discontinuation of IMP 
Subjects will permanently discontinue IMP in any of the treatment periods in the event of: 
• Evidence of pregnancy. 
• An AE that, in the opinion of the investigator or sponsor’s medical expert, 
contraindicates further dosing. 
• Initiation of prohibited medication which cannot be safely replaced by other 
non-prohibited medications. 
• Clinically significant abnormal ECG parameter (e.g., QTcF >500 ms or change in 
QTcF from baseline (pre-dose ECG) > 60 ms). 
• Symptomatic infection with SARS-CoV-2 that is likely to have an impact on efficacy or 
safety data (i.e., patients with a SARS-CoV-2 infection without or very mild symptoms 
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only (e.g., rhinitis or sore throat) might continue with the study at investigator’s 
discretion and in accordance with the applicable local regulations). 
• Other reasons, at the discretion of the investigator. If other, a specification should be 
provided. 
It is not allowed to restart IMP treatment after discontinuation of IMP. 
The primary reason for permanent discontinuation of IMP must be recorded in the medical 
records. 
Data to be recorded in the eCRF 
The primary reason for permanent discontinuation of IMP must also be recorded on the end of 
treatment form in the eCRF where the following options are available:  
• Evidence of pregnancy. 
• Adverse event (including but not limited to clinically significant abnormal ECG 
parameter (e.g., QTcF >500 ms or change in QTcF from baseline (pre-dose 
ECG) > 60 ms) 
• Use of prohibited concomitant medication 
• Withdrawal by subject 
• Lost to follow-up 
• Death 
• Other reasons, at the discretion of the investigator. 
If ‘adverse event’ or ‘other’ is selected, a specification must be provided in the eCRF.  
If ‘adverse event’ is selected, the AE in question will be linked to the discontinuation of IMP.  
If ‘withdrawal by subject’ is selected, it will be recorded whether the subject withdrew 
informed consent or not. 
Discontinuation of IMP due to COVID-19 pandemic will be collected and specified in the 
‘Other’ category. 
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10.3 Early termination assessments 
Permanent discontinuation of IMP 
Subjects who permanently discontinue IMP for any reason will be asked to attend an early 
termination visit as soon as possible after last administration of IMP and return to the trial site 
for an additional visit (safety follow-up visit) as indicated below. See the schedule of trial 
procedures (Section 4) for data to be collected at these visits. The investigator will review any 
AEs which will be followed up according to Section 13.7, if the subject agrees. 
Subjects who permanently discontinue IMP will be asked to attend: 
• Early termination visit (as soon as possible following the last administration of IMP, 
i.e. not more than 3 days after last IMP administration. If no early termination visit can 
be performed within this time frame, only the safety follow-up visit should be 
performed). 
• Safety follow-up visit 3 (+4) days after last administration of IMP (in addition if early 
termination visit was performed within 3 days after last IMP administration). 
Withdrawal from trial 
Subjects who withdraw from the trial for any reason should attend a safety follow-up visit 
(see the schedule of trial procedures (Section 4) for data to be collected at safety follow-up 
visit). The investigator will review any AEs which will be followed up according to 
Section 13.7, if the subject agrees. 
Details on data to be recorded in the eCRF for subjects who withdraw from the trial can be 
found in Section 11.8. 
10.4 Lost to follow-up 
A subject will be considered lost to follow-up if they repeatedly fail to return for scheduled 
visits and if the trial site is not able to get in contact with the subject.  
The following actions must be taken if a subject fails to return to the trial site for a required 
visit: 
• The trial site must attempt to contact the subject and reschedule the missed visit as 
soon as possible and counsel the subject on the importance of maintaining the 
assigned visit schedule and ascertain whether or not the subject wishes to continue 
in the trial. 
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• Before a subject is deemed lost to follow-up, the investigator or designee must 
make every effort to regain contact with the subject. These contact attempts should 
be documented in the subject’s medical record. Should the subject continue to be 
unreachable, they will be considered to have withdrawn from the trial with a 
primary reason of lost to follow-up. 
10.5 Criteria for the termination of the trial 
The Sponsor, the signatory investigator, the IECs or regulatory authorities may decide to 
temporarily halt / suspend the trial, to stop the trial, parts of the trial or an investigational site 
at any time. 
 
10.5.1 Termination of the whole trial 
The discontinuation of the whole trial may be due but not limited to the following reasons: 
• If risk-benefit ratio becomes unacceptable owing to, for example, 
o Safety findings from this trial (e.g. if (S)AEs occur with a frequency or 
intensity which significantly differ from the data reported in the IB, e.g. 
occurrence of severe QT-prolongation defined as QTcF > 500 ms or change in 
QTcF > 60 ms from baseline (pre-dose ECG) in more than 10% (i.e. more than 
3 subjects) of the planned trial subjects) 
o Results of parallel clinical trials 
o Results of parallel animal studies (on e.g. toxicity, teratogenicity, 
carcinogenicity or reproduction toxicity). 
• If the trial conduct (e.g. recruitment rate; drop-out rate; data quality; protocol 
compliance) does not suggest a proper completion of the trial within a reasonable 
time frame. 
• The development of the test product is discontinued, a market authorization is no 
longer intended, or the trial proves not to meet the expected goal. 
• A regulatory authority demands that the trial be terminated. 
• Revocation of Ethics Committee’s favorable opinion or national regulatory 
authority’s approval of the trial. 
• Other important or unforeseen circumstances. 
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10.5.2 Termination of the trial at an individual trial site 
The Sponsor has the right to close a single trial site at any time. 
Conditions that may warrant termination of a trial site include, but are not limited to: 
• The trial site fails to comply with the requirements of the protocol 
• The trial site fails to comply with GCP standards 
• The first subject fails to be recruited within a reasonable period after initiation of 
the trial site 
 
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11 Trial assessments and procedures 
11.1 Overview 
Evaluations to be done at each visit are shown in the schedule of trial procedures in Section 4. 
Refer to Section 7.1 for further details on the trial design. Assessments and procedures at each 
trial visit should be performed as shown in Panel 6:  
Panel 6: Sequence of assessments 
Baseline treatment period A (V2) 
Baseline treatment period B (V4 or V4a) 
 
 
 
Vital signs, physical examination
Urine pregnancy test for WOBC
Histamine SPT
Photography of designated non-lesional
biopsy sites and 1st biopsy, if applicable
UASprovo
Randomisation
Photography of designated lesional biopsy
sites and 2nd biopsy, if applicable
Biomarker blood sampling
IMP intake
Patient reported outcomes (PROs)*
Investigator assessments*
ECG (60 ± 15 minutes after IMP dose)
PK sampling
Vital signs, physical examination
Urine pregnancy test for WOBC
Histamine SPT
UASprovo
Biomarker blood sampling
IMP intake
Patient reported outcomes(PROs)*
Investigator assessments*
ECG (60 ± 15 minutes after IMP dose)
PK sampling
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Visit 3 /Visit 5 
 
*timing of assessments at the visit day is variable as long as PROs are performed prior to investigator’s 
assessments 
Subjects participating in the trial will be under careful supervision of a principal investigator 
who must be a dermatologist or allergist. Investigators must be experienced in treating 
cholinergic urticaria and have documented experience and/or training in use of the 
assessments required by the protocol and must be either a physician or certified physician’s 
assistant. 
AEs must be assessed by medically qualified personnel (Section 13.2). 
Physical examination, vital signs
PK sampling
Only V3: Photography of designated non-
lesional biopsy sites and 3rd biopsy, if
applicable
IMP intake
Patient reported outcomes (PROs)*
Investigator assessments*
ECG (60 ± 15 minutes after IMP dose)
PK sampling
Blood sampling safety + biomarker
Histamine SPT
UASprovo
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11.2 Assessments performed only at screening/baseline 
11.2.1 Demographics  
The following demographic data will be recorded: 
• Age (year of birth). 
• Sex: female, male. 
• Race: American Indian or Alaska native, Asian, Black or African American, native 
Hawaiian or other Pacific islander, White, other [requires a specification to be 
provided]. 
• Ethnic origin (self-reported by the subject): “Hispanic” or “Latino”, not “Hispanic 
or Latino”. 
11.2.2 Medical history 
Relevant medical history must be recorded:  
• Skin disease history and history of CholU (to confirm the inclusion criteria): all 
past and current skin disease history should be collected; for each condition or 
diagnosis, the start date and stop date will be recorded (it will also be recorded if 
the diagnosis is ongoing). 
• Other medical and surgical history including concurrent diagnoses within the 
previous 12 months. For each condition, diagnosis, or surgical procedure, the start 
date and stop date will be recorded (it will also be recorded if the condition, 
diagnosis, or surgical procedure is ongoing). 
Relevant medical history also includes diseases which are specifically listed as exclusion 
criteria and diseases for which specific treatments are listed as exclusion criteria. 
11.2.3 Height and weight 
The subject’s height (without shoes) will be measured; the subject’s weight (in indoor 
clothing and without shoes) will be measured.  
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11.3 Efficacy assessments 
11.3.1 Urticaria Activity Score post-provocation (UASprovo) 
A pulse-controlled ergometry provocation test will be performed, and the investigator will 
assess the Urticaria Activity Score post-provocation (UASprovo). In addition, the time until 
sweating and whealing during the exercise will be determined. 
The UASprovo will be performed according to the schedule of trial procedures (Section 4). 
Screening provocation test is optional if patients had a prior provocation test within 6 months 
of day 1 (visit 2). If subjects fail to meet inclusion threshold during screening provocation 
test, then they are allowed one additional screening attempt. There should be at least 7 days 
between provocation tests, including between screening provocation test and visit 2 
provocation test. Subjects not meeting the inclusion criteria of a UASprovo ≥ 3 (with a 
minimum wheal score of ≥ 1 and minimum itch score of ≥ 1) at visit 2 must not be 
randomised.  
Subjects who don’t demonstrate UASprovo ≥ 3 (with a minimum wheal score of ≥ 1 and 
minimum itch score of ≥ 1) at Visit 4 may not progress to treatment period B and will be 
required to attend an additional study visit (visit 4a) 7±1 days later to repeat the provocation 
test. If at visit 4a subjects do not demonstrate a UASprovo ≥ 3, then they will be terminated 
from the trial. 
UASprovo and the time until sweating and whealing will be recorded in the eCRF. 
Pulse-controlled ergometry (PCE) provocation test 
The pulse-controlled ergometry (PCE) provocation test is a standardized test for diagnosing 
and investigating CholU [26]. The test involves moderate physical exercise appropriate to the 
patient’s age and general condition to the point of sweating and up to 15 minutes beyond. For 
this pulse-controlled incremental ergometry test, patients are seated on the bicycle ergometer 
and instructed to cycle in a pulse controlled manner, i.e. to speed up or slow down their 
pedalling speed to achieve an increase in pulse rate of 15 beats per minute every 5min to a 
final maximum increase of 90 beats per minute above the starting level. 
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Assessment of the Urticaria Activity Score 
Starch-iodine powder will be applied to the subject’s lower back to detect sweating. During 
exercise, the time of the start of the sweating, defined as the appearance of the first blue dots 
in the starch-iodine powder and the time of the start of whealing will be recorded.  
Subjects will be rated after the PCE test on their number of wheals and their itch severity, 
resulting in a sum score for the Urticaria Activity Score post-provocation (UASprovo) ranging 
from 0 to 6 points. 
 a) Numbers of wheals (0 = 0; 1 to 20 wheals = 1; 20 to 50 wheals = 2; > 50 wheals = 3)  
b) Itching (none = 0, mild = 1, moderate = 2, severe = 3) 
11.3.2  Physician’s Global Assessment of Disease Severity by VAS 
The Physician’s Global Assessment (PhGA) is an instrument used in clinical trials to rate the 
subject’s current disease severity using a Visual Analogue Scale (VAS) ranging from 0 
(absence) to 10 (worst possible severity).  
The PhGA score will be assessed according to the schedule of trial procedures (Section 4). 
The assessment will be based on the condition of the disease at the time of evaluation and not 
in relation to the condition at a previous visit.  
The disease activity assessment score will be recorded in the eCRF. 
11.3.3 Histamine Skin Prick Testing 
The Histamine Skin Prick Testing (SPT) is widely accepted method used in allergy clinics to 
test for histamine sensitivity causing pruritus, skin flare and a skin wheal.  A solution of the 
challenge agent will be applied using the skin prick method as described in The Global 
Allergy and Asthma European Network (GA2LEN) Guidelines [27]. The skin prick method 
involves placing a drop of histamine solution onto the skin and using a lancet to gently pierce 
the superficial layer of the skin. The excess histamine is then wiped away.  
• histamine 
• negative control – saline 
Pruritus during the SPT will be assessed by subjects every minute for 15 minutes total using a 
100mm VAS scale with 0 indicating ‘no itch’ and 10 indicating ‘worst itch imaginable’. 
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The absolute wheal/flare size will be measured.  
A positive test is defined as a wheal and flare reaction (≥ 3mm in diameter relative to negative 
control). Study assessment will commence 15 - 20 mins after the skin has been pricked. 
The Histamine SPT will be performed according to the schedule of trial procedures (Section 4). 
The result (positive/negative), the wheal size and pruritus evaluation by subjects will be 
recorded in the eCRF. 
11.3.4 Patient-reported outcomes 
All patient-reported outcomes (PROs) in this trial will be provided to the subjects as paper 
versions. 
11.3.4.1 Patient’s Global Assessment of Severity by VAS 
Patient’s Global Assessment of Severity (PGA-S) is a single item designed to capture the 
subject’s overall perception of their symptoms over the past week on a Visual Analogue Scale  
ranging from 0 (absence) to 10 [28]. The PGA-S will be completed at the trial site according 
to the schedule of trial procedures in Section 4. 
11.3.4.2 Urticaria Control Test 
Subjects will complete the UCT and mUCT questionnaire at visits according to the schedule 
of trial procedures (Section 4). The UCT is a disease-specific measure consisting of four 
questions that retrospectively assesses patients’ burden of disease over the previous 4 weeks. 
For this study, in addition to having patients complete the traditional UCT, the recall period 
will be modified to assess the burden of disease over the past week (mUCT) to capture 
changes over a shorter recall period. Concepts covered include disease activity, QoL survey, 
disease control, and therapy. Each of the four questions are scored on a scale of 0 to 4 (see 
Panel 7). The UCT score is derived by adding up the scores from each of the four questions. A 
total score from 0 (no control) to 16 points (complete control) is derived, with a score of ≥ 12 
indicating well-controlled disease. The UCT has high levels of validity and reliability, and 
accurately identifies patients with insufficiently controlled disease. Its minimal clinically 
important difference (MCID) is 3 points [29]. 
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Panel 7: (Modified) Urticaria Control Test 
1. How much have you suffered from the physical symptoms of the urticaria (itch, hives 
(welts) and/or swelling) in the last four weeks (in the last week)* 
 
very much (0) 
much (1) 
somewhat (2) 
a little (3) 
not at all (4) 
2. How much was your quality of life affected by the urticaria in the last 4 weeks (in the 
last week)? 
 
very much (0) 
much (1) 
somewhat (2) 
a little (3) 
not at all (4) 
3. How often was the treatment for your urticaria in the last 4 weeks (in the last week) not 
enough to control your urticaria symptoms? 
 
very often (0) 
often (1) 
sometimes (2) 
seldom (3) 
not at all (4) 
4. Overall, how well have you had your urticaria under control in the last 4 weeks (in the 
last week) 
 
not at all (0) 
a little (1) 
somewhat (2) 
well (3) 
very well (4) 
* wording for mUCT is given in brackets 
11.3.4.3 Cholinergic Urticaria Activity Score 7 
The Cholinergic Urticaria Activity Score 7 (CholUAS7) is a validated tool to assess disease 
symptoms in CholU subjects [30], consisting of overall 4 different items. Among all items of 
the CholUAS7, the hive severity score (HSS) and the itch severity score (ISS) will be 
summed over 7 days using once daily diary-based documentation. The weekly CholUAS7 for 
these 2 items is the sum of the daily HSS score and the daily ISS score for 7 consecutive days. 
The possible range of the weekly UAS7 score based on the HSS and the ISS is 0-42 with 
higher values indicating higher disease severity [9]. 
Hive count 
The wheals (hive) severity score (HSS) defined by the number of hives, will be recorded by 
the subject once daily in their diary on a scale of 0 (none) to 3 (intense/severe) see Panel 8. A 
weekly score (HSS7) is derived by adding up the daily scores of the 7 days preceding the 
visit. The possible range of the weekly score is 0-21 with higher values indicating greater 
hives severity.  
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Panel 8: Hive severity score 
Score 
Wheals (Hives) 
0 
None 
1 
Mild (1-20 hives/24 hours) 
2 
Moderate (21 – 50 hives /24 hours) 
3 
Severe (>51 hives /24 hours) 
 
Handling of missing data when calculating the HSS7: 
If a subject has at least 5 available daily scores within the 7 days prior to the study visit, the 
weekly score is calculated as the sum of the available daily scores in that week, divided by the 
number of days with the available score, multiplied by 7. If there are less than 5 available 
daily scores within the prior 7 days, then the weekly score is missing for the week. 
Itch severity score (ISS): 
The severity if the itch will be recorded by the subject daily in their diary on a scale of 0 
(none) to 3 (intense/severe) (see Panel 9). A weekly score (ISS7) is derived by adding up the 
daily scores of the 7 days preceding the visit. 
Panel 9: Itch severity score 
Score 
Pruritus (Itch) 
0 
None 
1 
Mild (minimal awareness, easily tolerable) 
2 
Moderate (definite awareness, bothersome but tolerable) 
3 
Severe (difficult to tolerate) 
  
Handling of missing data when calculating the ISS7: 
If a subject has at least 5 available daily scores within the 7 days prior to the study visit, the 
weekly score is calculated as the sum of the available daily scores in that week, divided by the 
number of days with available score multiplied by 7. If there are less than 5 available daily 
scores within the prior 7 days, then the weekly score is missing for this week. 
 
