Conditions: Healthy
Allocation: NON_RANDOMIZED | Intervention model: PARALLEL
Enrollment: 50
Healthy volunteers: yes

Brief summary:
The primary objective of this trial is to investigate pharmacokinetics, including dose proportionality, following single intravenous and subcutaneous doses of spesolimab in healthy Chinese subjects.

Detailed description:

Arms:
arm 1: A single dose of 450 mg Spesolimap was administered as solution for infusion intravenously over 90 minutes (mins) after an overnight fast. arm 2: A single dose of 900 mg Spesolimap was administered as solution for infusion intravenously over 90 mins after an overnight fast. arm 3: A single dose of 1200 mg Spesolimap was administered as solution for infusion intravenously over 90 mins after an overnight fast. arm 4: A single dose of 300 mg Spesolimap was administered as solution for injection subcutaneously in the abdominal region within 60 seconds (s) after an overnight fast. arm 5: A single dose of 600 mg Spesolimap was administered as solution for injection subcutaneously in the abdominal region within 60 s after an overnight fast.

Interventions: intervention 1: Spesolimap
Intervention descriptions: intervention 1: Spesolimap

Protocol document:
Prot_000.pdf: 
001-MCS-40-106-RD-11 (6.0) / Saved on: 13 Jun 2018
Clinical Trial Protocol
TITLE PAGE
Document Number:
c27981303-05
BI Trial No.
1368-0043
BI Investigational
Medicinal Product
BI 655130 (Spesolimab)
Title
An open-label phase I trial to assess pharmacokinetics and safety 
of single subcutaneous doses and single intravenous doses of      
BI 655130 in healthy Chinese male and female subjects (single 
doses, open-label study in parallel-group design).
Lay Title
A trial in healthy Chinese volunteers to test how different doses 
of BI 655130 are taken up in the body.
Clinical Phase
I
Trial Clinical Leader
Phone: 
 
Fax: 
Principal 
Investigator
Phone:
Fax: 
Status
Final Protocol (Revised Protocol (based on global amendment 
04))
Version and Date
Version: 5.0
Date: 26 Feb 2021
Page 1 of 76
Proprietary confidential information
© 2021 Boehringer Ingelheim International GmbH or one or more of its affiliated companies. All rights reserved.
This document may not - in full or in part - be passed on, reproduced, published or otherwise used without prior written permission


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CLINICAL TRIAL PROTOCOL SYNOPSIS
Company name
Boehringer Ingelheim (BI)
Protocol date
29 Jul 2019
Revision date
26 Feb 2021
BI trial number
1368-0043
Title of trial
An open-label phase I trial to assess pharmacokinetics and safety of 
single subcutaneous doses and single intravenous doses of BI 655130 in 
healthy Chinese male and female subjects (single doses, open-label 
study in parallel-group design).
Principal Investigator 
Trial site
Phone:
Fax:
Email:
Clinical phase
I
Trial rationale
To investigate the PK and safety of spesolimab in Chinese healthy
subjects
Trial objectives
To investigate PK, including dose proportionality, following single SC
and IV doses of spesolimab in healthy Chinese subjects
Trial endpoints
Primary endpoint 
AUC0-∞and Cmax of spesolimab
Secondary endpoints:
The occurrence of treatment-emergent adverse events (AEs)
The occurrence of drug-related AEs
Trial design
Open-label without placebo, parallel-group design


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Number of subjects
Up to 60 subjects including up to 10 subjects for replacement of early 
discontinuation
total entered
each treatment
10 per dose group
Diagnosis
Not applicable
Main criteria
for inclusion
Healthy male or female subjects (at least three subjects for each gender 
within each dose group) Age of 18 to 45 years (inclusive)
Body weight ≥50 kg for male and ≥45 kg for female 
Body mass index (BMI) ≥19 and <26 kg/m2 for male and female at visit 
1
Test product 1
BI 655130 (60 mg/mL) solution for infusion
dose
Single dose of 450 mg, 900 mg and 1200 mg
        mode of admin
IV as 90 min infusion
Test product 2
BI 655130 (150 mg/mL) solution for injection
        dose
Single dose of 300 mg and 600 mg
         mode of admin
SC injection
Comparator product
Not applicable
dose
Not applicable
mode of admin
Not applicable
Duration of treatment
One day (single dose) for each treatment
Statistical methods
Descriptive statistics will be calculated for all endpoints.
Dose proportionality of Spesolimab will be explored using a regression 
model for AUC0-∞and Cmax for IV doses. A 90% confidence interval (CI) 
for the slope will be computed.


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FLOW CHART S.C.
Single dose group for SC
Single dose of Spesolimab as 300 mg and 600 mg SC (subjects will receive only one dose)
Visit
Day
Time relative to first drug 
administration (planned 
time) [h:min]
Approx. time (actual time) 
[h:min]
Event and comment
PKblood 4
Plasma ADA8
Laboratory3
Body weight
12-lead ECG
Vital signs (BP, PR, RR,
body temperature)10
Query on AEs, 
concomitant therapies11
1
-28 to -3
screening1
X14
X
X
X
-2
-48:00
8:00
ambulatory visit
X13
X13
2
-1
-12:00
20:00
admission to
trial site
X9
X
1
-2:00
6:30
X2
X2
X2,14
X2
X2
X2,5
0:00
8:00
drug administration
0:10
8:10
X
0:30
8:30
X
X
X
X5
1:00
9:00
X
1:30
9:30
X
X
2:00
10:00
light breakfast6
X
X
X
3:00
11:00
X
X
4:00
12:00
lunch6
X
X
X5
6:00
14:00
X
X
8:00
16:00
X
X
10:00
18:00
dinner6
12:00
20:00
X
X
X
X5
2
24:00
8:00
breakfast6
X
X
X
X5
28:00
12:00
lunch6
32:00
16:00
X
34:00
18:00
dinner6
X5
3
48:00
8:00
breakfast6 discharge 
from trial site
(confirmation of 
fitness7)
X
X
X
X5
4
72:00
8:00
ambulatory visit
X
X
X5
5
96:00
8:00
ambulatory visit
X
X5
6
120:00
8:00
ambulatory visit
X
X5
7
144:00
8:00
ambulatory visit
X
X5
8
168:00
8:00
ambulatory visit
X
X
X
X
X5
15
336:00
8:00
ambulatory visit
X
X
X5
22
504:00
8:00
ambulatory visit
X
X
X
X
X
29
672:00
8:00
ambulatory visit
X
X
X
X
X
X5
36
840:00
8:00
ambulatory visit
X
X
43
1008:00
8:00
ambulatory visit
X
X
X
57
1344:00
8:00
ambulatory visit
X
X
X5
71
1680:00
8:00
ambulatory visit
X
X
X
92 ±2
2184:00
8:00
ambulatory visit
X
X
X14
X
120 ±3
2856:00
8:00
ambulatory visit
X
X
X
148 ±3
3528:00
8:00
ambulatory visit
X
X
X
3
176 ±3 
4200:00
8:00
EoTrial 12
X
X
X14
X
X
X
X5


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1.
Screening with subject information, informed consent as the first measure, includes physical 
examination, check of vital signs including temperature, respiratory rate (RR), systolic and diastolic 
blood pressure (BP) and pulse rate (PR), 12-lead electrocardiogram (ECG), safety laboratory parameters 
(under fasting conditions), pregnancy test, drug screening, alcohol breath test, demographics (including 
determination of body height and weight, smoking and alcohol history), relevant medical history, 
concomitant therapy and review of inclusion/exclusion criteria. 
2.
The time is approximate; procedures are to be performed and completed within three hours prior to drug 
administration. Within three hours prior to the planned dosing, planned time -2:00 will be used.
3.
Safety laboratory parameters include clinical chemistry, haematology, coagulation and urinalysis; in 
addition at screening: serology (hepatitis B virus [HBV], hepatitis C virus [HCV], human 
immunodeficiency virus [HIV], tuberculosis (QuantiFERON TB test), Follicle-stimulating hormone
(FSH) and estradiol evaluation in questionable cases for determining postmenopausal status), and drug 
screening.
4.
PK sampling times may be adapted based on information obtained during trial conduct.
5.
Standardised assessment of local tolerability using the criteria swelling, induration, heat, redness, pain 
or other findings. 
6.
If several actions are indicated at the same time point, the intake of meals will be the last action.
7.
Confirmation of fitness includes physical examination.
8.
ADAs will be taken at baseline, Day 15, Day 29, Day 43, Day 57, Day 71, Day 92, Day 120, Day 148 
and Day 176.
9.
Only drug screening and alcohol breath test.
10.
Evaluate vital signs at baseline, 10 minutes after and 1 hour post infusion/injection and in case of 
suspicion of hypersensitivity reaction including anaphylactic reaction.
11.
AEs and concomitant therapies will be recorded throughout the trial, but will be specifically asked for at 
the time points indicated in the Flow Chart above.
12.
EoTrial (end of trial) examination includes physical examination, body weight, vital signs, 12-lead ECG, 
safety laboratory parameters, recording of AEs and concomitant therapies. EoTrial to be performed not 
before last PK and ADA sampling. 
13.
Safety laboratory parameters are to be taken within two days prior to trial medication administration
under fasting conditions and can be omitted if the screening examination is performed between Day -5 
and Day -3. Also the AEs and concomitant therapies will be queried on Day -1.
14.        At these time points, a urine pregnancy test will be done for female subjects.


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FLOW CHART I.V.
Single dose group for IV
Single dose of Spesolimab as 450 mg, 900 mg and 1200 mg IV. (Subjects will receive only one 
dose)
Visit
Day
Time relative to first 
drug administration 
(planned time) [h:min]
Approx. time (actual 
time) [h:min]
Event and comment
PKblood 4
Plasma ADA8
Laboratory3
Body weight
12-lead ECG
Vital signs (BP, PR, RR, 
body temperature)11
Query on AEs, 
concomitant therapies12
1
-28 to -3
screening1
X15
X
X
X
-2
-48:00
8:00
ambulatory visit
X14
X14
2
-1
-12:00
20:00
admission to
trial site
X10
X
1
-2:00
6:30
X2
X2
X2,15
X2
X2
X2,5
0:00
8:00
drug administration
start of infusion
0:10
8:10
│
X
0:30
8:30
│
X
X
X5
1:00
9:00
│
X
1:30
9:30
▼
end of infusion9
X
X
X
2:00
10:00
light breakfast6
X
X
X
3:00
11:00
X
X
4:00
12:00
lunch6
X
X
X5
6:00
14:00
X
X
8:00
16:00
X
X
10:00
18:00
dinner6
12:00
20:00
X
X
X
X5
2
24:00
8:00
breakfast6
X
X
X
X5
28:00
12:00
lunch6
32:00
16:00
X
34:00
18:00
dinner6
X5
3
48:00
8:00
breakfast6discharge from trial 
site
(confirmation of fitness7)
X
X
X
X5
4
72:00
8:00
ambulatory visit
X
X
X5
5
96:00
8:00
ambulatory visit
X
X5
6
120:00
8:00
ambulatory visit
X
X5
7
144:00
8:00
ambulatory visit
X
X5
8
168:00
8:00
ambulatory visit
X
X
X
X
X5
15
336:00
8:00
ambulatory visit
X
X
X5
22
504:00
8:00
ambulatory visit
X
X
X
X
X
29
672:00
8:00
ambulatory visit
X
X
X
X
X
X5
36
840:00
8:00
ambulatory visit
X
X
43
1008:00
8:00
ambulatory visit
X
X
X
57
1344:00
8:00
ambulatory visit
X
X
X5
71
1680:00
8:00
ambulatory visit
X
X
X
92 ±2
2184:00
8:00
ambulatory visit
X
X
X15
X
120 ±3
2856:00
8:00
ambulatory visit
X
X
X
148 ±3
3528:00
8:00
ambulatory visit
X
X
X
3
176 ±3
4200:00
8:00
EoTrial 13
X
X
X15
X
X
X
X5


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1.
Screening with subject information, informed consent as the first measure, includes physical 
examination, check of vital signs including temperature, RR, systolic and diastolic BP and PR, 12-lead 
ECG, safety laboratory parameters (under fasting conditions), pregnancy test, drug screening, 
demographics (including determination of body height and weight, smoking and alcohol history), 
relevant medical history, concomitant therapy and review of inclusion/exclusion criteria. 
2.
The time is approximate; procedures are to be performed and completed within three hours prior to drug 
administration. Within three hours prior to the planned dosing, planned time -2:00 will be used.
3.
Laboratory tests (safety laboratory parameters) include clinical chemistry, haematology, coagulation and 
urinalysis; in addition at screening: serology (HBV, HCV, HIV, QuantiFERON TB test, FSH and 
estradiol evaluation in questionable cases for determining postmenopausal status), and drug screening.
4.
PK sampling times may be adapted based on information obtained during trial conduct.
5.
Standardised assessment of local tolerability using the criteria swelling, induration, heat, redness, pain 
or other findings. 
6.
If several actions are indicated at the same time point, the intake of meals will be the last action.
7.
Confirmation of fitness includes physical examination.
8.
ADA samples will be taken at baseline, Day 15, Day 29, Day 43, Day 57, Day 71, Day 92, Day 120, Day 
148 and Day 176 (EoTrial).
9. 
First measure after completion of infusion collection of PK sample. 
10.
Only drug screening and alcohol breath test.
11. 
Evaluate vital signs at baseline, 10 minutes after and 1hour post infusion/injection and in case of 
suspicion of hypersensitivity reaction including anaphylactic reaction.
12.
AEs and concomitant therapies will be recorded throughout the trial, but will be specifically asked for at 
the time points indicated in the Flow Chart above.
13.
EoTrial includes physical examination, body weight, vital signs, 12-lead ECG, safety laboratory
parameters, recording of AEs and concomitant therapies. EoTrial to be performed not before last PK and 
ADA sampling. 
14.
Safety laboratory parameters are to be taken within two days prior to trial medication administration 
under fasting conditions and can be omitted if the screening examination is performed between Day -5 
and Day - 3. Also the AEs and concomitant therapies will be queried on Day -1.
15.
At these time points, a urine pregnancy test will be done for female subjects.


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TABLE OF CONTENTS
TITLE PAGE ......................................................................................................1
CLINICAL TRIAL PROTOCOL SYNOPSIS ................................................2
FLOW CHART S.C............................................................................................4
FLOW CHART I.V.............................................................................................6
TABLE OF CONTENTS ...................................................................................8
ABBREVIATION ............................................................................................ 12
1.
INTRODUCTION.................................................................................... 15
1.1
MEDICAL BACKGROUND.............................................................................15
1.2
DRUG PROFILE................................................................................................16
Nonclinical Pharmacology....................................................................................16
Toxicology ..............................................................................................................16
Nonclinical pharmacokinetics ..............................................................................17
Prediction of human pharmacokinetics ..............................................................17
Clinical experience in humans..............................................................................18
Residual Effect Period...........................................................................................20
Drug product..........................................................................................................21
1.3
RATIONALE FOR PERFORMING THE TRIAL.........................................21
1.4
BENEFIT - RISK ASSESSMENT.....................................................................21
2.
TRIAL OBJECTIVES AND ENDPOINTS........................................... 25
2.1
MAIN OBJECTIVES, PRIMARY AND SECONDARY ENDPOINTS........25
Main objectives......................................................................................................25
Primary endpoint ..................................................................................................25
Secondary endpoint...............................................................................................25
Safety and tolerability .............................................................................................25
3.
DESCRIPTION OF DESIGN AND TRIAL POPULATION.............. 27
3.1
OVERALL TRIAL DESIGN AND PLAN .......................................................27
3.2
DISCUSSION OF TRIAL DESIGN, INCLUDING THE CHOICE OF 
CONTROL GROUPS.........................................................................................27
3.3
SELECTION OF TRIAL POPULATION .......................................................28
Main diagnosis for trial entry...............................................................................28
Inclusion criteria....................................................................................................28
Exclusion criteria...................................................................................................29
Withdrawal of subjects from treatment or assessments....................................30
Discontinuation of trial treatment............................................................................30


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Withdrawal of consent to trial participation............................................................31
Discontinuation of the trial by the sponsor .............................................................31
Replacement of subjects........................................................................................32
4.
TREATMENTS........................................................................................ 33
4.1
INVESTIGATIONAL TREATMENTS ...........................................................33
Identity of the Investigational Medicinal Products............................................33
Selection of doses in the trial ................................................................................34
Method of assigning subjects to treatment groups.............................................34
Drug assignment and administration of doses for each subject........................34
Blinding and procedures for unblinding.............................................................35
Blinding...................................................................................................................35
Packaging, labelling, and re-supply.....................................................................36
Storage conditions .................................................................................................36
Drug accountability...............................................................................................36
4.2
OTHER TREATMENTS, EMERGENCY PROCEDURES, 
RESTRICTIONS ................................................................................................37
Other treatments and emergency procedures ....................................................37
Restrictions.............................................................................................................37
Restrictions regarding concomitant treatment.........................................................37
Restrictions on diet and life style ............................................................................37
4.3
TREATMENT COMPLIANCE........................................................................38
5.
ASSESSMENTS ....................................................................................... 39
5.1
ASSESSMENT OF EFFICACY........................................................................39
5.2
ASSESSMENT OF SAFETY.............................................................................39
Physical examination.............................................................................................39
Vital signs...............................................................................................................39
Safety laboratory parameters...............................................................................39
Electrocardiogram.................................................................................................42
12-lead resting ECG................................................................................................42
Continuous ECG monitoring...................................................................................42
Other safety parameters .......................................................................................43
Local tolerability .....................................................................................................43
Suicidality assessment.............................................................................................43
Assessment of adverse events ...............................................................................43
Definitions of adverse events ..................................................................................43
5.2.6.1.1 Adverse event..........................................................................................................43
5.2.6.1.2 Serious adverse event ..............................................................................................43
5.2.6.1.3 AEs considered ‘Always Serious’...........................................................................44
5.2.6.1.4 Adverse events of special interest ...........................................................................44
5.2.6.1.5 Intensity (severity) of AEs ......................................................................................45
5.2.6.1.6 Causal relationship of AEs......................................................................................45
Adverse event collection and reporting...................................................................46


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5.2.6.2.1 AE collection...........................................................................................................46
5.2.6.2.2 AE reporting to the sponsor and timelines..............................................................47
5.2.6.2.3 Information required................................................................................................47
5.2.6.2.4 Pregnancy................................................................................................................47
5.3
DRUG CONCENTRATION MEASUREMENTS AND 
PHARMACOKINETICS...................................................................................48
Assessment of pharmacokinetics..........................................................................48
Methods of sample collection................................................................................48
Blood sampling for pharmacokinetic analysis ........................................................48
Blood sampling for anti-drug antibody (ADA) analysis.........................................48
5.4
BIOBANKING ....................................................................................................49
5.5
APPROPRIATENESS OF MEASUREMENTS..............................................49
6.
INVESTIGATIONAL PLAN.................................................................. 50
6.1
VISIT SCHEDULE.............................................................................................50
6.2
DETAILS OF TRIAL PROCEDURES AT SELECTED VISITS .................51
Screening period....................................................................................................51
Treatment period...................................................................................................51
Follow-up period and trial completion................................................................51
7.
STATISTICAL METHODS AND DETERMINATION OF
SAMPLE SIZE......................................................................................... 52
7.1
STATISTICAL DESIGN – MODEL ................................................................52
7.2
NULL AND ALTERNATIVE HYPOTHESES ...............................................52
7.3
PLANNED ANALYSES.....................................................................................52
Primary endpoint analyses ...................................................................................53
Secondary endpoint analyses................................................................................54
Safety analyses.......................................................................................................54
Pharmacokinetic-pharmacodynamic analyses ...................................................55
7.4
INTERIM ANALYSES ......................................................................................55
7.5
HANDLING OF MISSING DATA ...................................................................55
Safety ......................................................................................................................55
Pharmacokinetics ..................................................................................................56
7.6
RANDOMISATION ...........................................................................................56
7.7
DETERMINATION OF SAMPLE SIZE .........................................................56


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8.
INFORMED CONSENT, TRIAL RECORDS, DATA 
PROTECTION, PUBLICATION POLICY, AND 
ADMINISTRATIVE STRUCTURE...................................................... 57
8.1
TRIAL APPROVAL, SUBJECTS INFORMATION, INFORMED 
CONSENT ...........................................................................................................57
8.2
DATA QUALITY ASSURANCE ......................................................................58
8.3
RECORDS...........................................................................................................58
Source documents..................................................................................................58
Direct access to source data and documents.......................................................59
Storage period of records......................................................................................60
8.4
EXPEDITED REPORTING OF ADVERSE EVENTS ..................................60
8.5
STATEMENT OF CONFIDENTIALITY AND SUBJECT PRIVACY........60
Collection, storage and future use of biological samples and corresponding 
data .........................................................................................................................60
8.6
TRIAL MILESTONES.......................................................................................61
8.7
ADMINISTRATIVE STRUCTURE OF THE TRIAL ...................................61
9.
REFERENCES......................................................................................... 63
9.1
PUBLISHED REFERENCES............................................................................63
9.2
UNPUBLISHED REFERENCES......................................................................64
10. APPENDICES .......................................................................................... 66
10.1
CLINICAL EVALUATION OF LIVER INJURY ..........................................66
Introduction ...........................................................................................................66
Procedures..............................................................................................................66
Diagnosis of Anaphylaxis......................................................................................67
11. DESCRIPTION OF GLOBAL AMENDMENT(S).............................. 68
11.1
GLOBAL AMENDMENT 1 ..............................................................................68
11.2
GLOBAL AMENDMENT 2 ..............................................................................70
11.3
GLOBAL AMENDMENT 3 ..............................................................................73
11.4
GLOBAL AMENDMENT 4 ..............................................................................75


