Conditions: Healthy
Allocation: RANDOMIZED | Intervention model: PARALLEL
Enrollment: 47
Healthy volunteers: yes

Brief summary:
Investigation of safety and tolerability of BI 655088 following intravenous infusion of single rising doses and exploration of the pharmacokinetics and pharmacodynamics of BI 655088 after single dosing

Detailed description:

Arms:
arm 1: None arm 2: None

Interventions: intervention 1: BI 655088 intervention 2: Placebo
Intervention descriptions: intervention 1: None intervention 2: None

Protocol document:
Prot_000.pdf: 
001-MCS-40-106-RD-11 (5.0) / Saved on: 25 Jun 2014
Clinical Trial Protocol
TITLE PAGE
Document Number:
c02155664-05
EudraCT No.:
BI Trial No.:
2014-002413-29
1339.1
BI Investigational
Product:
BI 655088
Title:
Safety, tolerability, pharmacokinetics and pharmacodynamics of 
single rising doses of BI 655088 administered by intravenous infusion 
in healthy male subjects (single-blind, partially randomised within 
dose groups, placebo-controlled, parallel group design)
Clinical Phase:
I
Trial Clinical Monitor:
Phone:
Fax: 
Principal Investigator:
Phone: 
Fax: 
Status:
Final Protocol (Revised Protocol (based on global amendment 3))
Version and Date:
Version: 4.0
Date: 22 November 2017
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© 2017 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
Name of company:
Tabulated
Trial Protocol
Boehringer Ingelheim
Name of finished product:
Not applicable
Name of active ingredient:
BI 655088
Protocol date:
Trial number:
Revision date:
22 Nov 2017
03 December 2015
1339.1
Title of trial:
Safety, tolerability, pharmacokinetics and pharmacodynamics of single rising doses of 
BI 655088 administered by intravenous infusion in healthy male subjects (single-
blind, partially randomised within dose groups, placebo-controlled, parallel group 
design)
Principal Investigator:
Trial site:
Clinical phase:
I
Objectives:
To investigate safety, tolerability, pharmacokinetics and pharmacodynamics following 
single rising doses of BI 655088 administered as intravenous (IV) infusion
Methodology:
Single-blind, partially randomised within dose groups, placebo-controlled, parallel-
group design
No. of subjects: 
total entered:
48*
each treatment:
8 per dose group (6 on active drug and 2 on placebo)
* Additional subjects may be entered to allow for testing of additional intermediate doses 
within the planned dose range on the basis of experience gained during the trial conduct (e.g. 
safety or preliminary PK/PD data), i.e. the actual number of subjects entered may exceed 48
Diagnosis:
Not applicable
Main criteria
for inclusion:
Healthy male subjects, age of 18 to 50 years, body mass index (BMI) of 18.5 to 
29.9 kg/m2
Test product:
BI 655088 
dose:
mode of admin.:
IV infusion for 120 minutes
Comparator product:
Matching placebo (buffer solution)
dose:
Not applicable
mode of admin.:
IV infusion for 120 minutes
Duration of treatment: Single dose


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Name of company:
Tabulated
Trial Protocol
Boehringer Ingelheim
Name of finished product:
Not applicable
Name of active ingredient:
BI 655088
Protocol date:
Trial number:
Revision date:
22 Nov 2017
03 December 2015
1339.1
Criteria for
pharmacokinetics:
Secondary endpoints: Cmax, AUC0-tz, and AUC0-∞
 
Criteria for 
pharmacodynamics:
 
Criteria for safety:
Primary endpoint to assess safety and tolerability of BI 655088 is the number [N (%)] 
of subjects with drug-related adverse events (AEs).
Further criteria of interest:
AEs including clinically relevant findings from the physical examination, safety 
laboratory tests, 12-lead electrocardiogram (ECG), continuous ECG monitoring, vital 
signs (blood pressure [BP], pulse rate [PR], oral body temperature), oral glucose 
tolerance test (oGTT), bleeding time, anti-drug antibodies (ADA).
Statistical methods:
Descriptive statistics will be calculated for all endpoints.
 


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TABLE OF CONTENTS
TITLE PAGE ......................................................................................................1
CLINICAL TRIAL PROTOCOL SYNOPSIS ................................................2
FLOW CHART...................................................................................................4
TABLE OF CONTENTS ...................................................................................6
ABBREVIATIONS.......................................................................................... 11
1.
INTRODUCTION.................................................................................... 14
1.2
DRUG PROFILE...............................................................................................14
1.2.4
Clinical experience in humans.............................................................21
2.
RATIONALE, OBJECTIVES, AND BENEFIT - RISK 
ASSESSMENT ......................................................................................... 24
2.1
RATIONALE FOR PERFORMING THE TRIAL........................................24
2.1.1
Starting dose..........................................................................................25
2.1.2
Maximum dose and dose escalation ....................................................26
2.2
TRIAL OBJECTIVES.......................................................................................26
2.3
BENEFIT - RISK ASSESSMENT ...................................................................27
3.
DESCRIPTION OF DESIGN AND TRIAL POPULATION.............. 31
3.1
OVERALL TRIAL DESIGN AND PLAN ......................................................31
3.1.1
Administrative structure of the trial...................................................32
3.2
DISCUSSION OF TRIAL DESIGN, INCLUDING THE CHOICE OF 
CONTROL GROUP..........................................................................................33
3.3
SELECTION OF TRIAL POPULATION ......................................................34


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3.3.1
Main diagnosis for study entry............................................................34
3.3.2
Inclusion criteria...................................................................................34
3.3.3
Exclusion criteria ..................................................................................34
3.3.4
Removal of subjects from therapy or assessments.............................36
3.3.4.1
Removal of individual subjects................................................36
3.3.4.2
Discontinuation of the trial by the sponsor..............................36
3.3.5
Replacement of subjects .......................................................................37
4.
TREATMENTS........................................................................................ 38
4.1
TREATMENTS TO BE ADMINISTERED....................................................38
4.1.1
Identity of BI investigational product and comparator product......38
4.1.2
Method of assigning subjects to treatment groups ............................39
4.1.3
Selection of doses in the trial................................................................39
4.1.4
Drug assignment and administration of doses for each subject .......39
4.1.5
Blinding and procedures for unblinding ............................................40
4.1.5.1
Blinding....................................................................................40
4.1.5.2
Procedures for emergency unblinding .....................................40
4.1.6
Packaging, labelling, and re-supply ....................................................40
4.1.7
Storage conditions.................................................................................41
4.1.8
Drug accountability ..............................................................................41
4.2
CONCOMITANT THERAPY, RESTRICTIONS, AND RESCUE 
TREATMENT....................................................................................................42
4.2.1
Rescue medication, emergency procedures, and additional 
treatments ..............................................................................................42
4.2.2
Restrictions............................................................................................42
4.2.2.1
Restrictions regarding concomitant treatment .........................42
4.2.2.2
Restrictions on diet and life style.............................................42
4.3
TREATMENT COMPLIANCE.......................................................................43
5.
VARIABLES AND THEIR ASSESSMENT ......................................... 44
5.1
EFFICACY - CLINICAL PHARMACOLOGY.............................................44
5.1.1
Endpoints of efficacy.............................................................................44
5.1.2
Assessment of efficacy...........................................................................44
5.2
SAFETY..............................................................................................................44
5.2.1
Endpoints of safety................................................................................44
5.2.2
Assessment of adverse events...............................................................44
5.2.2.1
Definitions of adverse events...................................................44
5.2.2.2
Adverse event collection and reporting ...................................47
5.2.3
Assessment of safety laboratory parameters......................................49
5.2.3.1
Oral glucose tolerance test (oGTT)..........................................52
5.2.3.2
Bleeding time...........................................................................52
5.2.4
Electrocardiogram................................................................................52
5.2.4.1
12-lead resting ECG.................................................................52
5.2.4.2
Continuous ECG monitoring ...................................................53


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5.2.5
Assessment of other safety parameters...............................................54
5.2.5.1
Vital signs ................................................................................54
5.2.5.2
Medical examinations..............................................................54
5.2.5.3
Local tolerability......................................................................54
5.3
OTHER...............................................................................................................54
5.4
APPROPRIATENESS OF MEASUREMENTS.............................................54
5.5
DRUG CONCENTRATION MEASUREMENTS AND 
PHARMACOKINETICS..................................................................................54
5.5.1
Pharmacokinetic endpoints..................................................................55
5.5.1.1
Secondary endpoints................................................................55
5.5.2
Methods of sample collection...............................................................56
5.5.2.1
Plasma sampling for pharmacokinetic analysis.......................56
5.5.3
Analytical determinations ....................................................................59
5.5.3.1
Analytical determination of BI 655088 plasma concentration 59
5.6
BIOMARKERS..................................................................................................59
5.6.1
Biomarkers for assessment of target engagement..............................59
5.6.2
Methods of sample collection...............................................................60
5.6.3
Analytical determinations ....................................................................61
5.7
PHARMACOKINETIC - PHARMACODYNAMIC RELATIONSHIP .....61
6.
INVESTIGATIONAL PLAN.................................................................. 62
6.1
VISIT SCHEDULE............................................................................................62
6.2
DETAILS OF TRIAL PROCEDURES AT SELECTED VISITS ................63
6.2.1
Screening period....................................................................................63
6.2.2
Treatment period ..................................................................................63
6.2.3
End of trial period.................................................................................63
7.
STATISTICAL METHODS AND DETERMINATION OF
SAMPLE SIZE......................................................................................... 64
7.1
STATISTICAL DESIGN – MODEL ...............................................................64
7.1.1
Objectives...............................................................................................64
7.2
NULL AND ALTERNATIVE HYPOTHESES ..............................................64
7.3
PLANNED ANALYSES....................................................................................64
7.3.1
Primary analyses...................................................................................65
7.3.2
Secondary analyses ...............................................................................65
7.3.3
Safety analyses.......................................................................................66


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7.3.4
Preliminary PK and PD analyses ........................................................67
7.3.5
Pharmacokinetic analyses ....................................................................68
7.4
HANDLING OF MISSING DATA ..................................................................68
7.4.1
Safety......................................................................................................68
7.4.2
Plasma
drug concentration - time profiles ...............................68
7.4.3
Pharmacokinetic parameters...............................................................68
7.5
RANDOMISATION ..........................................................................................69
7.6
DETERMINATION OF SAMPLE SIZE ........................................................69
8.
INFORMED CONSENT, DATA PROTECTION, TRIAL
RECORDS ................................................................................................ 70
8.1
STUDY APPROVAL, SUBJECT INFORMATION, AND INFORMED 
CONSENT ..........................................................................................................70
8.2
DATA QUALITY ASSURANCE .....................................................................70
8.3
RECORDS..........................................................................................................71
8.3.1
Source documents .................................................................................71
8.3.2
Direct access to source data and documents.......................................71
8.4
LISTEDNESS AND EXPEDITED REPORTING OF ADVERSE 
EVENTS..............................................................................................................71
8.4.1
Listedness...............................................................................................71
8.4.2
Expedited reporting to health authorities and IECs/IRBs................71
8.5
STATEMENT OF CONFIDENTIALITY.......................................................72
8.6
COMPLETION OF TRIAL..............................................................................72
9.
REFERENCES......................................................................................... 73
9.1
PUBLISHED REFERENCES...........................................................................73
9.2
UNPUBLISHED REFERENCES.....................................................................75
10. APPENDICES .......................................................................................... 76
10.1
RECONSTITUTION OF IMP AND INSTRUCTION FOR USE ................76
10.1.1 Equipment and material for reconstitution and administration......77
10.1.2 Preparation of trial product including placebo for IV infusion .......78


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11. DESCRIPTION OF GLOBAL AMENDMENT(S).............................. 84


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ABBREVIATIONS
AE
Adverse event
AESI
Adverse events of special interest
ANOVA
Analysis of variance
ApoE
Apolipoprotein E
AUC0-∞
Area under the concentration-time curve of the analyte in plasma over the 
time interval from 0 extrapolated to infinity
AUC0-tz
Area under the concentration-time curve of the analyte in plasma over the 
time interval from 0 to the last quantifiable data point
β
Slope parameter associated with the power model used to evaluate dose 
proportionality
BA
Bioavailability
BI
Boehringer Ingelheim
BLQ
Below limit of quantification
BMI
Body mass index (weight divided by height squared)
BP
Blood pressure
BSA
Bovine serum albumin
CA
Competent authority
CI
Confidence interval
Cmax(,ss)
Maximum measured concentration of the analyte in plasma (at steady 
state)
CRF
Case report form
CTP
Clinical trial protocol
CTR
Clinical trial report
CV
Coefficient of variation
DILI
Drug induced liver impairment
DP
Drug product
ECG
Electrocardiogram
EDTA
Ethylenediaminetetraacetic acid
(e)GFR
(Estimated) glomerular filtration rate
ELISA
Enzyme linked immunosorbent assay
HR
Heart rate
IB
Investigator’s brochure
IC50
Half-maximal inhibitory concentration


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IEC
Independent Ethics Committee
IRB
Institutional Review Board
ISF
Investigator site file
IV
Intravenous
Ki
Inhibition constant
KI
Knock-in
LC-MS/MS
Liquid chromatography tandem mass spectrometry
MedDRA
Medical Dictionary for Regulatory Activities
MoE
Multiple of exposure
NC
Not calculated
NK
Natural killer
NOA
Not analysed
NOAEL
No observed adverse effect level
NOP
No peak detectable
NOR
No valid result
NOS
No sample available
NSTEMI
Non-ST segment elevation myocardial infarction
oGTT
Oral glucose tolerance test
PD
Pharmacodynamic(s)
PE
Polyethylene
PK
Pharmacokinetic(s)
PKS
Pharmacokinetic set
PP
Polypropylene
PR
Pulse rate
QT
Time between start of the Q-wave and the end of the T-wave in an 
electrocardiogram
QTc
QT interval corrected for heart rate using the method of Fridericia (QTcF) 
or Bazett (QTcB)
R
Reference product or treatment
REP
Residual effect period
SAE
Serious adverse event
SC
Subcutaneous
SCR
Screening
SRD
Single-rising dose
ss
(at) steady state
SUSAR
Suspected Unexpected Serious Adverse Reaction
T
Test product or treatment
TE
Thromboembolism
TGF
Transforming growth factor
t1/2
Terminal half-life of the analyte in plasma


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TDMAP
Trial Data Management and Analysis Plan
TMF
Trial master file
TS
Treated set
TSAP
Trial statistical analysis plan
UACR
Urinary albumin / creatinine ratio
ULN
Upper limit of normal


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1.
INTRODUCTION
1.2
DRUG PROFILE


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1.2.4
Clinical experience in humans
This is the first clinical trial with single intravenous administration of BI 655088 in man. The 
trial was started in March 2016 at a dose level of 
 to the first cohort of healthy male 
volunteers (5 on active, 2 on placebo). Three days after receiving a 
 dose of BI 655088 a 
serious adverse event (non-ST segment elevation myocardial infarction (NSTEMI) with 
coronary artery occlusion (thrombus)) occurred in a 47 year old male subject. A 
coronarography was performed and identified a 90% stenosis of the right coronary artery; the 
subject underwent insertion of a drug-eluting stent, leading to a successful angioplasty.
Beside smoking, the subject had no other coronary risk factors, no known history of 
cardiovascular disease nor any finding during the screening examinations indicating coronary 
artery disease.   
The investigator assessed this SAE as being not related to the study medication. Based on the 
clinical course and the time-to-onset BI has assessed that there is not a reasonable possibility 
of a causal association between the event NSTEMI and the study medication. A thorough 
review of the ECGs, vital signs and relevant laboratory parameters of the whole dosing group 
did not show clinically relevant changes and, more specifically, did not reveal relevant 
changes involving the cardiac system or the coagulation profile.
Despite the above, as a precautionary measure BI decided to temporarily put the trial on hold 
to allow sufficient time for further investigation of this observation before any further 
subjects will be dosed with the study medication.
 
