Conditions: Healthy
Allocation: RANDOMIZED | Intervention model: PARALLEL
Enrollment: 85
Healthy volunteers: yes

Brief summary:
To evaluate the photosensitivity potential of BI 730357

Detailed description:

Arms:
arm 1: None arm 2: None arm 3: None arm 4: None

Interventions: intervention 1: BI 730357 intervention 2: Placebo to match BI 730357 intervention 3: Ciprofloxacin
Intervention descriptions: intervention 1: Film-coated tablet intervention 2: Film-coated tablet intervention 3: Film-coated tablet

Protocol document:
Prot_000.pdf: 
ABCD
001-MCS-40-106_RD-03 (17.0) / Saved on 18 Mar 2019
Clinical Trial Protocol
TITLE PAGE
TITLE PAGEDocument Number:
c27983101-03
BI Trial No.
1407-0037
BI Investigational
Medicinal Product(s)
BI 730357
Title
Partially-blind, randomized, parallel group, placebo and active 
comparator-controlled Phase I clinical trial to evaluate the 
photosensitivity potential of BI 730357
Lay Title
Evaluation of photosafety of BI 730357 compared to placebo and 
the known photosensitizing agent ciprofloxacin
Clinical Phase
Phase I
Clinical Trial Leader
Tel.:
Principal 
Investigator
Tel: 
Version and Date
Version: 3.0
Date: 01 Apr 2020
Page 1 of 79
Proprietary confidential information.
2020 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
Protocol date
27 Sep 2019
Revision date
01 Apr 2020
BI trial number
1407-0037
Title of trial
Partially-blind, randomized, parallel group, placebo and active 
comparator-controlled Phase I clinical trial to evaluate the 
photosensitivity potential of BI 730357
Principal Investigator 
Trial site
Clinical phase
Phase I
Trial rationale
To evaluate photosafety of BI 730357
Trial objective(s)
The objective of this trial is to evaluate the photosensitivity potential 
of BI 730357 compared to placebo and a mild photosensitizer
ciprofloxacin as positive control, assessed by the Photosensitivity 
Index (PI), changes in MED, erythema, and local skin reactions 
following exposure to UVA and UVB radiation.
In addition, the relationship between the photosensitivity response 
and pharmacokinetics of BI 730357 may be evaluated.
Trial endpoints
The primary endpoints are:

Phototoxicity index at 24 h under condition 1

Phototoxicity index at 24 h under condition 2
The secondary endpoints are:

Phototoxicity index at 10 min under condition 1

Phototoxicity index at 1 h under condition 1

Phototoxicity index at 10 min under condition 2 

Phototoxicity index at 1 h under condition 2 

Minimum Erythema Dose (MED) percent change from baseline at 
10min, 1h, and 24h measured under condition 1 and condition 2
All endpoints are applicable for both treatment parts.
Trial design
This is a partially blind, randomized, parallel group, placebo-
controlled study conducted in two treatment arms. 
Treatment Part A will be conducted according to a randomized, 


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double blind, placebo-controlled design to assess the photosensitivity 
potential, safety, tolerability, and pharmacokinetics of multiple doses 
of BI 730357. Subjects will be randomized in a 3:1 manner to receive 
BI 730357 or placebo.
Subjects will receive 400mg QD of BI 730357 or placebo over 8
days, or 300 mg BID of BI 730357 or placebo over 7 days with a 
single dose on day 8. Separate randomizations will be carried out for 
400 mg QD/placebo and 300 mg BID/placebo.
Photosensitivity assessments will occur at baseline and following the 
last dose of either BI 730357 or placebo.
Treatment Part B will be conducted according to an open-label, 
observer-blinded design to assess the photosensitivity potential of 
ciprofloxacin (a mild photosensitizer) as a positive control.
Subjects will receive 500 mg ciprofloxacin twice-daily starting on
Day 3 through to the morning of Day 8.
Photosensitivity assessments will occur at base line and following the 
last dose of ciprofloxacin.
Total number of subjects
randomised
Approximately 84 subjects will be enrolled to allow for at least 74
completed subjects
Number of subjects on 
each treatment
36 subjects in Part A for 400 mg QD
36 subjects in Part A 300 mg BID
12 subjects in Part B  
Diagnosis
Healthy volunteers
Main in- and exclusion 
criteria
Healthy male and female subjects as determined by past medical 
history, physical examination, vital signs, electrocardiogram, and 
laboratory tests at screening;
aged ≥18 to ≤55 years, with a BMI range: ≥18 to ≤ 35 kg/m 
Fitzpatrick skin type I, II, or III 
Fitzpatrick Skin Type Description:
I Always burns easily, never tans
II Always burns easily, tans minimally
III Burns moderately, tans gradually
Test product(s)
BI 730357 100 mg tablets 
dose
400mg once daily 
300mg twice daily
mode of 
p.o.


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administration
Comparator product(s)
Placebo matching BI 730357
dose
Not applicable
mode of
administration
p.o.
Comparator product(s)
Ciprofloxacin
dose
500mg twice daily
mode of
administration
p.o.
Duration of treatment
BI 730357 tablets or matching placebo over 8 days
Ciprofloxacin over 5.5 days
Statistical methods
A mixed model for repeated measures on Phototoxicity index (PI)
values will be utilized for the analysis of primary and secondary 
endpoints.  The model will include treatment (BI 730357, Placebo, 
ciprofloxacin), time (10min, 1h, 24h, 48h, and 72h), and treatment-
time interaction as fixed effects and subject as a random effect.  
Adjusted means and differences in PI and 90% CIs for the contrasts
of interest (i.e. BI 703357 – placebo at 24h) will be calculated from 
the model.
The analysis will be carried out separately for condition 1 and 
condition 2
Descriptive statistics will be tabulated for all endpoints.


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FLOW CHART TREATMENT A 400 MG QD
Day
Planned time
[h:min]
Approx. time
[h:min]
Event and 
comment
Drug 
administration
Laboratory1
UVB/UVA 
irradiation
Photosensitivity 
assessment4
Physical Exam
12-lead ECG3
Vital signs 3
AE/Concomitant 
Medication
-28 
to 
-3
Screening
X
X
X
X
X
-3
X4
X6
X
-2
X7
X5
X
-1
Admission
X
X8
X5
X
X
X
X
1
-1:00
7:00
Predose/
Randomization
X7
X
0:00
8:00
X
4:00
12:00
X
2
24:00
8:00
X
X
3
48:00
8:00
X
X
4
72:00
8:00
X
X
5
96:00
8:00
X
X
6
120:00
8:00
X
X
7
144:00
8:00
X
X
8
168:00
8:00
X
X
X
169:00
9:00
170:00
10:00
X
170:10
10:10
X
171:00
11:00
X
172:00
12:00
174:00
14:00
180:00
20:00
9
192:00
8:00
X
194:00
10:00
X
10
216:00
8:00
X
218:00
10:00
X
11
240:00
8:00
X
X
X
X
242:00
10:00
Discharge
X
15 
EOT2
X
X
X
X
X


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FLOW CHART TREATMENT A 300 MG BID
Day
Planned time9
[h:min]
Approx. time 
[h:min]
Event and 
comment
Drug 
administration
Laboratory1
UVB/UVA 
irradiation
Photosensitivity 
assessment4
Physical Exam
12-lead ECG3
Vital signs 3
AE/Concomitant 
Medication
-28 
to 
-3
Screening
X
X
X
X
X
-3
X4
X6
X
-2
X7
X5
X
-1
Admission
X
X8
X5
X
X
X
X
1
-1:00
7:00
Predose/
Randomization
X7
X
0:00
8:00
X
1:00
9:00
2:00
10:00
3:00
11:00
4:00
12:00
X
6:00
14:00
8:00
16:00
10:00
18:00
12:00
20:00
X
2
24:00
8:00
X
X
36:00
20:00
X
3
48:00
8:00
X
X
60:00
20:00
X
4
72:00
8:00
X
X
84:00
20:00
X
5
96:00
8:00
X
X
108:00
20:00
X
6
120:00
8:00
X
X
132:00
20:00
X
7
144:00
8:00
X
X
156:00
20:00
X
8
168:00
8:00
X
X
X
169:00
9:00
170:00
10:00
X


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Day
Planned time9
[h:min]
Approx. time 
[h:min]
Event and 
comment
Drug 
administration
Laboratory1
UVB/UVA 
irradiation
Photosensitivity 
assessment4
Physical Exam
12-lead ECG3
Vital signs 3
AE/Concomitant 
Medication
170:10
10:10
X
171:00
11:00
X
172:00
12:00
174:00
14:00
180:00
20:00
9
192:00
8:00
X
194:00
10:00
X
10
216:00
8:00
X
218:00
10:00
X
11
240:00
8:00
X
X
X
X
242:00
10:00
Discharge
X
15 
EOT2
X
X
X
X
X
1
For the laboratory tests performed at each particular visit refer to the Tables: 5.2.3:1 and 5.2.3:2
for Photosensitivity assessments refer to the section 5.1.
2
Patients who discontinue trial treatment prematurely should undergo the End of Treatment (EOT) visit 
7 days thereafter. 
3
Measurements of vital signs (BP; PR; BT) and ECG should precede blood sampling 
4
Photosensitivity assessment on day -2/-1 will be performed 10 (+/-2) min, 1h (+/-5min), 24h (+/-
10min) after irradiation
5
Preliminary estimation of MED
6
Outpatient irradiation and baseline MED testing for Irradiation Condition 1 and Irradiation Condition 2 
will occur on Day -2. Two areas of the back will be defined for irradiation, followed by MED 
assessments at 10 ±2 minutes, 1 hour ±5 minutes (Day -2) and at 24 hours ±10 minutes (Day -1) post 
irradiation.
7
Baseline irradiation for Irradiation Condition 3 will occur on Day -1 with baseline inflammatory 
responses assessed at 10 ±2 minutes, 1-hour ±5 minutes (Day -1) and at 24 hours ±10 minutes (Day 1) 
post Day -1 irradiation. 
8
Preliminary MED irradiation will be performed on Day -3 with confirninng evaluation on Day -2.
9
Planned time relative to the drug administration
10
 samples should be taken before drug administration


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FLOW CHART TREATMENT B
Day
Planned time
[h:min]
Approx. time
[h:min]
Event and 
comment
Drug 
administration
Laboratory1
UVB/UVA 
irradiation 
Photosensitivity 
assessment
Physical Exam
12-lead ECG4
Vital signs 4
AE/Concomitant 
Mediation
-28 
to 
-3
Screening
X
X
X
X
X
-3
X4
X6
X
-2
X7
X5
X
-1
Admission
X
X8
X5
X
X
X
X
1
0:00
8:00
Randomization
X7
X
2
24:00
8:00
X
3
48:00
8:00
X
X
20:00
X
4
72:00
8:00
X
X
20:00
X
5
96:00
8:00
X
X
20:00
X
6
120:00
8:00
X
X
20:00
X
7
144:00
8:00
X
X
20:00
X
8
168:00
8:00
X
X
X
170:00
10:00
X
170:10
10:10
X
171:00
11:00
X
9
192:00
8:00
X
194:00
10:00
X
10
216:00
8:00
X
218:00
10:00
X
11
240:00
8:00
X
X
X
X
242:00
10:00
Discharge
X
15 
EOT2
X
X
X
X
X


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1
For the laboratory tests performed at each particular visit refer to the Tables: 5.2.3:1 and 5.2.3:2
for Photosensitivity assessments refer to the section 5.1.
2
Patients who discontinue trial treatment prematurely should undergo the End of Treatment (EOT) visit 
7 days thereafter. 
3
Measurements of vital signs (BP; PR; BT) and ECG should precede blood sampling 
4
Photosensitivity assessment on day -2/-1 will be performed 10 (+/-2) min, 1h (+/-5min), 24h (+/-
10min) after irradiation
5
Preliminary estimation of MED
6
Outpatient irradiation and baseline MED testing for Irradiation Condition 1 and Irradiation Condition 2 
will occur on Day -2. Two areas of the back will be defined for irradiation, followed by MED 
assessments at 10 ±2 minutes, 1 hour ±5 minutes (Day -2) and at 24 hours ±10 minutes (Day -1) post 
irradiation.
7
Baseline irradiation for Irradiation Condition 3 will occur on Day -1 with baseline inflammatory 
responses assessed at 10 ±2 minutes, 1-hour ±5 minutes (Day -1) and at 24 hours ±10 minutes (Day 1) 
post Day -1 irradiation. 
8
Preliminary MED irradiation will be performed on Day -3 with confirming evaluation on Day -2.
9
Planned time relative to the drug administration


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TABLE OF CONTENTS
TITLE PAGE ...........................................................................................................................1
CLINICAL TRIAL PROTOCOL SYNOPSIS .....................................................................2
FLOW CHART TREATMENT A 400 MG QD ...................................................................5
FLOW CHART TREATMENT A 300 MG BID ..................................................................6
FLOW CHART TREATMENT B .........................................................................................8
TABLE OF CONTENTS ......................................................................................................10
ABBREVIATIONS................................................................................................................14
1.
INTRODUCTION...............................................................................................17
1.1
MEDICAL BACKGROUND.............................................................................17
1.2
DRUG PROFILE................................................................................................17
1.3
RATIONALE FOR PERFORMING THE TRIAL.........................................21
1.4
BENEFIT - RISK ASSESSMENT.....................................................................21
1.4.1
Benefits.................................................................................................................21
1.4.2
Risks .....................................................................................................................21
1.4.3
Discussion.............................................................................................................26
2.
TRIAL OBJECTIVES AND ENDPOINTS......................................................28
2.1
MAIN OBJECTIVES, PRIMARY AND SECONDARY ENDPOINTS........28
2.1.1
Main objectives....................................................................................................28
2.1.2
Primary endpoint(s)............................................................................................28
2.1.3
Secondary endpoint(s) ........................................................................................28
3.
DESCRIPTION OF DESIGN AND TRIAL POPULATION.........................31
3.1
OVERALL TRIAL DESIGN.............................................................................31
3.2
DISCUSSION OF TRIAL DESIGN, INCLUDING THE CHOICE OF 
CONTROL GROUP(S)......................................................................................32
3.3
SELECTION OF TRIAL POPULATION .......................................................33
3.3.1
Main diagnosis for trial entry ............................................................................34
3.3.2
Inclusion criteria .................................................................................................34
3.3.3
Exclusion criteria ................................................................................................35
3.3.4
Withdrawal of patients from treatment or assessments..................................36
3.3.4.1
Discontinuation of trial treatment .........................................................................36
3.3.4.2
Withdrawal of consent to trial participation .........................................................37
3.3.4.3
Discontinuation of the trial by the sponsor...........................................................37
4.
TREATMENTS...................................................................................................38


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4.1
INVESTIGATIONAL TREATMENTS ...........................................................38
4.1.1
Identity of the Investigational Medicinal Products..........................................38
4.1.2
Selection of doses in the trial and dose modifications......................................39
4.1.3
Method of assigning subjects to treatment groups ..........................................39
4.1.4
Drug assignment and administration of doses for each patient......................40
4.1.5
Blinding and procedures for unblinding...........................................................41
4.1.5.1
Blinding.................................................................................................................41
4.1.5.2
Unblinding and breaking the code ........................................................................42
4.1.6
Packaging, labelling, and re-supply...................................................................42
4.1.7
Storage conditions...............................................................................................42
4.1.8
Drug accountability.............................................................................................43
4.2
OTHER TREATMENTS, EMERGENCY PROCEDURES, 
RESTRICTIONS ................................................................................................43
4.2.1
Other treatments and emergency procedures..................................................43
4.2.2
Restrictions ..........................................................................................................43
4.2.2.1
Restrictions regarding concomitant treatment ......................................................43
4.2.2.2
Restrictions on diet and life style..........................................................................44
4.2.2.3
Contraception requirements..................................................................................44
4.3
TREATMENT COMPLIANCE........................................................................44
5.
ASSESSMENTS..................................................................................................45
5.1
ASSESSMENT OF PHOTOSENSITIVITY ....................................................45
5.2
ASSESSMENT OF SAFETY.............................................................................47
5.2.1
Physical examination ..........................................................................................47
5.2.2
Vital signs.............................................................................................................47
5.2.3
Safety laboratory parameters ............................................................................48
5.2.4
Electrocardiogram ..............................................................................................51
5.2.5
Other safety parameters.....................................................................................52
5.2.6
Assessment of adverse events.............................................................................52
5.2.6.1
Definitions of AEs ................................................................................................52
5.2.6.1.1
Adverse event........................................................................................................52
5.2.6.1.2
Serious adverse event............................................................................................52
5.2.6.1.3
AEs considered “Always Serious”........................................................................53
5.2.6.1.4
Adverse events of special interest.........................................................................53
5.2.6.1.5
Intensity (severity) of AEs....................................................................................54
5.2.6.1.6
Causal relationship of AEs....................................................................................54
5.2.6.2
Adverse event collection and reporting ................................................................55
5.2.6.2.1
AE Collection........................................................................................................55
5.2.6.2.2
AE reporting to the sponsor and timelines............................................................56
5.2.6.2.3
Pregnancy..............................................................................................................56
5.2.6.2.4
Exemptions to SAE reporting ...............................................................................56
5.3
DRUG CONCENTRATION MEASUREMENTS AND 
PHARMACOKINETICS...................................................................................56
5.3.1
Assessment of pharmacokinetics .......................................................................56


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5.3.2
Methods of sample collection .............................................................................57
5.4
ASSESSMENT OF BIOMARKER(S) ..............................................................58
5.5
BIOBANKING ....................................................................................................58
5.6
OTHER ASSESSMENTS...................................................................................58
5.7
APPROPRIATENESS OF MEASUREMENTS..............................................58
6.
INVESTIGATIONAL PLAN.............................................................................59
6.1
VISIT SCHEDULE.............................................................................................59
6.2
DETAILS OF TRIAL PROCEDURES AT SELECTED VISITS .................59
6.2.1
Screening and run-in period(s)..........................................................................59
6.2.2
Treatment period(s)............................................................................................60
6.2.3
Follow-up period and trial completion..............................................................61
7.
STATISTICAL METHODS AND DETERMINATION OF SAMPLE SIZE
...............................................................................................................................62
7.1
NULL AND ALTERNATIVE HYPOTHESES ...............................................62
7.2
PLANNED ANALYSES.....................................................................................63
7.2.1
General considerations .......................................................................................63
7.2.2
Primary endpoint analyses.................................................................................64
7.2.3
Secondary endpoint analyses .............................................................................64
7.2.5
Safety analyses.....................................................................................................65
7.2.6
Other Analyses ....................................................................................................66
7.2.7
Interim Analyses .................................................................................................66
7.3
HANDLING OF MISSING DATA ...................................................................66
7.4
RANDOMISATION ...........................................................................................66
7.5
DETERMINATION OF SAMPLE SIZE .........................................................67
8.
INFORMED CONSENT, TRIAL RECORDS, DATA PROTECTION, 
PUBLICATION POLICY, AND ADMINISTRATIVE STRUCTURE ........68
8.1
TRIAL APPROVAL, PATIENT INFORMATION, INFORMED 
CONSENT ...........................................................................................................68
8.2
DATA QUALITY ASSURANCE ......................................................................69
8.3
RECORDS...........................................................................................................69
8.3.1
Source documents ...............................................................................................69
8.3.2
Direct access to source data and documents.....................................................70
8.3.3
Storage period of records ...................................................................................70
8.4
EXPEDITED REPORTING OF ADVERSE EVENTS ..................................70
8.5
STATEMENT OF CONFIDENTIALITY AND PATIENT PRIVACY........71
8.5.1
Collection, storage and future use of biological samples and corresponding 
data.......................................................................................................................71
8.6
TRIAL MILESTONES.......................................................................................71
8.7
ADMINISTRATIVE STRUCTURE OF THE TRIAL ...................................72


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9.
REFERENCES....................................................................................................73
9.1
PUBLISHED REFERENCES............................................................................73
9.2
UNPUBLISHED REFERENCES......................................................................73
10.
APPENDICES.....................................................................................................74
10.1
RESTRICTED MEDICATION AND FOOD...................................................74
10.2
TIME SCHEDULE FOR PHARMACOKINETIC (PK) BLOOD 
SAMPLING.........................................................................................................75
11.
DESCRIPTION OF GLOBAL AMENDMENT(S) .........................................77
11.1
GLOBAL AMENDMENT 1 ..............................................................................77
11.2
GLOBAL AMENDMENT 2 ..............................................................................78


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ABBREVIATIONS
AE
Adverse Event
AESI
Adverse Event of Special Interest
ALCOA
Attributable, Legible, Contemporaneous, Original, Accurate 
ALT
Alanine Aminotransferase
AS
Ankylosing spondylitis
AST
Aspartate Aminotransferase
b.i.d.(BID)
bis in die (twice daily dosing)
BI
Boehringer Ingelheim
BP
Blood Pressure
CA
Competent Authority
CI
Confidence Interval
CRA
Clinical Research Associate
CRF
Case Report Form, paper or electronic (sometimes referred to as “eCRF”)
CRO
Contract Research Organisation
CT Leader
Clinical Trial Leader
CT Manager
Clinical Trial Manager
CTP
Clinical Trial Protocol
CTR
Clinical Trial Report
DBL
Database Lock
DDI
Drug Drug Interaction
DILI
Drug Induced Liver Injury
EC
Ethics Committee
ECG
Electrocardiogram
eCRF
Electronic Case Report Form
eDC
Electronic Data Capture
EoT
End of Treatment


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EoTrial
End of Trial
EudraCT
European Clinical Trials Database
FC
Flow Chart
FOT
Fully Outcourced Trial
FUP
Follow-up
GCP
Good Clinical Practice
GMP
Good Manufacturing Practice
HA
HIV
Health Authority
Human Immunodeficiency Virus
i.v.
intravenous
IB
Investigator’s Brochure
IC
Inhibitory Concentration
IEC
Independent Ethics Committee
IGRA
Interferon-Gamma-Release-Assay
INN
International Non-Proprietary Name
IRB
Institutional Review Board
IRT
Interactive Response Technology
ISF
Investigator Site File
IUD
Intrauterine Device
IUS
Intrauterine Hormone-Releasing System
LPLT
Last Patient Last Treatment
LPLV
MED
Last Patient Last Visit
Minimum Erythema Dose
MedDRA
Medical Dictionary for Drug Regulatory Activities
MRD
Multiple Rising Dose 
NOAEL
No Adverse Effect Level
OPU
Operative Unit
p.o.
per os (oral)
PK
Pharmacokinetics
PR
Puls Rate
PsA
Psoriatic Arthritis