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11.4 Safety assessments 
11.4.1 Vital signs 
Vital signs (resting blood pressure, pulse, and body temperature) must be assessed according 
to the schedule of trial procedures (Section 4) and prior to randomisation. Vital signs will be 
measured following at least 5 minutes of rest. 
If an abnormal vital sign at screening and/or baseline is considered to be clinically significant 
by the investigator, it will be at the discretion of the investigator if the subject should be 
randomised into the trial. During the trial, if a subject presenting with a clinically significant 
abnormal vital sign, the investigator must take appropriate action, at their discretion. 
In case of abnormal findings, the vital sign measurement can be repeated approximately 
15 minutes later to verify the first measurement. Should the repeated measurement result in a 
normal value, the measurement must be repeated once more. If the third measurement verifies 
the second (normal) value, the first measurement should be considered false and the second 
measurement should be recorded in the eCRF. If the third measurement confirms the first 
measurement (abnormal), the second measurement will be considered false and the first 
measurement should be recorded in the eCRF. 
Reporting in eCRF 
It will be recorded in the eCRF if vital signs were measured; if not, a reason should be 
provided. Vital signs, arm used to measure blood pressure, the temperature measuring method 
(axillary, ear, oral, rectal, other), and the date and time vital signs were measured will be 
recorded in the eCRF. Clinically significant abnormal vital signs at the screening visit and 
baseline (as the subjects has not been administered treatment) will be documented as medical 
history in the eCRF. At subsequent visits, any clinically significant deterioration of a pre-
existing condition as well as any new clinically significant sign, symptom, or illness occurring 
after randomisation will be reported as an AE in accordance with Section 0. 
11.4.2 Physical examination 
A physical examination of the subject including general appearance, regional lymph nodes, 
and dermatologic examination of the skin must be conducted according to the schedule of trial 
procedures (Section 4). Subjects with clinically significant findings on physical examination 
meeting any of the exclusion criteria (Section 8.3) must not be randomised. 
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Reporting in eCRF 
It will be recorded in the eCRF if a physical examination was performed and, if applicable, 
the investigator’s evaluation (‘normal’, ‘abnormal, not clinically significant’, ‘abnormal, 
clinically significant’); if a physical examination was not performed, a reason should be 
given. 
Clinically significant abnormal findings at the screening visit will be documented as medical 
history in the eCRF. At subsequent visits, any clinically significant deterioration of a pre-
existing condition as well as any new clinically significant sign, symptom or illness occurring 
after randomisation will be reported as an AE in accordance with Section 13.3. 
11.4.3 ECG 
A 12-lead resting digital ECG will be recorded after the subject has been supine for at least 5 
minutes at the visits indicated in the schedule of trial procedures (Section 4). ECGs must be 
measured before any blood samples scheduled at the same visit. At the screening visit 
3 consecutive ECGs must be measured and the average QTcF derived (see exclusion 
criterion 6). 
At baseline visits for each treatment period, V3 and V5 post dose ECGs must be measured 
1 hour±15 min after IMP dosing at the site. 
A pre-evaluation of the ECGs will be performed by the investigators to evaluate immediate 
subject safety. In case of a suspected abnormal ECG, the investigator must take appropriate 
action, as further detailed below. At a minimum, the date of ECG collection will be recorded 
in the source documents. 
The ECG data will be transferred to a central ECG service company for central evaluation. A 
cardiologist at the ECG service company will analyse and interpret the ECG data. The ECG 
service company will provide ECG evaluation reports to the trial sites. The investigator must 
evaluate all abnormal ECG results (‘clinically significant’ or ‘not clinically significant’) and 
sign and date. The investigator is responsible for taking the final decision about the clinical 
significance of any abnormal ECG. 
Subjects with a clinically significant abnormal ECG at screening must not be included in the 
trial (exclusion criterion 6). In addition, subjects meeting any of the exclusion criteria 7 and 8 
must not be included in the trial. I.e. subjects with clinically significant ECG findings meeting 
any of the exclusion criteria (Section 8.3) must not be randomised.  
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If the subject presents with a severe QT-prolongation post-baseline (i.e. after the first use of 
the IMP), i.e. QTcF > 500 ms or a change in QTcF > 60 ms from baseline (pre-dose ECG), the 
ECG should be repeated. If the QTcF or change in QTcF from baseline (pre-dose ECG) are 
confirmed, the subject must permanently be discontinued from IMP and withdrawn from the 
trial. 
If the subject presents with a moderate QT prolongation, i.e. 480 ms < QTcF ≤ 500 ms or 
30 ms < change in QTcF from baseline (pre-dose ECG) ≤ 60 ms, the ECG should be repeated. 
If the QTcF or change in QTcF from baseline (pre-dose ECG) are confirmed, a subject at 
investigator’s discretion may continue with the trial, but an additional ECG must be done at 
the safety follow-up in order to check if QTcF returned to normal values. 
The collection and transmission of ECG data will be described in a separate ECG manual. 
Reporting in eCRF 
It must be recorded in the eCRF if an ECG was measured. If not, a reason must be provided. 
The investigator’s assessment of ECG result (‘normal’, ‘abnormal, not clinically significant’, 
‘abnormal, clinically significant’) must also be recorded in the eCRF.  
Clinically significant abnormal ECG findings at the screening visit will be documented as 
medical history in the eCRF. At subsequent visits, any new clinically significant abnormal 
ECG finding, symptoms, or illnesses after randomisation will be reported as an AE in 
accordance with Section 13.3, as well in accordance with Section 13.6.1, as prolonged 
electrocardiogram QT corrected intervals will be regarded as an AE of special interest (AESI), 
considering QTcF > 450 ms as a clinically significant QT-prolongation. 
11.4.4 Laboratory testing 
11.4.4.1 Overview 
Pregnancy tests in female subjects of child-bearing potential must be performed at visits 
according to the schedule of trial procedures (Section 4). At visit 1 (screening), a serum hCG 
test is to be made, on the other visits, urine hCG dip tests will be made. At visit 2 (start of 
treatment), the test must be made prior to randomisation. Pregnant women must not be 
randomised into the trial. 
Blood and urine samples will be collected according to the schedule of trial procedures 
(Section 4).  
SARS-CoV-2 test at Screening and if necessary, at further study visits will be performed 
according to current local regulations and requirements. 
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The evaluations shown in Panel 10 will be performed.  
Panel 10: Clinical laboratory tests 
Chemistry 
Haematology 
Sodium 
Potassium 
Magnesium 
Creatinine1 
Urea nitrogen 
Total and free calcium (albumin-corrected) 
Alkaline phosphatase 
Aspartate aminotransferase 
Alanine aminotransferase 
Gamma glutamyl transferase 
Bilirubin2 
Lactate dehydrogenase 
Cholesterol 
LDL cholesterol 
HDL cholesterol 
Triglycerides 
Glucose (non-fasting) 
Albumin 
Total Protein 
CRP 
Erythrocytes 
Haematocrit 
Haemoglobin 
Erythrocyte mean corpuscular volume 
Erythrocyte mean corpuscular haemoglobin 
concentration 
Leukocytes 
Neutrophils 
Lymphocytes 
Monocytes 
Eosinophils 
Basophils 
Thrombocytes 
Serology3 
Hepatitis B virus surface antigen 
Hepatitis B virus surface antibody 
Hepatitis B virus core antibody 
Hepatitis C virus antibody 
HIV-1 antibody 
HIV-2 antibody 
 
Biomarker4 
 
IgE 
 
Serum pregnancy test3,5 
 
Choriogonadotropin beta (beta hCG) 
 
Local tests 
 
Urine pregnancy test5 
 
SARS-CoV-2 test6 
1) Estimated glomerular filtration rate (eGFR) calculated with Chronic Kidney Disease-Epidemiology 
Collaboration (CKD-EPI) creatinine equation 
2) If bilirubin is above upper limit of normal, direct and indirect bilirubin will also be measured.  
3) Measured at screening only. 
4) At V2 to V5, only 
5) Only women of childbearing potential. 
6) In accordance with current local regulations and requirements; mandatory at screening only. 
Abbreviations: HDL = high density lipoprotein; LDL = low density lipoprotein, CRP = C-reactive protein; HIV 
= human immunodeficiency virus, IgE = immunoglobulin E, SARS-CoV-2 = Severe acute respiratory syndrome 
coronavirus 2. 
 
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11.4.4.2 Investigator evaluation of laboratory samples 
Central laboratory 
Chemistry, haematology, serology, and serum pregnancy tests will be analysed by a central 
laboratory which will provide results to the trial sites. The investigator must evaluate all 
results outside the reference range (‘clinically significant’ or ‘not clinically significant’) and 
sign and date the evaluation. The signed and dated version will be filed with the investigator’s 
trial documentation. Clinically significant abnormal tests must be repeated to confirm the 
abnormality. 
If a screening laboratory result is abnormal and of clinical significance, it will be at the 
investigator’s discretion to decide if the subject should be randomised into the trial. During 
the trial, if a subject presents with a clinically significant abnormal laboratory result, the 
investigator must take appropriate action, at their discretion (see also Section 10.2). 
A laboratory manual will be provided to the trial sites specifying the procedures for 
collection, processing, storage, and shipment of samples, as well as laboratory contact 
information specific to this trial. 
Tests performed at the trial site 
Women of childbearing potential will have a urine pregnancy test with a dipstick performed at 
the trial site at baseline prior to randomisation. A woman with a positive urine pregnancy test 
at Week 0 (baseline) must not be randomised in the trial. During the trial the test will be 
performed at trial visits as displayed in the schedule of trial procedures in Section 4. A woman 
with a positive urine pregnancy test during the trial must immediately and permanently 
discontinue IMP and be withdrawn from the trial. A positive urine pregnancy test must be 
verified with a serum pregnancy test. 
Reporting in eCRF 
The site staff will record in the eCRF if a blood sample was taken, if not, a reason should be 
provided. The date the sample was taken as well as the investigator’s assessment of the results 
(‘normal’, ‘abnormal, not clinically significant’, ‘abnormal, clinically significant’) will be 
recorded in the eCRF. 
It will be recorded in the eCRF if the subject is a woman of childbearing potential and if a 
urine pregnancy test was performed, if not, a reason should be provided. Also, the date and 
the outcome of the urine pregnancy test will be recorded in the eCRF (‘positive’, ‘negative’). 
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Clinically significant abnormal laboratory results at the screening visit will be documented as 
medical history in the eCRF. At subsequent visits, any clinically significant deterioration of a 
pre-existing condition will be reported as an AE. Any new clinically significant sign, 
symptom, or illness occurring after randomisation will be reported as an AE in accordance 
with Section 13.3. 
11.4.5 Test for SARS-CoV-2 infection 
A test for active SARS-CoV-2 infection (COVID-19) is required for all subjects at screening. 
Testing will be performed in accordance with institutional guidelines and national/local 
regulations.  
At subsequent visits subjects will be monitored for SARS-CoV-2. If an active SARS-CoV-2 
infection is suspected, the respective testing should be performed at the discretion of the 
investigator.  
Results will only be recorded in subject’s medical record. 
Subjects with active and confirmed SARS-CoV-2 infection will be managed in accordance 
with institutional guidelines with regards to trial site visits. 
11.5 Pharmacokinetic assessments 
11.5.1 Blood sampling for analysis of drug  
Blood samples for PK assessments will be collected at the visits as specified in the schedule 
of trial procedures (Section 4).  
PK blood sampling should be performed at baseline of each treatment period after IMP intake 
at site and at V3 and V5 prior to and approximately 
 after administration of the 
IMP on site. 
Reporting in eCRF 
It will be recorded in the eCRF if the PK sample was taken; if not, a reason will be provided. 
The date and time of the last IMP administration prior to the PK sample being taken must be 
recorded in the eCRF. 
Collection, handling, and shipment instructions for PK blood samples are provided in a 
laboratory manual. 
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11.6 Pharmacodynamics assessments 
Biomarkers will be analysed to evaluate pharmacodynamic markers of drug effects. Samples 
for assessment of biomarkers in blood samples and skin biopsies will be collected at the time 
points specified in the schedule of trial procedures (Section 4). Taking of skin biopsies is 
optional. 
11.6.1 Blood biomarkers 
Serum samples for biomarker analyses (proteomics and IgE) will be taken according to the 
schedule of trial procedures (Section 4). Serum sampling for biomarker analysis at baseline 
visits (i.e. visit 2 and visit 4/4a) should be taken prior to the intake of the IMP and sampling at 
the end of treatment visits (i.e. visit 3 and visit 5) for each of the treatment periods should be 
done after the IMP intake. It will be recorded in the eCRF if the sample was taken; if not, a 
comment should be provided. 
Collection, handling, and shipment instructions for serum biomarker samples are provided in 
a separate laboratory manual. 
Results will be included in the CTR. 
11.6.2 Skin biopsies 
Subjects will be asked to participate in an exploratory component involving skin biopsies. 
Participation in this component of the trial requires that the subject provides additional 
informed consent. 
3 mm skin punch biopsies for histologic analysis and transcriptomics will be taken at the 
time-points specified in the schedule of trial procedures (Section 4). At visit 2 (day 1), two 
non-lesional biopsies  (from an area, that usually develops wheal and flare upon provocation) 
will be taken prior to the provocation test and two lesional biopsies will be taken, after the 
provocation test. At visit 3 (day 8), subjects will have two biopsies performed on non-lesional 
skin prior to the provocation test. 
It will be recorded in the eCRF if skin biopsies were taken from the lesional and non-lesional 
area as described above; if a skin biopsy was not taken, a reason will be provided. 
A check of skin biopsy wound healing including removal of suture, if applicable, will be 
performed at the next trial visit (at visit 3 or visit 4, respectively).  
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Collection, handling, and shipment instructions for skin biopsy samples are provided in a 
separate laboratory manual. 
Results will be included in the CTR. 
11.7 Other assessments 
11.7.1 Patient-reported outcomes 
Each subject must make individual assessments relating to their perception of their disease 
and quality of life. These will be performed prior to the investigator performing his/her 
efficacy assessments. All PROs will be provided to the subjects in paper versions and data 
will be transferred into the eCRF by site personnel. 
11.7.1.1 Diary 
At screening the subjects will receive a paper diary to document the CholUAS7 (see 
Section 11.3.4.3) and the use of medications taken to treat their disease symptoms as well as 
of other medications (except usual ongoing medication), if any. The subjects need to complete 
the diary each day throughout the whole trial duration.  
During the treatment periods the subject should also document the intake of IMP specifying 
date and time. Compliance with the diary completion will be reviewed by the trial site staff at 
each visit. The diary will be collected to the site as outlined in the schedule of trial procedures 
(Section 4). 
11.7.1.2 Dermatology Life Quality Index 
The Dermatology Life Quality Index (DLQI) is a validated questionnaire with content 
specific to those with dermatology conditions [31]. It consists of 10 items addressing the 
subject’s perception of the impact of their skin disease on different aspects of their quality of 
life over the last week such as dermatology-related symptoms and feelings, daily activities, 
leisure, work or school, personal relationships, and the treatment. Each item is scored on a 
4-point Likert scale (0 = ‘not at all ⁄not relevant’; 1 = ‘a little’; 2 = ‘a lot’; 3 = ‘very much’). 
The total score is the sum of the 10 items (0 to 30); a high score is indicative of a poor quality 
of life. The DLQI will be completed at the trial site according to the schedule of trial 
procedures in Section 4. 
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11.7.1.3 Cholinergic Urticaria Quality of Life Questionnaire  
The cholinergic urticaria quality of life questionnaire (CholU-QoL) is validated questionnaire 
with content specific to those with conditions of cholinergic urticaria [32]. It consists of 28‐
items, addressing 5 different aspects over the last 7 days (symptoms, functional life, social 
interaction, therapy and emotions). Each item is score with 5‐point Likert scale (LS) with the 
answer options “not at all”; “somewhat”; “moderately”; “much”; “very much” as well as 
“never,” “seldom,” “occasionally,” “often” and “very often”. 
The CholU-QoL will be completed at the trial site according to the schedule of trial 
procedures in Section 4. 
11.7.2 Photography 
Subjects who consented in skin biopsy will have a mandatory photography component of the 
biopsy site. The digital photography assessments will serve as documentation of biopsy 
location to check for possible irregularities in case of unexpected results. No further 
evaluations or publications are planned. Consent to this photography component will be 
requested in the additional informed consent for the biopsies. 
Digital colour photographs will be taken of the selected skin area for biopsies before the 
biopsy according to the schedule of trial procedures (Section 4). It will be recorded in the 
eCRF if at least one photo was taken; if not, a comment should be provided. 
The trial sites will use their own equipment to take the photographs and photographs will be 
stored at trial sites according to local practice and local regulations. 
Visit date and time of photography should be indicated on the images. Beside this information 
the photographs will have no other subject identifier than the subject ID.  
Images will be transmitted electronically to LEO Pharma using a secure file transfer protocol 
and will solely be used to evaluate the biopsy sites in case of suspected irregularities. Images 
will be stored for no longer than 12 months after completion of the CTR. 
 