Except for the subject with the myocardial infarction who decided to stop participating, the 
remaining 6 subjects treated with 
 BI 655088 or placebo continued the trial as planned. 
For these subjects, no clinically relevant changes in vital signs, ECG and clinical laboratory
parameters including oGTT were observed throughout the approx. 3 months post-dose 
observation period, except an intermittent, transient but marked increase in lipase and 


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amylase of subject 
 This increased amylase/lipase was not associated with any clinical 
symptoms.
A total of 4 baseline AEs and 18 postdose (treatment emergent) AEs were reported by 7 out 
of 7 subjects. Two AEs each were of moderate and severe intensity; all remaining AEs were 
of mild intensity. AEs categorized as related to treatment were observed in 1 subject each 
treated with BI 655088 and placebo, respectively. An overall summary on adverse events 
reported by the subjects treated in the first dose group is given in Table 1.2.4: 1 below.
Table 1.2.4: 1
Overall summary of adverse events in 
 dose group
BI 655088, 
  N   (%)
Placebo
N   (%)
Number of subjects
5 (100.0)
2
(100.0)
Subjects with any AE
5 (100.0)
2
(100.0)
Subjects with moderate AEs
2   (40.0)
0
    (0.0)
subject #
 indigestion
subject #
 dyspnoea
Subjects with severe AEs
1   (20.0)
0
    (0.0)
subject #
 acute myocardial 
infarction, thoracic pain
Subjects with investigator defined 
drug related AEs
1   (20.0)
1
  (50.0)
subject #
 sleepiness
subject #
 headache
Subjects with serious AEs
1   (20.0)
0
    (0.0)
subject #
 acute myocardial 
infarction
From these data, it is concluded that 
 of BI 655088 or Placebo is safe and well tolerated.
The preliminary PK analysis (based on planned times) confirmed the predicted PK profile, 
which was based on preclinical data. The geometric mean Cmax was 0.59 µg/ml (15.2 nM,
n=5) with a range of 0.53 to 0.65 µg/ml. 
 


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The PK and PD profile of the subject experiencing the SAE did not differ from the profiles of 
the other four subjects receiving active drug within the first dose group. 
 


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2.
RATIONALE, OBJECTIVES, AND BENEFIT - RISK 
ASSESSMENT
2.1
RATIONALE FOR PERFORMING THE TRIAL
As a transition from preclinical investigations to clinical development in this first-in-man
trial, safety, tolerability, pharmacokinetics and pharmacodynamics of BI 655088 will be 
assessed in healthy male volunteers using single rising intravenous doses in order to provide 
the basis for a potential ongoing clinical development of BI 655088 in the indication of 
The administration of the study drug as IV infusion is considered advantageous since the 
administration of BI 655088 can be immediately stopped in case safety concerns arise during 
the running infusion. A further advantage of the IV route is the possibility to investigate 
supratherapeutic exposure unbiased from individual variability in bioavailability. The study 
will be conducted in healthy volunteers, since healthy volunteers provide a relatively stable 
physiological, biochemical and hormonal basis for studying drug effects, without an impact 
by underlying disease or concomitant medication. Healthy volunteers are easy to recruit, easy 
to select for age and sex, and can be tested under standardized conditions. Therefore, the 
study population of the planned SRD trial will consist of healthy male subjects aged 18 - 50
years.
Within each dose group, all actively treated individuals will receive the same BI 655088
dose. The next higher dose will only be administered to the next group if the treatment in the 
preceding dose group was safe and well tolerated (see Section 3.1). The background for dose 
selection and escalation steps is described below.
Based on EMA’s Guideline on strategies to identify and mitigate risks for first-in-human 
clinical trials with investigational medicinal products (R09-6036), BI 655088 can be regarded 
as a 
risk compound for the first-in-man trial. EMA identifies 3 main criteria for 
risk assessment:
•
the mode of action
•
the nature of the target
•
the relevance of animal models


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Although BI 655088 is not considered as being a 
risk compound, a conservative 
approach in calculating the starting dose has been chosen and safety of participants will be 
enhanced by appropriate safety measures in the first-in-man trial.
2.1.1
Starting dose
Using the criteria that are described in the EMA Guideline on Strategies to Identify and
Mitigate Risks for First-in-Human Clinical Trials with Investigational Medicinal Products
(R09-6036) it would be justified to use a NOAEL approach to select the Maximum 
Recommended Starting Dose (MRSD) for the first application in humans. 
 
A very similar safe starting dose was defined by PK/PD modeling. 
 
For the first in human trial, 
g has been chosen as the starting dose. Taken all data 
together, 
 is expected to be safe and well tolerated.


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2.1.2
Maximum dose and dose escalation
Following the initial dose of 
, it is planned to continue the trial with intravenous doses of 
. Dose escalation will not exceed factor 3 and from 
 onwards
factor 2. This escalation approach is considered to be safe in the clinical setting where only 
one single dose will be administered. The selected doses are expected to cover the range of 
subtherapeutic, lowest to highest anticipated therapeutic as well as supratherapeutic doses
(for corresponding exposure values, see Table 2.1.2: 1). The IV doses will be administered by 
infusion over 120 minutes.
2.2
TRIAL OBJECTIVES
The primary objective of this trial is to investigate the safety and tolerability of BI 655088 in 
healthy male subjects following intravenous infusion of single rising doses.
Secondary objective is the exploration of the pharmacokinetics and pharmacodynamics of BI 
655088 after single dosing.
A description of the endpoints to be determined, and the observations along with specific 
information as how to collect the data for that information, is provided in Section 5.


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2.3
BENEFIT - RISK ASSESSMENT
Participation in this study is without any (therapeutic) benefit for healthy subjects. Their 
participation in the study, however, is of major importance to the development of a new 
treatment modality to the current insufficient therapeutic armamentarium of 
. The 
subjects are exposed to the risks of the study procedures and the risks related to the exposure 
to the trial medication.
Procedure-related risks
The use of an indwelling venous catheter for the purpose of blood sampling and on the 
contralateral arm for the administration of study drug may be accompanied by mild bruising 
and also, in rare cases, by transient inflammation of the wall of the vein. In addition, in rare 
cases a nerve might be injured while inserting the venous catheter, potentially resulting in 
paresthesia, reduced sensibility, and/or pain for an indefinite period. The same risks apply to 
venipuncture for blood sampling.
The total volume of blood drawn during the entire study per subject might slightly exceed the 
volume of a normal blood donation (500 mL). No health-related risk to healthy subjects is 
expected from this blood withdrawal considering that this amount is taken over a period of 3 
months.
Drug-related risks and safety measures


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Although rare, a potential for drug-induced liver injury is under constant surveillance by
sponsors and regulators. Therefore, this study requires timely detection, evaluation, and
follow-up of alterations in selected liver laboratory parameters to ensure subjects´ safety.
The following safety measures will be applied in this study in order to minimize the risks for 
trial participants:

Careful dose selection as described in Section 2.1.1 and 2.1.2 with large safety 
margins up to the maximum dose, and based on a sound preclinical data package 
including 6 week repeat dose toxicity studies.

The use of the IV administration has been included in this trial because IV infusions 
can be stopped should any safety concern arise during administration. The dose will 
be infused slowly over a period of 2 hours. 

For safety reasons, each dose group is divided into 3 cohorts. On the first study day of 
each dose level, only 2 subjects (first cohort) will be treated: one will receive active 
treatment, the other subject will receive placebo. If BI 655088 treatment is safe and 
tolerated in this first cohort, the following 2 subjects on active will be treated in the 
second cohort. The second subject on active will be treated at least 2 days after the 
administration of the first subject. The remaining 4 subjects (either active or placebo) 
are the third cohort and will be treated no sooner than 2 days following the 2nd cohort. 
A time interval of at least 10 min will be maintained between each administration of 
the study drug (start of infusion) to the individual subjects of the 2nd and 3rd cohort.
This design ensures that between first and second active dose of each dose level there 
is a time interval of at least 2 days, which is expected to be sufficient to cover the 
period of highest risk/peak effect.

Dose escalation will be shallow. In addition, a time interval of at least 21 days will be 
maintained between first administration of study drug in the actual dose level and first 
administration in the next dose level, which is expected to cover the period of highest 
risk / peak effect. The decision to proceed to the next dose will be based upon the 
safety and tolerability of the preceding dose. The next dose will only be given if no 
safety concerns arise in the previous dose group (i.e. no dose-limiting events occur) 
and if none of the pre-specified trial-specific stopping criteria are met (Section 3.3.4).

Doses will only be escalated if previously approved by the principal investigator (or 
an authorised deputy) and the trial clinical monitor (or an authorised deputy) during 
its regular Safety Review meetings that will take place prior to each dose escalation 
(see Section 3.1).


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
Extensive monitoring of ECG and vital signs is incorporated, with continuous ECG 
monitoring over 4 hours post infusion start to cover the anticipated period of highest 
drug exposure and additional repeated single 12-lead ECGs following drug 
administration.

Extensive safety laboratory testing, determination of bleeding time, and oral glucose 
tolerance testing will be performed.

The subjects will stay at the clinical site for at least 48 hours following study drug 
administration at each dose level. During in-house-confinement the subjects will be 
under close medical observation and thoroughly monitored for both expected and 
unexpected adverse events.

Measurement of BI 655088 plasma concentrations and preliminary determination of 
pharmacokinetic parameters will be done as described in Section 7.3.4. For 
precautionary reasons, in a first place maximum drug plasma concentrations of 
 
 and drug exposure levels 
, respectively, will be
considered as a preliminary threshold (see Section 2.1.1). Further dose progression
would only be allowed after a safety interim analysis and filing and approval of a
pertinent protocol amendment.


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3.
DESCRIPTION OF DESIGN AND TRIAL POPULATION
3.1
OVERALL TRIAL DESIGN AND PLAN
This single-rising dose trial is designed as single-blind, partially randomised, and placebo-
controlled within parallel dose groups. “Partially” means that randomisation is done only in 
the second half of subjects of each dose level. For safety reasons the first half of subjects
within each dose group will be administered study drug in a fixed sequence which is 
unknown to the volunteers: first subject active, second placebo, third active, fourth active.
A total of 48 healthy male subjects is planned to participate in the trial, according to 6
sequential groups comprising 8 subjects per group. However, additional subjects may be 
entered to allow testing of intermediate doses within the planned dose range on the basis of 
experience gained during trial conduct (e.g. preliminary PK data), i.e. the actual number of 
subjects entered may exceed 48. Such changes may be implemented via non-substantial CTP 
Amendments.
Within each dose group, 6 subjects will receive the active drug and 2 will receive placebo. 
Only one dose is tested within each dose group. Each dose group will consist of 3 cohorts 
which will be treated subsequently for safety reasons (see also Section 2.3).
The dose groups to be evaluated are outlined in Table 3.1: 1 below.
Table 3.1: 1
Dose groups
Dose Group
1
2
3
4
5
6
Dose (mg)
Number of subjects
8
8
8
8
8
8
Subjects receiving placebo
2
2
2
2
2
2
Subjects receiving active drug
6
6
6
6
6
6
Subject numbers
Replacement numbers
The dose groups will be investigated consecutively in ascending order of doses, maintaining a 
time interval of at least 21 days between the first drug administration in the previous dose 
group and treatment of a subject in the subsequent dose group. The decision to proceed to the 
next dose group will be based upon the safety and tolerability data of the preceding dose 
groups. The next dose will only be given if, in the opinion of the investigator, no safety 
concerns arose in the preceding dose group (i.e. no dose-limiting events occurred) and if none 
of the pre-specified trial-specific stopping criteria were met (refer to Section 3.3.4.2).
A documented Safety Review must take place prior to each dose escalation, but not earlier 
than 7 days after administration of last subject of a given dose level. Furthermore, an 
unscheduled safety review meeting can be requested anytime for any reasonable cause by the 


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Principal Investigator (or an authorised deputy) or the sponsor of the study, e.g. because of 
any unforeseen adverse events, etc. Dose escalation will only be permitted if no safety 
concerns exist in the opinion of the Principal Investigator (or an authorised deputy) and the 
Trial Clinical Monitor (or an authorised deputy).
The minimum data set for review consists of the following data (for the current dose group, 
safety data of at least 6 subjects having completed Day 8 will be required):

AEs in the current and preceding dose groups (including clinically relevant findings 
from ancillary safety testing listed below) (Note: AEs may be ongoing at the time of 
Safety Reviews and AE information may be subject to change prior to Database Lock)

Results from 12-lead EGG and continuous ECG monitoring in the current and 
preceding dose groups.

Vital signs in the current and preceding dose groups

Clinical laboratory tests in the current and preceding dose groups

Preliminary PK/PD data for selected dose groups and time points as per Section 7.3.4

Check of criteria for stopping subject treatment as per Section 3.3.4.1
The decision to escalate the dose will be made jointly by the Principal Investigator (or an 
authorised deputy) and the Trial Clinical Monitor (or an authorised deputy) after in-depth 
analysis of all available safety data, especially SAEs (if occurred), AEs and out-of-range 
laboratory results (if considered clinically significant). 
Safety Reviews can be conducted face-to-face or by video/telephone conference. The 
investigator or project management team at the clinical site will be responsible for 
organization and minutes of the review meetings. Safety data will be provided and presented 
by the Principal Investigator (or an authorised deputy). Preliminary PK/PD will be provided 
by the sponsor as per Section 7.3.4. Minutes will be signed off by the Principal Investigator 
(or an authorised deputy) and the Trial Clinical Monitor (or an authorised deputy) and filed in 
the ISF and TMF.
The investigator (after consultation with the sponsor) is allowed to alter the scheduled dose 
levels (e.g. add an intermediate dose level) within the planned dose range on the basis of 
experience gained during the study. In this case, the total number of subjects in this trial 
might increase. The investigator and/or the sponsor should stop dose escalation in case the 
safety evaluation leads to concerns that would not allow higher dosing.
An overview of all relevant trial activities is provided in the Flow Chart. For visit schedules 
and details of trial procedures at selected visits, refer to Sections 6.1 and 6.2, respectively.
3.1.1
Administrative structure of the trial
The trial will be conducted at the Clinical Pharmacology Unit (CPU) of 
 
, under the supervision of the Principal Investigator.
The trial medication will be provided by the Clinical Trial Supplies Unit (CTSU), BI Pharma 
GmbH & Co. KG, Biberach, Germany. 


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On-site monitoring will be performed by BI or a contract research organisation appointed by 
BI.
Safety laboratory tests will be performed by local laboratories of the trial site (e.g.
 
).
The analyses of BI 655088 concentrations in plasma will be performed by the Department of 
Drug Metabolism and Pharmacokinetics, Boehringer Ingelheim, Ridgefield, USA.
The analyses of ADA will be performed in the Bioanalytical Laboratories of 
, 
.
The analyses of exploratory biomarkers in blood will be performed at the Department of 
TMCP/TMBT, BI Pharma GmbH & Co. KG, Biberach, Germany.
The digitally recorded 12-lead ECGs may be sent to a specialised contract research 
organisation (e.g. 
) for additional central evaluation.
The trial is sponsored by Boehringer Ingelheim Pharma GmbH & Co. KG, Germany.
3.2
DISCUSSION OF TRIAL DESIGN, INCLUDING THE CHOICE OF 
CONTROL GROUP
For single-rising dose trials, the design described in Section 3.1 is viewed favourable under 
the provision not to expose the subjects involved to undue risks since the main study 
objective is to investigate safety and tolerability of BI 655088.
With the rising dose design, single-blind conditions regarding the subject’s treatment (active 
or placebo) are maintained within each dose group. However, the current dose level will be 
known to subjects. The disadvantage of this trial design is a possible observer bias with 
regard to the dose-depending effects as well as time effects, but it has the virtue of 
minimizing subject risk by sequentially studying ascending doses. As time-effects are 
expected to be small relative to the differences between the doses in the broad range 
investigated, unbiased comparisons between treatments can still be expected.
The single-blind conditions may introduce additional observer bias, e.g. when assessing AEs
in this first-in human trial. Thus every effort will be made to enhance the objectivity of
investigator’s observations. The same applies especially to the second subject of each dose 
level who is administered placebo treatment by defined study procedure.
It is standard in trials involving healthy volunteers to include a placebo group as control for 
the evaluation of safety, tolerability and pharmacodynamic effects. Each dose group consists 
of 8 subjects with 6 on active treatment, and 2 on placebo. The placebo control group 
includes all subjects of all dose groups treated with placebo. 6 subjects per active treatment 
group are in general considered as sufficient for exploratory evaluations.