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PsO
QD (q.d.)
Plaque Psoriasis
Once daily
REP
Residual Effect Period
s.c.
subcutaneous
SAE
Serious Adverse Event
SC
Steering Committee
SOP
Standard Operating Procedure
SRD
Single Rising Dose
SUSAR
Suspected Unexpected Serious Adverse Reactions
TMF
Trial Master File
ULN
Upper Level of Normal
WHO
World Health Organisation
WOCBP
Woman of childbearing potential


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1.
INTRODUCTION
1.1
MEDICAL BACKGROUND
Retinoic acid-related orphan receptor γt (ROR) γt is a nuclear hormone receptor/transcription 
factor expressed in Th17 cells and in distinct subsets of lymphoid cells including natural 
killer (NK) cells, innate lymphoid cells (ILCs), and T cells. Upon cell activation, in 
response to multiple activation signals including cytokines and T cell receptor engagement,
RORγt regulates the transcription of IL-17A, IL-17F, IL-22 genes, and of the IL-23 receptor 
gene. Emerging clinical science indicates a pivotal role for the Th17 axis in the pathogenesis 
of psoriasis (PsO) and other immunologically-mediated diseases. By blocking RORγt-
mediated transcription of pro-inflammatory cytokines and IL-23R, and consequently their 
downstream signaling, RORγt antagonism could prove efficacious in the treatment of Th17-
mediated diseases.
1.2
DRUG PROFILE
Boehringer Ingelheim (BI) is developing the new chemical entity (NCE), ROR γt antagonist
BI 730357, for the treatment of patients with plaque PsO, and other disease indications (e.g., 
psoriatic arthritis (PsA), ankylosing spondylitis (AS), axial spondyloarthritis (axSpA),
Crohn’s disease (CD), and non-alcoholic steatohepatitis (NASH).
Mode of action
BI 730357 binds in the ligand-binding domain (LBD) of ROR γt and inhibits co-activator 
peptide recruitment, thereby bloking the RORγt-mediated transcription of pro inflammatory 
cytokines, and of IL-23R.
Residual Effect Period
The Residual Effect Period (REP) of BI 730357 is 7 days. This is the period after the last 
dose with measurable drug levels and/or pharmacodynamic effects still likely to be present.
Data from non-clinical studies and toxicology studies
Relevant non-clinical pharmacology, PK, and toxicology study results are summarized 
below.
BI 730357 was profiled in cellular assays in primary human cells central to the pathogenesis 
underlying PsO, PsA, and axSpA. BI 730357 provided consistent potency across all stimuli, 


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cell types, and animal species tested, including in whole blood conditions. BI 730357 
provided substantial inhibition of disease-relevant biomarker and histology reads in 
mechanistic preclinical in vivo mouse models of inflammation. The anticipated human 
therapeutic exposure for BI 730357 was determined based on the effective plasma 
concentration required to reduce the tissue level of IL-17 by 80% in an IL-23 induced 
minicircle mouse model (c09228382 Current version, n00250111 Current version]. The data 
showed that 80% inhibition of tissue IL-17A mRNA at trough is required for maximal 
inhibition (>80%) of the histology endpoints. The trough exposure was normalized using the 
mouse whole blood IC50.
Translating to humans using human whole blood IC50, the required trough for maximum 
effect on histology endpoints for BI 730357 is 140 nM.
BI 730357 demonstrated good off-target selectivity; exhibited low-level inverse-agonism 
against RORα, low-level antagonism against hLXRα and low-level agonism activity against 
hPXR. No activity on RORβ was detected. No other off-target activities were detected.
The disposition of BI 730357 in rat, dog, and minipig is characterized by low clearance and 
moderate volume of distribution. Moderate-to-high oral bioavailability was observed across 
species. The plasma protein binding was high across all tested species (mouse, rat, dog, and 
human), and there was no preferential partitioning into red blood cells. Biliary excretion or 
fecal excretion was the major route of elimination of [14C]-BI 730357-derived radioactivity 
in rat and dog. In a quantitative whole body autoradiography study in pigmented rats, [14C]-
BI 730357-derived radioactivity was moderately distributed to tissues. Tissue-to-blood 
exposure ratios of radioactivity into melanin-containing tissues of the ocular bulb was 
moderate to high.
In human hepatocyte incubations, approximately 90% of the metabolism of BI 730357 occurs 
via oxidation by CYP3A4 to an N-oxide metabolite (CD 6975). As such, concomitant 
medications that are inhibitors or inducers of CYP3A may cause clinically significant 
changes in BI 730357 exposure. Furthermore, data from in vitro studies indicate that 
BI 730357 may cause clinically relevant induction of CYP1A2 and CYP2B6 and inhibition 
of hepatic P-glycoprotein (P-gp) and renal MATE1 or MATE2-K. In addition, inhibition of 
intestinal BCRP in humans is also possible at oral BI 730357 doses > 22 mg.
The toxicity profile of BI 730357 has been assessed in safety pharmacology, genetic toxicity, 
embryo-fetal development, and repeat dose toxicity studies up to 26- and 39-weeks in rat and 
dog, respectively. In general, BI 730357 appears to be well tolerated at clinically-relevant 
plasma exposure in toxicity studies. BI 730357 revealed no evidence of teratogenicity in 
embryo-fetal development studies in rats and rabbits. In the repeat dose studies up to 26- and
39-weeks in rats and dogs, there were no effects on male or female reproductive organs. 
BI 730357 is considered non-genotoxic. Based on long half-lives of radioactivity in dermal 
tissues and results from an in vitro and in vivo phototoxicity assay, BI 730357 has 
phototoxicity potential.
In summary, non-clinical BI 730357 safety data demonstrated an acceptable profile to 
support clinical trials in males and females, including women of childbearing potential


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(WoCBP). Human exposures up to those achieved at the no observed adverse effect level
(NOAEL) of 5 mg/kg/day in the 4- and 13- weeks dog studies (Cmax 6,660 nM, and AUC0-24
127,400 nM•h in males and females combined) are considered safe for dosing up to 13 weeks 
in clinical trials. For clinical trials that exceed 13 weeks duration, human exposures up to 
those achieved at the NOAEL of 1 mg/kg/day in the 39-weeks dog study (Cmax 1210 nM, and 
AUC0-24 22,100 nM•h in males and females combined) are considered safe.
The nonclinical safety package supports long-term administration of BI 730357 to human 
subjects, including WoCBP.
Data from clinical trials
Two clinical trials have been performed in healthy volunteers.
66 male adult subjects receiving BI 730357 in the Single Rising Dose study 1407.1. 
Safety evaluations included physical examination, vital signs, ECG, laboratory tests, and 
adverse events (AEs). AEs, which generally reflected commonly-occurring events of short 
duration, and were mostly mild or moderate in severity, were distributed without discernible 
trend among recipients of placebo and rising dose levels of BI 730357. No serious AEs
(SAEs) were reported.
Phase Ib trial 1407-0002 evaluated MRD of BI 730357 ranging from 25 mg to 400 mg, 
administered as film-coated tablets to healthy male adult subjects aged 18 to 45 years.
83 subjects entered into the trial; each group of 12 subjects was randomized (9 active: 3 
placebo) into one of 4 sequential dose groups under fasting conditions (25 mg, 50 mg, 100 
mg, 200 mg), and into one of 3 sequential dose groups under fed conditions (50 mg, 200 mg, 
and 400 mg). Comparison of the mean BI 730357 plasma concentrations indicated that 
exposure was related to dose, such that exposures increased with increasing dose. When BI 
730357 was administered to subjects in the fed state, higher
BI 730357 plasma levels and exposures were observed, with a delayed peak in concentrations 
compared to fasted conditions. Median tmax values ranged from 1.00 to 2.75 h in the fasted 
state and increased to 2.55 to 4.00 h in the fed state. Concentrations following multiple 
dosing appeared to be approximately double those following a single dose, with no relevant 
difference seen between 2 and 4 week profiles. Subjects were evaluated for safety (physical 
examination, ECG and laboratory studies, AEs, and SAEs) and PK during once daily study 
drug treatment for 14 days (dose groups up to 100 mg) or 28 days (200 mg and 400 mg dose 
groups), and for approximately one week after completion of treatment. Safety data indicate 
that with respect to the kind, incidence and severity of the AEs, there were no notable 
differences among dose groups. The most frequently reported AEs were headache in 26.5% 
and diarrhea in 10.8% of subjects, of subjects across BI 730357 dose groups. No SAEs were
reported during the trial. ECG recordings, clinical laboratory evaluation, and vital signs 
showed no clinically-relevant changes compared to baseline. Overall, administration of BI 
730357 to healthy male subjects at doses up to 400 mg for up to 28 days was well tolerated.


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A phase II trial (1407-0030) in patients with moderate-to-severe chronic plaque psoriasis is 
ongoing, 178 patients were included and randomized in a blinded manne to receive 25 mg, 50 
mg, 100 mg, or 200 mg of BI 730357, or placebo, q.d., under fasted conditions, for 24 weeks. 
Primary analysis data from trial 1407-0030 demonstrate that PsO patients had higher 
exposure (up to 2.1 fold) compared to those of healthy volunteers in 1407-0002. Moreover, 
the exposures in PsO patients appear to be increasing with increasing dose, up to the highest 
(200 mg) dose evaluated, in a close to dose- proportional manner.
Administration of BI 730357 to patients with moderate-to-severe plaque PsO at doses up to 
200 mg for at least 12 weeks has been well tolerated. Through Week 12, the overall 
frequency of patients with at least 1 treatment emergent adverse events (TEAE) was 50.6% 
for patients receiving BI 730357 (range 47.5% to 53.8%, vs. 55.0% of placebo recipients). 
The most commonly reported AEs, by preferred term, were “upper respiratory tract infection” 
(10.1%, range 2.5% to 15.4%, vs. 15.0% among placebo recipients), “nasopharyngitis” 
(6.3%, range 5.0% to 7.7%, vs. 0% among placebo recipients), and “headache” (3.2%, range 
0% to 5.1%, vs. 0% among placebo recipients). ECG recordings, laboratories, and vital signs 
showed no clinically-relevant changes compared to baseline.
The non-clinical BI 730357 safety data together with the safety data from the two trials in 
healthy volunteers (HV) and patients in plaque psoriasis demonstrated an acceptable profile 
to support clinical trials in males and females, including WoCBP. These data justify the oral 
dose of 400 mg BI 730357, taken once daily and 300 mg BI 730357 taken twice daily, over 8
days in healthy male and female volunteers. It is anticipated that higher mean BI 730357 
exposures as expected with 300 mg dosed b.i.d. under fed conditions for 8 days will not 
exceed the NOAEL thresholds observed in 13 weeks general toxicity studies.
For a more detailed description of the profile of BI 730357 please refer to the current
Investigator’s Brochure (IB) (c09228382).
Ciprofloxacin
CIPRO is a fluoroquinolone antibacterial indicated to treat or prevent infections that are 
proven or strongly suspected to be caused by bacteria.
The absolute bioavailability of ciprofloxacin when given as an oral tablet is approximately 
70% with no substantial loss by first pass metabolism. 
Maximum serum concentrations are attained 1 to 2 hours after oral dosing. Steady-state Cmax
and AUC of Ciprofloxacin following administration of multiple oral doses to healthy subjects 
are 2.97 and 13.7 mcg•hr/mL respectively. When CIPRO Tablet is given concomitantly with 
food, there is a delay in the absorption of the drug, resulting in peak concentrations that occur 
closer to 2 hours after dosing rather than 1 hour.
For a more detailed description of the profile of Ciprofloxacin please refer to the
ciprofloxacin hydrochloride tablet U.S. prescribing information (R19-2246 and R19-3127).


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1.3
RATIONALE FOR PERFORMING THE TRIAL
BI 730357 is being developed for the treatment of patients with moderate-to-severe PsO, and 
other disease indications (e.g., psoriatic arthritis (PsA) axSpA, CD, and NASH) where there 
remains an unmet medical need.
Preclinical data indicate that BI 730357 has phototoxicity potential. 
The current trial is being performed to assess the photosafety of BI 730357 compared to 
placebo and the known photosensitizing agent ciprofloxacin in healthy volunteers.
Safety data provided by this trial will support further clinical development program of BI 
730357 in patients with diverse indications. 
1.4
BENEFIT - RISK ASSESSMENT
1.4.1
Benefits
Participation in this trial is without any (therapeutic) benefit for healthy subjects. Their 
participation in the trial, however, is of major importance to the development of BI 730357
and may help to generate future benefit for larger groups of patients with many disease 
indications.
1.4.2
Risks
The subjects are exposed to the risks related to the exposure to the trial medication and the 
risks of the trial procedures. 
Drug-related risks and safety measures
BI 730357 
The pharmacological effects of BI 730357 are dose dependent, and no evidence for prolonged 
or irreversible effects has been observed. 
As described in Section 1.2, the non-clinical BI 730357 safety data together with the safety 
data from trials in healthy volunteers (HV) and patients with plaque PsO demonstrated an 
acceptable profile to support clinical trials in males and females, including WoCBP.
Since preclinical data indicate that BI 730357 has phototoxicity potential, subjects in this trial 
will be kept in the clinic on all dosing days up until completion of photosensitivity 
assessments 72 hours after last dose and not allowed to expose themselves to the direct 
sunlight. Additionally, subjects will be advised to apply protection measures up to the end of
trial visit, as described in section 4.2.2.2 .


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Preclinical data indicate that BI 730357 has DDI potential. During the trial, drugs or foods 
which are known strong or moderate inhibitors or inducers of CYP3A4, or drugs which are 
sensitive substrates of CYP1A2 or CYP2B6 will be prohibited. Additionally, substrates of 
P-gp are also to be excluded during the trial BI 730357 is confirmed as a sensitive 
cytochrome P450 (CYP) 3A substrate, based on clinical drug-drug interaction (DDI) 
evaluation with itraconazole, a CYP3A inhibitor, in trial 1407-0014. Drugs or foods that are 
known CYP3A inhibitors or strong or moderate CYP3A inducers should not be co-
administered in clinical trials with BI 730357. Based on in vitro data, BI 730357 could 
potentially induce CYPs 1A2, 2B6, 2C8, 2C9, or 2C19 in human. Substrates of CYPs 1A2, 
2B6, 2C8, 2C9, or 2C19 for which a reduction in exposure could present a potential patient 
risk should not be given together with BI 730357. Additionally, based on in vitro data, BI 
730357 may inhibit a number of transporters in human; based on the magnitudes of the in 
vitro inhibition, it is recommended that sensitive substrates of P-gp, BCRP, OATP1B1, 
OATP1B3, OAT3, OCT2, MATE1, and MATE2-K that have narrow therapeutic windows 
should be avoided (refer to Appendix 10.1).
As with other immune-targeted therapies, impaired host defence is a theoretical target-related 
toxicity, potentially resulting in increased risk of infection and/or malignancy. Subjects with 
latent TB infection or TB disease, also subjects with HBV, HCV, HIV or any other clinically 
relevant bacterial or fungal infections will be excluded at screening. 
Risk to subjects will also be minimized in this trial by implementing conservative eligibility 
criteria. 
Homozygous, but not heterozygous RORC knockout mice have a high incidence of T cell 
lymphoma, thought to originate in the Thymus. While the translatability of the knockout 
phenotype to pharmacological RORγ antagonism and to humans is unknown, this raises the 
hypothetical concern for clinical T cell lymphoma risk. The exact cause of T cell lymphomas 
in RORC knockout mice is not fully understood, but changes in homeostasis in the thymus, 
such as thymocyte apoptosis and proliferation, are thought to play a role. AEs and SAEs 
consistent with malignancy, and specifically those representing lymphoma, will be carefully 
monitored and evaluated as well as monitoring of peripheral blood lymphocyte subsets will 
be integrated into this clinical trial.
An in vivo phototoxicity study in rats was conducted in pigmented rats. No cutaneous 
reactions indicative of phototoxic response were seen at 10 mg/kg/day, which corresponded 
to mean Cmax and AUC0-24 values of 4,520 nM and 35,200 nM•h, respectively. No ophthalmic 
changes indicative of phototoxicity were seen up to 30 mg/kg/day, which corresponded to a 
mean Cmax and AUC0-24 values of 13,500 nM and 107,000  nM•h, respectively.
Dose 400 mg BI 730357 planned to be tested in this study was administered once daily over a 
period of 4 weeks in the MRD study 1407-0002. The pharmacokinetic parameters observed 
in this study - AUC0-24 [nmol*h/L] 15,600 (AUCτ,ss [nmol*h/L] 35,500) and Cmax [nmol/L] 
1320 (Cmax,ss [nmol/L] 2210) indicate that the plasma concentrations and exposures, which 
might be achieved in this study, are lower than those observed in in vivo phototoxicity study 
in rat where the phototoxic responses have been seen.


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Ciprofloxacin
The most frequently reported adverse reactions, from clinical trials of all formulations, all 
dosages, all drug therapy durations, and for all indications of ciprofloxacin therapy were 
nausea (2.5%), diarrhoea (1.6%), liver function tests abnormal (1.3%), vomiting (1%), and 
rash (1%).
Changes in laboratory parameters while on CIPRO are listed below:
Hepatic -Elevations of ALT (SGPT), AST (SGOT), alkaline phosphatase, LDH, serum 
bilirubin.
Hematologic-Eosinophilia, leukopenia, decreased blood platelets, elevated blood platelets, 
pancytopenia.
Renal-Elevations of serum creatinine, BUN, crystalluria, cylindruria, and hematuria have 
been reported.
Other changes occurring were: elevation of serum gammaglutamyl transferase, elevation of 
serum amylase, reduction in blood glucose, elevated uric acid, decrease in hemoglobin, 
anemia, bleeding diathesis, increase in blood monocytes, and leucocytosis.
Fluoroquinolones, including CIPRO, have been associated with disabling and potentially 
irreversible serious adverse reactions from different body systems that can occur together in 
the same patient. These adverse reactions include:

Tendinitis and Tendon Rupture 

Peripheral Neuropathy 

Central Nervous System Effects 

Exacerbation of Myasthenia Gravis 

Other Serious and Sometimes Fatal Adverse Reactions 

Hypersensitivity Reactions 

Hepatotoxicity 

Serious Adverse Reactions with Concomitant Theophylline 

Clostridium difficile Associated Diarrhea 

Prolongation of the QT Interval 

Musculoskeletal Disorders in Pediatric Patients 

Photosensitivity/Phototoxicity 

Development of Drug Resistant Bacteria 
These reactions can occur within hours to weeks after starting CIPRO. Patients of any age or 
without pre-existing risk factors have experienced these adverse reactions. These events may 
be severe and generally occur following the administration of multiple doses.


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As with all drugs, the potential for hypersensitivity and allergic reactions has to be taken into 
consideration.
Although rare, a potential for drug-induced liver injury (DILI) is 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 patients´ 
safety (see also section 5.2.6.1.4).
Special precautions
The following safety measures will be applied in order to minimize the risk for healthy 
volunteers:

Dose selection is based on a sound preclinical package, and safety, tolerability and PK 
data from MRD administration of BI 730357 up to 400 mg in healthy volunteers and 
preliminary safety data for up to 200 mg in patients with plaque psoriasis.

Dose duration of 500 mg of ciprofloxacin bid over 5.5 days is a standard, well 
tolerated clinical dose 

Individual stopping rules as described in section 3.3.4.1 will be applied.

UV-light protection measures as described in section 4.2.2.2 will be required until the
end of study visit.

The subjects will be kept in a Phase I unit during trial medication administration until 
completion of photosensitivity assessments 72 hours after last dose for safety
evaluations. A careful clinical examinations will be performed during the trial, before 
the subjects are discharged from the clinic, and at the end of trial visit.

Adverse events, body temperature, vital signs, ECGs and safety laboratories will be 
monitored at different time points during the trial. During the safety follow-up period 
all AEs, regardless of relatedness, will be collected up to 7 days after the last 
administration of trial medication.
Procedure-related risks
Blood sampling by venepuncture or through an indwelling venous catheter 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 paraesthesia, reduced sensibility, and/or pain for an indefinite 
period. 
The total volume of blood withdrawn per subject during this trial will not exceed the volume 
of a normal blood donation (500 mL). No health-related risk is expected from this blood 
withdrawal.


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Based on the findings in the nonclinical studies conducted to date and in accordance with 
international regulatory guidelines, the inclusion of women of childbearing potential 
(WoCBP) in this study is justified. To minimize the risk of unintentional exposure of an 
embryo or foetus to the investigational drug, WoCBP must agree to the requirements for
pregnancy testing and contraceptive methods described in this protocol. There are no specific 
contraceptive requirements for male participants.
Potential risks of clinical 
relevance for this trial
Summary of data, 
rationale for the risk
Mitigation strategy
Investigational Medicinal Products:

Drug-induced liver 
injury (DILI)

Rare but severe 
event, thus under 
constant surveillance 
by Sponsors and 
regulators.

Timely detection, 
evaluation, and follow-up of 
laboratory alterations in 
selected liver laboratory 
parameters to ensure 
patients´ safety.

Drug interruption or 
discontinuation if 
applicable.

Infection and/or 
malignancy 

Impaired host 
defence typical for 
immune-targeted 
therapies

Subjects with latent TB 
infection or TB disease at 
screening will be excluded.

Patients with HBV, HCV or 
HIV infection will be 
excluded. 

AEs and serious adverse 
events (SAEs) consistent 
with malignancy or
infections are to be 
evaluated. 

Phototoxicity potential

Long persistence of 
BI 730357 in dermal 
tissues.

Known phototoxicity 
potential of 
Ciprofloxacin

Apply protection measures 
such as sunscreen and 
sunglasses during therapy
and up to 7 days after last 
drug exposure. Prohibition 
of treatment with ultraviolet 
light or medications with
known phototoxicity 
potential up to 7 days after 
last drug exposure.


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Potential risks of clinical 
relevance for this trial
Summary of data, 
rationale for the risk
Mitigation strategy
Investigational Medicinal Products:

Hypersensitivity

General precautions

Subjects with known 
hypersensitivity to 
investigational drugs will be 
excluded at screening.

Discontinue investigational 
drugs immediately at the 
first appearance of a skin 
rash, jaundice, or any other 
sign of hypersensitivity and 
supportive measures 
instituted.

Prolongation of the QT 
Interval 

Known potential of 
Ciprofloxacin

Subjects with known 
prolongation of the QT 
interval, risk factors for QT 
prolongation or torsade de 
pointes will be excluded at 
screening.
Trial procedures

Inflammation of the wall 
of the vein. Injuring of a 
nerve while inserting the 
venous catheter, 
potentially resulting in 
paraesthesia, reduced 
sensibility, and/or pain 
for an indefinite period. 

