Clinical trial NCT02852824
Conditions: Healthy
Sponsor: Boehringer Ingelheim
Start date: 2016-08-10; Completion date: 2017-08-01
Enrollment: 40 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
The primary objective of this trial is to investigate the safety and tolerability of BI 655130 in healthy male subjects following IV administration of multiple rising doses. The study will also explore safety and tolerability following a single IV administration.

Detailed description:

Arms: arm 1: None arm 2: None
Interventions: intervention 1: BI 655130 (spesolimab) intervention 2: Placebo
Intervention descriptions: intervention 1: None intervention 2: None

Protocol documents:
Prot_000.pdf: 
001-MCS-40-106-RD-11 (5.0) / Saved on: 25 Jun 2014
Clinical Trial Protocol
TITLE PAGE
Document Number:
c09105854-05
EudraCT No.:
BI Trial No.:
2016-001235-12
BI 1368.2
BI Investigational
Product:
BI 655130
Title:
Safety, tolerability, pharmacokinetics and pharmacodynamics of 
multiple rising intravenous doses of BI 655130 (double-blind, 
partially randomised within dose groups, placebo-controlled parallel 
group design) and one single intravenous dose of BI 655130 (single-
blind, partially randomised, placebo-controlled) in healthy male 
subjects
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: 02 Aug 2017
Page 1 of 102
Proprietary confidential information
© 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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02 Aug 2017
BI Trial No.: 1368.2
Doc. No.: c09105854-05
Trial Protocol
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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 655130
Protocol date:
Trial number:
Revision date:
02 Aug 2017
23 Jun 2016
1368.2
Title of trial:
Safety, tolerability, pharmacokinetics and pharmacodynamics of multiple rising 
intravenous doses of BI 655130 (double-blind, partially randomised within dose 
groups, placebo-controlled parallel group design) and one single intravenous dose of 
BI 655130 (single-blind, partially randomised, placebo-controlled) in healthy male 
subjects
Principal Investigator:
Trial site:
Clinical phase:
I
Objectives:
To investigate safety, tolerability, pharmacokinetics and pharmacodynamics of single 
and multiple rising intravenous doses of BI 655130
Methodology:
Multiple rising dose: double-blind, randomised, placebo-controlled within dose 
groups
Single dose: single blind, partially randomised, placebo controlled
No. of subjects: 
total entered:
40
each treatment:
8 per dose group* (6 on active drug and 2 on placebo)
* Additional subjects may be entered to allow for testing of intermediate doses on the basis of 
experience gained during the trial conduct (e.g. preliminary PK data), provided the planned and 
approved highest dose will not be exceeded. Thus, the actual number of subjects entered may 
be increased, but will not exceed 48 subjects. 
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 655130 (20 mg/mL) solution for infusion
dose:
Multiple dose: 3 mg/kg, 6 mg/kg, 10 mg/kg and 20 mg/kg body weight
Single dose: 20 mg/kg body weight


Boehringer Ingelheim
02 Aug 2017
BI Trial No.: 1368.2
Doc. No.: c09105854-05
Trial Protocol
Page 3 of 102
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001-MCS-40-106-RD-11 (5.0) / Saved on: 25 Jun 2014
Name of company:
Tabulated
Trial Protocol
Boehringer Ingelheim
Name of finished product:
Not applicable 
Name of active ingredient:
BI 655130
Protocol date:
Trial number:
Revision date:
02 Aug 2017
23 Jun 2016
1368.2
mode of admin.:
Intravenous as 30 min infusion for 3 mg/kg and 6 mg/kg multiple dose
Intravenous as 60 min infusion for 10 mg/kg multiple dose and 20 mg/kg single dose
Intravenous as 90 min infusion for 20 mg/kg multiple dose 
Comparator product:
Matching placebo for BI 655130 solution for infusion
dose:
Not applicable
mode of admin.:
Intravenous as 30 min, 60 min or 90 min infusion
Duration of treatment: Dose group 3 mg, 6 mg,10 mg/kg and 20 mg/kg
Single intravenous dose once a week (within 4 weeks single intravenous doses
on Day 1, Day 8, Day 15, and Day 22)
Dose group 20 mg/kg
Single intravenous dose 
Criteria for 
pharmacokinetics:
Secondary endpoints:
Single dose (20 mg/kg b.w.)
Cmax, AUC0-∞
Multiple dose (3 mg/kg, 6 mg/kg, 10 mg/kg, 20 mg/kgb.w.)
After the first dose:
AUCτ,1 and Cmax
After the last dose:
AUCτ,ss and Cmax,ss
Criteria for 
pharmacodynamics:
 


Boehringer Ingelheim
02 Aug 2017
BI Trial No.: 1368.2
Doc. No.: c09105854-05
Trial Protocol
Page 4 of 102
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001-MCS-40-106-RD-11 (5.0) / Saved on: 25 Jun 2014
Name of company:
Tabulated
Trial Protocol
Boehringer Ingelheim
Name of finished product:
Not applicable 
Name of active ingredient:
BI 655130
Protocol date:
Trial number:
Revision date:
02 Aug 2017
23 Jun 2016
1368.2
Criteria for safety:
Primary endpoint to assess safety and tolerability of BI 655130 is the number [N (%)] 
of subjects with drug-related adverse events (AEs).
Further criteria of interest:
Physical examination, vital signs (BP, PR, body temperature, continuous cardio-
monitoring), 12-lead ECG, laboratory tests (including haematology, clinical 
chemistry, urinalysis, coagulation parameters, cytokines and ADA), adverse events 
and local tolerability.
Statistical methods:
Descriptive statistics will be calculated for all endpoints.
Dose proportionality of BI 655130 will be explored using a regression model. A 95% 
confidence interval (CI) for the slope will be computed.
Linearity index will be estimated using a linear model providing a two-sided 95% CI.
Attainment of steady state will be analysed by a repeated measures linear model for 
trough concentrations of BI 655130 with dose as an additional covariate if 
permissible.


Boehringer Ingelheim
02 Aug 2017
BI Trial No.: 1368.2
Doc. No.: c09105854-05
Trial Protocol
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001-MCS-40-106-RD-11 (5.0) / Saved on: 25 Jun 2014
FLOW CHART
Flow Chart (3 mg and 6 mg/kg b.w. dose group, multiple dose) 
Visit
Day
Time relative to first drug 
administration (planned 
time [h:min]
Approx. time (actual time) 
[h:min]
Event and comment
PKplasma 
4
PDblood 
4 
Plasma ADA9
Safety laboratory/
Urinalysis 3
Body Temperature
Body Weight
12-lead ECG
ECG monitoring
Vital signs  (BP, PR)
Query on adverse events, 
concomitant therapies12
1
-28
to -3
screening1
X
X
X
2
-2
-48:00
8:00
ambulatory visit
X14
X
-1
-12:00
20:00
admission to
trial site
X11
X
1
-2:00
6:00
X2
X2
X2
X2, 10
X2
X2, 5
X2
X2
0:00
8:00
drug administration
start of infusion
▲
│
0:15
8:15
│
│
X
X
0:30
8:30
▼
end of infusion15
X
X
X
X5
│
│
│
X
X
1:00
9:00
│
X
1:30
9:30
│
│
X
2:00
10:00
light breakfast7
X
X5
▼
X
3:00
11:00
X
4:00
12:00
Lunch7
X10
X
X6
6:00
14:00
X
X5
X
8:00
16:00
snack (voluntary)7
X
10:00
18:00
Dinner7
12:00
20:00
X
X
X5
X
X6
2
24:00
8:00
Breakfast7
X
X10
X
X5
X
X6
28:00
12:00
Lunch7
32:00
16:00
snack (voluntary)7
X
X
34:00
18:00
Dinner7
X
3
48:00
8:00
Breakfast7
discharge from
trial site
(confirmation of 
fitness8)
X5
X
X
4
72:00
8:00
ambulatory visit
X
X
5
96:00
8:00
ambulatory visit
X
X


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BI Trial No.: 1368.2
Doc. No.: c09105854-05
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001-MCS-40-106-RD-11 (5.0) / Saved on: 25 Jun 2014
Visit
Day
Time relative to first drug 
administration (planned 
time [h:min]
Approx. time (actual time) 
[h:min]
Event and comment
PKplasma 
4
PDblood 
4 
Plasma ADA9
Laboratory/
Urinalysis 3
Body Temperature
12-lead ECG
ECG monitoring
Vital signs  (BP, PR)
Query on adverse events, 
concomitant therapies12
2
7
156:00
20:00
admission to
trial site
X11
X
8
166:00
6:00
X2
X2
X2
X2, 10
X2
X2, 5
X2
X2
168:00
8:00
drug administration
start of infusion
▲
│
168:15
8:15
│
│
X
X
168:30
8:30
▼
end of infusion15
X
X
X
X5
│
│
│
X
X
169:00
9:00
│
X
169:30
9:30
│
│
X
170:00
10:00
light breakfast7
X
X5
▼
X
171:00
11:00
X
172:00
12:00
Lunch7
X10
X
X6
174:00
14:00
X
X5
X
176:00
16:00
snack (voluntary)7
X
178:00
18:00
Dinner7
180:00
20:00
X
X
X5
X
X6
9
192:00
8:00
Breakfast7
X
X10
X
X5
X
X6
196:00
12:00
Lunch7
200:00
16:00
snack (voluntary)7
X
X
202:00
18:00
Dinner7
X
10
216:00
8:00
Breakfast7
discharge from
trial site
(confirmation of 
fitness8)
X5
X
X
11
240:00
8:00
ambulatory visit
X
X
12
264:00
8:00
ambulatory visit
X
X


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001-MCS-40-106-RD-11 (5.0) / Saved on: 25 Jun 2014
Visit
Day
Time relative to first drug 
administration (planned 
time [h:min]
Approx. time (actual time) 
[h:min]
Event and comment
PKplasma 
4
PDblood 
4 
Plasma ADA9
Laboratory/
Urinalysis 3
Body Temperature
12-lead ECG
ECG monitoring
Vital signs  (BP, PR)
Query on adverse events, 
concomitant therapies12
2
14
324:00
20:00
admission to
trial site
X11
X
15
334:00
6:00
X2
X2
X2
X2, 10
X2
X2, 5
X2
X2
336:00
8:00
drug administration
start of infusion
▲
│
336:15
8:15
│
│
X
X
336:30
8:30
▼
end of infusion15
X
X
X
X5
│
│
│
X
X
337:00
9:00
│
X
337:30
9:30
│
X
338:00
10:00
light breakfast7
X
X5
▼
X
339:00
11:00
X
340:00
12:00
Lunch7
X10
X
X6
342:00
14:00
X
X5
X
344:00
16:00
snack (voluntary)7
X
346:00
18:00
Dinner7
348:00
20:00
X
X
X5
X
X6
16
360:00
8:00
Breakfast7
X
X10
X
X5
X
X6
364:00
12:00
Lunch7
368:00
16:00
snack (voluntary)7
X
X
370:00
18:00
Dinner7
X
17
384:00
8:00
Breakfast7
discharge from
trial site
(confirmation of 
fitness8)
X5
X
X
18
408:00
8:00
ambulatory visit
X
X
19
432:00
8:00
ambulatory visit
X
X


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BI Trial No.: 1368.2
Doc. No.: c09105854-05
Trial Protocol
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001-MCS-40-106-RD-11 (5.0) / Saved on: 25 Jun 2014
Visit
Day
Time relative to first drug 
administration (planned 
time [h:min]
Approx. time (actual time) 
[h:min]
Event and comment
PKplasma 
4
PDblood 
4 
Plasma ADA9
Laboratory/
Urinalysis 3
Body Temperature
12-lead ECG
ECG monitoring
Vital signs  (BP, PR)
Query on adverse events, 
concomitant therapies12
2
21
492:00
20:00
admission to
trial site
X11
X
22
502:00
6:00
X2
X2
X2
X2, 10
X2
X2, 5
X2
X2
504:00
8:00
drug administration
start of infusion
▲
│
504:15
8:15
│
│
X
X
504:30
8:30
▼
end of infusion15
X
X
X
X5
│
│
│
X
X
505:00
9:00
│
X
505:30
9:30
│
X
506:00
10:00
light breakfast7
X
X5
▼
X
507:00
11:00
X
508:00
12:00
Lunch7
X10
X
X6
510:00
14:00
X
X5
X
512:00
16:00
snack (voluntary)7
X
514:00
18:00
Dinner7
516:00
20:00
X
X
X5
X
X6
23
528:00
8:00
Breakfast7
X
X10
X
X5
X
X6
532:00
12:00
Lunch7
536:00
16:00
snack (voluntary)7
X
X
538:00
18:00
Dinner7
X
24
552:00
8:00
Breakfast7
discharge from
trial site
(confirmation of 
fitness8)
X5
X
X
25
576:00
8:00
ambulatory visit
X
X
26
600:00
8:00
ambulatory visit
X
X


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BI Trial No.: 1368.2
Doc. No.: c09105854-05
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Visit
Day
Time relative to first drug 
administration (planned 
time [h:min]
Approx. time (actual time) 
[h:min]
Event and comment
PKplasma 
4
PDblood 
4 
Plasma ADA9
Laboratory/
Urinalysis 3
Body Temperature
12-lead ECG
ECG monitoring
Vital signs  (BP, PR)
Query on adverse events, 
concomitant therapies12
2
29
672:00
8:00
ambulatory  visit
X
X
X
X
36
840:00
8:00
ambulatory visit
X
X
43
1008:00
8:00
ambulatory visit
X
X
X
50
1176:00
8:00
ambulatory visit
X
X
X
57
1344:00
8:00
ambulatory visit
X
X
64
1512:00
8:00
ambulatory visit
X
X
78
1848:00
8:00
ambulatory visit
X
X
X
X
92
2184:00
8:00
ambulatory visit
X
X
X
120 ±3
2856:00
8:00
ambulatory visit
X
X
X
X
148 ±3
3528:00
8:00
ambulatory visit
X
X
X
3
176 ±3
4200:00
8:00
EOT13
X16
X
X16
X
X
X
X
1.
Screening with subject information, informed consent as the first measure, includes physical examination, check 
of vital signs, ECG, safety laboratory (under fasting conditions), drug screening, demographics (including 
determination of body height and weight, smoking and alcohol history), relevant medical history, concomitant 
therapy and review of inclusion/exclusion criteria. 
2.
The time is approximate; procedures are to be performed and completed within 3 h prior to drug administration. 
Within 3 hours prior to the planned dosing, planned time -2:00 will be used. 
3.
Laboratory tests (safety laboratory) include clinical chemistry, haematology, coagulation and urinalysis; in 
addition at screening: serology (HBV, HCV, HIV), and drug screening.
4.
PK and PD sampling times may be adapted based on information obtained during trial conduct.
5.
Triple ECG
6.
Local tolerability inclusive.
7.
If several actions are indicated at the same time point, the intake of meals will be the last action.
8.
Confirmation of fitness includes physical examination.
9.
ADAs samples will be taken at baseline, Day 8, Day 15, Day 22, Day 29, Day 43, Day 57, Day 78, Day 92, Day 
120, Day 148 and Day 176 (EOT).
10. The cytokines IL1, IL6, TNF-and IFNwill be collected at baseline, 4h and 24h postdose after each of the 4 
single infusions. These samples are only to be analyzed in case of specific adverse events occur that are
suggestive for a cytokine release.
11. Only drug screening.
12. AEs and concomitant therapies will be recorded throughout the trial, but will be specifically asked for at the time 
points indicated in the Flow Chart above.
13. EOT (End of trial examination) includes physical examination, body weight, vital signs, ECG, safety laboratory, 
recording of AEs and concomitant therapies. EOT to be performed not before last PK sampling. 
14. Safety laboratory is to be taken within three days prior to study drug administration and can be omitted, if the 
screening examination is performed between Day -5 to Day -3.
15. First measure after completion of infusion is collection of PK and PD sample
16. In case plasma levels still exceed LOQ additional PK and ADA samples may be collected beyond Day 176


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Doc. No.: c09105854-05
Trial Protocol
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Flow Chart (10 mg/kg b.w. dose group, multiple dose) 
Visit
Day
Time relative to first drug 
administration (planned 
time [h:min]
Approx. time (actual time) 
[h:min]
Event and comment
PKplasma 
4
PDblood 
4 
Plasma ADA9
Safety laboratory/
Urinalysis 3
Body Temperature
Body Weight
12-lead ECG
ECG monitoring
Vital signs  (BP, PR)
Query on adverse events, 
concomitant therapies12
1
-28
to -3
screening1
X
X
X
2
-2
-48:00
8:00
ambulatory visit
X14
X
-1
-12:00
20:00
admission to
trial site
X11
X
1
-2:00
6:00
X2
X2
X2
X2, 10
X2
X2, 5
X2
X2
0:00
8:00
drug administration
start of infusion
▲
│
0:15
8:15
│
│
X
X
0:30
8:30
│
X
│
X
X
1:00
9:00
▼
end of infusion15
X
X
X
X5
│
│
X
X
1:30
9:30
│
X
2:00
10:00
light breakfast7
X
X5
▼
X
3:00
11:00
X
4:00
12:00
Lunch7
X10
X
X6
6:00
14:00
X
X5
X
8:00
16:00
snack (voluntary)7
X
10:00
18:00
Dinner7
12:00
20:00
X
X
X5
X
X6
2
24:00
8:00
Breakfast7
X
X10
X
X5
X
X6
28:00
12:00
Lunch7
32:00
16:00
snack (voluntary)7
X
X
34:00
18:00
Dinner7
X
3
48:00
8:00
Breakfast7
discharge from
trial site
(confirmation of 
fitness8)
X5
X
X
4
72:00
8:00
ambulatory visit
X
X
5
96:00
8:00
ambulatory visit
X
X


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02 Aug 2017
BI Trial No.: 1368.2
Doc. No.: c09105854-05
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Visit
Day
Time relative to first drug 
administration (planned 
time [h:min]
Approx. time (actual time) 
[h:min]
Event and comment
PKplasma 
4
PDblood 
4 
Plasma ADA9
Laboratory/
Urinalysis 3
Body Temperature
12-lead ECG
ECG monitoring
Vital signs  (BP, PR)
Query on adverse events, 
concomitant therapies12
2
7
156:00
20:00
admission to
trial site
X11
X
8
166:00
6:00
X2
X2
X2
X2, 10
X2
X2, 5
X2
X2
168:00
8:00
drug administration
start of infusion
▲
│
168:15
8:15
│
│
X
X
168:30
8:30
│
X
│
X
X
169:00
9:00
▼
end of infusion15
X
X
X
X5
│
│
X
X
169:30
9:30
│
X
170:00
10:00
light breakfast7
X
X5
▼
X
171:00
11:00
X
172:00
12:00
Lunch7
X10
X
X6
174:00
14:00
X
X5
X
176:00
16:00
snack (voluntary)7
X
178:00
18:00
Dinner7
180:00
20:00
X
X
X5
X
X6
9
192:00
8:00
Breakfast7
X
X10
X
X5
X
X6
196:00
12:00
Lunch7
200:00
16:00
snack (voluntary)7
X
X
202:00
18:00
Dinner7
X
10
216:00
8:00
Breakfast7
discharge from
trial site
(confirmation of 
fitness8)
X5
X
X
11
240:00
8:00
ambulatory visit
X
X
12
264:00
8:00
ambulatory visit
X
X


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BI Trial No.: 1368.2
Doc. No.: c09105854-05
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Visit
Day
Time relative to first drug 
administration (planned 
time [h:min]
Approx. time (actual time) 
[h:min]
Event and comment
PKplasma 
4
PDblood 
4 
Plasma ADA9
Laboratory/
Urinalysis 3
Body Temperature
12-lead ECG
ECG monitoring
Vital signs  (BP, PR)
Query on adverse events, 
concomitant therapies12
2
14
324:00
20:00
admission to
trial site
X11
X
15
334:00
6:00
X2
X2
X2
X2, 10
X2
X2, 5
X2
X2
336:00
8:00
drug administration
start of infusion
▲
│
336:15
8:15
│
│
X
X
336:30
8:30
│
X
│
X
X
337:00
9:00
▼
end of infusion15
X
X
X
X5
│
│
X
X
337:30
9:30
│
X
338:00
10:00
light breakfast7
X
X5
▼
X
339:00
11:00
X
340:00
12:00
Lunch7
X10
X
X6
342:00
14:00
X
X5
X
344:00
16:00
snack (voluntary)7
X
346:00
18:00
Dinner7
348:00
20:00
X
X
X5
X
X6
16
360:00
8:00
Breakfast7
X
X10
X
X5
X
X6
364:00
12:00
Lunch7
368:00
16:00
snack (voluntary)7
X
X
370:00
18:00
Dinner7
X
17
384:00
8:00
Breakfast7
discharge from
trial site
(confirmation of 
fitness8)
X5
X
X
18
408:00
8:00
ambulatory visit
X
X
19
432:00
8:00
ambulatory visit
X
X