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3.3
SELECTION OF TRIAL POPULATION
It is planned that 48 healthy male will enter the study. The actual number of subjects entered 
may exceed the total of 48 if additional intermediate doses will be tested (see Section 3.1). 
Subjects will be recruited from the volunteers' pool of the trial site.
Only male subjects will be included into the study because hitherto no data on reproductive 
toxicology are available.
A log of all subjects enrolled into the study (i.e. having given informed consent) will be 
maintained in the ISF at the investigational site irrespective of whether they have been treated 
with investigational drug or not.
3.3.1
Main diagnosis for study entry 
The study will be performed in healthy subjects.
3.3.2
Inclusion criteria
Subjects will only be included into the trial, if they meet the following criteria:
1. Healthy male subjects according to the investigator’s assessment, based on a complete 
medical history including a physical examination, vital signs (BP, PR), 12-lead ECG, and 
clinical laboratory tests 
2. Age of 18 to 50 years (incl.)
3. BMI of 18.5 to 29.9 kg/m2 (incl.)
4. Signed and dated written informed consent prior to admission to the study in accordance 
with GCP and local legislation
3.3.3
Exclusion criteria
Subjects will not be allowed to participate if any of the following general criteria apply:
1. Any finding in the medical examination (including BP, PR or ECG) is deviating from 
normal and judged as clinically relevant by the investigator
2. Repeated measurement of systolic blood pressure outside the range of 90 to 140 mmHg, 
diastolic blood pressure outside the range of 50 to 90 mmHg, or pulse rate outside the 
range of 45 to 90 bpm
3. Any laboratory value outside the reference range that the investigator considers to be of 
clinical relevance
4. Any evidence of a concomitant disease judged as clinically relevant by the investigator
5. Gastrointestinal, hepatic, renal, respiratory, cardiovascular, metabolic, immunological or 
hormonal disorders
6. Diseases of the central nervous system (including but not limited to any kind of seizures 
or stroke), migraine, and other relevant neurological or psychiatric disorders
7. History of relevant orthostatic hypotension, fainting spells, or blackouts
8. Chronic or relevant acute infections


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9. History of relevant allergy or hypersensitivity (including allergy to the trial medication or 
its excipients) 
10. Use of drugs (including any biological agent) with a long half-life (more than 24 h) 
within 30 days or less than 10 half-lives of the respective drug (whichever is greater) 
prior to administration of trial medication
11. Within 10 days prior to administration of trial medication, use of drugs that might 
reasonably influence the results of the trial or that might prolong the QT/QTc interval
12. Participation in another trial where an investigational drug has been administered within 
60 days or 10 half-lives (whichever is greater) prior to planned administration of trial 
medication
13. Smoker
14. Ex-smoker who has stopped smoking less than one year prior to enrolment and/or who 
has a history of equal or more than 10 pack years
15. Alcohol abuse (consumption of more 30 g per day)
16. Drug abuse or positive drug screening
17. Blood donation of  more than 100 mL within 30 days prior to administration of trial 
medication or intended donation during the trial
18. Intention to perform excessive physical activities within one week prior to administration 
of trial medication or during the trial
19. Inability to comply with dietary regimen of trial site
20. A marked baseline prolongation of QT/QTc interval (such as QTc intervals that are 
repeatedly greater than 450 ms) or any other relevant ECG finding at screening
21. A history of additional risk factors for Torsades de Pointes (such as heart failure, 
hypokalemia, or family history of Long QT Syndrome)
22. Subject is assessed as unsuitable for inclusion by the investigator, for instance, because 
considered not able to understand and comply with study requirements, or has a condition 
that would not allow safe participation in the study
23. History of tuberculosis infection and/or a confirmed positive Quantiferon TB-Gold test
24. Subjects who in the investigator’s judgement are perceived as having an excessive risk of 
thromboembolism (TE) for example because of a personal history and/or a first degree 
relative with a personal history with onset under the age of 55 of significant TE, including 
but not limited to deep vein thrombosis, pulmonary embolism, cortical sinus thrombosis, 
coronary and cerebrovascular events, cardiovascular disease, and peripheral arterial 
insufficiency
25. Abnormal results of coagulation values indicating an increased risk for bleeding or 
thromboembolism or complicating the safety evaluation during the study as determined 
by the investigator.
26. Deficiency of antithrombin III or protein S or protein C
27. Clinically relevant abnormal result of oral glucose tolerance test at baseline
28. Estimated glomerular filtration rate (eGFR) according to CKD-EPI formula < 90 mL/ min 
at screening (R12-1392)


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29. Urinary albumin/creatinine ratio (UACR) ≥ 30 mg albumin / g creatinine at screening
For study restrictions, refer to Section 4.2.2.
3.3.4
Removal of subjects from therapy or assessments
3.3.4.1
Removal of individual subjects
An individual subject is to be removed from the trial if:
1. The subject withdraws consent, without the need to justify the decision
2. The subject needs to take concomitant drugs that interfere with the investigational  
product or other trial medication
3. The subject is no longer able to participate for other medical reasons (such as surgery, 
adverse events, or diseases)
4. An AE or clinically significant laboratory change or abnormality occurred that the 
investigator judges to warrant discontinuation of treatment. This may include cases of 
sustained symptomatic hypotension (BP <90/50 mmHg) or hypertension (BP >180/100 
mmHg) or of clinically relevant changes in ECG requiring intervention as well as 
unexplained liver enzyme elevations at any time during the trial.
5. The subject shows an elevation of AST and/or ALT ≥3-fold ULN combined with an 
elevation of total bilirubin ≥2-fold ULN (measured in the same blood sample) and/or 
needs to be followed up according to the ‘DILI checklist’ provided in the ISF.
In addition to these criteria, the physician may discontinue subjects at any time based on his 
or her clinical judgment.
A subject can also be removed from the trial if eligibility criteria are being violated or if the 
subject fails to comply with the protocol (for instance, by non-adherence to dietary rules, or 
non-attendance at study assessments).
If a subject is removed from or withdraws from the trial prior to the administration of trial 
medication, the data of this subject will not be entered in the case report form (CRF) or trial 
database and will not be reported in the clinical trial report (CTR). If a subject is removed 
from or withdraws from the trial after administration of trial medication, this will be 
documented and the reason for discontinuation must be recorded in the CRF. In this case, the 
data will be included in the CRF/trial database and will be reported in the CTR. At the time 
of discontinuation a complete end of trial examination will be performed if possible and the 
information will be recorded in the CRFs. These discontinuations will be discussed in the 
CTR.
3.3.4.2
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 any of the following reasons:
1. New toxicological or clinical findings or serious adverse events invalidating the earlier 
positive benefit-risk-assessment. More specifically, the trial will be terminated if more 


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than 50% of the subjects show drug-related and clinically relevant adverse events of 
moderate or severe intensity, or if at least one drug-related serious adverse event is 
reported that is considered to be unacceptable.
2. The expected enrolment goals overall or at a particular trial site are not met
3. Violation of GCP, or the CTP, or the contract with BI by a trial site or investigator, 
disturbing the appropriate conduct of the trial
4. The sponsor decides to discontinue the further development of the investigational 
product.
5. Dose escalation will be stopped as soon as at least 2 subjects at one dose level on active 
drug showed relevant individual QT prolongation, i.e. a QTc increase of greater 60 ms 
from baseline in connection with absolute QT or QTc greater than 500 ms, which has 
been confirmed by a repeat ECG recording.
6. Dose escalation will be stopped based on the preliminary PK results as per Section 7.3.4, 
The investigator / the trial site will be reimbursed for reasonable expenses incurred in case of 
trial termination (except in case of the third reason).
3.3.5
Replacement of subjects
In case some subjects do not complete the trial, the trial clinical monitor together with the 
trial pharmacokineticist and the trial statistician are to decide if and how many subjects will 
be replaced. A replacement subject will be assigned a unique study subject number, and will 
be assigned to the same treatment as the subject he replaces.


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4.
TREATMENTS
4.1
TREATMENTS TO BE ADMINISTERED
4.1.1
Identity of BI investigational product and comparator product
The characteristics of the test product are given below:
Substance:
BI 655088
Pharmaceutical formulation: Solution for infusion (filled in 10R clear glass vials)
Source:
BI Pharma RCV GmbH & Co. KG, Austria
Unit strength:
Posology:
1-0-0
Route of administration:
IV infusion
Duration of use:
Single dose 
The characteristics of the reference product (placebo) are given below:
Substance:
Placebo to BI 655088
Pharmaceutical formulation: Solution for infusion (filled in 10R clear glass vials)
Source:
BI Pharma RCV GmbH & Co. KG, Austria
Unit strength:
Posology:
1-0-0
Route of administration:
IV infusion
Duration of use:
Single dose
The dilution solution (diluent), a buffer
 and water for 
injection, will be provided in 20R clear glass vials.


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4.1.2
Method of assigning subjects to treatment groups
Prior to the screening visit, subjects will be contacted in writing and informed about the 
planned visit dates. The subjects willing to participate will be recruited to dose groups and 
cohorts according to their temporal availability. As soon as enough subjects have been 
allocated to a dose cohort, the following subjects will be allocated to one of the other dose 
cohorts. Therefore, the allocation of subjects to dose cohorts is not influenced by trial 
personnel, but only by the subjects’ temporal availability. As the study includes healthy 
subjects from a homogenous population, relevant imbalances between the dose groups are not 
expected.
The randomisation list with study subject numbers and allocated treatments will be provided
to the trial site in advance. The allocation of subjects to study subject numbers will be 
performed prior to the administration of trial medication in ascending order (e.g. in dose 
group 1 the first subject will be 
 the next 
 …). Subjects will be allocated to a study 
subject number by the order of their subscription for the trial. Once a subject number has 
been assigned, it cannot be reassigned to any other subject.
The randomisation procedure is described in Section 7.5.
4.1.3
Selection of doses in the trial
The doses selected for this trial cover the subtherapeutic as well as the estimated therapeutic 
range and include a safety margin (see Section 2.1).
4.1.4
Drug assignment and administration of doses for each subject
The treatments to be evaluated are outlined in Table 4.1.4: 1 below. The dose volume for 
placebo corresponds to dose volume of the respective dose level.
Table 4.1.4: 1
BI 655088 and placebo treatments, intravenous administration
Dose
group
Substance
Pharmaceutical 
form
Concentration of active 
drug in reconstituted
solution
Dose volume
(single infusion over 2 hours)
Total dose
1
BI 655088
IV solution
2
BI 655088
IV solution
3
BI 655088
IV solution
4
BI 655088
IV solution
5
BI 655088
IV solution
6
BI 655088
IV solution
1-6
Placebo*
IV solution
--
identical to active treatment
--
* Subjects receiving placebo are equally distributed across dose groups 
The solution for intravenous infusion (active drug and placebo) will be prepared according to 
the instruction given in Appendix 10.1 by qualified pharmacy staff members or qualified
medical study personnel at the trial site under the responsibility of the investigator.


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The so-called four-eye principle (two-person rule) should be applied for preparation and 
administration of trial medication, if correct dosage cannot be ensured otherwise. For the 
purpose of drug accountability, the infusion set will be weighed before and after drug 
administration.
The trial medication will be administered to the subjects while in a semi-supine position
under supervision of the investigating physician or an authorised designee. Subjects are 
requested to fast overnight for at least 10 h before the scheduled start of infusion.
Subjects will be kept under close medical surveillance until at least 48 h following start of 
infusion. During infusion and up to 2 h thereafter, they are not allowed to lie down (i.e. no 
declination of the upper body of more than 45 degrees from upright posture except for 
medical examination), or to sleep. For restrictions with regard to diet see Section 4.2.2.2.
4.1.5
Blinding and procedures for unblinding
4.1.5.1
Blinding
The treatments administered (active or placebo) will be single-blind (blinded to subjects 
only). However, the current dose level will be known to the subjects. 
4.1.5.2
Procedures for emergency unblinding
As this trial will be conducted single-blind, the treatment information will be known to the 
investigator. Therefore, no emergency envelopes will be provided.
4.1.6
Packaging, labelling, and re-supply
Drug supplies will be provided by the Department of Pharmaceutical Development of 
Boehringer Ingelheim Pharma GmbH & Co. KG, Biberach, Germany.
The clinical trial supply consists of containers holding the trial medication which are labelled 
with trial identification. The required information according to local law as well as Annex 
13/EU GMP Guideline will be provided on the containers. Smaller boxes within the clinical 
trial supply containers will be labelled with:

BI trial number

Name of product and strengths or identification code

Pharmaceutical dosage form, quantity of dosage units 

Route and mode of administration

Term ‘For Clinical Trial Use’ (domestic language)

Sponsor name, address, and telephone number

Storage conditions

Use-by date

Batch number

Investigator 
The vials in the box are labelled with reduced requirements.


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The telephone number of the trial site is given in the subject information form. The EudraCT 
number is indicated on the title page of this protocol as well as on the subject information and 
informed consent forms. Examples of the labels will be available in the ISF.
Re-supply of trial medication will be done as necessary (e.g. to replace expired supplies). 
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 (labelled) storage conditions. A temperature log must be 
maintained to make certain that the drug supplies are stored at the correct temperature. If the 
storage conditions are found to be outside the specified range, the local clinical monitor (as 
provided in the list of contacts) is to be immediately contacted.
4.1.8
Drug accountability
The investigator / pharmacist / investigational drug storage manager will receive the 
investigational drugs delivered by the sponsor when the following requirements are fulfilled:

Approval of the study protocol by the IRB / ethics committee

Availability of a signed and dated clinical trial contract between the sponsor and the 
Head of Trial Centre

Approval/notification of the regulatory authority, e.g. competent authority

Availability of the curriculum vitae of the principal investigator

Availability of a signed and dated clinical trial protocol or immediately imminent 
signing of the clinical trial protocol 
Only authorised personnel as documented in the form ‘Site Delegation Log’ may dispense
medication to trial subjects. The trial medication must be administered in the manner 
specified in the CTP. All unused medication will be disposed locally by the trial site upon 
written authorisation by the clinical monitor. Receipt, usage and disposal must be
documented on the respective forms. Account must be given for any discrepancies. 
The investigator / pharmacist / investigational drug storage manager must maintain records of 
the product’s delivery to the trial site, the inventory at the site, the use by each subject, and 
the return to the sponsor or alternative disposal of unused products. 
These records will include dates, quantities, batch / serial numbers, expiry (‘use-by’) dates, 
and the unique code numbers assigned to the investigational products and trial subjects. The 
investigator / pharmacist / investigational drug storage manager will maintain records that 
document adequately that the subjects were provided the doses specified by the CTP, and that
reconcile all investigational products received from the sponsor. At the time of disposal, the 
investigator / pharmacist / investigational drug storage manager must verify that no remaining 
supplies are in the investigator’s possession.


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4.2
CONCOMITANT THERAPY, RESTRICTIONS, AND RESCUE 
TREATMENT
4.2.1
Rescue medication, emergency procedures, and additional treatments
There are no specific rescue drugs foreseen for the treatment of AEs. No special emergency 
procedures are to be followed. No additional treatment is planned. However, in case of 
adverse events in need of treatment, the investigator can authorise symptomatic therapy. In 
those cases, subjects will be treated as necessary and, if required, kept under supervision at 
the trial site or transferred to a hospital until all medical evaluation results have returned to an 
acceptable level.
4.2.2
Restrictions
4.2.2.1
Restrictions regarding concomitant treatment
In principle, no concomitant therapy is allowed. All concomitant or rescue therapies will be 
recorded (including time of intake on study days) on the appropriate pages of the CRF.
4.2.2.2
Restrictions on diet and life style
While admitted to the trial site the subjects are restricted from consuming any other foods or 
drinks than those provided by the staff. Standardised meals will be served at the time points 
described in the Flow Chart. No food is allowed from at least 10 hours before drug 
administration until at least 30 minutes after end of infusion.
From drug administration until 30 min after end of infusion, no liquid intake is allowed.
During the days of urine collection, total fluid intake should be at least 1.5 litres and should 
not exceed 3.5 litres.
Alcoholic beverages are not allowed from five days before the administration of trial drug 
until after trial assessments of Day 29 have been completed. Thereafter subjects may drink up 
to 20 g alcohol per day, corresponding to 0.5 L beer or 0.2 L white wine.
Dietary supplements and products including St. John's wort (Hypericum perforatum) are not 
permitted starting 7 days before the administration of trial medication until after the end of 
trial examination.
During in-house confinement at the trial site, smoking and consumption of methylxanthine-
containing drinks or foods (such as coffee, tea, cola, energy drinks, and chocolate) is not 
allowed.
Excessive physical activity (such as competitive sport) should be avoided starting 7 days 
before the administration of trial medication until the end of trial examination.
Direct exposure to the sun or exposure to solarium radiation should be avoided during the 
entire study.