General risk, 
acceptable in frame 
of the study 
participation

Evaluation of the medical 
expertise of the trial sites is 
part of site feasibility 
assessment
1.4.3
Discussion
The nature of the target and the mechanism of action of BI 730357 as well as of 
Ciprofloxacin are well understood.
In the context of the unmet medical need and anticipated benefit of BI 730357, the benefit-
risk evaluation of the compounds, based upon preclinical and clinical information available to 
date, is considered favourable and healthy subjects in this trial will not be exposed to undue 


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safety risks in relation to the important information expected from this trial as a basis for 
further clinical development of BI 730357. 
Considering the medical need of the development of a better tolerated and more effective oral 
treatment for patients with PsO and other Th17-mediated diseases, the Sponsor considers that 
the benefit outweighs the potential risks and justifies exposure of healthy human volunteers.


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2.
TRIAL OBJECTIVES AND ENDPOINTS
2.1
MAIN OBJECTIVES, PRIMARY AND SECONDARY ENDPOINTS
2.1.1
Main objectives
The main objective of this trial is to evaluate the photosensitivity potential of BI 730357.
All endpoints are applicable for both treatment parts.
2.1.2
Primary endpoint(s)
The primary endpoints are:

Phototoxicity index at 24 h under condition 1

Phototoxicity index at 24 h under condition 2
Where condition 1 is full range solar UVB/UVA exposures and Condition 2 is UVA exposure 
only.  Refer to Section 5.1 for the details of photosensitivity assessments and these 
conditions.
Refer to Section 7.2.2 for the endpoint definitions
2.1.3
Secondary endpoint(s)

Phototoxicity index at 10 min under condition 1

Phototoxicity index at 1 h under condition 1

Phototoxicity index at 10 min under condition 2 

Phototoxicity index at 1 h under condition 2 

MED percent change from baseline at 10min, 1h, and 24h measured under condition 1 
and condition 2
Where conditions 1 and 2 are described above in Section 2.1.2.
Refer to Section 7.2.3 for the endpoint definitions.


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3.
DESCRIPTION OF DESIGN AND TRIAL POPULATION
3.1
OVERALL TRIAL DESIGN 
The trial will be performed as partially-blind, randomized, parallel group, placebo and active 
comparator controlled Phase I clinical trial in healthy male and female subjects aged 18 to 
55 years in order to evaluate the photosensitivity potential of BI 730357 compared to 
placebo and active comparator, and to assess the relationship between the photosensitivity 
response and pharmacokinetics of the BI 730357. The subjects will be randomized to one of 
the two treatments parts (Treatment Part A or Treatment Part B).
In total, approximately 84 healthy male and female subjects (36 subjects each dose group in 
Treatment A; 12 subjects in Treatment B) are planned to be randomized in this trial to allow 
for at least 74 completed subjects.
Treatment A will be conducted according to a randomized, double blind, placebo-controlled 
design to assess the photosensitivity potential, safety and tolerability, and pharmacokinetics 
of multiple doses of BI 730357. Subjects will be randomized in a 3:1 manner to receive BI 
730357 or placebo.
Subjects will receive 400mg of BI 730357 or placebo once daily over 8 days, or 300 mg of BI 
730357 or placebo twice daily over 7 days with a single dose on day 8, in order to reach 
pharmacokinetic steady state;  
Light exposure will occur 2 hours (+/-10 min) after the last dose of either IP or placebo, and 
on-treatment photosensitivity assessments (determination of MEDOn drug and evaluation of 
erythema/local skin reactions) will be performed at 10 minutes, and 1, 24, 48, and 72 hours 
after irradiation.
Treatment B will be conducted according to an open-label, observer-blinded design to assess 
the photosensitivity potential of ciprofloxacin (a mild photosensitizer) as a positive control.
Subjects will receive 500 mg ciprofloxacin starting on the morning of Day 3. Twelve (12) 
hours later, subjects received their second dose of 500 mg ciprofloxacin. Subjects continued a 
twice-daily dosing regimen through to the morning of Day 8 to ensure they reached 
pharmacokinetic steady state. 
Light exposure will occur on Day 8 at 2 hours (+/-10 min) post-dose, and on-treatment 
photosensitivity assessments (determination of MEDOn drug and evaluation of erythema/local 
skin reactions) were performed at 10 minutes, and 1, 24, 48, and 72 hours after irradiation.
This trial will have a screening period of up to 28 days including preliminary photosensitivity 
assessment on Day -3. Eligible subjects will undergo base line photosensitivity assessment 
starting after irradiation on day -2 10 min, 1h, 24 hours after irradiation, and will be admitted 
to the clinical site on Day -1.


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Subjects confirmed eligible will be dosed on Day 1 and be resident until the Day 11. All 
subjects will remain in the clinic until day 11. The subject will then return to the clinic for 
ambulatory visit approx. 7 days after the last drug administration for safety follow up (e.o.t.).
Additionally, all AEs, regardless of relatedness, will be collected until 7 days after the 
administration of trial medication. Adverse events not fully resolved at the End of Trial visit 
will be followed until recovery or in case of persistency, sufficient characterization has been 
achieved and the investigator and medical monitor agree to not pursue them further.
For details for treatments to be administered refer to Section 4.1.
An overview of all relevant trial activities is provided in Flow Chart. For visit schedule and 
details of trial procedures at selected visits, refer to Section 6.1 and Section 6.2, respectively.
3.2
DISCUSSION OF TRIAL DESIGN, INCLUDING THE CHOICE OF 
CONTROL GROUP(S)
This is an approximately 8 weeks Phase I trial in healthy volunteers consisting of the two 
treatment parts.
The design of this clinical photosensitivity study followed the general concepts of ICH S10 (a 
recently published international guideline on “Photosafety Evaluation of Pharmaceuticals”), 
and included ciprofloxacin as a positive control (R19-2247). 
Three distinct exposure conditions were included to account for seasonal and regional 
differences in human exposure to sunlight.
A two-layer randomization process will be employed:
Allocation to the Study part: Subjects will be randomly allocated to part A or part B in a 3:1 
ratio in an open-label manner. Randomization numbers defining subject allocation to study 
part will be assigned in ascending, sequential order to eligible subjects.
Treatment Part A will be conducted according to a randomized, double blind, placebo-
controlled design. 
It is standard in trials involving healthy volunteers to include a placebo group as control for 
the evaluation of safety. Treatment Part A group will consist of 36 subjects in 400 mg QD 
group and 36 subjects in 300 mg BID group, with each group having 27 on active treatment 
and 9 on placebo.
The treatment will be blinded throughout the whole trial, to minimize any bias that could be 
introduced by knowledge of the treatment by either the investigator or the subject.
Treatment Part B will be conducted according to an open-label, observer-blinded design to 
assess the photosensitivity potential of ciprofloxacin (a mild photosensitizer) as a positive 
control.


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12 subjects will receive 500 mg ciprofloxacin b.i.d. over 5 days with a single dose on the 6th
day.
The open-label treatment is not expected to bias the photosafety results, since the trial
endpoints derived from the photosensitivity assessments will be provided by an observer
performing skin evaluations which is blinded to treatment allocation.
3.3
SELECTION OF TRIAL POPULATION
It is planned that in total up to 84 healthy male and female subjects will enter the trial. 
Subjects who prematurely discontinue the trial due to any reason may be replaced to ensure 
sufficient number complete the trial. Thus the planned number of subjects entered may 
exceed a total of 84. They will be recruited from the volunteers’ 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 Investigator Site File (ISF) irrespective of whether they have been treated 
with investigational drug or not.
If a subjects is enrolled in error (does not meet all inclusion criteria or meets one or more 
exclusion criteria on the day of enrolment), the sponsor should be contacted immediately.


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3.3.1
Main diagnosis for trial entry
The trial will be performed in healthy male and female subjects.
Please refer to section 8.3.1 (Source Documents) for the documentation requirements 
pertaining to the in- and exclusion criteria.
3.3.2
Inclusion criteria
1. Healthy male and female subjects according to the assessment of the Investigator, based 
on a complete medical history, physical examination (including dermatological skin type 
assessment), vital signs (blood pressure, pulse rate), 12-lead ECG, and clinical laboratory 
tests
2. 18 to 55 years old
3. BMI 18 to 35 kg/m (incl.)
4. Fitzpatrick skin type I, II, or III:
-
I Always burns easily, never tans
-
II Always burns easily, tans minimally
-
III Burns moderately, tans gradually
5. No ultraviolet exposure of the test areas 4 weeks prior to baseline photo testing
6. Normal skin response during preliminary photo testing.
7. Signed and dated written informed consent in accordance with ICH-GCP and local 
legislation prior to admission to the trial.
8. 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 patient information
                                                
1 A woman is considered of childbearing potential (WOCBP), i.e. fertile, following menarche and until becoming post-
menopausal unless permanently sterile. 
Permanent sterilisation methods include hysterectomy, bilateral salpingectomy and bilateral oophorectomy.
Tubal ligation is NOT a method of permanent sterilisation.
A postmenopausal state is defined as no menses for 12 months without an alternative medical cause.


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3.3.3
Exclusion criteria
1. Any finding in the medical examination (including blood pressure, pulse rate or ECG)
deviating from normal and judged as clinically relevant by the Investigator.
2. Any laboratory value outside the reference range that the Investigator considers to be of
clinical relevance.
3. Gastrointestinal, hepatic, renal, respiratory, cardiovascular, metabolic, immunological or 
hormonal disorders or any evidence of a concomitant disease judged as clinically relevant 
by the Investigator.
4. Major surgery (major according to the investigator’s assessment) performed within 10
weeks prior to randomisation or planned within 2 months after screening.
5. 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 or in situ 
carcinoma of uterine cervix.
6. Active skin disorders on the back where photosensitivity testing will be performed.
7. Subjects who must or wish to continue the intake of restricted medications (see section 
4.2.2.1) or any drug considered likely to interfere with the safe conduct of the trial.
8. Subjects not expected to comply with the protocol requirements or not expected to 
complete the trial as scheduled (e.g. chronic alcohol or drug abuse or any other condition 
that, in the investigator’s opinion, makes the subject an unreliable trial participant).
9. Currently enrolled in another investigational device or drug trial, or less than 30 days (or 
5 half-lives (whichever longer)) since ending another investigational drug trial.
10. Women who are pregnant, nursing, or who plan to become pregnant while in the trial.
11. History of relevant allergy or hypersensitivity (including allergy to the trial medication or
its excipients).
12. History of hypersensitivity to ciprofloxacin, any member of the quinolone class of 
antibacterials.
13. History of hypersensitivity to sunlight or artificial source of intense light, especially UV 
light.
14. Chronic or acute infections which are of relevance in the opinion of the Investigator.
15. Positive result for HIV, HBV, and hepatitis C (Hep C) at screening.
16. History of TB or positive finding in IGRA.
17. Unwillingness/inability to refrain from intake of alcoholic beverages from 48 hours prior 
to the trial medication administration and until Day 7 post trial medication administration.
18. Positive drug screening.
19. Blood donation of more than 500 mL within 30 days prior to administration of trial 
medication or intended donation during the trial.
20. Intention to perform excessive physical activities within 4 days prior to administration of 
trial medication or contact sport during the entire trial and unwilling to avoid vigorous 
exercise for 7 days post dosing.


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21. Inability to comply with dietary regimen of trial site.
22. Unwillingness to adhere to the rules of UV-light protection as described in section 4.2.2.
23. Received a live vaccination within 12 weeks prior to randomisation (visit 2), or any plan 
to receive a live vaccination during the conduct of this trial.
24. Subjects with known prolongation of the QT interval, risk factors for QT prolongation or 
torsade de pointes.
3.3.4
Withdrawal of patients 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 below.
Every effort should be made to keep the subjects in the trial: if possible on treatment, or at 
least to collect important trial data.
Measures to control the withdrawal rate include careful subjects’ selection, appropriate 
explanation of the trial requirements and procedures prior to trial enrolment, as well as the
explanation of the consequences of withdrawal. 
The decision to discontinue trial treatment or withdraw consent to trial participation and the 
reason must be documented in the subject files and CRF. If applicable, consider the 
requirements for Adverse Event collection reporting (please see sections 5.2.6.2.1 and 
5.2.6.2).
3.3.4.1
Discontinuation of trial treatment
An individual subject will discontinue trial treatment if:

The subject wants to discontinue trial treatment, without the need to justify the decision.

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.

The subject needs to take concomitant medication that interferes with the investigational 
medicinal product or other trial treatment listed in section 4.2.2 and appendix 10.1

The subject can no longer receive trial treatment for medical reasons (such as surgery, 
adverse events, other diseases, or pregnancy).

During the course of treatment the subject experiences any clinically significant adverse 
event (including laboratory abnormalities). The physician may discontinue subjects at any 
time based on his or her clinical judgment.
If new efficacy/safety information becomes available, Boehringer Ingelheim will review the
benefit-risk-assessment and, if needed, discontinue the trial treatment for all subjects or take 
any other appropriate action to guarantee the safety of the trial participants. 


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Even if the trial treatment is discontinued, the subjects remain in the trial and, given their
agreement, will undergo the procedures for early treatment discontinuation and follow-up as 
outlined in the Flow Chart and section 6.2.3.
For all participants, the reason for withdrawal from trial treatment (e.g., AE) must be 
recorded in the CRF. These data will be included in the trial database and reported. 
In case some subjects do not complete the trial, the clinical trial lead together with the clinical 
project lead and the trial statistician will decide if and how many subjects will be replaced. A 
replacement subject will be assigned to the same treatment as the subject he/she replaces.
3.3.4.2
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 continued 
follow-up after trial treatment discontinuation, please see section 3.3.4.1 above.
3.3.4.3
Discontinuation of the trial by the sponsor
Boehringer Ingelheim reserves the right to discontinue the trial overall or at a particular trial
site at any time for the following reasons:
1. Failure to meet expected enrolment goals overall or at a particular trial site.
2. Emergence of any efficacy/safety information invalidating the earlier positive benefit-
risk-assessment that could significantly affect the continuation of the trial.
3. Deviations from GCP, the trial protocol, or the contract impairing the appropriate conduct 
of the trial.
Further follow up of subjects affected will occur as described in section 6.2.3.
The investigator / the trial site will be reimbursed for reasonable expenses incurred in case of 
trial termination (except in case of the third reason).


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4.
TREATMENTS
4.1
INVESTIGATIONAL TREATMENTS
BI 730357, Placebo to match BI 730357.
Ciprofloxacin.
4.1.1
Identity of the Investigational Medicinal Products
Table 4.1.1:1 Test product 1
Substance:
BI 730357
Pharmaceutical formulation:
Film-coated tablet
Source:
Boehringer Ingelheim Pharma GmbH & Co KG
Unit strength:
100 mg
Posology:
QD over 8 days, or
BID over 7 days with a single dose on day 8
Method and route of administration:
Per os
Table 4.1.1:2 Test product 2
Substance:
Placebo to match BI 730357
Pharmaceutical formulation:
Film-coated tablet
Source:
Boehringer Ingelheim Pharma GmbH & Co KG
Unit strength:
NA
Posology:
QD over 8 days, or 
BID over 7 days with a single dose on day 8
Method and route of administration:
Per os


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Table 4.1.1:3 Comparator drug
Substance:
Ciprofloxacin
Pharmaceutical formulation:
Film-coated tablet
Source:
Unit strength:
500 mg 
Posology:
BID over 5 days from day 3 with a single dose on 
day 8
Mode of administration:
Per os
4.1.2
Selection of doses in the trial and dose modifications
The dose of 400 mg BI 730357 QD or 300 mg BID for this trial are selected on the basis of 
the PK and safety data obtained in the SRD and MRD trials 1407.0001 and 1407-0002, 
preliminary PK and safety data obtained in patients with plaque psoriasis in the ongoing 
1407.30 study, combined with the preclinical data (see section 1.1), are intended to cover the 
highest therapeutic dose range (including safety margin) chosen for the future clinical 
development of BI 730357 in diverse indications.
In the SRD trial, single dose levels up to 800 mg and in the MRD trial, multiple dose levels 
up to 400 mg were well tolerated in healthy volunteers, and doses up to 200mg were well 
tolerated in plaque psoriasis patients.
Blinded photosafety data will be evaluated by the independent Investigator and BI medical 
team after completion of the 400 mg BI 730357 or placebo QD treatment.
If no photo-safety concerns have been observed in the Treatment A group,300 mg BI 730357 
or placebo BID will be conducted. 
The Ciprofloxacin dose selected in this trial reflects the standard clinical dose with acceptable
safety profile. Ciprofloxacin was chosen as the positive control based on its property as mild 
photosensitizer (R 19-2246, R 19-3127).
4.1.3
Method of assigning subjects to treatment groups
After the assessment of all in- and exclusion criteria, each eligible subject will be first 
randomly allocated to part A 400 mg QD or part B in a 3 : 1 ratio, where Part A is initially set 
of patients who will either receive BI 730357 400mg QD or placebo. 
Randomization list for this first step randomization process will be provided by BI to the 
dedicated staff.


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Consequently, subjects allocated to the treatment Part A will be randomised according to a 
randomisation plan in a 3:1 ratio following the double blind design, which reflects the ratio of 
subjects receiving BI 730357 to placebo on Day 1.
Additionally, 12 subjects allocated to the treatment Part B will be assigned to receive 
Ciprofloxacin treatment.
A second set of 36 patients will be enrolled to either receive BI 730357 300mg BID or 
placebo.  These patients will be randomized using the same double blind design and 
procedures as described for Part A above (for BI 730357 400mg QD or placebo) and 
randomized in a 3:1 ratio to BI 730357 300mg BID or placebo. Randomization list for this set 
of patients will also be provided by BI to the dedicated staff.
The appropriate medication number will be assigned and documented in the CRF.
4.1.4
Drug assignment and administration of doses for each patient
The trial medication will be administered to the subjects as an oral dose together with about 
240 mL of water under supervision of the investigating physician or an authorised designee. 
To ensure a dosing interval of 24 and 12 hours for treatment group Part A and 12 hours in 
treatment Part B, the administration of trial medication should take place at the same time 
every day within a deviation of no more than +/-15 min. A standard continental breakfast 
(table 4.1.4:1) should be taken after blood sampling and before the study drug administration
(the safety laboratory samples will be taken as the first morning sample from all subjects after 
at least 6 hours fast prior). The consumption of the continental breakfast will occur within 30 
minutes prior to dosing and can occur as for Days 2 -Days 8 before PK samples are collected. 
A light morning snack can be consumed in the mornings if dosing occurs after 11 am. 
Further, subjects will consume a snack within 30 minutes prior to their evening dosing.
The medication phase will be followed by a 7 day follow-up and wash-out period.
Table 4.1.4: 1
Composition of the standard continental breakfast as an example
Ingredients
kcal
1 bread roll
164
15 g butter 
113
1 slice of Gouda cheese (approximately 40g)
146
1 slice of meat (approximately 20g)
33
1 cup of decaffeinated coffee or tea (without sugar)
2
Sum1
458
1
The total caloric content is supplied approximately as following: approx. 88 kcal as protein, approx. 133 kcal 
as carbohydrate, and approx. 237 kcal as fat.


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Table 4.1.4: 2
BI 730357, placebo and ciprofloxacin treatments
Treat
ment
group
Fasting 
condition 
predose
Substance
Pharmaceutical 
form
Unit       
strength
Number of units /dose   
volume per administration
Total 
dose
A
Fed1
BI 730357
Film-coated 
tablet
100 mg
4 tablets QD
400 mg
A
Fed1
Placebo
Film-coated 
tablet
--
4 tablets QD
--
B
Fed1
Ciprofloxacin
Film-coated 
tablet
500 mg
1 tablet BID
1000mg
A
Fed2
BI 730357
Film-coated 
tablet
100 mg
3 tablets BID
600 mg
A
Fed1
Placebo
Film-coated 
tablet
--
3 tablets BID
--
1
Drug administration after a standard continental breakfast 
2
Drug administration after a standard continental breakfast  and evening snack
4.1.5
Blinding and procedures for unblinding
4.1.5.1
Blinding
At the trial site, access to the randomization schedule to treatment A or B will be restricted to 
pharmacists and dedicated staff members. 
The Treatment A parts (BI 400 mg QD/placebo and BI 300 mg BID/placebo) of this study are
designed double-blind with regard to the subjects and the Investigators (as well as the 
research staff at the trial site) in order to eliminate observer or performance bias. This means 
avoiding systematic differences in assessments regarding the subj
A
Fed1
Placebo
Film-coated 
tablet
--
4 tablets QD
--
ect’s treatment (active or placebo). 
Subjects, investigators, and everyone involved in trial conduct or analysis or with any other
interest in this double-blind part of the trial will remain blinded with regard to the randomised 
treatment assignments until after database lock.
The subjects, Investigators and study site staff will not be aware of the treatment allocation 
(i.e., active vs placebo) from the time of randomization at Day 1 until database lock. 
The access to the randomisation code will be kept restricted until its release for analysis.


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The randomisation codes will be provided to bioanalytics prior to last patient completed to 
allow for the exclusion from the analyses of pharmacokinetic (PK) samples taken from 
placebo subjects. Bioanalytics will not disclose the randomisation code or the results of their 
measurements until the trial is officially unblinded.
In addition, the trial pharmacokineticist may receive the blinded (dummy subject numbers 
will be used) results of the measurements to perform the preliminary PK analysis. 
Treatment B of this study will be conducted according to an open-label design however, the 
sub-investigator conducting photosensitivity assessments will be blinded. This means that the 
photosensitivity assessments will be evaluated by persons who are independent of the other 
clinical trial procedures and not involved in other aspects of the trial. Treatment B will be 
administered on the same days as Treatment A.
4.1.5.2
Unblinding and breaking the code
An emergency code break (envelope) for treatment A will be available to the investigator.
This code break may only be opened in an emergency situation when the identity of the trial
drug must be known to the investigator in order to provide appropriate medical treatment or 
otherwise assure safety of trial participants. If the code break for a patient is opened, the 
sponsor must be informed immediately about the unblinding. The treatment allocation should 
not be disclosed to the sponsor unless this is explicitly requested. The reason for opening the 
code break must be documented on the envelope and/or appropriate CRF page.
Due to the requirements to report Suspected Unexpected Serious Adverse Reactions 
(SUSARs), it may be necessary for a representative from BI’s Pharmacovigilance group to 
access the randomisation code for individual subjects during trial conduct. The access to the 
code will only be given to authorised Pharmacovigilance representatives for processing in the 
PV database system and not be shared further. 
4.1.6
Packaging, labelling, and re-supply
The investigational medicinal products will be provided by BI. They will be packaged and 
labelled in accordance with the principles of Good Manufacturing Practice (GMP).
For details of packaging and the description of the label, refer to the ISF.
4.1.7
Storage conditions
Drug supplies will be kept in their original packaging and in a secure limited access storage 
area according to the recommended storage conditions on the medication label. A
temperature log must be maintained for documentation
If the storage conditions are found to be outside the specified range, the Clinical Research
Associate (CRA), as provided in the list of contacts, must be contacted immediately.