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ABBREVIATION
ABBREVIATIONS
ADA
Anti-drug antibody
ADCC
Antibody-dependent cellular cytotoxicity
AE
Adverse event
AESI
Adverse events of special interest
ALT
Alanine transaminase
AST
Aspartate transaminase
AtD
Atopic dermatitis
AUC0-∞
Area under the concentration-time curve of the analyte in plasma over the 
time interval from 0 extrapolated to infinity
AUCt1-t2
Area under the concentration-time curve of the analyte in plasma over the 
time interval t1 to t2
AUC0-tz
Area under the concentration-time curve of the analyte in plasma over the 
time interval from 0 to the last quantifiable data point
%AUCtz-∞
The percentage of AUC0-∞obtained by extrapolation
BI
Boehringer Ingelheim
BMI
Body mass index (weight divided by height squared)
BP
CA
Blood pressure
Competent authority
CD
Crohn’s Disease
CDC
CRA
Complement-dependent cytotoxicity
Clinical Research Associate
CRF
Case report form
CRP
C-Reactive Protein
CL
Total clearance of the analyte in plasma after intravenous administration
CL/F
Apparent clearance of the analyte in plasma after extravascular 
administration
Cmax
CTL
CTM
Maximum measured concentration of the analyte in plasma
Clinical trial leader
Clinical trial manager
CTP
Clinical trial protocol
CTR
Clinical trial report
DILI
Drug-induced liver impairment
ECG
Electrocardiogram
EDC
Electronic Data Capture
EoTrial
End of trial
FIH
First-in-Human
FSH
Follicle-stimulating hormone
GCP
Good Clinical Practice


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GPP
Generalised pustular psoriasis
HBV
Hepatitis B virus
HCV
Hepatitis C virus
HIV
HS
Human Immunodeficiency Virus
Hidradenitis suppurativa
IB
Investigator’s brochure
IBD
ICF
IEC
Inflammatory bowel disease
Informed consent form
Independent Ethics Committee
IgE
Immunoglobulin E
IL36R
IQRM
IPD
IRB
Interleukin 36 receptor
Integrated Quality and Risk Management
Important protocol deviation
Institutional Review Board
ISF
Investigator site file
ITE
Indirect target engagement
IV
Intravenous
z
Terminal rate constant in plasma
mAb
Monoclonal antibody
MRT
Mean residence time of the analyte in the body after intravenous bolus 
administration
PD
PK
PKS
Pharmacodynamic(s)
Pharmacokinetic(s)
Pharmacokinetic parameter analysis set
PPP
ppPASI
Palmoplantar pustulosis
Palmoplantar Pustular Psoriasis Area and Severity Index
PR
Pulse rate
QT
Time between start of the Q-wave and the end of the T-wave in an 
electrocardiogram
QTc
QT interval corrected for heart rate using the method of Fridericia (QTcF) 
or Bazett (QTcB)
REP
Residual Effect Period
RR
Respiratory Rate
SAE
Serious adverse event(s)
SC
Subcutaneous
t1/2
Terminal half-life of the analyte in plasma
tmax
Time from dosing to maximum measured concentration of the analyte in 
plasma


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TS
Treated set
UC
Ulcerative colitis
Vss
Volume of distribution at steady state after single intravenous 
administration
Vz
Volume of distribution during the terminal phase after intravascular 
administration
Vz/F
Apparent volume of distribution during the terminal phase after 
extravascular administration


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1.
INTRODUCTION
1.1
MEDICAL BACKGROUND
Spesolimab is a humanised antagonistic monoclonal IgG1 antibody that blocks human
interleukin 36 receptor (IL36R) signaling. Binding of Spesolimab to IL36R is anticipated to 
prevent the subsequent activation of IL36R by cognate ligands (IL36α, β and γ) and 
downstream activation of pro-inflammatory and pro-fibrotic pathways in inflammatory skin 
and bowel diseases such as generalised pustular psoriasis (GPP), palmoplantar pustulosis 
(PPP), atopic dermatitis (AtD), hidradenitis suppurativa (HS) and inflammatory bowel disease 
(IBD).Genetic human studies have established a strong link between IL36R signaling and skin
inflammation, as demonstrated by the occurrence of GPP in patients with a loss-of-function
mutation in IL36Rα, the gene encoding the endogenous inhibitor of IL36R, which resulted in 
uncontrolled IL36R signaling [R14-5158, R15-1421]. Mutations in other genes linked to the 
IL36 pathway such as CARD14 also lead to GPP [R16-0929]. IL36R signaling drives skin 
inflammation in several animal models, further supporting the strong link between IL36R 
biology and skin disorders based on human genetics [R14-5158].
IL36R is identified as a target for psoriasis based on (i) the abundant expression of all three 
stimulating ligands in human psoriatic lesional skin [R14-4037], (ii) IL36α overexpression in 
murine keratinocytes inducing a psoriatic-like phenotype [R15-1432], (iii) IL36R KO mice 
protecting against Imiquimod-induced skin inflammation [R15-1447], and (iv) IL36R blockade 
ameliorating skin inflammation in a transplanted psoriatic skin model [R15-1399].The link 
between IL36R-driven inflammation and epithelial inflammation has led to the hypothesis that 
IL36R signaling may play an important role in IBD. This hypothesis was tested using a suite 
of in vitro and in vivo assays. Immunostaining studies demonstrated that both IL36R and its 
ligands are expressed in intestinal biopsies taken from Crohn’s disease (CD) patients. Human 
IL36 ligands enhance intestinal barrier permeability, a hallmark of IBD pathogenesis, using 
primary human intestinal epithelial cells co-cultured with intestinal myofibroblasts. The link 
between IL36R signaling and IBD was further strengthen by demonstrating that antagonist 
anti-mouse IL36R antibodies ameliorated intestinal inflammation in both acute chemically-
induced and chronic T cell driven murine colitis models. 
In addition, the therapeutic rational for an IL36R antagonist in IBD is based on the correlation 
of a set of IL36-induced genes upregulated in primary human intestinal myofibroblast, a 
disease relevant cell type, with gene signatures observed in ulcerative colitis (UC) and CD
patients. Finally IL36R signaling in disease relevant cells such as intestinal myofibroblasts and 
macrophages induce both pro-inflammatory and tissue remodeling-related mediators (e.g. 
TGF-β, MMPs). 
Altogether, these findings support a prominent role for IL36R in driving skin and intestinal 
inflammation and support anti-human IL36R antibody Spesolimab as a therapeutic agent for 
epithelial-mediated inflammatory diseases such as GPP, PPP, and IBD.
GPP is characterised by systemic inflammation of the skin and internal organs [R15-1421;
R16-0933]. Acute GPP is difficult to treat and no approved or standard of care therapy is
available in the US or EU. Current treatment options aiming to control acute GPP and maintain


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response are cyclosporine, acitretin, and methotrexate [R16-0933]. Secukinumab, infliximab,
brodalumab, and ixekizumab have been approved for GPP exclusively in Japan based on small 
local uncontrolled studies. To date, treatment is commonly not effective in suppressing acute
flares during induction and recurrences emerge frequently.
PPP is a form of chronic PP characterised by sterile pustules limited to palms and soles [R16-
0927]. Current, no approved or effective treatment is available.
Both UC and CD are characterised by abdominal pain, fever, bloody diarrhoea, and
inflammatory lesions in the gastrointestinal mucosa. Current treatment options include
aminosalicylates, glucocorticoid therapy, azathioprine, 6-mercaptopurine, and biologics
(blocking TNF or integrin α4β7). Treatment of CD and UC is associated with a significant
number of patients with primary and secondary non-response. In addition, treatment may be
limited due to safety and tolerability issues. Therefore, despite progress, there remains a
significant unmet medical need for new treatment options with an improved safety and efficacy 
profile compared with the current therapeutic standard.
1.2
DRUG PROFILE
Nonclinical Pharmacology
Spesolimab is a humanised monoclonal antibody (mAb) of the IgG1 isotype that is directed
against human IL36R. It is derived from mouse antibody 81B4 (BI 674308) cloned into a
human IgG1 Kappa backbone. Spesolimab binds to human IL36R with a binding avidity of 
less than 1 pM. Spesolimab inhibits IL36 ligand-stimulated NF-kB activation in transformed 
epithelial cells and in primary human keratinocytes, dermal fibroblasts and intestinal 
myofibroblasts with IC90 values in a consistent range of 0.7 to 3.7 nM. Spesolimab also 
inhibits IL8 release in dermal fibroblasts and keratinocytes and IFNγ secretion in human 
peripheral blood mononuclear cell) stimulated with IL36α, IL36β, or IL36γ combined with 
IL12.
Mutations of two key residues (L234 and L235) to alanine were made to Spesolimab to 
abrogate FcR binding activity and function. Direct assessment of the impact of the mutations 
in the IgG1 FcR binding sites on both antibody-dependent cellular cytotoxicity (ADCC) and 
complement-dependent cytotoxicity (CDC) effector functions revealed that the mutations 
abrogate both ADCC and CDC effector functions and indicate that Spesolimab will be a 
non-depleting therapy in vivo.
Toxicology
Spesolimab does not bind to IL36R from common toxicology species. Therefore, meaningful 
toxicity studies cannot be performed in any animal species with Spesolimab. Hazard 
identification studies were performed in mice using a mouse specific anti-IL36R mAb (BI 
674304), a mouse IgG2a mAb with rat variable regions. In a 13-week intravenous (IV) toxicity 
study of BI 674304 in mice, no adverse effects of IL36R antagonism were seen at a dose (50 
mg/kg, twice weekly) that was 5-fold higher than the dose that was protective in an 


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experimental mouse colonic inflammation model [n00243876]. In the 26-week toxicity study, 
male and female mice (20-30/sex/group at 0, 10 and 50 mg/kg/day) were administered BI 
674304 twice weekly for 26 weeks by IV injection via the caudal vein [n00257882]. The in 
vitro cytokine release and tissue cross-reactivity assays demonstrate that the risk of transient 
cytokine release in humans is low and that, as expected, Spesolimab stains epithelium in a 
variety of tissues [n00240832, n00239291]. There were no signs of local irritation after single, 
1 mL injections of the subcutaneous (SC) formulation in rabbits [n00248748]. These preclinical 
data suggest Spesolimab may be safely administered to humans.
Nonclinical pharmacokinetics
Spesolimab has a very weak binding affinity to cynomolgus monkeys. Its pharmacokinetics 
(PK) characteristics in cynomolgus monkeys therefore addresses only the overall catabolic 
stability and FcRn recycling properties of the molecule, rather than full PK evaluation 
including possible specific target-mediated drug disposition. The PK of Spesolimab in 
cynomolgus monkeys were approximately dose linear following the IV administration of 0.3, 
1.5, and 10 mg/kg of Spesolimab. The clearance, steady-state volume of distribution, and 
terminal half-life (t1/2) for the three dose groups were similar ranging from 0.168-0.219 
mL/h/kg, 65.2-83 mL/kg, and 284-349 h, respectively. The SC bioavailability was 62.6%
[n00243168]. Anti-drug antibodies (ADA) were observed in both the 10 mg/kg IV and 1.5 
mg/kg SC. dose groups, whereas the 0.3 and 1.5 mg/kg IV monkeys tested negative for ADA.
In the two-week GLP toxicology study in CD-1 mice with Spesolimab, exposure increased 
proportionally from 10 to 50 mg/kg, and there was no apparent difference in Spesolimab serum 
exposure between male and female mice [n00255537].
Prediction of human pharmacokinetics
PK data suggest TMDD kinetics for Spesolimab [c09985235]. The saturation of the non-linear 
elimination pathway is likely to occur after 0.3 mg/kg and Spesolimab exhibits linear kinetics
from the next dose-level onwards up to 10 mg/kg. Based on the PK results in GPP patients, the 
elimination t1/2 of Spesolimab was observed to be approximately three weeks in patients who 
are ADA-negative and approximately one week in patients who tested ADA-positive
[c17444370]. Steady state was not attained after four weekly doses in the multiple dosing 
groups and the accumulation ratios were similar for the various dose groups. Preliminary PK 
data suggest the exposure of a 300 mg SC dose of Spesolimab is similar when administered as 
a single 2 mL injection or two separate 1 mL injections, which potentially provides flexibility 
to dose 300 mg with either 1 mL or 2 mL pre-filled syringes in future trials.
Pharmacodynamic (PD) effects in this first-in-human (FIH)
single-rising-dose
trial 
[c03361085] were assessed by indirect target engagement (ITE) of IL36R by Spesolimab using 
an ex vivo whole blood stimulation assay. Preliminary analyses indicate that >99% peripheral 
IL36R receptor occupancy is achieved with doses ≥1 mg/kg from 30 minutes post infusion to 
ten week.


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Clinical experience in humans
As of Sep 2020, six phase I trials and four phase II trials have been completed for Spesolimab, 
five phase I trials were conducted in healthy subjects, one phase I trial in GPP patients and four
phase II trials in PPP, UC, AD patients.
The trial 1368-0001 was a single-rising-dose trial that assessed safety, tolerability, PK and PD 
of Spesolimab in healthy subjects [c09985235]. A total of 59 subjects received Spesolimab IV 
infusions from 0.001 mg/kg to 10 mg/kg while 19 subjects received placebo administration.
Safety and tolerability of all tested IV doses were good. The most frequent treatment-emergent 
adverse events (AEs) were nasopharyngitis (Spesolimab: 20.7%; placebo: 15.0%), headache 
(Spesolimab: 8.6%; placebo: 15.0%), influenza-like illness (Spesolimab: 6.9%; placebo: 
10.0%), and diarrhoea (Spesolimab: 3.4%; placebo: 10.0%). There were two AEs of moderate 
intensity (injection site haematoma, headache), all remaining AEs were of mild intensity. There 
were no serious adverse events (SAEs), no AEs that led to discontinuation of trial medication, 
no protocol-specified AEs of special interest and no other significant AEs. Furthermore, no 
relevant changes were observed in safety laboratory parameters, vital signs, and 12-lead ECGs. 
Importantly, there were no relevant differences in frequencies of subjects with treatment 
emergent AEs between the treatment groups, and no dose dependency was observed.
In the multiple-rising-dose trial 1368-0002, a total of 40 healthy male subjects were enrolled 
in five sequential groups comprising eight subjects per group. The trial consisted of four dose 
groups receiving rising multiple doses of 3 mg/kg, 6 mg/kg, 10 mg/kg or 20 mg/kg. In addition,
one dose group received one single dose (20 mg/kg) only. Within each of the five dose groups, 
six subjects have been randomised to receive the active drug and two received placebo. In trial 
1368.2, no dose dependency was observed for all AEs. The incidences of drug related AEs 
were balanced across treatment groups up to 10 mg/kg bw dose, while higher incidences were 
reported in the 20 mg/kg bw dose group. However, all AEs were of mild or moderate intensity.
Overall, multiple IV doses of 3 mg/kg, 6 mg/kg, and 10 mg/kg, as well as single and multiple 
doses of 20 mg/kg Spesolimab were found to be safe and well tolerated by the subjects in this 
trial. The incidences of drug-related AEs were balanced across treatment groups up to 10 mg/kg 
dose, while higher incidences were reported in the 20 mg/kg dose group. All AEs were of mild 
or moderate intensity. No dose-dependent AEs or other clinically relevant changes in safety 
laboratory parameters, vital signs, or 12-lead ECG were observed.
The relative bioavailability trial 1368-0003 explores PK as well as safety and tolerability of an 
SC formulation of Spesolimab at two different dose strengths of 150 mg (1 mL) and 300 mg 
(2 mL) in an open-label, sequential group design. In addition, the trial determines the relative 
bioavailability of the 300 mg SC dose (test group) compared to one single 300 mg IV dose of
Spesolimab (reference group). The trial has been conducted in 36 healthy male and female 
subjects with 12 subjects per dose group. Local tolerability of the SC formulation was as well 
tolerated. Following an SC injection of 150 mg of Spesolimab, there were two cases of redness 
and one case of swelling at the injection site in 12 subjects. For the 300 mg SC dose there was 
one further report of redness in 12 subjects dosed. All local events were of mild intensity, 
occurred within 30 minutes after injection and completely resolved within 4 hours. There were 
no reports of injection site pain. The type, intensity and duration of systemic AEs were similar 


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to what has been observed in the preceding single-rising dose / multiple rising dose studies 
1368-0001 and 1368-0002. Most of the AEs were of mild intensity, there were no AEs 
considered to be dose limiting, and no SAEs.
In the single-rising-dosing trial in Japanese healthy subjects 1368-0009, 32 healthy Japanese 
male subjects were enrolled in four dose groups each comparing eight subjects per group. The 
trial consisted of three dose groups receiving single rising IV infusion doses of Spesolimab
(300 mg, 600 mg, and 1200 mg) and one dose group receiving single SC doses of Spesolimab
(300 mg). In each dose group, 6 subjects received Spesolimab and two subjects’ placebo. A 
total of three of 18 subjects (16.7%) on IV doses of Spesolimab (one subject per IV dose level) 
were reported with an AE compared with two of eight subjects (25%) on placebo. No subject 
was reported with an AE following subcutaneous administration of spesolimab. AEs by 
preferred term reported on placebo were vomiting, chest comfort, and allergic rhinitis, while 
AEs reported on Spesolimab were upper respiratory infection (300 mg IV), contusion (600 mg 
IV), gastroenteritis (1200 mg IV), and temporomandibular joint syndrome (1200 mg IV). None 
of the observed AEs were judged by the investigator as related to the trial medication. SAEs, 
deaths, AEs of special interest (AESI) or other significant AEs (according to project definition) 
were not observed and no subject discontinued the trial due to an AE. The overall AE frequency 
following administration of single doses of 300 to 1200 mg IV or 300 mg SC. Spesolimab was 
comparable with placebo.
In 1368-0001 and 1368-0002 trials, TMDD-related PK profile was observed. The exposure 
showed dose-proportional profile from 0.05 mg/kg to 20 mg/kg in single IV infusion group. In 
1368-0009 trial, the exposure was also dose proportional within the evaluated dose range (300 
mg to 1200 mg). No severe AE was observed in the each trials.
The relative bioavailability trial 1368-0029 explored PK as well as safety and tolerability of an 
SC formulation of Spesolimab in four treatment groups [periumbilical injection of 300 mg SC 
given at one (x 2 mL) or two (2 x 1 mL) injection sites, periumbilical injection of 600 mg SC 
(2 x 2 mL) and 300 mg SC (1 x 2mL) given to the thigh]. A total of 48 subjects entered the trial 
and completed the planned observation time according to the clinical trial protocol. To sum up, 
Spesolimab was safe and well tolerated by the healthy subjects and no safety signal was 
identified in trial 1368-0029.


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Residual Effect Period
The residual effect period (REP) of Spesolimab is 16 weeks. This is the period after the last 
dose with measurable drug levels and/or PD effects still likely to be present.


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Drug product
For a more detailed description of the Spesolimab profile, please refer to the current 
investigator’s Brochure (IB) [c03320877].
1.3
RATIONALE FOR PERFORMING THE TRIAL
 
A recently completed Japanese Phase I trial (1368-0009) explored safety, tolerability, and PK 
of Spesolimab following IV administration of single-rising- doses (300, 600, 1200 mg) and 
single SC dose (300 mg) in healthy Japanese male subjects. In this trial, the Spesolimab
exposure after IV administration increased with increasing dose in a dose-proportional manner 
across the tested dose range from 300 mg to 1200 mg. The relative bioavailability of 
Spesolimab after 300 mg SC administration was 73.5%. The dose-normalised exposure 
maximum measured concentration of the analyte in plasma (Cmax) and Area under the 
concentration-time curve of the analyte in plasma over the time interval from 0 extrapolated to 
infinity (AUC0-∞) after single IV administration of Spesolimab were comparable and no large 
differences were observed between Japanese healthy subjects (trial 1368-0009) and non-
Japanese healthy subjects (trial 1368-0001 and trial 1368-0002). The similar Spesolimab
exposures was observed between Japanese healthy subjects and non-Japanese healthy subjects 
after single SC dose (300 mg; trial 1368-0009 and trial 1368-0003). The evaluation of the 
relative bioavailability between 300 mg SC and 600 mg SC was completed with Caucasian 
healthy volunteers (1368-0029).
The current trial will investigate the PK and safety of Spesolimab in healthy Chinese subjects.
At the consultation meeting with NMPA held on Dec 2018, therapeutic dose was required to 
evaluate in this trial. The dose amount was set to cover the therapeutic dose of all indications.
1.4
BENEFIT - RISK ASSESSMENT
Participation in this trial is without any (therapeutic) benefit to healthy subjects. Their 
participation in the trial, however, is of major importance to the development of a new therapy 
 The subjects are exposed to the risks of the trial
procedures and the risks related to the exposure to the trial medication.
Procedure-related risks
The use of an indwelling venous catheter for the purpose of blood sampling, may be 
accompanied by mild bruising and also, in rare cases, by transient inflammation of the wall of 
the vein. In addition, in rare cases a nerve might be injured while inserting the venous catheter, 
potentially resulting in paresthesia, reduced sensibility, and/or pain for an indefinite period. 
The same risks apply to vein puncture for blood sampling. Other risks of related to trial-specific 
procedures include IV infusion or SC administration of study medication, which can cause 
local bruising, inflammation, nerve damage and pain.