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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 (for further procedures, please see Section 3.3.4.1). 


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5.
VARIABLES AND THEIR ASSESSMENT
5.1
EFFICACY - CLINICAL PHARMACOLOGY
5.1.1
Endpoints of efficacy
No efficacy endpoints will be evaluated in this trial.
5.1.2
Assessment of efficacy
Not applicable.
5.2
SAFETY
5.2.1
Endpoints of safety
Primary endpoint to assess safety and tolerability of BI 655088 is the number [N (%)] of 
subjects with drug-related AEs.
Further criteria of interest:

AEs (including clinically relevant findings from the physical examination and local 
tolerability)

Safety laboratory tests

12-lead ECG

Continuous ECG monitoring 

Vital signs (blood pressure, pulse rate, oral body temperature)

Oral glucose tolerance test

Bleeding time
5.2.2
Assessment of adverse events
5.2.2.1
Definitions of adverse events
Adverse event
An adverse event (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.
Serious adverse event
A serious adverse event (SAE) is defined as any AE which:

results in death, 


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
is life-threatening, this 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, 
or 

is deemed serious for any other reason if it is an important medical event when based 
upon appropriate medical judgment which may jeopardise the patient and may 
require medical or surgical intervention to prevent one of the other outcomes listed in 
the above definitions.
Examples of such events are intensive treatment in an emergency room or at home for 
allergic bronchospasm, blood dyscrasias or convulsions that do not result in hospitalisation or 
development of dependency or abuse. 
AEs considered ‘Always Serious’
Cancers of new histology and exacerbations of existing cancer must be reported as a serious 
event regardless of the duration between discontinuation of the drug and the occurrence of the 
cancer.
In accordance with the European Medicines Agency initiative on Important Medical Events, 
Boehringer Ingelheim has set up a list of further AEs, which by their nature, can always be 
considered to be ‘serious’ even though they may not have met the criteria of an SAE as given 
above.
The latest list of ‘Always Serious AEs’ can be found in the Remote Data Capture (RDC)
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 above.
Adverse events of special interest (AESIs)
The term 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. AESI 
need to be reported to the sponsor’s Pharmacovigilance Department within the same 
timeframe that applies to SAE, please see above.
The following are considered as AESIs in this trial:

Hepatic injury, as defined by the following alterations of hepatic laboratory 
parameters: 
o
an elevation of AST and/or ALT ≥3-fold ULN combined with an elevation of 
total bilirubin ≥2-fold ULN measured in the same blood sample, and/or
o
marked peak aminotransferase (ALT, and/or AST) elevations ≥10 fold ULN
These lab findings constitute a hepatic injury alert and the patients 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 


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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.
Intensity of AEs
The intensity of the AE should be judged based on the following:
Mild:
Awareness of sign(s) or symptom(s) that is/are easily tolerated
Moderate:
Enough discomfort to cause interference with usual activity
Severe:
Incapacitating or causing inability to work or to perform usual activities
Causal relationship of AEs
Medical judgment should be used to determine the relationship, considering all relevant 
factors, including pattern of reaction, temporal relationship, de-challenge or re-challenge, 
confounding factors such as concomitant medication, concomitant diseases and relevant 
history.
Arguments that may suggest that there is a reasonable possibility of a causal relationship 
could be:

The event is consistent with the known pharmacology of the drug 

The event is known to be caused by or attributed to the drug class.

A plausible time to onset of the event relative to the time of drug exposure.

Evidence that the event is reproducible when the drug is re-introduced

No medically sound alternative aetiologies that could explain the event (e.g. pre-
existing or concomitant diseases, or co-medications).

The event is typically drug-related and infrequent in the general population not 
exposed to drugs (e.g. Stevens-Johnson syndrome).

An indication of dose-response (i.e. greater effect size if the dose is increased, smaller 
effect size if dose is diminished).
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.


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
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 study drug treatment continues or remains 
unchanged.
5.2.2.2
Adverse event collection and reporting
AEs collection
Upon enrolment into a trial, the subject’s baseline condition is assessed (for instance, by 
documentation of medical history/concomitant diagnoses), and relevant changes from 
baseline are noted subsequently. 
Subjects will be required to report spontaneously any AEs as well as the time of onset, end, 
and intensity of these events. In addition, each subject will be regularly assessed by the 
medical staff throughout the clinical trial and whenever the investigator deems necessary. As 
a minimum, subjects will be questioned for AEs (and concomitant therapies) at the time 
points indicated in the Flow Chart. Assessment will be made using non-specific questions 
such as ‘How do you feel?’. Specific questions will be asked wherever necessary in order to 
more precisely describe an AE.
A careful written record of all AEs shall be kept by the investigator in charge of the trial. 
Records of AEs shall include data on the time of onset, end time, and intensity of the event as 
well as any treatment or action required for the event and its outcome.
The following must be collected and documented on the appropriate CRF(s) by the 
investigator:

From signing the informed consent onwards through the residual effect period (REP), 
until individual subject’s end of trial: 
o
All AEs (serious and non-serious) and all AESIs.
o
The only exception to this rule are AEs (serious and non-serious) and AESIs
in Phase I trials in healthy volunteers, when subjects discontinue from the trial 
due to screening failures prior to administration of any trial medication. In 
these cases, the subjects’ data must be collected at trial site but will not be 
entered in the CRF or trial database and will not be reported in the CTR.

After the individual subject’s end of trial: 
o
The investigator does not need to actively monitor the subject for AEs but 
should only report relevant SAEs and relevant AESIs of which he may 
become aware of.


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The residual effect period (REP) for BI 655088, when measurable drug levels or PD effects 
are still likely to be present, is not known for this first-in-human trial. Therefore all AEs 
reported until the end of trial examination will be considered on treatment; please see 
Section 7.3.3. Events which occurred after the end of trial examination will be considered as 
post treatment events.
The follow-up period describes the period of time from the last administration of trial 
medication until the end of trial examination (last per protocol visit).
AE reporting to 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 of 
awareness) to the sponsor’s unique entry point (country specific contact details will be 
provided in the ISF). This immediate report is required irrespective of whether the 
investigational product has been administered or not and irrespective of causal relationship. 
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.
Information required
For each AE, the investigator should provide the information requested on the appropriate 
CRF pages and the BI SAE form (if applicable). The investigator should determine the causal 
relationship to the trial medication. The following should also be recorded as an (S)AE in the 
CRF and on the 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 pre-exist prior trial inclusion they will be considered as
baseline conditions.


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All (S)AEs, including those persisting after individual subject’s end of trial must be followed 
up until they have resolved, have been sufficiently characterised, or no further information 
can be obtained.
5.2.3
Assessment of safety laboratory parameters
For the assessment of laboratory parameters, blood and urine samples will be collected by the 
trial site at the time points indicated in the Flow Chart after the subjects have fasted for at 
least 10 h. Overnight fasting is not required at the discretion of the investigator or designee
for retests and for time points planned to occur after a meal.
The parameters that will be determined are listed in Tables 5.2.3: 1 and 5.2.3: 2. Reference 
ranges will be provided in the ISF, Section 10.
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.
Though not necessary for clinical management, timed blood will be drawn from subjects that 
experience hypersensitivity or infusion reactions to help determine whether these were 
immune- or non-immune mediated. In accordance with clinical guidelines (R15-5401), such 
samples will be taken as soon as possible (without interfering with emergency treatment), 
preferably within 1-2 hours, but not later than 4 hours after onset of the reaction for the 
determination of tryptase, histamine, cytokines and complement (R15-5400). For details refer 
to Table 5.2.3:1. A further blood sample will be drawn 12-24 hours later after resolution of 
symptoms as a baseline reference.
The routine safety laboratory and exclusionary tests listed in Table 5.2.3: 1 and 5.2.3: 2 will
be performed at 
 with the exception of the drug 
screening tests and Quantiferon analysis. Drug screening tests will be performed at the trial 
site using “Alere Triage TOX Drug Screen”. Quantiferon TB-Gold test as well as additional 
laboratory tests in case of potential systemic hypersensitivity or infusion reaction or incipient 
albuminuria (see Table 5.2.3:1) will be done at 
 and 
, respectively.
Laboratory data will be transmitted electronically from the laboratory (
 
) to the trial site or via paper print-outs).


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Table 5.2.3: 1
Safety laboratory tests
Functional lab 
group
Test name 
SCR
Day -5 to 
-1
Within 
period
End-of-
trial
Haematology
Haematocrit
Haemoglobin
Red blood cell count (RBC)
Reticulocyte count
White blood cell count (WBC)
Platelet count
Glycated haemoglobin A1c (HbA1c)
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)
Neutrophils
Eosinophils
Basophils
Monocytes
Lymphocytes
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
Manual WBC 
differential 
(if automatic is 
abnormal)
Polymorphnuclear neutrophils (segs)
Band neutrophils (stabs)
Eosinophils
Basophils
Monocytes
Lymphocytes
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
Coagulation
Activated partial thromboplastin time (aPTT)
Prothrombin time (Quick’s test and INR)
Fibrinogen
Antithrombin III
Protein S
Protein C
x
x
x
x
x
x
x
x
x
-
-
-
x
x
x
-
-
-
x
x
x
-
-
-
Enzymes
Aspartate transaminase (AST/GOT)
Alanine transaminase (ALT/GPT)
Alkaline phosphatase (AP)
Gamma-glutamyl transferase (GGT)
Creatine kinase (CK)
CK-MB, only if CK is elevated 
Lactate dehydrogenase (LDH)
Lipase
Amylase
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
x
x
x
x
x
x
x
x
x
Hormones
Thyroid stimulating hormone (TSH)
Insulin
x
-
-
x1
-
x1
-
-
Substrates
Plasma glucose
Serum creatinine
eGFR (CKD-EPI for creatinine)
Cystatin C
Total bilirubin 
Direct bilirubin
Total protein
Albumin
C-Reactive Protein (CRP) 
Uric acid 
Total cholesterol 
Triglycerides
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
x
x
x
-
-
-
x
x
x
x
x
x
x
x
x
x
x
x
1
Only on study days with oral glucose tolerance test (see Flow Chart and Section 5.2.3.1)


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Table 5.2.3: 1
Safety laboratory tests (cont).
Functional lab 
group
Test name 
SCR
Day -5 to 
-1
Within 
period
End-of-
trial
Electrolytes
Sodium
Potassium
Chloride
Calcium
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
Urinalysis1 (Stix) Urine nitrite
Urine protein
Urine glucose
Urine ketone
Urobilinogen
Urine bilirubin
Urine erythrocytes
Urine leukocytes
Urine pH
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x
x1
x1
x1
x1
x1
x1
x1
x1
x1
x
x
x
x
x
x
x
x
x
Urine sediment1
(microscopic 
examination if 
erythrocytes, 
leukocytes nitrite 
or protein are 
abnormal in 
urine)
Only positive findings will be reported (for 
instance, the presence of sediment bacteria, casts 
in sediment, squamous epithelial cells, 
erythrocytes, leukocytes)
x
x
x1
x
Spot urine 1,2
Creatinine
Albumin
Albumin to creatinine ratio
x
x
x
x
x
x
x1
x1
x1
x
x
x
Additional
laboratory tests in 
case of potential 
systemic 
hypersensitivity
or infusion 
reaction
Serum tryptase
Histamine
IL-2
IL-4
IL-6
IL-8
IL-10 
IL-12
TNFα
IFNγ
C3a
C4a
C5a
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
-
x3
x3
x3
x3
x3
x3
x3
x3
x3
x3
x3
x3
x3
-
-
-
-
-
-
-
-
-
-
-
-
-
1
Not required at time point 4:00 on Day 1
2
Preferably 2nd morning urine
3
Only in case of a potential systemic hypersensitivity or infusion reaction; sampling as soon as possible after 
onset of event and approx. 12h to 24h after resolution of event
The tests listed in Table 5.2.3: 2 are exclusionary laboratory tests which may be repeated as 
required. The results will not be entered in the CRF/database and will not be reported in the 
CTR. Except for drug screening, it is planned to perform these tests during screening only. 


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Drug screening will be performed at screening and at the start of the inhouse period prior to
drug administration on Day 1.
Table 5.2.3: 2
Exclusionary laboratory tests
Functional lab group
Test name 
Drug screening (urine)
Amphetamine
Barbiturates
Benzodiazepine
Cannabis
Cocaine 
Opiates 
Infectious serology (blood)
Hepatitis B surface antigen (qualitative)
Hepatitis B core antibody (qualitative)
Hepatitis C antibodies (qualitative)
HIV-1 and HIV-2 antibody (qualitative)
Quantiferon TB-Gold
To encourage compliance with alcoholic restrictions, a breath alcohol test (Alcotest® 6510 
and Alcotest® 5510, Dräger, Belgium) will be performed at admission to trial site 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.
5.2.3.1
Oral glucose tolerance test (oGTT)
An oGTT will be performed on the morning of Day –5 to –1 (baseline) and Day 29. After 
blood drawing for determination of fasting plasma glucose and serum insulin, 75 g of glucose 
will be dissolved in 200 mL water and swallowed by the subject. Thirty minutes, 1, 2 and 3 
hours after intake of the glucose solution, further blood samples will be taken for glucose and 
insulin measurement. Blood samples for glucose measurements will be drawn in a 2 mL 
sodium fluoride (NaF) tube. Blood samples for insulin measurements will be drawn in a 2.5 
mL serum tube.
5.2.3.2
Bleeding time
Bleeding time will be measured according to Duke Method at the time points given in the 
Flow Chart. The subject will be pricked with a lancet in the earlobe, after having been 
swabbed with alcohol. The prick should be about 1.5-2 mm deep. Then the blood will be 
wiped every 30 seconds with a filter paper. The test ceases when bleeding ceases. The usual 
time is about 1-3 minutes. Abnormal findings will be reported as AEs (during the trial) or 
baseline conditions if judged clinically relevant by the investigator.
5.2.4
Electrocardiogram
5.2.4.1
12-lead resting ECG
Twelve-lead resting ECGs (I, II, III, aVR, aVL, aVF, V1 - V6) will be recorded using a 
computerised electrocardiograph (Cardionics SA, Brussels, Belgium) at the time points given 
in the Flow Chart.


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In order to achieve a stable heart rate at rest and to assure high quality recordings at 
comparable resting phases, all ECGs will be recorded for 10-sec duration after the subjects 
have rested for at least 5 min in a supine position. The site personnel will be instructed to 
assure a relaxed and quiet environment so that all subjects are at complete rest during the
recordings. ECG assessment will always precede all other study procedures of the same time 
point (except blood drawing from an intravenous cannula which is already in place) to avoid 
impact of sampling on the ECG quality.
Electrode placement will be performed according to the method of Wilson, Goldberger and 
Einthoven. Precise electrode placement will be marked with an indelible mark on the skin to 
allow reproducible placement on day 1 and 2.
Triple ECGs (recorded within 180 sec) will be recorded at screening, as the baseline before 
drug administration and up to 30 hours after start of infusion. At all other time points single 
ECGs will be recorded.
All locally printed ECGs will be evaluated by the investigator or a designee.
ECGs may be repeated for quality reasons (like alternating current artefacts, muscle 
movements, electrode dislocation). For time points with triple ECGs, all three single ECGs 
will be repeated. For the repeats due to quality reasons, only the repeated ECG recordings 
will be used for analysis provided quality was better than with the initial ECG. 
Additional (unscheduled) ECGs may be collected by the investigator for safety reasons. 
These ECGs are assigned to the prior scheduled time point. Unscheduled ECGs will not be 
included into the statistical analysis of interval lengths (if analysis is done). 
For the inclusion or exclusion (see Section 3.3) of a subject and for the assessment of cardiac 
safety during the study, the QT and QTcB values generated by the ECG machines or their 
manual corrections by the investigators will be used. In doubtful cases, ECGs may be sent 
upfront for external evaluation. In this case, these externally measured results would overrule 
any other results obtained.
Abnormal findings will be reported as AEs (during the trial) or baseline conditions (at 
screening) if judged clinically relevant by the investigator. Any ECG abnormalities will be 
monitored carefully and, if necessary, the subject will be removed from the trial and will 
receive the appropriate medical treatment.
All ECGs will be stored electronically at site in order to enable a centralised re-evaluation of 
all 12-lead ECGs by an independent ECG laboratory if needed.
5.2.4.2
Continuous ECG monitoring
Cardiac rhythm (including heart rate) will be monitored by means of continuous 2-lead ECG 
recording for at least 15 min before (for baseline assessment) and constantly for 4 h after start 
of infusion using the Dräger Telemetry monitoring system, Infinity M300.