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4.1.8
Drug accountability
The investigator or designee will receive the investigational drugs delivered by the sponsor
when the following requirements are fulfilled:

Approval of the clinical trial protocol by the IRB / ethicsAvailability of a signed and 
dated clinical trial contract between the sponsor and the investigational site,

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 clinical trial protocol,

Availability of the proof of a medical license for the Principal Investigator,

Availability of FDA Form 1572.
Investigational drugs are not allowed to be used outside the context of this protocol. They 
must not be forwarded to other investigators or clinics. 
The investigator or designee 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 warehouse / 
drug distribution centre or alternative disposal of unused products. If applicable, the sponsor 
or warehouse / drug distribution centre will maintain records of the disposal. 
These records will include dates, quantities, batch / serial numbers, expiry (‘use- by’) dates, 
and the unique code numbers assigned to the investigational medicinal product and trial
subjects. The investigator or designee will maintain records that document adequately that the 
subjects were provided the doses specified by the Clinical Trial Protocol (CTP) and reconcile 
all investigational medicinal products received from the sponsor. At the time of return to the 
sponsor or appointed CRO, the investigator or designee must verify that all unused or 
partially used drug supplies have been returned and that no remaining supplies are in the 
investigator’s possession.
4.2
OTHER TREATMENTS, EMERGENCY PROCEDURES, 
RESTRICTIONS
4.2.1
Other treatments and emergency procedures
There are no special emergency procedures to be followed.
4.2.2
Restrictions
4.2.2.1
Restrictions regarding concomitant treatment
In principle, no concomitant treatments are allowed. 


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In case of AEs in need of treatment, symptomatic therapy according to investigator judgment 
will be permitted. All concomitant and/or rescue therapies will be recorded on the appropriate 
pages of the eCRF. 
In addition, a list of medications with potential drug-drug interactions, transport and 
phototoxic interactions and/or references can be found in the Appendix 10.1. For further 
guidance investigators are referred to the actual Investigator´s Brochure or may contact the 
sponsor.
4.2.2.2
Restrictions on diet and life style
Subjects must be fasted for at least 6 hours prior to collection of the safety laboratory 
samples.
Foods which are known strong or moderate inhibitors of CYP 3A (e.g., fruit juices from star 
fruit, paw paw, grapefruit) should be avoided during the study participation.
The use of tanning beds is not allowed during the study.
Throughout their participation in the study, participants should avoid direct sunlight. When 
exposed to sunlight study participants should protect skin areas not covered by clothes by 
using sun-protection creams and lip balms with sun protection factor 30 or higher with 
protection against UV-A and UV-B. Additionally, subjects should wear sunglasses when 
exposed to direct sun or other sources of UV-light.
These protection measures must be applied until the EOT visit.
4.2.2.3
Contraception requirements
Women of childbearing potential must 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 patient
information.
4.3
TREATMENT COMPLIANCE
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 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


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5.
ASSESSMENTS
5.1
ASSESSMENT OF PHOTOSENSITIVITY
Two Multiport Solar Simulator models 601 (
 will 
be used for irradiation (150 W or 300 W xenon arc lamp, dichroic mirror, and equipped with 
filters to produce UVA or UVA+B (290-400nm) outputs). This light source is equipped with 
6 liquid light wave guides extending out of the case and an automated shutter device allowing 
for precise delivery of UV light doses per individual wave guide. Actual irradiation values 
delivered by the individual light guides will be recorded throughout the study using a 
PMA2100 Radiometer (
) equipped with a 
PMA2113 UVA sensor (physical irradiation in the range of 320 to 400 nm) and with a 
PMA2103 UVB sensor (biologically weighted, erythemal effective irradiation).
A series of unprotected naive skin test sites on the back will be irradiated with the following 
three different conditions, meant to simulate three different environmental sunlight exposure 
scenarios/conditions:
1. Condition 1: Full range solar UVB/UVA (290 to 400 nm, UBV content ~10%), simulating 
midday summer outdoor sun exposure (assessed in µw/cm2).
2. Condition 2: UVA only (320 to 400 nm, UVB content <0.03%), simulating indoor 
exposure behind window glass with a secondary assessment of erythema and local skin 
reactions at 25 J cm−2(assessed in mw/cm2).
Subjects will be exposed to a series of 6 graded full range solar UVB/UVA exposures 
(Condition 1) and UVA only exposures (Condition 2), each 25% greater than the previous 
dose. Following irradiation, skin sites will be evaluated for erythema or skin darkening (for 
UVA-only exposure in the absence of additional, drug-induced phototoxicity). 
The MED will be defined as the lowest dose that produced uniform redness (condition 1) or 
darkening (condition 2) (assessed in joules (J) for UVA and millijoules (mJ) for UVB/UVA). 
An approximate MEDpreliminary will be irradiated on day -3 and will be evaluated 10 min, 1 h 
and 24 h post irradiation. The initial MEDpreliminary will be used to fine-tune the irradiation 
range for the determination of a precise MEDbaseline on day -2. The MEDbaseline irradiation will 
occur on day-2 and will be evaluated 10 min, 1 h and 24 h post irradiation. 
Outpatient pre-treatment photosensitivity testing will occur prior to the dose administration 
on day 1 as follows:
Day -3 

Irradiate Preliminary MEDs (Condition 1 and Condition 2) followed by MED 
assessments at 10 ±2 minutes, 1 hour ±5 minutes


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Day -2

Assessment of Preliminary MEDs at at 24 hours ±10 minutes post irradiation.  

Irradiate Baseline MEDs (Condition 1 and Condition 2, +/- 30 min to planned time) 
followed by MED assessments at 10 ±2 minutes, 1 hour ±5 minutes   
Day -1

Assessment of Baseline MEDs (Condition 1 and Condition 2) at 24 hour±10 minutes 
post irradiation.  

Irradiate Baseline Condition 3 (+/- 30 min to planned time) followed by assessments 
at 10 ±2 minutes and 1-hour ±5 minutes. 
Day 1
Post-treatment photosensitivity testing will occur 2 hours (±10 minutes) after final dose 
administration on day 8, with the same irradiation conditions as on day -1 as follows:
Day 8

Irradiate MEDs (Condition 1 and Condition 2) followed by MED assessments at 10 
±2 minutes, 1 hour ±5 minutes

Irradiate Condition 3 followed by assessments at 10 ±2 minutes, 1 hour ±5 minutes
Day 9

Assessment of MEDs (Condition 1 and Condition 2) at 24 hour±10 minutes post 
irradiation.  

Assessment of Condition 3 at 24 hours post hours ±10 minutes post irradiation.  
The photosensitivity index (PI) will be calculated as the ratio of the MEDbaseline versus 
MEDon drug for irradiation Conditions 1 and Conditions 2.
Additionally, inflammatory responses (erythema and local skin reactions) and superficial skin 
effects will be scored (see scales in Table below) under all conditions at baseline (10 min, 1 h 
and 24 h post-irradiation), and post-treatment day 8 (10 min, 1 h, 24 h, 48 h and 72 h post-
irradiation).


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Inflammatory skin reactions will be scored according to:
Skin Reaction Grading Scales
Erythema Grading Scale
Local Skin Reaction
Superficial Effects Grading
0 No evidence of erythema
E Edema-swelling, spongy
feeling when palpated
g Glazing
1 Very slight erythema
(barely perceptible)
P Papule-red, solid,
elevation
y Peeling
2 Well defined erythema
V Vesicle-small elevation
containing fluid
c Scab, dried film of serous
exudate of vesicular or
bullous reaction
3 Moderate to severe     
erythema
B Bullous reaction-fluid
filled lesion (blister)
d Hyperpigmentation
(reddish-brown
discoloration of test-site)
4 Severe erythema (beet
   redness)
S Spreading-evidence of
the reaction beyond the
irradiated area
h Hypopigmentation (loss
of visible pigmentation at
test site)
W Weeping-result of a
Vesicular or bullous reaction 
serious exudate
f Fissuring-grooves in the
superficial layers of the skin
I   Induration-solid, elevated,
hardened, thickened skin
- Response occurs ≤25% of
test site
5.2
ASSESSMENT OF SAFETY
5.2.1
Physical examination
A complete physical examination will be performed at the time points specified in the 
flowchart. It includes at a minimum general appearance, skin, head, neck, throat, lymph 
nodes, lungs, cardiovascular and neurological systems, abdomen, and extremities. 
Measurements of height and body weight will be performed at screening only.
The results must be included in the source documents available at the site. 
5.2.2
Vital signs
Vital signs will be evaluated at the time points specified in the flowchart, prior to blood 
sampling.


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This includes systolic and diastolic blood pressure and pulse rate (electronically or by 
palpation count for 1 minute) in a supine position after 5 minutes of rest. The results must be 
included in the source documents available at the site.
5.2.3
Safety laboratory parameters
Safety laboratory parameters to be assessed are listed in Table 5.2.3: 1 below. For the 
sampling time points please see the flowchart. Additional testing for infectious deseases can 
be added at any timepont during the study, as requested by the authority, or judged by the 
investigator.
All analyses will be performed by a site local laboratory, the respective reference ranges will 
be provided in the ISF. 
Subjects have to be fasted for at least 6 hours prior to the blood sampling for the safety 
laboratory. 
The laboratory will send reports to the investigator. It is the responsibility of the investigator
to evaluate the laboratory reports. Clinically relevant abnormal findings as judged by the 
investigator will be reported as adverse events (please refer to section 5.2.6).
In case the criteria for hepatic injury are fulfilled, a number of additional measures will be 
performed (please see section 5.2.6.1 and the DILI Checklist provided in the ISF. The amount 
of blood taken from the patient concerned will be increased due to this additional sampling.
The clinical local laboratory will transfer the results of the analysis to the sponsor/ sponsor 
representative.
Table 5.2.3: 1 Safety laboratory
Functional lab group
Test name 
A1
B2
C3
Haematology
Haematocrit
Haemoglobin
Red blood cells (RBC)
White blood cells (WBC)
Platelet count
MCV
MCH
MCHC
RDW
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Automatic WBC 
differential 
(relative and absolute)
Neutrophiles total
Lymphocytes total
Eosinophiles 
Basophiles 
Monocytes 
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X


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Lymphocytes 
X
X
X
Manual differential WBC 
(if automatic differential 
WBC is abnormal)
Polymorphnuclear neutrophils (segs), band 
neutrophils (stabs), eosinophils, basophils, 
monocytes, lymphocytes 
Coagulation
Activated partial thromboplastin time (aPTT)
Prothrombin Time (PT)
INR
X
X
X
Functional lab group
Test name 
Enzymes
Aspartate aminotransferase (AST) 
Alanine aminotransferase (ALT) 
Alkaline phosphatase (AP)
Gammaglutamyl transferase (GGT)  
Creatine kinase (CK)
Lipase
Amylase
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Substrates
Glucose
Creatinine
Urea Nitrogen
Uric Acid
Total bilirubin 
Direct bilirubin
Total protein
Albumin
Globulin
Albumin/Globulin ratio
C-Reactive Protein (CRP) 
Total cholesterol 
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Electrolytes
Calcium
Sodium
Potassium
Chloride
Phosphate
X
X
X
X
X
X
X
X
X
X
Serum Pregnancy test 
(only for female subjects 
of childbearing potential) 
at screening, day -1 and if 
urine pregnancy test is 
positive
Human Serum Chorionic Gonadotropin
X
X4
Urinalysis (Stix)
Urine nitrite
Urine protein
Urine glucose
Urine ketone
Urine bilirubin
Urine Blood
Urine leukocyte esterase
Urine pH
Specific gravity
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X


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1 A: parameters to be determined at screening examination
2 B: parameters to be determined on Days 1 and 8
3 C: parameters to be determined at end of trial examination
4 Day -1 only
Manual differential white blood cell count or urine sediment examinations will only be 
performed if there is an abnormality in the automatic blood cell count or in the urinalysis, 
respectively.
The tests listed in Table 5.2.3: 1 and Table 5.2.3: 2 may be repeated as required. The results 
of the Exclusionary laboratory tests listed below will not be entered in the CRF/database and 
will not be reported in the CTR. Except for drug screening, it is planned to perform these 
tests during screening only. Drug screening will be performed at screening and prior to 
administration of trial medication on Day -1 (for time points refer to Flow Chart).
Urine sediment 
(microscopic examination 
if erythrocytes, leukocytes 
nitrite or protein are 
abnormal in urine)
Only positive findings will be reported (e.g. 
presence of sediment bacteria, casts in sediment, 
squamous epithelial cells, erythrocytes,
leukocytes)
Urine Pregnancy test (only 
for female subjects of 
childbearing potential) at 
EoT
Human Chorionic Gonadotropin in the urine
X


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Table 5.2.3: 2
Exclusionary laboratory tests
Functional lab group
Test name 
Drug screening (urine)
Amphetamine
Barbiturates
Buprenorphine
Benzodiazepine
Cocaine 
Methadone methabolite
Methadone
Methamphetamine
Ecstasy
Morphine
Opiates 
Oxycodone
Phencyclidine
Tricyclic antidepressants
Marijuana
Infectious serology (blood)1
Hepatitis B surface antigen (qualitative)
Hepatitis B core antibody (qualitative)
Hepatitis C antibodies (qualitative)
HIV-1 and HIV-2 antibody (qualitative)
IGRA-T (e.g. QuantiFERON®-TB Gold IT Test)
1 Additional testing for infectious deseases can be added as requared
To encourage compliance with alcoholic restrictions, a breath alcohol test will be performed 
prior to admission on Day -1, and may be repeated at any time during the study at the 
discretion of an Investigator or designee. The results will not be included in the CTR.
Laboratory data will be transmitted electronically from the laboratory to the trial site.
5.2.4
Electrocardiogram
The 12-lead ECGs must be administered by a qualified technologist and results will be 
recorded as scheduled in the flowchart. The investigator or a designee will evaluate whether 
the ECG is normal or abnormal and assess clinical relevance. ECGs may be repeated for 
quality reasons and a repeated recording used for analysis. 
Additional ECGs may be recorded for safety reasons. Dated and signed printouts of ECG 
with findings should be documented in subject’s medical record.
Clinically relevant abnormal findings will be reported either as baseline condition (if 
identified at the screening visit) or otherwise as AEs and will be followed up and/or treated as 
medically appropriate.


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5.2.5
Other safety parameters
Not applicable.
5.2.6
Assessment of adverse events
5.2.6.1
Definitions of AEs 
5.2.6.1.1
Adverse event
An AE is defined as any untoward medical occurrence in a patient or clinical investigation 
subject 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, ECG, physical examination and laboratory test results, if they 
are judged clinically relevant by the investigator.
If such abnormalities already exist prior to trial inclusion, they will be considered as baseline 
conditions and should be collected in the eCRF.
5.2.6.1.2
Serious adverse event
A serious adverse event (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 or 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 
on appropriate medical judgement which may jeopardise the patient and may require 
medical or surgical intervention to prevent one of the other outcomes listed in the 
above definitions. Examples of such events are intensive treatment in an emergency 


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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”
In accordance with the European Medicines Agency initiative on Important Medical Events, 
Boehringer Ingelheim has set up a list of 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 
defined above.
The latest list of “Always Serious AEs” can be found in the eDC system. A copy of the latest 
list of “Always Serious AEs” will be provided upon request. These events should always be 
reported as SAEs as described in section 5.2.6.2.
Cancers of new histology and exacerbations of existing cancer must be classified as a serious 
event regardless of the time since discontinuation of the drug and must be reported as 
described in 5.2.6.2, subsections “AE Collection” and “AE reporting to sponsor and 
timelines”.
5.2.6.1.4
Adverse events of special interest
The term adverse events 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:
Hepatic injury
A hepatic injury is defined by the following alterations of hepatic laboratory parameters: 

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 draw sample, or

Aminotransferase (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.


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Severe infections (according to RCTC grading)
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), 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), HCV progression.
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 judgement should be used to determine whether there is a reasonable possibility of a 
causal relationship between the adverse event and the given study treatment, 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.


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
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).
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 half-lives).
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 drug treatment continues or remains 
unchanged.
5.2.6.2
Adverse event collection and reporting
5.2.6.2.1
AE Collection
The investigator shall maintain and keep detailed records of all AEs in the subject files.
The following must be collected and documented on the appropriate CRF(s) by the 
investigator:
•
From signing the informed consent onwards until the individual subject’s end of trial (the 
End of Trial (EoTrial) visit): 
all AEs (serious and non-serious) and all AESIs.
•
After the individual subject’s end of trial: 
the investigator does not need to actively monitor the subject for new AEs but should 
only report any occurrence of cancer and trial treatment related SAEs and trial treatment 
related AESIs of which the investigator may become aware of by any means of 
communication, e.g. phone call. Those AEs should be reported on the BI SAE form (see 
section 5.2.6.2.2), but not on the CRF.


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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. All (S)AEs, including those persisting after individual patient’s end of trial must 
be followed up until they have resolved, have been assessed as “chronic” or “stable” , or no 
further information can be obtained.
5.2.6.2.3
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 Studies (Part B).
The ISF will contain the Pregnancy Monitoring Form for Clinical Studies (Part A and 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 Studies 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.
5.2.6.2.4
Exemptions to SAE reporting
Not applicable
5.3
DRUG CONCENTRATION MEASUREMENTS AND 
PHARMACOKINETICS
5.3.1
Assessment of pharmacokinetics
PK parameters for exposure and disposition will be calculated. Standard multiple dose PK 
parameters will be calculated and further specified in the TSAP.


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The relationship between BI 730357 plasma concentrations, photosensitivity endpoints, and 
AEs may be assessed.
5.3.2
Methods of sample collection
For quantification of BI 730357) plasma concentrations, 4 mL of blood will be taken from an 
antecubital or forearm vein into a K-3EDTA (tripotassium ethylenediaminetetraacetic acid)-
anticoagulant blood drawing tube at the times indicated in the Flow Chart and in Appendix 
10.2. Blood will be withdrawn by means of either an indwelling venous catheter or by 
venepuncture with a metal needle.
After blood draw all samples have to be protected against direct sunlight to avoid conversion 
of present metabolite into parent drug BI 730357. The EDTA-anticoagulated blood samples 
will be centrifuged for about 10 minutes at app. 1000 to 2000 g at about 2 to 4°C. Two 
plasma aliquots will be obtained and stored in polypropylene tubes. The first aliquot should 
contain at least 0.5 mL plasma the second aliquot should contain the remaining plasma. The 
process from blood collection until transfer of plasma aliquots into the freezer should be 
completed within 120 minutes, with interim storage at room temperature. For each aliquot the 
time when the sample was placed in the freezer will be documented. Until transfer on dry ice 
to the analytical laboratory, the aliquots will be stored upright at about -20°C or below at the 
trial site. The second aliquot will be transferred to the analytical laboratory after the 
bioanalyst has acknowledged safe arrival of the first aliquot. At the analytical laboratory the 
plasma samples will be stored at about -20°C or below until analysis.
Quantification of ciprofloxacin plasma concentrations will not be performed.
At a minimum, the sample tube labels should list the following information: BI trial number, 
subject number, visit, and planned sampling time. Further information, such as matrix and 
analyte, may also be provided. 
After completion of the trial, the plasma samples may be used for further methodological 
investigations, e.g., for stability testing, assessment of metabolites. However, only data 
related to the analyte and/or its metabolite(s) will be generated by these additional 
investigations. The study samples will be discarded after completion of the additional 
investigations, but not later than 5 years after the final study report has been signed.
The results of any further investigations are not planned to be part of the CTR but can be
included into the CTR if necessary.


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5.4
ASSESSMENT OF BIOMARKER(S)
Not applicable.
5.5
BIOBANKING
Not applicable.
5.6
OTHER ASSESSMENTS
Not applicable.
5.7
APPROPRIATENESS OF MEASUREMENTS
All measurements performed during this trial, except from the skin type and photosensitivity 
assessments, are standard measurements in clinical trials and will be performed in order to 
monitor safety aspects in an appropriate way.
UV photo safety testing (conduct and interpretation of ultraviolet (UV) irradiation) is well 
established at the clinical site and will be performed by clinical, medical and technical staff 
which is appropriately trained and familiar with the methods and assessments required in this 
trail.
The number of investigator designees performing skin evaluations is kept as small as possible 
to ensure consistency. All dermatological assessments will be performed in a room with 
standardized environmental conditions (e.g., light conditions, temperature).
Therefore, the appropriateness of all measurements applied in this trial is given.


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6.
INVESTIGATIONAL PLAN
6.1
VISIT SCHEDULE
All subjects have to adhere to the visit schedule as specified in the Flow charts. Each visit 
date is to be counted from Day 1. 
Additional visits for the purpose of re-testing of laboratory parameters or AE monitoring may 
be included as deemed necessary by the investigator.
Study procedures to be performed at each visit are listed in the Flow Charts and the 
respective protocol sections. Additional details on procedures at selected visits are provided 
below.
Measurement of vital signs should precede blood sampling. All blood samplings on all visits 
which are not intensive PK-days should occur prior to the intake of medication.
For detailed description of the trial procedures, please refer to the Flow Charts.
6.2
DETAILS OF TRIAL PROCEDURES AT SELECTED VISITS
6.2.1
Screening and run-in period(s)
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 study. 
The screening should take place no more than 28 days before Day 1.
At the screening visit, the medical examination will include documentation of subject 
information, informed consent, demographics including height and body weight, smoking 
and alcohol history, relevant medical history and concomitant therapy, review of inclusion 
and exclusion criteria, review of vital signs (BP, PR, and temperature), 12-lead ECG, 
laboratory tests, and a physical examination. Subjects who have laboratory test value (e.g.,
platelet count) clinically outside acceptable ranges, may have the test repeated once to 
determine eligibility; however, the result of re-assessment must be available prior to 
randomisation (Day 1).
After all general screening clinical assessments were performed, only subjects who meet
eligibility criteria will undergo UV irradiation and preliminary photosafety testing will be 
performed.