 
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11.8 End of trial 
End of treatment form 
An end of treatment form will be completed in the eCRF for all subjects when they have had 
their last administration of IMP in any treatment period. This form will also be completed for 
subjects who permanently discontinue IMP and subjects who withdraw from trial (see 
Section 10.3 for early termination assessments). 
The date and time of last administration of IMP will be recorded on the end of treatment form. 
It will also be recorded if the subject completed the treatment. If not, the primary reason for 
permanent discontinuation of IMP must be recorded (see Section 10.2.1). 
End of trial form 
An end of trial form must be completed in the eCRF for all screened subjects. The following 
data will be collected:  
• Screening failure. 
• Did the subject complete the trial. 
• Which was the last visit (including phone call) the subject attended in this trial. 
• Date of last contact. 
• Primary reason for withdrawing from the trial (death, pregnancy, adverse event, 
lack of efficacy, screening failure, withdrawal by subject, lost to follow-up, or other 
[if other, a specification should be provided]).  
• If the subject attended the primary endpoint visit (visit 5). If not, the primary reason 
for not attending the visit (death, pregnancy, adverse event, lack of efficacy, 
withdrawal by subject, lost to follow-up, or other [if other, a specification should be 
provided]). 
• If the subject attended the safety follow-up visit (visit 6). If not, the primary reason 
for not attending the visit (death, pregnancy, adverse event, lack of efficacy, 
withdrawal by subject, lost to follow-up, or other [if other, a specification should be 
provided]). 
The end of trial form will be completed when the subject turned out to be a screening failure 
or has had their last visit (that is the safety follow-up visit 6, or early termination visit). 
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11.9 Estimate of total blood volume collected 
Blood samples will be drawn for haematology, biochemistry, serology, PK and PD. The total 
volume of blood to be drawn is approximately 100 mL. If additional blood samples are 
required, the amount of blood drawn may be more than this stated value; however, the total 
volume of blood drawn will be much less than that taken during a blood donation 
(approximately 500 mL). 
11.10 Storage of biological samples 
Laboratory samples (chemistry/haematology/serology) will not be stored for more than a few 
days after sampling and analysis. 
Primary samples for PK will be discarded by the bioanalytical lab upon finalisation of the 
CTR whereas backup samples stored at the Central Lab will be retained for as long as the 
quality of the material permits evaluation but for no longer than 12 months after completion 
of the CTR. Any backup samples that have been sent to the Bioanalytical Lab will also be 
discarded upon finalisation of the CTR. 
Biomarker samples (skin biopsies and PD blood samples) will be retained for as long as the 
quality of the material permits evaluation but for no longer than 12 months after completion 
of the CTR unless the subject has given additional consent allowing storage in a biobank for 
future research. 
If the subject consents to this, LEO Pharma will store these biomarker samples and/or the 
material isolated from these biomarker samples in a biobank established by LEO Pharma and 
hosted by Brooks Life Sciences. The residual biological samples will be used for future 
research conducted by LEO Pharma. The samples will be transferred from the relevant 
laboratory to the biobank. The samples will be labelled with the trial ID, subject ID, and 
sample date to protect the privacy of the subjects and to allow continued blinding for future 
analyses. The samples will be stored in the biobank for as long as the quality of the material 
permits evaluation and will then be destroyed. 
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12Scientific rationale for trial design and appropriateness of assessments 
12.1 Scientific rationale for trial design 
EXP-2177 is a randomised, double-blind, placebo-controlled, multi-centre, 7-day cross-over 
trial. The cross-over trial design is optimal to ensure a clear and unbiased evaluation of the 
efficacy and safety of the drug effects since each subject serves as his/her own placebo 
control. This 7-day cross-over trial design is possible due to the short IMP half-life, expected 
rapid onset of action, and inducible nature of the signs/symptoms of CholU with a 
provocation test (UASprovo [9, 31]). The treatment periods consist of 7-day treatment each 
with LEO 152020 or placebo. The placebo treatment period will serve as a reference and has 
been added to establish efficacy and safety of LEO 152020. The use of placebo is considered 
to be appropriate because of the short treatment period. Randomisation to the sequential order 
of treatment periods will minimize allocation bias and baseline confounding, as well as permit 
the evaluation of any possible carry-over effect(s) from treatment with LEO 152020. Double-
blinding will minimize ascertainment bias.  
IMP will be supplied as 
 tablets with 
 mg free based per 
tablet. Dose is 
 for 7 days. The dose of 
 mg daily is chosen based on the 
predicted efficacious dose from an ex vivo pharmacodynamic assay (e.g. eosinophil shape 
change assay). Divided dosing ensures high exposure around the clock. The medication will 
be administered with an interval of at least 9 hours between dosing and as specified in 
Section 9.2. Steady state concentration is expected to be reached in 2-3 days (half-life 6-7 
hours), therefore a short treatment period of 7 days is possible.  
The trial population is adult patients with CholU that are poorly controlled based on the UCT 
[33]. Subjects will have a recent history (within 6 months) with documented inadequate 
response to standard dose (as to marketing authorization) H1 antihistamines, which is the 
current standard of care for CholU. This trial population represents the patients with highest 
remaining unmet clinical need and can be applied to the general population.  
Due to the potential important risk of QT prolongation, exclusion criteria are in place to 
exclude subjects at risk (see Section 8.3 for the exclusion criteria and Section 5.5 for more 
information about mitigation of the risk of QT prolongation). The other eligibility criteria 
have been chosen to ensure inclusion of the targeted patient population and safety of the 
subjects and to minimize factors which could interfere with the efficacy and safety 
assessments (Sections 8.2 and 8.3). 
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12.2 Appropriateness of assessments 
Patient‐related outcomes are important to be looked at in the treatment for urticaria including 
CholU. A number of questionnaires and scores have been developed and are widely used to 
assess treatment efficacy. For evaluation of the disease severity and treatment effects the UAS 
[34] is used, a generally recognised instrument for the assessment of disease severity of 
CholU. Due to the inducible character of the disease the signs/symptoms of CholU will be 
evaluated after a provocation test (UASprovo) [9, 26]. 
Further assessments as UCT [33], CholUAS7 and CholU-QoL are also widely used and 
validated assessments for determination of disease severity and impact on quality of life and 
changes thereof. 
To gain more information about the mechanism /mode of action of the potential treatment 
benefit pharmacodynamic assessments in terms of evaluation of biomarkers in blood and skin 
will be assessed. 
 