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The total volume of blood withdrawn during the entire trial per subject will not exceed the 
volume of a normal blood donation (400 mL). No health-related risk to healthy subjects is 
expected from this blood withdrawal.
Drug-related risks and safety measures
The toxicology package conducted in mice with a mouse-specific antibody (BI 674304) 
includes 4-, 13- and 26-week toxicity studies and reproductive/developmental toxicity studies 
without any findings which would preclude clinical studies in humans (see IB [c03320877]). 
There have been no dose or exposure-related abnormalities in safety laboratory parameters and 
no safety or tolerability concerns that would preclude further clinical development of 
Spesolimab.
Spesolimab has been tested and found safe and tolerable in humans in single- and multiple-
rising-dose trials 1368-0001, 1368-0002, 1368-0003, 1368-0009 and 1368.29 in healthy male 
and female subjects and in trial and in several completed trials in patients 
 
 No clinically relevant abnormalities 
on treatment with Spesolimab with respect to safety laboratory parameters and vital signs were
observed (see IB [c03320877]).
Based on studies in healthy subjects and patients, no specific drug-related risks are anticipated. 
Nevertheless, the following safety measures are/will be applied in this trial in order to minimise 
the risk for the healthy subjects:

Careful dose selection based on data of the completed studies. In the first dose group 
of 300 mg SC, the exposure is projected to be similar to the Japanese healthy subjects 
who were enrolled in trial 1368-0009 and received the same SC dose.

For the IV dose groups, the administration as 90 minutes infusion allows immediate 
discontinuation of drug administration should any safety concern arise.

For both IV and SC dose groups, a time interval of at least two weeks will be maintained 
between first administration of trial medication in the actual dose level and first 
administration in the next dose level, which is expected to cover the period of highest 
risk/peak effect. The next dose will only be given if no safety concerns arise in the 
previous dose group and if none of the pre-specified trial-specific stopping criteria are 
met within each IV and SC dose groups.

Extensive monitoring of 12-lead ECG and vital signs is incorporated, with 12-lead ECG 
to cover the anticipated period of highest drug exposure. As an additional measure, 
repeated single 12-lead ECGs are scheduled in the further course of the trial. The 
rationale for the intensified 12-lead ECG monitoring is not due to expected increased 
risk of Spesolimab mediated effects on cardiac repolarization, rather, it is been 
implemented to collect 12-lead ECG data at an early point in clinical development to 
perform 12-lead ECG interval assessment under drug. In general, for biologics, Time 
between start of the Q-wave and the end of the T-wave in an electrocardiogram (QT)
prolongation is not usually an issue unless there are mechanistic effects with the mAb 
which can lead indirectly to the 12-lead ECG changes [R09-2768] but this is not 
expected to be the case for Spesolimab. 

Extensive safety laboratory testing will be performed.


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
After each dosing, the subjects will stay at the site for at least 48 hours following drug 
administration.

During in-house-confinement the subjects will be under close medical observation and 
thoroughly monitored for both expected and unexpected AEs.

Close monitoring of subjects’ signs and symptoms for hypersensitivity reactions during 
and after trial drug administration. Hypersensitivity reactions should be treated 
according to local medical standards [R11-4890].
Currently there are no data available to suggest interactions of Spesolimab [c03320877].
Although rare, potential for drug-induced liver injury (DILI) will be under constant 
surveillance by sponsors and regulators. Therefore, this trial requires timely detection, 
evaluation, and follow-up of laboratory alterations in selected liver laboratory parameters to 
ensure subjects’ safety; see also section 5.2.6.1.4, AEs of special interest.
As an antagonist of IL36R, Spesolimab affects one target of the immune system which is 
ubiquitously expressed. Due to the antagonistic effect, it is considered remote that Spesolimab
may lead to an amplification of an effect that might not be sufficiently controlled by a 
physiologic feedback mechanism. In addition, preclinical investigations and BI’s clinical 
programme have demonstrated no cases of cytokine release syndrome induced by Spesolimab
to date.
Due to the lack of mechanism- or compound-related safety signals and the antagonistic mode 
of action of Spesolimab, it is considered that healthy subjects will not be exposed to undue 
risks in relation to the information expected from this trial. Considering the medical need for
the development of an effective and well-tolerated drug for the therapy of 
 
 the expected benefit of this trial is considered to outweigh the potential risks and 
justifies the exposure of healthy subjects.
Benefit-Risk Assessment in context of COVID-19 pandemic for subjects participating in 
clinical trials investigating Spesolimab:
A thorough assessment has been conducted to evaluate whether spesolimab may pose a 
higher risk associated with COVID-19 infection.  The key aspects of the assessment are 
summarized below.
Spesolimab is an immune-modulating humanized monoclonal antibody that blocks the human 
IL-36 receptor and thereby the pro-inflammatory IL-36 pathway. Available non-clinical and 
clinical data in 604 subjects (see c03320877) have not shown an increased risk of infections 
with spesolimab. However, similar to other immune modulating biological treatments, 
spesolimab may hypothetically increase the risk of infections. Therefore, risk mitigation 
measures, such as close monitoring of adverse events, as well as guidance on handling of 
acute infections occurring during the trial have been included within this clinical trial 
protocol.
The investigator may choose to perform COVID-19 testing as per his/her discretion if useful 
based on individual medical consideration and in the case of suspected COVID-19 infection. 


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As any other acute infection, a suspected or diagnosed COVID-19 infection should be treated 
according to the standard of care.
The investigators will take the totality of information related to each single subject and the 
local COVID-19 situation into consideration when performing the individual benefit-risk 
assessment on a case-by-case basis. Considering all aspects, the investigator will decide upon 
each subject’s (continued) participation in the planned trials. BI as the sponsor, where 
required, will support the investigator in their decision finding. It is acknowledged that the 
investigator may decide to implement protocol deviations where this protects the safety, 
wellbeing, and/or is in the best interest of the patient.
To address potential risks associated with operational aspects related to the participation in 
clinical trials in context of COVID-19 pandemic, different risk mitigation measures are 
considered in ongoing and planned spesolimab clinical trials based on local requirements and 
development of the pandemic.
The benefit-risk assessment of spesolimab remains favourable in the context of the COVID-
19 pandemic.


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2.
TRIAL OBJECTIVES AND ENDPOINTS
2.1
MAIN OBJECTIVES, PRIMARY AND SECONDARY ENDPOINTS
Main objectives
The primary objective of this trial is to investigate PK, including dose proportionality, 
following single IV and SC doses of spesolimab in healthy Chinese subjects.
Primary endpoint
AUC0-∞and Cmax of spesolimab.
Secondary endpoint
The occurrence of treatment-emergent AEs.
The occurrence of drug-related AEs.
Safety and tolerability
Safety and tolerability of Spesolimab will be assessed based on:

Safety laboratory parameters

12-lead ECG

Vital signs (blood pressure [BP], pulse rate [PR], respiratory rate [RR], body
temperature)

Immunogenicity (ADA )


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3.
DESCRIPTION OF DESIGN AND TRIAL POPULATION
3.1
OVERALL TRIAL DESIGN AND PLAN
This single-doses and parallel-group design for IV and SC administration trial is designed as 
open label, within dose groups.
It is planned to include up to 60 healthy male and female subjects in the trial. The subjects will 
be assigned to 5 groups each consisting of 10 subjects with at least 3 subjects for each gender
within each dose group; In case of subjects not completed the trial, up to 10 replacement will 
be recruited for whole study. The cohorts within each SC and IV dose groups will be dosed 
sequentially (see Table 3.1: 1). 
Only one dose is tested within each dose group. The dose groups to be evaluated are outlined 
in Table 3.1: 1.
Table 3.1: 1
Dose groups
Dose group
1
2
3
4
5
Dose
IV
SC
450 mg
900mg
1200 mg
300 mg
600 mg 
No. of subjects entered
10
10
10
10
10
No. of subjects receiving 
active
10
10
10
10
10
The investigator is allowed to interrupt further dose escalation in the event the safety evaluation 
leads to concerns until alignment with sponsor is achieved.
The cohorts will be dosed consecutively in ascending order within IV and SC dose groups, and 
a time interval of at least two weeks will be maintained between the first drug administration 
to subjects in the previous dose group and the first drug administration to subjects in the 
subsequent dose group. The decision to treat the next dose cohort will be based upon safety. 
An overview of all relevant trial activities is provided in the Flow Chart. For visit schedules 
and details of trial procedures at selected visits, refer to sections 6.1 and 6.2, respectively.
3.2
DISCUSSION OF TRIAL DESIGN, INCLUDING THE CHOICE OF 
CONTROL GROUPS
The trial will be conducted in an open-label fashion. Blinding is not possible because the 
treatments are distinguishable. The open-label treatment is not expected to cause bias results, 
since the pharmacokinetic endpoints are derived from measurement of plasma concentrations 
of the analyte.


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For safety reasons, a time interval of at least two weeks (taking into consideration that the t1/2
of Spesolimab is four weeks) will be maintained between the first drug administration in the 
previous dose group and the first drug administration of the subsequent dose group within each 
SC and IV dose groups. 
3.3
SELECTION OF TRIAL POPULATION
It is planned that up to 60 including 10 replaced healthy male and female subjects (at least three
of each sex within each dose group) will enter the trial. Subjects will be recruited from the 
subjects' pool of the trial site. 
A log of all subjects enrolled into the trial (i.e. who have signed informed consent) will be 
maintained in the ISF irrespective of whether they have been treated with investigational drug 
or not.
Main diagnosis for trial entry 
The trial will be performed in healthy subjects.
Inclusion criteria
Subjects will only be included in the trial if they meet the following criteria:
1. Healthy male or female subjects (at least three subjects for each gender within each dose 
group) according to the assessment of the investigator, as based on a complete medical 
history including a physical examination, vital signs (BP, PR, RR, body temperature), 12-
lead ECG, and clinical laboratory tests.
2. Chinese ethnicity, according to the following criteria:
Ethnic Chinese, born in China and have 4 ethnic grandparents who were all born in 
China.
3. Age of 18 to 45 years (inclusive). 
4. Body weight ≥50 kg for male and ≥45 kg for female with body mass index (BMI) range 
≥19 and <26 kg/m2 at visit 1.
5. Signed and dated written informed consent prior to admission to the trial, in accordance 
with GCP and local legislation.
6. Female subjects who meet any of the following criteria from at least 30 days before the 
first administration of trial medication until 16 weeks after trial completion [c03320877]: 
- Women of childbearing potential (WOCBP)1 must be ready and able to use highly 
effective methods of birth control per ICH M3 (R2) that result in a low failure rate of less 
than 1% per year when used consistently and correctly. A list of contraception methods 
meeting these criteria is provided in the subject information
- A vasectomised sexual partner (vasectomy at least one year prior to enrolment)
- Surgically sterilised (including hysterectomy)
- Postmenopausal, defined as at least one year of spontaneous amenorrhoea (in 
questionable cases a blood sample with simultaneous levels of FSH above 40 U/L and 
estradiol below 30 mg/L is confirmatory).


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Exclusion criteria
Subjects will be excluded in the trial if they meet the following criteria: 
1. Major surgery (major according to the investigator’s assessment) performed within 12 
weeks prior to treatment or planned within 12 months after screening, e.g. hip replacement.
2. Any finding in the medical examination (including BP, PR, RR, Body temperature or 12-
lead ECG) deviating from normal and assessed as clinically relevant by the investigator.
3. Repeated measurement of systolic BP outside the range of 90 to 140 mmHg, diastolic BP
outside the range of 50 to 90 mmHg, or PR outside the range of 50 to 90 bpm.
4. Any laboratory value outside the reference range that the investigator considers to be of 
clinical relevance.
5. Any evidence of a concomitant disease assessed as clinically relevant by the investigator. 
6. Gastrointestinal, hepatic, renal, respiratory, cardiovascular, metabolic, immunological or 
hormonal disorders. Diseases of the central nervous system (including but not limited to 
any kind of seizures or stroke), and other relevant neurological or psychiatric disorders. 
7. History of relevant orthostatic hypotension, fainting spells, or blackouts. 
8. Chronic or relevant acute infections including active and latent tuberculosis, human 
immunodeficiency virus (HIV) or viral hepatitis; QuantiFERON TB test will be performed 
at screening.
9. History of allergy/hypersensitivity to the systemically administered trial medication agent 
or its excipients.
10. Use of any Chinese traditional medicines and drugs (including prescription drug or over 
the counter) within 30 days of planned administration of trial medication.
11. Subject has been treated with any investigational drug of chemical or biologic nature within 
a minimum of 60 days or five t1/2 (whichever is longer) of the drug prior to the Baseline 
(Week 0) Visit, or concurrent participation in another clinical trial in which investigational 
drug is administered.
12. Administered live vaccine within six weeks prior to treatment or have plans for 
administration of live vaccines during the trial period.
13. Smoker (more than ten cigarettes or three cigars or three pipes/day).
14. Inability to refrain from smoking on specified trial days.
15. Alcohol abuse (consumption of more than 20 g/day for females and 30 g/day for males).
16. Drug abuse or positive drug screening.
17. Blood donation of more than 100 mL within 30 days prior to administration of trial 
medication or intended blood donation during the trial.
18. Intention to perform excessive physical activities within one week prior to the 
administration of trial medication or during the trial.
19. Inability to comply with the dietary regimen of the trial site.
20. A marked baseline prolongation of QT/QTc interval (such as QTc intervals that are 
repeatedly greater than 450 ms in male or repeatedly greater than 470 ms in females) or 
any other relevant 12-lead ECG finding at screening.
21. A history of additional risk factors for Torsade de Pointes (such as heart failure, 
hypokalaemia, or family history of Long QT Syndrome).
22. Subject is assessed as unsuitable for inclusion by the investigator, for instance, because the 
subject is not considered able to understand and comply with trial requirements, or has a 
condition that would not allow safe participation in the trial.


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23. Any documented active or suspected malignancy or history of malignancy within 5 years 
prior to screening, except appropriately treated basal cell carcinoma of the skin, squamous 
cell carcinoma of the skin or in situ carcinoma of uterine cervix.
24. Female subjects will be excluded in the trial if they meet the following criteria: 
- Positive pregnancy test, pregnancy or plans to become pregnant up to 16 weeks of trial
drug administration
- Lactation
For trial restrictions, refer to section 4.2.2.
Withdrawal of subjects from treatment or assessments
Subjects may discontinue trial treatment or withdraw consent to trial participation as a whole 
(‘withdrawal of consent’) with very different implications; please see sections 3.3.4.1 and 
3.3.4.2.
If a subject is removed from or withdraws from the trial prior to the first administration of trial 
medication, the data of this subject will not be entered in the case report form (CRF) and will 
not be reported in the clinical trial report (CTR). If a subject is removed from or withdraws 
from the trial after the first administration of trial medication, this will be documented and the 
reason for discontinuation must be recorded in the CRF; in addition, the data will be included 
in the CRF and will be reported in the CTR.
At the time of discontinuation, a complete EoTrial examination will be performed, if possible, 
and the information will be recorded in the CRF. If the discontinuation occurs before the end 
of the REP (see section 1.2.6), the discontinued subject should if possible be questioned for 
AEs and concomitant therapies at or after the end of the REP in order to ensure collection of 
AEs and concomitant therapies throughout the REP, if not contrary to any consent withdrawal 
of the subject.
If it is known that a subject becomes pregnant during the trial, administration of the trial 
medication is to be stopped immediately, and the subject is to be removed from the trial. The 
subject is to be followed until she has given birth or until the end of the pregnancy. The 
subject’s data are to be collected until the end of the trial (last visit of last subject) and reported 
in the CTR. For the reporting of pregnancy and associated events, refer to section 5.2.6.2.4.
Discontinuation of trial treatment
An individual subject will discontinue trial treatment if:
1. The subject wants to discontinue trial treatment, without the need to justify the decision
2. The subject has repeatedly shown to be non-compliant with important trial procedures 
and, in the opinion of both the investigator and sponsor representative, is not willing or 
able to adhere to the trial requirements in the future 
3. The subject needs to take concomitant medication that interferes with the investigational 
medicinal product or other trial treatment


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4. The subject can no longer receive trial treatment for medical reasons (such as pregnancy, 
surgery, AEs, or diseases)
5. An AE or clinically significant laboratory change or abnormality occurs that the 
investigator assesses as warranting discontinuation of treatment. This may include cases 
of sustained symptomatic hypotension (BP <90/50 mmHg) or hypertension (BP >180/100 
mmHg), clinically relevant changes in 12-lead ECG requiring intervention, or
unexplained hepatic enzyme elevations at any time during the trial
6. The subject has an elevation of AST and/or ALT ≥3-fold ULN and an elevation of total 
bilirubin ≥2-fold ULN (measured in the same blood sample) and/or needs to be followed 
up according to the DILI checklist provided in the ISF
In addition to these criteria, the investigator may discontinue subjects at any time based on his 
or her clinical judgment.
Even if the trial treatment is discontinued, the subject remains in the trial and, given his/her 
agreement, will undergo the procedures for early treatment discontinuation and follow up as 
outlined in the Flow Chart and section 6.2.3.
Withdrawal of consent to trial participation
Subjects may withdraw their consent to trial participation at any time without the need to justify 
the decision. If a subject wants to withdraw consent, the investigator should be involved in the 
discussion with the subject and explain the difference between trial treatment discontinuation 
and withdrawal of consent to trial participation, as well as explain the options for continuous
follow up after trial treatment discontinuation, please see section 3.3.4.1.
Discontinuation of the trial by the sponsor
Boehringer Ingelheim (BI) reserves the right to discontinue the trial at any time for any of the 
following reasons:
1. Failure to meet expected enrolment goals overall or at a particular trial site.
2. New toxicological findings, SAEs, or any safety information invalidating the earlier 
positive benefit-risk assessment. Dose escalation will be terminated if more than 50% of 
the subjects at one dose level show drug-related and clinically-relevant AEs of moderate 
or severe intensity, or if at least one drug-related SAEs is reported.
3. Violation of GCP or the clinical trial protocol (CTP) or the contract with BI impairing the 
appropriate conduct of the trial.
4. The sponsor decides to discontinue the further development of the investigational 
product.
5. Dose escalation will be stopped if at least two subjects at one dose level have relevant 
individual QT prolongations, i.e. a QTc increase of greater than 60 ms from baseline in 
connection with absolute QT or QTc greater than 500 ms, as confirmed by a repeated
ECG recording. The investigator/trial site will be reimbursed for reasonable expenses 
incurred in case of trial termination (except if item three applies).


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Replacement of subjects
If some subjects do not complete the trial, the Clinical Trial Leader (CTL) together with the 
Trial Pharmacokineticist and the Trial Statistician are to decide, if subjects will be replaced. A 
replacement subject will be assigned a unique trial subject number, and will be assigned to the 
same treatment as the subject he or she replaces. Up to 10 subjects will be replaced for whole 
study. Data from replaced subjects will be available in the database.


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4.
TREATMENTS
4.1
INVESTIGATIONAL TREATMENTS
The investigational product is manufactured by BI Pharma GmbH & Co. KG, Biberach, 
Germany. The spesolimab molecule is a heterodimer with a molecular weight of approximately 
146 kDa.
Identity of the Investigational Medicinal Products
For subcutaneous administration
The characteristics of the test product are given below:
Substance:
BI 655130
Pharmaceutical 
formulation:
Solution for injection
Source:
BI Pharma GmbH & Co. KG, Germany
Unit strength:
150 mg/mL
Posology:
1-0-0
Route of 
administration:
SC injection (abdominal region)
Duration of use:
Single dose (300 mg, 600 mg)
For intravenous administration
The characteristics of the test product are given below:
Substance:
BI 655130
Pharmaceutical 
formulation:
Solution for infusion
Source:
BI Pharma GmbH & Co. KG, Germany
Unit strength:
60 mg/mL, 7.5 mL (per 10R glass vial)
Posology:
1-0-0
Route of 
administration:
IV infusion
Duration of use:
Single dose (450 mg, 900 mg, 1200 mg)
At the time of use, the IV solution for dosing will be prepared as detailed in the instruction 
given in ISF.


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Selection of doses in the trial
Dose strengths will be investigated for both SC administration and IV administration in this 
trial. Doses for SC and IV will each cover potential therapeutic dose ranges and provide a safety 
margin for future development. Dose proportionality of exposure will be evaluated for IV 
group.
This trial is designed to evaluate the PK and safety of Spesolimab in Chinese healthy subjects.
Method of assigning subjects to treatment groups
Prior to the screening visit, subjects will be contacted and informed about the planned visit 
dates. The subjects who are willing to participate will be recruited to dose groups according to 
their temporal availability. As soon as enough subjects have been allocated to one of the 5 dose 
groups, the following subject will be allocated to one of the other dose groups. Therefore, the 
allocation of subjects to dose groups is not influenced by trial personnel, but only by the 
subjects’ temporal availability. If more available subjects than target number for a cohort, the 
subjects will be enrolled according to the subsequence of signed ICF by subjects and gender 
ratio required by study. As the trial includes healthy subjects of only Chinese ethnicity, relevant 
imbalances between the dose groups are not expected.
The randomisation list of subject and medication numbers will be provided to the trial site in 
advance. The allocation of subject to trial subject number will be performed prior to the first 
administration of trial medication. Once a subject number has been assigned, it cannot be 
reassigned to any other subject.
It is an open-label trial without randomisation.
Drug assignment and administration of doses for each subject
The treatments to be evaluated are outlined in Table 4.1.4: 1. Each subject will receive one 
single dose of trial medication. For further details concerning timing see Flow Chart. Detailed 
instructions for the preparation are provided in ISF.
Table 4.1.4: 1
Final dose of BI 655130 in solution containing active drug
Dose group
Final dose of BI 655130 [mg]
1
450 mg (IV infusion)
2
900 mg (IV infusion)
3
1200 mg (IV infusion)
4
300 mg (SC injection)
5
600 mg (SC injection)


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For intravenous administration
Administration of trial medication will be performed after subjects have fasted overnight; 
fasting is to start no later than 10 h before the scheduled dosing. The detailed instructions for 
the dilution of the trial medication, the preparation of the infusion solution and the volume to 
be administered is provided in ISF. In all subjects, the infusion solution will be intravenously 
administered over 90 minutes approximately between 8:00 and 10:00 of the respective trial
day. Start and end time of the infusion will be recorded.
In case of safety concerns, e.g. due to infusion reactions, the investigator or his/her designee 
should stop of the infusion. Based on his medical judgment, he/she will provide medications 
such as steroids, etc. as needed.
For administration of the infusion, an IV indwelling catheter is placed into an arm vein of the 
subject for saline infusion. A second indwelling catheter used for collection of blood samples 
will be placed on the contralateral arm.
The administration of the trial medication on all trial days will be done under supervision of 
the investigating physician or a designee. The so-called four-eye principle (two-person rule) 
should be applied for administration of trial medication and – if applicable – its preparation 
(e.g. reconstitution), if correct dosage cannot be ensured otherwise. 
Water is allowed except for one hour before start of infusion and 1.5 hours after end of infusion.
For subcutaneous administration
Administration of trial medication will be performed after subjects have fasted overnight; 
fasting is to start no later than 10 h before the scheduled dosing. Trial medication will be 
injected subcutaneously in the abdominal region. The skin is sanitised before injection. Needle 
is placed subcutaneously and solution with trial medication is injected within 60 seconds. 
Detailed handling instructions will be provided in the ISF.
For all dose groups, standardised meals will be served as outlined in the Flow Chart. Subjects 
will be kept under close medical surveillance until 48 hours following drug administration. 
Thereafter subjects will be discharged and further assessments will be conducted in an 
ambulatory fashion. For restrictions with regard to diet see also section 4.2.2.2. 
Blinding and procedures for unblinding
Blinding
The trial will be conducted in an open-label fashion. 
This Phase I trial will be handled in an open fashion throughout (that is, during the conduct, 
including data cleaning and preparation of the analysis). This is considered acceptable because 
the potential for bias is low and does not outweigh practical considerations. Emergency 
envelopes will not be provided, since the treatments of all subjects are known in this open-label 
trial.