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The preliminary photosensitivity examination will be performed no later than Day -3, 
followed by the base line irradiation and photosensitivity assesments stariting on day -2.
Baseline Conditions
Subjects eligible for the study participation will be admitted to the clinical site on day -1, and
check of In/Exclusion criteria as well as Base-line photosensitivity assessment will be 
performed.
If possible, spare subjects will be provided for each group to guarantee the start of a complete 
group. The spare subjects will participate in all trial activities up to Day 1, i.e. on Day -1 they 
will be admitted to the clinic and all examinations, which have been scheduled up to drug 
administration on Day 1 will be performed. The spare subjects from one group will be given 
the option to participate in the next planned group.
6.2.2
Treatment period(s)
Treatment A
Subjects will be randomized in the morning on Day 1 and receive 400mg of BI 730357 or 
placebo once daily over 8 days, or 300mg of BI 730357 or placebo twice daily 12 hours apart 
over 8 days with the single dose on day 8, in order to reach pharmacokinetic steady state;  
UVB/UVA irradiation will occur  2 hours after the last dose of either IP or placebo, and 
photosensitivity assessments (determination of MEDOn drug and evaluation of erythema/local 
skin reactions) will be performed at 10 (+/- 2) minutes, and 1 (+/- 5 min), 24(+/- 10 min)
Treatment B
Subjects will receive their first dose of 500 mg ciprofloxacin on the morning of Day 3. 
Twelve (12) hours later, subjects received their second dose of 500 mg ciprofloxacin. 
Subjects continued a twice-daily dosing regimen through to the morning of Day 8 to ensure 
they have reached pharmacokinetic steady state
UVB/UVA irradiation will occur 2 hours after the last dose of Ciprofloxacin, and 
photosensitivity assessments (determination of MEDOn drug and evaluation of erythema/local 
skin reactions) were performed at 10 (+/- 2) minutes, and 1(+/- 5 min), 24(+/- 10 min), 
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 end of trial 
examination.


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6.2.3
Follow-up period and trial completion
End of Trial
Subjects who completed the treatment according to the protocol, as well as subjects who 
discontinued treatment before the end of the planned treatment period should undergo the end 
of trial visit 7 days after last intake of the study medication.
For AE assessment, laboratory tests, recording of ECG and vital signs, and physical 
examination during the end of trial refer to the Flow charts.
All abnormal values (including laboratory parameters) that are judged 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 subject’s end of trial must be followed 
up until they have resolved, have been sufficiently characterized, 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
The objective of this trial is to investigate the photosensitivity under three distict exposure 
conditions of BI 730357 following 8 days of administration (i.e. steady state) on the basis of 
the primary and secondary endpoints.  The trial is designed to allow comparisons between BI 
730357 and placebo as well as BI 730357 and a positive control (ciprofloxacin).  These 
comparisons will be evaluated statistically by use of a mixed model for repeated measures.
Each double blind randomization group (Part A: BI 730357 400 QD/placebo and BI 730357 
300 BID/placebo) will be analysed separately for the assessment of photosensitivity.
7.1
NULL AND ALTERNATIVE HYPOTHESES
BI 730357 vs placebo
The assessment for absence of photosensitivity will be based upon the differences in mean 
photosensitivity index (PI) between BI 730357 and placebo two-sided 90% confidence 
intervals (CIs) for the differences in the photosensitivity index (Section 7.2.2) between BI 
730357 and placebo using an acceptance range of -0.4 to 0.4.  This method is equivalent to 
the two-sided t-test procedure, each at the 5% significance level.
The following comparisons will be performed:

BI 730357 400 mg QD vs placebo 400 mg QD

BI 730357 300 mg BID vs placebo 300 mg BID
The following hypotheses are tested: 
Null hypothesis H0 (Photosensitive):
µBI - µpbo ≤ -ẟor µBI - µpbo ≥ ẟ
Where µBI and µpbo are the means of the endpoint for BI 730357 and placebo, respectively, 
and δ is the limit that defines the acceptance range for photosensitivity equivalence.
Alternative hypothesis Ha (Absence of photsensitivity):
-ẟ< µBI - µpbo < ẟ
In this trial, the equivalence limit δ is 0.4 which is consistent with historical criteria used for 
positive photosensitivity for a drug (R19-3037).
The rejection of the null hypothesis at the = 0.05 level is equivalent to the inclusion of the 
90% confidence interval for µBI - µpbo in the acceptance range (-δ, δ).
Although there are multiple endpoints where the photosensitivity index will be statistically 
compared, an alpha adjustment is not needed because it is required that all endpoints meet the 
equivalence criterion as described above simultaneously.


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BI 730357 vs ciprofloxacin, Placebo vs ciprofloxacin
Comparisons between the mean PI between BI 730357 and ciprofloxacin as well as between 
placebo and ciprofloxacin at the different timepoints under conditions 1 and 2 will be 
performed.
The planned comparisons are:

BI 730357 400 mg QD vs ciprofloxicin

BI 730357 300 mg BID vs ciprofloxicin

Placebo for 400 mg QD vs ciprofloxicin

Placebo for 300 mg BID vs ciprofloxicin
At each timepoint the null hypothesis will be that there is no difference in the mean PI of BI 
730357 compared to ciprofloxacin:
Null hypothesis H0:
µBI/pbo - µcipro = 0
Where µBI/pbo and µcipro are the means of the endpoint for BI 730357 or placebo and 
ciprofloxicin, respectively
The alternative hypothesis will be that the means are not equal:
Alternative hypothesis Ha:
µBI/pbo - µcipro ≠0
A significant finding of increased photosensitivity of ciprofloxacin compared to BI 730357 
and to placebo at the p<0.05 level will be supportive in concluding that the trial was 
appropriately designed to test the photosensitivity of BI 730357.
7.2
PLANNED ANALYSES
7.2.1
General considerations
Analysis sets
Statistical analyses will be based on the following analysis sets:

Treated set (TS): The treated set includes all subjects who were randomized and 
treated with at least one dose of study drug. The treated set will be used for safety 
analyses.
Full analysis set (FAS): This set includes all subjects in the treated set (TS) who 
provide at least one photosensitivity endpoint that was defined as primary or 
secondary and was not excluded due to a protocol deviation relevant to the evaluation


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of photosensitivity. Descriptive and model based analyses of photosensitivity 
endpoints will be based on the FAS.
Additional analysis sets, refinements of the above definitions, or other relevant details may be 
specified in the TSAP.  The implications that patients with important protocol deviations 
(including receiving incorrect medication) might have on the analysis will be discussed at the 
report planning meeting(s) and decisions will be documented in the decision log.
7.2.2
Primary endpoint analyses
Photosensitivity index (PI)
The photosensitivity index (PI) under conditions 1 and 2 is the measurement used for the 
primary endpoints.  It is defined as the ratio of the precise MEDbaseline to the MEDon-drug (see 
Section 5.1) at each respective post-irradiation timepoint.  Therefore, there will be MED
baseline at 10 min, 1h, and 24h that will be used for the respective PI calculations, PI10min, PI1h, 
and PI24h.  For example, the PI1h will be the precise MEDbaseline/MEDon-drug where each MED 
was measured at the 1 hour post-irradiation time point.  The two primary endpoints are PI at 
24 hours under conditions 1 and 2.
A mixed model for repeated measures on PI values will be utilized for the analysis.  The 
model will include treatment (BI 730357, Placebo, ciprofloxacin), time (10min, 1h, 24h, 48h, 
and 72h), and treatment-time interaction as fixed effects and subject as a random effect.  
Adjusted means and differences in PI and 90% CIs for the 2 contrasts of interest (i.e. BI 
703357 – placebo at 24h) will be calculated from the model.
The analysis will be carried out separately for condition 1 and condition 2.
Additional details, including the full specification of the FAS (if needed) and the handling of 
patients who may not have post-baseline data, will be included in the TSAP.
7.2.3
Secondary endpoint analyses
The secondary endpoints for differences in PI at 10min and 1h under conditions 1 and 2 will 
be calculated from the same model as described for the primary analyses.
Additionally percent change from baseline in MED at 10min, 1h, and 24h will be calculated 
as ((MEDon-drug-MEDbaseline)/ MEDbaseline)*100 at each timepoint and the same model using 
described in the primary analysis will be used in the analyses of these endpoints.


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7.2.5
Safety analyses
Adverse events will be coded using the Medical Dictionary for Drug Regulatory Activities
(MedDRA). Standard BI summary tables and listings will be produced. All adverse events 
with an onset between start of treatment and end of the REP, a period of 7 days after the last 
dose of trial medication, will be assigned to the on-treatment period for evaluation.
The safety analysis will be done by ‘randomised treatment’.
All treated subjects will be included in the safety analysis. In general, safety analyses will be 
descriptive in nature and will be based on BI standards. No hypothesis testing is planned.
Statistical analysis and reporting of adverse events will concentrate on treatment-emergent 
adverse events, i.e. all adverse events occurring between start of treatment and end of the 
REP. Adverse events that start before first drug intake and deteriorate under treatment will 
also be considered as ‘treatment-emergent’.
Frequency, severity, and causal relationship of adverse events will be tabulated by system 
organ class and preferred term after coding according to the current version of the Medical 
Dictionary for Drug Regulatory Activities (MedDRA) at database lock.


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Laboratory data will be analysed both quantitatively as well as qualitatively. The latter will 
be done via comparison of laboratory data to their reference ranges. Values outside the 
reference range as well as values defined as clinically relevant will be summarised. Treatment 
groups will be compared descriptively with regard to distribution parameters as well as with 
regard to frequency and percentage of subjects with abnormal values or clinically relevant 
abnormal values.
Vital signs, physical examinations, or other safety-relevant data observed at screening, 
baseline, during the course of the trial and at the end-of-trial evaluation will be assessed with 
regard to possible changes compared to findings before start of treatment.
7.2.6
Other Analyses
Details of other analyses, if needed, will be included in the TSAP.
7.2.7
Interim Analyses
No statistical interim analysis is planned. However, after completion of the 400mg dose 
group the independent Investigator and BI medical representatives will review blinded 
photosafety data of treatment A group to determine the acceptability of photosafety. After the 
team review of these data, it may be recommended, or in case of unfavourable results - to test 
the higher dose of 300mg BID for treatment A. In addition, a preliminary blinded PK analysis 
will be performed to estimate the PK exposure.
7.3
HANDLING OF MISSING DATA
No imputation is planned for missing MED, PI, or assessments of skin reaction data.
7.4
RANDOMISATION
The first set of subjects will be first randomised to the Treatment A (BI 400 mg QD/placebo) 
or Treatment B group in a 3:1 ratio. The random list will be provided by BI to the dedicated
study staff. 
Subjects allocated to the treatment group A will be randomised in a 3:1 ratio in a double blind 
manner, which reflects the ratio of subjects receiving active drug to placebo.
Subjects allocated to treatment B group will receive ciprofloxacin.
In order to investigate a second BI730357 dose of 300 mg BID, a second set of subjects be 
randomised in a 3:1 ratio in the same double blind manner described for Treatment A above, 
which reflects the ratio of subjects receiving active drug to placebo.


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BI will arrange for the randomisation as well as packaging and labelling of trial medication
for treatment A. The randomisation list will be generated using a validated system, which 
involves a pseudo-random number generator so that the resulting treatment will be both 
reproducible and non-predictable. The block size will be documented in the Clinical Trial 
Report. Access to the codes will be controlled and documented.
More details can be found in section 4.1.5.
7.5
DETERMINATION OF SAMPLE SIZE
It is planned to include initially a total of 84 healthy male and female subjects (36 subjects for
Treatment A 400 mg QD, 36 subject for Tretment A 300 mg BID; 12 subjects for Treatment
B) in this trial.
The planned numbers of subjects should be sufficient for the exploratory evaluation of photo-
safety of each of the BI 730357 dose groups.  Based on a similarly designed study for 
evaluation of pradigastat the observed mean (standard deviation) over all PI measurements 
for 9 patients who received placebo and 12 subjects who received ciprofloxacin was 1.08 
(0.12) and 1.61 (0.55), respectively (R19-3037).  
Assuming a common standard deviation of 0.15 and an expected difference in mean PI of 0 
between BI 730357 and placebo, each of the two group 0.05 one-sided t-tests will have 99% 
power to reject the null hypothesis that BI 730357 and placebo are not equivalent (the 
difference in means, µBI - µpbo, is ≥ 0.4 and µBI - µpbo ≤-0.4) in favor of the alternative 
hypothesis that the means of the two groups are equivalent (nQuery Advisor, version 7).
Additionally, for the planned comparison of mean PIs for BI 730357 and ciprofloicin, a two 
group Satterthwaite t-test with a 0.05 two-sided significance level will have 87% power to 
detect a difference in means of 0.6 (the difference between µcipro of 1.60 and a µBI of 1.0) 
assuming standard deviation of ciprofloxacin is 0.600 and standard deviation for BI 730357 is 
0.15 when the sample sizes in the two groups are 12 and 27, respectively (nQuery Advisor, 
version 7).  Using the same assumptions and calculation for 12 ciprofloxacin and 9 placebo 
instead of 27 BI 370357 subjects the power is 86%.  Based on the similar study of 
pradigastat, the drop-out rate will be minimal. Further details will be discussed  in the TSAP.


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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 ethical principles laid down 
in the Declaration of Helsinki, in accordance with the ICH Harmonized Guideline for Good 
Clinical Practice (GCP), relevant BI Standard Operating Procedures (SOPs), the EU directive 
2001/20/EC / EU regulation 536/2014 and other relevant regulations. Investigators and site 
staff must adhere to these principles. Deviation from the protocol, the principles of ICH GCP 
or applicable regulations as will be treated as “protocol deviation”.
Standard medical care (prophylactic, diagnostic and therapeutic procedures) remains the 
responsibility of the treating physician of the patient.
The investigator will inform the sponsor immediately of any urgent safety measures taken to 
protect the trial participants against any immediate hazard, as well as of any serious breaches 
of the protocol or of ICH GCP.
The Boehringer Ingelheim 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 rule, no trial results should be published prior to finalisation of the Clinical Trial Report.
8.1
TRIAL APPROVAL, PATIENT 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 patient participation in the trial, written informed consent must be obtained from each 
patient (or the patient’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 patient-
information form retained by the investigator as part of the trial records. A signed copy of the 
informed consent and any additional patient information must be given to each patient or the 
patient’s legally accepted representative.”


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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 Integrated Quality and Risk 
Management 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. See section 4.1.5.2 for rules 
about emergency code breaks. For drug accountability, refer to section 4.1.8.
8.3.1
Source documents
In accordance with regulatory requirements, the investigator should prepare and maintain 
adequate and accurate source documents and trial records that include all observations and 
other data pertinent to the investigation on each trial patient. Source data as well as reported 
data should follow the “ALCOA principles” and be attributable, legible, contemporaneous, 
original and accurate. Changes to the data should be traceable (audit trail).
Data reported on the CRF must be consistent with the source data or the discrepancies must 
be explained.
Before providing any copy of subjects’ source documents to the sponsor, the investigator 
must ensure that all patient identifiers (e.g. patient’s name, initials, address, phone number, 
social security number) have properly been removed or redacted from any copy of the 
subjects’ source documents.
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: gender, year of birth (in accordance with local laws and 
regulations)

Subject participation in the trial (substance, trial number, patient number, date patient was 
informed)

Dates of Subject’s visits, including dispensing of trial medication

Medical history (including trial indication and concomitant diseases, if applicable)


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
Medication history

Adverse events and outcome events (onset date (mandatory), and end date (if available))

Serious adverse events (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)

Completion of Subject’s participation in the trial” (end date; in case of premature 
discontinuation document the reason for it).

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.
8.3.2
Direct access to source data and documents
The investigator /institution will allow site trial-related monitoring, audits, IRB / IEC review 
and regulatory inspections. Direct access must be provided to the CRF and all source 
documents/data, including progress notes, copies of laboratory and medical test results, which 
must be available at all times for review by the CRA, auditor and regulatory inspector 
(e.g. FDA). They may review all CRFs and informed consents. The accuracy of the data will 
be verified by direct comparison with the source documents described in section 8.3.1. The 
sponsor will also monitor compliance with the protocol and GCP.
8.3.3
Storage period of records
Trial site(s):
The trial site(s) must retain the source and essential documents (including ISF) according to 
contract or the local requirements valid at the time of the end of the trial (whatever is longer).
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. 
Exemptions from expedited reporting are described in section 5.2.6.2.4, if applicable.


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8.5
STATEMENT OF CONFIDENTIALITY AND PATIENT PRIVACY
Data protection and data security measures are implemented for the collection, storage and 
processing of patient data in accordance with the principles 7 and 12 of the WHO GCP 
handbook.
Individual patient data obtained as a result of this trial is considered confidential and 
disclosure to third parties is prohibited with the following exceptions:
Personalised treatment data may be given to the patient’s personal physician or to other 
appropriate medical personnel responsible for the patient’s welfare. Data generated at the site
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.
8.5.1
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 ICF is in place

A fit for the purpose documentation (biomarker proposal, analysis plan and report) 
ensures compliant usage

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 the whole trial
(“Last Patient Completed”). The “Last Patient Last Treatment” (LPLT) date is defined as 
the date on which the last patient in the whole trial is administered the last dose of trial 
treatment (as scheduled per protocol or prematurely). Individual investigators will be notified 
of SUSARs occurring with the trial medication until 30 days after LPLT at their site.


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Early termination of the trial is defined as the premature termination of the trial due to 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.
A final report of the clinical trial data will be written only after all subjects have completed 
the trial to incorporate and consider all data in the report.
8.7
ADMINISTRATIVE STRUCTURE OF THE TRIAL
The trial is sponsored by Boehringer Ingelheim (BI).
The trial will be conducted at one clinical site. A Principal Investigator is responsible to 
coordinate co-investigators at the site participating in this trial. Tasks and responsibilities are
defined in a contract. 
Relevant documentation on the participating Investigators (e.g. their curricula vitae) will be 
filed in the ISF.
BI has appointed a Clinical Trial Leader (CT Leader), responsible for coordinating all 
required activities, in order to 
-
manage the trial in accordance with applicable regulations and SOPs applicable in a 
FOT setting,
-
direct the clinical trial team in the preparation, conduct, and reporting of the trial,
-
ensure appropriate training and oversight of the vendors.
The organisation of the trial will be performed by a Contract Research Organisation (CRO) 
with which the responsibilities and tasks will have been agreed and a written contract filed 
before initiation of the clinical trial.
CRO will perform Project Management, Clinical Field Monitoring, Medical Monitoring,
Data Management, Statistical Evaluation and Reporting. 
Tasks and functions assigned in order to organise, manage, and evaluate the trial are defined 
according to BI and CRO 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
R19-2246
Highlights of prescribing information, CIPRO (ciprofloxacin hydrochloride) 
tablet, for oral use.
R19-3127
Ciprofloxacin 
US PI 03-2019
R19-2247
S10 Photosafety Evaluation of Pharmaceuticals. Guidance for Industry.
R19-3037
 
TheDGAT 1inhibitor pradigastat does not induce photosensitivity in healthy 
human subjects: a randomized controlled trial using three defined sunlight 
exposure conditions. Photochem Photobiol Sci 15 (9), 1155 - 1162 (2016)
9.2
UNPUBLISHED REFERENCES
001-MCS-36-472 Standards and processes for analyses performed within Clinical 
Pharmacokinetics/Pharmacodynamics. Current version.
c09228382
Investigators´s Brochure. BI 730357. Psoriasis (ankylosing spondylitis, 
psoriatic arthritis, asthma, inflammatory bowel disease). Current version.
n00250111
 
Prediction of BI 730357 Pharmacokinetics and Therapeutic Dose in Human. 
Current version.


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10.
APPENDICES
10.1
RESTRICTED MEDICATION AND FOOD 
Other investigational products
•
30 days or 5 half-lives, whatever is longer, prior 
to randomization through EOT
Disease, surgery
•
Major surgery performed within 8 weeks prior 
to screening visit or planned within 8 weeks
after screening visit (e.g. hip replacement)
-Drugs or foods (e.g., seville oranges, 
grapefruit, paw paw and their products) which 
are strong or moderate inhibitors or inducers of 
CYP3A4 (e.g, rifampicin, phenytoin), or
-Sensitive substrates of CYP1A2 (e.g., 
alosetron, duloxetine, melatonin, ramelteon, 
tasimelteon, theophylline, tizanidine, and 
caffeine when used as a medication), or 
-Sensitive substrates of CYP 2B6 (e.g., 
bupropion).
•
One week prior to randomisation until EOT
(Sensitive substrates of CYP3A4 are not 
excluded from the trial).
Drugs which are substrates of P-gp (e.g. 
dabigatran, digoxin and fexofenadine etc.)
•
One week prior to randomisation until EOT
Drugs with known phototoxic or photoallergic 
potential
(e.g., tetracyclines, fluoroquinolones)
•
One week prior to randomisation until EOT
BCG (Bacillus Calmette-Guérin) vaccine
•
1 year prior to randomisation through 1 year 
after last administration of study drug


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10.2
TIME SCHEDULE FOR PHARMACOKINETIC (PK) BLOOD 
SAMPLING
Table 10.2: 1
Time schedule for PK blood sampling during treatment course A 400 
mg QD
Day
Time Point 
[hh:min]1
CRF 
Time
/PTM
Event
Sample 
No.
1
Just before drug 
administration
-1:00
PK Blood
1
0:00
0:00
1st Drug 
administr.
---
4:00
4:00
PK Blood
2
2
8:00/Predose
24:00
PK Blood
3
3
8:00/Predose
48:00
PK Blood
4
4
8:00/Predose
72:00
PK Blood
5
5
8:00/Predose
96:00
PK Blood
6
6
8:00/Predose
120:00
PK Blood
7
7
8:00/Predose
144:00
PK Blood
8
8 
8:00/Predose
168:00
PK Blood
9
9:00
169:00
PK Blood
10
10:00
170:00
PK Blood
11
11:00
171:00
PK Blood
12
12:00
172:00
PK Blood.
13
14:00
174:00
PK Blood
14
20:00
180:00
PK Blood
15
9
8:00
192:00
PK Blood
16
10
8:00
216:00
PK Blood
17
11
8:00
240:00
PK Blood
18
1 Time windows allowed for PK sampling:
Within 1 h pre-dose and 4 h post dose on day 1; -10 min pre-dose samples on days 2 to 8; +/-
5 min 1/2/3/4/6/12 h on day 8; +/- 15 min on days 9/10/11. 