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13Adverse events 
13.1 Definition and classification of adverse events 
Adverse events (AEs) and serious adverse events (SAEs) are defined in Appendix 1. 
Classification of AEs in terms of severity, causality and outcome is defined in Appendix 2. 
13.2 Collection of adverse event reports 
AE data must be collected from time of first trial-related activity after the subject has signed 
the informed consent form (ICF) until subject’s completion of the clinical trial (all trial 
periods including the safety follow-up visit (visit 6) see Section 7.3). 
AEs must be assessed by medically qualified personnel. 
At all visits, the subject will be asked a non-leading question by the investigator about AEs, 
e.g.: “How have you felt since I saw you last?” No specific symptoms should be asked for. It 
is important that the investigator also observes the subject for any changes not reported by the 
subject and records these changes. 
Principles for data recording in the eCRF are described in Sections 11.4.1 to 11.4.5. 
13.3 Reporting of adverse events 
AEs reported by the subject or observed by the investigator must be recorded on the AE form 
of the eCRF and should be described in the following manner: 
The AE term must be in precise English medical terminology (that is, not necessarily the exact 
words used by the subject). Whenever possible, a specific diagnosis should be stated (for 
example ‘allergic contact dermatitis’). 
The duration of the AE must be reported by the start date and stop date of the event, unless 
the event is ongoing. If the event is ongoing, it will be marked as ongoing. In addition, it will 
be recorded if the AE started prior to first administration of IMP in treatment period A or 
treatment period B, respectively. 
AEs must be classified in terms of severity, causality, and outcome according to the 
definitions in Appendix 2. 
Action taken with IMP: any action taken with IMP as a consequence of the AE must be 
recorded (dose not changed, drug interrupted, drug withdrawn, not applicable, unknown). 
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Other action taken: any other action taken as a result of the AE must be recorded (none, 
concomitant medication, concurrent procedure). 
Withdrawn from trial due to this AE: it must be recorded whether the AE led to withdrawal 
from the trial. 
13.4 Reporting of serious adverse events 
The criteria that define an AE as serious (that is, an SAE) are defined in Appendix 1. SAE 
criteria are also listed on the SAE form. 
13.4.1 Investigator reporting responsibilities 
Any SAE must be reported to LEO Pharma on the (paper) SAE form immediately, without 
undue delay but not later than within 24 hours of first knowledge. This report should contain 
amongst others an assessment of available information on seriousness, severity, causal 
relationship to the IMP(s) or trial procedure, the action taken, the outcome to date, and a 
narrative description of the course of the event. For more details regarding reporting of any 
SAE, please see the guidance text on the SAE form. 
By signing and dating the SAE form, the investigator acknowledges that he/she is aware of 
the SAE and has assessed the causal relationship of the IMP(s) and any of the other 
medications to the SAE. 
The actual reporter, if not the investigator, should also sign and date the SAE report. 
The completed SAE form must be faxed or scanned and e-mailed to Global Safety at LEO 
Pharma using the e-mail address or fax number below: 
Global Safety at LEO Pharma 
E-mail address: drug.safety@leo-pharma.com 
Fax number: +45 69102468 
If relevant, the investigator will enclose other information with the SAE form, such as 
anonymised reports of diagnostic procedures, hospital records, autopsy reports, etc. 
Additionally, Global Safety at LEO Pharma may request further information in order to fully 
assess the SAE. The investigator must forward such information to LEO Pharma upon request 
by fax or e-mail (see contact details above). 
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The investigator must notify the local IEC(s) of SAEs, as required by current applicable 
legislation for the concerned country. 
SAEs occurring after the completion of the clinical trial should not routinely sought or 
collected. However, such events should be reported to Global Safety at LEO Pharma (see 
contact details above) if the investigator becomes aware of them. 
13.4.2 LEO reporting responsibilities 
Global Safety at LEO Pharma is responsible for assessing whether an SAE is expected. The 
relevant reference safety information document for this clinical trial is the IB, Section 7.2 ed. 
3.0 [8] and subsequent updates. 
Global Safety at LEO Pharma will notify the regulatory authorities and concerned 
investigators of SAEs according to the current applicable legislation for the concerned 
country. 
The IEC(s) will be notified of SAEs according to the current applicable legislation for the 
concerned country. 
For all non-US countries, the following reporting requirements apply: all SAEs which are 
assessed as causally related to the IMP by either the investigator or LEO Pharma [35], and 
which are unexpected (suspected, unexpected serious adverse reactions [SUSARs]), are 
subject to expedited reporting to regulatory authorities, IEC(s)) according to the current 
applicable legislation in the concerned country. Investigators will be notified of the evolving 
safety profile of the IMP on an ongoing basis. 
13.5 Other events that require expedited reporting 
13.5.1 Pregnancy 
Any pregnancy occurring after first exposure to IMP and until the subject has completed the 
trial must be reported to LEO Pharma within 24 hours of first knowledge using the (paper) 
pregnancy form (part I). All pregnancies must be followed up until delivery or termination, 
and outcome must be reported on the (paper) pregnancy form (part II) within 24 hours of first 
knowledge.  
The completed pregnancy forms must be faxed or scanned and e-mailed to Global Safety at 
LEO Pharma. Contact details are given in Section 13.4.1. 
Pregnant subjects must immediately discontinue IMP permanently (Sections 10.2.1 and 10.3). 
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In the eCRF pregnancy should be provided as reason for withdrawal (see Section 10.2.1). 
13.5.2 Adverse events of special interest 
AEs considered AESIs in this trial are described in more detail in Section 13.6.1. If an AESI 
qualifies as an SAE, expedited reporting will be required (Section 13.4). 
13.6 Reporting of other events 
13.6.1 Adverse events of special interest 
The events listed in Panel 11 are considered AESIs in this trial and will require additional data 
to be recorded in the eCRF. LEO Pharma may request that the investigator forwards 
additional test results, as appropriate. An AESI may be serious or non-serious. Serious AESIs 
require expedited reporting via the SAE form as described in Section 13.4. 
Panel 11: Adverse events of special interest 
Adverse event of special 
interest 
Additional data to be recorded 
Data collection 
method 
Electrocardiogram QT 
corrected interval 
prolonged 
• ECG (measured at relevant 
timepoints according to the schedule 
of trial procedures [Section 4]). 
• Severity of the QT/QTcF 
prolongation (mild, moderate, 
severe, see severity criteria in Panel 
12). 
• Symptoms believed to be related to 
the QT/QTcF prolongation and 
duration of the symptoms. 
eCRF 
For serious cases, the 
safety database as per 
procedure 
Abbreviations: ECG = electrocardiogram; eCRF = electronic case report form; QT = QT interval; QTcF = QT 
interval corrected by Fridericia's formula. 
AESIs of electrocardiogram QT corrected interval prolonged 
If at any ECG measurement a subject presenting with QTc >450 ms, this must be reported as 
an AE if it occurs after intake of IMP at day 1. Severity of the AE must be reported in the 
eCRF (see Panel 12 for guidance). Clinically significant abnormal findings at the screening 
visit will be documented as medical history in the eCRF. 
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Panel 12: Severity specifications for adverse event of electrocardiogram QT corrected 
interval prolonged 
Grade 1 (mild) 
Grade 2 (moderate) 
Grade 3 (severe) 
450 ms< average QTc <480 ms 
481 ms< average QTc <500 ms 
or  
30 ms < change in QTc from 
baseline (pre-dose ECG) to 
measurement ≤ 60 ms 
Average QTc ≥501 ms 
or 
Change in QTc from baseline 
(pre-dose ECG) to 
measurement >60 ms 
Modified from (Common Terminology Criteria for Adverse Events [CTCAE] Version 5.0 [36]) 
13.6.2 Medication error 
Medication error refers to any unintentional error in the dispensing or administration of an 
IMP while in the control of the investigator or subject. Medication errors include 
administration of wrong medication, wrong dose accidental overdose and underdose), wrong 
dosing schedule (
), wrong route, and 
administration of expired IMP. 
Reporting in eCRF  
The medication error category must be documented on the AE form in the eCRF. Only 
accidental overdose or underdose and wrong dosing schedule where a clinical consequence 
occurred or could have occurred based on the investigator’s judgement should be recorded in 
the eCRF. In addition, any clinical consequence of the medication error must be recorded as a 
separate AE on the AE form. If the AE originating from the medication error qualifies as an 
SAE, expedited reporting will be required (Section 13.4).  
13.6.3 Misuse or Abuse 
The terms misuse and abuse are similar in terms that they both represent the intentional use of 
a drug in a way other than intended. 
Misuse refers to situations where the IMP is intentionally and inappropriately used for 
therapeutic purposes not in accordance with the protocol. 
Abuse refers to situations where the IMP is intentionally used for what could be considered 
desirable non-therapeutic effects (e.g. sedative, stimulant, euphoric effects). 
Misuse and abuse must be recorded on the AE form in the eCRF. In addition, any clinical 
consequence of misuse or abuse must be recorded as a separate AE on the AE form. If the AE 
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originating from the misuse or abuse qualifies as an SAE, expedited reporting will be required 
(Section 13.4). 
13.6.4 Aggravation of condition 
Any clinically significant aggravation/exacerbation/worsening of any medical condition(s) 
(including the trial disease), compared to screening, must be reported as an (S)AE in 
accordance with Sections 13.3 and 13.4. 
13.7 Follow-up for final outcome of adverse events 
During the trial, the investigator should follow up for final outcome on all AEs (including 
SAEs). Once a subject leaves the clinical trial, the investigator should follow up on the 
outcome of all non-serious AEs classified as possibly or probably related to the IMP until the 
safety follow up visit (visit 6) or until the final outcome is determined, whichever comes first. 
Non-serious AEs classified as not related to the IMP do not need to be followed up for the 
final outcome.  
All SAEs must be followed up until a final outcome has been established, that is, the 
follow-up may continue beyond the end of the clinical trial. For SAEs which have stabilised 
and from which the subject cannot be expected to recover during the trial or the safety 
follow-up periods, e.g. chronic or stabilised conditions, the final outcome at the investigator’s 
discretion should be reported as ‘recovering/resolving’ or ‘not recovered/not resolved’. In 
addition, a statement detailing why the subject cannot be expected to recover during the trial, 
e.g. that the SAE has stabilised or is chronic, should be added to the narrative description of 
the SAE on the SAE form. 
13.8 Handling of an urgent safety measure 
An urgent safety measure is a measure taken to implement an action/protocol deviation under 
an emergency. This is defined as “…the occurrence of any new event relating to the conduct 
of the trial or the development of the investigational medicinal product where that new event 
is likely to affect the safety of the subjects, the sponsor and the investigator shall take 
appropriate urgent safety measures to protect the subjects against any immediate 
hazard.” [37]. 
If the investigator becomes aware of information that requires an immediate change in a 
clinical trial procedure or a temporary halt of the clinical trial to protect clinical trial subjects 
from any immediate hazard to their health and safety, the investigator can do so without prior 
approval from LEO Pharma, regulatory authorities, or IRBs/IECs. 
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The investigator must immediately inform LEO Pharma – by contacting the clinical project 
manager or medical expert – of this change in a clinical trial procedure or of the temporary 
halt; the investigator will provide full details of the information and the decision-making 
process leading to the implementation of the urgent safety measure. 
LEO Pharma must act immediately upon receipt of the urgent safety measure notification in 
accordance with internal procedures and local legislation. 
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14 Statistical methods 
14.1 Sample size 
The sample size is based on the primary endpoint (change from baseline in UASprovo). A 
sample size of 28 randomised subjects with an assumed attrition rate of no more than 10%, 
i.e. less than 3 subjects to be excluded from analysis, will provide at least 25 subjects for 
analysis. 
This is based on the following assumptions on distributional characteristics [9]: 
• Baseline mean +/- SD = 4.7 +/- 1.1 
• Placebo change from baseline 0.6 (12.8%) 
• Active change from baseline 1.2 (25.5%)  
Furthermore, the standard deviation is assumed to be reduced by 33% due to the intra-
individual comparison implicit in the cross-over design. This follows from the removal of 
variation between subjects from the total variation of the endpoint, such that the standard 
deviation is assumed to be reduced from 1.1 to 0.73.  
With a SD of 0.73 and alpha of 0.05, this will then provide at least 80% power for the 
hypothesis of a statistically significant difference between treatments, measured by UAS 
provocation test.  
14.2 Trial analysis sets 
All screened subjects will be accounted for in the CTR. 
All subjects randomised will be included in the full analysis set and will be analysed for 
efficacy. Exclusions from the full analysis set (FAS) can be considered in special cases as 
described in ICH E9, Section 5.2.1, Full Analysis Set. If it is decided to exclude a randomised 
subject from the full analysis set, a justification addressing ICH E9 will be given. 
A per protocol analysis set (PPS) will be defined by excluding subjects from the full analysis 
set who fulfil any of the following criteria:  
• Receive treatment with at most one IMP.  
• Provide no efficacy data following start of treatment. 
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• Are known to have taken the wrong IMP throughout at least one treatment period 
of the trial. 
• Do not fulfil the disease defining inclusion criteria (that is, inclusion criteria 2, 3, 
and 6). 
Further exclusion of subjects or subject data will be decided upon after a blind review of the 
data; this blinded review will include a review of all the remaining in- and exclusion criteria, 
concomitant medication that may affect trial disease, compliance/adherence issues, and 
violations of visit windows. Further exclusion of subjects or subject data may be considered 
based on input from the pharmacologist or in regard of the biomarker analysis. 
A safety analysis set (SAF) will be defined as all subjects who received IMP.  
A PK analysis set will be defined as all subjects who received IMP and provided samples for 
analysing plasma drug concentrations.  
The decisions regarding inclusion/exclusion of subjects or subject data from the trial analysis 
sets will be documented in the minutes of the blind data review meeting, i.e. the document 
with analysis set definition before breaking the randomisation code and reported in the 
clinical trial report. 
14.3 Statistical analysis 
An observed-cases approach will be used for tabulations of data by visit (that is, involving 
only those subjects who attended each specific visit). 
Parameters assessed during treatment periods will be summarised descriptively at baseline 
and at the end of the treatment period by treatment including change from baseline, where 
baseline is defined by treatment start within period. Unless otherwise specified descriptive 
statistics will additionally be presented for all measurements by treatment at each visit. 
Categorical data will be summarised using the number and percentage of subjects in each 
category and treatment at each visit. Continuous data will be summarised using the mean, 
median, standard deviation (SD), minimum and maximum values. 
A statistical analysis plan (SAP) will be written in addition to the protocol, including a more 
technical and detailed elaboration of the statistical analyses. 
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14.3.1 Disposition of subjects 
The number of randomised subjects in each analysis set and the number of subjects who 
complete the trial will be given. The reasons for permanent discontinuation of IMP or 
withdrawal from trial will be presented for all randomised subjects by last visit attended and 
by treatment sequence. 
14.3.2 Demographics and other baseline characteristics 
Descriptive statistics of demographics and other baseline characteristics will be presented for 
all randomised subjects by treatment. Other baseline characteristics cover the subject’s height 
and weight, the medical history, concomitant medication, and serology parameters. In 
addition, the investigator assessments UASprovo, histamins SPT, and PGA as well as the 
patient reported outcomes (CholUAS7, UCT, DLQI, CholU-QoL and the subject global 
assessment of severity will be summarised by treatment at treatment start within period. 
Presentations of age, sex, ethnicity, race will also be given by site. 
14.3.3 Exposure and treatment compliance 
The number of subjects exposed, the duration of exposure and the number of used tablets 
(administrations) will be tabulated. In addition, the number of subjects who complied with the 
IMP dosing schedule and instructions (yes, no) as well as the primary reason for non-
compliance as provided in the eCRF will be given by period and treatment.  
The duration of exposure to treatment in a specific visit interval will be calculated as the 
number of days from date of first administration of IMP in that period to the date of last 
administration of IMP in that period, both days included. 
Exposure to treatment will be presented for the safety analysis set as days of exposure per 
treatment. Treatment compliance will be presented for the safety analysis set per treatment as 
the percentages of missed administrations. 
14.3.4 Testing strategy 
The primary efficacy endpoint will be compared between treatments by means of a linear 
mixed model. The analyses of all other efficacy endpoints are considered exploratory in this 
phase 2a trial. In addition, no interim analysis is planned. Therefore, there will be no 
adjustment for multiplicity and no further testing strategy necessary controlling the overall type 
I error rate. 
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14.3.5 Analysis of primary efficacy endpoint 
The primary endpoint, change from baseline (V2 in treatment period A and V4 or V4a, 
respectively in treatment period B) in post-provocation Urticaria Activity Score (UASprovo) 
to the end of the treatment period, will be compared between treatments with the null 
hypothesis that they are equal against the alternative that they are different. The analysis will 
be performed both for the full analysis set (primary) and for the per protocol set (supportive) 
with imputing missing values at the end of treatment period (baseline value at the beginning 
of the period carried forward). 
The primary efficacy endpoint will be analysed using a linear mixed model, containing 
treatment, period and carryover effects, the factor site and additionally the value of UASprovo 
at baseline as a covariate. Formally, if Yijkl denotes the change from baseline in UASprovo for 
subject i, treatment j and period k, then the following model equation will be used: 
Yijkl = µ + tj + pk + tpik +bik + sl+ γi + εijk, 
where µ is the overall mean, tj is the j-th treatment (j=1,2), pk is the k-th period (k=1,2), sl is 
the l-th site, tpik is the treatment-period interaction, which represents the carry-over effect, bik 
is the baseline value of UASprovo at V2 (k=1) and V4 or V4a (k=2), respectively, γi 
(i=1,…,n) is the random subjects effect, and εijkl is the residual random error. 
It will be assumed that the random subject effects as well as the residual errors are normally 
distributed. Both terms will be assumed to be independent. Within each subject, the residual 
random errors will be allowed to be correlated, assuming a compound symmetry covariance 
structure. 
In a first step, the hypothesis H0: tp = 0 vs. H1: tp ≠ 0 will be tested. If H0 cannot be rejected, 
it will be assumed that no carry-over effect is present. Analysis will then proceed as follows: 
The interaction term will be deleted from the model, and the model without the interaction 
term will be fitted to the data. To test the effect of treatment on the primary efficacy endpoint, 
the hypothesis H0: t = 0 vs H1: t ≠ 0 will be tested, and a two-sided 95% confidence interval 
will be provided for the difference between treatments in addition to the test probability. In 
addition, least square means for each treatment will be provided. 
In case a carry-over effect is present, the model will remain unchanged, and least square 
means are calculated, but no testing will be performed. 
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UASprovo will be summarised as mean, SD, median, minimum and maximum values at 
baseline as well as at the end of treatment period by treatment. Changes from baseline will 
also be included. For the visit at the end of the treatment period (visit 3, visit 5 respectively) 
both observed data and completed data (with missing data imputed using baseline value 
carried forward) will be presented. Means will be plotted by sequence and period. In addition, 
subject profiles will be displayed by treatment, separately for each sequence. 
14.3.6 Analysis of secondary efficacy endpoints 
The analyses of all secondary efficacy endpoints are considered exploratory in this phase 2a 
trial and will be analysed for the full analysis set. Only subjects with available data at baseline as 
well as at the end of the treatment period for at least one period will be included in the analysis.  
There will be no adjustment for multiplicity. 
Panel 13: Overview of statistical analyses for secondary efficacy endpoints 
Endpoint 
Hypothesis 
Methods of analysis 
Change from baseline in 
CholUAS7 at the end of the 
treatment period 
Difference between treatments 
measured by change in CholUAS7 
is different from zero 
Linear mixed model 
Change from baseline in UCT at 
the end of the treatment period 
Difference between treatments 
measured by change in UCT is 
different from zero 
Linear mixed model 
Change from baseline in PhGA 
of disease severity at the end of 
the treatment period by VAS 
Difference between treatments 
measured by change in physician’s 
global assessment of disease 
severity is different from zero 
Linear mixed model 
Change from baseline in PGA-S 
at the end of the treatment period 
by VAS 
Difference between treatments 
measured by change in patient’s 
global assessment of severity is 
different from zero 
Linear mixed model 
Change from baseline in time to 
onset of provocation-induced 
whealing at the end of the 
treatment period 
Difference between treatments 
measured by change in  time to 
onset is different from zero 
Linear mixed model 
Change from baseline in time to 
onset of provocation-induced 
sweating at the end of the 
treatment period 
Difference between treatments 
measured by change in  time to 
onset of provocation induced 
sweating is different from zero 
Linear mixed model 
Change from baseline of 
histamine SPT wheal/flare size. 
Difference between treatments 
measured by change in proportion 
of responders is different from 
zero 
Linear mixed model 
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Endpoint 
Hypothesis 
Methods of analysis 
Change from baseline of pruritus 
assessed at histamine SPT. 
Difference between treatments 
measured by change in pruritus is 
different from zero 
Linear mixed model 
Change from baseline in DLQI at 
the end of the treatment period  
Difference between treatments 
measured change from baseline in 
DLQI is different from zero 
Linear mixed model 
Change from baseline in CholU-
QoL at the end of the treatment 
period  
Difference between treatments 
measured by change in CholU-
QoL is different from zero 
Linear mixed model 
See List of abbreviations for explanation of abbreviations used in the panel 
The exploratory endpoints change from baseline at the end of treatment period of the 
parameters (CholUAS7, UCT, Physician’s Global Assessment by VAS, Patient’s Global 
Assessment by VAS, time to onset of provocation induced sweating and whealing, 
respectively, histamine SPT wheal/flare size and pruritus assessed at histamine SPT, as well as 
(total) DLQI, CholU-QoL) will be analysed using linear mixed models, with the same 
assumptions and the same model equation as finally applied for the primary endpoint, 
containing treatment effects, period effects and the baseline value of the respective endpoint at 
V2 and V4 or V4a, respectively. A carryover effect will be only included if it is contained in 
the final model for the analysis of the primary endpoint. 
Estimated difference between treatments, two-sided 95% confidence intervals and least square 
means will be presented in addition to the test probability.  
Each parameter (CholUAS7, UCT; Physician’s Global Assessment by VAS, Patient’s Global 
assessment by VAS, time to onset of provocation induced sweating and whealing, 
respectively, as well as (total) DLQI, CholU-QoL) will be summarised as mean, SD, median, 
minimum and maximum values by treatment including changes from baseline of the 
corresponding treatment period. 
In addition, absolute wheal/flare size and the extent of pruritus during SPT, assessed by the 
subject, will be summarised as mean, SD, median, minimum and maximum values by 
treatment. Derivation of extent of pruritus measured every minute for 15 minutes in total 
during histamine SPT will be further specified in the SAP. 
14.3.7 Analysis of patient-reported outcomes 
Descriptive statistics (mean, SD, median, minimum and maximum values) will be presented 
at each visit by treatment for: 
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• UCT questions covering disease activity, QoL survey, disease control, therapy  
• CholUAS-7 subscores wheals (hive) severity score (HSS) and itch severity score (ISS) 
• DLQI subdomains concerning dermatology-related symptoms and feelings, daily 
activities, leisure, work or school, personal relationships, and the treatment 
• CholU-QoL subdomains addressing the aspects symptoms, functional life, social 
interaction, therapy and emotions. 
Parameters will be analysed for the full analysis set. 
14.3.8 Analysis of pharmacodynamics and pharmacogenomics 
Descriptive statistics will be presented for the change from baseline in expression of disease 
biomarkers in blood and skin to the end of the treatment period by treatment. Disease 
biomarkers are specified in Section 11.6. 
Disease biomarkers will be analysed for the full analysis set but will not be evaluated for all 
subjects. Further details will be specified in the statistical analysis plan. 
14.3.9 Analysis of safety 
The analysis of safety will be based on the safety analysis set. 
14.3.9.1 Adverse events 
AEs will be coded during the course of the trial according to Medical Dictionary for 
Regulatory Activities (MedDRA). AEs will be presented by preferred term and primary 
system organ class (SOC). 
Treatment-emergent AEs will be summarised; however, all AEs recorded during the course of 
the trial will be included in subject data listings. An event will be considered 
treatment-emergent if started after the first use of IMP in each treatment period or if started 
before the first use of IMP and worsened in severity after first dose of IMP in each treatment 
period. The tabulations described in the following will only include the treatment-emergent 
events summarised according to the onset of AE. In each of the tabulations, AEs are defined 
by MedDRA preferred terms within primary SOC. 
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An overall summary of the number of events and the number (percentage) of subjects with 
any treatment-emergent AEs, deaths, SAEs, premature discontinuations from the trial due to 
AEs, treatment-related AEs, and severe AEs will be presented. 
The number of AEs and number of subjects with AEs will be tabulated by SOC and PT for 
each treatment. The percentage of subjects with AEs will be compared between treatments by 
Fisher’s exact test. 
Related AEs are defined as AEs for which the investigator has not described the causal 
relationship to IMP as ‘not related’. The number of related AEs and the number of subjects 
with each type of related AE will be tabulated. The percentage of subjects with related AEs 
will be compared between treatments by Fisher’s exact test. 
AEs which start during wash out phase or during follow-up phase within 3 days after last 
administration of IMP will be allocated as treatment-emergent AEs to the treatment applied in 
the prior period. In addition, AEs will be listed that do not have an outcome before the 
beginning of the second treatment period. 
AESIs, defined as prolonged Electrocardiogram QT corrected interval will be listed by 
treatment. AESIs will in addition be presented by severity categories, as severity of AESIs 
will be categorized based on CTCAE (Version 5.0) [36]. 
SAEs and AESIs will be evaluated separately. Narrative will be provided for SAEs and 
serious AESIs.  
AEs leading to withdrawal from trial and/or permanent discontinuation of IMP will be 
tabulated and listed. The detailed listing will provide an overview of the individual cases and 
include the age and sex of the subject, treatment received at the time of AE onset, the AE 
preferred and reported terms, causality and severity of the AE, the action taken with the IMP, 
AE outcome, start and stop date of AE, duration of AE, and number of days since first and last 
IMP administration. No narratives will be given. 
14.3.9.2 Vital signs 
Vital signs (resting blood pressure, pulse, and body temperature) will be summarised as mean, 
standard deviation (SD), median, minimum, and maximum values at each scheduled visit 
during screening, treatment periods and at the end of follow-up by treatment. 
Similar tables will also be provided for each of the vital signs at baseline and at the end of the 
treatment period (visit 2 and visit 3, visit 4 or visit 4a, if applicable and visit 5, respectively) 
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by treatment. In addition, change from baseline to the end of treatment period will be included 
in the tabular display. 
14.3.9.3  Physical examination 
Physical examination findings will be assessed by the investigator as ‘normal’, ‘abnormal, not 
clinically significant’ or ‘abnormal, clinically significant’. A shift table will be produced 
showing for each treatment period the categories at baseline against those at the end of the 
treatment period by treatment. Subjects with abnormal and clinically significant findings at 
physical examination will be listed. 
14.3.9.4 ECG 
All of the ECG parameters (QTc, QTcF, QTcB) which are centrally evaluated will be 
summarised as mean, standard deviation (SD), median, minimum, and maximum values at 
each scheduled visit during screening and the treatment periods by treatment. 
Similar tables will also be provided for each of the ECG parameter at baseline after first IMP 
administration and at the end of the treatment period before and after the last IMP 
administration by treatment. Change from screening will be included in the tabular display. 
In addition, the change prior to post administration of IMP at the end of each treatment period 
will be summarised by treatment. 
ECGs results will be assessed by the investigator as ‘normal’, ‘abnormal, not clinically 
significant’ or ‘abnormal, clinically significant’. A shift table will be produced showing the 
categories at screening against those during treatment period (after first IMP dosing, before 
and after last IMP dosing) by treatment. Another shift table will be presented showing the 
categories prior to last IMP administration against those after last IMP administration by 
treatment. 
Subjects with abnormal ECGs will be listed as evaluated by the investigator or by the central 
lab. 
14.3.9.5 Clinical laboratory evaluation 
The descriptive statistics arithmetic and geometric mean, SD, median, minimum, and 
maximum values will be provided for each of the laboratory parameters at screening (visit 1), 
at the end of each treatment period (visit 3 and visit 5, respectively) and at the end of the 
follow-up period (visit 6) by treatment sequence.  
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Similar tables will also be provided for each of the laboratory parameters at screening (visit 1) 
and at the end of the treatment periods (visit 3, visit 5 respectively) by treatment. In addition, 
the change in each of the laboratory parameters from baseline to the end of treatment period 
will be included in the tabular display. Baseline will be the last value during screening period.  
Laboratory parameters will be classified as ‘low’, ‘normal’ or ‘high’, depending on whether 
the value is below, within, or above the reference range, respectively. A shift table will be 
produced showing the categories at baseline against those at the end of the treatment period 
by treatment. Baseline will be the last value during screening period. Subjects with laboratory 
parameters outside the reference range will be listed. 
14.3.10 
Pharmacokinetic analysis 
The analysis of PK will be based on the PK analysis set.  
To analyse systemic exposure of LEO 152020 the following PK parameters will be calculated 
after first dose of each treatment period (visit 2 and visit 4 or 4a, respectively) and pre- and 
post-dose at the end of each treatment period (visit 3 and visit 5, respectively): AUC0-t, AUC0-
inf, Cmax, tmax and t1/2. 
For PK drug concentrations measured at visits 2-5, arithmetic and geometric mean, SD, 
coefficient of variation (CV), median, minimum and maximum values will be provided by 
visit. 
14.3.11 
Interim analysis 
No interim analysis is planned. 
14.3.12 
General principles 
All significance tests will be two-sided using the 5% significance level. All confidence 
intervals will be presented with 95% degree of confidence, unless otherwise specified. 
All the analyses specified in the protocol will be reviewed in relation to the blinded data 
actually obtained and the statistical analysis plan will be finalised before the unblinding. 
Any changes from the statistical analyses planned in this clinical trial protocol will be 
described and justified in a protocol amendment and/or the statistical analysis plan and/or in 
the CTR, dependent on the type of change. 
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14.3.13 
Handling of missing values 
In case a subject permanently discontinued IMP during a treatment period the early 
termination visit will be taken for the end of treatment visit. This applies for the investigator 
measurements UASprovo (including time to sweating and time to whealing) and the lab 
parameters of serum chemistry and haematology.  
Concerning the analysis of the primary efficacy endpoint, the baseline value of the 
corresponding treatment period will be carried forward, if the value at end of treatment period 
is not available. No imputation will be performed when the baseline value is not available. 
A sensitivity analysis will be performed for the primary endpoint based on subjects from the 
FAS with values available at baseline as well as at the end of the treatment period for both 
periods (complete cases analysis). 
For secondary / exploratory endpoints of efficacy, no imputation of missing values will be 
performed. 
Sum scores are only derived if all item scores are available. 
CholUAS-7 score will only be calculated when the wheals (hives) severity score and the itch 
severity score (ISS) for the last seven days are available: If a subject has at least 5 available 
daily scores within the 7 days prior to the study visit, the weekly score is calculated as the 
sum of the available daily scores in that week, divided by the number of days with available 
score multiplied by 7. If there are less than 5 available daily scores within the 7 days prior to 
the study visit, then the weekly score is missing for this week. 
Missing values of safety parameters will generally be treated as such and will not be replaced. 
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15 References 
1. 
Godse, K., et al., Prevalence of cholinergic urticaria in Indian adults. Indian 
dermatology online journal, 2013. 4(1): p. 62-63. 
2. 
Zuberbier, T., et al., Prevalence of cholinergic urticaria in young adults. J Am Acad 
Dermatol, 1994. 31(6): p. 978-81. 
3. 
Altrichter, S., et al., Atopic predisposition in cholinergic urticaria patients and its 
implications. Journal of the European Academy of Dermatology and Venereology, 
2016. 30(12): p. 2060-2065. 
4. 
Petalas, K., K. Kontou-Fili, and C. Gratziou, Bronchial hyperresponsiveness in 
patients with cholinergic urticaria. Ann Allergy Asthma Immunol, 2009. 102(5): p. 
416-21. 
5. 
Adachi, J., T. Aoki, and A. Yamatodani, Demonstration of sweat allergy in cholinergic 
urticaria. Journal of Dermatological Science, 1994. 7(2): p. 142-149. 
6. 
Takahagi, S., et al., Sweat antigen induces histamine release from basophils of patients 
with cholinergic urticaria associated with atopic diathesis. Br J Dermatol, 2009. 
160(2): p. 426-8. 
7. 
Hiragun, M., et al., Elevated serum IgE against MGL_1304 in patients with atopic 
dermatitis and cholinergic urticaria. Allergol Int, 2014. 63(1): p. 83-93. 
8. 
LEO 152020. Investigator’s Brochure - Atopic Dermatitis, 06-Nov-2020. ed 03. 
9. 
Koch, K., et al., Antihistamine updosing reduces disease activity in patients with 
difficult-to-treat cholinergic urticaria. J Allergy Clin Immunol, 2016. 138(5): p. 1483-
1485.e9. 
10. 
Kollmeier, A., et al., The histamine H(4) receptor antagonist, JNJ 39758979, is 
effective in reducing histamine-induced pruritus in a randomized clinical study in 
healthy subjects. J Pharmacol Exp Ther, 2014. 350(1): p. 181-7. 
11. 
Jemima, E.A., A. Prema, and E.B. Thangam, Functional characterization of histamine 
H4 receptor on human mast cells. Mol Immunol, 2014. 62(1): p. 19-28. 
12. 
Buckland, K.F., T.J. Williams, and D.M. Conroy, Histamine induces cytoskeletal 
changes in human eosinophils via the H(4) receptor. Br J Pharmacol, 2003. 140(6): p. 
1117-27. 
13. 
Ling, P., et al., Histamine H4 receptor mediates eosinophil chemotaxis with cell shape 
change and adhesion molecule upregulation. Br J Pharmacol, 2004. 142(1): p. 161-71. 
14. 
Hirschmann, J.V., et al., Cholinergic urticaria. A clinical and histologic study. Arch 
Dermatol, 1987. 123(4): p. 462-7. 
15. 
Gutzmer, R., et al., The histamine H4 receptor is functionally expressed on T(H)2 
cells. J Allergy Clin Immunol, 2009. 123(3): p. 619-25. 
16. 
Kay, A.B., et al., Elevations in T-helper-2-initiating cytokines (interleukin-33, 
interleukin-25 and thymic stromal lymphopoietin) in lesional skin from chronic 
spontaneous ('idiopathic') urticaria. Br J Dermatol, 2015. 172(5): p. 1294-302. 
17. 
Asady, A., et al., Cholinergic urticaria patients of different age groups have distinct 
features. Clin Exp Allergy, 2017. 47(12): p. 1609-1614. 
18. 
WMA, World Medical Association Declaration of Helsinki: ethical principles for 
medical research involving human subjects. Jama, 2013. 310(20): p. 2191-4. 
19. 
EMA/CHMP/ICH/135/1995, Guideline for good clinical practice - ICH topic E6 (R2). 
2017. 
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20. 
Werfel, T., et al., Efficacy and safety of the histamine H<sub>4</sub> receptor 
antagonist ZPL-3893787 in patients with atopic dermatitis. Journal of Allergy and 
Clinical Immunology, 2019. 143(5): p. 1830-1837.e4. 
21. 
EMA: Points to consider on implications of Coronavirus disease (COVID-19) on 
methodological aspects of ongoing clinical trials. 25-MAR-2020. DRAFT. 
22. 
FDA: Guidance on Conduct of Clinical Trials of Medical Products during COVID-19 
Public Health Emergency. March 2020;  Updated on September 21, 2020. 
23. 
Supplementary recommendations of BfArM and PEI to the European Guidance on the 
Management of Clinical Trials during the COVID-19 (Coronavirus) pandemic - 
version 3. 2020. 
24. 
Finlay, A.Y. and G.K. Khan, Dermatology Life Quality Index (DLQI)—a simple 
practical measure for routine clinical use. Clinical and Experimental Dermatology, 
1994. 19(3): p. 210-216. 
25. 
Ruft, J., et al., Development and validation of the Cholinergic Urticaria Quality-of-
Life Questionnaire (CholU-QoL). Clin Exp Allergy, 2018. 48(4): p. 433-444. 
26. 
Altrichter, S., et al., Development of a standardized pulse-controlled ergometry test for 
diagnosing and investigating cholinergic urticaria. Journal of Dermatological Science, 
2014. 75(2): p. 88-93. 
27. 
Heinzerling, L., et al., The skin prick test - European standards. Clin Transl Allergy, 
2013. 3(1): p. 3. 
28. 
FDA, Food and Drug Administration. Patient-Focused Drug Development Guidance 
Public Workshop. Methods to Identify What is Important to Patients & Select, Develop 
or Modify Fit-for-Purpose Clinical Outcomes Assessments. 15-16 Oct. 2018. 
29. 
Ohanyan, T., et al., Responsiveness and minimal important difference of the urticaria 
control test. J Allergy Clin Immunol, 2017. 140(6): p. 1710-1713.e11. 
30. 
Zuberbier, T., et al., The EAACI/GA(2) LEN/EDF/WAO Guideline for the definition, 
classification, diagnosis, and management of urticaria: the 2013 revision and update. 
Allergy, 2014. 69(7): p. 868-87. 
31. 
Finlay, A.Y. and G.K. Khan, Dermatology Life Quality Index (DLQI)--a simple 
practical measure for routine clinical use. Clin Exp Dermatol, 1994. 19(3): p. 210-6. 
32. 
Ruft, J., et al., Development and validation of the Cholinergic Urticaria Quality-of-
Life Questionnaire (CholU-QoL). Clinical & Experimental Allergy, 2018. 48(4): p. 
433-444. 
33. 
Weller, K., et al., Development and validation of the Urticaria Control Test: a patient-
reported outcome instrument for assessing urticaria control. J Allergy Clin Immunol, 
2014. 133(5): p. 1365-72, 1372.e1-6. 
34. 
Hawro, T., et al., Comparison and interpretability of the available urticaria activity 
scores. Allergy, 2018. 73(1): p. 251-255. 
35. 
ICH, International Council for Harmonisation of Technical Requirements for 
Pharmaceuticals for Human Use: Clinical Safety Data Management. Definitions and 
Standards for Expected Reporting (E2A), Step 4; 27-Oct. 1994. 
36. 
Common Terminology Criteria for Adverse Events (CTCAE) Version 5.0.  November-
27-2017]; Available from: 
https://ctep.cancer.gov/protocoldevelopment/electronic_applications/docs/CTCAE_v5
_Quick_Reference_8.5x11.pdf  
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37. 
European Parliament Union and C.o.T. European, Directive 2001/20/EC of the 
European Parlament and of the Council of 4 April 2001 on the approximation of the 
laws, regulations and administrative provisions of the Member States relating to the 
implementation of good clinical practice in the conduct of clinical trials on medicinal 
products for human use, 2001, Ema, Editor. 2001. 
38. 
CIOMS, International Ethical Guidelines for Health-related Research Involving 
Humans. Council for International Organizations of Medical Sciences. 2016: Geneva. 
39. 
ICH, International Council for Harmonisation of Technical Requirements for 
Pharmaceuticals for Human Use. Integrated addendum to ICH E6(R1): Guideline for 
good clinical practice E6(R2). 2016. 
40. 
Schulz, K.F., D.G. Altman, and D. Moher, CONSORT 2010 Statement: updated 
guidelines for reporting parallel group randomised trials. BMC Med, 2010. 8: p. 18. 
 