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Packaging, labelling, and re-supply
The investigational medicinal products will be provided by 
 
. They will be packaged and 
labelled in accordance with local law and the principles of Good Manufacturing Practice. 
For details of packing and the description of the label, refer to the ISF.
The telephone number of the sponsor and the name, address and telephone number of the trial 
site are provided in the subject information form. Examples of the labels will be available in 
the ISF.
Storage conditions
Drug supplies will be kept in their original packaging and in a secure storage area with limited 
access according to the recommended (labelled) storage conditions. Where necessary, a 
temperature log must be maintained to ensure that the drug supplies are stored at the correct 
temperature. If the storage conditions are found to be outside the specified range, the clinical 
trial manager (CTM) (as provided in the list of contacts) is to be immediately contacted.
Drug accountability
The investigator/pharmacist/investigational drug storage manager will receive the 
investigational drugs delivered by the sponsor when the following requirements are fulfilled:

Approval of the trial protocol by the IRB/ethics committee

Availability of a signed and dated clinical trial contract between the sponsor and the 
Head of Trial Centre

Approval/notification of the regulatory authority, e.g. competent authority

Availability of the curriculum vitae of the principal investigator

Availability of a signed and dated CTP or immediately imminent signing of the CTP
Only authorised personnel as documented in the form ‘Trial Staff List’ may dispense trial 
medication to trial subjects. The trial medication must be administered in the manner specified 
in the CTP. All unused trial medication must be returned to the sponsor. All used medication 
will be disposed locally by the trial site. Receipt, usage, return and disposal must be 
documented on the respective forms in ISF. Account must be given for any discrepancies. 
The investigator/pharmacist/investigational drug storage manager must maintain records of the 
product’s delivery to the trial site, the inventory at the site, the use by each subject, and the 
return to the sponsor or alternative disposal of unused or partially used products. 
These records will include dates, quantities, batch/serial numbers, expiry (‘use-by’) dates, and 
the unique code numbers assigned to the investigational products and trial subjects. The 
investigator/pharmacist/investigational drug storage manager will maintain records that 
document adequately that the subjects were provided the doses specified by the CTP, and that 
reconcile all investigational products received from the sponsor. At the time of disposal or


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return to the sponsor, the investigator/pharmacist/investigational drug storage manager must 
verify that no remaining supplies are in the investigator’s possession.
4.2
OTHER TREATMENTS, EMERGENCY PROCEDURES,
RESTRICTIONS
Other treatments and emergency procedures
There are no specific rescue drugs foreseen for the treatment of AEs. No special emergency 
procedures are to be followed. No additional treatment is planned. However, in case of AEs in 
need of treatment, the investigator can authorise symptomatic therapy. In those cases, subjects
will be treated as necessary and, if required, kept under supervision at the trial site or transferred 
to a hospital until all results of medical evaluations are acceptable.
Restrictions
Restrictions regarding concomitant treatment
In principle, no concomitant therapy is allowed. All concomitant or rescue therapies will be 
recorded (including time of intake on trial days) on the appropriate pages of the CRF.
Restrictions on diet and life style
While admitted to the trial site, the subjects are restricted from consuming any other foods or 
drinks than those provided by the staff. Standardised meals will be served at the time points 
described in the Flow Chart. On Day 1 for all subjects, no food is allowed for at least 10 hours
before and 1.5 hours after administration of the trial medication (= end of infusion for IV dose 
group).
On all days of drug administration, starting from one hour before drug administration until 1.5 
hours after the completion of administration liquid intake is not allowed. At 24 hours post-dose 
water intake will be within 1000 to 3000 mL. Total fluid intake on all 24 hours inhouse days is 
recommended to be at least 1500 mL and should not exceed 3500 mL.
Smoking is not allowed during in-house confinement at the trial site. On the ambulatory days 
it is restricted to not more than ten cigarettes or three cigars or three pipes/day.
Methylxanthine-containing drinks or foods (such as coffee, tea, cola, energy drinks, and 
chocolate) are not allowed during inhouse confinement. Alcoholic beverages are not permitted 
starting 7 days before the first administration of trial medication until Day 28. From Day 29 
onwards, alcohol consumption is restricted to 20 g alcohol/day corresponding to 500 mL beer 
or 200 mL of white wine/day.
Excessive physical activity (such as competitive sport) should be avoided starting 7 days before 
the first administration of trial medication until the EoTrial examination. 
If female subjects of child-bearing potential are included in the trial, adequate contraception is 
to be maintained throughout the course of the trial (see section 3.3.2 for the definition of 
adequate measures). 


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4.3
TREATMENT COMPLIANCE
Compliance will be assured by administration of all trial medication in the trial centre under 
supervision of the investigating physician or a designee. The measured plasma concentrations 
will provide additional confirmation of compliance.
Subjects who are non-compliant (for instance, who do not appear for scheduled visits or violate 
trial restrictions) may be removed from the trial and the CRF will be completed accordingly 
(for further procedures, please see section 3.3.4.1). 


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5.
ASSESSMENTS
5.1
ASSESSMENT OF EFFICACY
Not applicable. No efficacy endpoints will be evaluated in this trial.
5.2
ASSESSMENT OF SAFETY
Physical examination
At the screening visit, the medical examination will include documentation of subject
information, informed consent, demographics including height, body weight, smoking and 
alcohol history, relevant medical history and concomitant therapy, review of inclusion and 
exclusion criteria, review of vital signs (BP, PR, RR and body temperature), 12-lead ECG, 
laboratory tests (including drug screen and pregnancy test), as well as physical examination. 
At the EoTrial examination, it will include review of vital signs, 12-lead ECG, laboratory tests, 
and a physical examination including determination of weight.
Vital signs
Systolic and diastolic BP, body temperature, respiratory rate (RR) as well as PR or heart rate 
(heart rate is considered to be equal to PR in healthy subjects) will be measured by a BP monitor 
at the time points indicated in the Flow Chart, after subjects have rested for at least 5minutes
in a supine position. All recordings should be made using the same type of BP recording 
instrument on the same arm if possible.
Safety laboratory parameters
For the assessment of laboratory parameters, blood and urine samples will be collected by the 
trial site at the time points indicated in the Flow Chart after the subjects have fasted for at least 
10 h. Overnight fasting is not required at the discretion of the investigator or designate for 
retests.
The parameters that to be determined are listed in Tables 5.2.3: 1 and 5.2.3: 2. Reference ranges 
will be provided in the ISF. 
Urine sediment examinations will only be performed if there is a clinically relevant abnormality 
in the urinalysis, and it is deemed clinically necessary by the investigator.


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Table 5.2.3: 1
Routine laboratory tests
Functional lab group
Test name 
Haematology
Haematocrit
Haemoglobin
Red blood cell count (RBC)
Reticulocyte count
White blood cell count (WBC)
Platelet count
Automatic WBC differential 
(relative and absolute cell count)
Neutrophils, eosinophils, basophils, monocytes, lymphocytes
Coagulation
Activated partial thromboplastin time (aPTT)
Prothrombin time (Quick’s test and INR)
Fibrinogen
Enzymes
Aspartate transaminase (AST/GOT)
Alanine transaminase (ALT/GPT)
Alkaline phosphatase (ALP))
Gamma-glutamyl transferase (GGT)
Creatine kinase (CK)
CK-MB, only if CK is elevated 
Lactate dehydrogenase (LDH)
Serum Immunoglobulin E (IgE) 1
Hormones 2
Thyroid stimulating hormone (TSH)
fT3, fT4
Substrates
Serum glucose
Creatinine 
Total bilirubin 
Direct bilirubin
Total protein
Protein electrophoresis (Protein EP) 3
Albumin 
Globulin
CRP 
Uric acid 
Total cholesterol 
Triglycerides
Electrolytes
Sodium
Potassium
Chloride
Calcium
Inorganic phosphate (IP)


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Table 5.2.3: 1
Routine laboratory tests (cont.)
Functional lab group
Test name 
Urinalysis (Stix)
Urine nitrite
Urine protein
Urine glucose
Urine ketone
Urobilinogen
Urine bilirubin
Urine erythrocytes
Urine leukocytes
Urine pH
Urine sediment 4
Only positive findings will be reported (for instance, the presence 
of sediment bacteria, casts in sediment, squamous epithelial cells, 
erythrocytes, leukocytes)
1.
In case of a potential systemic allergic reaction blood samples for determination of serum IgE will be collected 0.5 h, 2 h, 6 h and 24 h after onset of 
the event.
2.
Only at screening
3.
Only test at screening if total protein is abnormal and it is deemed clinically necessary by the investigator
4.
Only if erythrocytes, leukocytes, nitrite or protein are abnormal in urinalysis and it is deemed clinically necessary by the investigator
The tests listed in Table 5.2.3: 2 are exclusionary laboratory tests which may be repeated as 
required. The results will not be entered in the CRF/database and will not be reported in the 
CTR. Except for pregnancy test, it is planned to perform these tests during screening only.
Drug screening will be performed at screening. Pregnancy testing in women will be performed 
at screening, prior to treatment on Day 92, and as part of the EoTrial examination.
Table 5.2.3: 2
Exclusionary laboratory tests
Functional lab group
Test name 
Drug screening (urine)
Amphetamine/MDA
Benzodiazepine
Cannabis
Cocaine 
Opiates 
Infectious screening (blood) 1
Pregnancy test (Urine)
Determining Postmenopausal 
status(blood)
Hepatitis B surface antigen (HBsAg, qualitative)
Hepatitis B core antibody (Anti-HBs, qualitative)
Hepatitis C antibodies (Anti-HCV, qualitative)
HIV antibody (Anti-HIV, qualitative)
QuantiFERON (qualitative)
Beta human chorionic gonadotropin (beta-HCG)
FSH test (quantitative)
Estradiol test (quantitative)
1.
Only at screening


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To encourage compliance with alcoholic restrictions, a breath alcohol test will be performed at 
screening, and may be repeated at any time during the trial at the discretion of an investigator 
or designate. The results will not be included in the CTR. 
The laboratory tests listed in Tables 5.2.3: 1 and 5.2.3: 2 will be performed by the local 
laboratory of the trial site or/and at a clinical research organization designated by the sponsor.
Electrocardiogram
12-lead resting ECG
Recording
Twelve-lead resting ECGs (I, II, III, aVR, aVL, aVF, V1 - V6) will be recorded using a 
computerised electrocardiograph at the time points given in the Flow Chart.
In order to achieve a stable heart rate at rest and to assure high quality recordings at comparable 
resting phases, all ECGs will be recorded for a 10-sec duration after the subjects have rested 
for at least 5minutes in a supine position. The site personnel will be instructed to assure a 
relaxed and quiet environment so that all subjects are at complete rest during the recordings. 
ECG assessment will always precede all other trial procedures of the same time point (except 
blood drawing from an IV cannula which is already in place) to avoid impact of sampling on 
the ECG quality. Electrode placement will be performed according to the method of Wilson, 
Goldberger and Einthoven.
At all time points single ECGs will be recorded. All locally printed ECGs will be evaluated by 
the investigator or a designee. ECGs may be repeated for quality reasons (like alternating 
current artefacts, muscle movements, electrode dislocation). Additional (unscheduled) ECGs 
may be collected by the investigator for safety reasons. These ECGs are assigned to the prior 
scheduled time point. Unscheduled ECGs will not be included into the statistical analysis of 
interval lengths. 
For the inclusion or exclusion (see section 3.3) of a subject and for the assessment of cardiac 
safety during the trial, the QT and QTcF values generated by the ECG machines or their manual 
corrections by the investigators will be used. 
Abnormal findings will be reported as AEs (during the trial) or baseline conditions (at 
screening) if judged clinically relevant by the investigator. Any ECG abnormalities will be 
monitored carefully and, if necessary, the subject will be removed from the trial and will 
receive the appropriate medical treatment. 
Continuous ECG monitoring
Not applicable.


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Other safety parameters
Local tolerability
Local tolerability will be assessed by the investigator on the basis of ‘swelling’, ‘induration’, 
‘heat’, ‘redness’, ‘pain’, or ‘other findings’.
Suicidality assessment
Not applicable.
Assessment of adverse events
Definitions of adverse events
5.2.6.1.1
Adverse event
An adverse event (AE) is defined as any untoward medical occurrence in a patient or clinical 
investigation patient administered a medicinal product and which does not necessarily have to 
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 
product, whether or not considered related to the medicinal product.
The following should also be recorded as an AE in the CRF and BI SAE form (if applicable):

Worsening of the underlying disease or of other pre-existing conditions 

Changes in vital signs, 12-lead ECG, physical examination, and laboratory test 
results, if they are judged clinically relevant by the investigator
If such abnormalities already pre-exist prior to trial inclusion, they will be considered as 
baseline conditions and should be collected in the eCRF only.
5.2.6.1.2
Serious adverse event
A SAE is defined as any AE which fulfils at least one of the following criteria:

Results in death 

Is life-threatening, which refers to an event in which the patient was at risk of death at 
the time of the event; it does not refer to an event that hypothetically might have caused 
death if more severe, 

Requires inpatient hospitalisation

Requires prolongation of existing hospitalisation

Results in persistent or significant disability or incapacity 

Is a congenital anomaly/birth defect 

Is deemed serious for any other reason if it is an important medical event when based 
upon appropriate medical judgment which may jeopardise the patient and may require 
medical or surgical intervention to prevent one of the other outcomes listed in the above 


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definitions. Examples of such events are intensive treatment in an emergency room or 
at home for allergic bronchospasm, blood dyscrasias or convulsions that do not result 
in hospitalisation or development of dependency or abuse
5.2.6.1.3
AEs considered ‘Always Serious’
Cancers of new histology and exacerbations of existing cancer must be classified as a serious 
event regardless of the time since discontinuation of the trial medication and must be reported 
as described in section 5.2.6.2.1, subsections ‘AE Collection’ and ‘AE reporting to sponsor 
and timelines’.
In accordance with the European Medicines Agency initiative on Important Medical Events, 
BI has set up a list of further AEs, which by their nature, can always be considered to be 
‘serious’ even though they may not have met the criteria of an SAE as given above.
The latest list of ‘Always Serious AEs’ can be found in the EDC system, a remote data capture 
system which allows the entry of trial data at the trial site. These events should always be 
reported as SAEs as described above.
5.2.6.1.4
Adverse events of special interest
The term AEs of special interest (AESI) relates to any specific AE that has been identified at 
the project level as being of particular concern for prospective safety monitoring and safety 
assessment within this trial, e.g. the potential for AEs based on knowledge from other 
compounds in the same class. AESIs need to be reported to the sponsor’s Pharmacovigilance 
Department within the same timeframe that applies to SAEs, please see section 5.2.6.2.2.
The following are considered as AESIs in this trial:

Hepatic injury, as defined by the following alterations of hepatic laboratory 
parameters:
o
an elevation of AST and/or ALT ≥3-fold ULN combined with an elevation of 
total bilirubin ≥2-fold ULN measured in the same blood sample, or
o
ALT, and/or AST elevations ≥10-fold ULN
These lab findings constitute a hepatic injury alert and the subjects showing these lab 
abnormalities need to be followed up according to the ‘DILI checklist’ provided in the 
ISF. In case of clinical symptoms of hepatic injury (icterus, unexplained 
encephalopathy, unexplained coagulopathy, right upper quadrant abdominal pain, etc.) 
without lab results (ALT, AST, total bilirubin) available, the Investigator should make 
sure these parameters are analysed, if necessary in an unscheduled blood test. Should 
the results meet the criteria of hepatic injury alert, the procedures described in the DILI 
checklist should be followed.

Systemic hypersensitivity including infusion reaction and anaphylactic reaction:
o
Any suspicion of severe infusion reaction systemic/hypersensitivity reaction 
and of any potential cases of anaphylaxis should be defined and assessed using 
the criteria discussed in the statement paper from Sampson HA (Appendix 
10.1.3, R11-4890).

Severe infections (according to RCTC grading in ISF)


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
Opportunistic and mycobacterium tuberculosis infections
o
These include pneumocystis jirovecii, BK virus disease including PVAN, 
CMV, post-transplant lymphoproliferative disorder (EBV), progressive 
multifocal 
leucoencephalopathy, 
bartonellosis 
(disseminated 
only), 
blastomycosis, 
toxoplasmosis, 
coccidioidomycosis, 
histoplasmosis, 
aspergillosis 
(invasive 
only), 
candidiasis 
(invasive 
or 
pharyngeal), 
cryptococcosis, other invasive fungi (mucormycosis (zygomycosis, rhizopus, 
mucor, 
lichtheimia), 
scedosporium/pseudallescheria 
boydii, 
fusarium), 
legionellosis, listeria monocytogenes (invasive only), tuberculosis, nocardiosis, 
non-tuberculous mycobacterium, salmonellosis (invasive only), hepatitis B 
virus [HBV] reactivation, herpes simplex (invasive only), herpes zoster, 
strongyloides (hyperinfection syndrome and disseminated forms only), 
paracoccidioides, penicillium marneffei, sporothrix schenckii, cryptosporidium 
species (chronic only), microsporidiosis, leishmaniasis (visceral only), 
trypanosoma cruzi infection (Chagas’ disease) (disseminated only), 
campylobacteriosis (invasive only), shigellosis (invasive only), vibriosis 
(invasive due to vibrio vulnificus), hepatitis C virus [HCV] progression (R17-
2617).
5.2.6.1.5
Intensity (severity) of AEs
The intensity (severity) of the AE should be judged based on the following:
Mild:
Awareness of sign(s) or symptom(s) that is/are easily tolerated
Moderate:
Sufficient discomfort to cause interference with usual activity
Severe:
Incapacitating or causing inability to work or to perform usual activities
5.2.6.1.6
Causal relationship of AEs
Medical judgment should be used to determine the relationship, considering all relevant factors, 
including pattern of reaction, temporal relationship, de-challenge or re-challenge, confounding 
factors such as concomitant medication, concomitant diseases and relevant history.
Arguments that may suggest that there is a reasonable possibility of a causal relationship 
could be:

The event is consistent with the known pharmacology of the drug 

The event is known to be caused by or attributed to the drug class

A plausible time to onset of the event relative to the time of drug exposure

Evidence that the event is reproducible when the drug is re-introduced

No medically sound alternative aetiologies that could explain the event (e.g. pre-
existing or concomitant diseases, or co-medications)

The event is typically drug-related and infrequent in the general population not exposed 
to drugs (e.g. Stevens-Johnson syndrome)

An indication of dose-response (i.e. greater effect size if the dose is increased, smaller 
effect size if dose is reduced)


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Arguments that may suggest that there is no reasonable possibility of a causal relationship 
could be:

No plausible time to onset of the event relative to the time of drug exposure is evident 
(e.g. pre-treatment cases, diagnosis of cancer or chronic disease within days/weeks of 
drug administration; an allergic reaction weeks after discontinuation of the drug 
concerned).

Continuation of the event despite the withdrawal of the medication, taking into account 
the pharmacological properties of the compound (e.g. after 5 t1/2). Of note, this criterion 
may not be applicable to events whose time course is prolonged despite removing the 
original trigger.

Additional arguments amongst those stated before, like alternative explanation (e.g. 
situations where other drugs or underlying diseases appear to provide a more likely 
explanation for the observed event than the drug concerned).