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Table 10.2: 2
Time schedule for PK blood sampling during treatment course A 300 
mg BID
Day
Time Point 
[hh:min]1,2
CRF 
Time
/PTM
Event
Sample 
No.
1
Just before drug 
administration
-1:00
PK Blood
1
8:00
0:00
1st Drug 
administr.
---
9:00
1:00
PK Blood
2
10:00
2:00
PK Blood
3
11:00
3:00
PK Blood
4
12:00
4:00
PK Blood
5
14:00
6:00
PK Blood
6
16:00
8:00
PK Blood
7
18:00
10:00
PK Blood
8
20:00
12:00
PK Blood
9
5
8:00/Predose
96:00
PK Blood
10
6
8:00/Predose
120:00
PK Blood
11
7
8:00/Predose
144:00
PK Blood
12
8 
8:00/Predose
168:00
PK Blood
13
9:00
169:00
PK Blood
14
10:00
170:00
PK Blood
15
11:00
171:00
PK Blood
16
12:00
172:00
PK Blood.
17
14:00
174:00
PK Blood
18
20:00
180:00
PK Blood
19
9
8:00
192:00
PK Blood
20
10
8:00
216:00
PK Blood
21
11
8:00
240:00
PK Blood
22
1 Time windows allowed for PK sampling:
Within 1 h pre-dose  and 4 h post dose on day 1; -10 min pre-dose samples on days 5 to 8; +/-
5 min 1/2/3/4/12 h on day 8; +/- 15 min on days 9/10/11. 
2 All timepoints are relative to the drug administration time.


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11.
DESCRIPTION OF GLOBAL AMENDMENT(S)
11.1
GLOBAL AMENDMENT 1
Date of amendment
05 Mar 2020
BI Trial number
1407-0037
BI Investigational Medicinal 
Product
BI 730357
Title of protocol
Partially-blind, randomized, parallel group, placebo 
and active comparator-controlled Phase I clinical 
trial to evaluate the photosensitivity potential of BI 
730357
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
4.1.5.1 Blinding; 
7.2.7 Interim analysis;
Description of change
The following sentence was added on page 38:
In addition, the trial pharmacokineticist may receive 
the blinded (dummy subject numbers will be used) 
results of the measurements to perform the 
preliminary PK analysis.
The following sentence was added on page 62:
In addition, a preliminary blinded PK analysis will 
be performed to estimate the PK exposure.
Rationale for change
The administrative amendment is incorporated to 
allow preliminary analysis of blinded PK data. The 
results from the blinded PK analysis will be 
compared with the historical data upon which the 
study was designed. This blinded evaluation 
possibility was overseen in the original protocol, 
and is now added per this non-substantial 
amendment  


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11.2
GLOBAL AMENDMENT 2
Date of amendment
01 Apr 2020
BI Trial number
1407-0037
BI Investigational Medicinal 
Product
BI 730357
Title of protocol
Partially-blind, randomized, parallel group, placebo 
and active comparator-controlled Phase I clinical 
trial to evaluate the photosensitivity potential of BI 
730357
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
Synopsis; Flow chart 300 mg BID; 
1.4.2 Risks; 
3.1 Overall Trial Design; 3.2 Discussion of Trial 
Design; 
4.1.1 Investigational Treatments;
4.1.2 Selection of doses in the trial and dose 
modifications
7.5 Determination of Sample size analysis;
Description of change
Additional dose group 300 mg of BI 730357 or 
Placebo BID has been added.
Rationale for change
Results of the Week 12 primary analysis for trial 
1407-0030 demonstrated proof-of-concept, as well 
as acceptable safety and tolerability in the treatment 
of patients with moderate-to-severe plaque PsO for 
BI 730357 at the 200 mg dose;
Modelling of primary analysis data indicates that the 
efficacy plateau of BI 730357 may not have been 
reached with 200 mg dose q.d., and that higher 
exposures may provide better efficacy. Therefore
efficacy, safety, tolerability, and pharmacokinetics 
of BI 730357 400 mg q.d. and 200 mg b.i.d. will be 


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evaluated as possible therapeutic doses in patients.
Psoriasis patients have shown higher exposures than 
those of healthy volunteers; therefore in order to 
investigate possible phototoxic effects in exposures 
which approximate those of patients treated with 
200 mg b.i.d., healthy volunteers will be treated with 
300 mg b.i.d. under fed conditions in this trial. 


 
 
 
 
APPROVAL / SIGNATURE PAGE 
 
Document Number: 
 
Technical Version Number:
 
Document Name: 
 
 
 
                                                                                                                 
 
Title: 
 
 
 
 
                                                                                                                   
 
Signatures (obtained electronically) 
 
Meaning of Signature  
Signed by 
Date Signed 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
c27983101
3.0
clinical-trial-protocol-version-03
Partially-blind, randomized, parallel group, placebo and active comparator-controlled
Phase I clinical trial to evaluate the photosensitivity potential of BI 730357
Author-Clinical Trial Leader
01 Apr 2020 14:53 CEST
Author-Trial Statistician
01 Apr 2020 15:02 CEST
Author-Trial Clinical
Pharmacokineticist
01 Apr 2020 16:00 CEST
Approval-Therapeutic Area 
01 Apr 2020 16:19 CEST
Approval-Team Member Medicine
01 Apr 2020 18:37 CEST
Verification-Paper Signature
Completion
01 Apr 2020 18:38 CEST


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Document Number: 
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(Continued) Signatures (obtained electronically) 
 
Meaning of Signature  
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Date Signed 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
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BOEHRINGER INGELHEIM 
STATISTICAL ANALYSIS PLAN: PROTOCOL 1407-0037 
Page 1 of 43 
 
STATISTICAL ANALYSIS PLAN 
 
 
1407-0037 
PARTIALLY-BLIND, RANDOMIZED, PARALLEL GROUP, PLACEBO AND ACTIVE 
COMPARATOR-CONTROLLED PHASE I CLINICAL TRIAL TO EVALUATE THE 
PHOTOSENSITIVITY POTENTIAL OF BI 730357 
 
 
AUTHOR:
VERSION NUMBER AND DATE: V2.0, 23JUL2020 
 
 
 
 












24 Jul 2020


 
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730357 or placebo) which was added as 
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STATISTICAL ANALYSIS PLAN: PROTOCOL 1407-0037 
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TABLE OF CONTENTS 
1. INTRODUCTION ................................................................................................................................ 9 
2. STUDY OBJECTIVES ......................................................................................................................... 9 
2.1. 
Primary Objective ........................................................................................................................................9 
2.1.1. 
Primary Endpoints ....................................................................................................................................10 
2.1.2. 
Secondary Endpoints ................................................................................................................................10 
2.3. 
Safety Objectives ....................................................................................................................................... 11 
3. STUDY DESIGN ............................................................................................................................... 11 
3.1. 
General Description ................................................................................................................................... 11 
3.2. 
Schedule of Events..................................................................................................................................... 12 
3.3. 
Changes to Analysis from Protocol ............................................................................................................ 12 
4. PLANNED ANALYSES .................................................................................................................... 13 
4.1. 
Interim Analysis ......................................................................................................................................... 13 
4.2. 
Final Analysis ............................................................................................................................................. 13 
5. ANALYSIS SETS .............................................................................................................................. 13 
5.1. 
Enrolled Set (ES) ........................................................................................................................................ 13 
5.2. 
Treated Set (TS) ......................................................................................................................................... 13 
5.3. 
Full Analysis Set (FAS) ................................................................................................................................ 14 
5.4. 
Pharmacokinetic Set (PKS) ......................................................................................................................... 14 
6. GENERAL CONSIDERATIONS ..................................................................................................... 14 


 
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6.1. 
Summary Statistics .................................................................................................................................... 14 
6.2. 
Treatment Summarization ......................................................................................................................... 15 
6.3. 
Precision .................................................................................................................................................... 15 
6.4. 
Reference Start Date and Study Day .......................................................................................................... 15 
6.5. 
Baseline ..................................................................................................................................................... 16 
6.6. 
Retests, Unscheduled Visits and Early Termination Data ........................................................................... 16 
6.7. 
Common Calculations ................................................................................................................................ 16 
6.8. 
Software Versions ..................................................................................................................................... 16 
7. STATISTICAL CONSIDERATIONS ............................................................................................. 17 
7.1. 
Missing data .............................................................................................................................................. 17 
8. OUTPUT PRESENTATIONS ......................................................................................................... 17 
9. DISPOSITION AND WITHDRAWALS ....................................................................................... 17 
10. 
DEMOGRAPHIC AND OTHER BASELINE CHARACTERISTICS ...................................... 18 
10.1. 
Derivations ............................................................................................................................................ 18 
11. 
PROTOCOL DEVIATIONS ......................................................................................................... 18 
11.1. 
Deviations Related to Study Conduct ..................................................................................................... 18 
12. 
MEDICAL HISTORY AND PREVIOUS SURGICAL PROCEDURES ................................... 20 
13. 
MEDICATIONS ............................................................................................................................ 20 
14. 
STUDY MEDICATION EXPOSURE .......................................................................................... 20 


 
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15. 
ANALYSIS OF PHOTOSENSITIVITY ...................................................................................... 21 
15.1. 
Assessment of Photosensitivity ............................................................................................................. 21 
15.2. 
Primary Analysis of Photosensitivity ...................................................................................................... 22 
15.3. 
Null and Alternative Hypotheses ........................................................................................................... 23 
15.3.1. 
400 mg QD Dose Cohort ...........................................................................................................................23 
15.3.2. 
300 mg BID Dose Cohort ...........................................................................................................................24 
15.4. 
Primary Endpoint Analysis of Photosensitivity Index ............................................................................. 24 
15.5. 
Secondary Endpoint Analyses ................................................................................................................ 25 
17. 
SAFETY OUTCOMES .................................................................................................................. 26 
17.1. 
Adverse Events ...................................................................................................................................... 27 
17.1.1. 
TEAEs Leading to Discontinuation of Study Medication ...........................................................................28 
17.1.2. 
Serious Adverse Events .............................................................................................................................28 
17.1.3. 
Adverse Events of Special Interest ...........................................................................................................28 
17.2. 
Deaths ................................................................................................................................................... 29 
17.3. 
Laboratory Evaluations .......................................................................................................................... 29 
17.3.1. 
Drug Induced Liver Injury (DILI) ................................................................................................................30 
17.3.2. 
Laboratory Reference Ranges and Abnormal Criteria ..............................................................................30 
17.4. 
Vital Signs .............................................................................................................................................. 31 
17.5. 
ECG Evaluations ..................................................................................................................................... 31 
17.6. 
Physical Examination ............................................................................................................................. 31 
18. 
REFERENCES ............................................................................................................................... 32 


 
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Page 8 of 43 
APPENDIX 1. PROGRAMMING CONVENTIONS FOR OUTPUTS ............................................... 33 
Output Conventions .............................................................................................................................................. 33 
Dates & Times ....................................................................................................................................................... 35 
Spelling Format ..................................................................................................................................................... 35 
Presentation of Treatment Groups ....................................................................................................................... 35 
Presentation of Visits ............................................................................................................................................ 36 
Presentation of Nominal Times ............................................................................................................................. 36 
Listings .................................................................................................................................................................. 36 
APPENDIX 2. PARTIAL DATE CONVENTIONS .............................................................................. 38 
Algorithm for Treatment Emergence of Adverse Events: ...................................................................................... 38 
Algorithm for Prior / Concomitant Medications: ................................................................................................... 39 
APPENDIX 3. LABORATORY TESTS ................................................................................................. 41 
 
 


 
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1. INTRODUCTION 
As per ICH E9, 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, 
randomization 
This TSAP Version 2.0 is based on Protocol Version 3.0, (ie, Amendment 2) dated 01 April 2020 and is an 
amendment to the TSAP Version 1.0 which was finalized on 26 February 2020. This TSAP amendment 
adds a description of the statistical analysis of the additional dose group of 300 mg BID (subjects 
randomized to BI 730357 300 mg BID or placebo 300 mg BID) added to the study by the above mentioned 
protocol. 
For the assessment of photosensitivity, statistical analyses for both the double-blind randomized 400 mg 
QD dose group (subjects randomized to BI 730357 400 mg QD or placebo) and the double-blind 
randomized 300 mg BID dose group (randomized to BI 730357 300 mg BID or placebo) will be identical 
but will be performed separately.  
This TSAP is developed using the 
 statistical analysis plan templates. The operating procedures 
(SOPs) and programming standards of the Sponsor will be followed for this study. 
2. STUDY OBJECTIVES 
2.1. PRIMARY OBJECTIVE 
The primary objective of this trial is to evaluate the photosensitivity potential of BI 730357 compared to 
placebo and a mild photosensitizer ciprofloxacin as positive control, assessed by the Photosensitivity 
Index (PI), changes in Minimum Erythema Dose (MED), erythema, and local skin reactions following 
exposure to UVA and UVB radiation. All endpoints are applicable for Treatment A and Treatment B parts. 


 
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2.1.1. 
PRIMARY ENDPOINTS 
• 
Photosensitivity index at 24 hours under Condition 1 (i.e., under full range of UVB/UVA 
exposure) 
• 
Photosensitivity index at 24 hours under Condition 2 (i.e., under UVA exposure only) 
2.1.2. 
SECONDARY ENDPOINTS 
• 
Photosensitivity index at 10 minutes under Condition 1 
• 
Photosensitivity index at 1 hour under Condition 1 
• 
Photosensitivity index at 10 minutes under Condition 2 
• 
Photosensitivity index at 1 hour under Condition 2 
• 
MED percent change from baseline at 10 minutes, 1 hour, and 24 hours measured under 
Condition 1 and Condition 2 
 


 
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2.3. SAFETY OBJECTIVES 
Safety and tolerability objectives are to be assessed in terms of adverse events (AEs), including AEs of 
special interest (AESIs), laboratory assessments, vital signs, electrocardiograms (ECG), and physical 
examination. 
3. STUDY DESIGN 
3.1. GENERAL DESCRIPTION 
The trial will be performed as partially-blind, randomized, parallel group, placebo and active comparator 
controlled Phase I clinical trial in healthy male and female subjects aged ≥18 to ≤ 55 years. The subjects 


 
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will be randomized to one of the two treatments parts (Treatment Part A [Treatment A] or Treatment 
Part B [Treatment B]) in a 3:1 (A:B) manner first and then Treatment Part A will be conducted according 
to a randomized, double-blind, placebo-controlled design to assess the photosensitivity potential, safety 
and tolerability, and pharmacokinetics of multiple doses of BI 730357. In Treatment A, subjects enrolled 
under the original protocol Version 1.0 will be randomized in a 3:1 manner to receive 400 mg QD of BI 
730357 or placebo and subjects enrolled under the protocol Version 3.0 will be randomized in a 3:1 
manner to receive 300 mg BID of BI 730357 or placebo. 
Treatment Part B will be conducted according to an open-label, observer-blinded design to assess the 
photosensitivity potential of ciprofloxacin (a mild photosensitizer) as a positive control. 
In total, approximately 84 healthy male and female subjects (36 subjects in Treatment A for 400 mg QD; 
36 subjects in Treatment A for 300 mg BID; 12 subjects in Treatment B) are planned to be randomized 
in this trial to allow for at least 74 completed subjects. 
Treatment A: 
Subjects enrolled under Protocol Version 1.0 will receive 400 mg of BI 730357 or placebo once daily over 
8 days in order to reach pharmacokinetic steady state.  Similarly, subjects enrolled under Protocol 
Version 3.0 will receive 300 mg of BI 730357 or placebo twice daily 12 hours apart over 7 days with a 
single dose on Day 8 in order to reach pharmacokinetic steady state. Photosensitivity assessments will 
occur at baseline and following the last dose of either BI 730357 or placebo. 
Treatment B: 
Subjects will receive 500 mg ciprofloxacin starting on the morning of Day 3. Twelve (12) hours later, 
subjects received their second dose of 500 mg ciprofloxacin. Subjects continued a twice-daily dosing 
regimen through to the morning of Day 8 to ensure they reached pharmacokinetic steady state. 
Photosensitivity assessments will occur at baseline and following the last dose of ciprofloxacin. 
3.2. SCHEDULE OF EVENTS 
Visit schedules can be found in the protocol (see Flow Chart for Treatment A and Flow Chart for 
Treatment B). 
3.3. CHANGES TO ANALYSIS FROM PROTOCOL 
The further objective of 
 
 will not be performed for this study. 
The primary, secondary 
 endpoints referred in the protocol as “Phototoxicity index” are 
changed to the appropriate name “Photosensitivity index” (see Sections 2.1.1, 2.1.2 and 2.2.1 above). 


 
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Page 13 of 43 
4. PLANNED ANALYSES 
4.1. INTERIM ANALYSIS  
There are no formal statistical interim analyses planned for this study. However, after completion of the 
400mg dose group, the independent Investigator and BI medical representatives will review blinded 
photosafety data of treatment A group to determine the acceptability of photosafety. After the team 
review of these data, it may be recommended to terminate the trial based on favourable results of 
400mg, or in case of unfavourable results - to test the lower dose in of 200mg for treatment A. However, 
primary analysis of ongoing PoC trial have shown higher exposures in Psoriasis patients than those of 
healthy volunteers; therefore, in order to investigate possible phototoxic effects in exposures which 
approximate those of patients treated with 200 mg BID, healthy volunteers should be treated with 
300 mg BID. under fed conditions in this trial. 
4.2. FINAL ANALYSIS  
All final, planned analyses identified for non-PK data in this SAP will be performed by 
 Biostatistics 
following sponsor authorization of this Statistical Analysis Plan, identification of important protocol 
deviations requiring analysis exclusions, database lock, determination of analysis sets, and unblinding of 
treatment. All final, planned analyses for PK data will be performed by the Sponsor. 
5. ANALYSIS SETS 
Agreement and authorization of subjects included/ excluded from each analysis set will be conducted 
prior to the unblinding of the study. 
5.1. ENROLLED SET (ES) 
The enrolled set will contain all subjects who provide informed consent for this study. Subjects in this 
population will be used for disposition summaries and listings as appropriate. 
5.2. TREATED SET (TS) 
The treated set includes all subjects who were randomized and treated with at least one dose of study 
drug (BI 730357, Placebo or ciprofloxacin). The treated set will be used for safety analyses and 
randomized treatment will be used for safety analysis. 


 
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5.3. FULL ANALYSIS SET (FAS) 
This set includes all subjects in the treated analysis set who provide at least one photosensitivity 
endpoint that was defined as primary or secondary and was not excluded due to an important protocol 
deviation relevant to the evaluation of photosensitivity. Descriptive and model based analyses of 
photosensitivity endpoints will be based on the FAS. 
5.4. PHARMACOKINETIC SET (PKS) 
The pharmacokinetic set includes all subjects who were randomized and treated with at least one dose 
of study drug BI 730357 and have at least one evaluable primary PK parameter, and are without 
important protocol deviations thought to have a relevant impact on the PK of BI730357. Whether a 
protocol deviation is relevant will be decided no later than in the report planning meeting. 
6. GENERAL CONSIDERATIONS 
Derivation of the PK parameters for BI 730357, in plasma, and generation of the PK analysis datasets, 
and statistical outputs (table, listing and figures), will be the responsibility of the sponsor. 
 
biostatistics is only responsible for generating PK SDTM datasets PC and PP using the PK concentration 
and PK parameter data files received from the sponsor. 
The summaries and data listings of all non-PK data as well as the statistical inferential analyses of the 
primary, secondary and further endpoints of photosensitivity variables will be the responsibility of the 
study biostatistician at 
 
Some minor modifications may be necessary to the planned design of tables, figures, and listings to 
accommodate data collected during the actual study conduct. 
6.1. SUMMARY STATISTICS 
For qualitative variables, the population size (N for sample size and n for available data) and the 
percentage (of available data) for each class of the variable will be presented.  Quantitative variables 
will be summarized using descriptive statistics, including n, mean, standard deviation (SD), median, 
interquartile range (IQR calculated as third quartile [Q3] minus first quartile [Q1]), minimum, and 
maximum values.  In addition, 10th percentile (P10), 90th percentile (P90), coefficient of variation (CV%), 
geometric mean (gMean) and geometric CV% (gCV%) will also be presented for PK concentration data 
and all PK parameters, where applicable. 
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 (%) relative to the respective treatment 


 
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group. The category missing will be displayed only if there are actually missing values. 
6.2. TREATMENT SUMMARIZATION 
In general, data will be presented for each treatment group (BI 730357 400 mg QD, Placebo QD, BI 
730357 300 mg BID, Placebo BID and ciprofloxacin 500 mg BID). Data for subjects in the following 
combined treatment groups will also be presented when appropriate: 
• 
All subjects combined, presented as Overall 
• 
All BI 730357 treated subjects combined from the 2 dose groups, presented as BI 730357 Pooled 
• 
All placebo treated subjects combined from the 2 dose groups, presented as Placebo Pooled 
6.3. PRECISION 
Non-PK variables (ie, primary, secondary, further endpoints and safety variables), including derivations 
thereof, will be reported to the same precision as the source data. Derived variables will be reported 
using the same precision to those from which they were derived. For the reporting of descriptive 
statistics, the minimum and maximum values will be presented to the same precision as the source data 
(base precision); base precision+1 for the mean, median and confidence intervals (CIs); and base 
precision+2 for the SD and IQR (see APPENDIX 1). Percentages will be presented with one decimal point. 
6.4. REFERENCE START DATE AND STUDY DAY 
Study Day will be calculated from the reference start date, and will be used to show start/stop day of 
assessments and events.  
Reference start date is defined as the day of the first dose of study medication (Day 1 is the day of the 
first dose of study medication), and will appear in every listing where an assessment date or event date 
appears.  
• 
If the date of the event is on or after the reference date then:  


 
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Study Day = (date of event – reference date) + 1. 
• 
If the date of the event is prior to the reference date then:  
Study Day = (date of event – reference date). 
In the situation where the event date is partial or missing, Study Day, and any corresponding durations 
will appear partial or missing in the listings. 
6.5. BASELINE 
Unless otherwise specified, baseline is defined as the last scheduled non-missing measurement taken 
prior to dosing and will generally correspond to Day -1 or Day 1, predose for safety assessments.  
However, if a subject is missing the planned baseline collection, the previous non-missing scheduled 
evaluation will become the baseline value. In the case where the last scheduled non-missing 
measurement (except for AEs and concomitant medications [CMs]) and the date and/or time of study 
drug coincide, that measurement will be considered as collected prior to study drug administration. 
Baseline for photosensitivity assessments will be the assessment collected on Day -2 (Conditions 1 and 
2) or Day -1 (Condition 3) (see Section 15.1 for the definitions of baseline for photosensitivity 
assessment) 
6.6. RETESTS, UNSCHEDULED VISITS AND EARLY TERMINATION DATA 
Unscheduled measurements will not be included in summary statistics, but will contribute to the 
best/worst case value where required (e.g. shift tables) and assessment of clinical outliers.  Early 
termination results will be recorded as such, and included with the end-of-treatment (EOT) summaries. 
In the case of a retest of a scheduled assessment, the earliest available measurement for that scheduled 
time (i.e. the original assessment) will be used for summaries unless flagged as invalid.  
Listings will include all scheduled, unscheduled, retest and early discontinuation data. 
6.7. COMMON CALCULATIONS 
For quantitative measurements, change from baseline will be calculated as: 
 