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Appendix 1: Definitions of adverse events and serious adverse events 
Adverse event definition 
An AE is defined as any untoward medical occurrence in a patient or clinical investigation 
subject administered a pharmaceutical product and which does not necessarily have a causal 
relationship with this treatment. An AE can therefore be any unfavourable and unintended 
sign (including an abnormal laboratory finding), symptom, or disease temporally associated 
with the use of a medicinal (investigational) product, whether or not related to the medicinal 
(investigational) product. [35] 
This definition includes: 
• Accidental injuries. 
• Events related to trial procedures. 
• Reasons for any unfavourable and unplanned change in medication (drug 
and/or dose). 
• Clinically significant worsening of pre-existing conditions. 
• Reasons for admission to hospital or surgical procedures unless these were 
planned before the subject consented to trial participation. 
• AEs commonly observed and AEs anticipated based on the pharmacological 
effect of the IMP.  
• Any laboratory abnormality assessed as clinically significant by the 
investigator (see Section 11.4.4.2). 
Serious adverse event definition 
An SAE is any untoward medical occurrence that: 
• Results in death. 
• Is life-threatening – at risk of death at the time of the SAE (not an event that 
hypothetically might have caused death if more severe). 
• Requires inpatient hospitalization or prolongation of existing hospitalization*. 
• Results in persistent or significant disability/incapacity. 
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• Is a congenital anomaly/birth defect. 
• Is a medically important condition. Events that may not be immediately 
life-threatening or result in death or hospitalisation but may jeopardise the 
subject or may require intervention to prevent one of the other outcomes listed 
in the definition above. Examples are intensive treatment in an emergency 
room or at home for allergic bronchospasm, blood dyscrasias, and convulsions 
that do not result in hospitalisation, development of drug dependency, or drug 
abuse. 
Additionally, all malignancies, incl. skin malignancies, should be reported as SAEs.  
*Hospitalization for procedures or treatments planned prior to the subject consented to trial 
participation does not constitute an AE and should therefore not be reported as AE or SAE. 
Hospitalization for elective treatment of a pre-existing condition which did not worsen from 
the subject consented to trial participation is not considered an AE and should therefore not be 
reported as AE or SAE, even if not planned before consent to trial participation. 
Hospitalization for routine scheduled treatment or monitoring not associated with any 
aggravation of the condition does not constitute an AE and should therefore not be reported as 
AE or SAE. 
Hospitalization for administrative purpose does not constitute an AE and should therefore not 
be reported as AE or SAE. 
Complications that occur during hospitalization are AEs. If a complication prolongs 
hospitalization, the event is an SAE. 
When in doubt as to whether hospitalization occurred, the AE should be considered serious. 
Definition of adverse events of special interest 
An AESI (serious or non-serious) is an event type of scientific and medical concerns specific 
to the product or development program, for which additional monitoring may be appropriate. 
Such an event might warrant further investigation in order to characterise and understand it. 
Depending on the nature of the event, rapid communication by the investigator to the sponsor 
and/or from the sponsor to other parties (e.g. regulators) might also be warranted. 
AESIs are described in Section 13.5.2 and Section 13.6.1. 
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Appendix 2: Classification of adverse events 
Severity 
The severity of the AE should be described in terms of mild, moderate, or severe according to 
the investigator’s clinical judgement. 
Mild 
An AE that is usually transient and may require only minimal treatment or 
therapeutic intervention. The event does not generally interfere with usual 
activities of daily living. 
Moderate 
An AE that is usually alleviated with additional specific therapeutic 
intervention. The event interferes with usual activities of daily living, 
causing discomfort but poses no significant or permanent risk of harm to the 
subject. 
Severe 
An AE that interrupts usual activities of daily living, or significantly affects 
clinical status, or may require intensive therapeutic intervention. 
If the severity of an AE worsens, a new AE should be recorded. 
Causality 
The causal relation of the AE to the use of the IMP should be described in terms of probably, 
possibly, or not related according to the investigator’s clinical judgement.  
Probably 
related 
Follows a reasonable temporal sequence from administration of the IMP. 
 
