Clinical trial NCT04232839
Conditions: Healthy
Sponsor: Boehringer Ingelheim
Start date: 2020-02-25; Completion date: 2020-11-30
Enrollment: 24 participants; Allocation: RANDOMIZED; Intervention model: CROSSOVER

Brief summary:
The main objective of this trial is to select a formulation principle (tablet vs. capsule) and to optimize the identified extended release formulation of BI 894416, if needed.

Detailed description:

Arms: arm 1: Sequence I+T5, with treatments in the following order: T3-R1-T1-T4-T2-T5 with a washout period of at least 4 days between treatments. All test treatments (T1-T6) were one single dose of 62.5 milligram. R1 and T1-T4: taken orally with 240 milliliter (mL) of water after an overnight fast of at least 10 hours. T5-T6: taken orally with 240 mL of water following a high-fat high-calorie breakfast.

Reference (R1): 60 milligram (mg) (6 x 10 mg tablets) BI 894416 Reference Formulation, immediate release (IR) tablets.

Test 1 (T1): 1 tablet BI 894416 Formulation A2, extended release (ER) tablet (fast release rate, FRR).

Test 2 (T2): 1 tablet BI 894416 Formulation C2, ER tablet (slow release rate, SRR).

Test 3 (T3): 1 capsule BI 894416 Formulation D2, ER capsule (FRR). Test 4 (T4): 1 capsule BI 894416 Formulation F2, ER capsule (SRR). Test 5 (T5): 1 tablet BI 894416 Formulation C2, ER tablet (SRR). Test 6 (T6): 1 capsule BI 894416 Formulation F2, ER capsule (SRR). arm 2: Sequence I+T6, with treatments in the following order: T3-R1-T1-T4-T2-T6 with a washout period of at least 4 days between treatments. All test treatments (T1-T6) were one single dose of 62.5 milligram. R1 and T1-T4: taken orally with 240 milliliter (mL) of water after an overnight fast of at least 10 hours. T5-T6: taken orally with 240 mL of water following a high-fat high-calorie breakfast.

Reference (R1): 60 milligram (mg) (6 x 10 mg tablets) BI 894416 Reference Formulation, immediate release (IR) tablets.

Test 1 (T1): 1 tablet BI 894416 Formulation A2, extended release (ER) tablet (fast release rate, FRR).

Test 2 (T2): 1 tablet BI 894416 Formulation C2, ER tablet (slow release rate, SRR).

Test 3 (T3): 1 capsule BI 894416 Formulation D2, ER capsule (FRR). Test 4 (T4): 1 capsule BI 894416 Formulation F2, ER capsule (SRR). Test 5 (T5): 1 tablet BI 894416 Formulation C2, ER tablet (SRR). Test 6 (T6): 1 capsule BI 894416 Formulation F2, ER capsule (SRR). arm 3: Sequence II+T5, with treatments in the following order: T2-T1-T3-R1-T4-T5with a washout period of at least 4 days between treatments. All test treatments (T1-T6) were one single dose of 62.5 milligram. R1 and T1-T4: taken orally with 240 milliliter (mL) of water after an overnight fast of at least 10 hours. T5-T6: taken orally with 240 mL of water following a high-fat high-calorie breakfast.

Reference (R1): 60 milligram (mg) (6 x 10 mg tablets) BI 894416 Reference Formulation, immediate release (IR) tablets.

Test 1 (T1): 1 tablet BI 894416 Formulation A2, extended release (ER) tablet (fast release rate, FRR).

Test 2 (T2): 1 tablet BI 894416 Formulation C2, ER tablet (slow release rate, SRR).

Test 3 (T3): 1 capsule BI 894416 Formulation D2, ER capsule (FRR). Test 4 (T4): 1 capsule BI 894416 Formulation F2, ER capsule (SRR). Test 5 (T5): 1 tablet BI 894416 Formulation C2, ER tablet (SRR). Test 6 (T6): 1 capsule BI 894416 Formulation F2, ER capsule (SRR). arm 4: Sequence II+T6, with treatments in the following order: T2-T1-T3-R1-T4-T6 with a washout period of at least 4 days between treatments. All test treatments (T1-T6) were one single dose of 62.5 milligram. R1 and T1-T4: taken orally with 240 milliliter (mL) of water after an overnight fast of at least 10 hours. T5-T6: taken orally with 240 mL of water following a high-fat high-calorie breakfast.