Boehringer Ingelheim
02 Aug 2017
BI Trial No.: 1368.2
Doc. No.: c09105854-05
Trial Protocol
Page 13 of 102
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001-MCS-40-106-RD-11 (5.0) / Saved on: 25 Jun 2014
Visit
Day
Time relative to first drug 
administration (planned 
time [h:min]
Approx. time (actual time) 
[h:min]
Event and comment
PKplasma 
4
PDblood 
4 
Plasma ADA9
Laboratory/
Urinalysis 3
Body Temperature
12-lead ECG
ECG monitoring
Vital signs  (BP, PR)
Query on adverse events, 
concomitant therapies12
2
21
492:00
20:00
admission to
trial site
X11
X
22
502:00
6:00
X2
X2
X2
X2, 10
X2
X2, 5
X2
X2
504:00
8:00
drug administration
start of infusion
▲
│
504:15
8:15
│
│
X
X
504:30
8:30
│
X
│
X
X
505:00
9:00
▼
end of infusion15
X
X
X
X5
│
│
X
X
505:30
9:30
│
X
506:00
10:00
light breakfast7
X
X5
▼
X
507:00
11:00
X
508:00
12:00
Lunch7
X10
X
X6
510:00
14:00
X
X5
X
512:00
16:00
snack (voluntary)7
X
514:00
18:00
Dinner7
516:00
20:00
X
X
X5
X
X6
23
528:00
8:00
Breakfast7
X
X10
X
X5
X
X6
532:00
12:00
Lunch7
536:00
16:00
snack (voluntary)7
X
X
538:00
18:00
Dinner7
X
24
552:00
8:00
Breakfast7
discharge from
trial site
(confirmation of 
fitness8)
X5
X
X
25
576:00
8:00
ambulatory visit
X
X
26
600:00
8:00
ambulatory visit
X
X


Boehringer Ingelheim
02 Aug 2017
BI Trial No.: 1368.2
Doc. No.: c09105854-05
Trial Protocol
Page 14 of 102
Proprietary confidential information © 2017 Boehringer Ingelheim International GmbH or one or more of its affiliated companies
001-MCS-40-106-RD-11 (5.0) / Saved on: 25 Jun 2014
Visit
Day
Time relative to first drug 
administration (planned 
time [h:min]
Approx. time (actual time) 
[h:min]
Event and comment
PKplasma 
4
PDblood 
4 
Plasma ADA9
Laboratory/
Urinalysis 3
Body Temperature
12-lead ECG
ECG monitoring
Vital signs  (BP, PR)
Query on adverse events, 
concomitant therapies12
2
29
672
8:00
ambulatory  visit
X
X
X
X
36
840:00
8:00
ambulatory visit
X
X
43
1008:00
8:00
ambulatory visit
X
X
X
50
1176:00
8:00
ambulatory visit
X
X
X
57
1344:00
8:00
ambulatory visit
X
X
64
1512:00
8:00
ambulatory visit
X
X
78
1848:00
8:00
ambulatory visit
X
X
X
X
92
2184:00
8:00
ambulatory visit
X
X
X
120 ±3
2856:00
8:00
ambulatory visit
X
X
X
X
148 ±3
3528:00
8:00
ambulatory visit
X
X
X
3
176 ±3
4200:00
8:00
EOT13
X16
X
X16
X
X
X
X
1.
Screening with subject information, informed consent as the first measure, includes physical examination, check 
of vital signs, ECG, safety laboratory (under fasting conditions), drug screening, demographics (including 
determination of body height and weight, smoking and alcohol history), relevant medical history, concomitant 
therapy and review of inclusion/exclusion criteria. 
2.
The time is approximate; procedures are to be performed and completed within 3 h prior to drug administration. 
Within 3 hours prior to the planned dosing, planned time -2:00 will be used. 
3.
Laboratory tests (safety laboratory) include clinical chemistry, haematology, coagulation and urinalysis; in 
addition at screening: serology (HBV, HCV, HIV), and drug screening.
4.
PK and PD sampling times may be adapted based on information obtained during trial conduct.
5.
Triple ECG
6.
Local tolerability inclusive.
7.
If several actions are indicated at the same time point, the intake of meals will be the last action.
8.
Confirmation of fitness includes physical examination.
9.
ADAs samples will be taken at baseline, Day 8, Day 15, Day 22, Day 29, Day 43, Day 57, Day 78, Day 92, Day 
120, Day 148 and Day 176 (EOT).
10. The cytokines IL1, IL6, TNF-and IFNwill be collected at baseline, 4h and 24h postdose after each of the 4 
single infusions. These samples are only to be analyzed in case of specific adverse events occur that are
suggestive for a cytokine release.
11. Only drug screening.
12. AEs and concomitant therapies will be recorded throughout the trial, but will be specifically asked for at the time 
points indicated in the Flow Chart above.
13. EOT (End of trial examination) includes physical examination, body weight, vital signs, ECG, safety laboratory, 
recording of AEs and concomitant therapies. EOT to be performed not before last PK sampling. 
14. Safety laboratory is to be taken within three days prior to study drug administration and can be omitted, if the 
screening examination is performed between Day -5 to Day -3.
15. First measure after completion of infusion collection of PK and PD sample
16. In case plasma levels still exceed LOQ additional PK and ADA samples may be collected beyond Day 176


Boehringer Ingelheim
02 Aug 2017
BI Trial No.: 1368.2
Doc. No.: c09105854-05
Trial Protocol
Page 15 of 102
Proprietary confidential information © 2017 Boehringer Ingelheim International GmbH or one or more of its affiliated companies
001-MCS-40-106-RD-11 (5.0) / Saved on: 25 Jun 2014
Flow Chart (20 mg/kg b.w. dose group, multiple dose) 
Visit
Day
Time relative to first drug 
administration (planned 
time [h:min]
Approx. time (actual time) 
[h:min]
Event and comment
PKplasma 
4
PDblood 
4 
Plasma ADA9
Safety laboratory/
Urinalysis 3
Body Temperature
Body Weight
12-lead ECG
ECG monitoring
Vital signs  (BP, PR)
Query on adverse events, 
concomitant therapies12
1
-28
to -3
screening1
X
X
X
2
-2
-48:00
8:00
ambulatory visit
X14
X
-1
-12:00
20:00
admission to
trial site
X11
X
1
-2:00
6:00
X2
X2
X2
X2, 10
X2
X2, 5
X2
X2
0:00
8:00
drug administration
start of infusion
▲
│
0:15
8:15
│
│
X
X
0:30
8:30
│
X
│
X
X
1:00
9:00
│
▼
│
│
X
X
1:30
9:30
end of infusion15
X
X
X
X5
│
X
X
2:00
10:00
X
X5
▼
X
3:00
11:00
light breakfast7
X
4:00
12:00
Lunch7
X10
X
X6
6:00
14:00
X
X5
X
8:00
16:00
snack (voluntary)7
X
10:00
18:00
Dinner7
12:00
20:00
X
X
X5
X
X6
2
24:00
8:00
Breakfast7
X
X10
X
X5
X
X6
28:00
12:00
Lunch7
32:00
16:00
snack (voluntary)7
X
X
34:00
18:00
Dinner7
X
3
48:00
8:00
Breakfast7
discharge from
trial site
(confirmation of 
fitness8)
X5
X
X
4
72:00
8:00
ambulatory visit
X
X
5
96:00
8:00
ambulatory visit
X
X


Boehringer Ingelheim
02 Aug 2017
BI Trial No.: 1368.2
Doc. No.: c09105854-05
Trial Protocol
Page 16 of 102
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001-MCS-40-106-RD-11 (5.0) / Saved on: 25 Jun 2014
Visit
Day
Time relative to first drug 
administration (planned 
time [h:min]
Approx. time (actual time) 
[h:min]
Event and comment
PKplasma 
4
PDblood 
4 
Plasma ADA9
Laboratory/
Urinalysis 3
Body Temperature
12-lead ECG
ECG monitoring
Vital signs  (BP, PR)
Query on adverse events, 
concomitant therapies12
2
7
156:00
20:00
admission to
trial site
X11
X
8
166:00
6:00
X2
X2
X2
X2, 10
X2
X2, 5
X2
X2
168:00
8:00
drug administration
start of infusion
▲
│
168:15
8:15
│
│
X
X
168:30
8:30
│
X
│
X
X
169:00
9:00
▼
│
│
X
X
169:30
9:30
end of infusion15
X
X
X
X5
│
X
X
170:00
10:00
X
X5
▼
X
171:00
11:00
light breakfast7
X
172:00
12:00
Lunch7
X10
X
X6
174:00
14:00
X
X5
X
176:00
16:00
snack (voluntary)7
X
178:00
18:00
Dinner7
180:00
20:00
X
X
X5
X
X6
9
192:00
8:00
Breakfast7
X
X10
X
X5
X
X6
196:00
12:00
Lunch7
200:00
16:00
snack (voluntary)7
X
X
202:00
18:00
Dinner7
X
10
216:00
8:00
Breakfast7
discharge from
trial site
(confirmation of 
fitness8)
X5
X
X
11
240:00
8:00
ambulatory visit
X
X
12
264:00
8:00
ambulatory visit
X
X


Boehringer Ingelheim
02 Aug 2017
BI Trial No.: 1368.2
Doc. No.: c09105854-05
Trial Protocol
Page 17 of 102
Proprietary confidential information © 2017 Boehringer Ingelheim International GmbH or one or more of its affiliated companies
001-MCS-40-106-RD-11 (5.0) / Saved on: 25 Jun 2014
Visit
Day
Time relative to first drug 
administration (planned 
time [h:min]
Approx. time (actual time) 
[h:min]
Event and comment
PKplasma 
4
PDblood 
4 
Plasma ADA9
Laboratory/
Urinalysis 3
Body Temperature
12-lead ECG
ECG monitoring
Vital signs  (BP, PR)
Query on adverse events, 
concomitant therapies12
2
14
324:00
20:00
admission to
trial site
X11
X
15
334:00
6:00
X2
X2
X2
X2, 10
X2
X2, 5
X2
X2
336:00
8:00
drug administration
start of infusion
▲
│
336:15
8:15
│
│
X
X
336:30
8:30
│
X
│
X
X
337:00
9:00
▼
│
│
X
X
337:30
9:30
end of infusion15
X
X
X
X5
│
X
X
338:00
10:00
X
X5
▼
X
339:00
11:00
light breakfast7
X
340:00
12:00
Lunch7
X10
X
X6
342:00
14:00
X
X5
X
344:00
16:00
snack (voluntary)7
X
346:00
18:00
Dinner7
348:00
20:00
X
X
X5
X
X6
16
360:00
8:00
Breakfast7
X
X10
X
X5
X
X6
364:00
12:00
Lunch7
368:00
16:00
snack (voluntary)7
X
X
370:00
18:00
Dinner7
X
17
384:00
8:00
Breakfast7
discharge from
trial site
(confirmation of 
fitness8)
X5
X
X
18
408:00
8:00
ambulatory visit
X
X
19
432:00
8:00
ambulatory visit
X
X


Boehringer Ingelheim
02 Aug 2017
BI Trial No.: 1368.2
Doc. No.: c09105854-05
Trial Protocol
Page 18 of 102
Proprietary confidential information © 2017 Boehringer Ingelheim International GmbH or one or more of its affiliated companies
001-MCS-40-106-RD-11 (5.0) / Saved on: 25 Jun 2014
Visit
Day
Time relative to first drug 
administration (planned 
time [h:min]
Approx. time (actual time) 
[h:min]
Event and comment
PKplasma 
4
PDblood 
4 
Plasma ADA9
Laboratory/
Urinalysis 3
Body Temperature
12-lead ECG
ECG monitoring
Vital signs  (BP, PR)
Query on adverse events, 
concomitant therapies12
2
21
492:00
20:00
admission to
trial site
X11
X
22
502:00
6:00
X2
X2
X2
X2, 10
X2
X2, 5
X2
X2
504:00
8:00
drug administration
start of infusion
▲
│
504:15
8:15
│
│
X
X
504:30
8:30
│
X
│
X
X
505:00
9:00
▼
│
│
X
X
505:30
9:30
end of infusion15
X
X
X
X5
│
X
X
506:00
10:00
X
X5
▼
X
507:00
11:00
light breakfast7
X
508:00
12:00
Lunch7
X10
X
X6
510:00
14:00
X
X5
X
512:00
16:00
snack (voluntary)7
X
514:00
18:00
Dinner7
516:00
20:00
X
X
X5
X
X6
23
528:00
8:00
Breakfast7
X
X10
X
X5
X
X6
532:00
12:00
Lunch7
536:00
16:00
snack (voluntary)7
X
X
538:00
18:00
Dinner7
X
24
552:00
8:00
Breakfast7
discharge from
trial site
(confirmation of 
fitness8)
X5
X
X
25
576:00
8:00
ambulatory visit
X
X
26
600:00
8:00
ambulatory visit
X
X


Boehringer Ingelheim
02 Aug 2017
BI Trial No.: 1368.2
Doc. No.: c09105854-05
Trial Protocol
Page 19 of 102
Proprietary confidential information © 2017 Boehringer Ingelheim International GmbH or one or more of its affiliated companies
001-MCS-40-106-RD-11 (5.0) / Saved on: 25 Jun 2014
Visit
Day
Time relative to first drug 
administration (planned 
time [h:min]
Approx. time (actual time) 
[h:min]
Event and comment
PKplasma 
4
PDblood 
4 
Plasma ADA9
Laboratory/
Urinalysis 3
Body Temperature
12-lead ECG
ECG monitoring
Vital signs  (BP, PR)
Query on adverse events, 
concomitant therapies12
2
29
672
8:00
ambulatory  visit
X
X
X
X
36
840:00
8:00
ambulatory visit
X
X
43
1008:00
8:00
ambulatory visit
X
X
X
50
1176:00
8:00
ambulatory visit
X
X
X
57
1344:00
8:00
ambulatory visit
X
X
64
1512:00
8:00
ambulatory visit
X
X
78
1848:00
8:00
ambulatory visit
X
X
X
X
92
2184:00
8:00
ambulatory visit
X
X
X
120 ±3
2856:00
8:00
ambulatory visit
X
X
X
X
148 ±3
3528:00
8:00
ambulatory visit
X
X
X
3
176 ±3
4200:00
8:00
EOT13
X16
X
X16
X
X
X
X
1.
Screening with subject information, informed consent as the first measure, includes physical examination, check 
of vital signs, ECG, safety laboratory (under fasting conditions), drug screening, demographics (including 
determination of body height and weight, smoking and alcohol history), relevant medical history, concomitant 
therapy and review of inclusion/exclusion criteria. 
2.
The time is approximate; procedures are to be performed and completed within 3 h prior to drug administration. 
Within 3 hours prior to the planned dosing, planned time -2:00 will be used. 
3.
Laboratory tests (safety laboratory) include clinical chemistry, haematology, coagulation and urinalysis; in 
addition at screening: serology (HBV, HCV, HIV), and drug screening.
4.
PK and PD sampling times may be adapted based on information obtained during trial conduct.
5.
Triple ECG
6.
Local tolerability inclusive.
7.
If several actions are indicated at the same time point, the intake of meals will be the last action.
8.
Confirmation of fitness includes physical examination.
9.
ADAs samples will be taken at baseline, Day 8, Day 15, Day 22, Day 29, Day 43, Day 57, Day 78, Day 92, Day 
120, Day 148 and Day 176 (EOT).
10. At baseline of each dosing day, cytokines (IL1, IL6, TNF-and IFNsamples will be collected together with 
safety lab. Additional cytokines samples IL1, IL6, TNF-and IFNwill be collected at 4h and 24h post-dose
after each of the 4 single infusions. Cytokines samples are only to be analysed from an individual subject in case 
of specific adverse events in this subject that are suggestive for a cytokine release. At 4h and 24h post-dose no 
safety lab needs to be taken.
11. Only drug screening.
12. AEs and concomitant therapies will be recorded throughout the trial, but will be specifically asked for at the time 
points indicated in the Flow Chart above.
13. EOT (End of trial examination) includes physical examination, body weight, vital signs, ECG, safety laboratory, 
recording of AEs and concomitant therapies. EOT to be performed not before last PK sampling. 
14. Safety laboratory is to be taken within three days prior to study drug administration and can be omitted, if the 
screening examination is performed between Day -5 to Day -3.
15. First measure after completion of infusion collection of PK and PD sample
16. In case plasma levels still exceed LOQ additional PK and ADA samples may be collected beyond Day 176


Boehringer Ingelheim
02 Aug 2017
BI Trial No.: 1368.2
Doc. No.: c09105854-05
Trial Protocol
Page 20 of 102
Proprietary confidential information © 2017 Boehringer Ingelheim International GmbH or one or more of its affiliated companies
001-MCS-40-106-RD-11 (5.0) / Saved on: 25 Jun 2014
Flow Chart (20 mg/kg b.w. dose group, single dose) 
dose group, single 
Day
Time relative to first drug 
administration (planned 
time [h:min]
Approx. time (actual time) 
[h:min]
Event and comment
PKplasma
4
PDblood 
4 
Plasma ADA9
Laboratory/
Urinalysis 3
Body Temperature
Body Weight
12-lead ECG
ECG monitoring
Vital signs  (BP, PR)
Query on adverse events, 
concomitant therapies12
1
-28
to -3
screening1
X
X
X
2
-2
-48:00
8:00
ambulatory visit
X14
X
-1
-12:00
20:00
admission to
trial site
X11
X
1
-2:00
6:30
X2
X2
X2
X2,10
X2
X2,5
X2
X2,6
0:00
8:00
drug administration
start of infusion
▲
│
0:30
8:30
│
X
X5
│
X
X6
1:00
9:00
▼
end of infusion15
X
X
X
X5
│
X
X6
1:30
9:30
X5
│
│
X
2:00
10:00
light breakfast7
X
X
X5
▼
X
2:30
10:30
3:00
11:00
X
X5
X
4:00
12:00
Lunch7
X
X10
X5
X
X6
6:00
14:00
X
X5
X
8:00
16:00
snack (voluntary)7
X
X5
X
10:00
18:00
Dinner7
12:00
20:00
X
X
X5
X
X6
2
24:00
8:00
Breakfast7
X
X10
X
X5
X
X6
28:00
12:00
Lunch7
32:00
16:00
snack (voluntary)7
X
X5
X
34:00
18:00
Dinner7
X
3
48:00
8:00
Breakfast7
discharge from
trial site
(confirmation of 
fitness8)
X
X5
X
X
4
72:00
8:00
ambulatory visit
X
X
X
5
96:00
8:00
ambulatory visit
X
X
8
168:00
8:00
ambulatory visit
breakfast 
(voluntary)
X
X
X
X
X
X
X
15
336:00
8:00
ambulatory visit
X
X
22
504:00
8:00
ambulatory visit
breakfast 
(voluntary)
X
X
X
X
X
X
29
672:00
8:00
ambulatory visit
breakfast 
(voluntary)
X
X
X
X
X
X
X


Boehringer Ingelheim
02 Aug 2017
BI Trial No.: 1368.2
Doc. No.: c09105854-05
Trial Protocol
Page 21 of 102
Proprietary confidential information © 2017 Boehringer Ingelheim International GmbH or one or more of its affiliated companies
001-MCS-40-106-RD-11 (5.0) / Saved on: 25 Jun 2014
Visit
Day
Time relative to first drug 
administration (planned 
time [h:min]
Approx. time (actual time) 
[h:min]
Event and comment
PKblood 
4
PDblood 
4
Plasma ADA9
Laboratory/
Urinalysis 3
Body Temperature
12-lead ECG
ECG monitoring
vital signs  (BP, PR)
Query on adverse events, 
concomitant therapies12
2
36
840:00
8:00
ambulatory visit
X
X
43
1008:00
8:00
ambulatory visit
X
X
X
X
57
1344:00
8:00
ambulatory visit
X
X
X
71
1680:00
8:00
ambulatory visit
X
X
X
X
92 ±2
2184:00
8:00
ambulatory visit
X
X
X
120 ±3
2856:00
8:00
ambulatory visit
X
X
X
X
148 ±3
3528:00
8:00
ambulatory visit
X
X
3
176 ±3 
4200:00
8:00
EOT13
X16
X
X16
X
X
X
X
1.
Screening with subject information, informed consent as the first measure, includes physical examination, check of 
vital signs, ECG, safety laboratory (under fasting conditions), drug screening, demographics (including 
determination of body height and weight, smoking and alcohol history), relevant medical history, concomitant 
therapy and review of inclusion/exclusion criteria.
2.
The time is approximate; procedures are to be performed and completed within 3 h prior to drug administration. 
Within 3 hours prior to the planned dosing, planned time -2:00 will be used.
3.
Laboratory tests (safety laboratory) include clinical chemistry, haematology, coagulation and urinalysis; in 
addition at screening: serology (HBV, HCV, HIV), and drug screening.
4.
PK and PD sampling times may be adapted based on information obtained during trial conduct.
5.
From Day 1 (predose) to Day 3 (discharge from the unit) ECGs will be recorded as triple ECG.
6.
Local tolerability inclusive.
7.
If several actions are indicated at the same time point, the intake of meals will be the last action.
8.
Confirmation of fitness includes physical examination.
9.
ADAs samples will be taken at baseline, Day 8, Day 29, Day 43, Day 57, Day 71, Day 92, Day 120, Day 148 and
Day 176 (EOT) after BI 655130 administration.
10. 
The cytokines IL1, IL6, TNF-and IFNwill be collected at baseline, 4h and 24h postdose. At 4 h there will be 
only an assessment of cytokines, while at baseline and 24 h cytokines will be determined together with safety lab. 
The cytokine samples only to be analyzed in case of specific adverse events suggestive for cytokine release.
11
Only drug screening.
12.
AEs and concomitant therapies will be recorded throughout the trial, but will be specifically asked for at the time 
points indicated in the Flow Chart above.
13.
EOT (End of trial examination) includes physical examination, body weight, vital signs, ECG, safety laboratory, 
recording of AEs and concomitant therapies. EOT to be performed not before last PK and ADA sampling. 
14.
Safety laboratory is to be taken within three days prior to study drug administration and can be omitted, if the
screening examination is performed between Day -5 to Day -3.
15.
First measure after completion of infusion collection of PK and PD sample
16.
In case plasma levels still exceed LOQ additional PK samples may be collected beyond Day 176.