Could not be reasonably explained by the subject’s clinical state, 
environmental or toxic factors or other therapies administered to the 
subject. 
 
Follows a known pattern of response to the IMP. 
 
Disappears or decreases on cessation or reduction in dose of the IMP. 
 
Reappears or worsens upon re-challenge. 
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Possibly 
related 
 
Follows a reasonable temporal sequence from the administration of the 
IMP. 
 
Could also be reasonably explained by the subject’s clinical state, 
environmental or toxic factors or other therapies administered to the 
subject. 
 
Follows a known pattern of response to the IMP. 
Not related 
 
Does not follow a reasonable temporal sequence from administration of the 
IMP. 
 
Is better explained by other factors like the subject’s clinical state, 
environmental or toxic factors or other therapies administered to the 
subject. 
 
Does not reappear or worsen upon re-challenge. 
 
Does not follow a known pattern of response to the IMP. 
 
Outcome 
The outcome of the event according to the investigator’s clinical judgement should be 
classified using the categories below. 
Recovered/ 
resolved 
The event has stopped. The stop date of the event must be recorded. 
Recovering/ 
resolving 
The subject is clearly recovering from an event. The event is not yet 
completely resolved.  
Not 
recovered/ 
not resolved 
Event is still ongoing.  
Recovered/   
resolved with 
sequelae 
The event has reached a state where no further changes are expected and the 
residual symptoms are assumed to persist. An example is hemiparesis after 
stroke. 
The stop date of the event must be recorded. In case of a SAE, the sequelae 
should be specified. 
Fatal 
The subject has died as a consequence of the event. Date of death is recorded 
as stop date for the AE. 
Unknown 
Unknown to investigator, e.g. subject lost to follow-up. 
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LEO Pharma definitions versus CDISC definitions 
Note that as per the above definition, LEO Pharma uses “recovered/resolved” only if an event 
has actually stopped. According to the CDISC definition, the category “recovered/resolved” 
also includes events which have improved. However, following the LEO Pharma definitions 
above, such an improved event will instead be classified as “not recovered/not resolved” or 
“recovering/resolving”. 
Similarly, it should be noted that as per the above definition, LEO Pharma uses 
“recovered/resolved with sequelae” only if an event has reached a state where the residual 
symptoms are assumed to persist. According to CDISC, an event is considered “with 
sequelae”, if it has “retained pathological conditions”. Consequently, it is likely that some of 
the events classified by LEO Pharma with the outcome “recovered/resolved with sequelae” 
could have been classified with the outcome “recovered/resolved” according to the CDISC 
definition. 
In summary, the definitions used by LEO Pharma are more conservative than those used by 
CDISC. 
.  
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Appendix 3: Trial governance considerations 
Appendix 3A: Regulatory and ethical considerations 
This trial will be conducted in accordance with the protocol and with the following: 
• Consensus ethical principles derived from international guidelines including the 
current version of the Declaration of Helsinki [18] and Council for International 
Organizations of Medical Sciences (CIOMS) International Ethical Guidelines [38]. 
• Current version of applicable International Council for Harmonisation Good Clinical 
Practice (ICH GCP) Guidelines [39]. 
• EU General Data Protection Regulation 2016/679 of 27 April 2016. 
• Applicable laws and regulations. 
 The German regulatory authority must approve the clinical trial as required. 
Any documents that the IRB/IEC may need to fulfil its responsibilities (such as the trial 
protocol, protocol amendments, investigator’s brochure [as applicable], subject information 
sheet, and informed consent form(s), or advertisements) will be submitted to the IRB/IEC. 
These documents must be reviewed and approved by the IRB/IEC before the trial is initiated. 
Any amendments to the protocol must be approved by/receive favourable opinion from 
German regulatory authority and IRBs/IECs, as required, prior to implementation. 
The principal investigator will be responsible for the following, if required by local 
legislation: 
• Providing written summaries of the status of the trial to the IRB/IEC annually or more 
frequently in accordance with the requirements, policies, and procedures established 
by the IRB/IEC. 
• Notifying the local IRB/IEC of SAEs or other significant safety findings as required 
by IRB/IEC procedures. 
• Providing oversight of the conduct of the trial at the trial site and ensuring adherence 
to applicable national and international legislation. 
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Appendix 3B: Informed consent process  
Subjects will receive written and verbal information concerning the clinical trial. This 
information will emphasise that participation in the clinical trial is voluntary and that the 
subject may withdraw from the clinical trial at any time and for any reason. All subjects will 
be given an opportunity to ask questions and will be given sufficient time to consider before 
consenting. 
The subject’s signed and dated informed consent to participate in the clinical trial will be 
obtained prior to any clinical trial-related procedure being carried out in accordance with 
ICH GCP and all applicable laws and regulations. The authorised person obtaining the 
informed consent must also sign the ICF. 
Subjects will be re-consented to the most current version of the ICF(s) during their 
participation in the trial, if required. 
A copy of the ICF(s) must be provided to the subject.  
Subject card 
At randomisation, subjects will be provided with a card stating that they are participating in a 
clinical trial and which contains contact address and telephone number(s) of relevant trial site 
staff including the number for the investigator in case of emergency situations. The subject 
card also includes subject’s randomisation code number and a local telephone number for the 
emergency unblinding CRO to be used if the investigator or delegated site staff cannot be 
reached.  
Appendix 3C: Subject and data confidentiality 
This clinical trial protocol as well as all other information, data, and results relating to this 
clinical trial and/or to the IMP is confidential information of LEO Pharma and shall not be 
used by the investigator for purposes other than this clinical trial. 
The investigator agrees that LEO Pharma may use any and all information, data, and results 
from this clinical trial in connection with the development of the IMPs and, therefore, may 
disclose and/or transfer information, data and/or results to other investigators, regulatory 
authorities, and/or commercial partners. 
Trial subjects will be assigned a unique identifier (subject ID) by LEO Pharma. Any subject’s 
records or datasets that are transferred to LEO Pharma will contain the identifier only; subject 
names or any information which would make the subject identifiable will not be transferred.  
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Trial subjects must be informed that their personal trial-related data will be used by LEO 
Pharma in accordance with local data protection law.   
Trial subjects must be informed and consent to that their medical records may be examined by 
clinical quality assurance auditors or other authorised personnel appointed by LEO Pharma, 
by appropriate IRB/IEC members, and by inspectors from regulatory authorities. 
Trial subjects must be informed that LEO Pharma might keep their trial-related data for as 
long as they are useful for developing treatments for the disease or other diseases and future 
research. 
Processing of personal data 
This protocol specifies the personal data on trial subjects (for example race, ethnicity, age, 
gender, health condition, medical history, test results, etc.) which shall be collected as part of 
the clinical trial and processed during and after trial completion. 
Personal data collected as part of the clinical trial will be transferred to/from the 
institution/investigator, LEO Pharma, and third parties acting on behalf of LEO Pharma. 
Processing of personal data on behalf of LEO Pharma requires a written agreement between 
LEO Pharma and the relevant party which covers collection, processing, and transfer of 
personal data in the clinical trial. In certain cases, an agreement on transfer of personal data 
may also be required. 
Investigators and LEO Pharma must ensure that collection, processing and transfer of 
personal data are in compliance with applicable legislation on data protection and privacy, 
including but not limited to the EU General Data Privacy Regulation. 
Subjects must be asked to consent to the collection, processing, and transfer of their personal 
data to EU and non-EU countries for the purpose of conducting the clinical trial, research and 
development of new or existing products/services, improving existing products/services, 
applying for marketing authorisations for products/services, marketing of products/services 
and other related activities. 
LEO Pharma has obtained the necessary authorisations for the processing of personal data 
collected in the trial. 
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Appendix 3D: Record keeping, quality control, and data handling 
Source data at trial sites 
For all data recorded, the source document must be defined in a source document agreement 
or similar document at each trial site. There must only be 1 source defined at any time for any 
data elements. 
Source data should as a general rule be recorded in the subject’s medical record or other 
defined document normally used at the trial site. Source data not normally collected as a 
routine part of the clinical practice at the site may be entered on a worksheet. Clinical 
assessments/safety evaluations must be signed and dated by medically qualified investigators. 
If the worksheet does not become part of the subject’s medical record, the following should as 
a minimum be added to the subject’s medical record: 
• Subject ID. 
• Randomisation code number. 
• The fact that the subject is participating in a clinical trial in cholinergic 
urticaria including treatment with LEO 152020 and placebo for up to 6 weeks. 
• Other relevant medical information. 
Trial monitoring 
During the course of the trial, CRA(s) will visit the trial site. These visits have the following 
objectives: (i) to continually verify source data to confirm that data entered into the eCRF by 
authorised site personnel are accurate, complete, and verifiable from source documents; (ii) to 
confirm that the safety and rights of subjects are being protected; and (iii) to confirm that the 
trial is being conducted in accordance with the currently approved protocol and any other trial 
agreements, ICH GCP, and all applicable regulatory requirements. 
A risk-based monitoring approach will be applied. The monitoring visit intervals will depend 
on the trial site’s recruitment rate and the compliance of the trial site with the protocol and 
ICH GCP. The level of source data verification, data checks, and visit intervals will be 
specified in the monitoring guideline.  
In addition to on-site monitoring, pre-specified trial data will undergo central monitoring as 
specified in the trial’s data review plan.   
In order to perform their role effectively, CRAs and persons involved in quality assurance and 
inspections will need direct access to source data, for example, medical records, laboratory 
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reports, appointment books, etc. If the electronic medical record does not have a visible audit 
trail, the investigator must provide the CRA with signed and dated printouts. In addition, 
relevant site staff should be available for discussions at monitoring visits and between 
monitoring visits (e.g. by telephone). 
Protocol compliance 
Protocol deviations will be documented and notified to the investigator. Protocol deviations 
will be assessed by LEO Pharma and major deviations described in the CTR. 
Sponsor audits, IRB/IEC review, and regulatory agency inspections 
The clinical trial will be subject to audits conducted by LEO Pharma or inspections from 
domestic or foreign regulatory authorities or from IRBs/IECs. Audits and inspections may 
take place during or after the trial. The investigator and the site staff as well as LEO Pharma 
staff have an obligation to cooperate and assist in audits and inspections. This includes giving 
auditors and inspectors direct access to all source documents and other documents at the trial 
site relevant to the clinical trial. This includes permission to examine, verify, and reproduce 
any records and reports that are important to the evaluation of the trial. 
If the trial site is contacted for an inspection by competent authorities, LEO Pharma must be 
notified immediately. 
Data handling 
Data will be collected by means of electronic data capture unless transmitted electronically to 
LEO Pharma or designee (e.g., laboratory data). The investigator or staff authorised by the 
investigator will enter subject data into electronic CRFs (eCRF). Data recorded in the eCRF 
will be accessible to the trial site and LEO Pharma personnel immediately after entry. The 
eCRF must be maintained in an up-to-date state by the trial site at all times. 
The investigator must verify the correctness of the data entered by the site by electronically 
dating and signing all eCRF used. This signature information will be kept in the audit trail and 
cannot be altered. Any correction(s) made by the investigator or authorised site staff to the 
eCRF after original entry will be documented in the audit trail. Changes to data already 
approved will require re-signature by the investigator. The person making the change to the 
data, and the date, time, and reason for the change will be identified in the audit trail. 
Subject data should be entered into the eCRF no later than 5 working days after each visit, 
unless a different deadline is stated in the clinical trial agreement. Queries for discrepant data 
will be generated automatically by the system upon entry or manually by the CRA, sponsor’s 
medical expert, or the data manager. All queries will be raised electronically within the 
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electronic data capture system. This systematic validation will ensure that a clean and 
consistent database is provided for the statistical analysis. 
External data transfers from vendors to LEO Pharma will be transmitted and handled via a 
secure file transfer protocol site.  
Transmissions of data are documented in more detail in appropriate plans such data 
management plan which is part of the trial master file.  
Used standards 
CDISC controlled terminology version 06-Nov-2020 was used for definition of controlled 
terminology used throughout this protocol and will be used for statistical programming and 
output. SDTM version 1.7 will be used for data tabulations. 
Archiving of trial documentation 
The investigator at each trial site must make arrangements to store the essential trial 
documents, including the investigator trial file [39]. Essential trial documents must be stored 
until LEO Pharma informs the investigator that the documents are no longer to be retained, or 
longer if required by local regulations. 
In addition, the investigator is responsible for the archiving of all relevant source documents 
so that the trial data can be compared against source data after the completion of the trial (for 
example in case of an inspection from regulatory authorities). 
The investigator is required to ensure the continued storage of the documents even if the 
investigator leaves the trial site or retires before the end of the required storage period. 
No documents may be destroyed during the retention period without the written approval of 
LEO Pharma. No documents may be transferred to another location or party without written 
acceptance from LEO Pharma. 
The destruction process must ensure confidentiality of data and must be done in accordance 
with local regulatory requirements. 
For archiving purposes, each investigator will be supplied with an electronic copy of the 
eCRFs for all screened subjects at the trial site. This is done after completion of the trial and 
before access to the eCRF is revoked. Audit trail information will be included. eCRFs must be 
available for inspection by authorised representatives from LEO Pharma, from regulatory 
authorities and/or IRBs/ IECs. 
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Appendix 3E: Registration, reporting and publication policy 
Trial disclosure 
LEO Pharma is committed to be transparent with respect to its clinical trials. 
Basic information of this clinical trial will be registered in the global data registry, 
www.ClinicalTrials.gov before the first subject enters into the trial. The trial may also become 
registered in other online data registries, according to applicable law and regulations. 
Results of this clinical trial will be posted on the corporate website of LEO Pharma in 
accordance with our Position on Public Access to Clinical Trial Information no later than 
12 months after trial completion. Trial results may also become reported in 
www.ClinicalTrials.gov, www.clinicaltrialsregister.eu and national data registries in 
accordance with applicable law and regulations after clinical trial completion or premature 
termination.   
LEO Pharma may also provide researchers access to anonymised patient-level data for further 
research. Publication and access will be in accordance with the Position on Public Access to 
Clinical Trials which can be found on the LEO Pharma website. Moreover, LEO Pharma may 
re-use the same patient-level data for other projects within the same purpose as the trial.  
Publications 
The investigator shall be entitled to make publications of the results generated by the 
investigator in accordance with the process described here. 
A multi-site publication will be submitted for publication within 18 months after the clinical 
trial has been completed or terminated at all trial sites and all data have been received, defined 
as database lock of the clinical trial. After such multi-site publication is made public, or if no 
multi-site publication has been submitted with the above-described deadline, the investigator 
shall have the right to publish the results from the clinical trial generated by the investigator, 
subject to the following notice requirements: 
Prior to submission for publication or presenting a manuscript relating to the clinical trial, the 
investigator shall provide to LEO Pharma a copy of all such manuscripts and/or presentations. 
LEO Pharma shall have rights to review and comment. The investigator shall consider 
comments provided by LEO Pharma but is not required to modify the manuscript and/or 
presentation based on such comments, provided, however, that the investigator upon the 
request of LEO Pharma remove any confidential information (other than results generated by 
the investigator) prior to submitting or presenting the manuscripts. The investigator shall, 
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upon the request of LEO Pharma withhold the publication or presentation to allow LEO to 
protect its inventions and other intellectual property rights described in any such manuscripts.  
In case no multi-site publication has been made public at the time of investigator’s 
notification of an independent publication to LEO Pharma, LEO Pharma and the writing 
group may also delay the publication or presentation if the manuscript is deemed to harm the 
ongoing multi-site publication. 
In case of publications made by the investigator after the first multi-site publication has been 
published, the above-mentioned requirements must still be followed. 
Any publication must comply with Good Publication Practice (GPP3) standards. 
LEO Pharma complies with GPP3 standards and the recommendations from the International 
Committee of Medical Journal Editors. LEO Pharma complies with the positions of the 
International Federation of Pharmaceutical Manufacturers & Associations (IFPMA), 
European Federation of Pharmaceutical Industries and Associations (EFPIA), Japan 
Pharmaceutical Manufacturers Association (JPMA), Pharmaceutical Research and 
Manufacturers of America (PhRMA), and the joint position statement by the American 
Medical Writers Association (AMWA), the European Medical Writers Association (EMWA), 
and the International Society for Medical Publication Professionals (ISMPP) on disclosure of 
information about clinical trials, trial results and authorship. LEO Pharma also follows the 
CONSORT reporting guidelines [40]. 
Appendix 3F: Insurance 
LEO Pharma has taken out relevant insurances covering the subjects in the present clinical 
trial in accordance with applicable laws and regulations. 
Appendix 3G: Financial disclosure 
Investigators will provide LEO Pharma with sufficient, accurate financial information as 
requested to allow LEO Pharma to submit complete and accurate financial certification or 
disclosure statements to the appropriate regulatory authorities. Investigators are responsible 
for providing information on financial interests during the course of the clinical trial and for 
1 year after completion of the clinical trial, or for a longer period of time if required by local 
legislation. 
 