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5.2.5
Assessment of other safety parameters
5.2.5.1
Vital signs
Systolic and diastolic blood pressures (BP) as well as pulse rate (PR) or heart rate (heart rate 
is considered to be equal to pulse rate) will be measured by a blood pressure monitor (e.g. 
Welch Allyn 530TP and 530TO devices) at the times indicated in the Flow Chart, after 
subjects have rested for at least 5 min in a supine position. All recordings should be made 
using the same type of blood pressure recording instrument on the same arm if possible.
Oral body temperature will be determined using a digital thermometer at the time points 
indicated in the Flow Chart. 
5.2.5.2
Medical examinations
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), 12-lead ECG, laboratory tests, and a 
physical examination. At the end of trial examination, it will include review of vital signs, 12-
lead ECG, laboratory tests, and a physical examination.
5.2.5.3
Local tolerability
Local tolerability will be assessed by the investigator according to ‘swelling’, ‘induration’, 
‘heat’, ‘redness’, ‘pain’, or ‘other findings’.
5.3
OTHER
Not applicable.
5.4
APPROPRIATENESS OF MEASUREMENTS
All measurements performed during this trial are standard measurements and will be 
performed in order to monitor subjects’ safety and to determine pharmacokinetic parameters
and biomarkers in an appropriate way. The scheduled measurements will allow monitoring of
changes in vital signs, standard laboratory values, and ECG parameters that might occur as a 
result of administration of trial medication. The safety assessments are standard, are accepted 
for evaluation of safety and tolerability of an intravenously administered drug, and are widely 
used in clinical trials. The pharmacokinetic parameters and measurements outlined in 
Section 5.5 are generally used assessments of drug exposure. The biomarkers outlined in 
Section 5.6 are of exploratory nature only.
5.5
DRUG CONCENTRATION MEASUREMENTS AND 
PHARMACOKINETICS
Date and clock time of drug administration and pharmacokinetic sampling will be recorded in 
the CRFs.


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PK sampling times and periods may be adapted during the trial based on information 
obtained during trial conduct (e.g. preliminary PK data) including addition of samples and 
visits as long as the total blood volume taken per subject does not exceed 550 mL. Such
changes would be implemented via non-substantial CTP Amendments.
5.5.1
Pharmacokinetic endpoints
The following pharmacokinetic parameters will be determined if feasible:
5.5.1.1
Secondary endpoints

Cmax (maximum measured concentration of the analyte in plasma)

AUC0-tz (area under the concentration-time curve of the analyte in plasma over the 
time interval from 0 to the last quantifiable data point)

AUC0-∞(area under the concentration-time curve of the analyte in plasma over the 
time interval from 0 extrapolated to infinity)
Further pharmacokinetic parameters might be calculated as appropriate.


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5.5.2
Methods of sample collection
5.5.2.1
Plasma sampling for pharmacokinetic analysis
For quantification of BI 655088 plasma concentrations, 2.7 mL of blood will be taken from 
an antecubital or forearm vein into a K3-EDTA (tripotassium ethylenediaminetetraacetic
acid)-anticoagulant blood drawing tube at the times indicated in the Flow Chart. Blood will 
be withdrawn by means of either an indwelling venous catheter or by venipuncture with a 
metal needle. Within the first 6 hours following start of infusion, blood samples should be 
taken from the contralateral arm used for infusion.
The K3-EDTA-anticoagulated blood samples will be centrifuged for about 10 min at about 
2000 g to 4000 g and at 4 to 8 °C. Two plasma aliquots will be obtained and stored in 
polypropylene tubes. The first aliquot should contain at least 0.5 mL plasma. The process 
from blood collection until transfer of plasma aliquots into the freezer should be completed 
within 60 min, with interim storage of blood samples in ice water or on ice. 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.
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) including anti-drug antibodies (if applicable) 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 upon the final study 
report has been signed.


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5.5.3
Analytical determinations
5.5.3.1
Analytical determination of BI 655088 plasma concentration
BI 655088 concentrations in plasma will be determined by a validated assay. All details of 
the analytical method will be available prior to the start of sample analysis.
As described in Section 4.1.5, the bioanalyst will be unblinded during sample analysis.
5.6
BIOMARKERS 
5.6.1
Biomarkers for assessment of target engagement
The pharmacodynamic (PD) assessment of this trial comprises determination of exploratory 
target engagement biomarkers:


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5.6.2
Methods of sample collection
PD sampling times and periods may be adapted during the trial based on information 
obtained during trial conduct (e.g. preliminary PK/PD data), including addition of samples 
and visits, as long as the total blood volume taken from each subject does not exceed 550 mL. 
Such changes would be implemented via non-substantial CTP Amendments.


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The laboratory should be contacted prior to shipment (
.
After completion of the study the samples may be used for further biomarker investigations, 
assay development and validation purposes, e.g. method comparison or sample stability 
studies. These analyses may be performed in laboratories other than Boehringer Ingelheim, 
Germany, if necessary. The study samples will be discarded after completion of any 
additional investigations but not later than 5 years after the CTR has been signed.
5.6.3
Analytical determinations
Samples will be measured at Boehringer Ingelheim, TMCP/TMBT, Biberach, Germany. 
Characteristics of the analytical methods will be given in the clinical study report.
Left over samples for biomarker analysis may be used for further assay development and 
validation purposes, e.g. method comparison or sample stability studies. These analyses may 
be performed in laboratories other than Boehringer Ingelheim, Germany, if necessary.
5.7
PHARMACOKINETIC - PHARMACODYNAMIC RELATIONSHIP
The PK and PD (biomarker) data from this study may be used for an exploratory 
investigation of PK/PD relationship of BI 655088.


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6.
INVESTIGATIONAL PLAN
6.1
VISIT SCHEDULE
Exact times of measurements outside the permitted time windows will be documented. The 
acceptable time windows for screening and end of trial examination are given in the 
Flow Chart.
Oral glucose tolerance test at baseline may be done within 8 days prior to the drug 
administration, i.e. the acceptable deviation from Day -5 will be -3 days.
Study measurements and assessments scheduled to occur ‘before’ trial medication 
administration on Day 1 are to be performed and completed within a 3 h-period prior to the 
start of trial drug administration (including blank values for PK and biomarkers).
The acceptable deviation from the scheduled time for vital signs (BP, PR, and body
temperature) and ECG will be:

± 15 min up to including 12 h

± 30 min from after 12h up to including 48 h
The acceptable deviation from the scheduled time for laboratory samples and bleeding time:

± 5 min up to including 2 h

± 15 min from after 2h up to including 12 h

± 30 min from after 12h up to including 48 h

± 120 min from after 48 h up to Day 8

± 4 hours from after Day 8 up to Day 29

±  1, 2 or 3 days from after Day 29 up to the last measurement as indicated in the 
Flow Chart
If scheduled in the Flow Chart at the same time as a meal, blood sampling, vital signs and 12-
lead ECG recordings have to be done first. Furthermore, if several measurements including 
venipuncture are scheduled for the same time, venipuncture should be the last of the 
measurements due to its inconvenience to the subject and possible influence on physiological
parameters.
For planned individual plasma concentration sampling times 
refer to the Flow Chart. While these nominal times should be adhered to as closely as 
possible, the actual sampling times will be recorded and used for determination of 
pharmacokinetic parameter. The same applies to biomarker sampling and pharmacodynamic 
parameters.
If a subject misses an appointment, it will be rescheduled if possible. The relevance of 
measurements outside the permitted time windows will be assessed no later than at the Report 
Planning Meeting.


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6.2
DETAILS OF TRIAL PROCEDURES AT SELECTED VISITS
6.2.1
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.
For information regarding laboratory tests (including drug and virus screening), ECG, vital
signs, and physical examination, refer to Sections 5.2.3 to 5.2.5.
6.2.2
Treatment period
Each subject will receive one dose of the respective trial medication (BI 655088 or placebo) 
at Visit 2.
Trial medication will be administered as IV infusion by the investigating physician or his 
designee. Details on treatments and procedures of administration are described in 
Section 4.1.4.
Study participants will be admitted to the trial site in the evening of Day -1 and kept under 
close medical surveillance for at least 48 h following the start of infusion. The subjects will 
then be allowed to leave the trial site after formal assessment and confirmation of their fitness 
by the investigator or 
 designee. On all other study days, the study will be performed in an 
ambulatory fashion.
For details on time points and procedures for collection of blood
 samples for PK 
analysis, refer to Flow Chart and Section 5.5.2. 
The safety measurements performed during the treatment period are specified in Section 5.2
of this protocol and in the Flow Chart. For details on time points for all other trial procedures, 
refer to the Flow Chart. AEs and concomitant therapy will be assessed continuously from 
screening until the end of trial examination.
6.2.3
End of trial period 
For AE assessment, laboratory tests, recording of ECG and vital signs, and physical 
examination during the end of trial period, see Sections 5.2.2 to 5.2.5.
Subjects who discontinue before the end of the treatment period should undergo the end of 
trial visit.
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. Adverse events persisting after trial completion must be 
monitored until they have normalised or have been sufficiently characterised. 
The end of the trial as a whole is defined by the ‘last regular visit completed by last subject’ 
or ‘end date of the last open AE’ or ‘date of the last follow-up test’ or ‘date of an AE has 
been decided as sufficiently followed-up’, whichever is latest.


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7.
STATISTICAL METHODS AND DETERMINATION OF
SAMPLE SIZE
7.1
STATISTICAL DESIGN – MODEL
The trial design and dose groups are outlined in Section 3.1 and discussed in 3.2.
7.1.1
Objectives
The primary objective of this trial is to investigate the safety and tolerability of BI 655088 in 
healthy male subjects following intravenous infusion of single rising doses of 
Within the parallel group design the treatment groups (dose levels and pooled placebo) will 
be compared by using descriptive statistics. The primary endpoint is defined in Section 5.2.1. 
Inferential statistics is not planned (as explained in Section 7.2).
The secondary objective is the exploration of the pharmacokinetics (PK) and 
pharmacodynamics (PD) of BI 655088. Endpoints as specified in Section 5.5.1 and 5.6.1 will 
be analysed by descriptive statistics. Secondary endpoints Cmax, AUC0-tz, and AUC0-∞as 
defined in Section 5.5.1.1 will be subjected to analysis of dose proportionality by use of the 
power model. 
7.2
NULL AND ALTERNATIVE HYPOTHESES
Safety and tolerability of the different dose groups of BI 655088 are to be determined on the 
basis of the investigated parameters in comparison to placebo. It is not planned to test any 
statistical hypotheses with regard to these variables in a confirmatory sense. Instead, they will 
be described in their entirety and evaluated by descriptive statistical methods.
Confidence intervals will be computed and will have to be interpreted in the perspective of 
the exploratory character of the study, i.e. confidence intervals are considered as interval 
estimates for effects.
7.3
PLANNED ANALYSES
The following analysis data sets will be used in this trial:
The Randomised set includes all randomised subjects, whether treated or not. This set will be 
used for Listings. Subjects not randomised will not be analysed in the CTR.
The Treated set (TS) includes all subjects who were dispensed study medication and were 
documented to have taken at least one dose of investigational treatment. This set will be used 
for analyses of safety data, refer to Section 7.3.3.
The PK parameter analysis set (PKS) is a per protocol set with regard to PK endpoints, refer 
to Section 7.3.2. A full analysis set in the sense of ICH E9 will not be used in this trial.
Adherence to the protocol (such as inclusion/exclusion criteria, times of measurement, 
compliance with intake of trial medication, treatment dispensing errors, prohibited 
concomitant medication, completeness and consistency of data) will be checked. Important 


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protocol violations will be identified no later than in the Report Planning Meeting and 
provided in the TSAP.
7.3.1
Primary analyses
Analysis of safety and tolerability is described in Section 7.3.3.
7.3.2
Secondary analyses
The secondary parameters (refer to Section 5.5.1) will be calculated according to the BI 
Standard Operating Procedure (SOP) ‘Standards and processes for analyses performed within 
Clinical Pharmacokinetics/Pharmacodynamics’ (001-MCS-36-472). 
Plasma 
 concentration data and parameters of a subject will be included in the
statistical pharmacokinetic (PK) analyses if they are not flagged for exclusion due to a 
protocol violation relevant to the evaluation of PK (to be decided no later than in the Report 
Planning Meeting) or due to PK non-evaluability (as revealed during data analysis, based on 
the criteria specified below). Exclusion of a subject’s data will be documented in the CTR.
Relevant protocol violations may be:

Incorrect trial medication taken, i.e. the subject received at least one dose of trial 
medication the subject was not assigned to

Incorrect dose of trial medication taken

Use of restricted medications.
Plasma 
 concentrations and parameters of a subject will be considered as non-
evaluable, if for example:

Missing samples/concentration data at important phases of PK disposition curve
The PK parameter analysis set (PKS) includes all subjects in the Treated Set (TS as defined 
in Section 7.3) who provide at least one PK parameter that was not excluded according to the 
description above. 
Assessment of dose proportionality
Dose proportionality will be assessed using the pharmacokinetic endpoints Cmax, AUC0-tz, and
AUC0-∞as specified in Section 5.5.1.1.
The basic model for the investigation of dose proportionality will be a power model that 
describes the functional relationship between the dose and PK endpoints.
ij
i
ij
ε
)
X
exp(
)
exp(Y







The model consists of a regression model applied to log-transformed data. The corresponding 
ANCOVA model includes the logarithm of the dose as a covariate. 
Together with
)
exp(


and
)
exp(
ε
ij
ij



, taking natural logarithms converts this model 
to a linear form as follows:


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ij
i
ij
ε
X
β
α
Y




where
ij
Y
logarithm of the pharmacokinetic endpoint for subject j at dose level i; 
where i = 1, 2, …, j = 1, 2, …, ni;

intercept parameter;
β
slope parameter;
i
X
logarithm of dose i;
ij
ε
random error associated with subject j at dose level i (assumed to be 
independent and identically normally distributed).
This equation can be fit as a linear regression model.
Based on the estimate for slope parameter (β), a 2-sided 95% CI for the slope will be 
computed. Perfect dose proportionality would correspond to a slope of 1. The assumption of a 
linear relationship between the log-transformed pharmacokinetic endpoint and the log-
transformed dose will be checked.
If dose proportionality over the entire dose range investigated cannot be shown, an attempt 
will be made to identify dose range(s), where dose proportionality can be assumed.
Graphical displays
To support the analyses of dose proportionality, graphical representations of the data might 
be created. These might include (but are not limited to) individual time-courses of plasma 
concentrations and the (geometric) mean plasma concentration time profiles as well as Cmax, 
AUC0-tz, and AUC0-∞versus dose.
7.3.3
Safety analyses
Safety will be assessed for the endpoints listed in Section 5.2.1. The TS as defined in 
Section 7.3 will be included in the safety analyses.
Safety analyses will be descriptive in nature and will be based on BI standards.
Treatments will be compared in a descriptive way. The placebo control group in the safety 
evaluation will consist of all placebo treated subjects, regardless of the dose group in which 
they were treated. The active treatment groups will be compared to the placebo group in a 
descriptive way. Tabulations of frequencies/proportions will be used for the evaluation of 
categorical (qualitative) data, and tabulations of descriptive statistics will be used to analyse 
continuous (quantitative) data.
The analyses will be done by ‘treatment at onset’.
Measurements (such as ECG, vital signs, or laboratory parameters) or AEs will be assigned to 
treatments (see Section 4.1) based on the actual treatment at the planned time of the 
measurement or on the recorded time of AE onset (concept of treatment emergent AEs).
Therefore, measurements planned or AEs recorded prior to administration of trial medication 
will be assigned to 'screening', those between start of drug administration until the end of trial 
visit will be assigned to the treatment period, and those after the end of trial examination will 


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be assigned to ‘post-treatment’. These assignments including the corresponding time intervals 
will be defined in detail in the TSAP.
Adverse events will be coded using the Medical Dictionary for Regulatory Activities 
(MedDRA). Frequency, intensity and causal relationship of AEs will be tabulated by 
treatment, primary system organ class and preferred term. SAEs, AESIs (see Section 5.2.2.1) 
and other significant AEs (according to ICH E3) will be listed separately. 
Laboratory data will be compared to their reference ranges. Values outside the reference 
range will be flagged. Additionally, differences from baseline will be evaluated. Results of 
the oGTT, i.e. further plasma glucose and serum insulin measurements will be evaluated in 
the same way as laboratory data but presented separately. In addition, graphical 
representations of individual time-courses of plasma glucose and insulin measurements and 
the (geometric) mean time profiles will be presented.
Area under the curve will be calculated for glucose and insulin according to the linear 
trapezoidal rule.
Changes in AUCs for glucose and insulin (oGTT measurements) from baseline to post-
treatment will be compared between BI 655088 and placebo.
Descriptive statistics of bleeding time at the time points given in the Flow Chart and for the 
difference from baseline will be provided.
Descriptive statistics of vital signs and for the difference from baseline will be presented per 
planned time. ECG data will not be listed but clinically relevant abnormal findings will be 
reported as adverse events.
7.3.4
Preliminary PK and PD analyses
A preliminary analysis of PK parameters (AUC0-168 and Cmax of BI 655088), provided as 
individual values and geometric means, will be performed for 

dose levels 1, 2, 3, 4 (n) before proceeding to dose level 3, 4, 5, 6 (n+2)
In addition, exploratory analyses of pharmacodynamics 
will be performed for each dose level in parallel.
In contrast to the final PK/PD calculations, the preliminary analyses will be based on planned 
sampling times rather than on actual times, regardless of whether actual times were within the 
time windows or not. Therefore, minor deviations of preliminary and final results may occur. 
The preliminary analyses will provide individual and mean concentration/effect-time profiles 
and summary statistics of individual values without subject identification.
The preliminary PK/PD results will be distributed to the Investigator and the trial team. 
Depending on the results of available preliminary PK/PD analyses, the tolerability and safety 
of the compound, and changes of dosing schedule (e.g. additional intermediate doses) 
additional PK/PD preliminary analysis may be performed based on the request of the Trial 
Clinical Monitor, the investigator, or Trial Clinical Pharmacokineticist. No formal 
preliminary PK/PD report will be written.