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TABLE OF CONTENTS
TITLE PAGE ........................................................................................................1
CLINICAL TRIAL PROTOCOL SYNOPSIS ................................................2
FLOW CHART...................................................................................................5
TABLE OF CONTENTS ................................................................................ 22
ABBREVIATIONS.......................................................................................... 26
2.
RATIONALE, OBJECTIVES, AND BENEFIT - RISK 
ASSESSMENT ......................................................................................... 37
2.2
TRIAL OBJECTIVES.......................................................................................38
3.
DESCRIPTION OF DESIGN AND TRIAL POPULATION.............. 42
3.1
OVERALL TRIAL DESIGN AND PLAN ......................................................42
3.1.1
Administrative structure of the trial...................................................43
3.2
DISCUSSION OF TRIAL DESIGN, INCLUDING THE CHOICE OF 
CONTROL GROUP..........................................................................................44
3.3
SELECTION OF TRIAL POPULATION ......................................................45
3.3.1
Main diagnosis for study entry............................................................45
3.3.2
Inclusion criteria...................................................................................45
3.3.3
Exclusion criteria ..................................................................................45
3.3.4
Removal of subjects from therapy or assessments.............................47
3.3.4.1
Removal of individual subjects................................................47
3.3.4.2
Discontinuation of the trial by the sponsor..............................48
3.3.5
Replacement of subjects .......................................................................48
4.
TREATMENTS........................................................................................ 49
4.1
TREATMENTS TO BE ADMINISTERED....................................................49
4.1.1
Identity of BI investigational product and comparator product......49
4.1.2
Method of assigning subjects to treatment groups ............................50
4.1.3
Selection of doses in the trial................................................................50
4.1.4
Drug assignment and administration of doses for each subject .......50


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4.1.5
Blinding and procedures for unblinding ............................................51
4.1.5.1
Blinding....................................................................................51
4.1.5.2
Procedures for emergency unblinding .....................................52
4.1.6
Packaging, labelling, and re-supply ....................................................52
4.1.7
Storage conditions.................................................................................53
4.1.8
Drug accountability ..............................................................................53
4.2
CONCOMITANT THERAPY, RESTRICTIONS, AND RESCUE 
TREATMENT....................................................................................................54
4.2.1
Rescue medication, emergency procedures, and additional 
treatments ..............................................................................................54
4.2.2
Restrictions............................................................................................54
4.2.2.1
Restrictions regarding concomitant treatment .........................54
4.2.2.2
Restrictions on diet and life style.............................................54
4.3
TREATMENT COMPLIANCE.......................................................................55
5.
VARIABLES AND THEIR ASSESSMENT ......................................... 56
5.1
EFFICACY - CLINICAL PHARMACOLOGY.............................................56
5.1.1
Endpoints of efficacy.............................................................................56
5.1.2
Assessment of efficacy...........................................................................56
5.2
SAFETY..............................................................................................................56
5.2.1
Endpoints of safety................................................................................56
5.2.2
Assessment of adverse events...............................................................56
5.2.2.1
Definitions of adverse events...................................................56
5.2.2.2
Adverse event collection and reporting ...................................59
5.2.3
Assessment of safety laboratory parameters......................................61
5.2.4
Electrocardiogram................................................................................64
5.2.4.1
12-lead resting ECG.................................................................64
5.2.4.2
Continuous ECG monitoring and oxygen monitoring.............65
5.2.5
Assessment of other safety parameters...............................................65
5.2.5.1
Vital signs ................................................................................65
5.2.5.2
Medical examinations..............................................................66
5.2.5.3
Local tolerability......................................................................66
5.2.5.4
Oral body temperature .............................................................66
5.3
OTHER...............................................................................................................66
5.3.1
Pharmacogenomic evaluation..............................................................66
5.3.2
Other endpoints.....................................................................................66
5.3.3
Other assessments .................................................................................66
5.4
APPROPRIATENESS OF MEASUREMENTS.............................................66
5.5
DRUG CONCENTRATION MEASUREMENTS AND 
PHARMACOKINETICS..................................................................................67
5.5.1
Pharmacokinetic endpoints..................................................................67
5.5.1.1
Secondary endpoints................................................................67


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5.5.2
Methods of sample collection...............................................................69
5.5.2.1
Plasma sampling for pharmacokinetic analysis.......................69
5.5.2.2
Plasma sampling for ADA assessment ....................................70
5.5.3
Analytical determinations ....................................................................70
5.5.3.1
Analytical determination of BI 655130 plasma concentration 70
5.5.3.2
Assessment of ADA to BI 655130...........................................70
5.7
PHARMACODYNAMICS................................................................................72
5.7.1
Pharmacodynamic endpoints...............................................................72
5.7.2
Methods of sample collection...............................................................72
5.8
PHARMACOKINETIC - PHARMACODYNAMIC RELATIONSHIP .....72
6.
INVESTIGATIONAL PLAN.................................................................. 73
6.1
VISIT SCHEDULE............................................................................................73
6.2
DETAILS OF TRIAL PROCEDURES AT SELECTED VISITS ................74
6.2.1
Screening................................................................................................74
6.2.2
Treatment period ..................................................................................74
6.2.3
End of trial and follow-up period........................................................75
7.
STATISTICAL METHODS AND DETERMINATION OF
SAMPLE SIZE......................................................................................... 76
7.1
STATISTICAL DESIGN – MODEL ...............................................................76
7.1.1
Objectives...............................................................................................76
7.2
NULL AND ALTERNATIVE HYPOTHESES ..............................................76
7.3
PLANNED ANALYSES.....................................................................................76
7.3.1
Primary analyses...................................................................................77
7.3.2
Secondary analyses ...............................................................................77
7.3.3
Safety analyses.......................................................................................80
7.3.4
Interim analyses ....................................................................................81
7.3.5
Pharmacokinetic analyses ....................................................................81
7.4
HANDLING OF MISSING DATA ..................................................................82
7.4.1
Safety......................................................................................................82
7.4.2
Plasma/urine drug concentration - time profiles ...............................82
7.4.3
Pharmacokinetic parameters...............................................................82
7.5
RANDOMISATION ..........................................................................................82
7.6
DETERMINATION OF SAMPLE SIZE ........................................................83


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8.
INFORMED CONSENT, DATA PROTECTION, TRIAL
RECORDS ................................................................................................ 84
8.1
STUDY APPROVAL, SUBJECT INFORMATION, AND INFORMED 
CONSENT ..........................................................................................................84
8.2
DATA QUALITY ASSURANCE .....................................................................84
8.3
RECORDS..........................................................................................................85
8.3.1
Source documents .................................................................................85
8.3.2
Direct access to source data and documents.......................................85
8.3.3
Storage period of records.....................................................................85
8.4
EXPEDITED REPORTING OF ADVERSE EVENTS .................................85
8.5
STATEMENT OF CONFIDENTIALITY.......................................................86
8.6
COMPLETION OF TRIAL..............................................................................86
9.
REFERENCES......................................................................................... 87
9.1
PUBLISHED REFERENCES...........................................................................87
9.2
UNPUBLISHED REFERENCES.....................................................................88
10. APPENDICES .......................................................................................... 89
10.1
CLINICAL EVALUATION OF LIVER INJURY .........................................89
10.1.1 Introduction...........................................................................................89
10.1.2 Procedures .............................................................................................89
10.2
RECONSTITUTION INSTRUCTION(S).......................................................91
11. DESCRIPTION OF GLOBAL AMENDMENT(S).............................. 97


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ABBREVIATIONS
ADA
Anti-drug antibodies
ADCC
Antibody -dependent cellular cytotoxicity
AE
Adverse event
AESI
Adverse events of special interest
ALT
Alanine amino transferase
ANCOVA
Analysis of Covariance
API
Active Pharmaceutical Ingredient
AST
Aspartate amino transferase
AUC
Area under the curve
AUC0-∞
Area under the concentration-time curve of the analyte in plasma over the 
time interval from 0 extrapolated to infinity
AUCt1-t2
Area under the concentration-time curve of the analyte in plasma over the 
time interval t1 to t2
AUCτ,ss
Area under the concentration-time curve of the analyte in plasma at steady
state over a uniform dosing interval τ
AUCτ,1
Area under the concentration-time curve of the analyte in plasma over a
uniform dosing interval τ after administration of the first dose
AUC0-tz
Area under the concentration-time curve of the analyte in plasma over the 
time interval from 0 to the last quantifiable data point
%AUCtz-∞
the percentage of AUC0-∞obtained by extrapolation
β
Slope parameter associated with the power model used to evaluate dose 
proportionality
BI
Boehringer Ingelheim
BLQ
Below limit of quantification
BMI
Body mass index (weight divided by height squared)
BP
Blood pressure
BW
Body weight
CA
Competent authority
CDC
Complement-dependent cytotoxicity
CI
Confidence interval
CL
Total clearance of the analyte in plasma after intravenous administration
CL/F
Apparent clearance of the analyte in plasma after extravascular 
administration
Cmax
Maximum measured concentration of the analyte in plasma
Cmin
Minimum measured concentration of the analyte in plasma 
CPU
Clinical Pharmacology Unit
CRF
Case report form
CRO
Clinical Research Organization
CTP
Clinical trial protocol
CTR
Clinical trial report
DILI
Drug induced liver impairment
DP
Drug product


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ECG
Electrocardiogram
EDTA
Ethylenediaminetetraacetic acid
EMEA
European Agency for the Evaluation of Medicinal Products
EOT
End of trial
FDA
Food and Drug Administration
FIH
First in Human
FIM
First in Man
GCP
Good Clinical Practice
gMean
Geometric mean
GMP
Good Manufacturing Practice
HBV
Hepatitis B virus
HCV
Hepatitis C virus
HIV
Human Immunodeficiency Virus
IB
Investigator’s brochure
ICH
International Conference of Harmonisation
IEC
Independent Ethics Committee
IPV
Important protocol violations
IRB
Institutional Review Board
ISF
Investigator site file
z
Terminal rate constant in plasma
kDA
Kilodalton
LI
linearity index
LLOQ
Lower Limit of Quantification
LOQ
Limit of Quantification
mAb
Monoclonal antibody
MedDRA
Medical Dictionary for Regulatory Activities
mmHg
Millimeters Mercury
MMP
Matrix metalloproteinase
MRD
Multiple Rising Dose
MRT
Mean residence time of the analyte in the body after intravenous bolus 
administration
N
Number
NC
Not calculated
NF-kB
Nuclear factor kappa-light-chain-enhancer of activated B cells
NOA
Not analysed
NOAEL
No observed adverse effect level
NOP
No peak detectable
NOR
No valid result
NOS
No sample available
PBMC
peripheral blood mononuclear cells
PD
Pharmacodynamic(s)
Ph.Eur
Pharmacopoea Europaea
PK
Pharmacokinetic(s)


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PKSD
Pharmacokinetic set for descriptive analysis
PKSI
Pharmacokinetic set for inferential analysis
pM
Picomolar
PR
Pulse rate
PTF
Peak-trough fluctuation
PTM
Planned Time
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)
RA,AUC
accumulation ratio based on AUC0-τ
RA,Cmax
accumulation ratio based on Cmax,ss
REP
Residual effect period
RPM
Report Planning Meeting
RR
Riva Rocci
SAE
Serious adverse event
SCR
Screening
SOP
Standard Operating Procedure
SRD
Single-rising dose
ss
(at) steady state
SUSAR
Suspected Unexpected Serious Adverse Reaction
t1/2
Terminal half-life of the analyte in plasma
tmax
Time from dosing to maximum measured concentration of the analyte in 
plasma
TDMAP
Trial Data Management and Analysis Plan
TGF
Transforming growth factor
TMDD
Target mediated drug disposition
TMF
Trial Master File
TSAP
Trial statistical analysis plan
UC
Ulcerative colitis
ULN
Upper limit of normal
USP
United States Pharmacopeia
Vss
Volume of distribution at steady state after single intravenous 
administration
Vz
Volume of distribution during the terminal phase after intravascular 
administration
Vz/F
Apparent volume of distribution during the terminal phase after 
extravascular administration
WBC
White Blood Cells
WFI
Water for Injection


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2.
RATIONALE, OBJECTIVES, AND BENEFIT - RISK 
ASSESSMENT


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2.2
TRIAL OBJECTIVES
The primary objective of this trial is to investigate the safety and tolerability of BI 655130 in 
healthy male subjects following IV administration of multiple rising doses of 3 mg/kg, 6 
mg/kg and 10 mg/kg b.w.. The study will also explore safety and tolerability following a 
single IV administration of 20 mg/kg b.w.. In case previous doses were shown to be safe and 
well tolerated multiple doses of 20 mg/kg may be studied as well to provide a further safety 
window to potential therapeutic doses in patients.
Secondary objectives are the exploration of the pharmacokinetics of BI 655130 after single 
and multiple IV administration.
A further objective is the exploration of pharmacodynamics and the evaluation of additional 
pharmacokinetic parameters beyond those already covered in secondary objectives.
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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3.
DESCRIPTION OF DESIGN AND TRIAL POPULATION
3.1
OVERALL TRIAL DESIGN AND PLAN
The multiple-rising dose part of the trial is designed as double-blind, randomised, and 
placebo-controlled within parallel dose group. The placebo-controlled single dose part will be 
conducted single-blind and partially randomised.
A total of 40 healthy male subjects is planned to participate in the trial, according to 5
sequential groups comprising 8 subjects per group. However, additional subjects may be 
entered to allow testing of additional intermediate doses based on the basis of experience 
gained during the trial conduct (e.g. preliminary PK data), provided the planned and approved 
highest dose will not be exceeded. Thus, the actual number of subjects entered may exceed 
40, but will not exceed 48 subjects. 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 of the MRD part up to 20
mg/kg b.w. (within 4 weeks single intravenous doses on Day 1, Day 8, Day 15, and Day 22) 
will consist of 2 cohorts (in each cohort 3 on active and one on placebo) which will be treated 
subsequently for safety reasons. Dose group 4 (single dose of 20 mg/kg of BI 655130 or 
placebo) will consist of 3 cohorts (see 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
Dose regimen
MRD
MRD
MRD
SD
MRD
Dose (mg/kg b.w.)
3
6
10
20
20
Number of subjects
8
8
8
8
8
Subjects receiving placebo
2
2
2
2
2
Subjects receiving active drug
6
6
6
6
6
The dose groups will be investigated consecutively in ascending order of doses, maintaining a 
time interval of at least 14 days between the last drug administration in the previous dose 
group and the first drug administration of 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. Furthermore, an 
unscheduled safety review meeting can be requested anytime for any reasonable cause by the 
Principal Investigator (or an authorised deputy) or the sponsor of the study, e.g. because of 


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any unforeseen adverse events. 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). In addition, at least 6 evaluable subjects per dose 
level are required to decide about dose escalation to the next higher dose level.
The minimum data set for review consists of the following data:

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 ECG 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

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 trial clinical monitor is responsible for 
organization and minutes of the reviews. Minutes will be signed off by the Principal 
Investigator (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 low and/or intermediate dose levels) on the basis of experience gained during 
the study, provided the planned and approved highest dose is not exceeded. In this case, the 
total number of subjects in this trial might increase. The investigator and/or the sponsor 
should stop further dosing in case the safety evaluation leads to concerns that would not 
allow further 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 is sponsored by Boehringer Ingelheim (BI) Pharma GmbH & Co. KG, Germany.
BI has appointed a Trial Clinical Monitor, responsible for coordinating all required activities, 
in order to 
-
manage the trial in accordance with applicable regulations and internal SOPs,
-
direct the clinical trial team in the preparation, conduct, and reporting of the trial,
-
ensure appropriate training and information of local clinical monitors (CML), Clinical 
Research Associates (CRAs), and participating trial sites.


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The trial will be conducted at the 
 
 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. 
On-site monitoring will be performed by BI or a contract research organisation appointed by 
BI.
Safety laboratory tests will be performed by ZNA Klinisch Laboratorium, Lindendreef 1, 
2020 Antwerpen, Belgium.
 
 
 
The analyses of BI 655130 concentrations in plasma will be performed at QPS in Newark, 
DE 19711, USA. 
The digitally recorded 12-lead ECGs will be sent to a specialised contract research 
organisation (
) for evaluation.
The trial is sponsored by Boehringer Ingelheim Pharma GmbH & Co. KG, Germany.
Data management and statistical evaluation will be done by BI according to BI SOPs.
Tasks and functions assigned in order to organise, manage, and evaluate the trial are defined 
according to BI SOPs. A list of responsible persons and relevant local information can be 
found in the ISF.
3.2
DISCUSSION OF TRIAL DESIGN, INCLUDING THE CHOICE OF 
CONTROL GROUP
For multiple-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 655130.
With the rising dose design, double-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 and investigators. 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.


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After completion of the second dose group of the multiple-rising dose part the single dose 
part (20 mg/kg b.w. dose group) will start, which is conducted single-blind and partially 
randomised. This design was selected because a single infusion of 20 mg/kg b.w. was not 
tested in the preceding FIH study (section 1.2).
Provided that infusions of BI 655130 were well tolerated in the preceding dose groups the 
study may continue with dose group 5 (multiple doses of 20 mg/kg).
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 the exploratory evaluation of 
pharmacokinetics.
3.3
SELECTION OF TRIAL POPULATION
It is planned that 40 healthy male subjects will enter the study. The actual number of subjects 
entered may exceed the total of 40 if additional intermediate doses will be tested (see Section 
3.1). Thus, the actual number of subjects entered may be increased, but will not exceed 48
subjects. 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 trial (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:


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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), and other relevant neurological or psychiatric disorders
7. History of relevant orthostatic hypotension, fainting spells, or blackouts
8. Chronic or relevant acute infections
9. History of relevant allergy or hypersensitivity (including allergy to the trial medication or 
its excipients) 
10. Use of drugs within 30 days prior to administration of trial medication if that might 
reasonably influence the results of the trial (incl. QT/QTc interval prolongation)
11. Participation in another trial where an investigational drug has been administered within 
60 days prior to planned administration of trial medication, or current participation in 
another trial involving administration of investigational drug.
12. Smoker (more than 10 cigarettes or 3 cigars or 3 pipes per day)
13. Inability to refrain from smoking on specified trial days
14. Alcohol abuse (consumption of more than 30 g per day)
15. Drug abuse or positive drug screening
16. Blood donation of  more than 100 mL within 30 days prior to administration of trial 
medication or intended donation during the trial
17. Intention to perform excessive physical activities within one week prior to administration 
of trial medication or during the trial
18. Inability to comply with dietary regimen of trial site
19. A marked baseline prolongation of QT/QTc interval (such as QTc intervals that are 
repeatedly greater than 450 ms in males) or any other relevant ECG finding at screening
20. A history of additional risk factors for Torsades de Pointes (such as heart failure, 
hypokalemia, or family history of Long QT Syndrome)
21. 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 
For study restrictions, refer to Section 4.2.2.