Reference (R1): 60 milligram (mg) (6 x 10 mg tablets) BI 894416 Reference Formulation, immediate release (IR) tablets.

Test 1 (T1): 1 tablet BI 894416 Formulation A2, extended release (ER) tablet (fast release rate, FRR).

Test 2 (T2): 1 tablet BI 894416 Formulation C2, ER tablet (slow release rate, SRR).

Test 3 (T3): 1 capsule BI 894416 Formulation D2, ER capsule (FRR). Test 4 (T4): 1 capsule BI 894416 Formulation F2, ER capsule (SRR). Test 5 (T5): 1 tablet BI 894416 Formulation C2, ER tablet (SRR). Test 6 (T6): 1 capsule BI 894416 Formulation F2, ER capsule (SRR). arm 5: Sequence III+T5, with treatments in the following order: T4-T3-R1-T2-T1-T5 with a washout period of at least 4 days between treatments. All test treatments (T1-T6) were one single dose of 62.5 milligram. R1 and T1-T4: taken orally with 240 milliliter (mL) of water after an overnight fast of at least 10 hours. T5-T6: taken orally with 240 mL of water following a high-fat high-calorie breakfast.

Reference (R1): 60 milligram (mg) (6 x 10 mg tablets) BI 894416 Reference Formulation, immediate release (IR) tablets.

Test 1 (T1): 1 tablet BI 894416 Formulation A2, extended release (ER) tablet (fast release rate, FRR).

Test 2 (T2): 1 tablet BI 894416 Formulation C2, ER tablet (slow release rate, SRR).

Test 3 (T3): 1 capsule BI 894416 Formulation D2, ER capsule (FRR). Test 4 (T4): 1 capsule BI 894416 Formulation F2, ER capsule (SRR). Test 5 (T5): 1 tablet BI 894416 Formulation C2, ER tablet (SRR). Test 6 (T6): 1 capsule BI 894416 Formulation F2, ER capsule (SRR). arm 6: Sequence III+T6, with treatments in the following order: T4-T3-R1-T2-T1-T6 with a washout period of at least 4 days between treatments. All test treatments (T1-T6) were one single dose of 62.5 milligram. R1 and T1-T4: taken orally with 240 milliliter (mL) of water after an overnight fast of at least 10 hours. T5-T6: taken orally with 240 mL of water following a high-fat high-calorie breakfast.

Reference (R1): 60 milligram (mg) (6 x 10 mg tablets) BI 894416 Reference Formulation, immediate release (IR) tablets.

Test 1 (T1): 1 tablet BI 894416 Formulation A2, extended release (ER) tablet (fast release rate, FRR).

Test 2 (T2): 1 tablet BI 894416 Formulation C2, ER tablet (slow release rate, SRR).

Test 3 (T3): 1 capsule BI 894416 Formulation D2, ER capsule (FRR). Test 4 (T4): 1 capsule BI 894416 Formulation F2, ER capsule (SRR). Test 5 (T5): 1 tablet BI 894416 Formulation C2, ER tablet (SRR). Test 6 (T6): 1 capsule BI 894416 Formulation F2, ER capsule (SRR). arm 7: Sequence IV+T5, with treatments in the following order: T1-T4-T2-T3-R1-T5 with a washout period of at least 4 days between treatments. All test treatments (T1-T6) were one single dose of 62.5 milligram. R1 and T1-T4: taken orally with 240 milliliter (mL) of water after an overnight fast of at least 10 hours. T5-T6: taken orally with 240 mL of water following a high-fat high-calorie breakfast.

Reference (R1): 60 milligram (mg) (6 x 10 mg tablets) BI 894416 Reference Formulation, immediate release (IR) tablets.

Test 1 (T1): 1 tablet BI 894416 Formulation A2, extended release (ER) tablet (fast release rate, FRR).