• 
Value after baseline – Baseline Value 
6.8. SOFTWARE VERSIONS 
All derivations, statistical analyses, summaries and listings will be generated using SAS version 9.4 or 


 
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higher (SAS Institute, Inc., Cary, North Carolina). Non-compartmental pharmacokinetic parameter 
calculations will be performed using Phoenix® WinNonLin 64 Build 8.1.0.3530. 
7. STATISTICAL CONSIDERATIONS 
7.1. MISSING DATA 
Missing safety data will not be imputed. 
8. OUTPUT PRESENTATIONS 
APPENDIX 1 shows conventions for presentation of data in outputs. 
The templates provided with this TSAP describe the presentations for this study and therefore the 
format and content of the summary tables, figures and listings to be provided by 
 Biostatistics. 
9. DISPOSITION AND WITHDRAWALS 
Subject disposition and withdrawals will be tabulated by treatment part/treatment for the enrolled set 
by summarizing the number (percent) of subjects: 
• 
Enrolled 
• 
Failed screening 
• 
Randomized 
• 
Treated 
• 
Completed treatment 
• 
Discontinued treatment prematurely, and the reason for early discontinuation 
• 
Completed study  
• 
Discontinued study prematurely, and the reason for early discontinuation. 
The denominator for calculating percentages will be the number of subjects in the respective treatment 
group. 
A listing of subject disposition data will be provided. In a separate listing, the inclusion/exclusion of 
subjects in the different analysis sets will be presented. 
Listings of study eligibility, treatment randomization, and study treatment administration will be 


 
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provided. 
10. DEMOGRAPHIC AND OTHER BASELINE CHARACTERISTICS 
The following demographic and baseline characteristics will be tabulated by treatment and overall for 
the treated set: 
• 
Age (years) 
• 
Sex 
• 
Childbearing status 
• 
Race 
• 
Ethnicity 
• 
Height (cm) 
• 
Weight (kg) 
• 
Body mass index (BMI) (kg/m2) 
• 
Fitzpatrick skin type. 
Descriptive statistics (n, mean, SD, median, IQR, minimum, and maximum) will be presented for 
continuous variables. Frequency counts and percentages will be presented for categorical variables. No 
statistical testing will be carried out for demographic or other baseline characteristics. 
Individual subject demographics and baseline characteristics will be presented in listings. 
10.1. DERIVATIONS 
• 
BMI (kg/m2) = weight (kg)/ height (m)2 
• 
Age (years) = Integer value of [(Date of informed consent – date of birth + 1)/365.25] 
11. PROTOCOL DEVIATIONS 
11.1. DEVIATIONS RELATED TO STUDY CONDUCT 
A protocol deviation is any noncompliance with the clinical trial protocol, good clinical practice (GCP), or 
Manual of Procedure requirements.  The noncompliance may be either on the part of the subject, the 
site principal investigator, or the study site staff. Protocol deviations will be listed including a 


 
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classification of minor, major or critical as determined by clinical staff. Whether a protocol deviation is 
relevant for the statistical analysis will be decided no later than in the final blinded report planning 
meeting. 
The reasons for exclusion of single data may include (but are not limited to): 
• 
Incorrect trial medication taken 
• 
Important violation of treatment compliance 
• 
Use of restricted medications 
• 
Important violation of inclusion/exclusion criteria 
• 
Inclusion Criteria 1 - Healthy male and female subjects according to the assessment of the 
Investigator, based on a complete medical history, physical examination (including 
dermatological skin type assessment), vital signs (blood pressure, pulse rate), 12-lead ECG, 
and clinical laboratory tests 
• 
Inclusion Criteria 4 - Fitzpatrick skin type I, II, or III (I: always burns easily, never tans; II: 
always burns easily, tans minimally; and III: burns moderately, tans gradually) 
• 
Inclusion Criteria 5 - No ultraviolet exposure of the test areas 4 weeks prior to baseline photo 
testing 
• 
Inclusion Criteria 6 - Normal skin response during preliminary photo testing 
• 
Exclusion Criteria 6 - Active skin disorders on the back where photosensitivity testing will be 
performed 
• 
Exclusion Criteria 7 - Subjects who must or wish to continue the intake of restricted 
medications or any drug considered likely to interfere with the safe conduct of the trial 
• 
Exclusion Criteria 12 - -History of hypersensitivity to ciprofloxacin, any member of the 
quinolone class of antibacterials 
• 
Exclusion Criteria 22 - -Unwillingness to adhere to the rules of UV-light protection as 
described in section 4.2.2 of the protocol 


 
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12. MEDICAL HISTORY AND PREVIOUS SURGICAL PROCEDURES 
Medical History and previous surgical procedures coded using Medical Dictionary for Regulatory 
Activities (MedDRA) will be listed for the treated set. 
13. MEDICATIONS 
Medication usage will be coded using the WHO Drug Dictionary Global (Enhanced w/WHO Herbal 
Dictionary) B3 format. No Anatomical Therapeutic Chemical (ATC) class coding will be performed. 
• 
‘Prior’ medications are medications which started and stopped prior to the first dose of study 
medication. 
• 
‘Concomitant’ medications are medications which were taken during the treatment period, or 
specifically:  
o 
started on or after the first dose of study medication or 
o 
started prior to the first dose of study medication and were continued after the first dose 
of study medication 
• 
‘Post’ medications are medications which started after following the last dose of study 
medication. 
See APPENDIX 2 for handling of partial dates for medications, in the case where it is not possible to 
define a medication as prior, concomitant, or post treatment, the medication will be classified by the 
worst case; i.e. concomitant. 
All medications will be displayed in a listing, with an additional flag to state if the medication is a ‘Prior’, 
‘Concomitant’ or ‘Post’ medication will be provided for the treated set. 
14. STUDY MEDICATION EXPOSURE 
In 400 mg QD dose group, BI 730357 and matching placebo will be administered QD over 8 days from 


 
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Day 1 (total of 8 doses) in double-blind manner and ciprofloxacin will be administered BID over 5 days 
from Day 3 with a single dose on Day 8 (total of 11 doses) in an open-label manner.  In 300 mg BID dose 
group, BI 730357 and matching placebo will be administered BID over 7 days from Day 1 with a single 
dose on Day 8 (total of 15 doses) in double-blind manner.  Exposure to study medication as the number 
of doses administered will be presented by treatment for the treated set. 
Study medication administration data will be provided in a data listing. 
15. ANALYSIS OF PHOTOSENSITIVITY 
For the assessment of photosensitivity, statistical analyses described below will be performed separately 
for the 400 mg QD dose group (randomized to 400 mg QD BI 730357 or placebo QD) and 300 mg BID 
dose group (randomized to 300 mg BID BI 730357 or placebo BID). The same ciprofloxacin group will be 
used as a positive control group in both analyses. 
15.1. ASSESSMENT OF PHOTOSENSITIVITY 
Skin irradiation will be performed with the following three different conditions, meant to simulate three 
different environmental sunlight exposure scenarios/conditions: 
• 
Condition 1: Full range solar UVB/UVA (290 to 400 nm, UBV content ~10%), simulating midday 
summer outdoor sun exposure (assessed in μw/cm2) 
• 
Condition 2: UVA only (320 to 400 nm, UVB content <0.03%), simulating indoor exposure behind 
window glass with a secondary assessment of erythema and local skin reactions at 25 J cm−2 
(assessed in mw/cm2) 
Subjects will be exposed to a series of 6 graded full range solar UVB/UVA exposures (Condition 1) and UVA 
only exposures (Condition 2), each 25% greater than the previous dose. Following irradiation, skin sites 
will be evaluated for erythema or skin darkening (for UVA-only exposure in the absence of additional, drug-
induced phototoxicity). 
The minimum erythema dose (MED) is defined as the lowest dose that produced uniform redness 
(Condition 1) or darkening (Condition 2) (assessed in joules (J) for UVA and millijoules (mJ) for UVB/UVA). 
The value of MED will be reported on electronic case report form (eCRF) at 10 minutes, 1 hour, and 24 
hours post-irradiation on Day -3 (MEDpreliminary values) and Day -2 (MEDbaseline values) and at 10 minutes, 1 
hour, 24 hours, 48 hours, and 72 hours post-irradiation on Day 10 (MEDon drug values). For Conditions 1 and 
2, MED assessments on Day -2 will provide precise baseline MED values (ie, MEDbaseline) for determining 
the photosensitivity index (PI). 


 
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The PI is derived as the ratio of the MEDbaseline versus MEDon drug (ie, MEDon drug/MEDbaseline) for irradiation 
Conditions 1 and 2. 
The percentage change in MEDon drug at 10 minutes, 1 hour, 24 hours, 48 hours, and 72 hours post-
irradiation will be calculated as follows: 
• 
% change = ([MEDon drug - MEDbaseline]/ MEDbaseline) x 100 
Derivation of the PI and percent change in MED at 10 minutes, 1 hour, and 24 hours time points will be 
performed using precise MEDbaseline values at the corresponding time point and derivation at 48 hours 
and 72 hours timepoints will be performed using the precise MEDbaseline at 24-hour time point. 
MED values reported as “> X” on eCRF will be converted to X for the purpose of statistical data analysis, 
but will be presented as recorded, i.e. as “> X” in the listings. 
15.2. PRIMARY ANALYSIS OF PHOTOSENSITIVITY 
The objective of this trial is to investigate the photosensitivity under three distinct exposure conditions 
of BI 730357 following 8 days of administration (i.e. at steady state) on the basis of the primary and 
secondary endpoints.  The trial is designed to allow comparisons between BI 730357 and placebo as well 
as BI 730357 and a positive control (ciprofloxacin) for each of 2 dose cohorts (400 mg QD and 300 mg 
BID) separately.  These comparisons will be evaluated statistically for each dose cohort separately by use 
of a mixed model for repeated measures (MMRM). The analysis of primary, secondary and further 
endpoints will be based on the FAS. 
 
The photosensitivity index (PI) under conditions 1 and 2 is the measurement used for the primary 
endpoints.  It is defined as the ratio of the precise MEDbaseline to the MEDon-drug at each respective post-
irradiation timepoint.  Therefore, there will be MEDbaseline at 10 min, 1h, and 24h that will be used for the 
respective PI calculations, PI10min, PI1h, and PI24h.  For example, the PI1h will be the precise 
MEDbaseline/MEDon-drug where each MED was measured at the 1 hour post-irradiation time point.  The two 
primary endpoints are PI at 24 hours under conditions 1 and 2. 
 
For each dose cohort separately, a MMRM (with unstructured [UN] covariance) on PI values will be 
utilized for the primary analysis.  The model will include treatment (BI 730357 and Placebo from the 
respective dose cohort, Ciprofloxacin), time (10min, 1h, 24h, 48h, and 72h), and treatment-time 
interaction as fixed effects and subject as a random effect.  Adjusted means and differences in PI and 
90% CIs for the 2 contrasts of interest (i.e. BI 703357 – placebo at 24h) will be calculated from the model. 
 
The ANOVA model is described by the following equation: 
 
yijk =  + i + dij +  k + ()ik + eijk, where 
 
yijk = PI response measured at time k on subject j receiving treatment i, 
 
 = the overall mean, 


 
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i = the i-th treatment effect, i = 1, 2, 3,  
 
dij = the random effect associated with the j-th subject receiving treatment i,  
 
k = the k-th time effect, k = 1, 2, 3, 4, 5, and 
eijk = the random error associated with the j-th subject receiving treatment i at time k, 
where dij ~ MVN(0, i2I) and  eijk ~ MVN(0, 22I); MVN=multivariate normal. 
The SAS code for fitting the above ANOVA model will be similar to: 
PROC MIXED ; 
     CLASS treatment subject time ; 
     MODEL PI=treatment time treatment*time/DDFM=KR ; 
     REPEATED time / subject(treatment) type=un; 
     ESTIMATE statements to obtain point estimates and the corresponding 90%, 95% CIs for contrasts of 
interest; 
RUN ; 
 
For each dose cohort, the analysis will be carried out separately for Condition 1 and Condition 2. 
15.3. NULL AND ALTERNATIVE HYPOTHESES 
15.3.1. 
400 MG QD DOSE COHORT 
BI 730357 400 mg QD vs Placebo QD 
The assessment for absence of photosensitivity will be based upon the differences in mean 
photosensitivity index (PI) between BI 730357 400 mg QD and placebo QD two-sided 90% confidence 
intervals (CIs) for the differences in the photosensitivity index between BI 730357 400 mg QD and 
placebo QD using an acceptance range of -0.4 to 0.4.  This method is equivalent to the two-sided t-test 
procedure, each at the 5% significance level. 
The following hypotheses will be tested:  
Null hypothesis H0 (Photosensitive): 
 
µBI - µpbo ≤ -δ or µBI - µpbo ≥ δ 
Where µBI and µpbo are the means of the endpoint for BI 730357 400 mg QD and placebo QD, respectively, 
and δ is the limit that defines the acceptance range for photosensitivity equivalence.  
Alternative hypothesis Ha (Absence of photsensitivity): - δ < µBI - µpbo < δ 
In this trial, the equivalence limit δ is 0.4 which is consistent with historical criteria used for positive 
photosensitivity for a drug [1]. 
The rejection of the null hypothesis at the a = 0.05 level is equivalent to the inclusion of the 90% 
confidence interval for µBI - µpbo in the acceptance range (-δ, δ). 


 
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Although there are multiple endpoints where the photosensitivity index will be statistically compared, 
an alpha adjustment is not needed because it is required that all endpoints meet the equivalence 
criterion as described above simultaneously. 
BI 730357 400 mg QD vs ciprofloxacin, Placebo QD vs ciprofloxacin 
Comparisons between the mean PI between BI 730357 400 mg QD and ciprofloxacin as well as between 
placebo QD and ciprofloxacin at the different timepoints under conditions 1 and 2 will be performed. 
At each timepoint the null hypothesis will be that there is no difference in the mean PI of BI 730357 
400 mg QD compared to ciprofloxacin: 
Null hypothesis H0: 
 
µBI/pbo - µcipro = 0 
Where µBI/pbo and µcipro are the means of the endpoint for BI 730357 400 mg QD or placebo QD and 
ciprofloxacin, respectively. 
The alternative hypothesis will be that the means are not equal: 
Alternative hypothesis Ha: 
µBI/pbo - µcipro ≠ 0 
A significant finding of increased photosensitivity of ciprofloxacin compared to BI 730357 400 mg QD 
and to placebo QD at the p<0.05 level will be supportive in concluding that the trial was appropriately 
designed to test the photosensitivity of BI 730357 400 mg QD. 
15.3.2. 
300 MG BID DOSE COHORT 
For comparisons of BI 730357 300 mg BID vs placebo BID, BI 730357 300 mg BID vs ciprofloxacin, and 
placebo BID vs ciprofloxacin, null and alternative hypotheses will be identical to the respective null and 
alternative hypotheses described above for the 400 mg QD dose cohort. 
15.4. PRIMARY ENDPOINT ANALYSIS OF PHOTOSENSITIVITY INDEX 
400 mg QD Dose Cohort: 
The primary analysis will be based on FAS for both conditions 1 and 2 at the 24 hour assessment. 
Least squares (LS) mean for the difference between BI 730357 400 mg QD and placebo QD along with 
the corresponding 2-sided 90% CI will be obtained from the MMRM described in Section 15.2 above. 
Absence of photosensitivity between BI 730357 400 mg QD and placebo QD will be concluded if the 2-
sided 90% CI is fully contained within the acceptance range (-0.4, 0.4). 
A significant finding of increased photosensitivity of ciprofloxacin compared to BI 730357 400 mg QD 
and to placebo QD at the p<0.05 level will be supportive in concluding that the trial was appropriately 
designed to test the photosensitivity of BI 730357 400 mg QD. 


 
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Additionally, descriptive statistics by treatment will be provided for the primary endpoints. 
For Conditions 1 and 2, figures of LS mean PI (+/- standard error [SE]) versus time points will be provided. 
300 mg BID Dose Cohort: 
The primary endpoint analysis of PI for the 300 mg BID dose cohort will be identical to that described 
above for the 400 mg QD dose cohort. Comparisons of BI 730357 300 mg BID vs placebo BID, BI 730357 
300 mg BID vs ciprofloxacin, and placebo BID vs ciprofloxacin will be performed. 
15.5. SECONDARY ENDPOINT ANALYSES 
400 mg QD Dose Cohort: 
The secondary endpoints for differences in PI at 10 minutes and 1 hour under Conditions 1 and 2 will be 
calculated from the same MMRM model as described for the primary analyses.  
Additionally, percent change from baseline in MED at 10 minutes, 1 hour, and 24 hours will be analyzed   
at each timepoint using the same MMRM model described in the primary analysis. 
LS means along with corresponding 95% CIs and p-values for the difference between BI 730357 400 mg 
QD and placebo QD; between BI 730357 400 mg QD and ciprofloxacin; and between placebo QD and 
ciprofloxacin will be obtained from the MMRM described in Section 15.2 above. 
For Conditions 1 and 2, figures of LS mean % change (+/- SE) versus time points will be provided. 
Additionally, descriptive statistics by treatment will be provided for the secondary endpoints. 
300 mg BID Dose Cohort: 
The secondary endpoint analyses for the 300 mg BID dose cohort will be identical to those described 
above for the 400 mg QD dose cohort. Comparisons of BI 730357 300 mg BID vs placebo BID, BI 730357 
300 mg BID vs ciprofloxacin, and placebo BID vs ciprofloxacin will be performed. 


 
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Page 26 of 43 
17. SAFETY OUTCOMES 
All safety assessments, including AEs, clinical laboratory evaluations, and vital signs will be listed and 
where appropriate summarized with descriptive statistics by treatment and scheduled visit/time point. 
Safety summaries will be provided for the following treatment group: Placebo Pooled (pooled from 2 
dose groups), BI 730357 400 mg QD, BI 730357 300 mg BID, BI 730357 Pooled (pooled from 2 dose 
groups) and Ciprofloxacin 500 mg BID. All summaries for safety outcomes will be based on the treated 
set using the randomized treatment. 
No statistical hypothesis testing is planned for safety data, unless otherwise specified with the relevant 
section. 


 
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17.1. ADVERSE EVENTS 
An AE is defined as any untoward medical occurrence in a patient or clinical investigation subject 
administered a medicinal product and which does not necessarily have to have a causal relationship with 
this treatment. An AE can therefore be any unfavorable and unintended sign (including an abnormal 
laboratory finding), symptom, or disease temporally associated with the use of a medicinal product, 
whether or not considered related to the medicinal product. 
Protocol-specified Adverse Events of Special Interest (AESI) and infection AEs are identified on the eCRF 
by the investigator. 
All adverse events with an onset between start of study medication and 7 days after the last dose study 
medication (i.e., end of the residual effect period [REP]) will be assigned to the on-treatment period for 
evaluation and considered as on-treatment AEs. Only on treatment AEs are considered for the summary 
of adverse events. Adverse Events (AEs) will be coded using MedDRA. 
Treatment-emergent adverse events (TEAEs) are defined as AEs occurring between start of study 
medication and 7 days after the last dose study medication (i.e., end of the REP) inclusive. Adverse 
events that start before first study medication intake and deteriorate under treatment will also be 
considered as ‘treatment-emergent’. 
Pretreatment AEs are defined as AEs occurring prior to dosing.  These events will be presented in the 
listings only and are not included in the tabular summary of AEs. 
See APPENDIX 2 for handling of partial dates for AEs.  In the rare case where it is not possible to assess 
treatment emergence, the AE will be classified as treatment emergent (i.e. the worst case). 
Intensity (Severity) 
The AE intensity is classified as mild/moderate/severe. TEAEs starting after the first dose of study 
medication with a missing severity will be classified as severe for analysis purposes. If a subject reports 
a TEAE more than once within that system organ class (SOC)/preferred term (PT), the AE with the worst 
case severity will be used in the corresponding severity summaries. 
Causal Relationship to Study Medication 
Relationship to study medication, as indicated by the Investigator, is classified as “related” or “not 
related”. TEAEs with a missing relationship to study medication will be regarded as “related” to study 
medication for analysis purposes. If a subject reports the same AE more than once within that SOC/PT, 
the AE with the strongest case relationship to study medication will be used in the corresponding 
relationship summaries. 
As an overview incidence summary of TEAEs, number and percentage of subjects with TEAEs, treatment-
related TEAEs, mild TEAEs, moderate TEAEs, severe TEAEs, serious TEAEs, treatment-related serious 
TEAEs, Non-serious TEAEs, AESIs. TEAEs leading to study medication discontinuation, TEAEs leading to 
death and treatment-related TEAEs leading death will be presented by treatment. 