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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 for trial treatment or trial participation, 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 Appendix 10.1 of this clinical trial protocol and 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.
Infusion reactions should also lead to the removal of an individual subject. However, in mild 
transient cases of infusion reactions (with clinical symptoms such as dizziness, headache,
nausea) requiring no treatment the clinical investigator may pause the infusion or continue
with a reduced infusion rate as described for other therapeutic proteins [P16-06636].
However, the overall infusion time (including time of discontinuation) must not exceed 45 
minutes for 3 mg/kg b.w. and 6 mg/kg b.w. multiple dose and 90 minutes for 10 mg/kg b.w. 
multiple dose and 20 mg/kg b.w. single dose and 120 minutes for 20 mg/kg b.w. multiple 
dose.
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 first 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 first 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. If the discontinuation occurs before the end of the 
REP (see Section 5.2.2.2), the discontinued subject should if possible be questioned for AEs 
and concomitant therapies at or after the end of the REP in order to ascertain collection of 


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AEs and concomitant therapies throughout the REP, if not contrary to any consent 
withdrawal of the subject. 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 findings or serious adverse events invalidate the earlier positive 
benefit-risk-assessment. More specifically, the trial will be terminated if more 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.
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
 replaces.


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4.
TREATMENTS
4.1
TREATMENTS TO BE ADMINISTERED
The investigational product has been manufactured by BI Pharma GmbH & Co. KG. The BI
655130 molecule is a heterodimer with a molecular weight of approximately 146 kDa.
4.1.1
Identity of BI investigational product and comparator product
The characteristics of the test product are given below:
Substance:
BI 655130
Pharmaceutical formulation: solution for infusion
Source:
BI Pharma GmbH & Co. KG, Germany
Unit strength:
150 mg/7.5 mL (per 10 mL vial)
Posology:
1-0-0
Route of administration:
IV infusion
Duration of use:
Single dose (20 mg/kg b.w.)
Multiple dose (4 single IV administrations one week apart)
At the time of use, the IV solution for dosing will be prepared as detailed in the instruction 
given in Appendix 10.2.
The characteristics of the reference product (placebo) are given below:
Substance:
Placebo (citrate buffer, pH 6.5)
Pharmaceutical formulation: solution for infusion
Source:
BI Pharma GmbH & Co. KG, Germany
Unit strength:
not applicable
Posology:
1-0-0
Route of administration:
IV infusion
Duration of use:
Single dose (20 mg/kg b.w.)
Multiple dose (4 single IV administrations one week apart)


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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 
according to their temporal availability. As soon as enough subjects have been allocated to 1 
of the 11 dose cohorts (2 cohorts per dose group in the MRD part, 3 cohorts in the SRD part), 
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 (SRD part) and 
the list of subject and medication numbers (MRD part) will be provided to the trial site in 
advance. The allocation of subjects to study subject numbers will be performed prior to the 
first administration of trial medication. For this purpose, the subjects will be allocated to a 
study subject number by drawing lots. 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 1.2).
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 the dose volume of the respective dose level. For further details 
concerning timing see Flow Chart. Start and time of the infusion will be recorded.
Detailed instructions for the dilution of the trial product, the preparation of the infusion 
solution, the volume to be administered and the infusion rate is provided in Appendix 10.2. In 
all subjects the infusion solution will be intravenously administered over 30 minutes for dose 
group 3 mg/kg b.w. multiple dose and 6 mg/kg b.w. multiple dose and over 60 minutes for 
dose group 10 mg/kg b.w. multiple dose and 20 mg/kg b.w. single dose approximately 
between 8.00 h and 10.30 h of the respective study day. Multiple doses of 20 mg/kg b.w. will 
be administered over 90 minutes between 8.00 h and 12.00 h of the respective study day.
In case of safety concerns, e.g. due to infusion reactions, it is in the discretion of the 
investigator or his/her designee to adapt the infusion scheme, including but not limited 
slowing down the infusion rate, stopping of the infusion and provided no further safety 
concern exist restarting at a slower rate. Further based on 
 medical judgment he/she will 
provide medications such as steroids, etc. as needed.
For administration of the infusion, an intravenous indwelling catheter is placed into an arm 
vein of the subject and will be kept patent with a saline infusion. A second indwelling 
catheter used for collection of blood samples will be placed on the contralateral arm.
The administration of the trial medication on all study days will be done under supervision of 
the investigating physician or a designee. The so-called four-eye principle (two-person rule) 


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should be applied for administration of trial medication and – if applicable – its preparation 
(e.g. reconstitution), if correct dosage cannot be ensured otherwise. For the purpose of drug 
accountability, the infusion set will be weighed before and after drug administration.
Table 4.1.4: 1
Preparation of infusion solution containing active drug
Dose 
group
Final dose
of BI 655130 
[mg/kg]
Concentration of Application 
solution in infusion bag 
Infusion volume [mL]*/ 
Total dose [mg]
1
3
20 mg/mL
9 mL 180 mg
2
6
20 mg/mL
18 mL 360 mg
3
10
20 mg/mL
30 mL 600 mg
4
20
20 mg/mL
60 mL 1200 mg
5
20
20 mg/mL
60 mL 1200 mg
*Infusion volume for a body weight of 60 kg.
Water is allowed except for 1 hour before start of infusion and 1.5 h after end of infusion. On 
Day 1 for all dose groups and in addition Day 8, Day 15 and Day 22 for subjects receiving 
repeated doses (dose group 1 to 3) , from 2 hours post-dose, liquid intake is restricted at 
additional 3000 mL until the morning of Day 2. Standardised meals will be served as outlined 
in the Flow Chart. Subjects will be kept under close medical surveillance until 48 h following 
drug administration. Thereafter subjects will be discharged from the CPU and further 
assessments will be conducted in an ambulatory fashion. For restrictions with regard to diet 
see also Section 4.2.2.2.
4.1.5
Blinding and procedures for unblinding
4.1.5.1
Blinding
For the MRD part, the trial is designed double-blind with regard to the subjects and the 
investigators (as well as the research staff at the trial site) in order to eliminate observer or 
performance bias. This means avoiding systematic differences in assessments regarding the 
subject’s treatment (active or placebo). 
The administration of the 20 mg single dose (active or placebo) will be single-blind (to assure 
single-blind conditions, subjects will not be informed about treatment assignment on the 
study days, i.e. subjects will not be aware that the second cohort of each dose level will only 
receive active treatment). 
According to the rising dose design, the current dose level will be known to subjects and 
investigators.
At the trial site, access to the randomisation schedule is restricted to unblinded pharmacists, 
pharmacy staff members or staff who will reconstitute the drug solution. Access to the codes 
will be controlled and documented by a signed confidentiality statement, which will be stored 


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in the TMF. Persons directly involved in the clinical conduct of the trial will not have access 
to the treatment allocation prior to database lock.
Within the ECG laboratory, the staff involved with interval measurements and assessments 
will be blinded for the MRD part and unblinded for the SRD part with respect to the 
treatment and also with regard to the recording date and time as well as the time points of the 
ECGs. The interval measurements for a given subject will be performed in a random and 
blinded sequence by a single technician. No more than two different blinded readers will 
evaluate the ECGs of the study.
In addition, the trial bioanalyst will request the randomisation codes prior to official 
unblinding to perform the interim / preliminary PK analysis. He or she will confirm in writing 
that the codes will be treated confidentially.
Regarding the sponsor, the database of this trial will be handled open-label, meaning that the 
trial functions of the sponsor are unblinded (including clinical monitor, data manager, 
statistician, bioanalyst, pharmacokineticist, pharmacometrician, drug metabolism scientist as 
well as dedicated CRO personnel). The objective of the trial is not expected to be affected.
4.1.5.2
Procedures for emergency unblinding
For blinded trials, the investigator will be supplied with a set of sealed envelopes containing 
the medication codes for each subject according to the randomisation scheme. The envelopes 
will be kept unopened at the trial site until the end of data collection. An envelope may only 
be opened in emergency situations when the identity of the trial drug must be known to the 
investigator in order to provide appropriate medical treatment or to assure safety of trial 
participants. If the envelope for a subject is opened, the sponsor must be informed 
immediately. The reason for opening the code break must be documented on the envelope or 
appropriate CRF page along with the date and the initials of the person who broke the code. 
At the close-out visit all envelopes are collected.
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 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 and address

Storage conditions


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
Use-by date

Batch

Investigator
The vials are labelled with reduced requirements.
The telephone number of the sponsor and name, address and telephone number of the trial 
site are given in the subject information form. Examples of the labels will be available in the 
ISF.
Re-supply is planned.
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. Where necessary, 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 authorization 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 


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investigator / pharmacist / investigational drug storage manager must verify that no remaining 
supplies are in the investigator’s possession.
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. On Day 1 for all subjects and on Day 8, Day 15 and Day 22 for 
subjects receiving multiple doses of BI 655130, no food is allowed for at least 10 h before 
and 1.5 h after administration of the study drug (= end of infusion).
On all days of drug administration, starting from 1 hour before drug administration until 1.5 h 
after end of infusion liquid intake is not allowed. From breakfast until 24 hours post-dose 
water intake will be within 1000 to 3000 mL. Total fluid intake on all 24 hours inhouse days 
is recommended to be at least 1.5 liters and should not exceed 3.5 liters.
Smoking is not allowed during in-house confinement at the trial site. On the ambulatory days 
it is restricted to not more than 10 cigarettes or 3 cigars or 3 pipes per day
Methylxanthine-containing drinks or foods (such as coffee, tea, cola, energy drinks, and 
chocolate) are not allowed during inhouse confinement. Alcoholic beverages are not 
permitted starting 7 days before the first administration of trial medication until Day 28. 
From Day 28 onwards, alcohol consumption is restricted to 20 g alcohol per day 
corresponding to 0.5 L beer or 0.2 L of white wine per day.
Excessive physical activity (such as competitive sport) should be avoided starting 7 days 
before the first 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 655130 is the number [N (%)] of 
subjects with drug-related AEs.
Further criteria of interest:

AEs (including clinically relevant findings from the physical examination)

Safety laboratory tests

12-lead ECG

Continuous ECG monitoring

Vital signs (blood pressure, pulse rate)
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.
Adverse reaction
An adverse reaction is defined as a response to a medicinal product which is noxious and 
unintended. Response in this context means that a causal relationship between a medicinal 
product and an adverse event is at least a reasonable possibility. Adverse reactions may arise 
from use of the product within or outside the terms of the marketing authorisation or from 
occupational exposure. Conditions of use outside the marketing authorization include off-
label use, overdose, misuse, abuse and medication errors.


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Serious adverse event
A serious adverse event (SAE) is defined as any AE which:

results in death, 

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 to be 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.
Medical and scientific judgement should be exercised in deciding whether other situations 
should be considered serious reactions, such as important medical events that might not be 
immediately life threatening or result in death or hospitalisation but might jeopardise the 
patient or might require intervention to prevent one of the other outcomes listed above. 
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. Any suspected transmission via a medicinal product of 
an infectious agent is also considered a serious adverse reaction.
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 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.


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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 
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
The definition of an adverse reaction implies at least a reasonable possibility of a causal 
relationship between a suspected medicinal product and an adverse event. An adverse 
reaction, in contrast to an adverse event, is characterised by the fact that a causal relationship 
between a medicinal product and an occurrence is suspected.
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).


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
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.

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 


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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 
 may 
become aware of.
The REP for BI 655130, when measurable drug levels or PD effects are still likely to be 
present after the last administration, is not known at this early stage of development. 
Therefore, all AEs reported until the end of trial examination will be considered on treatment;
please see Section 7.3.3.
The follow-up period describes the period of time from the last administration of trial 
medication including the REP 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) to the 
sponsor’s unique entry point (country specific contact details will be provided in the ISF). 
The same timeline applies if follow-up information becomes available. In specific occasions 
the Investigator could inform the sponsor upfront via telephone. This does not replace the 
requirement to complete and fax the BI SAE form.
With receipt of any further information to these events, a follow-up SAE form has to be 
provided. For follow-up information the same rules and timeline apply as for initial 
information.
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 


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
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.
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.
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.


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Table 5.2.3: 1
Routine laboratory tests
Functional lab group
Test name 
Haematology
Haematocrit
Haemoglobin
Red blood cell count (RBC)
Reticulocyte count
White blood cell count (WBC)
Platelet count
Automatic WBC differential 
(relative and absolute cell count)
Neutrophils, eosinophils, basophils, monocytes, lymphocytes
Manual differential WBC (if automatic
differential WBC is abnormal)
Neutrophils (stabs), eosinophils, basophils, monocytes, 
lymphocytes 
Coagulation
Activated partial thromboplastin time (aPTT)
Prothrombin time (Quick’s test and INR)
Fibrinogen
Enzymes
Aspartate transaminase (AST/GOT)
Alanine transaminase (ALT/GPT)
Alkaline phosphatase (AP)
Gamma-glutamyl transferase (GGT)
Creatine kinase (CK)
CK-MB 
Lactate dehydrogenase (LDH)
Serum tryptase1
Hormones1
Thyroid stimulating hormone (TSH)
fT3, fT4
Substrates
Plasma glucose
Creatinine 
Total bilirubin 
Direct bilirubin
Total protein
Protein electrophoresis (only at screening examination)1
Albumin 
Alpha-1-Globulin
Alpha-2-Globulin
Beta-Globulin
Gamma-Globulin 
C-Reactive Protein (CRP)
Uric acid 
Total cholesterol 
Triglycerides
Electrolytes
Sodium
Potassium
Chloride
Calcium
Inorganic phosphate


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Table 5.2.3: 1
Routine laboratory tests (cont).
Functional lab group
Test name 
Urinalysis (Stix)
Urine nitrite
Urine protein
Urine glucose
Urine ketone
Urobilinogen
Urine bilirubin
Urine erythrocytes
Urine leukocytes
Urine pH
Urine sediment ( microscopic 
examination if urine analysis abnormal)
Only positive findings will be reported (for instance, the presence 
of sediment bacteria, casts in sediment, squamous epithelial cells,
erythrocytes, leukocytes)
1
Only at screening
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. Drug screening will be performed at screening and at admission to trial site the day 
prior to each treatment.
Table 5.2.3: 2
Exclusionary laboratory tests
Functional lab group
Test name 
Drug screening (urine)
Amphetamine/MDA
Barbiturates
Benzodiazepine
Cannabis
Cocaine
Opiates 
Infectious serology (blood)1
Hepatitis B surface antigen (qualitative)
Hepatitis B core antibody (qualitative)
Hepatitis C antibodies (qualitative)
HIV-1 and HIV-2 antibody (qualitative)
1
Only at screening
To encourage compliance with alcoholic restrictions, a breath alcohol test (Dräger Alcotest® 
6510 and Alcotest® 5510, Belgium) will be performed at screening and at start of the inhouse 
period (Day -1), and may be repeated at any time during the study at the discretion of an 
investigator or designate. The results will not be included in the CTR.
In case of a potential systemic allergic reaction blood samples for determination of serum 
tryptase will be collected 0.5 h, 2 h, 6 h and 24 h after onset of the event.
The laboratory tests listed in Tables 5.2.3: 1 and 5.2.3: 2 will be performed at ZNA Klinisch 
Laboratorium, Antwerpen, with the exception of the drug screening tests. These tests will be
performed at the trial site using “Alere Triage TOX Drug Screen”. Laboratory data will be 
transmitted electronically from the laboratory to the trial site.


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The cytokines IL1, IL6, TNF-and IFNwill be collected at baseline, 4h and 24h postdose
after each infusion (for all subjects on Day 1, for subjects receiving multiple doses also on 
Day 8/9, Day 14/15 and Day 22/23. The cytokine samples will be only analyzed in case of 
specific adverse events suggestive for cytokine release.
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 (MAC 5500, GE Healthcare) at the time points given in the 
Flow Chart.
In order to achieve a stable heart rate at rest and to assure high quality recordings at 
comparable resting phases, all ECGs will be recorded for a 10-sec duration after the subjects 
have rested for at least 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.
Triple ECGs (recorded within 180 sec) will be recorded as the baseline before any drug 
administration part up to 48 h after dosing. 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 analyzed by the central ECG lab, whereas the initially recorded ECGs will be 
discarded. 
Additional (unscheduled) ECGs may be collected by the investigator for safety reasons. 
These ECGs are assigned to the prior scheduled time point. Unscheduled ECGs will not be 
included into the statistical analysis of interval lengths. 
For the inclusion or exclusion (see Section 3.3) of a subject and for the assessment of cardiac 
safety during the 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 centralised evaluation (see below). In this case, these centrally 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. 


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In addition, a centralised evaluation of all 12-lead ECGs recorded from baseline up to 48 h 
after each dosing will be performed by an independent ECG laboratory. For this analysis, RR 
and QTall intervals will be determined semi-automatically, whereas PR and QRS intervals 
are determined by a validated GE 12-SL-algorithm or equivalent by the ECG core lab. Other 
parameters (e.g. cardiac axis) are determined by a validated GE 12-SL-algorithm or 
equivalent but do not undergo semi-automatic evaluation. For each QT interval, the RR 
interval preceding the QT will be measured to calculate the respective frequency corrected 
QTc intervals ‘QTcF’ according to Fridericia’s formula (QTcF = QT / RR1/3) and ‘QTcB’ 
according to Bazett’s formula (QTcB = QT / RR1/2). The QTcF correction will be used for 
evaluation and reporting. Abnormalities detected during centralised ECG evaluation will not 
necessarily qualify as AE. All interval measurements in one subject will be performed on the 
same lead. The intervals will be measured from four cardiac cycles (beats) in lead II. If lead 
II shows a flat T wave or is not measurable for any reason, lead V5 will be used, or if that 
lead is not measurable, then lead I will be used. The lead actually used will be reported in the 
CTR.
Within the ECG laboratory, the staff involved with ECG interval measurements and 
assessments will be blinded with regard to treatment, date and time as well as time points of 
the ECG measurements. The interval measurements for a given subject will be performed in 
random sequence by a single technician. No more than two different blinded readers will 
evaluate all ECGs of the study. For quality assurance and control of the measurements, all 
ECGs of a subject will be subsequently reviewed by the ECG technician supervisor or his/her 
designee with respect to the overall variance of the measured intervals, in order to detect 
accidentally switching of leads and/or false subject assignments of the ECGs. After the 
quality control the fiducial point markings will be reviewed by the cardiologist assigned to 
the study.
Assessed ECGs will comply with the ICH E14 guidance document and supplements 
[R05-2311], [R13-0801], [R13-4095] as well as the FDA requirements for annotated digital 
ECGs [R09-4830].
5.2.4.2
Continuous ECG monitoring and oxygen 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 2 h following start of 
infusion using the Dräger Telemetry monitoring system, Infinity M300. Oxygen saturation 
will be monitored by pulse oximetry using either Type NT1 handheld pulse oximeter from 
Newtech or Oxytrue A from Bluepoint Medical.
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 in healthy volunteers) will be measured by a blood 
pressure monitor (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 


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be made using the same type of blood pressure recording instrument on the same arm if 
possible.
5.2.5.2
Medical examinations
At the screening visit, the medical examination will include 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 with 
determination of weight.
5.2.5.3
Local tolerability
Local tolerability will be assessed by the investigator according to ‘swelling’, ‘induration’, 
‘heat’, ‘redness’, ‘pain’, or ‘other findings’.
5.2.5.4
Oral body temperature
Oral body temperature will be measured at the times indicated in the Flow Chart using a 
standard device.
5.3
OTHER
5.3.1
Pharmacogenomic evaluation
Not applicable.
5.3.2
Other endpoints
Not applicable.
5.3.3
Other assessments
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 and 
pharmacodynamic parameters 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 orally 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 and 


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pharmacodynamic parameters and measurements outlined in Section 5.6 and 5.7 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.
Exact time points of plasma sampling will be derived from electronic data capturing system 
LabPas and documented in the CRFs by the site personnel or sent as electronic files to the 
trial data manager. The actual sampling times will be used for determination of 
pharmacokinetic parameters.
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 500 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
Single dose part (20 mg/kg b.w.):

AUC0-∞(area under the concentration-time curve of the analyte in plasma over the 
time interval from 0 extrapolated to infinity)

Cmax (maximum measured concentration of the analyte in plasma)
Multiple dose part (3 mg/kg, 6 mg/kg, 10 mg/kg, 20 mg/kg b.w.):
After the first dose:

AUCτ,1 (area under the concentration-time curve of the analyte in plasma over a 
uniform dosing interval τ after administration of the first dose)

Cmax (maximum measured concentration of the analyte in plasma)
After the last dose:

AUCτ,ss (area under the concentration-time curve of the analyte in plasma at steady 
state over a uniform dosing interval τ)

Cmax,ss (maximum measured concentration of the analyte in plasma at steady state over 
a uniform dosing interval τ)


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5.5.2
Methods of sample collection
5.5.2.1
Plasma sampling for pharmacokinetic analysis
For quantification of BI 655130 plasma concentrations, approximately 3.0 mL of blood will 
be taken from a forearm vein into a K2EDTA (ethylendiaminetetraacetic acid) anticoagulant 
blood-drawing tube at the time points listed in the Flow Chart under plasma PK. 
Mix the K2EDTA-anticoagulated blood samples gently and place on ice until centrifugation 
at about +4°C. The blood should be centrifuged to produce plasma as soon as possible after 
collection, but not later than 30 minutes after withdrawal. Centrifugation will last for 
approximately 10 minutes (at 2000 to 4000 x g) at about +4°C. Two aliquots of EDTA 
plasma sample will be obtained in two labelled polypropylene cryotubes. At a minimum, the 
sample tube labels should list the following information: BI trial number, subject number, 
visit, PTM, aliquot #1 or #2, plasma and PK. 
The two aliquots should contain approximately 0.5 mL of plasma each. The plasma samples 
will be stored in a freezer set to -20°C or below at the clinical site(s) until shipment on dry ice 
to the central lab (with dry ice sufficient for at least 3 days transit), then stored in a freezer set 
to -20°C or below at the site until shipment to the analytical laboratory. Both aliquots will be 
shipped (in separate shipments with dry ice sufficient for 3 days transit) to the analytical 
laboratory for the determination of BI 655130. Both aliquots will be stored in in a freezer set 
to -20°C or below at the analytical laboratory until the finalization of the clinical trial report. 