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Appendix 3H: Trial and trial site closure 
Premature termination of trial or trial site 
LEO Pharma, the investigator, the IRB/IECs or competent authorities may decide to stop the 
clinical trial, part of the trial or a trial site at any time, but agreement on procedures to be 
followed must be obtained. 
If a clinical trial is suspended or prematurely terminated, the investigator must inform the 
subjects promptly and ensure appropriate therapy and follow-up. As specified by applicable 
regulatory requirements, the investigator or LEO Pharma must promptly inform IRB/IECs 
and provide a detailed written explanation. Relevant competent authorities must be informed. 
The trial must be terminated if the perception of the benefit/risk ratio (judged from clinical 
signs and symptoms, (S)AEs and/or remarkable safety laboratory changes) becomes 
unfavourable for the continuation of the trial. 
Reasons for the early closure of a trial site by LEO Pharma or investigator may include but 
are not limited to: 
• Failure of the investigator to comply with the protocol, the requirements of the 
IRB/IEC or local health authorities, LEO Pharma procedures, or GCP 
guidelines. 
• Inadequate recruitment of subjects by the investigator. 
Completion of trial 
Investigators will be informed when subject recruitment is to cease. Screening activities will 
be stopped at a trial site when the total requested number of subjects for the clinical trial has 
been obtained, irrespective of the specific site’s planned inclusion number. 
Trial sites will be closed upon trial completion. LEO Pharma will undertake arrangements for 
the collection and disposal of any unused trial material that the investigator is not required to 
keep in his/her files. A trial site is considered closed when all required documents and trial 
supplies have been collected and a trial site closure visit has been performed. 
 When the randomisation code has been broken, the investigators will receive information 
about the treatment allocation for the subjects randomised at their respective sites and will be 
asked to record this in the subject’s medical record.  
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Appendix 3I: Responsibilities 
The signatory investigator is responsible for the approval of the clinical trial protocol and 
the CTR on behalf of all clinical trial investigators and as agreed to in a signatory investigator 
agreement. 
Each participating investigator is responsible for all aspects of the clinical trial conduct at 
his/her trial site as agreed to in a clinical trial agreement.  
 
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Appendix 4: Examples of prohibited medication 
 
Medication known to inhibit the BCRP 
transporter 
Within 5 half-lives prior to baseline until 
Safety follow-up 
• Bempedoic acid 
• Obeticholic acid 
• Telmisartan 
• Teriflunomide 
 
Medications known to inhibit the P-gp 
transporter 
Within 5 half-lives prior to baseline until 
Safety follow-up 
• Amiodarone 
• Amlodipine 
• Atorvastatin (acid) 
• Azithromycin 
• Baloxavir marboxil 
• Bitopeectin 
• Canagliflozin 
• Carvedilol 
• Cefuroxime 
• Cetirizine 
• Clarithromycin 
• Diltiazem 
• Dronedarone 
• Elagolix 
• Erythromycin 
• Flibanserin 
• Fluvoxamine 
• Fostamatinib 
• Isavuconazole 
• Istradefylline 
• Itraconazole 
• Ivacaflor 
• Ketoconazole 
• Maribavir 
• Methadone 
 
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• Mirabegron 
• Naproxen 
• Nefazodone 
• Nystatin 
• Omeprazole 
• Pantoprazole 
• Paroxetine 
• Pilsicainide 
• Posaconazole 
• Praziquantel 
• Propafenone 
• Quinidine 
• Ranolazine 
• Rifampin 
• Risperidone 
• Rolapitant 
• Sarecycline 
• Suvorexant 
• Talinolol 
• Telithromycin 
• Tezacaftor 
• Ticagrelon 
• Tolvaptan 
• Valbenazine 
• Verapamil 
• Vorapaxor 
• Voriconazole 
Medication known to inhibit the OAT3 
Within 5 half-lives prior to baseline until 
Safety follow-up 
• Probenecid 
 
 
 
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Appendix 5: Short version of eligibility criteria 
 
Inclusion criteria 
No. 
Short version 
1 
Signed and dated informed consent 
2 
Subject with a history of CholU diagnosis for ≥ 6 months 
3 
Subject has active and uncontrolled CholU disease at the time of screening and randomisation, 
as defined by the following: 
a. 
Urticaria control test (UCT) < 12 at screening 
b. UASprovo ≥ 3 (with a minimum wheal score of ≥ 1 and minimum itch score of ≥ 1) at 
screening* and randomisation. 
*Screening provocation test is optional if patients had a prior provocation test that met 
threshold within 6 months of day 1 (visit 2) 
4 
Subjects aged ≥ 18 years 
5 
Subjects must not have more than one missing diary entry in the 7 days prior to randomisation. 
6 
Recent history CholU diagnosis (within 6 months) with documented inadequate response to 
standard dose as to marketing authorization H1 antihistamines 
7 
Female subjects of childbearing potential must use a double contraception (highly effective 
plus barrier forms) of contraception from screening until the end of the trial (safety follow up 
visit). 
8 
Male subjects with a female partner of child-bearing potential must use adequate double 
contraceptive methods (barrier from in conjunction with a highly effective form of female 
contraception for the partner) from randomisation to safety follow-up visit. 
Exclusion criteria 
No. 
Short version  
1 
Other forms of clearly dominating urticaria as aetiology for wheal and flare type reactions, 
including: 
a. 
Chronic spontaneous urticaria 
b. Inducible urticaria: urticaria factitia / symptomatic dermographism, cold-, heat-, solar-
, pressure-, vibratory-, aquagenic-, or contact-urticaria 
Note: The other forms of diseases mentioned above are allowed as comorbidities, if cholinergic 
urticaria is the dominating form of chronic urticaria 
2 
Clinically significant infection within 4 weeks prior to randomisation that may compromise the 
safety of the subject 
3 
History of lymphoproliferative disease or any known or history of malignancy within the past 5 
years 
4 
Risk factors for Torsades de Pointe including 
a. 
Uncorrected hypokalemia, hypocalcemia or hypomagnesemia, history of cardiac 
failure, or history of clinically significant/symptomatic bradycardia 
b. (Congenital) long QT syndrome or family history of idiopathic sudden death 
c. 
Concomitant medication(s) with a known risk of Torsades de Pointe 
d. Other cardiac arrhythmia risk factors at the discretion of the investigator 
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5 
Concomitant drugs with known prolongation of QT interval within 5 half-lives prior to 
screening 
6 
Resting QTcF (average of a triplicate measurement) < 300 msec or > 450 msec at screening  
7 
Known history of ventricular arrhythmias 
8 
Second- and third-degree atrioventricula block 
9 
Subjects with signs of renal impairment as determined by eGFR levels below 90 mL/min at 
screening 
10 
Subjects with signs of hepatic impairment as determined by abnormal liver function tests, 
defined as total bilirubin, aspartate aminotransferase or alanine aminotransferase >1.5 x the 
upper limit of normal (ULN) range, at screening 
11 
Infection with human immunodeficiency virus (HIV) 
12 
Presence of hepatitis B or C infection 
13 
Subjects with confirmed active infection with SARS-CoV-2 AND related COVID-19 
symptoms, which at the discretion of the investigator will jeopardize the safety of the subject or 
the integrity of the data collected. Additionally, any local requirements must be followed. 
14 
Any medication known to chronically alter drug absorption or elimination processes within 
30 days prior to the first dose of IMP 
15 
Systemic immunosuppressive medications within 4 weeks prior to screening  
16 
Systemic corticosteroids within 4 weeks prior to screening and throughout the trial (except for 
inhaled or intranasal steroids equivalent to doses up to 1 mg prednisone daily) 
17 
Drugs which are known inhibitors of the P-gp and BCRP transporters and the strong OAT3 
inhibitor probenecid within 1 weeks prior to randomisation or 5 half-lives (whichever is 
longer) 
18 
Systemic drugs (e.g. oral drug) with antihistamine properties including H1 antihistamines and 
some antidepressants (e.g. tricyclic antidepressants) and H2 antihistamines 1 week prior to 
randomization. However, topical antihistamines in the form of nasal spray and eyedrops are 
allowed in the standard prescribed dose. 
19 
Use of tanning beds or phototherapy within 4 weeks of screening 
20 
Known or suspected hypersensitivity to any component(s) of the IMP 
21 
Known hypersensitivity to iodine 
22 
Current participation in any other interventional clinical trial 
23 
Treatment with any non-marketed drug substance within last 3 months 
24 
Previous randomisation in this trial. 
25 
History of chronic alcohol or drug abuse within 12 months 
26 
Any subject dependent from trial site, sponsor or subcontractors 
27 
Subjects who are legally institutionalised 
28 
Female subject who are pregnant or lactating 
29 
Any unstable medical, surgical, psychiatric, or additional physical disorder which according to 
investigator’s opinion could  
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• 
Affect subject safety and well-being 
• 
Influence the findings of the trial. 
• 
Impede the subject’s ability to complete the trial. 
30 
Any clinically significant abnormal finding at screening and/or baseline which according to 
investigator’s opinion may 
• 
Affect subject safety and well-being 
• 
Influence the findings of the trial or subject’s ability to complete the trial. 
 
 
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Appendix 6: Contact list 
Contact details for the CPM, appointed CRA, and sponsor’s medical expert are provided to 
the trial sites as a separate contact list. 
Sponsor 
LEO Pharma A/S (referred to as ‘LEO Pharma’ or ‘the sponsor’ in this clinical trial protocol) 
is the sponsor of the clinical trial: 
LEO Pharma A/S  
Industriparken 55 
DK-2750 Ballerup 
Denmark 
 
Coordinating investigator 
Germany 
 
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Appendix 7: Protocol amendment history 
Amendment 5 (09-Mar-2022) 
This amendment is considered substantial based on the criteria set forth in Article 10(a) of 
Directive 2001/20/EC of the European Parliament and the Council of the European Union or 
subsequent regulation. 
Overall rationale for the amendment: 
Due to a change of location and the new foundation of the 
 
 under the direction of 
 and 
, the contact details of the Coordinating Investigator have changed 
and have been updated with this amendment. Furthermore, this amendment takes into account 
the change of the statistician. 
Section no.  
and name 
Description of change 
Brief rationale 
1. Protocol 
synopsis 
Appendix 6: 
Contact List 
Change of contact details for 
the Signatory Investigator 
(Coordinating Investigator): 
Formerly: 
New: 
Germany 
Change of address 
 
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Section no.  
and name 
Description of change 
Brief rationale 
Clinical trial 
protocol 
statements 
 has been replaced 
by 
, the new lead 
statistician at LEO Pharma A/S 
Due to personnel changes and changes 
in project responsibility at LEO 
Pharma A/S, it is necessary to adapt 
the Approval Statement accordingly 
 
 
 
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Amendment 4 (06-Dec-2021) 
This amendment is considered non-substantial based on the criteria set forth in Article 10(a) 
of Directive 2001/20/EC of the European Parliament and the Council of the European Union 
or subsequent regulation. 
Overall rationale for the amendment: 
Contact details of LEO Global Drug Safety have been updated 
Section no.  
and name 
Description of change 
Brief rationale 
9.10 Reporting 
Product 
Complaints 
13.4.1 
Investigator 
Reporting 
Responsibilities 
New Fax Number added:  
Global Safety at LEO Pharma 
E-mail address: 
drug.safety@leo-pharma.com 
Fax number:  +45 7226 3287 
+45 6910 2468  
 
Change of Fax Number 
 
 
 
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Amendment 3 (15-Jun-2021) 
This amendment is considered substantial based on the criteria set forth in Article 10(a) of 
Directive 2001/20/EC of the European Parliament and the Council of the European Union or 
subsequent regulation. 
Overall rationale for the amendment: 
As patients with cholinergic urticaria belong to a group of patients with a general 
predisposition to allergies, exclusion criterion 18 was changed to obtain a study population as 
representative as possible and to support recruitment by allowing patients to continue topical 
use of antihistamines if necessary to treat concomitant allergies. 
Section no.  
and name 
Description of change 
Brief rationale 
1 
Protocol 
synopsis 
8.3  
Exclusion 
criteria 
Appendix 5 
Short version 
of eligibility 
criteria 
Exclusion criterion 18 has been 
rephrased as follows, allowing 
previous or concomitant 
treatment with topical 
antihistamines. 
From: 
Drugs with antihistamine 
properties including H1 
antihistamines and some 
antidepressants (e.g. tricyclic 
antidepressants) and H2 
antihistamines 1 week prior to 
randomisation and throughout 
the trial. 
To: 
Systemic drugs (e.g. oral drug) 
with antihistamine properties 
including H1 antihistamines 
and some antidepressants (e.g. 
tricyclic antidepressants) and 
After recruitment of the first patients 
with cholinergic urticaria, it became 
apparent that a general prohibition of 
antihistamines would significantly 
limit the inclusion of a representative 
study population characterised by a 
general predisposition to allergies.  
As systemic availability of 
antihistamines after topical 
application is considered negligible, it 
was decided to allow the use of 
topical antihistamines (e.g. nasal 
sprays and eye drops) for the 
treatment of concomitant allergies 
(e.g. allergic rhinitis or hay fever), if 
applied in the standard prescribed 
dose. 
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Section no.  
and name 
Description of change 
Brief rationale 
H2 antihistamines 1 week prior 
to randomisation and 
throughout the trial. However, 
topical antihistamines in the 
form of nasal spray and 
eyedrops are allowed in the 
standard prescribed dose. 
4 
Schedule of 
trial procedures 
7.1.1 
Screening 
phase 
In line with the permission to 
continue treatment with topical 
antihistamines in the standard 
prescribed dose, the 
corresponding footnote in the 
schedule of study procedures 
(section 4) and the note on 
adherence to a 1-week washout 
period for antihistamines 
and/or medications with 
antihistamine properties in the 
description of the screening 
procedures (section 7.1.1) have 
been updated accordingly. 
 
9.7 
Prohibited 
medication(s) 
and procedures 
 
With the permission to 
continue treatment with topical 
antihistamines, it also became 
necessary to adapt panel 5 by 
introducing a note for H1 
antihistamines indicating that 
treatment with topical 
antihistamines will be allowed 
throughout the study if used in 
the standard prescribed dose. 
 