 
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Incidence summaries, including number of events will be presented by SOC and PT for each treatment 
for the following: 
• 
Overview summary across SOC and PT 
• 
 All TEAEs 
• 
TEAEs by causal relationship 
• 
All TEAEs by intensity 
• 
All treatment-related TEAEs by intensity 
• 
Non-serious TEAEs with incidence in preferred terms strictly greater than 5% in at least one of 
treatment groups. 
17.1.1. 
TEAES LEADING TO DISCONTINUATION OF STUDY MEDICATION 
Treatment-emergent AEs leading to permanent discontinuation of study medication are those TEAEs 
with response to action taken trial drug due to AE reported as “Drug Withdrawn” on the Adverse Events 
page of the eCRF. 
Treatment-emergent AEs leading to permanent discontinuation of study medication will be listed and 
summarized using an incidence table by SOC, and PT for each treatment. 
17.1.2. 
SERIOUS ADVERSE EVENTS 
Serious adverse events (SAEs) are those events recorded as “Serious” on the Adverse Events page of the 
eCRF, and will be listed. An incidence summary of serious TEAEs by SOC, and PT for each treatment will 
be prepared. 
Non-serious TEAEs with incidence in preferred terms strictly greater than 5% in at least one of treatment 
groups will be summarized by SOC, and PT for each treatment. 
17.1.3. 
ADVERSE EVENTS OF SPECIAL INTEREST 
The following AEs will be recorded as Adverse Events of Special Interest (AESIs) in this trial: 
Hepatic Injury 
Hepatic injury defined by the following alterations of liver parameters (for subjects with normal liver 
function at baseline):  
- 
An elevation of aspartate aminotransferase (AST) and/or alanine aminotransferase (ALT) ≥3 
times the upper limit of normal (ULN) combined with an elevation of bilirubin ≥2 times ULN 
measured in the same blood draw sample; 


 
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- 
Aminotransferase (ALT, and/or AST) elevations ≥10 fold ULN. 
Severe infections 
Opportunistic and mycobacterium tuberculosis infections 
These include pneumocystis jirovecii, BK virus disease including PVAN, CMV, posttransplant 
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), 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), 
HCV progression. 
The AESIs are those TEAEs with YES response to the question, “Adverse Event of Special Interest? “on 
the AE page of the eCRF and will be flagged in listing. 
Incidence summaries by SOC and PT will be prepared for each treatment for the following: 
• 
All AEs of hepatic injury 
• 
All AEs of hepatic injury by severity 
• 
All severe infections according to RCTC grading 
• 
All opportunistic and mycobacterium tuberculosis infections 
• 
All opportunistic and mycobacterium tuberculosis infections by severity. 
A summary of the number of subjects, percentages, and number of events within will be provided by 
SOC, PT, and treatment for all treatment-emergent AESI, TEAEs of hepatic injury AESI, infection AESI, 
serious infection AESI. 
17.2. DEATHS 
If any subject dies during the study as recorded on the adverse events page of the eCRF, the information 
will be presented in a data listing. 
17.3. LABORATORY EVALUATIONS 
Local laboratory results will be included in the reporting of this study for Hematology, Blood Chemistry 


 
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Page 30 of 43 
and Urinalysis. A list of laboratory assessments to be included in the outputs is included in APPENDIX 3.  
Presentations will use System International (SI) Units, as provided by the labs. 
Protocol-specified clinical laboratory tests will be summarized using descriptive statistics.  Clinical 
laboratory data collected during study conduct, which were not required per protocol, such as for special 
testing to evaluate an AE, will be listed separately and not summarized. 
Quantitative laboratory measurements reported as “< X”, i.e. below the lower limit of quantification 
(BLQ), or “> X”, i.e. above the upper limit of quantification (ULQ), will be converted to X for the purpose 
of quantitative summaries, but will be presented as recorded, i.e. as “< X” or “> X” in the listings. 
All available data will be listed. 
The following summaries by treatment will be provided for laboratory data: 
• 
Actual and change from baseline by visit (for quantitative measurements) 
• 
Incidence of as abnormal values according to normal range criteria for urinalysis 
• 
Incidence of Drug-Induced Liver Injury (DILI) findings 
• 
Listing of lab results outside the normal range. 
17.3.1. 
DRUG INDUCED LIVER INJURY (DILI) 
• 
Normal liver function at Baseline is defined as AST, ALT and total bilirubin values measured at 
baseline are each ≤ the respective ULN 
• 
For post baseline visits: 
o 
Subjects with normal liver function at baseline and AST and/or ALT ≥3 times ULN combined 
with total bilirubin ≥2 times ULN measured in the same blood draw sample 
o 
AST and/or ALT ≥10 times ULN. 
17.3.2. 
LABORATORY REFERENCE RANGES AND ABNORMAL CRITERIA 
Quantitative laboratory measurements will be compared with the relevant laboratory reference ranges 
by the lab vendors and categorized as: 
• 
Low: Below the lower limit of the laboratory reference range 
• 
Normal: Within the laboratory reference range (upper and lower limit included) 
• 
High: Above the upper limit of the laboratory reference range. 
Clinical laboratory reference/normal ranges will be listed.   


 
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Page 31 of 43 
17.4. VITAL SIGNS 
The following Vital Signs measurements will be reported for this study: 
• 
Supine Systolic and Diastolic Blood Pressure (mmHg) 
• 
Pulse Rate (bpm) 
• 
Body temperature (⁰C) 
• 
Weight (kg) 
• 
BMI (kg/m2). 
Vital signs will be summarized by treatment using descriptive statistics for baseline, each scheduled visit, 
and change from baseline to each visit. 
Vital signs data will be listed. 
17.5. ECG EVALUATIONS 
Clinically relevant abnormal findings will be reported either as baseline condition (if identified at the 
screening visit) or otherwise as AEs and will be followed up and/or treated as medically appropriate. 
17.6. PHYSICAL EXAMINATION 
The results of physical examination will be only be included in the source documents available at the 
site. 


 
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18. REFERENCES  
[1] Bauer D, Soon RL, Kulmatycki K, Chen Y, Noe A, Chen J, et al  
TheDGAT 1inhibitor pradigastat does not induce photosensitivity in healthy human subjects: a 
randomized controlled trial using three defined sunlight exposure conditions. Photochem Photobiol 
Sci 15 (9), 1155 - 1162 (2016) 
 
 
 
 
 
 
 
 
 


 
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Final V2.0 
 
 
Version Date: 
23JUL2020 
Template No:  CS_TP_BS016 – Revision 5 
Reference:  CS_WI_BS005 
Effective Date: 01Apr2018 
 
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BOEHRINGER INGELHEIM 
STATISTICAL ANALYSIS PLAN: PROTOCOL 1407-0037 
Page 33 of 43 
APPENDIX 1. PROGRAMMING CONVENTIONS FOR OUTPUTS 
OUTPUT CONVENTIONS 
TABLE AND LISTING OUTPUT CONVENTIONS 
General: 
The first row in the body of the table or listing should be blank. 
The left-hand column should start in column 1. No indenting or centering of the output should occur. 
Rounding should be done with the SAS function ROUND, if no further specification. 
Numbers in tables should be rounded, not truncated, if no further specification. 
Alphanumeric output should be left aligned. 
Numbers should be decimal point aligned. 
Whole numbers should be right aligned. 
Text values should be left aligned. 
The first letter of a text entry should be capitalized 
Listings of adverse events, concomitant medications, medical histories, etc. should be sorted in 
chronological order, with earliest adverse event, medication or history coming first. 
The trial drug should appear first in tables with treatments as columns. 
In general, only present totals (across treatment groups) at baseline/randomization, and do not present 
them post randomization. 
If possible, include 100% frequencies in the table shell, so that it is clear what the denominator is for 
percentage calculations. 
All listing outputs should be sorted (preferably by Treatment, Site Number and Subject Number). 
Do not use superscripts and subscripts. 
The width of the entire output should match the linesize option. 
 
Univariate Statistics: 
Statistics should be presented in the same order across tables (i.e., n, Mean, SD, Median, IQR, Minimum, 
Maximum or n, gMean, gCV, Mean, CV, SD, Median, Minimum, Maximum). 


 
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BOEHRINGER INGELHEIM 
STATISTICAL ANALYSIS PLAN: PROTOCOL 1407-0037 
Page 34 of 43 
Table statistics should line up under the N part of the (N=XXX) in the table header. All decimal points 
should line up. If the minimum and maximum are output on one line as Minimum, Maximum then the 
comma should line up with the decimal point. 
If the original data has N decimal places, then the summary statistics should have the following decimal 
places: 
o Minimum and maximum: N 
o Mean, gMean, median, gCV% and CV%: N + 1 
o SD, IQR: N + 2 
Frequencies and percentages (n and %): 
Percent values should be reported inside parentheses, with one space between the count and the left 
parenthesis of the percentage. Parentheses should be justified to accept a maximum of 100.0 as a value 
and padded with blank space if the percentage is less than 100.0. An example is given below: 
77 (100.0%) 
50 ( 64.9%) 
0 ( 0.0%) 
Percentages will be reported to one decimal place, except percentage <100.0% but >99.9% will be 
presented as ‘>99.9%’ (e.g., 99.99% is presented as >99.9%); and percentage < 0.1% will be presented 
as ‘<0.1%’ (e.g., 0.08% is presented as <0.1%). Rounding will be applied after the <0.1% and >99.9% rule.  
E.g., ( <0.1%) 
( 6.8%) 
(>99.9%) 
Percentages may be reported to 0 decimal places as appropriate (for example, where the denominator 
is relatively small). 
Where counts are zero, percentages of 0.0% should appear in the output.  
Confidence Intervals: 
As a rule, confidence intervals are output to one place more than the raw data, and standard deviations 
and standard errors to two places more than the raw data. 
Confidence intervals should be justified so that parentheses displayed on consecutive lines of a table 
“line up”. 
Boundary values of confidence intervals should be separated by a comma. 
Boundary values should be padded as necessary to accept negative values and to allow alignment of the 
decimal place. 


 
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Author: 
 
Version Number: 
Final V2.0 
 
 
Version Date: 
23JUL2020 
Template No:  CS_TP_BS016 – Revision 5 
Reference:  CS_WI_BS005 
Effective Date: 01Apr2018 
 
Copyright © 2009, 2010, 2012, 2016, 2018 
 All Rights Reserved. The contents of this document are confidential and 
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. and its subsidiaries. Unauthorized use, disclosure or reproduction is strictly prohibited. 
BOEHRINGER INGELHEIM 
STATISTICAL ANALYSIS PLAN: PROTOCOL 1407-0037 
Page 35 of 43 
An example is given below: 
(-0.12, -0.10) 
( 9.54, 12.91) 
P-values: 
P-values should be reported to three decimal places, except values <1.000 but >0.999 will be presented 
as ‘>0.999’ (e.g., 0.9998 is presented as >0.999); and values <0.001 will be presented as ‘<0.001’ (e.g., 
0.0009 is presented as <0.001). Rounding will be applied after the <0.001 and >0.999 rule 
Ratios: 
Ratios should be reported to one more decimal place than the original data.  
Spacing: 
There must be a minimum of 1 blank space between columns (preferably 2). 
Denominators: 
If a different count other than the population count is used for a denominator (within the table) to 
calculate percentages, there should be a row in the table that identifies that number “n”. 
Alternatively, a footnote should be included in each table with percentages to indicate the denominator 
for percentages. 
Missing values: 
A “0” should be used to indicate a zero frequency. 
A blank will be used to indicate missing data in an end-of-text table or subject listing. 
DATES & TIMES 
Depending on data available, dates and times will take the format yyyy-mm-dd; times will take the 
format hh:mm:ss; combined dates and times will take the format yyyy-mm-ddThh:mm:ss. 
SPELLING FORMAT 
English US. 
PRESENTATION OF TREATMENT GROUPS 
For outputs, treatment groups will be represented as follows and in that order: 


 
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Author: 
 
Version Number: 
Final V2.0 
 
 
Version Date: 
23JUL2020 
Template No:  CS_TP_BS016 – Revision 5 
Reference:  CS_WI_BS005 
Effective Date: 01Apr2018 
 
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 and its subsidiaries. Unauthorized use, disclosure or reproduction is strictly prohibited. 
BOEHRINGER INGELHEIM 
STATISTICAL ANALYSIS PLAN: PROTOCOL 1407-0037 
Page 36 of 43 
Treatment Group 
For Tables and Graphs 
For Listings 
Placebo QD 
Placebo QD 
Placebo QD 
BI 730357 400 mg QD 
BI 730357 400 mg QD 
BI 730357 400 mg QD 
Placebo BID 
Placebo BID 
Placebo BID 
BI 730357 300 mg BID 
BI 730357 300 mg BID 
BI 730357 300 mg BID 
Ciprofloxacin 500 mg BID 
Ciprofloxacin 500 mg BID or 
Cipro 500 mg BID 
Ciprofloxacin 500 mg BID or Cipro 
500 mg BID 
PRESENTATION OF VISITS 
For outputs, visits will be represented as follows and in that order: 
Long Name (default) 
Short Name  
Screening 
Scrn 
Day -1 
 
Day x or Day x prodose 
Dx or Dx predose 
Day x, y hour(s) 
Day x, y h 
End-of-Treatment 
EOT 
PRESENTATION OF NOMINAL TIMES 
For outputs, nominal times will be represented as follows and in that order: 
Long Name (default) 
Short Name  
x hour(s) 
x h 
LISTINGS 
All listings will be ordered by the following (unless otherwise indicated in the template): 
Randomized treatment group [in the order Placebo QD, BI 730357 400 mg QD and ciprofloxacin 500 mg 


 
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Author: 
 
Version Number: 
Final V2.0 
 
 
Version Date: 
23JUL2020 
Template No:  CS_TP_BS016 – Revision 5 
Reference:  CS_WI_BS005 
Effective Date: 01Apr2018 
 
Copyright © 2009, 2010, 2012, 2016, 2018 
 All Rights Reserved. The contents of this document are confidential and 
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 and its subsidiaries. Unauthorized use, disclosure or reproduction is strictly prohibited. 
BOEHRINGER INGELHEIM 
STATISTICAL ANALYSIS PLAN: PROTOCOL 1407-0037 
Page 37 of 43 
BID for the 400 mg QD dose group first and then, Placebo BID and BI 730357 300 mg BID for the 300 mg 
BID dose group] 
subject ID,  
date (where applicable), 
For listings where non-randomized subjects are included, these will appear in a category after the 
randomized treatment groups labelled ‘Not Randomized’. 
The visit as recorded in the eCRF will be displayed in the listings (and not the remapped visit). 
 
 


 
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0037_MZA56588\Biostatistics\Documentation\SAP 
Author: 
 
Version Number: 
Final V2.0 
 
 
Version Date: 
23JUL2020 
Template No:  CS_TP_BS016 – Revision 5 
Reference:  CS_WI_BS005 
Effective Date: 01Apr2018 
 
Copyright © 2009, 2010, 2012, 2016, 2018 
 All Rights Reserved. The contents of this document are confidential and 
proprietary to 
. and its subsidiaries. Unauthorized use, disclosure or reproduction is strictly prohibited. 
BOEHRINGER INGELHEIM 
STATISTICAL ANALYSIS PLAN: PROTOCOL 1407-0037 
Page 38 of 43 
APPENDIX 2. PARTIAL DATE CONVENTIONS 
Imputed dates will NOT be presented in the listings. 
ALGORITHM FOR TREATMENT EMERGENCE OF ADVERSE EVENTS: 
START DATE 
STOP DATE 
ACTION 
Known 
Known 
If start date < study med start date, then not TEAE 
If start date >= study med start date, then TEAE 
 
Partial 
If start date < study med start date, then not TEAE 
If start date >= study med start date, then TEAE 
 
Missing 
If start date < study med start date, then not TEAE 
If start date >= study med start date, then TEAE 
 
 
 
Partial, 
but 
known 
components show that it 
cannot be on or after 
study med start date 
Known 
Not TEAE 
 
Partial 
Not TEAE 
 
Missing 
Not TEAE 
 
 
 
Partial, could be on or 
after study med start 
date 
Known 
If stop date < study med start date, then not TEAE 
If stop date >= study med start date, then TEAE 
 
Partial 
Impute stop date as latest possible date (i.e. last day of 
month if day unknown or 31st December if day and 
month are unknown), then: 
If stop date < study med start date, then not TEAE 
If stop date >= study med start date, then TEAE 
 
Missing 
Assumed TEAE 
 
 
 


 
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Author: 
 
Version Number: 
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Version Date: 
23JUL2020 
Template No:  CS_TP_BS016 – Revision 5 
Reference:  CS_WI_BS005 
Effective Date: 01Apr2018 
 
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 All Rights Reserved. The contents of this document are confidential and 
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 and its subsidiaries. Unauthorized use, disclosure or reproduction is strictly prohibited. 
BOEHRINGER INGELHEIM 
STATISTICAL ANALYSIS PLAN: PROTOCOL 1407-0037 
Page 39 of 43 
START DATE 
STOP DATE 
ACTION 
Missing 
Known 
If stop date < study med start date, then not TEAE 
If stop date >= study med start date, then TEAE 
 
Partial 
Impute stop date as latest possible date (i.e. last day of 
month if day unknown or 31st December if day and 
month are unknown), then: 
If stop date < study med start date, then not TEAE 
If stop date >= study med start date, then TEAE 
 
Missing 
Assumed TEAE 
 
ALGORITHM FOR PRIOR / CONCOMITANT MEDICATIONS:  
START DATE 
STOP DATE 
ACTION 
Known 
Known 
If stop date < study med start date, assign as prior  
If stop date >= study med start date and start date <= end of 
treatment, assign as concomitant  
If stop date >= study med start date and start date > end of 
treatment, assign as post study  
 
Partial 
Impute stop date as latest possible date (i.e. last day of month if day 
unknown or 31st December if day and month are unknown), then: 
If stop date < study med start date, assign as prior 
If stop date >= study med start date and start date <= end of 
treatment, assign as concomitant 
If stop date >= study med start date and start date > end of 
treatment, assign as post treatment 
 
Missing 
If stop date is missing could never be assumed a prior medication 
If start date <= end of treatment, assign as concomitant 
If start date > end of treatment, assign as post treatment 
 
 
 


 
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Author: 
 
Version Number: 
Final V2.0 
 
 
Version Date: 
23JUL2020 
Template No:  CS_TP_BS016 – Revision 5 
Reference:  CS_WI_BS005 
Effective Date: 01Apr2018 
 
Copyright © 2009, 2010, 2012, 2016, 2018 
 All Rights Reserved. The contents of this document are confidential and 
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. and its subsidiaries. Unauthorized use, disclosure or reproduction is strictly prohibited. 
BOEHRINGER INGELHEIM 
STATISTICAL ANALYSIS PLAN: PROTOCOL 1407-0037 
Page 40 of 43 
START DATE 
STOP DATE 
ACTION 
Partial 
Known 
Impute start date as earliest possible date (i.e. first day of month if 
day unknown or 1st January if day and month are unknown), then: 
If stop date < study med start date, assign as prior 
If stop date >= study med start date and start date <= end of 
treatment, assign as concomitant 
If stop date >= study med start date and start date > end of 
treatment, assign as post treatment 
 
Partial 
Impute start date as earliest possible date (i.e. first day of month if 
day unknown or 1st January if day and month are unknown) and 
impute stop date as latest possible date (i.e. last day of month if day 
unknown or 31st December if day and month are unknown), then: 
If stop date < study med start date, assign as prior 
If stop date >= study med start date and start date <= end of 
treatment, assign as concomitant 
If stop date >= study med start date and start date > end of 
treatment, assign as post treatment 
 
Missing 
Impute start date as earliest possible date (i.e. first day of month if 
day unknown or 1st January if day and month are unknown), then: 
If stop date is missing could never be assumed a prior medication 
If start date <= end of treatment, assign as concomitant 
If start date > end of treatment, assign as post treatment 
 
 
 
Missing 
Known 
If stop date < study med start date, assign as prior 
If stop date >= study med start date, assign as concomitant 
Cannot be assigned as ‘post treatment’ 
 
Partial 
Impute stop date as latest possible date (i.e. last day of month if day 
unknown or 31st December if day and month are unknown), then: 
If stop date < study med start date, assign as prior 
If stop date >= study med start date, assign as concomitant 
Cannot be assigned as ‘post treatment’ 
 
Missing 
Assign as concomitant 
 
 
 
 


 
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BOEHRINGER INGELHEIM 
STATISTICAL ANALYSIS PLAN: PROTOCOL 1407-0037 
Page 41 of 43 
APPENDIX 3. 
LABORATORY TESTS 
Functional lab group 
Test name  
A1 
B2 
C3 
Haematology 
Haematocrit 
Haemoglobin 
Red blood cells (RBC) 
White blood cells (WBC) 
Platelet count 
MCV 
MCH 
MCHC 
RDW 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Automatic WBC 
differential  
(relative and absolute) 
 
Neutrophiles total 
Lymphocytes total 
Eosinophiles  
Basophiles  
Monocytes  
Lymphocytes  
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Manual differential 
WBC (if automatic 
differential WBC is 
abnormal) 
Polymorphnuclear neutrophils (segs), band 
neutrophils (stabs), eosinophils, basophils, 
monocytes, lymphocytes  
 
 
 
Coagulation 
Activated partial thromboplastin time (aPTT) 
Prothrombin Time (PT) 
INR 
X 
X 
X 
 
 
Functional lab group 
Test name  
 
 
 
Enzymes 
Aspartate aminotransferase (AST)  
Alanine aminotransferase (ALT)  
Alkaline phosphatase (AP) 
Gammaglutamyl transferase (GGT)   
Creatine kinase (CK) 
Lipase 
Amylase 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
 
X 
X 
X 
X 
 
X 
X 


 
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STATISTICAL ANALYSIS PLAN: PROTOCOL 1407-0037 
Page 42 of 43 
Substrates 
Glucose 
Creatinine 
Urea Nitrogen 
Uric Acid 
Total bilirubin  
Direct bilirubin 
Total protein 
Albumin 
Globulin 
Albumin/Globulin ratio 
C-Reactive Protein (CRP)  
Total cholesterol  
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
 
 
X 
X 
X 
X 
X 
X 
 
Electrolytes 
Calcium 
Sodium 
Potassium 
Chloride 
Phosphate 
X 
X 
X 
X 
X 
 
X 
X 
X 
X 
X 
Serum Pregnancy test 
(only for female 
subjects of childbearing 
potential) at screening, 
day -1 and  if urine 
pregnancy test is 
positive 
Human Serum Chorionic Gonadotropin 
X 
X4 
 
Urinalysis (Stix) 
 
Urine nitrite 
Urine protein 
Urine glucose 
Urine ketone 
Urine bilirubin 
Urine Blood 
Urine leukocyte esterase 
Urine pH 
Specific gravity 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Urine sediment 
(microscopic 
examination if 
erythrocytes, leukocytes 
nitrite or protein are 
abnormal in urine) 
Only positive findings will be reported (e.g. 
presence of sediment bacteria, casts in 
sediment, squamous epithelial cells, 
erythrocytes, leukocytes) 
 
 
 


 
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BOEHRINGER INGELHEIM 
STATISTICAL ANALYSIS PLAN: PROTOCOL 1407-0037 
Page 43 of 43 
 
 
 
 
1 A: parameters to be determined at screening examination 
2 B: parameters to be determined on Days 1 and 8  
3 C: parameters to be determined at end of trial examination 
4 Day -1 only 
 
 
 
 
 
Urine Pregnancy test 
(only for female 
subjects of childbearing 
potential) at EoT 
Human Chorionic Gonadotropin in the urine 
 
 
X