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After completion of the trial the plasma samples may be used for further methodological 
investigations, e.g. for stability testing. However, only data related to the analyte will be 
generated by these additional investigations. The study samples will be discarded after 
completion of the additional investigations but not later than 5 years after the final study 
report has been signed.
5.5.2.2
Plasma sampling for ADA assessment 
For ADA assessment, approximately 3.0 mL of blood will be taken from a forearm vein into 
a K2EDTA anticoagulant blood-drawing tube at the time points listed in the Flow Chart
under plasma ADA. 
Mix the K2EDTA-anticoagulated blood samples gently and place on ice until centrifugation 
at approximately +4°C. The blood should be centrifuged to produce plasma as soon as 
possible after collection, but not later than 30 minutes after withdrawal. Centrifugation will 
last for approximately 10 minutes (at 2000 to 4000 x g) at approximately +4°C. Two aliquots 
of EDTA plasma samples will be obtained in two labelled (label to include: trial number, 
subject number, visit, PTM, aliquot #1 or #2, plasma, and ADA) polypropylene cryotubes. 
The two aliquots should contain approximately 0.5 mL of plasma each. The plasma samples 
will be stored in a freezer set to -20°C or below at the clinical site(s) until shipment on dry ice 
to the central lab (with dry ice sufficient for at least 3 days transit), then stored in a freezer set 
to -20°C or below at the central lab until shipment to the analytical laboratory. Both aliquots 
will be shipped (in separate shipments with dry ice sufficient for 3 days transit) to the 
analytical laboratory for assessment of potential ADA to BI 655130. Once received at the 
analytical laboratory, both aliquots will be stored in in a freezer set to -20°C or below.
After completion of the trial the plasma samples may be used for further methodological 
investigations, e.g. for stability testing. However, only data related to the anti-drug antibodies
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.
5.5.3
Analytical determinations
5.5.3.1
Analytical determination of BI 655130 plasma concentration
BI 655130 concentrations will be determined by a validated Gyros affinity flow-through 
immunoassay. Analyses will be performed at QPS in Newark, DE 19711, USA.
5.5.3.2
Assessment of ADA to BI 655130
The presence of ADA to BI 655130 will be assessed via their detection using a validated 
immunoassay in a tiered approach (screening, confirmatory, and titration analysis as 
appropriate). Analyses will be performed at Charles River Laboratories, US.


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5.7
PHARMACODYNAMICS
 
 
5.7.2
Methods of sample collection
Please refer to Section 5.6.3.
5.8
PHARMACOKINETIC - PHARMACODYNAMIC RELATIONSHIP
The PK and PD data from this study may be used for an exploratory investigation of PK/PD 
relationship of BI 655130, however, it is not planned to report the results of this investigation 
into the clinical trial report of this study. 


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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.
Multiple dose part 
Study measurements and assessments scheduled to occur ‘before’ trial medication 
administration on Day 1, 8, 15 and 22 are to be performed and completed within a 3h-period 
prior to the trial drug administration (including blank and trough values for PK and 
biomarkers).
The acceptable deviation from the scheduled time for vital signs and ECG will be:

±15 min up to including 12 h after dosing after each dosing

±30 min from 12h up to including 48 h after each dosing

±60 min from 48 h up to Day 7 after each dosing

±24h from 8 days after last dosing (=from Day 30 onwards) up to Day 92

±72h from Day 120 up to the last measurements
The tolerance for pharmacokinetic/laboratory parameters will be:

±1 min up to including 30 min after each dosing

±5 min up to including 12 h after each dosing

±15 min up to including 48 h after each dosing

±60 min from 48 h up to Day 7 after each dosing

±24h from 8 days after last dosing (=from Day 30 onwards) up to Day 92

±72h from Day 120 up to the last measurements
Single dose part 
Study measurements and assessments scheduled to occur ‘before’ trial medication 
administration on Day 1 are to be performed and completed within a 2 h-period prior to the 
trial drug administration (including blank values for PK and biomarkers).
The acceptable deviation from the scheduled time for vital signs and ECG will be:

±15 min up to including 12 h

±30 min from 12h up to including 48 h

±60 min from 48 h up to Day 8

±24h from Day 8 up to Day 71

±48h on Day 92

±72h from Day 120 up to the last measurements
The tolerance for pharmacokinetic/laboratory parameters will be:

±1 min up to including 30 min

±5 min up to including12 h

±15 min up to including 48 h


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
±60 min from 48 h up to Day 8

±24h from Day 8 up to Day 71

±48h on Day 92

±72h from Day 120 up to the last measurements
Single/multiple dose part
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.
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 
Blinded Report Planning Meeting.
6.2
DETAILS OF TRIAL PROCEDURES AT SELECTED VISITS
6.2.1
Screening 
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
Multiple dose part
Each subject will receive a single dose of BI 655130 or placebo once weekly during Visit 2 
on Day 1, Day 8, Day 15 and Day 22. 
Study participants will be admitted to the trial site in the evening before dosing (Day -1, Day 
7, Day 14, Day 21) and kept under close medical surveillance for at least 48 h following after 
each dosing. The subjects will be kept hospitalized from the evening of Day -1 to the 
morning of Day 3, the evening of Day 7 to the morning of Day 10, the evening of Day 14 to 
the morning of Day 17, the evening of Day 21 to morning of Day 24. On all other time 
periods the study will be performed in an ambulatory fashion provided there are no medical 
reasons preventing the discharge from the unit.
Single dose part
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 drug administration. The subjects will 
then be allowed to leave the trial site after formal assessment and confirmation of their fitness 


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by the investigator or
 designee. On all other study days, the study will be performed in an 
ambulatory fashion.
Single/multiple dose part
Trial medication will be administered as IV infusion by the investigating physician or 
 
designee. Details on treatments and procedures of administration are described in Section 
4.1.4.
For details on time points and procedures for collection of plasma analysis, refer to Flow 
Chart and Section 5.5.2.
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 and follow-up period
For AE assessment, laboratory tests, collection of PK and ADA samples, 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 treatment before the end of the planned 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
7.1.1
Objectives
The primary objective of this trial is to investigate the safety and tolerability of BI 655130 by 
using descriptive statistics for all endpoints comparing active dose groups to placebo in 
healthy male subjects. The study will also explore safety and tolerability following a single 
IV administration of 20 mg/kg b.w. The primary endpoint is defined in Section 5.2.1. 
Inferential statistics is not planned (as explained in Section 7.2).
Secondary objectives are the exploration of the pharmacokinetics of BI 655130 after single 
and multiple IV administration.
A further objective is the exploration of pharmacodynamics and the evaluation of additional 
pharmacokinetic parameters beyond those already covered in secondary objectives.
The secondary objective is the exploration of the pharmacokinetics (PK) and 
pharmacodynamics (PD) of BI 655130. Endpoints as specified in 5.5.1 and 5.7.1 will be 
analysed by descriptive statistics. Secondary endpoints as defined in Section 5.5.1.1 will be 
subjected to analysis of dose proportionality by use of the power model. Trough
concentration values will be analysed regarding attainment of steady state as a pre-requisite 
for calculation of steady state parameters. Additionally, the linearity index will be estimated. 
7.2
NULL AND ALTERNATIVE HYPOTHESES
Safety and tolerability of 5 different dose groups of BI 655130 (Section 3.1) 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
All individual data will be listed.
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 
protocol violations (IPVs) will be identified no later than in the Blinded Report Planning 
Meeting and provided in the TSAP.


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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). Analyses will be 
performed for parent drug.
Pharmacokinetic parameters of a subject will be included in the analysis unless the subject 
has an important protocol violation relevant for the evaluation. Whether a protocol violation 
is important will be decided no later than in the Blinded Report Planning Meeting. 
Reasons for exclusion of single pharmacokinetic parameters may be:

The subject experiences emesis at or before two times median tmax. Median tmax is to 
be determined for the test product excluding the subjects experiencing emesis.

The subject experiences emesis at any time during the labelled dosing interval.

Time deviations

Use of restricted medications 
The subject set for the evaluation of PK endpoints (PKS) will include all treated subjects that 
provide at least one observation for at least one secondary endpoint without important 
protocol violations with respect to the statistical evaluation of PK endpoints. It will be 
decided in the Blinded Report Planning Meeting which subjects are to be included in the 
PKS.
Excluded subjects will be listed with their individual plasma concentrations and individual 
pharmacokinetic parameters, however, will not be included in descriptive statistics for plasma 
concentrations, pharmacokinetic parameters or other statistical assessment.
Assessment of dose proportionality
Dose proportionality will be assessed using the pharmacokinetic endpoints as specified in 
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:
ij
i
ij
ε
X
β
α
Y






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where
ij
Y
logarithm of the pharmacokinetic endpoint for subject j at dose level i; 
where number of dose groups i = 1, 2, …, 4, and j = 1, 2, …, N where N 
is the number of subjects per dose group;

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.
Linearity index
Linearity with respect to multiple administration will be explored using the linearity index 
(LI) that will be computed as follows:



0
,
AUC
AUC
LI
ss

In order to construct a confidence interval for LI, a statistical model using AUCτ,ss  and  AUC 
0-∞will be set up: A linear model on the logarithmic scale including effects for 'subject' and 
'AUC type' can be applied, where 'subject' is a random and 'AUC type' a fixed effect.
[1]
 =  + 
 + s + e , where

logarithm of the response (AUC after first dose, AUC after last dose) for subject j
and AUC type i; where i = 1 (after first dose) or 2 (after last dose) and j=1, 2,…, n

the overall mean


the AUC type i
s
the effect associated with subject j (random effect)
e
random error associated with subject j at AUC type i (assumed to be independent 
and identically normally distributed).
A pairwise comparison of both areas via the log transformed difference
log(
,
∞) = log(,) - log(∞)


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will then be performed including calculation of a 2-sided 95% CI. The back transformed 
point estimate then represents the estimate of  LI. Perfect linearity with respect to multiple 
administrations holds true if this index equals unity.
Generally, this model will be applied to each dose level separately. If there is evidence that 
the areas are comparable across dose levels, they can be analysed simultaneously. The 
corresponding model will then include the log transformed dose as (additional) covariate
Attainment of steady state
Attainment of steady state will be explored for the three dose-groups undergoing multiple 
dose administrations by using the trough concentrations of BI 655130 between days 4 and 22
and the concentrations taken directly at the end of the first and the last dosing interval (Cτ,1, 
Cτ,22) for each dose level. Pairwise comparisons of concentrations are performed using 2-
sided 95% CIs based on the t-distribution. The calculation is based on a repeated measures 
linear model on the logarithmic scale.
 =  + 
 + s + e , where

logarithm of the concentrations for subject j at time i, i = 1, 2, …I and
j=1, 2,…, nk , where I is the number of measured time points and nk is the  
                       number of subjects in dose group k

the overall mean,


the effect associated with time point i (repeated effect),
s
(random) effect of subject j, j=1, 2, ..., nk,  where nk is the number of subjects in 
                        dose group k
e
random error associated with subject j at time i (assumed to be independent
and identically normally distributed).
Dose can be included as an additional covariate if there is evidence that the trough 
concentration profiles are comparable across dose levels.
The model will be used to explore the time to steady state by pairwise comparing 
concentrations from different time points: log-transformed differences between all 
subsequent time points (log(Cpre,i/Cpre,j) = log(Cpre,i) - log(Cpre,j), where j>i) will be compared 
and adjusted means (Least Squares Means) as well as 2-sided 95% CIs will be calculated. 
Thereafter, these quantities will be back-transformed by exponentiation to give the 
corresponding (adjusted) ratio and CI.
Comparisons which reveal CIs (for the adjusted ratio) not including 100% will be inspected 
to determine if the differences between time points are resulting from not yet attaining 
steady-state. 
For further details refer to the TSAP (such as selection of covariance structure and 
comparison of time points).


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Investigation of relative bioavailability for single i.v. dose of 20 mg/kg weight
The investigation of relative bioavailability will be done on the secondary pharmacokinetic 
endpoints listed in Section 5.5.1.1 for the 20 mg/kg of weight dose group. 
The statistical model used for the analysis of relative bioavailability of BI 655130 will be an 
ANOVA (analysis of variance) model on the logarithmic scale.
7.3.3
Safety analyses
Safety will be assessed for the endpoints listed in Section 5.2.1. All treated subjects (that is,
all subjects who received at least one dose of study drug), will be included in the safety 
evaluation. 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. Separate listings will be provided for subjects under multiple 
drug administration and the ones with a single dose of 20 mg/kg.
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 first intake of trial medication will 
be assigned to 'screening', those between first trial medication intake until the end of trial visit 
will be assigned to the treatment period, and those after the end of trial examination will be 
assigned to ‘post-study’. These assignments including the corresponding time intervals will 
be defined in detail in the TSAP.
Additionally, further treatment intervals (analysing treatments) may be defined in order to 
provide summary statistics for time intervals, such as combined treatments, on-treatment 
totals or periods without treatment effects (such as screening and post-study intervals).
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.
For vital signs, the differences from baseline will be evaluated.
A centralised evaluation of all 12-lead ECGs recordings (see Section 5.2.4) will be the basis 
for the derivation of further ECG parameters based on the ECG variables QT, HR, QTcF, 
QTcB, PR, QRS, and RR. The baseline value of an ECG variable is defined as the mean of 
the triple ECG measurements prior to drug administration. The derivation of the quantitative 
and qualitative ECG endpoints and their analyses will be described in the TSAP.


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7.3.4
Interim analyses
No interim analysis is planned.
7.3.5
Pharmacokinetic analyses
The pharmacokinetic parameters listed in Section 5.5.1 for drug BI 655130 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 7.3.1.) will be reported with their 
individual plasma and individual pharmacokinetic parameters; however, they will not be 
included in descriptive statistics for plasma, 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).
If a predose concentration value is greater than 5% of Cmax, the subject’s pharmacokinetic 
data will be not included in any statistical evaluations, in accordance with international 
guidances. The individual pharmacokinetic parameters of such a subject will be calculated 
and listed separately. If a predose concentration is above BLQ, but less than or equal to 5% of 
the subject’s Cmax value, the subject’s data without any adjustments will be included in all 
pharmacokinetic measurements and calculations.


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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/urine 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 analysed), BLQ (below the lower limit of quantification), or NOP (no peak 
detectable) will be displayed as such and not replaced by zero at any time point (this rule also 
applies also to the lag phase, including the predose values). 
7.4.3
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 
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.
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.


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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 40 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 considered as sufficient for the exploratory evaluation of multiple dose safety and 
pharmacokinetics [R95-0013].
Additional subjects may be entered to allow testing of intermediate doses within the planned 
and approved 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 40.


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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 SOPs.
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 terms and conditions of the insurance coverage must be given to 
each subject and are made available to the investigator via documentation 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/her 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 or her 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. See Section 4.1.5.2 for rules 
about emergency code breaks. For drug accountability, refer to Section 4.1.8.
8.3.1
Source documents
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.
8.3.3
Storage period of records
Trial site:
The trial site must retain the source and essential documents (including ISF) according to the 
national or local requirements (whatever is longer) valid at the time of the end of the trial.
Sponsor:
The sponsor must retain the essential documents according to the sponsor’s SOPs.
8.4
EXPEDITED REPORTING OF ADVERSE EVENTS
BI is responsible to fulfil their legal regulatory reporting obligation and in accordance to the 
requirements defined in this CTP.


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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
P16-06636
Denis Choquette, Rafat Faraawi et al., J Rheumatol 2015;42;1105-1111
R05-2311
ICH E14: the clinical evaluation of QT/QTc interval prolongation and 
proarrhythmic potential for non-antiarrhythmic drugs (ICH harmonized 
tripartite guideline, recommended for adoption at step 4 of the ICH 
process.on 12 May 2005 by the ICH Steering Committee). 
www.emea.eu.int; 2005. p. 1-14
R09-2768
Vargas HM, Bass AS, Breidenbach A, Feldman HS, Gintant GA, Harmer 
AR, Heath B, Hoffmann P, Lagrutta A, Leishman D, McMahon N, 
Mittelstadt S, Polonchuk L, Pugsley MK, Salata JJ, Valentin JP. Scientific 
review and recommendations on preclinical cardiovascular safety 
evaluation of biologics. J Pharmacol Toxicol Methods 2008;58(2):72-76.
R09-4830
Brown BD, Badilini F. HL7 aECG implementation guide (March 21, 2005).
R13-0801
E14 Clinical Evaluation of QT/QTc Interval Prolongation and 
Proarrhythmic Potential for Non-Antiarrhythmic Drugs - Questions and 
Answers (R1). October 2012. 
website.fda.gov/Drugs/GuidanceComplianceRegulatoryInformation/Guidan
ces/ucm323656.htm
R13-2231
Baumgart DC, Sandborn WJ. Crohn's disease. Lancet 2012;380:1590-1605.
R13-2269
Sandborn WJ. State-of-the-art: immunosuppression and biologic therapy. 
Dig Dis 2010;28:536-542.
R13-3046
Ordas I, Mould DR, Feagan BG, Sandborn WJ. Anti-TNF monoclonal 
antibodies in inflammatory bowel disease: pharmacokinetics-based dosing 
paradigms. Clin Pharmacol Ther 2012;91(4):635-646.
R13-4095
European Medicines Agency (EMA). Committee for Medicinal Products 
for Human Use (CHMP): ICH guideline E14 - questions and answers: step 
5 (May 2012, EMA/CHMP/ICH/310133/2008). 
website.ema.europa.eu/docs/en_GB/document_library/Scientific_guideline/
2009/09/WC500002878.pdf
R14-4037
Towne JE, Renshaw BR, Douangpanya J, Lipsky BP, Shen M, Gabel CA, 
Sims JE. Interleukin-36 (IL-36) ligands require processing for full agonist 
(IL-36alpha, IL-36beta, and IL-36gamma) or antagonist (IL-36Ra) activity. 
J Biol Chem 2011;286(49):42594-42602.
R14-5049
Kauffman AL, Gyurdieva AV, Mabus JR, Ferguson C, Yan Z, Hornby 
PJ.Alternative functional in vitro models of human intestinal epithelia. 
Front Pharmacol 2013;4:79.


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R14-5051
Fischer A, Gluth M, Pape UF, Wiedenmann B, Theuring F, Baumgart DC. 
Adalimumab prevents barrier dysfunction and antagonizes distinct effects 
of TNF-alpha on tight junction proteins and signaling pathways in intestinal 
epithelial cells. Am J Physiol 2013;304:G970-G979.
R14-5158
Marrakchi S, et al. Interleukin-36-receptor antagonist deficiency and
generalized pustular psoriasis. N Engl J Med 2011;365(7):620-628.
R15-1343
Loftus EV. Clinical epidemiology of inflammatory bowel disease: 
incidence, prevalence, and environmental influences. Gastroenterology 
2004;126(6):1504-1517.
R15-1399
Blumberg H, Dinh H, Dean C, Trueblood ES, Beiley K, Shows D, 
Bhagavathula N, Aslam MN, Varani J, Towne JE, Sims JE. IL-1RL2 and 
its ligands contribute to the cytokine network in psoriasis. J Immunol 
2010;185(7):4354-4362.
R15-1421
Onouofriadis A, Simpson MA, Pink AE, Meglio P di, Smith CH, 
Pullabhatla V, Knight J, Spain SL, Nestle FO, Burden AD, Capon F,
Trembath RC, Barker JN. Mutations in IL36RN/IL1F5 are associated with 
the severe episodic inflammatory skin disease known as generalized 
pustular psoriasis. Am J Hum Genet 2011;89(3):432-437.
R15-1432
Blumberg H, Dinh H, Trueblood ES, Pretorius J, Kugler D, Weng N, 
Kanaly ST, Towne JE, Willis CR, Kuechle MK, Sims JE, Peschon JJ. 
Opposing activities of two novel members of the IL-1 ligand family 
regulate skin inflammation. J Exp Med 2007;204(11):2603-2614.
R15-1447
Tortola L, Rosenwald E, Abel B, Blumberg H, Schaefer M, Coyle AJ,
Renauld JC, Werner S, Kisielow J, Kopf M. Psoriasiform dermatitis is 
driven by IL-36-mediated DC-keratinocyte crosstalk. J Clin Invest
2012;122(11):3965-3976.
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.
9.2
UNPUBLISHED REFERENCES
001-MCS-36-472.Standards and processes for analyses performed within Clinical 
Pharmacokinetics/Pharmacodynamics. Current version
c03320876
 Investigator's Brochure BI 655130 
c03361085-07
 Single-blind, partially randomised, 
placebo-controlled Phase I study to investigate safety, tolerability, 
pharmacokinetics and pharmacodynamics of single rising intravenous doses 
of BI 655130 in healthy male volunteers, 1368.1, 27 Jan 2016.