Disappearance of the event even though the trial medication treatment continues or 
remains unchanged.
Adverse event collection and reporting
5.2.6.2.1
AE collection
Upon enrolment into a trial, the subjects baseline condition is assessed (for instance, by 
documentation of medical history/concomitant diagnoses), and relevant changes from baseline 
are noted subsequently. 
Subjects will be required to report spontaneously any AEs as well as the time of onset, end
time, and intensity of these events. In addition, each subject will be regularly assessed by the 
medical staff throughout the clinical trial and whenever the investigator deems necessary. As 
a minimum, subjects will be questioned for AEs (and concomitant therapies) at the time points 
indicated in the Flow Chart. Assessment will be made using non-specific questions such as 
‘How do you feel?’ Specific questions will be asked wherever necessary in order to more 
precisely describe an AE.
A careful written record of all AEs shall be kept by the investigator in charge of the trial. 
Records of AEs shall include data on the time of onset, end time, and intensity of the event as 
well as any treatment or action required for the event and its outcome.
The following must be collected and documented on the appropriate CRF(s) by the 
investigator:

From signing the informed consent onwards until an individual subject’s EoTrial: 
o
All AEs (serious and non-serious) and all AESIs. 
o
The only exception to this rule are AEs (serious and non-serious) and AESIs in 
Phase I trials in healthy subjects, when subjects discontinue from the trial due 
to screening failures prior to administration of any trial medication. In these 
cases, the subjects’ data must be collected at trial site but will not be entered in 
the CRF or trial database and will not be reported in the CTR.


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
After the individual subject’s EoTrial: 
o
The investigator does not need to actively monitor the subject for new AEs 
but should only report any occurrence of cancer and related SAEs and 
related AESIs of which the investigator may become aware of by any means 
of communication, e.g. phone call. Those AEs should, however, not be 
reported in the CRF.
5.2.6.2.2
AE reporting to the sponsor and timelines
The Investigator must report SAEs, AESIs, and non-serious AEs which are relevant for the 
reported SAE or AESI, on the BI SAE form via fax immediately (within 24 hours) to the 
sponsor’s unique entry point (country specific contact details will be provided in the ISF). The 
same timeline applies if follow-up information becomes available. In specific occasions the 
Investigator could inform the sponsor upfront via telephone. This does not replace the 
requirement to complete and fax the BI SAE form.
With receipt of any further information to these events, a follow-up SAE form has to be 
provided. For follow-up information the same rules and timeline apply as for initial 
information.
5.2.6.2.3
Information required
All (S)AEs, including those persisting after the individual subject’s EoTrial, must be followed 
up until they have resolved, have been assessed as ‘chronic’ or ‘stable’, or no further 
information can be obtained.
5.2.6.2.4
Pregnancy
In rare cases, pregnancy might occur in a clinical trial. Once a subject has been enrolled in the 
clinical trial and has taken trial medication, the investigator must report any drug exposure 
during pregnancy in a trial participant immediately (within 24 hours) by means of Part A of the 
Pregnancy Monitoring Form to the sponsor’s unique entry point. 
The outcome of the pregnancy associated with the drug exposure during pregnancy must be 
followed up and reported to the sponsor’s unique entry point on the Pregnancy Monitoring 
Form for Clinical Trials (Part B).
The ISF will contain the Pregnancy Monitoring Form for Clinical Trials (Part A and Part B).
As pregnancy itself is not to be reported as an AE, in the absence of an accompanying SAE 
and/or AESI, only the Pregnancy Monitoring Form for Clinical Trials and not the SAE form is 
to be completed. If there is an SAE and/or AESI associated with the pregnancy an SAE form 
must be completed in addition.


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5.3
DRUG CONCENTRATION MEASUREMENTS AND 
PHARMACOKINETICS
Assessment of pharmacokinetics
Date and clock times of drug administration and PK sampling will be recorded in the CRFs. 
The actual sampling times will be used for determination of PK parameters.
PK sampling times and periods may be adapted during the trial based on information obtained 
during trial conduct (e.g. as a result of preliminary PK data), including addition of samples and 
visits, as long as the total blood volume taken per subject does not exceed 400 mL. Such 
changes would be implemented via non-substantial CTP Amendments.
Methods of sample collection
Blood sampling for pharmacokinetic analysis
For quantification of Spesolimab plasma concentrations, approximately 3.0 mL of blood will 
be taken from a forearm vein (administrated arm is prohibited to use for blood sampling in IV
dose groups up to 48 hours after the administration) into a K2EDTA (ethylendiaminetetraacetic 
acid) anticoagulant blood-drawing tube at the time points listed in the Flow Chart under plasma 
PK. Blood will be withdrawn by means of either an indwelling venous catheter or by 
venipuncture with a metal needle. Two aliquots of plasma will need to be processed from the 
blood volume collected at each planned time point. The detailed procedure for sample 
processing and handling can be found in the Lab Manual.
After completion of the trial the plasma samples may be used for further methodological 
investigations, e.g. for stability testing. However, only data related to the analyte will be 
generated by these additional investigations. The trial samples will be discarded after 
completion of the additional investigations but not later than 5 years after the final trial report 
is archived.
Blood sampling for anti-drug antibody (ADA) analysis 
For ADA assessment, approximately 3.0 mL of blood for each sample will be taken from a 
forearm vein into a K2EDTA anticoagulant blood-drawing tube at the time points listed in the 
Flow Chart. Blood will be withdrawn by means of either an indwelling venous catheter or by 
venipuncture with a metal needle. Two aliquots of plasma for ADA will need to be processed 
from the blood volume collected at each planned time point. The detailed procedure for sample 
processing and handling can be found in the Lab Manual.
After completion of the trial the samples may be used for further methodological investigations, 
e.g. for stability testing. However, only data related to the anti-drug antibodies will be 
generated by these additional investigations. The trial samples will be discarded after 
completion of the additional investigations but not later than 5 years after the final trial report 
has been archived.


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5.4
BIOBANKING
Not applicable.
5.5
APPROPRIATENESS OF MEASUREMENTS
All measurements performed during this trial are standard measurements and will be performed 
in order to monitor subjects’ safety and to determine PK parameters in an appropriate way. The 
scheduled measurements will allow monitoring of changes in vital signs, standard laboratory 
values, and 12-lead ECG parameters that might occur as a result of administration of trial 
medication. The safety assessments are standard, are accepted for evaluation of safety and 
tolerability, and are widely used in clinical trials. The PK parameters and measurements 
outlined in section 5.3 are generally used assessments of drug exposure. 


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6.
INVESTIGATIONAL PLAN
6.1
VISIT SCHEDULE
Exact times of measurements outside the permitted time windows will be documented. The 
acceptable time windows for screening, observation visit, and EoTrial examination are given 
in the Flow Chart.
Trial
measurements and assessments scheduled to occur ‘before’ trial medication 
administration on Day 1 are to be performed and completed within a 2 hour-period prior to the 
trial medication administration (including blank values for PK).
The acceptable deviation from the scheduled time for vital signs and 12-lead ECG will be:

±15 minutes up to including 12 hours

±30 minutes from 12 hours up to including 48 hours

±60 minutes from 48 hours up to Day 8

±24 hours from Day 15 up to Day 71

±48 hours on Day 92

±72 hours from Day 120 up to the last measurements
The tolerance for PK/ADA /laboratory parameters starting from the investigational 
administration will be:

±1 minutes up to including 1 hour

±5 minutes up to including 12 hours

±15 minutes up to including 48 hours

±60 minutes from 48 hours up to Day 8

±24 hours from Day 15 up to Day 71

±48 hours on Day 92

±72 hours from Day 120 up to the last measurements
If scheduled in the Flow Chart at the same time as a meal, blood sampling, vital signs and 12-
lead ECG recordings have to be done first. Furthermore, if several measurements including 
venipuncture are scheduled for the same time, venipuncture should be the last of the 
measurements due to its inconvenience to the subject and possible influence on physiological 
parameters.
For planned individual plasma concentration sampling times refer to the Flow Chart. While 
these nominal times should be adhered to as closely as possible, the actual sampling times will 
be recorded and used for determination of PK parameter.
If a subject misses an appointment, it will be rescheduled if possible. The relevance of 
measurements outside the permitted time windows will be assessed no later than at the Report 
Planning Meeting.


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6.2
DETAILS OF TRIAL PROCEDURES AT SELECTED VISITS
Screening period
After having been informed about the trial, all subjects will give their written informed consent 
in accordance with GCP and local legislation prior to enrolment in the trial. 
For information regarding laboratory tests (including drug and virus screening), 12-lead ECG, 
vital signs, and physical examination, refer to sections 5.2.3 to 5.2.5. 
Treatment period
Each subject will receive one dose of trial medication (Spesolimab) at Visit 2.
Trial participants will be admitted to the trial site in the evening of Day-1 and kept under close 
medical surveillance for at least 48 hours following drug administration. The subjects will then 
be allowed to leave the trial site after formal assessment and confirmation of their fitness by 
the investigator or his designee. On all other trial days, the trial will be performed in an 
ambulatory fashion.
Trial medication will be administered as IV infusion or SC injection according to each dose 
group by the investigating physician or his designee. Details on treatments and procedures of 
administration are described in section 4.1.4.
For details on time points and procedures for collection of plasma analysis, refer to Flow Chart
and section 5.3.2.
The safety measurements performed during the treatment period are specified in section 5.2 of 
this protocol and in the Flow Chart. For details on time points for all other trial procedures, 
refer to the Flow Chart. AEs and concomitant therapy will be assessed continuously from 
screening until the EoTrial examination.
Follow-up period and trial completion
For AE assessment, laboratory tests, recording of 12-lead ECG and vital signs, and physical 
examination during the follow-up period, see sections 5.2.2 to 5.2.5.
Subjects who discontinue treatment before the end of the planned treatment period should 
undergo the EoTrial Visit.
All abnormal values (including laboratory parameters) that are assessed as clinically relevant 
by the investigator will be monitored using the appropriate tests until a return to a medically 
acceptable level is achieved. (S)AEs persisting after a subject’s EoTrial Visit must be followed 
until they have resolved, have been sufficiently characterised, or no further information can be 
obtained. 
The end of the trial as a whole is defined by the ‘last regular visit completed by last subject’ 
or ‘end date of the last open AE’ or ‘date of the last follow-up test’ or ‘date of an AE has 
been decided as sufficiently followed-up’, whichever is latest.


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7.
STATISTICAL METHODS AND DETERMINATION OF
SAMPLE SIZE
7.1
STATISTICAL DESIGN – MODEL
The primary objective of this trial is the evaluation and comparison of several PK parameters 
between all tested treatments, including an evaluation of dose proportionality for those in the 
IV dose groups. Endpoints as specified in section 2.1.2 will be assessed using descriptive 
statistics. AUC0-∞and Cmax for IV doses will be subjected to analysis of dose proportionality by 
use of the power model.
The secondary objective of this trial is the evaluation of safety and will be evaluated by 
descriptive statistics.
7.2
NULL AND ALTERNATIVE HYPOTHESES
It is not planned to test any statistical hypotheses in this trial.
Any confidence intervals computed are to be interpreted in the perspective of the exploratory 
character of the trial; i.e., confidence intervals are considered as interval estimates for effects.
7.3
PLANNED ANALYSES
Analysis sets
Statistical analyses will be based on the following analysis sets:

Treated set (TS): The treated set includes all subjects who were treated with at least one 
dose of trial drug. The treatment assignment will be determined based on the (first)
treatment the subjects received. The treated set will be used for safety analyses.
PK parameter analysis set (PKS): This set includes all subjects in the TS who provide 
at least one primary PK endpoint that was not excluded due to a protocol deviation 
relevant to the evaluation of PK or due to PK non-evaluability (as specified in the 
following subsection ‘Pharmacokinetics’). Descriptive and model based analyses of PK 
parameters will be based on the PKS. It is expected that PK data from replaced subjects 
is not evaluable and thus replaced subjects are not expected to be part of the PKS. 
Adherence to the protocol (such as inclusion/exclusion criteria, times of measurement,
compliance with intake of trial medication, treatment dispensing errors, prohibited concomitant 
medication, completeness and consistency of data) will be assessed by the trial team. Important 
protocol deviation (IPD) categories will be specified in the Integrated Quality and Risk 
Management (IQRM) Plan. IPDs will be identified no later than in the Report Planning 
Meeting, and the IPD categories will be updated as needed.


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Pharmacokinetics
The PK parameters listed in section 2.1 for drug spesolimab will be calculated according to the 
relevant SOP of the Sponsor (001-MCS-36-472). 
Plasma concentration data and parameters of a subject will be included in the statistical PK 
analyses if they are not flagged for exclusion due to a protocol deviation relevant to the 
evaluation of PK (to be decided no later than in the Report Planning Meeting) or due to PK 
non-evaluability (as revealed during data analysis, based on the criteria specified below). 
Exclusion of a subject’s data will be documented in the CTR.
Relevant protocol deviations may be

Incorrect trial medication taken, i.e. the subject received at least one dose of trial 
medication the subject was not assigned to

Incorrect dose of trial medication taken

Use of restricted medications
Plasma concentrations and/or parameters of a subject will be considered as non-evaluable, if 
for example

The subject experienced emesis that occurred at or before two times median tmax of the 
respective treatment (Median tmax is to be determined excluding the subjects 
experiencing emesis),

Missing samples/concentration data at important phases of PK disposition curve.
Plasma concentration data and parameters of a subject which is flagged for exclusion will be 
reported with its individual values but will not be included in the statistical analyses.
Only concentration values within the validated concentration range and actual sampling times 
will be used for the calculation of PK parameters. Concentrations used in the PK calculations 
will be in the same format as in the bioanalytical report (that is to the same number of decimal 
places provided in the bioanalytical report).
Primary endpoint analyses
The primary endpoint as specified in section 2.1.2 will be derived according to BI standards
(001-MCS-36-472). The analysis will be based on the PKS and will be descriptive in nature.
For IV doses the dose proportionality of AUC0-∞and Cmax will be analysed.
Assessment of dose proportionality
Dose proportionality will be explored via graphical checks and if applicable via the power 
model stated below. The analysis will be performed for the PK endpoints AUC/Cmax specified 
in section 2.1.2.
The power model describes the functional relationship between the dose level and PK 
endpoint on the log scale via
 =  log (xkm) = μ +   b ∙ log (Dk) +  ekm ,


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where 
ykm
logarithm of response (PK parameter) measured on subject mth receiving dose 
k,
μ
the overall mean,
β
slope parameter of linear regression line,
Dk
level of dose k, k=1, 2, 3,
ekm
the random error associated with the mth subject who was administered dose k 
(ekm~(0,2) iid).
This equation can be fit as a linear regression model.
The slope parameter β together with its two-sided 90% confidence interval will be estimated. 
Perfect dose proportionality would correspond to a slope of 1. Additionally, the r-fold change 
 together with its 90% CI will be derived.
Secondary endpoint analyses
Analysis of safety and tolerability is described in section 7.3.4.
Safety analyses
Safety will be assessed for the endpoints listed in section 2.1.2 and 2.2.2 based on the TS. 
Safety analyses will be descriptive in nature and will be based on BI standards. No hypothesis 
testing is planned. Treatments will be compared in a descriptive way. Tabulations of 
frequencies/proportions will be used for the evaluation of categorical (qualitative) data, and 
tabulations of descriptive statistics will be used to analyse continuous (quantitative) data.
Measurements (such as vital signs, or laboratory parameters) or AEs will be assigned to 
treatments (see section 4.1) based on the concept of treatment emergent AEs. Therefore, 


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measurements planned or AEs recorded prior to intake of trial medication will be assigned to 
'screening', those between trial medication intake and end of REP will be assigned to the 
treatment period. Events occurring after the REP but prior to trial termination date will be 
assigned to ‘follow-up’. These assignments including the corresponding time intervals will be 
defined in detail in the TSAP. Note that AEs occurring after the last per protocol contact but 
entered before database lock will be reported to Pharmacovigilance only and will not be 
captured in the trial database.
Additionally, further treatment intervals (called analysing treatments) may be defined in the 
TSAP in order to provide summary statistics for other than above periods, such as combined 
treatments, on-treatment totals or periods without treatment effects (such as screening and post-
trial intervals).
AEs will be coded using the Medical Dictionary for Regulatory Activities (MedDRA). 
Frequency, intensity and causal relationship of AEs will be tabulated by treatment, primary 
system organ class and preferred term. SAEs, AESIs (see section 5.2.6.1.4) and other 
significant AEs (according to ICH E3) will be listed separately. 
Laboratory data will be compared to their reference ranges. Values outside the reference range 
will be highlighted in the listings. Additionally, differences from baseline will be evaluated.
Vital signs or other safety-relevant data observed at screening, baseline, during the course of 
the trial and at the end-of-trial examination will be assessed with regard to possible changes 
compared to findings before start of treatment.
Pharmacokinetic-pharmacodynamic analyses
No analysis of the relationship between PK and PD parameters is planned for this trial.
7.4
INTERIM ANALYSES
If required for early interaction with regulatory agency, a first interim analysis may be 
conducted once all IV subjects have completed the study. In case this interim analysis will be 
done, an interim database lock will be conducted (for safety and PK data collected for IV 
subjects) and an interim report for the IV analysis will be written. Details of the analysis to be
performed will be described in the TSAP. 
A CTR including entire trial data (IV and SC subjects) will be prepared at the end of the trial.
7.5
HANDLING OF MISSING DATA
Safety
It is not planned to impute missing values for safety parameters.


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Pharmacokinetics
Handling of missing PK data will be performed according to the relevant SOP of the Sponsor 
(001-MCS-36-472).
Drug concentration data identified with NOS (no sample available), NOR (no valid result), 
NOA (not analysed), BLQ (below the lower limit of quantification), or NOP (no peak 
detectable) will be displayed as such and not replaced by zero at any time point (this rule also 
applies also to the lag phase, including the predose values). 
7.6
RANDOMISATION
It is an open-label trial without randomisation.
7.7
DETERMINATION OF SAMPLE SIZE
It is planned to include up to 60 subjects in this trial in order to have in total 50 PK evaluable 
subjects, 10 subjects per dose group. Up to 10 subjects might be replaced due to early 
termination. The planned sample size is not based on a power calculation. The size of 10 
subjects per dose group is commonly used in single dose studies of the present type and in 
general considered as sufficient for the exploratory evaluation of single dose safety and PK. 


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8.
INFORMED CONSENT, TRIAL RECORDS, DATA 
PROTECTION, PUBLICATION POLICY, AND 
ADMINISTRATIVE STRUCTURE
The trial will be carried out in compliance with the protocol, the principles laid down in the 
Declaration of Helsinki, in accordance with the ICH Harmonised Tripartite Guideline for Good 
Clinical Practice (GCP) and relevant BI SOPs.
Standard medical care (prophylactic, diagnostic, and therapeutic procedures) remains the 
responsibility of the subject’s treating physician.
The investigator should inform the sponsor immediately of any urgent safety measures taken 
to protect the trial subjects against any immediate hazard, and also of any serious breaches of 
the protocol or of ICH GCP.
The BI transparency and publication policy can be found on the following web page: 
trials.boehringer-ingelheim.com. The rights of the investigator and of the sponsor with regard 
to publication of the results of this trial are described in the investigator contract. As a general 
rule, no trial results should be published prior to finalisation of the CTR.
The certificate of the insurance cover is made available to the investigator and the subjects, and 
is stored in the ISF.
8.1
TRIAL APPROVAL, SUBJECTS INFORMATION, INFORMED 
CONSENT
This trial will be initiated only after all required legal documentation has been reviewed and 
approved by the respective Institutional Review Board (IRB)/Independent Ethics Committee 
(IEC) and competent authority (CA) according to national and international regulations. The 
same applies for the implementation of changes introduced by amendments.
Prior to a patient’s participation in the trial, written informed consent must be obtained from 
each subject (or the subject’s legally accepted representative) according to ICH GCP and to the 
regulatory and legal requirements of the participating country. Each signature must be 
personally dated by each signatory and the informed consent and any additional subject
information form are to be retained by the investigator as part of the trial records. A copy of 
the signed and dated written informed consent and any additional subject information must be 
given to each subject or the subject’s legally accepted representative.
The subject must be informed that his/her personal trial-related data will be used by BI in 
accordance with the local data protection law. The level of disclosure must also be explained 
to the subject.
The subject must be informed that his or her medical records may be examined by authorised 
monitors (CTM / Clinical Research Associate [CRA]) or Clinical Quality Assurance auditors 
appointed by BI, by appropriate IRB/IEC members, and by inspectors from regulatory 
authorities.