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7.3.5
Pharmacokinetic analyses
The pharmacokinetic parameters listed in Section 5.5.1 for BI 655088 will be calculated 
according to the BI SOP ‘Standards and processes for analyses performed within Clinical 
Pharmacokinetics/Pharmacodynamics’ (001-MCS-36-472).
Subjects who are not included in the PKS (refer to Section 7.3.2) will be reported with their 
individual plasma concentrations and individual pharmacokinetic parameters; however, they 
will not be included in descriptive statistics for plasma concentrations, pharmacokinetic 
parameters or other statistical assessment.
Only concentration values within the validated concentration range and actual sampling times 
will be used for the calculation of pharmacokinetic parameters. Concentrations used in the 
pharmacokinetic calculations will be in the same format provided in the bioanalytical report, 
(that is, to the same number of decimal places provided in the bioanalytical report).
7.4
HANDLING OF MISSING DATA
7.4.1
Safety
With respect to safety evaluations, it is not planned to impute missing values.
7.4.2
Plasma
 drug concentration - time profiles
Handling of missing PK data will be performed according to the relevant SOP of the Sponsor 
(001-MCS-36-472).
Drug concentration data identified with NOS (no sample available), NOR (no valid result), 
NOA (not analyzed), BLQ (below the lower limit of quantification), or NOP (no peak 
detectable) will be displayed as such and not replaced by zero at any time point (this rule also 
applies also to the lag phase, including the predose values). 
7.4.3
Pharmacokinetic parameters
Handling of missing PK data will be performed according to the relevant SOP of the Sponsor 
(001-MCS-36-472).
For the non-compartmental analysis, concentration data identified with NOS, NOR or NOA 
will generally not be considered. Concentration values in the lag phase identified as BLQ or 


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NOP will be set to zero. All other BLQ/NOP values of the profile will be ignored. The lag 
phase is defined as the period between time zero and the first time point with a concentration 
above the quantification limit.
7.5
RANDOMISATION
Subjects will be randomised within each dose group in a 3:1 ratio, which reflects the ratio of 
subjects receiving active drug to placebo. Due to the fixed drug administration of the 4 first 
subjects within each dose group (1st subject active, 2nd subject placebo, 3rd and 4th subject 
active), the trial is called “partially-randomised”. Each dose group consists of 3 cohorts. The 
random numbers are assigned to the cohorts sequentially per dose group.
The sponsor will arrange for the randomisation as well as packaging and labelling of trial 
medication. The randomisation list will be generated using a validated system, which 
involves a pseudo-random number generator and a supplied seed number so that the resulting 
allocation is both reproducible and non-predictable.
The randomisation list will contain additional blocks to allow for subject replacement (refer 
to Section 3.3.5).
7.6
DETERMINATION OF SAMPLE SIZE
It is planned to include a total of 48 subjects in this trial. The planned sample size is not based 
on a power calculation. The size of 8 subjects per dose group (6 on active treatment, and 2 on 
placebo) is commonly used in single-rising dose studies of the present type and is in general 
considered as sufficient for the exploratory evaluation of single dose safety and 
pharmacokinetics (R95-0013).
Additional subjects may be entered to allow testing of additional intermediate doses within 
the planned dose range on the basis of experience gained during trial conduct (e.g. 
preliminary PK data), i.e. the actual number of subjects entered may exceed 48.


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8.
INFORMED CONSENT, DATA PROTECTION, TRIAL
RECORDS
The trial will be carried out in compliance with the protocol, the principles laid down in the 
Declaration of Helsinki, in accordance with the ICH Harmonised Tripartite Guideline for 
Good Clinical Practice (GCP) and relevant BI.
The investigator should inform the sponsor immediately of any urgent safety measures taken 
to protect the study subjects against any immediate hazard, and also of any serious breaches 
of the protocol or of ICH GCP.
The rights of the investigator and of the sponsor with regard to publication of the results of 
this trial are described in a separate agreement between the investigator or the trial site and 
the sponsor. As a general rule, no trial results should be published prior to finalisation of the
CTR.
Insurance Coverage: The certificate of insurance cover is made available to the investigator 
and each subject, and is stored in the ISF.
8.1
STUDY APPROVAL, SUBJECT INFORMATION, AND INFORMED 
CONSENT
This trial will be initiated only after all required legal documentation has been reviewed and 
approved by the respective Institutional Review Board (IRB) / Independent Ethics Committee 
(IEC) and competent authority (CA) according to national and international regulations. The 
same applies for the implementation of changes introduced by amendments.
Prior to a subject’s participation in the trial, written informed consent must be obtained from 
each subject (or the subject’s legally accepted representative) according to ICH GCP and to 
the regulatory and legal requirements of the participating country. Each signature must be 
personally dated by each signatory and the informed consent and any additional subject 
information form are to be retained by the investigator as part of the trial records. A copy of 
the signed and dated written informed consent and any additional subject information must be 
given to each subject or the subject’s legally accepted representative.
The subject must be informed that his personal trial-related data will be used by Boehringer 
Ingelheim in accordance with the local data protection law. The level of disclosure must also 
be explained to the subject.
The subject must be informed that his medical records may be examined by authorised 
monitors (Clinical Monitor Local/Clinical Research Associate) or Clinical Quality Assurance 
auditors appointed by Boehringer Ingelheim, by appropriate IRB/IEC members, and by 
inspectors from regulatory authorities.
8.2
DATA QUALITY ASSURANCE
A quality assurance audit/inspection of this trial may be conducted by the sponsor or 
sponsor’s designees, by IRBs/IECs, or by regulatory authorities. The quality assurance 


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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.
The data management procedures to ensure the quality of the data are described in detail in 
the trial data management and analysis plan (TDMAP) available in the TMF.
8.3
RECORDS
CRFs for individual subjects will be provided by the sponsor. For drug accountability, refer 
to Section 4.1.8.
8.3.1
Source documents
Source documents provide evidence for the existence of the subject and substantiate the 
integrity of the data collected. Source documents are filed at the investigator’s site.
All data reported in the CRFs must be consistent with the source data or the discrepancies 
must be explained.
The investigator may need to request previous medical records or transfer records, depending 
on the trial.
8.3.2
Direct access to source data and documents
The investigator/institution will permit trial-related monitoring, audits, IRB/IEC review and 
regulatory inspection, providing direct access to all related source data/documents. CRFs and 
all source documents, including progress notes (if applicable) and copies of laboratory and 
medical test results must be available at all times for review by the sponsor’s clinical trial 
monitor, auditor and inspection by health authorities (e.g. FDA). The Clinical Research 
Associate/on site monitor and auditor may review all CRFs, and written informed consents. 
The accuracy of the data will be verified by reviewing the documents described in 
Section 8.3.1.
8.4
LISTEDNESS AND EXPEDITED REPORTING OF ADVERSE EVENTS
8.4.1
Listedness
To fulfil the regulatory requirements for expedited safety reporting, the sponsor evaluates 
whether a particular AE is ‘listed’, i.e. is a known side effect of the drug. Therefore a unique
reference document for the evaluation of listedness needs to be provided. For BI 655088 this 
is the current version of the Investigator’s Brochure (c02156503-03). The current version of 
this reference document is to be provided in the ISF. No AEs are classified as listed for 
matching placebo, study design, or invasive procedures.
8.4.2
Expedited reporting to health authorities and IECs/IRBs
Expedited reporting of serious adverse events, e.g. suspected unexpected serious adverse 
reactions (SUSARs) to health authorities and IECs/IRBs, will be done according to local 
regulatory requirements. Further details regarding this reporting procedure are provided in the
Investigator Site File.


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8.5
STATEMENT OF CONFIDENTIALITY
Individual subject medical information obtained as a result of this trial is considered 
confidential and disclosure to third parties is prohibited with the exceptions noted below. 
Subject confidentiality will be ensured by using subject identification code numbers.
Treatment data may be provided to the subject’s personal physician or to other appropriate 
medical personnel responsible for the subject’s welfare. Data generated as a result of the trial 
need to be available for inspection on request by the participating physicians, the sponsor’s 
representatives, by the IRB/IEC and the regulatory authorities, i.e. the CA.
8.6
COMPLETION OF TRIAL
The EC/competent authority in each participating EU member state needs to be notified about 
the end of the trial (last subject/subject out, unless specified differently in Section 6.2.3 of the 
CTP) or early termination of the trial.


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9.
REFERENCES 
9.1
PUBLISHED REFERENCES
R95-0013
Broom C. Design of first-administration studies in healthy man. Early 
Phase Drug Evaluation in Man. O'Grady J, Linet OI (Eds.), Macmillan 
Press: London, 1990, 206 213.
R09-4830 
Brown BD, Badilini F. HL7 aECG implementation guide (March 21, 
2005).
R09-6036
European Medicines Agency (EMEA). Committee for Medicinal Products 
for Human Use (CHMP): guideline on strategies to identify and mitigate 
risks for first-in-human clinical trials with investigational medicinal 
products (London, 19 July 2007, doc. ref.EMEA/CHMP/SWP/28367/07). 
http://www.emea.europa.eu 2007.
R12-0027
European Medicines Agency (EMA). Committee for medicinal products 
for human use (CHMP): ICH guideline S6 (R1) - preclinical safety 
evaluation of biotechnology-derived pharmaceuticals: step 5 (June 2011, 
EMA/CHMP/ICH/731268/1998). 
http://www.emea.europa.eu/docs/en_GB/document_library/Scientific_gui
deline/2009/ 09/WC500002828.pdf (access date: 10 January 2012); 
London: European Medicines Agency (EMA) 2011.


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R15-5400
Brown SGA, Stone SF, Fatovich DM, Burrows SA, Holdgate A. 
Anaphylaxis: clinical patterns, mediator release, and severity. J Allergy 
Clin Immunol 2013. 132(5):1141-1149.


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R15-5401
Anaphylaxis: assessment to confirm an anaphylactic episode and the 
decision to refer after emergency treatment for a suspected anaphylactic 
episode (NICE clinical guideline 134, issued: December 2011). 
http://www.nice.org.uk/guidance/cg134/resources/guidance-anaphylaxis-
assessmentto-confirm-an-anaphylactic-episode-and-the-decision-to-refer-
after-emergency-tre atment-for-a-suspected-anaphylactic-episode-pdf 
(access date: 16 October 2015); National Institute for Health and Clinical 
Excellence 2011.
9.2
UNPUBLISHED REFERENCES
001-MCS-36-472 Standards and processes for analyses performed within Clinical 
Pharmacokinetics/Pharmacodynamics. Current version
c02156503-03
Investigator’s Brochure BI 655088. Version 2; 28 September 2017.
c19231668-01
Clinical Overview Statement. 18 August 2017.


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10.
APPENDICES
10.1
RECONSTITUTION OF IMP AND INSTRUCTION FOR USE
Preparation of trial product is a defined part of reconstitution for application of various doses. 
It also includes marking of various syringes with a pen in order to avoid mix-up during 
processing and keep single-blind status.
The preparation steps as described below in Section 10.1.2 will be carried out by experienced 
and adequately trained staff at the site in a four-eye principle. Training will be provided by 
the sponsor at the trial initiation meeting or as adequate before dosing and documented in the 
TMF.
If a change of dose becomes necessary a referring instruction for dilution of trial product will 
be drawn and filed in the ISF. In this case, an amendment is not required.


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10.1.1
Equipment and material for reconstitution and administration
The following material will be used for dilution of trial product and administration:
Table 10.1.1: 1
List of material and equipment
No. Type
Description
Supplier
Vendor 
Reference
Usage
Material for IV preparation
1
1 mL syringe
Inject F, Luer
PP, latex free, PVC free
0.01 mL scale
B.Braun
9166017V
withdrawal, dilution
2
3 mL syringe
Omnifix, Luer Lock
PP, latex free, PVC free
0.1 mL scale
B.Braun
4617022V
withdrawal, dilution
3
5 mL syringe
Omnifix, Luer Lock
PP, latex free, PVC free
0.2 mL scale
B.Braun
4617053V
withdrawal, dilution
4
10 mL syringe
Omnifix, Luer Lock
PP, latex free, PVC free
0.5 mL scale
B.Braun
4617000V
withdrawal, dilution
5
50 mL perfusor 
syringe
PE, DEHP free, latex free, 
PVC free
1.0 mL scale
B.Braun
8728844F
withdrawal; contains ready 
prepared IV solution; insert
into perfusor pump
6
18G hypodermic 
needle
Latex free, needle with 
needle protection device
B.Braun
4658313
withdrawal
7
Combi stopper
for male and female luer 
lock syringes
B.Braun
4495101
lock of syringes in between 
dilution steps
8
Combifix adapter
Luer lock female/female
B.Braun
5206634
connection of syringes for 
dilution
9
Mini-spike
0.45 µm Air filter
latex free, PVC free
B.Braun
4550242
withdrawal of dilution 
medium from vial
Dilution medium
10
Diluent (buffer 
specific for BI 
655088
20R vials, 20 mL
Boehringer 
Ingelheim
---
dilution medium
Material and equipment for IV application
11
Perfusor tubing 
with luer lock
150 cm
PE, latex free
B.Braun
8722935
connection between perfusor 
syringe and filter
12
Filter 0.2 µm
Posidyne ELD Filter
Latex free
PALL
ELD96LLCE
connection between perfusor 
tubing and catheter
13
Catheter 
indwelling
Vasofix  Safety, 20 G, 
1.1x33 mm, 61 mL/min
PVC free, latex free
B.Braun
4268113S-01
connection between 
tubing/filter and subject
14
Infusion pump
Perfusomat fm
B.Braun
syringe pump, setting of 
application volume and time


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10.1.2
Preparation of trial product including placebo for IV infusion
The following doses of BI 655088 will be prepared for IV application:
Table 10.1.2: 1
Concentrations of BI 655088 for intravenous administration
IV dose 
group
Planned dose of 
BI 655088
Application 
volume
Concentration of BI 655088 in ready prepared infusion 
solution (perfusor syringe filled with 50 mL)
* overfill of syringe which might be necessary to pre-flush the infusion system (tubing, filter) is disregarded as the 
concentration per mL is still the same 
Placebo will be prepared and infused in the same way as corresponding active doses.
Overall instructions for all IV doses