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10.
APPENDICES
10.1
CLINICAL EVALUATION OF LIVER INJURY
10.1.1
Introduction
Alterations of liver laboratory parameters, as described in Section 5.2.2.1 (Protocol-specified 
AESIs), are to be further evaluated using the following procedures:
10.1.2
Procedures
Repeat the following laboratory tests: ALT, AST, and bilirubin (total and direct) - within 48 
to 72 h. If it is confirmed that ALT and/or AST values ≥3 fold ULN occur in conjunction 
with an elevation of total bilirubin of ≥2 fold ULN, the laboratory parameters listed below 
(clinical chemistry, serology, hormones, haematology) must be determined and made 
available to the investigator and to BI as soon as possible.
In addition, 

obtain a detailed history of current symptoms and concurrent diagnoses and medical 
history according to the ‘DILI checklist’ provided in the ISF 

obtain history of concomitant drug use (including non-prescription medications, 
herbal and dietary supplement preparations), alcohol use, recreational drug use, and 
special diets according to the ‘DILI checklist’ provided in the ISF;

obtain a history of exposure to environmental chemical agents (consider home and 
work place exposure) according to the ‘DILI checklist’ provided in the ISF;
and report these via the CRF.
Clinical chemistry
Alkaline phosphatase, albumin, PT or INR, CK, CK-MB, coeruloplasmin, α-1 antitrypsin, 
transferin, amylase, lipase, fasting glucose, cholesterol, triglycerides
Serology
Hepatitis A (Anti-IgM, Anti-IgG), Hepatitis B (HbsAg, Anti-HBs, DNA), Hepatitis C (Anti-
HCV, RNA if Anti-HCV positive), Hepatitis D (Anti-IgM, Anti-IgG), Hepatitis E (Anti-
HEV, Anti-HEV IgM, RNA if Anti-HEV IgM positive), Anti-Smooth Muscle antibody 
(titer), Anti-nuclear antibody (titer), Anti-LKM (liver-kidney microsomes) antibody, Anti-
mitochondrial antibody
Epstein Barr Virus (VCA IgG, VCA IgM), cytomegalovirus (IgG, IgM), herpes simplex virus 
(IgG, IgM), varicella (IgG, IgM), parvovirus (IgG, IgM), toxoplasmosis (IgG, IgM)
Hormones, tumormarker
TSH


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Haematology
Thrombocytes, eosinophils

Provide abdominal ultrasound to rule out biliary tract, pancreatic or intrahepatic 
pathology, e.g. bile duct stones or neoplasm.

Initiate close observation of subjects by repeat testing of ALT, AST, and total 
bilirubin (total and direct) at least weekly until the laboratory ALT and/or AST 
abnormalities stabilize or return to normal, then monitor further as specified in the 
CTP. Depending on further laboratory changes, additional parameters identified e.g. 
by reflex testing will be followed up based on medical judgement and Good Clinical 
Practices (GCP).


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10.2
RECONSTITUTION INSTRUCTION(S)
Preparation instructions for 3 mg/kg dose (drug concentration in infusion solution 5 mg/mL BI 655130):
Necessary Materials:
Drug Product and Dilution Media:
3 vials BI 655130 Solution for Infusion 20 mg/mL (correlates to 3 x 150 mg BI 655130)
1 bottle 0.9% sodium chloride solution (e.g. 500 mL, B.Braun, 401734)
Consumables:
1 x Blunt Fill needle 18 G (material: stainless steel/Polypropylene - e.g. BD, 305180)
2 x 1 mL syringe (material: Polycarbonate/Polypropylene - e.g. BD, 309628)
1 x 10 mL syringe (material: Polypropylene - e.g. BD, 300912)
2 x 20 mL syringe (material: Polypropylene - e.g. BD, 300629) 
1 x 50 mL syringe (material: Polypropylene - e.g. Omnifix B.Braun, 4617509F) 
5 x syringe closure (material: Polyethylene - e.g. Combi-Stopper B.Braun, 4495101)
4 x Spike (material: Polyolefine - e.g. Mini-Spike, 0.45 µm Air Filter B.Braun, 4550242)
Empty EVA (Ethylene vinyl acetate) infusion bag: 
e.g. Freka Mix Monolayer (Fresenius-Kabi, F2859061)
Preparation overview:
Dilution: 22.5 mL of BI 655130 Solution for Infusion 20 mg/mL + 67.5 mL 0.9% sodium chloride 90 mL 5.0 
mg/mL BI 655130 (in infusion bag)
1)
Put a Mini-Spike on a bottle containing 500 mL 0.9% sodium chloride solution
2)
Attach a 50 mL syringe to the Mini-Spike, withdraw 50 mL of the 0.9% sodium chloride Solution and 
disconnect the filled syringe. Close it with a Combi-Stopper.
3)
Attach a 20 mL syringe to the Mini-Spike, withdraw 17.0 mL of the 0.9% sodium chloride solution and 
disconnect the filled syringe. Close it with a Combi-Stopper. 
4)
Attach a 1 ml syringe to the Mini-Spike, withdraw 0.5 mL of the sodium chloride solution and 
disconnect the filled syringe. Close it with a Combi-Stopper.
5)
Put a Mini-Spike on each of two vials containing BI 655130 Solution for Infusion 20 mg/mL and 
connect one 20 mL syringe to the Mini-Spike. 
6)
Withdraw 7.5 mL of BI 655130 Solution for Infusion 20 mg/mL from each of the two so the total 
volume in the syringe is 15.0 mL (= 300 mg BI 655130).
7)
Disconnect the syringe and lock the syringe with a Combi-Stopper. 
8)
Put a Mini-Spike on the third vial containing BI 655130 Solution for Infusion 20 mg/mL and connect 
one 10 mL syringe to the Mini-Spike.
9)
withdraw 7.0 mL of BI 655130 Solution for Infusion 20 mg/mL from the vial (= 140 mg BI 655130)
10) Disconnect the syringe and lock the syringe with a Combi-Stopper.
11) Attach a 1 mL syringe to the Mini-Spike, withdraw 0.5 mL of BI 655130 Solution for Infusion 
20mg/mL from the vial (= 10 mg BI 655130) and disconnect the filled syringe. Close it with a Combi-
Stopper.
12) Lock the fill port of the empty infusion bag close to the bag. Open the injection port of the bag.
13) Remove the Combi-Stopper from the syringe obtained in step 6, attach an 18 G needle and transfer the 
complete contents of the syringe into the infusion bag via the injection port.
14) Disconnect the empty syringe from the needle and close the needle using a Combi-Stopper. Keep bag 
in an upright position to prevent leakage.


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15) Connect consecutively the second syringe containing BI 655130 Solution for Infusion (step 9) to the 
needle of the infusion bag containing BI 655130 Solution for Infusion 20 mg/mL (step 13) and transfer 
the content of the syringes completely into the infusion bag. Disconnect the empty syringe.
16) Connect the third syringe containing BI 655130 Solution for Infusion (step 11) to the needle of the 
infusion bag containing BI 655130 Solution for Infusion 20 mg/mL (step 12) and transfer the content 
of the syringe completely into the infusion bag. Disconnect the empty syringe.
17) Connect consecutively the syringes containing 0.9% sodium chloride solution (step 2,  3 and 4) to the 
needle of the infusion bag containing BI 655130 Solution for Infusion 20 mg/mL (step 13) and transfer 
the contents of the syringes completely into the infusion bag. Disconnect the empty syringe.
18) Remove the needle and mix solution in the bag by gently kneading and turning it.


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Preparation instructions for 6 mg/kg dose (drug concentration in infusion solution 10 mg/mL BI 655130):
Necessary Materials:
Drug Product and Dilution Media:
6 vials BI 655130 Solution for Infusion 20 mg/mL (correlates to 6 x 150 mg BI 655130)
1 bottle 0.9% sodium chloride solution (e.g. 500 mL, B.Braun, 401734)
Consumables:
1 x Blunt Fill needle 18 G (material: Stainless Steel/Polypropylene - e.g. BD, 305180)
2 x 50 mL syringe (material: Polypropylene - e.g. Omnifix B.Braun, 4617509F) 
3 x syringe closure (material: Polyethylene - e.g. Combi-Stopper B.Braun, 4495101)
7 x Spike (material: Polyolefine - e.g. Mini-Spike, 0.45 µm Air Filter B.Braun, 4550242)
Empty EVA (Ethylene vinyl acetate) infusion bag: 
e.g. Freka Mix Monolayer (Fresenius-Kabi, F2859061)
Preparation overview:
Dilution: 45 mL of BI 655130 Solution for Infusion 20 mg/mL + 45 mL 0.9% sodium chloride 90 mL 10.0 
mg/mL BI 655130 (in infusion bag)
1)
Put a Mini-Spike on a bottle containing 500 mL 0.9% sodium chloride solution
2)
Attach a 50 mL syringe to the Mini-Spike, withdraw 45 mL of the 0.9% sodium chloride Solution and 
disconnect the filled syringe. Close it with a Combi-Stopper.
3)
Put a Mini-Spike on each of the 6 vials containing BI 655130 Solution for Infusion 20 mg/mL and 
connect one 50 mL syringe to the Mini-Spike.
4)
Withdraw 7.5 mL of BI 655130 Solution for Infusion 20 mg/mL from each of the 6 vials so the total 
volume in the syringe is 45.0 mL (= 900 mg BI 655130).
5)
Disconnect the syringe and lock the syringe with a Combi-Stopper.
6)
Lock the fill port of the empty infusion bag close to the bag. Open the injection port of the bag.
7)
Remove the Combi-Stopper from the syringe obtained in step 4, attach an 18 G needle and transfer the 
complete contents of the syringe into the infusion bag via the injection port.
8)
Disconnect the empty syringe from the needle and close the needle using a Combi-Stopper. Keep bag 
in an upright position to prevent leakage. 
9)
Connect the syringe containing 0.9% sodium chloride solution (step 2) to the needle of the infusion bag 
containing BI 655130 Solution for Infusion 20 mg/mL (step 8) and transfer the contents of the syringe 
completely into the infusion bag. Disconnect the empty syringe.
10) Remove the needle and mix solution in the bag by gently kneading and turning it.


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Preparation instructions for 10 mg/kg dose (drug concentration in infusion solution 20 mg/mL 
BI 655130):
Necessary Materials:
Drug Product:
10 vials BI 655130 Solution for Infusion 20 mg/mL (correlates to 10 x 150 mg BI 655130)
Consumables:
1 x Blunt Fill needle 18 G (material: Stainless Steel/Polypropylene - e.g. BD, 305180)
2 x 50 mL syringe (material: Polypropylene - e.g. Omnifix B.Braun, 4617509F) 
3 x syringe closure (material: Polyethylene - e.g. Combi-Stopper B.Braun, 4495101) 
10 x Spike (material: Polyolefine - e.g. Mini-Spike, 0.45 μm Air Filter B.Braun, 4550242)
Empty EVA (Ethylene vinyl acetate) infusion bag: 
e.g. Freka Mix Monolayer (Fresenius-Kabi, F2859061)
Preparation overview:
75 mL of BI 655130 Solution for Infusion 20 mg/mL 20.0 mg/mL BI 655130 (in infusion bag)
1)
Put a Mini-Spike on each of 10 vials containing BI 655130 Solution for Infusion 20 mg/mL and connect 
one 50 mL syringe to one of the Mini-Spikes. 
2)
Withdraw 7.5 mL of BI 655130 Solution for Infusion 20 mg/mL from each of 6 vials so the total volume 
in the syringe is 45 mL (= 900 mg BI 655130). 
3)
Disconnect the syringe and lock the syringe with a Combi-Stopper. 
4)
Withdraw 7.5 mL of BI 655130 Solution for Infusion 20 mg/mL from each of 4 vials so the total volume 
in the syringe is 30 mL (= 600 mg BI 655130).
5)
Disconnect the syringe and lock the syringe with a Combi-Stopper. 
6)
Lock the fill port of the empty infusion bag close to the bag. Open the injection port of the bag. 
7)
Remove the Combi-Stopper from the syringe obtained in step 3, attach an 18 G needle and transfer the 
complete contents of the syringe into the infusion bag via the injection port. 
8)
Disconnect the empty syringe from the needle and close the needle using a Combi-Stopper. Keep bag in 
an upright position to prevent leakage. 
9)
Connect consecutively the second syringe containing BI 655130 Solution for Infusion (step 5) to the 
needle of the infusion bag containing BI 655130 Solution for Infusion 20 mg/mL (step 7) and transfer 
the content of the syringes completely into the infusion bag. Disconnect the empty syringe.
10) Remove the needle.


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Preparation instructions for 20 mg/kg dose (drug concentration in infusion solution 20 mg/mL 
BI 655130):
Necessary Materials:
Drug Product:
17 vials BI 655130 Solution for Infusion 20 mg/mL (correlates to 17 x 150 mg BI 655130)
Consumables:
1 x Blunt Fill needle 18 G (material: Stainless Steel/Polypropylene - e.g. BD, 305180)
3 x 50 mL syringe (material: Polypropylene - e.g. Omnifix B.Braun, 4617509F) 
4 x syringe closure (material: Polyethylene - e.g. Combi-Stopper B.Braun, 4495101)
17 x Spike (material: Polyolefine - e.g. Mini-Spike, 0.45 µm Air Filter B.Braun, 4550242)
Empty EVA (Ethylene vinyl acetate) infusion bag: 
e.g. Freka Mix Monolayer (Fresenius-Kabi, F2859061)
Preparation overview:
125 mL of BI 655130 Solution for Infusion 20 mg/mL 20.0 mg/mL BI 655130 (in infusion bag)
1)
Put a Mini-Spike on each of 6 vials containing BI 655130 Solution for Infusion 20 mg/mL and connect 
one 50 mL syringe to one of the Mini-Spikes.
2)
Withdraw 7.5 mL of BI 655130 Solution for Infusion 20 mg/mL from each of 6 vials so the total volume 
in the syringe is 45 mL (= 900 mg BI 655130).
3)
Disconnect the syringe and lock the syringe with a Combi-Stopper.
4)
Repeat Steps 1-3.
5)
Put a Mini-Spike on each of 5 vials containing BI 655130 Solution for Infusion 20 mg/mL and connect 
one 50 mL syringe to the Mini-Spike.
6)
Withdraw 7.5 mL of BI 655130 Solution for Infusion 20 mg/mL from each of 4 vials and 5 mL from a 
5th vial so the total volume in the syringe is 35 mL (= 700 mg BI 655130).
7)
Disconnect the syringe and lock the syringe with a Combi-Stopper.
8)
Lock the fill port of the empty infusion bag close to the bag. Open the injection port of the bag.
9)
Remove the Combi-Stopper from the syringe obtained in step 3, attach an 18 G needle and transfer the 
complete content of the syringe in the infusion bag via the injection port.
10) Disconnect the empty syringe from the needle and close the needle using a Combi-Stopper. Keep bag in 
an upright position to prevent leakage.
11) Connect consecutively the second syringe containing BI 655130 Solution for Infusion (step 4) to the 
needle of the infusion bag containing BI 655130 Solution for Infusion 20 mg/mL (step 10) and transfer 
the content of the syringe completely into the infusion bag. Disconnect the empty syringe. Close the 
needle using a Combi-Stopper.
12) Connect the third syringe containing BI 655130 Solution for Infusion (step 7) to the needle of the 
infusion bag containing BI 655130 Solution for Infusion 20 mg/mL (step 11) and transfer the content of 
the syringes completely into the infusion bag. Disconnect the empty syringe.
13) Remove the needle.


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Infusion Information:
Dose (mg/kg)
In-line Filter
Used?
Approximate 
Pre-flush 
Volume (mL)
Concentration 
of the ready to 
use i.v. bag BI 
655130  
(mg/mL)
Volume 
Delivered 
(mL/kg body 
weight)
Infusion Time 
(min)
3
Yes
30
5
0.6
Up to 240
6
Yes
15
10
0.6
Up to 240
10
Yes
15
20
0.5
Up to 240
20
Yes
15
20
1
Up to 240
After preparation, the solution for infusion may be stored at 2-8°C for up to 24 hours. After 
removal from 2-8°C storage or preparation, the solution must be administered within 60 
minutes if stored at  ≤25°C. Do not freeze.
Chemical and physical in-use stability has been demonstrated for 60 minutes at ≤ 25°C.  In 
addition the time for infusion must not exceed 240 minutes at ≤25°C.
From a microbiological point of view the drug should be used immediately.  If not used 
immediately, the in-use storage times and conditions prior to use are the responsibility of the 
user, and would normally not be longer than 24 hours at 2-8°C (36-46°F), unless preparation 
has taken place in controlled and validated aseptic conditions.


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11.
DESCRIPTION OF GLOBAL AMENDMENT(S)
Number of global amendment
1
Date of CTP revision
11 Oct 2016
EudraCT number
2016-001235-12
BI Trial number
1368.2
BI Investigational Product(s)
BI 655130
Title of protocol
Safety, tolerability, pharmacokinetics and 
pharmacodynamics of multiple rising intravenous 
doses of BI 655130 (double-blind, partially 
randomised within dose groups, placebo-
controlled parallel group design) and one single 
intravenous dose of BI 655130 (single-blind, 
partially randomised, placebo-controlled) in 
healthy male subjects
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. Synopsis; Flow Chart; Section 2.3 ; 
Section 3.3.4 ; Section 4.1.4
2. Section 10.2
3. Section 10.2
4. Flow Chart ; Section 6.1
5. Section 1.2.5 ; Section 3.1 ; Section 4.1.4 ; 
Section 4.1.5.1 ; Section 5.2.3 ; Section 
5.2.4 ; Section 6.1 ; Section 6.2.2
6. Section 5.5.2.2
7. Section 1.2.5


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Number of global amendment
1
Description of change
1. Infusion time for dose groups 10 mg/kg 
b.w. multiple doses and 20 mg/kg b.w. 
single dose was prolonged to 60 minutes
2. Update of reconstitution instructions:
a.
1 mL syringe was added in 3 mg 
dose group
b. Material information for 
consumables was added
c.
Infusion time was updated
3. Update of stability of reconstituted/diluted 
solution / In-Use-Stability
4. Update of study flow chart:
a.
Additional visits for follow-up 
observation (until 20 weeks after 
last dosing) with respective time-
windows were included for all 
dose groups
b. Infusion time for dose group 10 
mg/kg b.w. multiple doses and 20 
mg/kg b.w. single dose was 
extended to 60 minutes.
c.
Body weight measurement was  
included at visit 2/day -2
d. Time window for procedures 
performed before drug 
administration was adapted
5. Correction of inconsistencies and typing 
errors throughout the document
6. Update regarding blood sampling
7. Update to align with final data after 
database lock in July 2016
Rationale for change
1. Updated In-Use Stability Study with date 
from 24 August 2016
2. Updated In-Use Stability Study with date 
from 24 August 2016
3. Updated In-Use Stability Study with date 
from 24 August 2016
4.
a.
PK results from 1368.1 trial
suggest a half-life of BI 655130 of 
about 4 weeks for doses tested in 
the study. The evaluation is 
ongoing. However as 
precautionary measure we have 


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Number of global amendment
1
extended the observation period to 
Day 176 to cover at least 5 half-
lifes
b. Updated In-Use Stability Study 
with date from 24 August 2016
c.
Correction to align with eCRF
d. For logistical reasons
5. A few inconsistencies and typing errors 
were corrected
6. Left over blood samples will be discarded 
after 5 years instead of 3 years
7. Data were aligned with final data after 
database lock


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Number of global amendment
2
Date of CTP revision
05 Dec 2016
EudraCT number
2016-001235-12
BI Trial number
1368.2
BI Investigational Product(s)
BI 655130
Title of protocol
Safety, tolerability, pharmacokinetics and 
pharmacodynamics of multiple rising intravenous 
doses of BI 655130 (double-blind, partially 
randomised within dose groups, placebo-
controlled parallel group design) and one single 
intravenous dose of BI 655130 (single-blind, 
partially randomised, placebo-controlled) in 
healthy male subjects
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. Synopsis, Flow Chart, Section 2.1, Section 
2.2, Section 2.3, Section 3.1, Section 3.2, 
Section 3.3, Section 3.3.4, Section 4.1.2, 
Section 4.1.4, Section 5.5.1.1 and Section 
7.6 
Description of change
1. 20 mg/kg b.w. MRD (multiple dose 
group) added. To limit the amount of 
protein infused per minute the infusion 
time was prolonged to 90 minutes. Blood 
volume withdrawn during the study 
increases from 400 ml to 430 ml.
2. A few inconsistencies and typing errors 
were corrected throughout the document.
Rationale for change
1. This optional final dose group of 20 


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Number of global amendment
2
mg/kg multiple dose may further widen 
the safety margin in patients with 
who may require higher doses ≥ 10 mg/kg 
due to protein loss, up-regulation of the 
target, and a potentially higher clearance. 
The prolongation of the infusion time to 
90 minutes has been implemented to 
reduce the theoretical risk of an infusion 
reaction.
2. With amendment number 2 a few 
inconsistencies and typing errors were 
corrected throughout the document.