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The subject must be given sufficient time to consider participation in the trial. The investigator 
or delegate obtains written consent of the subject’s own free will with the informed consent 
form after confirming that the subject understands the contents. The investigator or his delegate 
must sign (or place a seal on) and date the informed consent form. If a trial collaborator has 
given a supplementary explanation, the trial collaborator also signs (or places a seal on) and 
dates the informed consent.
Re-consenting may become necessary when new relevant information becomes available and 
should be conducted according to the sponsor’s instructions.
The consent and re-consenting process should be properly documented in the source 
documentation.
8.2
DATA QUALITY ASSURANCE
A risk-based approach is used for trial quality management. It is initiated by the assessment of 
critical data and processes for trial subject protection and reliability of the results as well as 
identification and assessment of associated risks. An IQRM plan documents the rationale and 
strategies for risk management during trial conduct including monitoring approaches, vendor 
management and other processes focusing on areas of greatest risk. 
Continuous risk review and assessment may lead to adjustments in trial conduct, trial design 
or monitoring approaches. 
A quality assurance audit/inspection of this trial may be conducted by the sponsor, sponsor’s 
designees, or by IRB/IEC or by regulatory authorities. The quality assurance auditor will have 
access to all medical records, the investigator’s trial-related files and correspondence, and the 
informed consent documentation of this clinical trial.
8.3
RECORDS
CRFs for individual subjects will be provided by the sponsor. For drug accountability, refer 
to Section 4.1.8.
Source documents
Source documents provide evidence for the existence of the subject and substantiate the 
integrity of the data collected. Source documents are filed at the investigator’s site.
All data reported in the CRFs must be consistent with the source data or the discrepancies must 
be explained. 
The investigator may need to request previous medical records or transfer records, depending 
on the trial.
In accordance with regulatory requirements, the investigator should prepare and maintain 
adequate and accurate source documents and trial records for each trial subject that include all 


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observations and other data pertinent to the investigation. Source data as well as reported data 
should follow the ‘‘ALCOA-C principles’ and be attributable, legible, contemporaneous, 
original, accurate and complete. Changes to the data should be traceable (audit trail).
Before providing any copy of subjects’ source documents to the sponsor, the investigator must 
ensure that all subject identifiers (e.g., subject’s name, initials, address, phone number, and
identification card) have properly been removed or redacted to ensure subject confidentiality.
If the subject is not compliant with the protocol, any corrective action (e.g. re-training) must 
be documented in the subject file.
For the CRF, data must be derived from source documents, for example:

Subject identification: sex, year of birth (in accordance with local laws and regulations)

Subject participation in the trial (substance, trial number, subject number, date subject 
was informed)

Dates of subject’s visits, including dispensing of trial medication

Medical history (including trial indication and concomitant diseases, if applicable)

Medication history

AEs and outcome events (onset date [mandatory], and end date [if available])

SAEs (onset date [mandatory], and end date [if available])

Concomitant therapy (start date, changes)

Originals or copies of laboratory results and other imaging or testing results, with proper 
documented medical evaluation (in validated electronic format, if available)

12-lead ECG results (original or copies of printouts)

Completion of subject’s participation in the trial (end date; in case of premature 
discontinuation, document the reason for it, if known)

Prior to allocation of a subject to a treatment into a clinical trial, there must be 
documented evidence in the source data (e.g. medical records) that the trial participant 
meets all inclusion criteria and does not meet any exclusion criteria. The absence of 
records (either medical records, verbal documented feedback of the subject or testing 
conducted specific for a protocol) to support inclusion/exclusion criteria does not make 
the subject eligible for the clinical trial.
Direct access to source data and documents
The investigator/institution will permit trial-related monitoring, audits, IRB/IEC review and 
regulatory inspection, providing direct access to all related source data/documents. CRFs and 
all source documents, including progress notes (if applicable) and copies of laboratory and 
medical test results must be available at all times for review by the sponsor’s clinical trial 
monitor, auditor and inspection by health authorities (e.g. FDA). The CRA/on site monitor and 
auditor may review all CRFs, and written informed consents. The accuracy of the data will be 
verified by reviewing the documents described in section 8.3.1. The sponsor will also monitor 
compliance with the protocol and GCP.


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Storage period of records
Trial site:
The trial site must retain the source and essential documents (including ISF) for 15 years based 
on the site’s Trial Close-Out Visit date.
Sponsor:
The sponsor must retain the essential documents according to the sponsor’s SOPs.
8.4
EXPEDITED REPORTING OF ADVERSE EVENTS
BI is responsible to fulfil their legal and regulatory reporting obligation in accordance with 
regulatory requirements.
8.5
STATEMENT OF CONFIDENTIALITY AND SUBJECT PRIVACY
Individual subject medical information obtained as a result of this trial is considered 
confidential and disclosure to third parties is prohibited with the exceptions noted below. 
Subject confidentiality will be ensured by using subject identification code numbers.
Data protection and data security measures are implemented for the collection, storage and 
processing of subject data in accordance with the principles 6 and 12 of the WHO GCP 
handbook.
Personalised treatment data may be given to the subject’s personal physician or to other 
appropriate medical personnel responsible for the subject’s welfare. Data generated as a result 
of the trial need to be available for inspection on request by the participating physicians, the 
sponsor’s representatives, by the IRB/IEC and the regulatory authorities.
Collection, storage and future use of biological samples and corresponding 
data
Measures are in place to comply with the applicable rules for the collection, biobanking and 
future use of biological samples and clinical data, in particular

Sample and data usage has to be in accordance with the separate biobanking informed 
consent

The BI-internal facilities storing biological samples from clinical trial participants as 
well as the external banking facility are qualified for the storage of biological samples 
collected in clinical trials

An appropriate sample and data management system, incl. audit trail for clinical data 
and samples to identify and destroy such samples according to informed consent form 
(ICF) is in place

A fit for the purpose documentation (biomarker proposal, analysis plan and report) 
ensures compliant usage


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
A fit for purpose approach will be used for assay/equipment validation depending on 
the intended use of the biomarker data

Samples and/or data may be transferred to third parties and other countries as specified 
in the biobanking ICF
8.6
TRIAL MILESTONES
The start of the trial is defined as the date when the first subject in the whole trial signs 
informed consent.
The end of the trial is defined as the ‘date of the last visit of the last subject in whole trial’ 
(‘Last Subject Completed’) or ‘end date of the last open AE’ or ‘date of the last follow-up test’ 
or ‘date of an AE has been decided as sufficiently followed-up’, whichever is latest.
Early termination of the trial is defined as the premature termination of the trial for any 
reason before the end of the trial as specified in this protocol.
Temporary halt of the trial is defined as any unplanned interruption of the trial by the sponsor 
with the intention to resume it.
Suspension of the trial is defined as an interruption of the trial based on a Health Authority 
request.
8.7
ADMINISTRATIVE STRUCTURE OF THE TRIAL
The trial is sponsored by BI.
The trial will be conducted at site, under the supervision of the Principal Investigator. Relevant 
documentation on the participating (Principal) Investigators (e.g. their curricula vitae) will be 
filed in the ISF.
BI has appointed a CTL, responsible for coordinating all required trial activities, in order to

Manage the trial in accordance with applicable regulations and internal SOPs

Direct the clinical trial team in the preparation, conduct, and reporting of the trial

Ensure appropriate training and information of CTM, CRAs, and investigators of 
participating trial sites
The trial medication will be provided by the 
 
.
Safety laboratory tests will be performed by the local laboratory of the trial site and 
.
Analyses of Spesolimab concentrations and ADA in plasma will be performed at 
 in 
 
On-site monitoring will be performed by BI.
Data management and statistical evaluation will be done by BI or a contract research 
organisation appointed by BI.


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Tasks and functions assigned in order to organise, manage, and evaluate the trial are defined 
according to BI SOPs. A list of responsible persons and relevant local information can be found 
in the ISF.


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9.
REFERENCES 
9.1
PUBLISHED REFERENCES
R09-2768
Vargas HM, Bass AS, Breidenbach A, Feldman HS, Gintant GA, 
Harmer AR, Heath B, Hoffmann P, Lagrutta A, Leishman D, McMahon 
N, Mittelstadt S, Polonchuk L, Pugsley MK, Salata JJ, Valentin JP. 
Scientific review and recommendations on preclinical cardiovascular 
safety evaluation of biologics. J Pharmacol Toxicol Methods 2008;
58(2):72-76.
R11-4890
Sampson HA, Munoz-Furlong A, Campbell RL, Adkinson NF, Jr., Bock 
SA, Branum A, et al. Second symposium on the definition and 
management of anaphylaxis: summary report--Second National Institute 
of Allergy and Infectious Disease/Food Allergy and Anaphylaxis 
Network symposium. J Allergy Clin Immunol. 2006; 117(2):391-7.
R14-4037
Towne JE, Renshaw BR, Douangpanya J, Lipsky BP, Shen M, Gabel 
CA, Sims JE. Interleukin-36 (IL-36) ligands require processing for full 
agonist (IL-36alpha, IL-36beta, and IL-36gamma) or antagonist (IL-
36Ra) activity. J Biol Chem 2011;286(49):42594-42602.
R14-5158
Marrakchi S, et al. Interleukin-36-receptor antagonist deficiency and 
generalized pustular psoriasis. N Engl J Med 201; 365(7):620-628. 
R15-1399
Blumberg H, Dinh H, Dean C, Trueblood ES, Beiley K, Shows D, 
Bhagavathula N, Aslam MN, Varani J, Towne JE, Sims JE. IL-1RL2 and
its ligands contribute to the cytokine network n psoriasis. J Immunol
2010; 185(7):4354-4362.
R15-1421
Onouofriadis A, Simpson MA, Pink AE, Meglio P di, Smith CH,
Pullabhatla V, Knight J, Spain SL, Nestle FO, Burden AD, Capon F,
Trembath RC, Barker JN. Mutations in IL36RN/IL1F5 are associated 
with the severe episodic inflammatory skin disease known as generalized
pustular psoriasis. Am J Hum Genet 2011; 89(3):432-437.
R15-1432
Blumberg H, Dinh H, Trueblood ES, Pretorius J, Kugler D, Weng N,
Kanaly ST, Towne JE, Willis CR, Kuechle MK, Sims JE, Peschon JJ.
Opposing activities of two novel members of the IL-1 ligand family
regulate skin inflammation. J Exp Med 2007; 204(11):2603-2614.
R15-1447
Tortola L, Rosenwald E, Abel B, Blumberg H, Schaefer M, Coyle AJ,
Renauld JC, Werner S, Kisielow J, Kopf M. Psoriasiform dermatitis is
driven by IL-36-mediated DC-keratinocyte crosstalk. J Clin Invest 2012;
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Waal AC de, Kerkhof PCM van de; Pustulosis palmoplantaris is a 
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Berki DM, Liu L, Choon SE, Burden AD, Griffiths CEM, Navarini AA, 
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Allen MH, Vito P, Trembath RC, McGrath J, Smith CH, Capon F, 


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Barker JN; Activating CARD14 mutations are associated with 
generalized pustular psoriasis but rarely account for familial recurrence 
in psoriasis
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Choon SE, Lai NM, Mohammad NA, Nanu NM, Tey KE, Chew SF;
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pustular psoriasis: analysis of 102 cases seen in a tertiary hospital in 
Johor, Malaysia; Int J Dermatol 53, 676 - 684 (2014)
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Winthrop KL, Novosad SA, Baddley JW, Calabrese L, Chiller T, 
Polgreen P, et al. Opportunistic infections and biologic therapies in 
immunemediated inflammatory diseases: consensus recommendations 
for infection reporting during clinical trials and postmarketing 
surveillance. Ann Rheum Dis. 2015; 74(12):2107-16.
9.2
UNPUBLISHED REFERENCES
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study to investigate safety, tolerability, pharmacokinetics and 
pharmacodynamics of single rising intravenous doses of BI 655130 in 
healthy male volunteers; 07 April 2017
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Multi-centre, open-label, single arm, phase I study to investigate safety, 
tolerability, pharmacokinetics, pharmacogenomics and efficacy of a 
single intravenous dose of BI 655130 in patients with active generalized 
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 A Tissue cross-reactivity study of biotinylated BI 
655130 in normal human tissues; 31 March 2015
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(2015). Memo: Pre-Clinical Pharmacokinetic Studies for BI 
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n00243876
; BI 674304: A 13-week intravenous injection study in 
mice with a 4-week recovery period; 01 June 2016
n00248748
 BI 655130: A single-dose subcutaneous irritation 
study in rabbits; 10 February 2016
n00255537
Determination of BI 655130 in CD-1 Mouse Serum by ECL 
Assay; 31 March 2017
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Toxicity Study in the Mouse with a 4-Week Recovery Period
001-MCS-36-472
Standards and processes for analyses performed within Clinical 
Pharmacokinetics/Pharmacodynamics. Current version


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10.
APPENDICES
10.1
CLINICAL EVALUATION OF LIVER INJURY
Introduction
Alterations of liver laboratory parameters, as described in section 5.2.6.1.4 (Protocol-specified 
AESIs), are to be further evaluated using the following procedures:
Procedures
Repeat the following laboratory tests: ALT, AST, and bilirubin (total and direct) - within 48 to 
72 h. If it is confirmed that ALT and/or AST values ≥3-fold ULN occur in conjunction with an 
elevation of total bilirubin of ≥2-fold ULN, the laboratory parameters listed below (clinical 
chemistry, serology, hormones, haematology) must be determined and made available to the 
investigator and to BI as soon as possible.
In addition, 

obtain a detailed history of current symptoms and concurrent diagnoses and medical 
history according to the ‘DILI checklist’ provided in the ISF 

obtain history of concomitant drug use (including non-prescription medications, herbal 
and dietary supplement preparations), alcohol use, recreational drug use, and special 
diets according to the ‘DILI checklist’ provided in the ISF;

obtain a history of exposure to environmental chemical agents (consider home and work 
place exposure) according to the ‘DILI checklist’ provided in the ISF; and report these 
via the CRF.
Clinical chemistry
Alkaline phosphatase, albumin, PT or INR, CK, CK-MB, coeruloplasmin, α-1 antitrypsin, 
transferin, amylase, lipase, fasting glucose, cholesterol, triglycerides
Serology
Hepatitis A (Anti-IgM, Anti-IgG), Hepatitis B (HbsAg, Anti-HBs, DNA), Hepatitis C (Anti-
HCV, RNA if Anti-HCV positive), Hepatitis D (Anti-IgM, Anti-IgG), Hepatitis E (Anti-HEV, 
Anti-HEV IgM, RNA if Anti-HEV IgM positive), Anti-Smooth Muscle antibody (titer), Anti-
nuclear antibody (titer), Anti-LKM (liver-kidney microsomes) antibody, Anti-mitochondrial 
antibody
Epstein Barr Virus (VCA IgG, VCA IgM), cytomegalovirus (IgG, IgM), herpes simplex virus 
(IgG, IgM), varicella (IgG, IgM), parvovirus (IgG, IgM), toxoplasmosis (IgG, IgM)
Hormones, tumormarker
TSH
Haematology
Thrombocytes, eosinophils

Provide abdominal ultrasound to rule out biliary tract, pancreatic or intrahepatic 
pathology, e.g. bile duct stones or neoplasm.


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
Initiate close observation of subjects by repeat testing of ALT, AST, and total bilirubin 
(total and direct) at least weekly until the laboratory ALT and/or AST abnormalities 
stabilise or return to normal, then monitor further as specified in the CTP. Depending 
on further laboratory changes, additional parameters identified e.g. by reflex testing 
will be followed up based on medical judgement and GCP.
Diagnosis of Anaphylaxis
Clinical criteria for diagnosing anaphylaxis (R11-4890).
Anaphylaxis is highly likely when any one of the following three criteria are fulfilled
1. Acute onset of an illness (minutes to several hours) with involvement of the skin, 
mucosal tissue, or both (eg, generalized hives, pruritus or flushing, swollen lips-
tongueuvula)
AND AT LEAST ONE OF THE FOLLOWING
a.
Respiratory compromise (eg, dyspnea, wheeze-bronchospasm, stridor, reduced 
PEF,hypoxemia)
b. Reduced BP or associated symptoms of end-organ dysfunction (eg, hypotonia 
[collapse],syncope, incontinence)
2. Two or more of the following that occur rapidly after exposure to a likely allergen for 
that patient (minutes to several hours):
a.
Involvement of the skin-mucosal tissue (eg, generalised hives, itch-flush, swollen lips, 
tongue-uvula)
b. Respiratory compromise (eg, dyspnea, wheeze-bronchospasm, stridor, reduced 
PEF,hypoxemia)
c.
Reduced BP or associated symptoms (eg, hypotonia [collapse], syncope, incontinence)
d. Persistent gastrointestinal symptoms (eg, crampy abdominal pain, vomiting)
3. Reduced BP after exposure to known allergen for that patient (minutes to several 
hours):
a.
Infants and children: low systolic BP (age specific) or greater than 30% decrease in 
systolic BP*
b. Adults: systolic BP of less than 90 mm Hg or greater than 30% decrease from that 
person’s baseline
PEF, Peak expiratory flow; BP, blood pressure.
*Low systolic blood pressure for children is defined as less than 70 mm Hg from 1 month to 1 year, less 
than (70 mm Hg +[2 x age] from 1 to 10 years, and less than 90 mm Hg from 11 to 17 years.


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11.
DESCRIPTION OF GLOBAL AMENDMENT(S)
11.1
GLOBAL AMENDMENT 1 
Date of amendment
18 Sep 2019
EudraCT number
EU number
Not applicable
BI Trial number
1368-0043
BI Investigational Medicinal 
Product(s)
BI 655130 (Spesolimab)
Title of protocol
An open-label phase I trial to assess 
pharmacokinetics and safety of single subcutaneous 
doses and single intravenous doses of BI 655130 in 
healthy Chinese male and female subjects (single 
doses, open-label study in parallel-group design).
To be implemented only after approval of the IRB / IEC / Competent 
Authorities
To be implemented immediately in order to eliminate hazard – IRB / IEC / 
Competent Authority to be notified of change with request for approval
Can be implemented without IRB / IEC / Competent Authority approval as 
changes involve logistical or administrative aspects only
Section to be changed
Title Page
Description of change
Phone: 
Rationale for change
Update the contact information of Principal 
Investigator
Section to be changed
Flow Chart
Description of change
Annotation 8: ADAs/Nab samples will be taken at 
baseline, Day 15, Day 29, Day 43, Day 57, Day 71, 
Day 92, Day 120, Day 148 and Day 176 after BI 
655130 administration.
Rationale for change
The information has been corrected. 
Section to be changed
Table 5.2.3:1 Routine laboratory tests
Description of change
Protein electrophoresis (Protein EP)2 3 (only at 
screening examination)


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Updated the annotation 3: Only if erythrocytes, 
leukocytes, nitrite or protein are abnormal in 
urinalysis and it is deemed clinically necessary by 
the investigator Only test at screening if total 
protein is abnormal and it is deemed clinically 
necessary by the investigator.
Urine sediment 3 4
The annotation has been sequenced to 4.
Rationale for change
It is not mandatory to conduct protein 
electrophoresis at screening to assure healthy 
volunteers’ safety after more information obtained 
for BI 655130. Therefore, the specific annotation 
has been created.
Section to be changed
Table 5.2.3:2 Exclusionary laboratory tests
Description of change
FSH test (qualitative) (quantitative)
Estradiol test (qualitative) (quantitative)
Rationale for change
Correction: FSH test and Estradiol test should be 
quantitative


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11.2
GLOBAL AMENDMENT 2
Date of amendment
07 May 2020
EudraCT number
EU number
Not applicable
BI Trial number
1368-0043
BI Investigational Medicinal 
Product(s)
BI 655130 (Spesolimab)
Title of protocol
An open-label phase I trial to assess 
pharmacokinetics and safety of single subcutaneous 
doses and single intravenous doses of BI 655130 in 
healthy Chinese male and female subjects (single 
doses, open-label study in parallel-group design).
To be implemented only after approval of the IRB / IEC / Competent 
Authorities
To be implemented immediately in order to eliminate hazard – IRB / IEC / 
Competent Authority to be notified of change with request for approval
Can be implemented without IRB / IEC / Competent Authority approval as 
changes involve logistical or administrative aspects only
Section to be changed
Product name
Description of change
BI 655130 to spesolimab
Rationale for change
Globalize change
Section to be changed
Clinical Trial Protocol Synopsis
Description of change
Total entered was changed from 50 up to 60 
subjects including up to 10 subjects for replacement 
of early discontinuation
Rationale for change
Account up to 10 replaced subject number into total 
entered
Section to be changed
Flow Chart S.C.
Description of change

Vital Signs added 10 mins

Add description in annotation 13: Also the 
AEs and concomitant therapies will be 
queried on Day -1

AEs and concomitant therapies will be 
queried on Day 148.

Add wording to ‘urine’ in annotation 14.
Rationale for change
To provide clarification regarding to the activities
Section to be changed
Flow Chart I.V.
Description of change

Vital Signs added 10 mins


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
Add description in annotation 14: Also the 
AEs and concomitant therapies will be 
queried on Day -1.

AEs and concomitant therapies will be 
queried on Day 148.

Add wording to ‘urine’ in annotation 15.
Rationale for change
To provide clarification regarding to the activities
Section to be changed
1.2.5 Clinical experience in human
Description of change
Added 1368-0029 study result in protocol
Rationale for change
Updated it according to IB version 7.0
Section to be changed
3.1 Overall trial design and plan
Description of change

‘up to 60 healthy male and female subjects 
in the trial.’ replaced ‘a total of 50’.