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11.
DESCRIPTION OF GLOBAL AMENDMENT(S)
Number of global amendment
No. 1
Date of CTP revision
19 February 2016
EudraCT number
2014-002413-29
BI Trial number
1339.1
BI Investigational Product(s)
BI 655088
Title of protocol
Safety, tolerability, pharmacokinetics and 
pharmacodynamics of single rising doses of BI 
655088 administered by intravenous infusion in 
healthy male subjects (single-blind, partially 
randomised within dose groups, placebo-
controlled, parallel group design)
To be implemented only after 
approval of the IRB / IEC /
Competent Authorities
To be implemented 
immediately in order to 
eliminate hazard –
IRB / IEC / Competent 
Authority to be notified of 
change with request for 
approval
Can be implemented without 
IRB / IEC / Competent 
Authority approval as changes 
involve logistical or 
administrative aspects only
Section to be changed
1.
2.
3.
4.
Titel Page
Section 3.1.1 and 5.2.3 
Section 5.5.2.3
Section 6.1
Description of change
1.
2.
3.
4.
Telephone and fax number of principal 
investigator revised
Name of additional clinical laboratory added
Change of blood sampling tube for 
Time window for oGTT introduced
Rationale for change
1.
2.
3.
4.
New contact numbers
Name specified for administrative purpose
Analytical method developed for K2 EDTA
Logistic reason 


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Number of global amendment
No. 2
Date of CTP revision
12 October 2017
EudraCT number
2014-002413-29
BI Trial number
1339.1
BI Investigational Product(s)
BI 655088
Title of protocol
Safety, tolerability, pharmacokinetics and 
pharmacodynamics of single rising doses of BI 
655088 administered by intravenous infusion in 
healthy male subjects (single-blind, partially 
randomised within dose groups, placebo-
controlled, parallel group design)
To be implemented only after 
approval of the IRB / IEC /
Competent Authorities
To be implemented 
immediately in order to 
eliminate hazard –
IRB / IEC / Competent 
Authority to be notified of 
change with request for 
approval
Can be implemented without 
IRB / IEC / Competent 
Authority approval as changes 
involve logistical or 
administrative aspects only
Section to be changed
1.
2.
3.
4.
5.
6.
7.
8.
9.
10.
11.
12.
13.
Throughout the protocol as applicable
Titel Page and Synopsis
Flow Chart
Section 1.2.4
Section 2.3
Section 3.1.1 and 5.2.3
Section 3.3.3
Section 3.3.4
Section 4.1.6
Section 5.2.2.1
Section 5.5 and 7.3
Section 7.3.3
Section 1, 8.4.1 and 9.2 
Description of change
1.
2.
Formal corrections;
adjustment of doses to be tested, number of dose 
groups and number of subjects
Name and contact numbers of principal 
investigator revised


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Number of global amendment
No. 2
3.
4.
5.
6.
7.
8.
9.
10.
11.
12.
13.
Some of PK 
 blood sampling timepoints 
on Day 1 and 2 deleted; footnote amended
Data from 
 dose group and from additional 
nonclinical experiments amended.
Benefit-risk assessment for additional data added.
Name of additional clinical laboratory revised.
Exclusion criterion 13 and 14 revised to exclude 
current smokers or ex-smokers with a history of 
≥10 pack years
Criterion for stopping dose escalation added.
Re-supply of trial medication will be planned.
Update of AE definitions.
Deletion of erroneous text fragment.
Update of References.
Rationale for change
1.
2.
3.
4.  
5.
6.
7.
8.
9.
10.
11.
12.
13.
 
New principal investigator.
Timepoints not needed for PK/PD evaluation.
New data available.
New data available.
Administrative change.
To align with exclusion criterion 24.
To specify how 
 will be considered for the 
decision on dose escalation.
Due to temporary hold of the trial, initial supply 
might expire.
Administrative change.
 
 
Formal correction.
Updated or new references were issued.


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Number of global amendment
No. 3
Date of CTP revision
22 November 2017
EudraCT number
2014-002413-29
BI Trial number
1339.1
BI Investigational Product(s)
BI 655088
Title of protocol
Safety, tolerability, pharmacokinetics and 
pharmacodynamics of single rising doses of BI 
655088 administered by intravenous infusion in 
healthy male subjects (single-blind, partially 
randomised within dose groups, placebo-
controlled, parallel group design)
To be implemented only after 
approval of the IRB / IEC /
Competent Authorities
To be implemented 
immediately in order to 
eliminate hazard –
IRB / IEC / Competent 
Authority to be notified of 
change with request for 
approval
Can be implemented without 
IRB / IEC / Competent 
Authority approval as changes 
involve logistical or 
administrative aspects only
Section to be changed
1.
2.
3.
Flow Chart and Section 5.2.4
Section 1.2.4
Section 3.3.3
Description of change
1.
2.
3.
Triplicate 12-lead ECG introduced at screening
Editorial change; medical background 
information for subject with SAE added
Exclusion criterion no. 24 amended by 
cardiovascular disease
Rationale for change
1.
2.
3.
Recommended by competent authority
Amended for clarification 
To explicitly exclude personal or family history 
of cardiovascular disease


 
 
 
 
APPROVAL / SIGNATURE PAGE 
 
Document Number: 
 
Technical Version Number:
 
Document Name: 
 
 
 
                                                                                                                 
 
Title: 
 
 
 
 
                                                                                                                   
 
Signatures (obtained electronically) 
 
Meaning of Signature  
Signed by 
Date Signed 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
c02155664
5.0
clinical-trial-protocol-revision-03
Safety, tolerability, pharmacokinetics and pharmacodynamics of single rising doses
of BI 655088 administered by intravenous infusion in healthy male subjects
(single-blind, partially randomised within dose groups, placebo-controlled, parallel
group design)
Author-Trial Statistician
23 Nov 2017 13:18 CET
Author-Trial Clinical Monitor
23 Nov 2017 13:49 CET
Approval-Team Member Medicine
23 Nov 2017 15:28 CET
Approval-Clinical Pharmacokinetics
23 Nov 2017 17:16 CET
Approval-Therapeutic Area 
23 Nov 2017 20:10 CET
Verification-Paper Signature
Completion
27 Nov 2017 15:30 CET


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Document Number: 
 Technical Version Number:
 
 
 
(Continued) Signatures (obtained electronically) 
 
Meaning of Signature  
Signed by 
Date Signed 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
c02155664
5.0

SAP_001.pdf: 
TITLE PAGE
TRIAL STATISTICAL ANALYSIS PLAN
c12282163-01
BI Trial No.:
1339.1
Title:
Safety, tolerability, pharmacokinetics and pharmacodynamics of 
single rising doses of BI 655088 administered by intravenous 
infusion in healthy male subjects (single-blind, partially 
randomised within dose groups, placebo-controlled, parallel group 
design)
Including protocol amendments 1, 2, and 3 [c02155664-05]
Investigational
Product(s):
BI 655088
Responsible trial 
statistician(s):
Phone:
Fax: 
Phone: 
Fax: 
Date of statistical 
analysis plan:
25 MAR 2019 SIGNED
Version:
Final
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1.
TABLE OF CONTENTS
TITLE PAGE ...........................................................................................................................1
1.
TABLE OF CONTENTS......................................................................................2
LIST OF TABLES...................................................................................................................4
2.
LIST OF ABBREVIATIONS ..............................................................................5
3.
INTRODUCTION.................................................................................................7
4.
CHANGES IN THE PLANNED ANALYSIS OF THE STUDY......................8
5.
ENDPOINTS .........................................................................................................9
5.1
PRIMARY ENDPOINT .......................................................................................9
5.2
SECONDARY ENDPOINTS...............................................................................9
5.2.1
Key secondary endpoint .......................................................................................9
5.2.2
Secondary endpoints.............................................................................................9
......................................9
......................................9
......................................9
......................................9
......................................9
....................................10
6.
GENERAL ANALYSIS DEFINITIONS ..........................................................11
6.1
TREATMENTS...................................................................................................11
6.2
IMPORTANT PROTOCOL DEVIATIONS....................................................12
6.3
SUBJECT SETS ANALYSED...........................................................................13
.................................................................................................14
6.5
POOLING OF CENTRES .................................................................................14
6.6
HANDLING OF MISSING DATA AND OUTLIERS....................................14
6.7
BASELINE, TIME WINDOWS AND CALCULATED VISITS ...................15
7.
PLANNED ANALYSIS......................................................................................16
7.1
DEMOGRAPHIC AND OTHER BASELINE CHARACTERISTICS.........17
7.2
CONCOMITANT DISEASES AND MEDICATION .....................................17
7.3
TREATMENT COMPLIANCE........................................................................17
7.4
PRIMARY ENDPOINT .....................................................................................17
7.5
SECONDARY ENDPOINTS.............................................................................17
7.5.1
Key secondary endpoint .....................................................................................17
7.5.2
Secondary endpoints...........................................................................................17
......................................................................18
......................................................................18
......................................................................18
......................................................................18
7.7
EXTENT OF EXPOSURE.................................................................................18
7.8
SAFETY ANALYSIS..........................................................................................18
7.8.1
Adverse events.....................................................................................................18
7.8.2
Laboratory data ..................................................................................................20


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7.8.3
Vital signs.............................................................................................................20
7.8.4
ECG......................................................................................................................21
7.8.5
Others...................................................................................................................21
7.8.5.1
Bleeding time........................................................................................................21
7.8.5.2
Local tolerability...................................................................................................21
7.8.5.3
Physical examination ............................................................................................21
8.
REFERENCES....................................................................................................22
........................................................................23
10.
HISTORY TABLE..............................................................................................24


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LIST OF TABLES
Table 6.1: 1
Flow chart of analysis phases for adverse events, laboratory tests and vital 
signs..................................................................................................................11
Table 6.2: 1
Important protocol deviations...........................................................................13
Table 6.3: 1
Subject sets analysed ........................................................................................14
Table 10: 1
History table .....................................................................................................24


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2.
LIST OF ABBREVIATIONS
Term
Definition / description
ADS
Analysis data set
AE
Adverse event
AESI
Adverse event of special interest
BI
Boehringer Ingelheim
BLQ
Below the lower limit of quantification
BMI
Body mass index
CTP
Clinical Trial Protocol
CTR
Clinical Trial Report
CV
Arithmetic coefficient of variation
DBLM
Database lock meeting
ECG
Electrocardiogram
eCRF
electronic case report form
EMA
European Medicines Agency
EudraCT
European union drug regulating authorities clinical trials
gCV
Geometric coefficient of variation
gMean
Geometric mean
ICH
International Conference on Harmonisation
MedDRA
Medical Dictionary for Regulatory Activities
NOA
Not analysed
NOP
No peak detectable
NOR
No valid result
NOS
No sample available
PK
Pharmacokinetics
PKS
PK analysis set
PV
Protocol violation
R
Reference treatment
RAGe
Report Appendix Generator system
RPM
Report planning meeting
SAE
Serious adverse event
SD
Standard deviation


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Term
Definition / description
T
Test treatment
TS
Treated set
TSAP
Trial statistical analysis plan


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3.
INTRODUCTION
As per ICH E9 (1), the purpose of this document is to provide a more technical and detailed 
elaboration of the principal features of the analysis described in the revised Clinical Trial 
Protocol (CTP), 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 revised CTP. In
particular, the TSAP is based on the planned analysis specification as written in CTP 
Section 7 “Statistical Methods and Determination of Sample Size”. Therefore, TSAP readers 
may consult the CTP for more background information on the study, e.g., on study objectives, 
study design and population, treatments, definition of measurements and variables, planning 
of sample size, randomisation.
Study data will be stored in a trial database within the Oracle ClinicalTM system. 
The statistical analyses will be performed within the validated working environment CARE 
(Clinical data Analysis and Reporting Environment), including SASTM (current Version 9.4, 
by SAS Institute Inc., Cary, NC, USA), and a number of SASTM-based tools (e.g., macros for 
the analyses of adverse event (AE) data or laboratory data; Report Appendix Generator 
system (RAGe) for compilation/formatting of the clinical trial report (CTR) appendices). 
Pharmacokinetic (PK) parameters will be calculated using WinNonlinTM software 
(professional Network version Phoenix 6.3, Pharsight Corporation, Mountain View, CA 
94041-1530, USA).


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4.
CHANGES IN THE PLANNED ANALYSIS OF THE STUDY
Section 7.3 of the CTP specifies an analysis set of all randomised subjects, whether treated or
not. This subject set will be identical to the analysis set of all treated subjects (cf. Section 6.3),
since Section 3.3.4.1 of the CTP specifies that, if "a subject is removed from or withdraws 
from the trial prior to the administration of trial medication, the data of this subject will not be 
entered in the case report form (CRF) or trial database and will not be reported in the clinical 
trial report (CTR)". Therefore, it was considered to be sufficient to use the analysis set of all 
treated subjects in statistical analysis, and not to additionally use an analysis set of all
randomised subjects.
Section 7.3.3 of the CTP suggests the time point of the end-of-trial examination to be the end 
of the on-treatment phase. This phase is used for statistical analysis of AEs, laboratory values 
and vital signs. Section 7.3.3 says that “These assignments including the corresponding time 
intervals will be defined in detail in the TSAP”. This TSAP defines the time point of subjects’
trial termination date to be the end of the on-treatment phase. The trial termination date is the 
last contact with the subject and more appropriately defines the end of the study. There is no 
post-treatment or follow-up period defined for this trial.
All other analyses described in this TSAP are in accordance with the statistical methods 
described in the revised CTP.


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5.
ENDPOINTS
5.1
PRIMARY ENDPOINT
Primary endpoint is the number of subjects with drug-related AEs, as defined in Section 5.2.1 
of the CTP.
5.2
SECONDARY ENDPOINTS
5.2.1
Key secondary endpoint
Not applicable.
5.2.2
Secondary endpoints
Secondary endpoints of this trial are Cmax, AUC0-tz and AUC0-∞of BI 655088 in plasma, as 
defined in Section 5.5.1.1 of the CTP.


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6.
GENERAL ANALYSIS DEFINITIONS
6.1
TREATMENTS
For basic study information on treatments to be administered, assignments of dose groups, 
and selection of doses, cf. Section 4 of the CTP.
Subjects were planned to be treated either with

single dose of 
of BI 655088 (test treatments)
or

single doses of placebo (reference treatment)
All placebo subjects will be analysed in one pooled placebo group (i.e. no distinction between 
dose groups will be made for placebo subjects).
Analysis phases for statistical analysis of AEs, safety laboratory data, and vital signs are
defined for each subject as described in the table below.
Table 6.1: 1
Flow chart of analysis phases for adverse events, laboratory tests and vital 
signs
Study analysis 
phase
Label
Start (inclusive)
End (exclusive)
Screening
Screening
Date of informed consent 
Date/time of start of infusion 
of BI 655088 or placebo
On treatment
Pbo,
respectively
Date/time of start of infusion 
of BI 655088 or placebo
12:00 a.m. on day after 
subject's trial termination date
CTR Section 15, Appendix 16.1.13.1.8.2 and Appendix 16.1.13.1.8.3 AE displays will 
present results for the on-treatment phases only.
In CTR Section 15 AE tables (but not in Appendix 16.1.13.1.8.2 and Appendix 16.1.13.1.8.3
AE tables), the following totals will be provided in addition:

"Total BI", defined as the total over all on-treatment phases involving BI

"Total on-trt", defined as the total over all on-treatment phases, including placebo
CTR Appendix 16.1.13.1.8.1 displays will present results for the screening and on-treatment
phases.


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Additionally to the totals defined above, the following total will be provided in CTR Section 
16.1.13.1.8.1 AE tables:

"Total", defined as the total over all study phases (screening + on-treatment)
More details on the technical implementation of these analyses are provided in the ADS Plan 
of this TSAP.
6.2
IMPORTANT PROTOCOL DEVIATIONS
Data discrepancies and deviations from the CTP will be identified for all subjects entered and 
treated who did not fail during screening.
Consistency check listings (for identification of violations of time windows) and a list of 
protocol deviations (e.g. deviations in drug administration, in blood sampling times, etc.) will 
be provided to be discussed at the report planning and database lock meeting (RPM/DBLM). 
At this meeting, it will be decided whether a discrepant data value can be used in analyses or 
whether it must be corrected in the clinical database. Each protocol deviation must be 
assessed to determine whether it is an important protocol deviation (iPD). For definition of 
iPDs, and for the process of identification of these, refer to the Boehringer Ingelheim (BI) 
SOP "Identify and Manage Important Protocol Deviations (iPD)" (2).
If any iPDs are identified, they are to be summarised into categories and will be captured in 
the RPM/DBLM minutes via an accompanying Excel spreadsheet. The following table
(Table 6.2: 1) contains the categories which are considered to be iPDs in this trial. If the data 
show other iPDs, this table will be supplemented accordingly by the time of the RPM/DBLM.
iPDs will be summarised and listed.