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Section no.  
and name 
Description of change 
Brief rationale 
Approval 
statement LEO 
Pharma A/S 
The position of the medical 
lead has been changed from 
“Medical Sciences” to 
“Translational Medicine, 
Research & Early 
Development”. 
With the last Amendment 
(Amendment 2, dated 16-Apr-2021) 
 has been introduced 
as new medical lead. Due to internal 
reorganisation at LEO Pharma A/S, 
the position of the medical lead has 
changed and has now been adjusted 
accordingly in the Approval 
Statement. 
All sections 
Correction of typos and 
grammatical errors throughout 
the protocol. 
Not applicable 
 
 
 
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Amendment 2 (16-Apr-2021) 
This amendment is considered to be non-substantial based on the criteria set forth in Article 
10(a) of Directive 2001/20/EC of the European Parliament and the Council of the European 
Union or subsequent regulation because it neither significantly impacts the safety or 
physical/mental integrity of subjects nor the scientific value of the trial. 
Overall rationale for the amendment: 
The general study procedures, objectives, methods etc. are NOT altered; also, the in- and 
exclusion criteria are NOT changed. In those respects, Clinical Trial Protocol, version 
(Amendment 1) remains valid - with the corrections presented here. 
However, some inconsistencies and/or imprecision render an update of those passages 
necessary to clarify the intent of the original protocol. Furthermore, the Approval Statement 
needed to be updated due to personnel changes at LEO Pharma A/S. 
Section no. and 
name 
Description of change 
Brief rationale 
4 
Schedule of 
trial procedures 
 
 
 
 
 
 
 
 
A footnote has been added to 
the screening phase referring to 
the need for a 7 days screening 
period in minimum to ensure to 
ensure a 7-day documentation 
of the ChloUAS (in the 
patient's diary) for calculation 
of the CholUAS7 at baseline 
visit (visit 2), and if applicable 
to respect a) a minimum 
interval of 7 days between two 
UAS provocation tests and/or 
,b) a 1-week washout period 
for antihistamines and/or 
medications with antihistamine 
properties. 
 
In order to emphasise that a minimum 
screening period of 7 days is required, 
i.e. that the screening visit (visit 1) 
must be carried out at least 7 days 
before the baseline visit (visit 2) to 
allow all study procedures to be 
carried out in accordance with the 
protocol before randomisation, it was 
considered necessary to add this 
information explicitly. 
 
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Section no. and 
name 
Description of change 
Brief rationale 
 
7.1.1 
Screening 
phase 
 
To further describe that the 
patient’s diary must be handed 
over 7 days prior to the 
baseline visit at the latest, this 
information was added to 
section 7.1.1 providing an 
overview regarding the 
activities to be performed 
during the screening phase. 
4 
Schedule of 
trial procedures 
 
 
 
 
 
 
 
 
 
7.1.3 
Visit 6 – Safety 
Follow-up 
 
In footnote 1, information was 
added that the early termination 
(ET) visit (in addition to the 
safety follow-up visit) should 
be conducted as soon as 
possible after the last 
administration of the IMP to 
obtain a final efficacy 
assessment. Furthermore, it 
was clarified that no ET-visit 
needs to be conducted if this 
visit cannot be scheduled 
within a maximum of 3 days 
after the last administration of 
the IMP. In this latter case, 
every effort should be done to 
perform the regular safety 
follow-up (visit 6) as the last 
visit. 
 
The phrase “early termination / 
end of study visit” was 
changed to “early termination / 
During the development of the eCRF, 
it became apparent that the description 
of the visits to be conducted in the 
event of early withdrawal from the 
trial and the timing of their conduct 
were not entirely clear. It was 
therefore deemed necessary to amend 
the description of the respective visits 
accordingly and to further clarify that 
the ET-visit is primarily to obtain a 
final efficacy assessment, while the 
follow-up visit (regular visit 6) aims 
to ensure patient's safety. 
 
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Section no. and 
name 
Description of change 
Brief rationale 
 
 
10.3 
Early 
termination 
assessments 
end of treatment visit” to make 
sure that the ET-visit is to be 
performed as soon as possible 
after the last administration of 
the IMP. 
To be precise and to provide 
clear instructions, the 
information on the time frame 
for conducting the ET-visit 
and/or the safety follow-up 
visit (visit 6) has been revised. 
9.8.2 
Storage of Trial 
Products 
The reference to higher storage 
temperatures than those 
indicated on the label of the 
IMP has been deleted. 
To be consistent with the labelling of 
the IMP, it became necessary to delete 
the reference in regard to possibly 
higher storage temperatures of the 
IMP. 
11.3.4.2 
Urticaria 
Control Test 
The individual ratings for the 
response options for the 4 
questions of the Urticaria 
Control Test (UCT) have been 
added in Panel 7. 
For reasons of clarity, the response 
options to each of the 4 questions of 
the UCT in Panel 7 were 
supplemented by their individual 
rating on a scale from 0 to 4. 
11.3.4.3 
Cholinergic 
Urticaria 
Activity Score 
7 
The description of the 
Cholinergic Urticaria Activity 
Score 7 (CholUAS7) has been 
updated to correctly reflect that 
this validated questionnaire 
consists of a total of 4 
questions. 
During the final reconciliation 
between the protocol and the 
eCRF/patient diary, it was noticed that 
the description of the CholUAS7 in 
the original protocol was not 
completely correct, as the CholUAS7 
questionnaire consists of a total of 4 
questions and not of only 2 questions 
regarding the severity of hives and 
itching. Therefore, it was necessary to 
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Section no. and 
name 
Description of change 
Brief rationale 
correct the description of the 
CholUAS7 accordingly. 
Appendix 7 
Protocol 
Amendment 
History 
Newly added section, 
describing the changes 
implemented with Amendment 
1 (protocol version 2.0, dated 
09-Mar-2021). 
According to LEO SOPs it became 
necessary to add an additional 
Appendix, to reflect the changes 
implemented with the first 
Amendment, which became necessary 
in order to take account of objections 
raised by the BfArM (Federal Institute 
for Drugs and Medical Devices; 
German Regulatory Authority [RA]) 
and by the LAGeSo Berlin (Regional 
Office for Health and Social Affairs 
Berlin), the relevant German Ethics 
Committee (EC). 
Approval 
statement LEO 
Pharma A/S 
1) The lead in biostatistics was 
taken over by 
 
2) The medical lead was taken 
over by 
 
Due to personnel changes and changes 
in project responsibility at LEO 
Pharma A/S, it is necessary to adapt 
the Approval Statement accordingly 
All sections 
Correction of typos and 
grammatical errors throughout 
the protocol. 
Not applicable 
 
 
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Amendment 1 (09-Mar-2021) 
This amendment is considered substantial based on the criteria set forth in Article 10(a) of 
Directive 2001/20/EC of the European Parliament and the Council of the European Union or 
subsequent regulation. 
Overall rationale for the amendment: 
The Clinical Trial Protocol Version 2.0 became necessary in order to take account of 
objections raised by the BfArM (Federal Institute for Drugs and Medical Devices; German 
Regulatory Authority [RA]) received on 26-February-2021 and by the LAGeSo Berlin 
(Regional Office for Health and Social Affairs Berlin), the relevant German Ethics Committee 
(EC) received on 24-February-2021. 
Section no. 
and name 
Description of change 
Brief rationale 
Synopsis 
8.2 
Inclusion 
criteria 
12.1 
Scientific 
rationale for 
trial design 
 
Appendix 5 
To be unambiguous, “standard 
dose” in inclusion criterion #6 
has been defined as dose 
according to marketing 
authorization. 
The same definition for 
“standard dose” was in addition 
introduced in regard to the 
description of the trial 
population intended to be 
included into this trial as given 
in section 12.1 of the CTP. 
Short version of eligibility 
criteria was updated 
accordingly. 
The Regulatory Authority has asked to 
clarify whether the term "standard 
dose" of H1-antihistamines as used in 
EC#6 corresponds to a daily dose up 
to 4-fold higher than the licensed dose 
as recommended in the current 
guidelines. This would require an off-
label use of respective drugs. Since 
the sponsor and the investigator are of 
the opinion that off-label use should 
not be part of an inclusion criterion, it 
has been clarified that the term 
“standard dose” is meant in the sense 
of the licensed dose. 
8.2 
Inclusion 
criteria 
 
As a vasectomised partner is 
regarded as a highly effective 
birth control method only, if 
vasectomised partner is the sole 
sexual partner of the WOCBP 
To be in line with HMA/CTFG 
Recommendations related to 
contraception and pregnancy testing, 
version 1.1, 2020-09-21 and as 
requested by the regulatory authority, 
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Section no. 
and name 
Description of change 
Brief rationale 
trial participant and if 
vasectomised partner has 
received medical assessment of 
the surgical success, medical 
assessment of surgical success 
has been added to inclusion 
criterion #7. 
inclusion criterion #7 was updated 
accordingly. 
8.3 
Exclusion 
criteria 
 
11.4.4 
Laboratory 
testing 
 
Appendix 5 
Hypocalcaemia was added to 
inclusion criteria #7 as another 
risk factor for Torsades de 
Pointe, that need to be taken 
into consideration. 
Total and free calcium 
(albumin-corrected) as well as 
magnesium were added as 
additional lab parameters. 
Short version of eligibility 
criteria was updated 
accordingly. 
In agreement with the opinion of the 
Regulatory Authority, exclusion 
criterion #4 dealing with risk factors 
for Torsades de Pointe was updated 
including hypocalcaemia. 
Furthermore, the lab panel was 
accordingly updated in addition, as 
electrolyte imbalances are not 
necessarily accompanied with clinical 
symptoms. 
4 
Schedule of 
trial procedures 
 
 
 
 
 
 
In line with the implementation 
of additional ECG 
measurements in patients 
presenting with a moderate 
post-dose QT-prolongation, the 
schedule of procedures was 
adapted accordingly, by adding 
an additional ECG at the safety 
follow-up. Furthermore, it is 
pointed out now that ECG 
measurement at visits has to be 
repeated in case that an ECG 
measurement indicates a post-
dose QT-prolongation with a 
To be in line with the ICH guideline 
E14, the criteria for discontinuation 
and withdrawal due to QT-
prolongation was revised. The 
guideline only recommends a 
discontinuation if QTcF is equal or 
higher than 500 ms.  
To sufficiently ensure patients safety 
and well-being, additional ECG 
measures were implemented for 
patients presenting with a moderate 
post-dose QT-prolongation now. 
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Section no. 
and name 
Description of change 
Brief rationale 
 
 
 
10.2.1 
Reasons for 
permanent 
discontinuation 
of IMP 
 
 
11.4.3 
ECG 
 
 
 
 
 
 
 
 
 
 
 
 
QTcF of > 480 ms or a change in 
QTcF > 30 ms from baseline 
(pre-dose ECG) . 
Discontinuation from treatment 
with IMP due to QT-
prolongation has been changed 
from QTcF > 450 ms to 
QTcF > 500 ms or change in 
QTcF from baseline (pre-dose 
ECG) > 60 ms. 
The information that a subject 
should be discontinued from 
treatment with any clinically 
significant QT-prolongation, 
has been taken out and was 
replaced by the information 
that only subjects presenting 
with a severe QT prolongation 
(i.e. QTcF > 500 ms or a 
change in QTcF from baseline 
(pre-dose ECG) > 60 ms) 
should be discontinued from 
treatment and from the trial, if 
the severity of QT-prolongation 
has been confirmed by a 
second ECG. 
For subjects presenting with a 
moderate QT-prolongation (i.e. 
480 ms < QTcF ≤ 500 ms or 
30 ms < change in QTcF from 
baseline (pre-dose 
ECG) ≤ 60 ms) it is now 
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Section no. 
and name 
Description of change 
Brief rationale 
 
 
 
 
 
13.6.1 
Adverse events 
of special 
interest 
described, that the ECG should 
be repeated to confirm this QT-
prolongation, but that subjects 
at investigator’s discretion may 
continue with the trial and that 
an additional ECG must be 
done at the safety follow-up. 
The definition of the severity 
of the AESIs was detailed 
accordingly with the addition 
that moderate (grade 2) QT-
prolongation includes 
30 ms < change in QTcF from 
baseline (pre-dose 
ECG) ≤ 60 ms 
5.5 
Benefit/Risk 
assessment 
 
The potential benefit of a 
treatment with new 
LEO 152020 is now presented 
in the context of available 
therapeutic alternatives.  
The Regulatory Authority raised the 
objection that a summary presentation 
that puts the scientific evidence of 
known/potential/expected benefit to 
the available therapeutic alternatives 
was missing in the CTP, as required 
according to the principles of 
EMA/CHMP/ICH/135/1995 ICH 
E6[R2] "GCP" sections 2.2 and 6.2.3.. 
To address this objection, a 
corresponding section has been added 
to section 5.5. 
8.4  
Screening and 
screen failures 
The date of birth was replaced 
by the year of birth, 
respectively by subject’s age.  
The Regulatory Authority as well as 
the EC have pointed out that the 
documentation of the entire date of 
birth does not correspond to 
pseudonymization and is therefore not 
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11.2.1 
Demographics 
permissible according to Art. 32 para. 
1 a), Art. 5 para. 1 f) of Regulation 
(EU) 2016/679 (General Data 
Protection Regulation) and Sec. 40 
para. 2a p. 2 Cf. 1b) - d) AMG. 
To comply with the required 
pseudonymization, the date of birth 
was replaced by the year of birth 
(age). 
10.5 (added as 
new section) 
Criteria for the 
termination of 
the trial 
To comply with legal 
requirements, the following 
sentence has been added to the 
new section 10.5: 
“The Sponsor, the signatory 
investigator, the IECs or 
regulatory authorities may 
decide to temporarily halt / 
suspend the trial, to stop the 
trial, parts of the trial or an 
investigational site at any 
time.” 
The Regulatory Authority requested to 
supplement the CTP with the 
information that the sponsor must stop 
or terminate the study, if the favorable 
opinion or the approval is revoked 
(acc. to Sec. 42a Par. 1, 2, 4a, icw 4 
AMG). 
Outstanding information was added as 
requested. 
10.5.1 (added 
as new section) 
Termination of 
the whole trial 
10.5.2 (added 
as new section) 
Termination of 
the trial at an 
individual trial 
site 
To comply with Sec. 40 Par. 1 
S. 3 Cf. 2 AMG, a new section 
has been integrated in the CTP 
now, in which the reasons are 
specified, that may lead to the 
discontinuation of the whole 
trial or a single trial site, 
respectively. 
The Regulatory Authority also raised 
the objection that compelling and 
sufficiently specified reasons for 
premature discontinuation of the 
complete trial were missing in the 
protocol. 
To overcome this objection 
corresponding reasons including 
specific clinically measurable 
parameters have been defined. 
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Brief rationale 
4  
Schedule of 
trial procedures 
 
 
 
 
 
 
 
 
11.4.4. 
Laboratory 
testing 
 
 
 
 
 
 
 
 
1: The footnote addressing the 
sampling times for the 
biomarker sampling was not 
consistent with the 
corresponding details as given 
in section 11.6.1. 
Correspondingly this footnote 
was corrected, now stating that 
serum sampling for biomarker 
analysis at baseline visits (i.e. 
V2 and V4/4a) should be taken 
prior to the intake of the IMP 
and sampling at the end of 
treatment visits (i.e. V3 and 
V5) for each of the treatment 
periods should be done after 
the IMP intake. 
2: Regarding the lab panel 
(panel 10) it was overlooked, 
that there is the need to obtain 
the estimated glomerular 
filtration rate from the 
measurement of creatinine in 
order to check for exclusion 
criterion #9 (Subjects with 
signs of renal impairment as 
determined estimated 
glomerular filtration rate 
(eGFR) levels below 90 
mL/min at screening). 
A corresponding footnote has 
now been added to the lab 
During the review of the amended 
protocol some inconsistencies have 
been detected, that were corrected 
beside the requests from RA and 
relevant EC, to be unambiguous 
throughout the protocol. 
These changes do not change the 
intent of the original CTP. 
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Section no. 
and name 
Description of change 
Brief rationale 
 
Section 11.4.3 
ECG 
Section 13.6.1 
Adverse events 
of special 
interest 
 
panel, specifying the method to 
calculate the eGFR. 
3: As no ECG measurement 
prior to the first intake of the 
IMP was planned to be 
performed at baseline visit 
(V2), respective statements to 
document clinically significant 
abnormal ECG findings at 
baseline as medical history 
have been deleted. Only 
clinically significant abnormal 
ECG findings at screening (V1) 
have to be documented as 
medical history. 
 
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