Added’ In case of subjects not completed 
the trial, up to 10 replacement will be 
recruited for whole study’
Rationale for change
Account up to 10 replaced subject number into total 
entered
Section to be changed
Table 3.1:1 Dose Group
Description of change
Re-order the IV and SC group.
IV: 
group 1: 450 mg
group 2: 900 mg
group 3: 1200mg
SC:
group 4: 300mg
group 5: 600mg
Rationale for change
Make the consistence in section 4.1.4
Section to be changed
3.3 Selection of trial population
Description of change
‘up to 60 including 10 replaced’ replaced ‘50’ 
Rationale for change
Account up to 10 replaced subject number into total 
entered
Section to be changed
3.3.5 Replacement of subjects
Description of change
Added: Up to 10 subjects will be replaced for whole 
study. Data from replaced subjects will be available 
in the database.
Rationale for change
Clarified total number of replaced subjects in the 
protocol 
Section to be changed
4.2.2.2 Restriction on diet and life-style


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Description of change
Deleted’ Direct exposure to the sun or exposure to 
solarium radiation should be avoided during the 
entire trial.’
Rationale for change
Not required according to available data
Section to be changed
Table 5.2.3:1 Routine laboratory tests
Description of change
Delete ‘Manual Differential WBC’ test and its 
annotation
Rationale for change
No manual WBC test will be done 
Section to be changed
Table 5.2.3:2 Exclusionary laboratory tests
Description of change
Changed HBc to HCV
Rationale for change
It is typo to be corrected.
Section to be changed
6.1 Visit Schedule
Description of change
Clarified the tolerance for PK/ADA/Nab/laboratory 
parameters starting from the investigational 
administration 
Rationale for change
Clarify the time window requirement
Section to be changed
7.3 Planned analysis
Description of change
Clarified the replaced subjects will not be part of 
PKS
Rationale for change
Clarified how to deal with the replaced subjects
Section to be changed
7.4 Interim Analysis
Description of change
An interim analysis is not planned. If the results of 
this PK trial is requested during an needed for 
interaction with regulatory agency, a preliminary 
analysis of available safety tolerability and/or PK 
data may be performed in order to provide the 
preliminary results.
Rationale for change
Update the wording. 
Section to be changed
7.7 Determination of sample size
Description of change
Added 10 replaced subject into total subject number 
to ensure total 50 PK evaluable subjects
Rationale for change
Account up to 10 replaced subject number into total 
entered


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11.3
GLOBAL AMENDMENT 3
Date of amendment
01 Jul 2020
EudraCT number
EU number
Not applicable
BI Trial number
1368-0043
BI Investigational Medicinal 
Product(s)
BI 655130 (Spesolimab) 
Title of protocol
An open-label phase I trial to assess 
pharmacokinetics and safety of single subcutaneous 
doses and single intravenous doses of BI 655130 in 
healthy Chinese male and female subjects (single 
doses, open-label study in parallel-group design).
To be implemented only after approval of the IRB / IEC / Competent 
Authorities
To be implemented immediately in order to eliminate hazard – IRB / IEC / 
Competent Authority to be notified of change with request for approval
Can be implemented without IRB / IEC / Competent Authority approval as 
changes involve logistical or administrative aspects only
Section to be changed
4.1.3
Method of assigning subjects to treatment 
groups
Description of change
Deleted the regulation of contact in writing.
Added ‘If more available subjects than target 
number for a cohort, the subjects will be enrolled 
according to the subsequence of signed ICF by 
subjects and gender ratio required by study.’
Rationale for change
Clarified the method of assigning subjects qualified 
more than a cohort available 
Section to be changed
4.1.4 Drug assignment and administration of 
doses for each subject
Description of change
For intravenous administration
Deleted the sentence ‘For the purpose of drug 
accountability, the infusion set will be weighed 
before and after drug administration.’
Rationale for change
It was not applicable for this trial
Section to be changed
5.2.3
Safety laboratory parameters
Description of change
Deleted manual differential white blood cell count 
Rationale for change
It was not required any more
Section to be changed
Table 5.2.3: 2Exclusionary laboratory tests


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Description of change
Barbiturates test was deleted
Rationale for change
No availability of the test kit due to COVID-19 
logistics reasons and no requirement to conduct this 
test in all subjects to verify the exclusion criteria.


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11.4
GLOBAL AMENDMENT 4
Date of amendment
26 Feb 2021
EudraCT number
EU number
Not applicable
BI Trial number
1368-0043
BI Investigational Medicinal 
Product(s)
BI 655130 (Spesolimab) 
Title of protocol
An open-label phase I trial to assess 
pharmacokinetics and safety of single subcutaneous 
doses and single intravenous doses of BI 655130 in 
healthy Chinese male and female subjects (single 
doses, open-label study in parallel-group design).
To be implemented only after approval of the IRB / IEC / Competent 
Authorities
To be implemented immediately in order to eliminate hazard – IRB / IEC / 
Competent Authority to be notified of change with request for approval
Can be implemented without IRB / IEC / Competent Authority approval as 
changes involve logistical or administrative aspects only
Section to be changed
FLOW CHART
ABBREVIATION
2.2.2.1 Safety and tolerability
5.3.2.2 Blood sampling for anti-drug antibody 
(ADA) analysis
5.3.3.3 Analytical determination of ADA
VISIT SCHEDULE
8.7
ADMINISTRATIVE STRUCTURE OF 
THE TRIAL
Description of change
Removed Nab (neutralizing antibody) test from trial
Rationale for change
Study team decided not to test Nab in this trial due 
to inappropriate Nab drug tolerance for analysis 
method and low necessity
Section to be changed
ABBREVIATION


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Description of change
Added ‘Hidradenitis suppurativa’
Rationale for change
Updated according to IB 8.0
Section to be changed
1.2.5 CLINICAL EXPERIENCE IN HUMANS
Description of change
Updated trial information
Rationale for change
Updated study information according to 
IB 8.0
Section to be changed
BENEFIT - RISK ASSESSMENT
Description of change
Updated trial information and added Covid-19 
assessments 
Rationale for change
Updated trial information and summarized the key 
benefit-Risk Assessment in context of COVID-19 
pandemic for subjects participating in clinical trials 
investigating Spesolimab according to IB 8.0
Section to be changed
7.4 Interim analyses
Description of change
If required for early interaction with regulatory 
agency a first interim analysis may be conducted 
once all IV patients have completed the study
Rationale for change
The interim analysis result may be used for new 
drug application of Spesolimab.


 
 
 
 
APPROVAL / SIGNATURE PAGE 
 
Document Number: 
 
Technical Version Number:
 
Document Name: 
 
 
 
                                                                                                                 
 
Title: 
 
 
 
 
                                                                                                                   
 
Signatures (obtained electronically) 
 
Meaning of Signature  
Signed by 
Date Signed 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
c27981303
5.0
clinical-trial-protocol-version-05
An open-label phase I trial to assess pharmacokinetics and safety of single
subcutaneous doses and single intravenous doses of BI 655130 in healthy Chinese
male and female subjects (single doses, open-label study in parallel-group design).
Author-Clinical Trial Leader
26 Feb 2021 09:40 CET
Author-Trial Statistician
26 Feb 2021 09:48 CET
Approval-Clinical Pharmacokinetics
26 Feb 2021 15:18 CET
Approval-Team Member Medicine
08 Mar 2021 17:37 CET
Approval-
 Medicine
14 Mar 2021 19:32 CET
Approval-Clinical Trial Leader
15 Mar 2021 11:49 CET


Boehringer Ingelheim 
Page 2 of 2
Document Number: 
 Technical Version Number:
 
 
 
(Continued) Signatures (obtained electronically) 
 
Meaning of Signature  
Signed by 
Date Signed 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
c27981303
5.0

SAP_001.pdf: 
TITLE PAGE
TRIAL STATISTICAL ANALYSIS PLAN
c33844082-01
BI Trial No.:
1368-0043
Title:
An open-label phase I trial to assess pharmacokinetics and safety of 
single subcutaneous doses and single intravenous doses of BI 
655130 in healthy Chinese male and female subjects (single doses, 
open-label study in parallel-group design).
(including Protocol Amendments No.1-4 [c27981303-05])
Investigational
Product:
BI 655130 (Spesolimab)
Responsible trial 
statistician:
Phone: 
Fax: 
Date of statistical 
analysis plan:
09 MAR 2021 SIGNED
Version:
1
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1.
TABLE OF CONTENTS
TITLE PAGE............................................................................................................................1
1.
TABLE OF CONTENTS......................................................................................2
LIST OF TABLES ...................................................................................................................4
2.
LIST OF ABBREVIATIONS...............................................................................5
3.
INTRODUCTION.................................................................................................7
4.
CHANGES IN THE PLANNED ANALYSIS OF THE STUDY ......................8
5.
ENDPOINTS..........................................................................................................9
5.1
PRIMARY ENDPOINTS .....................................................................................9
5.2
SECONDARY ENDPOINTS ...............................................................................9
5.2.1
Key secondary endpoint........................................................................................9
5.2.2
Secondary endpoints .............................................................................................9
6.
GENERAL ANALYSIS DEFINITIONS...........................................................11
6.1
TREATMENTS...................................................................................................11
6.2
IMPORTANT PROTOCOL DEVIATIONS....................................................12
6.3
SUBJECT SETS ANALYSED ...........................................................................13
6.5
POOLING OF CENTRE....................................................................................14
6.6
HANDLING OF MISSING DATA AND OUTLIERS ....................................14
6.7
BASELINE, TIME WINDOWS AND CALCULATED VISITS....................15
7.
PLANNED ANALYSIS ......................................................................................16
7.1
DEMOGRAPHIC AND OTHER BASELINE CHARACTERISTICS .........18
7.2
CONCOMITANT DISEASES AND MEDICATION......................................18
7.3
TREATMENT COMPLIANCE ........................................................................18
7.4
PRIMARY ENDPOINTS ...................................................................................18
7.4.1
Primary analysis of the primary endpoints ......................................................18
7.4.2
Sensitivity analysis, subgroup analysis, exploratory analysis of the 
primary endpoints...............................................................................................19
7.5
SECONDARY ENDPOINTS .............................................................................19
7.5.1
Key secondary endpoint......................................................................................19
7.5.2
Secondary endpoints ...........................................................................................19
7.7
EXTENT OF EXPOSURE .................................................................................20
7.8
SAFETY ANALYSIS..........................................................................................20
7.8.1
Adverse Events ....................................................................................................20
7.8.2
Laboratory data...................................................................................................24
7.8.3
Vital signs.............................................................................................................25
7.8.4
ECG ......................................................................................................................25
7.8.5
Others ...................................................................................................................25
8.
REFERENCES ....................................................................................................27


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10.
HISTORY TABLE..............................................................................................29


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LIST OF TABLES
Table 6.1: 1
Labels for treatments for use in the CTR .........................................................11
Table 6.3: 1
Subject sets analysed ........................................................................................14
Table 7.8.1: 1 Project MEDDRA search criteria for User Defined Adverse Events 
Concepts ...........................................................................................................22
Table 10: 1
History table .....................................................................................................29


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2.
LIST OF ABBREVIATIONS
See Medicine Glossary:
http://glossary
Term
Definition / description
ALT
Alanine Aminotransferase
ANCOVA
Analysis of Covariance
AST
Aspartate Aminotransferase
AUC0-tz
Area under the concentration-time curve of the analyte in serum over the 
time interval from 0 to the last quantifiable drug concentration
AUC0-∞
Area under the concentration-time curve of the analyte in plasma over the 
time interval from 0 extrapolated to infinity
BLQ
Below limit of quantification
BMI
Body mass index
CI
Confidence Interval
Cmax
Maximum measured concentration of the analyte in plasma
CSD
Company standard displays
CV
Arithmetic Coefficient of Variation
DBLM
Database Lock Meeting
DILI
Drug induced liver injury
gCV
Geometric Coefficient of Variation
gMean
Geometric Mean
LLOQ
Lower limit of quantification
LLT
Lower Level Term
IQRMP
Integrated Quality and Risk Management Plan
Max
Maximum
Min
Minimum
N
Number non-missing observations
P10
10th percentile
P90
90th percentile
PKS
PK parameter analysis set
Q1
1st quartile
Q3
3rd quartile
RAGe
Report Appendix Generator system


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Term
Definition / description
RCTC
Rheumatology Common Toxicity Criteria
REP
Residual Effect Period
SD
Standard Deviation
tmax
Time from dosing to maximum measured concentration of the analyte in 
plasma
TS
Treated Set
UDAEC
User Defined Adverse Events Concepts
ULN
Upper Limit of Normal
WHO-DD
World Health Organization Drug Dictionary


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3.
INTRODUCTION
As per ICH E9 (1), the purpose of this document is to provide a more technical and detailed 
elaboration of the principal features of the analysis described in the protocol, and to include 
detailed procedures for executing the statistical analysis of the primary and secondary 
variables and other data.
This trial statistical analysis plan (TSAP) assumes familiarity with the Clinical Trial Protocol 
(CTP), including Protocol Amendments. In particular, the TSAP is based on the planned 
analysis specification as written in CTP Section 7 “Statistical Methods and Determination of 
Sample Size”. Therefore, TSAP readers may consult the CTP for more background 
information on the study, e.g., on study objectives, study design and population, treatments, 
definition of measurements and variables, planning of sample size, randomisation.
Study data (including data entered in the RAVE EDC system and external data provided by 
suppliers) will be stored in a Clinical Data Repository (CDR).
Pharmacokinetic (PK) parameters will be calculated using Phoenix WinNonlinTM software 
(version 6.3 or higher, 
).
The statistical analyses will be performed within the validated working environment CARE, 
including SAS® (current Version 9.4, by 
), and a number of 
SAS®-based tools (e.g., macros for the analyses of AE data or laboratory data; Report 
Appendix Generator system (RAGe) for compilation/formatting of the CTR appendices).


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4.
CHANGES IN THE PLANNED ANALYSIS OF THE STUDY
All analyses as planned in the CTP will be performed and are described in more detail in this 
TSAP. The following changes compared to the protocol will be made: 
In CTP section 7.3 the following was defined: Important protocol deviation (IPD) categories 
will be specified in the Integrated Quality and Risk Management (IQRM) Plan. IPDs will be 
identified no later than in the Report Planning Meeting, and the IPD categories will be 
updated as needed. Due to SOP changes, the IPD categories are no longer available in IQRM 
plan but included in an Excel spreadsheet (3). The IPD categories originally defined in IQRM 
plan were transferred to the IPD specification file. Minor changes regarding the IPD 
categories were performed only. 
In CTP section 5.2.6.1.4 the following definition was used for an AE of special interest:
Severe infections (according to RCTC grading in ISF). As it is a healthy volunteer study, no 
RCTC grades were applied, therefore the definition ‘Severe infections (according to AE 
intensity grades as ticked in eCRF)’ was used for analysis.
In CTP section 7.3, the following definition was included by mistake:
Plasma concentrations and/or parameters of a subject will be considered as non-evaluable, if
for example

The subject experienced emesis that occurred at or before two times median tmax of the 
respective treatment (Median tmax is to be determined excluding the subjects 
experiencing emesis),
As route of study drug administration is sc or iv, emesis has no effect on PK evaluability and 
will not be considered for PK analysis. 


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5.
ENDPOINTS
5.1
PRIMARY ENDPOINTS
The primary objective of this trial is to investigate PK, including dose proportionality,
following single IV and SC doses of Spesolimab in healthy Chinese subjects. Primary 
endpoints are AUC0-∞and Cmax of Spesolimab.
5.2
SECONDARY ENDPOINTS
5.2.1
Key secondary endpoint
This section is not applicable as no key secondary endpoints have been defined in the CTP.
5.2.2
Secondary endpoints
Section 2.1.3 of the CTP: 
The occurrence of treatment-emergent AEs (e.g. number of subjects with treatment-emergent 
AEs).
The occurrence of drug-related AEs (e.g. number of subjects with drug-related AEs).
Safety and tolerability of Spesolimab will be assessed based on:

Safety laboratory parameters

12-lead ECG

Vital signs (blood pressure [BP], pulse rate [PR], respiratory rate [RR], body
temperature)

Immunogenicity (ADA)


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5.4
OTHER VARIABLES
There are the following other parameters which will be listed and tabulated:
Subject information:

Informed consent

Relevant medical history

Concomitant therapy

Inclusion/Exclusion criteria
Demographic data:

Gender

Height

Weight

Smoking history

Alcohol history

Race 

Ethnicity
Age [years] will be determined as the difference between year of informed consent and year 
of birth.
BMI will be calculated as weight [kg] / (0.01 * height [cm])2.


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6.
GENERAL ANALYSIS DEFINITIONS
6.1
TREATMENTS
For basic study information on investigational products, assignment of treatment sequences 
and selection of doses, please see CTP, Sections 3 and 4.
The study will be performed as a single dose, open-label non-randomized study in parallel-
group design. 
It is planned to include up to 60 healthy male and female subjects in the trial. The subjects
will be assigned to 5 groups each consisting of 10 subjects with at least 3 subjects for each 
gender within each dose group. The cohorts within each SC and IV dose groups will be dosed 
sequentially.
For details of dosage and formulation see Table 6.1:1 below.
Table 6.1: 1
Labels for treatments for use in the CTR 
Dose 
group
Treatment
Short label
1
A
BI 655130, 450 mg, iv, once
Speso 450mg iv
2
B
BI 655130, 900 mg, iv, once
Speso 900mg iv
3
C
BI 655130, 1200 mg, iv, once
Speso 1200mg iv
4
D
BI 655130, 300mg, sc, once
Speso 300mg sc
5
E
BI 655130, 600mg, sc, once
Speso 600mg sc
The following separate study phases will be defined for the analyses of AEs:

Screening (ranging from 0:00h (midnight) on day of informed consent until first 
administration time of study drug Spesolimab))

On treatment
o
BI treatment (separately for each treatment, ranging from the time of first 
administration of Spesolimab / start of infusion of Spesolimab until time of 
administration + REP (defined as 16 weeks) / end of infusion + REP (defined as 
16 weeks))
o
Follow-up (F/U) (ranging from administration / end of infusion of Spesolimab + REP
until 0:00h (midnight) on the day after trial completion date))
The following AE displays will be provided in the report:
Section 15.3 and Appendix 16.1.13.1.8 (for ClinicalTrials.gov) of the CTR displays:
In these displays, the on treatment phase will be analysed (labelled with the name of the study 
treatment (short label)). Screening and Follow-up phases will not be included in this analysis. 


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The following totals will be provided in addition:

a total over all on treatment phases included in this analysis ("Total") (Appendix 
16.1.13.1.8 only) 

a total over all on treatment phases included in this analysis ("Total iv") (tables 
including iv treatment groups) 

a total over all on treatment phases included in this analysis ("Total sc") (tables 
including sc treatment groups) 
Tables for ClinicalTrials.gov will be provided including both sc and iv groups.
In Section 15.4 and Appendix 16.2 (Listings) of the CTR displays, the screening and follow-
up period will be included and no totals will be provided.
Tables of vital signs and laboratory values will present results for the above mentioned on 
treatment phase.
For detailed information on the handling of the treatments refer to Technical TSAP ADS 
(analysis data set) plan and Analysis Data Reviewers guide. 
6.2
IMPORTANT PROTOCOL DEVIATIONS
Data discrepancies and deviations from the CTP will be identified for all treated subjects.
Consistency check listings (for identification of deviations of time windows) and a list of 
protocol deviations (e.g. deviations in drug administration, in blood sampling times, etc.) will 
be provided to be discussed at the Report Planning Meeting and database lock meeting
(RPM/DBLM). At this meeting, all manual deviations identified at the sites by the CRAs and 
deviations too complex to program will be reviewed by the trial team to decide which are 
considered important. For definition of important protocol deviations (iPD), and for the 
process of identification of these, refer to the Boehringer Ingelheim (BI) SOP "Identify and 
Manage Important Protocol Deviations (iPD)" (2).
If any iPDs are identified, they are to be summarised into categories and will be captured in 
the RPM/DBLM minutes via an accompanying Excel spreadsheet.
Categories which are considered to be iPDs in this trial were defined in the integrated quality 
and risk management plan (IQRMP) prior to trial initiation. The IPD list was transferred into 
the IPD specification file (due to changes in the SOP) (3). Within this transfer some minor 
adaptations were done to comply with new naming conventions and categorisations. IPDs will 
be identified no later than in the Report Planning Meeting and the IPD categories will be 
updated as needed. The decision on exclusion of subjects from analysis sets will be made after 
discussion of exceptional cases and implications for analyses.
The iPDs will be summarised and listed.


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6.3
SUBJECT SETS ANALYSED
Section 7.3 of the CTP: Statistical analyses will be based on the following analysis sets:

Treated set (TS): The treated set includes all subjects who were treated with at least one 
dose of trial drug. The treatment assignment will be determined based on the (first) 
treatment the subjects received. The treated set will be used for safety analyses.

PK parameter analysis set (PKS): This set includes all subjects in the TS who provide at 
least one primary PK endpoint that was not excluded due to a protocol deviation relevant 
to the evaluation of PK or due to PK non-evaluability (as specified in the following 
subsection ‘Pharmacokinetics’). Descriptive and model based analyses of PK parameters 
will be based on the PKS. It is expected that PK data from replaced subjects is not 
evaluable and thus replaced subjects are not expected to be part of the PKS.
Plasma concentration data and parameters of a subject will be included in the statistical PK
analyses if they are not flagged for exclusion due to a protocol deviation relevant to the
evaluation of PK (to be decided no later than in the Report Planning Meeting) or due to PK
non-evaluability (as revealed during data analysis, based on the criteria specified below).
Exclusion of a subject’s data will be documented in the CTR.
Relevant protocol deviations may be

Incorrect trial medication taken, i.e. the subject received at least one dose of trial 
medication the subject was not assigned to

Incorrect dose of trial medication taken

Use of restricted medications
Plasma concentrations and/or parameters of a subject will be considered as non-evaluable, if
for example

Missing samples/concentration data at important phases of PK disposition curve.
Plasma concentration data and parameters of a subject which is flagged for exclusion will be 
reported with its individual values but will not be included in the statistical analyses.


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Table 6.3: 1
Subject sets analysed
Subject analysis set
Class of endpoint
Treated set
PKS
Analysis of PK endpoints
X
Safety parameters
X
Demographic/baseline parameters
X
Important protocol deviations
X
Disposition
X
6.5
POOLING OF CENTRE
This section is not applicable, because the study was performed in only one centre.
6.6
HANDLING OF MISSING DATA AND OUTLIERS
Handling of missing data and outliers will be performed as described in the CTP, Section 7.4.
The only exceptions where imputation might be necessary for safety evaluation are AE dates. 
Missing or incomplete AE dates are imputed according to BI standards (see BI-KMED-BDS-
HTG-0035 (4)).
Missing data and outliers of PK data are handled according to BI standards (see BI-KMED-
TMCP-MAN-0014) (5).
Missing baseline laboratory values will be imputed by the respective values from screening or 
from ambulatory visit (ptm -48:00) if available.


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6.7
BASELINE, TIME WINDOWS AND CALCULATED VISITS
The baseline value is defined as the last measurement before first administration of 
Spesolimab (= value at V2 Day 1, in case no actual time is given in data). 
The acceptable time windows for visits are given in the CTP Flow Chart and CTP Section 6.1.
Adherence to time windows will be checked via the consistency check listings at the 
RPM/DBLM.
Unscheduled measurements of laboratory data and vital signs data will be assumed to be 
repeat measurements of the most recent scheduled measurement (e.g. for follow-up or 
confirmation of a particular value). Therefore, unscheduled measurements will be assigned to 
the planned time point of the previous scheduled measurement. 