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Table 6.2: 1
Important protocol deviations
Category 
/ Code
Description
A
Entrance criteria not met
A1
Inclusion criteria violated
A2
Exclusion criteria violated
B
Informed consent
B1
Informed consent not available
B2
Informed consent too late
C
Trial medication and randomisation
C1
Incorrect trial medication administered
C2
Randomisation not followed
C3
Non-compliance
C4
Incorrect administration of trial medication
C5
Incorrect dose of trial medication administered
D
Concomitant medication
D1
Prohibited medication use
E
Missing data1
None
G
Other trial specific important deviations
G1
Certain deviations of procedures used to measure secondary PK endpoint data
Violations C1, C2, C4 and G1 can only be detected at the trial site.
1 Missing visits, evaluations, and tests will be considered missing data, not PDs
Source: BI SOP "Identify and Manage Important Protocol Deviations (iPD)" (2).
6.3
SUBJECT SETS ANALYSED
All entered subjects who received study medication will be included in the safety analysis and 
in the PK analysis depending on the availability of measurement values, and on their 
adherence to the CTP. 
The following subject sets will be defined for statistical analysis:

Treated set (TS):
This subject set includes all subjects who were documented to have received at least 
one dose of study drug. It will be used for analysis of safety, demographic data, 
baseline characteristics, and disposition.

PK analysis set (PKS): 
This subject set includes all subjects from the TS on active treatment who provide at 
least one PK endpoint value that was not excluded according to the description in 
Section 7.3.2 of the CTP.


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The discussion of all exceptional cases and problems and the decisions on the allocation of 
subjects to populations will be made at latest at the RPM/DBLM.
Table 6.3: 1
Subject sets analysed
Subject set
Class of endpoint
TS
PKS
Disposition, exposure
X
iPDs
X
Demographic/baseline endpoints
X
Primary endpoint
X
Other safety parameter
X
Secondary PK endpoints
X
Further PK endpoints
X
6.5
POOLING OF CENTRES
This section is not applicable, because the study will be performed in only one centre.
6.6
HANDLING OF MISSING DATA AND OUTLIERS
Data of screened subjects, who discontinued from the trial due to screening failures prior to 
administration of any trial medication, will not be included in the CTR. The safety data of 
treated subjects who were withdrawn from the trial prematurely will be reported as far as 
available. All withdrawals will be documented and the reason for withdrawal recorded.
CTP: With respect to safety evaluations, it is not planned to impute missing values.
The only exceptions where imputation might be necessary for safety evaluation are AE dates. 
Missing or incomplete AE dates are imputed according to BI standards (3).
Missing data and outliers of PK data are handled according to BI standards (4)REF5.
CTP: Drug concentration data identified with NOS (no sample available), NOR (no valid 
result), NOA (not analyzed), BLQ (below the lower limit of quantification), or NOP (no peak 
detectable) will be displayed as such and not replaced by zero at any time point (this rule also
applies also to the lag phase, including the predose values).
CTP: For the non-compartmental analysis, concentration data identified with NOS, NOR or 
NOA will generally not be considered. Concentration values in the lag phase identified as 
BLQ or NOP will be set to zero. All other BLQ/NOP values of the profile will be ignored. The 


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lag phase is defined as the period between time zero and the first time point with a 
concentration above the quantification limit.
6.7
BASELINE, TIME WINDOWS AND CALCULATED VISITS
For oral glucose tolerance test (i.e. further plasma glucose and serum insulin measurements), 
baseline is defined for each oral glucose tolerance test as the last measurement prior to the 
glucose intake. For all other analyses, baseline is defined as the last measurement before study 
drug administration.
Time windows are defined in Section 6.1 of the CTP. Adherence to time windows will be 
checked at the RPM/DBLM.


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7.
PLANNED ANALYSIS
The format of the listings and tables will follow the BI guideline "Reporting of clinical trials 
and project summaries" (5).
The individual values of all subjects will be listed, sorted by treatment group, subject number 
and visit (if visit is applicable in the respective listing). AE listings will be sorted by assigned 
treatment (see Section 7.8.1 below for details). The listings will be contained in Appendix 
16.2 (SDL) of the CTR.
The following standard descriptive statistical parameters will be displayed in summary tables 
of continuous variables:
N 
number of non-missing observations
Mean 
arithmetic mean
SD 
standard deviation
Min 
minimum
Median 
median
Max 
maximum
For plasma concentrations as well as for all PK parameters, the following descriptive statistics 
will additionally be calculated:
CV 
arithmetic coefficient of variation
gMean
geometric mean
gCV
geometric coefficient of variation
For PK parameters the following descriptive statistics will additionally be calculated:
P10
10th percentile
Q1
1st quartile
Q3
3rd quartile
P90
90th percentile
The data format for descriptive statistics of plasma concentrations will be identical with the 
data format of the respective concentrations. The descriptive statistics of PK parameters will 
be calculated using the individual values with the number of decimal places as provided by 
the evaluation program. Then the individual values as well as the descriptive statistics will be 
reported with three significant digits in the CTR.
Tabulations of frequencies for categorical data will include all possible categories and will 
display the number of observations in a category as well as the percentage (%) relative to the 
respective treatment group. Percentages will be rounded to one decimal place. The category 
missing will be displayed if and only if there are actually missing values. Percentages will be 
based on all subjects in the respective subject set whether they have non-missing values or 
not.


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7.1
DEMOGRAPHIC AND OTHER BASELINE CHARACTERISTICS
Only descriptive statistics are planned for this section of the report.
7.2
CONCOMITANT DISEASES AND MEDICATION
Concomitant diseases will be coded according to the most recent version of the Medical 
Dictionary for Regulatory Activities (MedDRA). Concomitant medication will be coded 
according to the most recent version of the World Health Organisation – Drug Dictionary.
Only descriptive statistics are planned for this section of the CTR based on the TS.
A medication will be considered concomitant to a treatment, if it

is ongoing at the time of administration of the respective treatment or

starts within the on-treatment phase of the respective treatment (see Section 6.1).
7.3
TREATMENT COMPLIANCE
Treatment compliance will not be analysed as a specific endpoint. Any deviations from 
complete drug administration will be addressed in the RPM/DBLM (cf. Section 6.2) and 
described in the CTR.
7.4
PRIMARY ENDPOINT
Refer to Section 7.8.1 for a description of the analysis of AEs, and in particular the analysis of 
the frequency of subjects with drug related AEs, which is the primary endpoint of this trial.
7.5
SECONDARY ENDPOINTS
7.5.1
Key secondary endpoint
Not applicable.
7.5.2
Secondary endpoints
The analysis of secondary endpoints will be based on the PKS.
Dose proportionality will be evaluated as defined in the CTP, Section 7.3.2, by use of the 
power model for the secondary endpoints Cmax, AUC0-tz and AUC0-∞of BI 655088 in plasma. 
Exclusion of PK parameters
The ADS ADPP contains column variables APEXC and APEXCO indicating 
inclusion/exclusion (APEXC) of a PK parameter and an analysis flag comment (APEXCO). 
All analyses based on the PKS are based on PK parameter values which are not flagged for 
exclusion, i.e. with APEXC equal to "Included".


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Exclusion of plasma concentrations
The ADS ADPC (PK concentrations per time-point or per time-interval) contains column 
variables ACEXC or ACEXCO indicating inclusion/exclusion (ACEXC) of a concentration 
and an analysis flag comment (ACEXCO). Exclusion of a concentration depends on the 
analysis flag comment ACEXCO. For example, if ACEXCO is set to "ALL CALC", the value 
will be excluded for all types of analyses based on concentrations. If ACEXCO is set to 
"DESC STATS" the value will be excluded from descriptive evaluations per planned time 
point/time interval. If ACEXCO contains the addition "TIME VIOLATION" or "TIME 
DEVIATION", the value can be used for further analyses based on actual times. If ACEXCO 
is set to "HALF LIFE", the value will be excluded from half-life calculation only; the value is 
included for all other analyses. Excluded concentration itself will be listed in the CTR 
associated with an appropriate flag.
Further details are given in "Noncompartmental Pharmacokinetic / Pharmacodynamic 
Analyses of Clinical Studies"(4)REF5 and "Description of Analytical Transfer Files and 
PK/PD Data Files" (6).
7.7
EXTENT OF EXPOSURE
Only descriptive statistics are planned for this section of the CTR. Exposure will be presented
by treatment groups.
7.8
SAFETY ANALYSIS
All safety analyses will be performed on the treated set.
7.8.1
Adverse events
AEs will be coded with the most recent version of MedDRA.
The analyses of AEs will be descriptive in nature. All analyses of AEs will be based on the 
number of subjects with AEs and not on the number of AEs.


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For analysis, multiple AE occurrence data on the electronic case report form (eCRF) will be 
collapsed into one event provided that all of the following applies:

All AE attributes are identical (lower level term, intensity, action taken, therapy required, 
seriousness, reason for seriousness, relationship, outcome, AE of special interest (AESI))

The occurrences were time-overlapping or time-adjacent (time-adjacency of two 
occurrences is given if the second occurrence started at most 1 hour after the first 
occurrence ended)
For further details on summarization of AE data, please refer to "Analysis and Presentation of 
Adverse Event Data from Clinical Trials" (7) and "Handling of missing and incomplete AE 
dates" (3). 
The analysis of AEs will be based on the concept of treatment emergent AEs. That means that 
all AEs will be assigned to the screening or on-treatment phase as defined in Section 6.1. AEs 
will be analysed based on actual treatments, as defined in Table 6.1.1.
An overall summary of AEs will be presented. This overall summary will comprise summary 
statistics for the class of other significant AEs according to ICH E3 (8) and for the class of 
AESIs.
CTP: The following are considered as AESIs in this trial: 

Hepatic injury, as defined by the following alterations of hepatic laboratory parameters:
○
an elevation of AST and/or ALT ≥3-fold ULN combined with an elevation of total 
bilirubin ≥2-fold ULN measured in the same blood sample, and/or
○
marked peak aminotransferase (ALT, and/or AST) elevations ≥10 fold ULN.
The investigator had to classify in the eCRF whether an observed AE was an AESI or not.
According to ICH E3 (8), AEs classified as "other significant" need to be reported and will 
include those non-serious and non-significant AEs
(i) which are marked haematological or other lab abnormalities, or
(ii) which were reported with "action taken = discontinuation" or "action taken = reduced", or
(iii) which lead to significant concomitant therapy as identified by the Clinical 
Monitor/Investigator at a Medical Quality Review Meeting.
The frequency of subjects with AEs will be summarised by treatment, primary system organ 
class and preferred term. AEs which were considered by the investigator to be drug related 
will be summarised separately (primary endpoint of this trial). Separate tables will also be 
provided for subjects with serious AEs (SAEs), subjects with AESIs and subjects with other 
significant AEs (according to ICH E3 (8)). The frequency of subjects with AEs and the 
frequency of subjects with AEs considered by the investigator to be drug related will also be 
summarised by maximum intensity, primary SOC and preferred term.
The system organ classes and preferred terms within system organ classes will be sorted by 
descending frequency over all treatment groups.
For disclosure of AE data on ClinicalTrials.gov, the frequency of subjects with non-serious 
AEs occurring with an incidence of greater than 5 % (in preferred terms) will be summarised 


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by treatment, primary system organ class and preferred term. The frequency of subjects with 
SAEs will also be summarised.
For disclosure of AE data in the EudraCT register, the frequency of AEs, the frequency of 
non-serious AEs with an incidence of greater than 5 % (in preferred terms) and the frequency 
of SAEs will be summarised.
For support of lay summaries, the frequency of subjects with drug-related SAEs will be 
summarised by treatment, primary system organ class and preferred term.
7.8.2
Laboratory data
The analyses of laboratory data will be descriptive in nature and will be based on BI standards
"Display and Analysis of Laboratory Data" (9).
Analyses will be based on normalised values, which mean transforming to a standard unit and 
a standard reference range. The original values will be analysed if the transformation into 
standard unit is not possible for a parameter.
CTP: Laboratory data will be compared to their reference ranges. Values outside the 
reference range will be flagged. Additionally, differences from baseline will be evaluated.
Descriptive statistics of laboratory values over time and for the difference from baseline (see 
Section 6.7) will be provided. Frequency tables of changes between baseline and last value on 
treatment with respect to the reference range will be presented.
The results of the oral glucose tolerance test (i.e. further plasma glucose and serum insulin 
measurements) will be presented separately using descriptive statistics. 
Additionally, individual time-course and (geometric) mean time profiles will be presented for 
plasma glucose and insulin. The change in the area under the curve for glucose and insulin
from baseline to post-treatment will be presented descriptively by treatment and compared 
between BI 655088 and placebo. An ANOVA model including “treatment” as a fixed effect
will be applied on the log-transformed AUCs for the comparison.
Possibly clinically significant abnormal laboratory values are only those identified either in 
the Investigator’s comments on the eCRF or at the RPM/DBLM at the latest. It is the 
investigator's responsibility to decide whether a lab value is clinically significant abnormal or 
not. Standard or project-specific rules for flagging clinically significant values will not be 
applied in this study.
Clinically relevant findings in laboratory data will be reported as baseline conditions (at 
screening) or as AEs (during the trial) if judged clinically relevant by the investigator, and 
will be analysed as such.
7.8.3
Vital signs
The analyses of vital signs will be descriptive in nature. Descriptive statistics of vital signs 
over time and for the difference from baseline (see Section 6.7) will be provided.


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Clinically relevant findings in vital signs data will be reported as baseline conditions (at 
screening) or as AEs (during the trial) if judged clinically relevant by the investigator, and 
will be analysed as such.
7.8.4
ECG
ECG data will not be listed but clinically relevant abnormal findings will be reported as 
adverse events.
7.8.5
Others
7.8.5.1
Bleeding time
Descriptive statistics of bleeding time and for the difference from baseline will be provided by 
time point.
7.8.5.2
Local tolerability
A frequency table will present the results of the local tolerability assessments by visit.
7.8.5.3
Physical examination
Physical examination findings will be reported as relevant medical history/baseline condition 
(i.e., a condition already existent before administration of study drug) or as AE and will be 
summarised as such. No separate listing or analysis of physical examination findings will be 
prepared.


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8.
REFERENCES
1
CPMP/ICH/363/96: "Statistical Principles for Clinical Trials", ICH Guideline Topic E9; 
Note For Guidance on Design, Conduct, Analysis and Evaluation of Clinical Trials, 
current version
2
001-MCS-40-413: “Identify and Manage Important Protocol Deviations (iPD)”, current 
version; IDEA for CON
3
001-MCG-156_RD-01: "Handling of missing and incomplete AE dates", current version; 
IDEA for CON
4
001-MCS-36-472_RD-01: "Noncompartmental Pharmacokinetic / Pharmacodynamic 
Analyses of Clinical Studies", current version; IDEA for CON
5
001-MCG-159: "Reporting of Clinical Trials and Project Summaries", current version; 
IDEA for CON
6
001-MCS-36-472_RD-03: "Description of Analytical Transfer Files and PK/PD Data 
Files", current version; IDEA for CON
7
001-MCG-156: "Analysis and Presentation of Adverse Event Data from Clinical Trials", 
current version; IDEA for CON
8
CPMP/ICH/137/95: "Structure and Content of Clinical Study Reports", ICH Guideline 
Topic E3; Note For Guidance on Structure and Content of Clinical Study Reports, 
current version
9
001-MCG-157: "Display and Analysis of Laboratory Data", current version; IDEA for 
CON


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10.
HISTORY TABLE
Table 10: 1
History table
Version
Date
(DD-MMM-YY)
Author
Sections 
changed
Brief description of change
Final
25-MAR-19
None
This is the final TSAP without any 
modification