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Number of global amendment
3
Date of CTP revision
02 August 2017
EudraCT number
2016-001235-12
BI Trial number
1368.2
BI Investigational Product(s)
BI 655130
Title of protocol
Safety, tolerability, pharmacokinetics and 
pharmacodynamics of multiple rising intravenous 
doses of BI 655130 (double-blind, partially 
randomised within dose groups, placebo-
controlled parallel group design) and one single 
intravenous dose of BI 655130 (single-blind, 
partially randomised, placebo-controlled) in 
healthy male subjects
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. Abbreviations
2. Section 5.5.3.1
Description of change
The PK testing platform will change from 
ELISA (enzyme linked immunosorbent assay) 
to Gyros affinity flow-through immunoassay.
The PK testing will be conducted at QPS, 
Newark, DE 19711, USA.
Rationale for change
Logistical reasons.


 
 
 
 
APPROVAL / SIGNATURE PAGE 
 
Document Number: 
 
Technical Version Number:
 
Document Name: 
 
 
 
                                                                                                                 
 
Title: 
 
 
 
 
                                                                                                                   
 
Signatures (obtained electronically) 
 
Meaning of Signature  
Signed by 
Date Signed 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
c09105854
5.0
clinical-trial-protocol-revision-03
Safety, tolerability, pharmacokinetics and pharmacodynamics of multiple rising
intravenous doses of BI 655130 (double-blind, partially randomised within dose
groups, placebo-controlled parallel group design) and one single intravenous dose of
BI 655130(single-blind, partially randomised, placebo-controlled) in healthy male
subjects
Author-Trial Statistician
02 Aug 2017 10:54 CEST
Approval-Team Member Medicine
02 Aug 2017 11:11 CEST
Approval-Therapeutic Area 
02 Aug 2017 14:51 CEST
Author-Trial Clinical
Pharmacokineticist
02 Aug 2017 15:10 CEST
Author-Trial Clinical Monitor
03 Aug 2017 09:44 CEST
Verification-Paper Signature
Completion
10 Aug 2017 14:35 CEST


Boehringer Ingelheim 
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Document Number: 
 Technical Version Number:
 
 
 
(Continued) Signatures (obtained electronically) 
 
Meaning of Signature  
Signed by 
Date Signed 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
c09105854
5.0

SAP_001.pdf: 
TITLE PAGE
Trial Statistical Analysis Plan
c19081897-01
BI Trial No.:
1368.2
Title:
Safety, tolerability, pharmacokinetics and pharmacodynamics of 
multiple rising intravenous doses of BI 655130 (double-blind, 
partially randomised within dose groups, placebo-controlled 
parallel group design) and one single intravenous dose of BI 
655130 (single-blind, partially randomised, placebo-controlled) in 
healthy male subjects
Final Protocol (including protocol revisions 1, 2 and 3 (c09105854-
05))
Investigational
Product:
BI 655130
Responsible trial 
statisticians:
Phone: 
Fax:
Phone:
Fax: 
Date of statistical 
analysis plan:
07 SEP 2017 SIGNED
Version:
Final
Page 1 of 35
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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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1.
TABLE OF CONTENTS
TITLE PAGE ...........................................................................................................................1
1.
TABLE OF CONTENTS......................................................................................2
LIST OF TABLES...................................................................................................................4
2.
LIST OF ABBREVIATIONS ..............................................................................5
3.
INTRODUCTION.................................................................................................8
4.
CHANGES IN THE PLANNED ANALYSIS OF THE STUDY......................9
5.
ENDPOINTS .......................................................................................................10
5.1
PRIMARY ENDPOINTS...................................................................................10
5.2
SECONDARY ENDPOINT ...............................................................................10
5.2.1
Key secondary endpoint .....................................................................................10
5.2.2
Secondary endpoint.............................................................................................10
5.3.2
Safety parameters ...............................................................................................10
5.4
OTHER VARIABLES........................................................................................12
5.4.1
Demographic and other baseline characteristics .............................................12
5.4.2
Treatment compliance and treatment exposure ..............................................13
6.
GENERAL ANALYSIS DEFINITIONS ..........................................................14
6.1
TREATMENTS...................................................................................................14
6.2
IMPORTANT PROTOCOL VIOLATIONS ...................................................15
6.3
SUBJECT SETS ANALYSED...........................................................................17
....................................................................................................18
6.5
POOLING OF CENTRES .................................................................................18
6.6
HANDLING OF MISSING DATA AND OUTLIERS....................................18
6.7
BASELINE, TIME WINDOWS AND CALCULATED VISITS ...................19
6.7.1
Time points and baseline for analysis of 12-lead ECG....................................19
6.7.2
Baseline in all other analyses..............................................................................20
6.7.3
Time windows for measurements......................................................................20
6.7.4
Pooled time points for comparison of endpoints at end of infusion ...............20
7.
PLANNED ANALYSIS......................................................................................22
7.1
DEMOGRAPHIC AND OTHER BASELINE CHARACTERISTICS.........22
7.2
CONCOMITANT DISEASES AND MEDICATION .....................................22
7.3
TREATMENT COMPLIANCE........................................................................23
7.4
PRIMARY ENDPOINTS...................................................................................23
7.5
SECONDARY ENDPOINT ...............................................................................23
7.5.1
Key secondary endpoint .....................................................................................23
7.5.2
Secondary endpoints...........................................................................................23
.............................................................................24
.............................................................................24


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..........................................24
..........................................24
..........................................25
7.7
EXTENT OF EXPOSURE.................................................................................25
7.8
SAFETY ANALYSIS..........................................................................................25
7.8.1
Adverse events.....................................................................................................25
7.8.2
Laboratory data ..................................................................................................27
7.8.3
Vital signs.............................................................................................................27
7.8.4
ECG......................................................................................................................27
7.8.5
Local tolerability .................................................................................................29
7.8.6
Others...................................................................................................................30
8.
REFERENCES....................................................................................................31
9.
ADDITIONAL SECTIONS ...............................................................................32
9.1
DETAILED DESCRIPTION OF ENDPOINTS FOR ECG...........................32
9.2
STEPS IN CASE OF CONVERGENCE PROBLEMS FOR REPEATED 
MEASURES MODEL IN ECG .........................................................................34
10.
HISTORY TABLE..............................................................................................35


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LIST OF TABLES
Table 6.1: 1
Flow chart of analysis phases for statistical analyses of AEs, safety 
laboratory data, vital signs and ECG................................................................14
Table 6.2: 1
Important protocol violations...........................................................................16
Table 6.3: 1
Subject sets analysed........................................................................................18
Table 6.7.1: 1 Time schedule of 12-lead ECG recordings with centralised evaluation ..........19
Table 6.7.4: 1 Duration of infusion .........................................................................................20
Table 6.7.4: 2 Time points for statistical analysis of vital signs, body temperature, ECG 
and biomarkers .................................................................................................21
Table 10: 1
History table .....................................................................................................35


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2.
LIST OF ABBREVIATIONS
Term
Definition / description
ADPC
Proper name of the analysis dataset containing PK concentrations per 
time-point or per time-interval
ADPP
Proper name of the analysis dataset containing calculated PK 
parameters
ADS
Analysis dataset
AE
Adverse event
AESI
Adverse event of special interest
AIC
Akaike's information criterion
ALT
Alanine aminotransferase
AST
Aspartate aminotransferase
AUC0-∞
Area under the concentration-time curve of the analyte in plasma over 
the time interval from 0 extrapolated to infinity
AUC,ss
Area under the concentration-time curve of the analyte in plasma at 
steady state over a uniform dosing interval τ
AUC,1
Area under the concentration-time curve of the analyte in plasma over 
a uniform dosing interval τ after administration of the first dose
AUECabove
Area above the biomarker effect vs. time curve above the baseline 
during the treatment interval
AUECbelow
Area under the biomarker effect vs. time curve below the baseline 
during the treatment interval
AUECdiff
Difference between AUECbelow and AUECabove
BI
Boehringer Ingelheim
BLQ
Below the lower limit of quantification
BMI
Body mass index
BMS
Biomarker set
CARE
Clinical data analysis and reporting environment
CI
Confidence interval
Cmax
Maximum measured concentration of the analyte in plasma after 
administration of the first dose
Cmax,ss
Maximum measured concentration of the analyte in plasma at steady 
state
CRF
Case report form


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Term
Definition / description
CTP
Clinical trial protocol
CTR
Clinical trial report
CV
Arithmetic coefficient of variation
DBLM
Database lock meeting
Ebase
Baseline effect of biomarker
ECG
Electrocardiogram
ECGPCS
Electrocardiogram plasma concentration set
eCRF
Electronic case report form
EMA
European Medicines Agency
Emax
Maximum effect of biomarker
EudraCT
European union drug regulating authorities clinical trials
gCV
Geometric coefficient of variation
gMean
Geometric mean
HR
Heart rate
ICH
International Council for Harmonisation of Technical Requirements 
for Pharmaceuticals for Human Use
IPV
Important protocol violation
MD
Multiple dose
MedDRA
Medical Dictionary for Regulatory Activities
NOA
Not analysed
NOP
No peak detectable
NOR
No valid result
NOS
No sample available
on-trt
on-treatment
PD
Pharmacodynamic(s)
PK
Pharmacokinetic(s)
PKS
Pharmacokinetic parameter analysis set
PR interval
ECG interval from the onset of P wave to the beginning of the QRS
PV
Protocol violation
QRS complex
Combination of the Q, R, and S waves
QT interval
ECG interval from the beginning of the QRS complex to the end of the 
T wave


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Term
Definition / description
QTcB
QT interval, heart rate corrected according to Bazett's formula
QTcF
QT interval, heart rate corrected according to Fridericia's formula
QTcN
QT interval, heart rate corrected according to study population formula
RAGe
Report appendix generator
RPM
Report planning meeting
RR interval
ECG interval from the peak of the R wave to the peak of the 
subsequent R wave
SAE
Serious adverse event
SD
Single dose [in dose group labels]
Standard deviation [otherwise]
SDL
Subject data listing
SOC
System organ class
TS
Treated set
TSAP
Trial statistical analysis plan
ULN
Upper limit of normal range


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3.
INTRODUCTION
As per ICH E9, the purpose of this document is to provide a more technical and detailed 
elaboration of the principal features of the analysis described in the revised CTP, and to 
include detailed procedures for executing the statistical analysis of the primary and secondary 
variables and other data.
This TSAP assumes familiarity with the CTP and its amendments. In particular, the TSAP is 
based on the planned analysis specification as written in CTP Section 7 "Statistical Methods 
and Determination of Sample Size". Therefore, TSAP readers may consult the CTP for more 
background information on the study, e.g., on study objectives, study design and population, 
treatments, definition of measurements and variables, planning of sample size, randomisation.
Study data will be stored in a trial database within the Oracle ClinicalTM system. 
The statistical analyses will be performed within the validated working environment CARE, 
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 AE data or laboratory data; Report 
Appendix Generator system (RAGe) for compilation/formatting of the CTR appendices). 
PK parameters will be calculated using Phoenix WinNonlinTM software (version 6.3, Certara 
USA Inc., Princeton, NJ, USA).


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4.
CHANGES IN THE PLANNED ANALYSIS OF THE STUDY
 
Deviating from CTP Section 7.3.2, the secondary analysis of relative bioavailability for 
single intravenous dose of 20 mg/kg weight based on secondary endpoints will not be 
conducted, since this analysis was considered not to be relevant.
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 ENDPOINTS
Primary endpoint is the number [N (%)] of subjects with drug-related AEs, as defined in 
Section 5.2.1 of the CTP.
5.2
SECONDARY ENDPOINT
5.2.1
Key secondary endpoint
Not applicable.
5.2.2
Secondary endpoint
Secondary endpoints in the single dose part of this trial are AUC0-∞and Cmax of BI 655130 in 
plasma.
Secondary endpoints in the multiple dose part of this trial are AUC,1, Cmax, AUC,ss and 
Cmax,ss of BI 655130 in plasma, as defined in Section 5.5.1.1 of the CTP.
5.3.2
Safety parameters
CTP: Further criteria of interest:

AEs (including clinically relevant findings from the physical examination)

Safety laboratory tests

12-lead ECG

Continuous ECG monitoring

Vital signs (blood pressure, pulse rate)
In addition, body temperature is a further parameter of interest.
Local tolerability is a further parameter of interest, and will be assessed as absence or 
presence of "swelling", "induration", "heat", "redness", "pain", or "other findings".
12-lead ECG endpoints
For the definition of baseline and a summary of time points please refer to Section 6.7.


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Quantitative ECG endpoints:
The following quantitative ECG endpoints will be determined for the ECG variables QTcN, 
QTcF, QT, HR, PR, QRS, RR, and QTcB derived as described in Additional Section 9.1:

absolute values (per time point)

changes from baseline (per time point)

percent changes from baseline (per time point; for HR, PR, QRS)
Categorical ECG endpoints
The following categorical ECG endpoints will be determined based on the quantitative ECG 
endpoints:

New onset (meaning that this or a higher category was not present at baseline) of 
maximum QTcN interval > 450 to 480 msec, > 480 to 500 msec, or > 500 msec on 
treatment (and similar for QTcF).
For assignment of a particular subject to one of the above categories, all time points on-
treatment (refer to Table 6.7: 1) will be considered. A missing value is obtained only in 
case that (i) all on-treatment values are missing and (ii) all baseline values are less than or 
equal to 500 msec or missing. If condition (i) is fulfilled but at least one baseline value is 
greater than 500 msec, this case will be categorized as "no new onset". If baseline is 
missing, but the maximum absolute QTcN interval falls in a category other than normal 
(i.e. when QTcN > 450 ms), then this is categorized as a new onset in the respective 
category. If baseline is missing, but the maximum absolute QTcN interval is normal, then 
it is categorized as "No new onset" (similar for QTcF).

Maximum change from baseline in QT interval ≤ 60 msec, or > 60 msec on treatment

Maximum change from baseline in QTcN interval ≤ 30 msec, > 30 to ≤ 60 msec, or 
> 60 msec on treatment (similar for QTcF)
The occurrence of any of the following will be viewed as "notable findings":

New onset (not present at baseline) of uncorrected QT interval > 500 msec at any time on 
treatment
If baseline is missing, any occurrence of QT interval > 500 msec at any time on treatment 
will be a notable finding

New onset of QTcN interval > 500 msec at any time on treatment (and similar for QTcF)
If baseline is missing, any occurrence of QTcN interval > 500 msec at any time on 
treatment will be a notable finding (similar for QTcF)

Increase in QTcN interval from baseline by > 60 msec at any time on treatment (similar 
for QTcF)

Increase in HR from baseline by ≥ 25%, when corresponding on-treatment value of HR is 
> 100 beats/min, or decrease in HR by ≥ 25%, when corresponding on-treatment value of 
HR is < 50 beats/min, at any time on treatment

Increase in the PR interval from baseline by ≥ 25%, when corresponding on-treatment 
value of PR interval is > 200 msec, at any time on treatment 


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
Increase in the QRS complex from baseline by ≥ 10%, when corresponding on-treatment 
value of QRS complex is > 110 msec, at any time on treatment
 
 
 
 
 
 
 
 
 
 
5.4
OTHER VARIABLES
5.4.1
Demographic and other baseline characteristics
CTP: At the screening visit, the medical examination will include demographics including 
height and body weight, smoking and alcohol history, relevant medical history and 
concomitant therapy […].
Age [years] will be determined as the difference between year of birth and year of informed 
consent.
BMI will be calculated as weight [kg] / (0.01 * height [cm])2. 


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5.4.2
Treatment compliance and treatment exposure
Treatment exposure is assessed by means of 

the total infused dose of BI 655130 [mg] per subject, the 

infused dose of BI 655130 [mg/kg body weight] per subject and infusion, 

the duration of infusion per subject and infusion, and 

the number of infusions per subject.
The total dose of BI 655130 [mg] received is calculated as the total infusion volume [mL], as 
documented on the eCRF, times the drug concentration in the infusion solution (which is 5 
mg/mL for subjects in the 3 mg/kg dose group, 10 mg/mL for subjects in the 6 mg/kg dose 
group, and 20 mg/mL for subjects in the 10 mg/kg and 20 mg/kg dose groups). The dose of 
BI 655130 [mg/kg body weight] will be calculated as the total dose of BI 655130 received 
divided by the body weight [kg] of the patient on Day -2.
The duration of the infusion of BI 655130 [minutes] will be calculated as the end of the 
infusion date/time minus the start of the infusion date/time.
Treatment compliance will be assessed based on the actual number of infusions, duration of 
infusions and dose per infusion.


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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 

four intravenous doses of 3 mg/kg, 6 mg/kg, 10 mg/kg or 20 mg/kg body weight of 
BI 655130 (test treatment) 
or

four intravenous doses of placebo (reference treatment)
or

a single intravenous dose of 20 mg/kg body weight of BI 655130 (test treatment)
or

a single intravenous dose of placebo (reference treatment).
All placebo subjects from multiple dose groups will be analysed in one pooled placebo group 
(i.e. no distinction between multiple dose groups will be made for placebo subjects). Placebo 
subjects from the single dose group will be analysed separately.
In displays of disposition, demographics and safety, results of statistical analysis for multiple 
dose groups will be presented side by side with those for the single dose group in the same 
tables.
For statistical analysis of AEs, safety laboratory data, vital signs and ECG, the following 
analysis phases are defined for each subject:
Table 6.1: 1
Flow chart of analysis phases for statistical analyses of AEs, safety laboratory 
data, vital signs and ECG
Study analysis 
phase
Label
Start (inclusive)
End (exclusive)
Screening
Screening
Date of informed consent
Date/time of first 
administration of study drug
On-treatment
Placebo MD,
Placebo SD,
BI 3 mg/kg MD,
BI 6 mg/kg MD,
BI 10 mg/kg MD,
BI 20 mg/kg MD,
or BI 20 mg/kg SD,
respectively
Date/time of first 
administration of study drug
12:00 AM on day after 
subject's trial termination 
date
CTR Section 15, Appendix 16.1.9.2.8.2 and Appendix 16.1.9.2.8.3 AE displays will present 
results for the on-treatment phase only.


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In CTR Section 15 AE tables (but not in Appendix 16.1.9.2.8.2 and Appendix 16.1.9.2.8.3 
AE tables), the following total will be provided in addition:

"Total on-trt BI MD", defined as the total over all on-treatment phases involving BI
multiple dose treatment only, ignoring placebo and single dose BI
CTR Appendix 16.1.9.2.8.1 displays will present results for the screening and on-treatment
phases.
More details on the technical implementation of these analyses are provided in the ADS Plan 
of this TSAP.
6.2
IMPORTANT PROTOCOL VIOLATIONS
Consistency check listings (for identification of violations of time windows) and a list of 
protocol deviations (e.g. deviations in drug administration) will be provided to be discussed 
at the RPM/DBLM. At this meeting, each protocol deviation must be assessed to determine 
whether it is an IPV. For definition of IPVs, and for the process of identification of these, 
refer to the BI reference document "Protocol Violation Handling Definitions" (1).
If any IPVs are identified, they are to be summarised into categories and will be captured in 
the RPM/DBLM minutes via an accompanying Excel spreadsheet (2). The following table 
contains the categories which are considered to be IPVs in this trial. If the data show other 
IPVs, this table will be supplemented accordingly by the time of the RPM/DBLM.
IPVs will be summarised and listed.


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Table 6.2: 1
Important protocol violations
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 taken
C2
Randomisation not followed
C3
Non-compliance
C4
Medication code broken inappropriately
C5
Incorrect intake of trial medication
D
Concomitant medication
D1
Concomitant medication with the potential to affect the assessment of the trial medication
E
Missing data
None1
G
Other trial specific important violations
G1
Certain violations of procedures used to measure secondary PK data
Violations C1, C2, C4, C5 and G1 can only be detected at the trial site.
1 Missing visits, evaluations, and tests will be considered missing data, not PVs
Source: BI reference document "Protocol Violation Handling Definitions" [001-MCS-50-413_RD-01] (1).


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6.3
SUBJECT SETS ANALYSED
The following subject sets will be defined for statistical analysis:

Treated set (TS):
This subject set includes all subjects who received study drug. 