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7.
PLANNED ANALYSIS
If not otherwise stated, tables and listings will be done separately for IV treatment
groups and SC treatment groups.
Safety analysis (refer to Section 7.8) will be performed by 
 and 
will be presented in Sections 15.1 to 15.4 of the CTR and in Appendix 16.2 and 16.1.13.1.
Inferential statistical analyses of PK endpoints (refer to Section 7.4.1 and Section 7.6) will 
also be performed by 
 and will be presented in Section 15.5 of
the CTR and in Appendix 16.1.13.3.
Descriptive data analysis of PK parameters and concentrations will be performed by the 
department 
 at 
 and will be 
presented in Section 15.6 of the CTR.
Descriptive data analysis of ADA will be performed by the department 
 
 at 
 and will be presented in Section 15.8 of 
the CTR.
The format of the listings and tables will follow the BI standards (see BI-KMED-BDS-HTG-
0045 (6)) with the exception of those generated for PK-calculations (5).
The individual values of all subjects will be listed, sorted by treatment group, subject number, 
and visit. 
The listings will be included in Appendix 16.2 of the CTR.
For end-of-text tables, the set of summary statistics for non-PK parameters is: 
N 
number non-missing observations
Mean
arithmetic mean
SD
standard deviation 
Min
minimum 
Median
median 
Max
maximum
For analyte concentrations, the following descriptive statistics will additionally be calculated:
CV 
arithmetic coefficient of variation
gMean
geometric mean
gCV
geometric coefficient of variation
For PK parameters, the following descriptive statistics will additionally be calculated:
CV 
arithmetic coefficient of variation
gMean
geometric mean
gCV
geometric coefficient of variation
P10 
10th percentile


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Q1 
1st quartile
Q3 
3rd quartile
P90 
90th percentile
The data format for descriptive statistics of concentrations will be identical with the data 
format of the respective concentrations. The descriptive statistics of PK parameters will be 
calculated using the individual values with the number of decimal places as provided by the 
evaluation program. Then the individual values as well as the descriptive statistics will be 
reported with three significant digits in the CTR.
Tabulations of frequencies for categorical data will include all possible categories and will 
display the number of observations in a category, as well as the percentage (%) for each 
treatment group. Percentages will be rounded to one decimal place and will be based on all 
subjects in the respective subject set whether they have non-missing values or not. The 
category 'missing' will be displayed only if there are actually missing values.
Exclusion of PK parameters
The ADS ADPP (PK parameters) contains column variables APEXC and APEXCO 
indicating inclusion/exclusion (APEXC) of a PK parameter and an analysis flag comment 
(APEXCO). All analyses based on the PKS will include parameters if they are not flagged for
exclusion, that is APEXC is equal to “Included”.
Exclusion of PK concentrations
The ADS ADPC (PK concentrations per time-point or per time-interval) contains column 
variables ACEXC or ACEXCO indicating inclusion/exclusion (ACEXC) of a concentration 
and an analysis flag comment (ACEXCO). Exclusion of a concentration depends on the 
analysis flag comment ACEXCO. For example, if ACEXCO is set to ‘ALL CALC’, the value 
will be excluded for all types of analyses based on concentrations. If ACEXCO is set to 
‘DESC STATS’, the value will be excluded from descriptive evaluations per planned time 
point/time interval. If ACEXCO contains the addition ‘TIME VIOLATION’ or ‘TIME 
DEVIATION’, the value can be used for further analyses based on actual times. If ACEXCO 
is set to ‘HALF LIFE’, the value will be excluded from half-life calculation (and, as a 
consequence, any calculation that relies on λz) only; the value is included for all other 
analyses.
Further details are given in BI-KMED-TMCP-MAN-0014 “Noncompartmental PK/PD 
analyses of Clinical Studies” (5).
Preliminary and interim analysis
If required for early interaction with regulatory agency, a preliminary snapshot will be 
conducted once all IV subjects have completed the study. This snapshot includes the complete 
clinical data of the iv group, but without PK/ADA data. 
Furthermore an interim lock will be conducted at a later time. This interim lock includes the 
complete clinical data of the iv group, inclusive PK/ADA data. An interim report for the IV 
analysis will be written. All analyses defined in this TSAP restricted to IV subjects will be 


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done for this interim analysis. For details on interim analysis, e.g. definition of topline results, 
please refer to Section 9.1. 
7.1
DEMOGRAPHIC AND OTHER BASELINE CHARACTERISTICS
Only descriptive statistics are planned for this section of the report, based on the TS.
The data will be summarised by treatment group and in total. 
7.2
CONCOMITANT DISEASES AND MEDICATION
Frequency tables are planned for this section of the report, based on the TS.
Concomitant diseases will be coded using the latest version of the coding system of the 
Medical Dictionary for Drug Regulatory Activities (MedDRA). Medications will be coded 
using the latest version of the World Health Organization Drug Dictionary (WHO-DD). The 
coding version number will be displayed as a footnote in the respective output.
The diagnoses and medications will be listed. Subjects without any concomitant diagnoses or 
concomitant therapies should be marked with a “No” in the respective column.
The relevance of the concomitant therapies to the evaluation of PK will be decided no later 
than at the RPM/DBLM.
7.3
TREATMENT COMPLIANCE
Section 4.3 of the CTP: Compliance will be assured by administration of all trial medication 
in the study centre under supervision of the investigating physician or a designee. The 
measured sample concentrations will provide additional confirmation of compliance.
It is not intended to list the compliance separately. Any deviations from complete intake will 
be addressed in the RPM/DBLM (see Section 6.2) and described in the CTR.
7.4
PRIMARY ENDPOINTS
7.4.1
Primary analysis of the primary endpoints
Section 7.1.3 of the CTP: The primary endpoint as specified in Section 5.1 will be derived 
according to BI standards (BI-KMED-TMCP-MAN-0014). The analysis will be based on the 
PKS and will be descriptive in nature.
For IV doses the dose proportionality of AUC0-∞and Cmax will be analysed.
Assessment of dose proportionality
Dose proportionality will be explored via graphical checks and if applicable via the power
model stated below. The analysis will be performed for the PK endpoints AUC/Cmax specified
in section 5.1.


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The power model describes the functional relationship between the dose level and PK
endpoint on the log scale via
ykm = log (xkm) = μ + b · log (Dk) + ekm ,
where
ykm
logarithm of response (PK parameter) measured on subject mth receiving dose
k,
μ 
the overall mean,
β
slope parameter of linear regression line,
Dk
level of dose k, k=1, 2, 3,
ekm
the random error associated with the mth subject who was administered dose k
(ekm~N(0, σ2) iid).
This equation can be fit as a linear regression model.
The slope parameter β together with its two-sided 90% confidence interval will be estimated.
Perfect dose proportionality would correspond to a slope of 1. Additionally, the r-fold change 
rβ-1 together with its 90% CI will be derived.
Graphical displays:
A regression plot will be performed, where the logarithm of dose is depicted versus logarithm 
of PK endpoint, including the estimated regression line from the power model and reference 
line of perfect proportionality (β=1).
This analysis will be based on the PKS.
7.4.2
Sensitivity analysis, subgroup analysis, exploratory analysis of the primary 
endpoints
Not applicable.
7.5
SECONDARY ENDPOINTS
7.5.1
Key secondary endpoint
This section is not applicable as no key secondary endpoint has been specified in the protocol.
7.5.2
Secondary endpoints
Refer to TSAP Section 7.8.1 for a description of the analysis of adverse events.


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7.7
EXTENT OF EXPOSURE
Descriptive statistics are planned for this section of the report based on the TS. The date and 
time of drug administration will be listed for each subject.
7.8
SAFETY ANALYSIS
All safety analyses will be performed on the TS.
Unless stated otherwise, the safety results will be sorted by treatment group.
The safety data for treated subjects who fail to complete the study (dropouts or withdrawals) 
will be reported as far as their data are available. All withdrawals will be documented and the 
reason for withdrawal recorded.
7.8.1
Adverse Events
AEs will be coded with the most recent version of MedDRA.
The analyses of AEs will be descriptive in nature and will be based on BI standards as 
presented in “Analysis and Presentation of Adverse Event Data from Clinical Trials – Display 
Template” [BI-KMED-BDS-HTG-0041] (8).


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The standard AE analyses will be based on the number of subjects with AEs (and not on the 
number of AEs). 
The analysis of AEs will be based on the concept of treatment emergent AEs. That means that 
all AEs will be assigned to ‘screening’, ‘on treatment’ or ‘follow-up’ phases as defined in 
Section 6.1. AEs will be analysed based on actual treatments, as defined in Table 6.1: 1.
Section 1.2.6 of the CTP: The residual effect period (REP) of Spesolimab is 16 weeks.
According to the clinical study protocol, adverse events of special interest (AESI) will be 
analysed:
Section 5.2.6.1.4 of the CTP: The following are considered as AESIs in this trial:

Hepatic injury, as defined by the following alterations of hepatic laboratory 
parameters:
o
an elevation of AST (Aspartate Aminotransferase) and/or ALT (Alanine 
Aminotransferase) ≥3-fold ULN combined with an elevation of total bilirubin 
≥2-fold ULN measured in the same blood sample, or
o
ALT, and/or AST elevations ≥10-fold ULN
These lab findings constitute a hepatic injury alert and the subjects showing these lab 
abnormalities need to be followed up according to the ‘DILI checklist’ provided in the 
ISF. In case of clinical symptoms of hepatic injury (icterus, unexplained 
encephalopathy, unexplained coagulopathy, right upper quadrant abdominal pain, 
etc.) without lab results (ALT, AST, total bilirubin) available, the Investigator should 
make sure that these parameters are analysed, if necessary in an unscheduled blood 
test. Should the results meet the criteria of hepatic injury alert, the procedures 
described in the DILI checklist should be followed.

Systemic hypersensitivity including infusion reaction and anaphylactic reaction:
Any suspicion of severe infusion reaction systemic/hypersensitivity reaction and of any 
potential cases of anaphylaxis should be defined and assessed using the criteria 
discussed in the statement paper from Sampson HA (Appendix 10.1.3, R11-4890).

Severe infections […]

Opportunistic and mycobacterium tuberculosis infections
These include pneumocystis jirovecii, BK virus disease including PVAN, CMV, post-
transplant lymphoproliferative disorder (EBV), progressive multifocal 
leucoencephalopathy, bartonellosis (disseminated only), blastomycosis, 
toxoplasmosis, coccidioidomycosis, histoplasmosis, aspergillosis (invasive only), 
candidiasis (invasive or pharyngeal), cryptococcosis, other invasive fungi 
(mucormycosis (zygomycosis, rhizopus, mucor, lichtheimia), 
scedosporium/pseudallescheria boydii, fusarium), legionellosis, listeria 
monocytogenes (invasive only), tuberculosis, nocardiosis, non-tuberculous 
mycobacterium, salmonellosis (invasive only), hepatitis B virus [HBV] reactivation, 
herpes simplex (invasive only), herpes zoster, strongyloides (hyperinfection syndrome 
and disseminated forms only), paracoccidioides, penicillium marneffei, sporothrix 


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schenckii, cryptosporidium species (chronic only), microsporidiosis, leishmaniasis
(visceral only), trypanosoma cruzi infection (Chagas’ disease) (disseminated only), 
campylobacteriosis (invasive only), shigellosis (invasive only), vibriosis (invasive due 
to vibrio vulnificus), hepatitis C virus [HCV] progression (R17- 2617).
According to ICH E3 (9), in addition to Deaths and Serious Adverse Events, ‘other 
significant’ AEs need to be listed in the clinical trial report. 
The definition of ‘other significant’ AE to be used in this trial is derived by the sponsor and is 
based upon that according to ICH E3, and will include AEs reported as non-serious adverse 
events with ‘action taken = Drug Withdrawn’ or ‘action taken = Drug Reduced’.
An overall summary of adverse events will be presented (including number of subjects with 
any AE, drug related AEs, serious AEs and drug related serious AEs).
The frequency of subjects with AEs will be summarised by treatment, primary system organ 
class (SOC) and preferred term (PT). Separate tables will be provided for subjects with SAEs, 
for subjects with drug-related AEs, patients with investigator-defined AESIs per CTP, and
patients with other User-Defined Adverse Event Concepts (UDAEC) (cf. Table 7.8.1: 1 
below). In addition, the frequency of subjects with AEs will be summarised by treatment, 
worst intensity, SOC and PT.
Table 7.8.1: 1 Project MEDDRA search criteria for User Defined Adverse Events Concepts
Important risk 
User-defined AE category
Label 
Description
Infections (serious/severe, 
opportunistic)
Infections ALL
Combined search strategy based on 
the individual UDAECs described 
below; the UDAEC “severe 
infections (investigator-defined) 
will be disregarded for this search
Opportunistic infections
Narrow SMQ “Opportunistic 
infections”
Tuberculosis related 
terms
BIcMQ “Infections”:
Narrow sub-search 8.2 
“Tuberculosis related terms” 
Serious infections
all serious events in SOC 
“Infections and infestations”
Severe infections
all events in SOC “Infections and 
infestations” of at least severe AE
grade
Severe infections 
(investigator defined)
as per tick box on the eCRF 
(investigator-defined)
* this is achieved by retrieving all cases found either by running subsearch 1 in narrow scope (BIcMQ search ID 32019093 ) or
subsearch 2 (BIcMQ serach ID 32019094 )


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Table 7.8.1: 1 Project MEDDRA search criteria for User Defined Adverse Events Concepts -
continued
Hypersensitivity
Hypersensitivity ALL
Combined search strategy based on 
the three individual UDAECs 
described below
Anaphylactic reaction
Narrow SMQ “Anaphylactic 
reaction”
Angioedema
Narrow SMQ “Angioedema”
Hypersensitivity
Narrow SMQ “Hypersensitivity”
Malignancies
Malignant tumours
Narrow Sub-SMQ “Malignant 
tumours”
Narrow Sub-SMQ “Haematological 
malignant tumours”
Narrow Sub-SMQ “Non-
Haematological malignant 
tumours”
Malignant skin tumours
Broad Sub-SMQ “Skin malignant 
tumours”
Skin melanomas
HLT Skin melanomas (excl. 
Ocular)
Non-melanoma skin 
cancer (NMSC) 
Broad Sub-SMQ “Skin malignant 
tumours” excluding 
HLT Skin melanomas (excl. 
Ocular)
Malignancies excluding 
NMSC 
Sub-SMQ “Malignant tumours”  
excluding 
NMSC, whereas NMSC is defined 
above
3-point MACE
BIcMQ 3-MACE with subsearch 
1.1 narrow and subsearch 1.2 
narrow *”
Torsades de pointes
Broad SMQ “Torsades de 
pointes/QT prolongation”
* this is achieved by retrieving all cases found either by running subsearch 1 in narrow scope (BIcMQ search ID 32019093 ) or
subsearch 2 (BIcMQ serach ID 32019094 )
The system organ classes will be sorted by frequency, PTs will be sorted by frequency (within 
SOC). The MedDRA version number will be displayed as a footnote in the respective output.
In addition, frequencies of subjects with non-serious AEs that had an incidence of > 5% for at 
least one treatment will be summarised by treatment, primary SOC and PT.


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7.8.2
Laboratory data
The analyses of laboratory data will be descriptive in nature and will be based on BI standards 
[BI-KMED-BDS-HTG-0042] (10).
For continuous safety laboratory parameters, normalized values will be derived. 
Normalisation means transformation to a standard unit and to a standard reference range. The 
process of normalisation, handling of repeat values at the same visit for by-visit displays, as 
well as standard analyses for safety laboratory data are described in the BI guidance for the 
Display and Analysis of Laboratory Data (10). All analyses considering multiple times of the 
ULN (as described below) will be based on standardized and not normalized values. For 
continuous safety laboratory parameters, differences to baseline will be calculated. For all 
outputs, the last assessment before the first randomized treatment at Day 1 is chosen as the 
baseline value.
Laboratory data will be analysed qualitatively via comparison of laboratory data to their 
reference ranges. Only patients with at least one available post-baseline value will be included 
in the analysis of an individual laboratory parameter. Values outside the reference range as 
well as values defined as possible clinically significant will be flagged in the data listings. 
Descriptive statistics of laboratory values and for the difference from baseline on-treatment 
(see Section 6.7) will be based upon standardized values and provided by visit (including 
summaries of the last value, the minimum value and the maximum value on treatment).
Possibly clinically significant abnormalities will be identified based on BI standard rules 
which are based on converted lab values and converted reference ranges, i.e. using SI units. 
These rules will be listed in the SDL appendix of the CTR. Frequency tables will summarize 
the number of patients with possibly clinically significant abnormalities. If applicable, 
patients having an abnormal lab value at baseline will be presented separately. A separate 
listing will present possibly clinically significant abnormal lab values; for each functional lab 
group all patient’s lab values will be listed, if there exists at least one lab value with clinically 
significant abnormality within the group. 
The frequency of patients with AST or ALT elevations ≥ 3xULN, ≥ 5xULN, ≥ 10xULN, and 
≥ 20xULN will be displayed based on standardized laboratory values. To support analyses of 
liver related adverse drug effects, the frequency of patients with AST and/or ALT ≥ 3xULN 
combined with a total bilirubin ≥ 2xULN in a 30 day period after AST/ALT elevation will be 
displayed, stratified by alkaline phosphatase < 2xULN and ≥ 2xULN (a patient can potentially 
be in both alkaline phosphatase strata in case of multiple AST/ALT and bilirubin elevations). 
The start of the 30 day time span is triggered by each liver enzyme elevation above the 
defined thresholds. This analysis will be based on standardized laboratory values. A graphical 
analysis of the ALT and total bilirubin during the on-treatment period will also be performed; 
the so called eDISH plot. In the graph, for each subject, the peak total bilirubin is presented as 
a fold increase over the ULN against the peak ALT as a fold increase over the ULN, on a 
log10 scale. The measurements displayed or total bilirubin and ALT may, or may not, occur 
on the same date. Two reference lines, 2xULN for total bilirubin and 3xULN for ALT, are 
drawn onto the graph in order to divide the plane into four quadrants. Normal cases are in the 
lower left quadrant, potential DILI cases are in the upper right quadrant (Hy’s Law quadrant), 


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while the lower right quadrant is known as the Temple’s corollary range (ALT ≥ 3xULN and 
total bilirubin < 2xULN).
Clinically relevant findings in laboratory data will be reported as adverse events if judged 
clinically relevant by the investigator, and will be analysed as such.
It is the investigator's responsibility to decide whether a lab value is clinically significant 
abnormal or not (at the RPM/DBLM at the latest).
7.8.3
Vital signs
Descriptive statistics over time including change from baseline will be performed for vital 
signs (blood pressure, pulse rate and respiratory rate)based on the last value of the subject at 
that planned time point (or assigned to that planned time point) and including summaries of 
the minimum value and the maximum value on treatment. In the listing the difference from 
baseline will also be displayed.
Body temperature will be listed only.
Clinically relevant findings in vital signs will be reported as AEs.
7.8.4
ECG
ECG recordings will be checked by the investigator for pathological results. Clinically 
relevant abnormal findings for ECG will be listed under 'Relevant Medical History / Baseline 
Conditions' (if they pre-exist prior to trial inclusion) or will be reported as AEs (if they 
occurred on treatment), and will be analysed as such.
No separate ECG listing will be provided.
7.8.5
Others
Physical examination
Physical examination findings, including general appearance, neck, lungs, cardiovascular 
system, abdomen, extremities, and skin will be reported as relevant medical history/baseline 
condition (i.e., a condition already existent before intake of study drug) or as AE and will be 
summarised as such. 
No separate listing or analysis of physical examination findings will be prepared.
Local tolerability
Local tolerability will be assessed by the investigator on the basis of ‘swelling’, ‘induration’,
‘heat’, ‘redness’, ‘pain’, or ‘other findings’. A frequency table with worst assessment by 
treatment group and in total will be provided.


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Body weight
Body weight will be determined at screening and end of trial visit. Descriptive statistics 
including change from baseline will be performed by treatment group and in total.


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8.
REFERENCES
1.
CPMP/ICH/363/96: "Statistical Principles for Clinical Trials", ICH Guideline Topic E9, 
Note For Guidance on Statistical Principles for Clinical Trials, current version.
2.
001-MCS-40-413: "Identify and Manage Important Protocol Deviations (iPD) ", current 
version, IDEA for CON
3.
BI-KMED-BDS-TMP-0059: “iPD specification document (sdtm-dv-domain-
specification)”, template, current version, KMED.
4.
BI-KMED-BDS-HTG-0035: "Handling of Missing and Incomplete AE Dates", current 
version; KMED.
5.
BI-KMED-TMCP-MAN-0014: “Noncompartmental PK/PD Analyses of Clinical Studies”, 
current version; KMED.
6.
BI-KMED-BDS-HTG-0045: “Standards for Reporting of Clinical Trials and Project 
Summaries”, current version; KMED.
7.
BI-KMED-TMCP-MAN-0012: “Standards and processes for analyses performed within 
Clinical Pharmacokinetics/Pharmacodynamics”, current version; KMED.
8.
BI-KMED-BDS-HTG-0041: “Analysis and Presentation of Adverse Event Data from 
Clinical Trials – Display Template”, current version; KMED.
9.
CPMP/ICH/137/95: “Structure and Content of Clinical Study Reports”, ICH Guideline 
Topic E3; Note For Guidance on Structure and Content of Clinical Study Reports, current 
version
10. BI-KMED-BDS-HTG-0042: "Handling, Display and Analysis of Laboratory Data", 
current version; KMED.


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10.
HISTORY TABLE
Table 10: 1
History table
Version
Date
(DD-MMM-YY)
Author
Sections 
changed
Brief description of change
1
09-MAR-21
None
This is the final TSAP