Pharmacokinetic parameter set (PKS):
This subject set includes all subjects of the TS who provide at least one observation 
for at least one secondary PK endpoint without important PVs with respect to the 
statistical evaluation of PK endpoints, as defined in Section 7.3.2 of the CTP.
 
 
.
All ECG analyses are performed on the TS, except for the exposure-response analyses, which 
are performed on the ECGPCS defined below.

ECG PC set (ECGPCS):
This subject set includes all subjects from the TS who provide at least one pair of a 
valid drug plasma concentration and a corresponding (i.e. time-matched) ECG 
endpoint to be used in the exposure-response analysis. For placebo subjects, the 
plasma concentration is set to 0 and hence always valid. For subjects treated with BI 
655130, the decision about concentration value validity needs to be assessed within 
the Clinical Pharmacology group. The decision whether a time deviation between PK 
blood sampling and ECG recording is acceptable (and thus whether the pair of values 
will be used) is to be made no later than at the RPM before data base lock.
The discussion of all exceptional cases and problems and the decisions on the allocation of 
subjects to analysis sets will be made at latest at the RPM/DBLM.


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Table 6.3: 1
Subject sets analysed
Subject set
Class of endpoint
TS
PKS
BMS
ECGPCS
Disposition
X
Exposure
X
IPVs
X
Demographic/baseline endpoints
X
Primary endpoint
X
ECG endpoints and plasma 
concentrations used in exposure-
response analysis
X
ECG endpoints in other analyses
X
Other safety parameters
X
Secondary PK endpoints
X
Further PK endpoints
X
Biomarkers
X
6.5
POOLING OF CENTRES
This section is not applicable, because the study was performed in only one centre.
6.6
HANDLING OF MISSING DATA AND OUTLIERS
CTP: If a subject is removed from or withdraws from the trial prior to first 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 first 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.
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 (see 001-MCG-
156_RD-01 (3)).


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Missing data and outliers of PK data are handled according to BI standards (see 001-MCS-
36-472_RD-01) (4). CTP: Drug concentration data identified with NOS (no sample 
available), NOR (no valid result), NOA (not analysed), BLQ (below the lower limit of 
quantification), or NOP (no peak detectable) will be displayed as such and not replaced by 
zero at any time point (this rule also applies also to the lag phase, including the predose 
values).
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 
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
6.7.1
Time points and baseline for analysis of 12-lead ECG
There will be a centralised evaluation of all 12-lead ECG recordings at the time points 
specified in Table 6.7: 1 below:
Table 6.7.1: 1 Time schedule of 12-lead ECG recordings with centralised evaluation
Visit
Day
Planned time [hh:mm]
(relative to respective 
drug administration)
Comment2
Study phase
2
1, 81, 151 and 221
-02:00
Baseline/on-trt3
00:30
only for BI 3 mg/kg MD, 6 mg/kg MD 
and BI 20 mg/kg SD
On-treatment
01:00
only for BI 10 mg/kg MD 
and BI 20 mg/kg SD
01:30
only for BI 20 mg/kg MD 
and BI 20 mg/kg SD
02:00
03:00
only for BI 20 mg/kg SD
04:00
only for BI 20 mg/kg SD
06:00
08:00
only for BI 20 mg/kg SD
12:00
2, 91, 161 and 231
24:00
32:00
only for BI 20 mg/kg SD
3, 101, 171 and 241 48:00
1 These days are only applicable to dose groups with multiple dosing
2 If no comment is given, time point is applicable to all dose groups in this trial
3 ECG recording at relative time -2:00 h prior to next dosing is considered to be baseline on Day 1 and to be on-treatment on 
other days 
Triple ECGs (3 single ECGs recorded within 180 sec) will be recorded on all time points with 
centralised ECG evaluation (as listed in the table above). On all other time points, single 
ECGs will be recorded.


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The value of an ECG variable at each of the time points with triple ECG is defined as the 
arithmetic mean of the 3 single ECG measurements. In particular, the baseline value of an 
ECG variable is defined as the mean of the triple ECG measurements prior to first drug 
administration.
For the exposure-response analysis, ECG measurements and corresponding plasma 
concentrations building pairs using the same planned time points will be used (e.g., QTcN
change from baseline and plasma concentration for planned time 0:30 will build one pair.)
Whether a time deviation between a PK sample and the corresponding ECG recording is too 
big and the respective pair has to be excluded, or whether a value has to be matched to 
another time point, will be decided no later than at the RPM/DBLM.
6.7.2
Baseline in all other analyses
In all other analyses (except for analyses of ECG variables), the last non-missing value 
determined prior to the first dosing of BI 655130 will be defined as baseline. 
6.7.3
Time windows for measurements
Time windows are defined in Section 6.1 of the CTP. Adherence to time windows will be 
checked at the RPM/DBLM.
6.7.4
Pooled time points for comparison of endpoints at end of infusion
The duration of infusion varies between dose groups, as shown in the table below.
Table 6.7.4: 1 Duration of infusion
Dose group
Duration of infusion
BI 3 mg/kg MD and matching placebo
30 min
BI 6 mg/kg MD and matching placebo
30 min
BI 10 mg/kg MD and matching placebo
60 min
BI 20 mg/kg MD and matching placebo
90 min
BI 20 mg/kg SD and matching placebo
60 min
Therefore, the planned time of measurements taken at the end of infusion also varies between 
dose groups (e.g., 0:30 h, 1:00 h or 1:30 h after infusion on Day 1). In order to allow 
comparison between dose groups at the end of infusion, the following time points will be 
defined for use in statistical analysis of vital signs, body temperature, ECG results and 
biomarkers. They will be created by pooling the time points at the end of infusion of all dose 
groups.


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Table 6.7.4: 2 Time points for statistical analysis of vital signs, body temperature, ECG and 
biomarkers
Planned time [hh:mm] (relative to first drug administration)
Visit Day Time point label
BI 3 mg/kg 
MD
BI 6 mg/kg 
MD
BI 10 mg/kg 
MD
BI 20 mg/kg 
MD
BI 20 mg/kg 
SD
2
1
Day 1, end of inf.
0:30
0:30
1:00
1:30
1:00
2
8
Day 8, end of inf.
168:30
168:30
169:00
169:30
NA
2
15
Day 15, end of inf.
336:30
336:30
337:00
337:30
NA
2
22
Day 22, end of inf.
504:30
504:30
505:00
505:30
NA
NA = Not applicable.


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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" (001-MCG-159) (9).
The individual values of all subjects will be listed. Listings will generally be sorted by dose 
group, subject number and visit (if visit is applicable in the respective listing). AE listings 
will be sorted by assigned analysis phase (see Table 6.1: 1 for a definition of analysis phases). 
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
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. Percentages will be rounded to one decimal place. The category missing 
will be displayed if and only if there actually are missing values. Percentages will be based 
on all subjects in the respective subject set whether they have non-missing values or not.
7.1
DEMOGRAPHIC AND OTHER BASELINE CHARACTERISTICS
Only descriptive statistics are planned for this section of the CTR.
7.2
CONCOMITANT DISEASES AND MEDICATION
Concomitant diseases will be coded according to the most recent version of MedDRA. 
Concomitant medication will be coded according to the most recent version of the World 
Health Organisation – Drug Dictionary.


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Only descriptive statistics are planned for this section of the CTR.
A medication will be considered concomitant to a treatment, if it

is ongoing at the time of first administration of the respective treatment or

starts within the analysis phase of the respective treatment (see Section 6.1 for a 
definition of treatments and analysis phases).
7.3
TREATMENT COMPLIANCE
Treatment compliance will not be analysed as a specific endpoint, but will be assessed based 
on the actual number of infusions (counts and percentages of subjects with a total of 1, 2, 3 or 
4 infusions), duration of infusions (descriptive statistics of duration) and dose per infusion
(descriptive statistics of the administered dose per infusion). Any deviations from complete 
intake will be addressed in the RPM/DBLM (cf. Section 6.2) and described in the CTR.
7.4
PRIMARY ENDPOINTS
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 ENDPOINT
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 of secondary endpoints will be evaluated as defined in the CTP, 
Section 7.3.2, by use of the power model, excluding the BI 20 mg/kg SD group.
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".
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 


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"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.
Further details are given in 001-MCS-36-472_RD-01 "Noncompartmental Pharmacokinetic / 
Pharmacodynamic Analyses of Clinical Studies" (4) and 001-MCS-36-472_RD-03 
"Description of Analytical Transfer Files and PK/PD Data Files" (5).


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7.7
EXTENT OF EXPOSURE
Only descriptive statistics are planned for this section of the CTR.
7.8
SAFETY ANALYSIS
All safety analyses will be performed on the TS.
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.
For analysis, multiple AE occurrence data on the 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, AESI)


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
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 "Handling and 
summarization of adverse event data for clinical trial reports and integrated summaries" (6) 
[001-MCG-156] and "Handling of missing and incomplete AE dates" (3) [001-MCG-
156_RD-01]. 
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 phase or on-treatment phase as defined in 
Section 6.1.
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 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 on 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 SOC and 
preferred term. AEs which were considered by the investigator to be drug related (primary 
endpoint) will be summarised separately. Separate tables will also be provided for subjects 
with 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 SOCs will be sorted according to the standard sort order specified by the EMA, preferred 
terms will be sorted by total frequency (within SOC).
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 
by treatment, primary SOC and preferred term. The frequency of subjects with SAEs will 
also be summarised.


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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.
7.8.2
Laboratory data
The analyses of laboratory data will be descriptive in nature and will be based on BI 
standards (7). If possible, analyses will be based on original values. If multiple reference 
ranges apply for a parameter (e.g. due to different age groups), analyses will be based on 
normalised values, which means transforming to a standard unit and a standard reference 
range.
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.
Possibly clinically significant abnormal laboratory values are only those identified either in 
the Investigator's comments 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 in an automated manner 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 (blood pressure, pulse rate, body temperature) 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.
Body weight will only be listed.
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
12-lead ECG
Abnormal findings will be reported as baseline conditions (at screening) or as AEs (during 
the trial) if judged clinically relevant by the investigator. 
All evaluation of ECG data except of exposure response analysis will be based on the TS. 
The exposure-response analysis will then be done on the ECGPCS.


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Listing of individual data
For all quantitative endpoints, listings of individual data will be shown in Appendix 16.2. 
Occurrences of notable findings (as defined in Section 5.3.2) will be flagged.
For all subjects with any notable finding in quantitative ECG recordings, a separate listing 
will be created as end-of-text display (based on the same display template as in Appendix 
16.2), and the corresponding time profiles will be shown.
Comments regarding the ECGs will be listed.
Descriptive analysis
Descriptive statistics (N, mean, SD, min, median, max) will be provided for the changes from 
baseline over time in all quantitative ECG variables, and time profiles of mean and SD for the 
changes from baseline on treatment will be displayed graphically by treatment.
Plasma concentrations and relationship to QTcN, QTcF, QT interval and HR change from 
baseline
For the following analyses, all time points with ECG recordings with centralised evaluation 
and corresponding plasma concentrations will be included.
The changes from baseline in QTcN (QTcN) will be investigated as response variable. The 
placebo subjects will be included in the analysis, with zero plasma concentrations. Time 
points with plasma concentrations "BLQ" in subjects in active dose groups will be ignored in 
this analysis.
As a first step, it will be investigated if there is a potential delayed or accelerated (e.g.
metabolites) effects of the drug on QTcN. A general visual impression of the PK-QT 
relationship is provided by overlaying time profiles of plasma concentrations and QTcN 
changes from baseline (QTcN). All figures will be generated for each subject (presented in 
Appendix 16.1.9.2 of the CTR), as well as for means per active treatment (presented in 
Section 15.3 of the CTR).
In case of non-linearity or if there is evidence for a delayed effect, further models will be 
explored that better characterise the PK/ECG relationship (effect compartment, non-linear 
model etc.).
If there is no non-linearity or delayed effect seen, the relationship between BI 655130 plasma 
concentrations and QTcN changes from baseline will be investigated in an exploratory 
manner using a random coefficient model approach to estimate the QTcN change from 
baseline and its 90% confidence interval at the geometric mean of the Cmax for each dose
(multiple dose groups as well as single dose group). Additionally, the estimated slope with its 
90% confidence interval will be provided. The used random coefficient model is based on 
Garnett et al. 2016 [R17-0553] (10):


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PROC MIXED DATA=myDATA METHOD=REML;
CLASS subject active(ref=FIRST) time;
MODEL ECGep = conc active time / NOINT CL ALPHA=0.1 ALPHAP=0.1 DDFM=KR
OUTPREDM=pred;
RANDOM INT conc / TYPE=UN SUBJECT=subject;
ESTIMATE 'Pred. value at conc. xx.xx' conc xx.xx active 1 -1 / CL
ALPHA=0.1;
ESTIMATE 'Slope estimate' conc 1 / CL ALPHA=0.1;
RUN;
Here "ECGep" is the QTcN change from baseline, "active" is a dummy 0/1 variable 
indicating the active treatment (1=active, 0=placebo), "conc" is the corresponding plasma 
concentration value of the drug, and "xx.xx" is the given concentration value (i.e. the value of 
the geometric mean Cmax of a given dose group). The class variable "time" is the time relative 
to the most recent infusion; here, measurements at time points at the end of infusion will not 
enter the model with the planned time, but only by means of the time points defined in Table 
6.7: 3. The "TYPE=UN" option causes the two specified random coefficients to have a 
bivariate normal distribution. In case of convergence problems see Section 9.2 for possible 
improvements (option "TYPE=FA0(2)" may also be used as a potential solution, it requests a 
G matrix estimate that is constrained to be nonnegative definite). If the note "estimated G 
matrix is not positive definite" occurs in the SAS log file, the random slope "conc" might be 
removed from the "RANDOM" statement. When the plasma concentrations are not normally 
distributed, the exposure-response model can be applied to log(conc) instead of the raw 
concentration.
For visualization, the BI 655130 plasma concentration against the response will be plotted as 
well as the (fixed effect) regression line, its 90% confidence interval and the geometric mean 
of Cmax for each dose. For each subject and each time point, subtract the mean value of all 
individual observed ΔQTc values from the placebo group for this time point from the 
individual observed ΔQTc value for this subject and time point. This results in estimates for 
"individual ΔΔQTc" values. These estimates should only be used for plotting purposes.
All of the above described graphical and statistical analyses will be also performed for QTcF, 
HR and QT in place of QTcN.
Categorical Endpoints
For the categorical endpoints, frequency tables will be provided.
For subjects with notable findings, the individual time courses of QTcN, QTcF, QT, HR, PR,
and QRS of these subjects will be presented in figures.
7.8.5
Local tolerability
Local tolerability (absence or presence of "swelling", "induration", "heat", "redness", "pain", 
or "other findings") will be summarized with counts and percentages overall (i.e. over all 
infusions and time points) as well as by infusion and time point.


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7.8.6
Others
Physical examination findings will be reported as relevant medical history/baseline condition 
(i.e., a condition already existent before intake of study drug) or as AE and will be 
summarised as such. No separate listing or analysis of physical examination will be prepared.


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8.
REFERENCES
1
001-MCS-50-413_RD-01: "Protocol Violation Handling Definitions", current 
version; IDEA for CON
2
001-MCS-50-413_RD-02: "Important Manual Protocol Violations Spreadsheet", 
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-MCS-36-472_RD-03: "Description of Analytical Transfer Files and PK/PD 
Data Files", current version; IDEA for CON
6
001-MCG-156: "Handling and summarisation of adverse event data for clinical 
trial reports and integrated summaries", current version; IDEA for CON
7
001-MCG-157: "Display and Analysis of Laboratory Data", 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-159: "Reporting of Clinical Trials and Project Summaries", current 
version; IDEA for CON
10
R17-0553: Garnett C, Needleman K, Liu J, Brundage R, Wang Y; Operational 
characteristics of linear concentration-QT models for assessing QTc interval in the 
thorough QT and phase I clinical studies. Clin Pharmacol Ther 100 (2), 170 - 178 
(2016)
11
R10-2920: Ring A: Statistical models for heart rate correction of the QT interval; 
Stat Med 29, 786 - 796 (2010)


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9.
ADDITIONAL SECTIONS
9.1
DETAILED DESCRIPTION OF ENDPOINTS FOR ECG
QT, PR, QRS and RR baseline and on-treatment measurements (see Table 6.7: 1) are 
included in the centralised ECG evaluation. 
For each single ECG with centralised evaluation, measurements of QT, PR, QRS and 
preceding RR interval of four cardiac cycles will be determined and stored in the database as 
raw data. Their mean values will be used as the QT, PR, QRS, and RR interval values, 
respectively, for this ECG.
QTcF, HR and QTcB will be calculated based on the derivation rules as follows:
From the four cardiac cycles of a single ECG, the HR (measured in beats/min) will be
calculated as
 [/] = 60 000

!!!!
where RR is the mean of the four RR intervals (measured in msec).
Similarly, the QT interval corrected for HR according to Fridericia's formula (QTcF) for a 
single ECG will be derived as
QTcF [msec] = )1000
RR
!!!!
+
QT
!!!! ,
where QT is the mean of the four QT intervals and RR is the mean of the corresponding 
preceding RR intervals of the four cardiac cycles for this ECG.
Likewise, the HR-corrected QT interval according to Bazett's formula (QTcB) for a single 
ECG is given by
QTcB [msec] = )1000
RR
!!!!
-
QT
!!!! .
In addition, data dependent population heart rate correction QTcN will be derived for a given 
pair of QT and RR values as
QTcN [msec] = 01000
 1
23456
∗89[:],
(RR and QT are given in msec). A common slope will be estimated for the whole population 
(all subjects in the TS) based on the random coefficient model described below. The RR and 


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QT intervals used for this slope estimation will be the arithmetic means of the four cardiac 
cycles from each single ECG on baseline and on placebo. If there is a missing baseline or 
placebo value, no imputed values will be used in the analysis described in the following:
A random coefficient model with covariate "log-transformed RR interval" is fit (natural log), 
which accounts for subject effects (Ring [R10-2920] (11)):
;< = = + < + (@A + A<)< + C< ,
where
Yik
log-transformed QT interval of the ith ECG of subject k;
μ0
the overall intercept;
s0k
the random intercept associated with subject k;
δ1
the regression effect of the covariate, i.e. the common slope associated with 
the 
relationship between the log-transformed QT and RR intervals;
s1k
the random slope associated with subject k;
xik
log-transformed RR interval of the ith ECG of subject k;
εik
the random error associated with the ith ECG of subject k.
The slope is then calculated as δ1.
The following SAS code will be used to fit the model:
PROC MIXED DATA=xxxx CL METHOD=REML; 
CLASS subject; 
MODEL lnQT = lnRR / DDFM= KENWARDROGER ALPHA=0.05 CL; 
RANDOM INT lnRR / TYPE=UN SUBJECT=subject; 
ESTIMATE 'Population slope' lnRR 1 / ALPHA=0.05 CL; 
RUN;
In case of triple ECGs at a time point, the respective ECG variable will be averaged over the 
triple ECG measurements at this time point (arithmetic mean). Note that in case of missing 
values the averaging is simply done for the available values.


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9.2
STEPS IN CASE OF CONVERGENCE PROBLEMS FOR REPEATED 
MEASURES MODEL IN ECG
In case of convergence problems one may try one (or more) of the following steps:
1.) Set MAXITER=100 (or even higher for PROC GLIMMIX) and/or MAXFUNC=200 (for 
PROC GLIMMIX, these options are available within the NLOPTIONS statement)
2.) Set SINGULAR=1E-10 as option (for PROC MIXED: in the model statement)
3.) Use option SCORING=4 in the final run to request a Fisher scoring algorithm to be used 
for the first 4 iterations
4.)
Include the additional statement in the PROC MIXED call:
PERFORMANCE NOTHREAD;
5.) Perform an initial run including the statement
ODS OUTPUT COVPARMS=covstart;
followed by a final run using
PARMS / PARMSDATA=covstart;
In the special case with the note "Convergence criteria met but final hessian is not 
positive definite" try instead/in addition
PARMS / OLS;
to request ordinary least squares starting values.
6.) One may also use estimates from a simpler model (e.g. using AR(1)) as starting values 
for the run with TYPE=UN or UNR
In case an unstructured covariance matrix (i.e. TYPE=UN or UNR) does not work, also in 
conjunction with all steps from 1)-6) mentioned above, the following covariance structures 
will be chosen, in the pre-defined order:

Toeplitz structure with heterogeneous variances (TOEPH) for the REPEATED effect

heterogeneous first-order autoregressive structure (ARH(1)) for the REPEATED effect

TOEPH for both the RANDOM and the REPEATED effect

ARH(1) for both the RANDOM and the REPEATED effect, but with the additional 
random statement  RANDOM INT / SUBJECT=subject;


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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
07-SEP-17
None
This is the final TSAP without any 
modification