Test 2 (T2): 1 tablet BI 894416 Formulation C2, ER tablet (slow release rate, SRR).

Test 3 (T3): 1 capsule BI 894416 Formulation D2, ER capsule (FRR). Test 4 (T4): 1 capsule BI 894416 Formulation F2, ER capsule (SRR). Test 5 (T5): 1 tablet BI 894416 Formulation C2, ER tablet (SRR). Test 6 (T6): 1 capsule BI 894416 Formulation F2, ER capsule (SRR). arm 8: Sequence IV+T6, with treatments in the following order: T1-T4-T2-T3-R1-T6 with a washout period of at least 4 days between treatments. All test treatments (T1-T6) were one single dose of 62.5 milligram. R1 and T1-T4: taken orally with 240 milliliter (mL) of water after an overnight fast of at least 10 hours. T5-T6: taken orally with 240 mL of water following a high-fat high-calorie breakfast.

Reference (R1): 60 milligram (mg) (6 x 10 mg tablets) BI 894416 Reference Formulation, immediate release (IR) tablets.

Test 1 (T1): 1 tablet BI 894416 Formulation A2, extended release (ER) tablet (fast release rate, FRR).

Test 2 (T2): 1 tablet BI 894416 Formulation C2, ER tablet (slow release rate, SRR).

Test 3 (T3): 1 capsule BI 894416 Formulation D2, ER capsule (FRR). Test 4 (T4): 1 capsule BI 894416 Formulation F2, ER capsule (SRR). Test 5 (T5): 1 tablet BI 894416 Formulation C2, ER tablet (SRR). Test 6 (T6): 1 capsule BI 894416 Formulation F2, ER capsule (SRR). arm 9: Sequence V+T5, with treatments in the following order: R1-T2-T4-T1-T3-T5 with a washout period of at least 4 days between treatments. All test treatments (T1-T6) were one single dose of 62.5 milligram. R1 and T1-T4: taken orally with 240 milliliter (mL) of water after an overnight fast of at least 10 hours. T5-T6: taken orally with 240 mL of water following a high-fat high-calorie breakfast.

Reference (R1): 60 milligram (mg) (6 x 10 mg tablets) BI 894416 Reference Formulation, immediate release (IR) tablets.

Test 1 (T1): 1 tablet BI 894416 Formulation A2, extended release (ER) tablet (fast release rate, FRR).

Test 2 (T2): 1 tablet BI 894416 Formulation C2, ER tablet (slow release rate, SRR).

Test 3 (T3): 1 capsule BI 894416 Formulation D2, ER capsule (FRR). Test 4 (T4): 1 capsule BI 894416 Formulation F2, ER capsule (SRR). Test 5 (T5): 1 tablet BI 894416 Formulation C2, ER tablet (SRR). Test 6 (T6): 1 capsule BI 894416 Formulation F2, ER capsule (SRR). arm 10: Sequence V+T6, with treatments in the following order: R1-T2-T4-T1-T3-T6with a washout period of at least 4 days between treatments. All test treatments (T1-T6) were one single dose of 62.5 milligram. R1 and T1-T4: taken orally with 240 milliliter (mL) of water after an overnight fast of at least 10 hours. T5-T6: taken orally with 240 mL of water following a high-fat high-calorie breakfast.

Reference (R1): 60 milligram (mg) (6 x 10 mg tablets) BI 894416 Reference Formulation, immediate release (IR) tablets.

Test 1 (T1): 1 tablet BI 894416 Formulation A2, extended release (ER) tablet (fast release rate, FRR).

Test 2 (T2): 1 tablet BI 894416 Formulation C2, ER tablet (slow release rate, SRR).

Test 3 (T3): 1 capsule BI 894416 Formulation D2, ER capsule (FRR). Test 4 (T4): 1 capsule BI 894416 Formulation F2, ER capsule (SRR). Test 5 (T5): 1 tablet BI 894416 Formulation C2, ER tablet (SRR). Test 6 (T6): 1 capsule BI 894416 Formulation F2, ER capsule (SRR).
Interventions: intervention 1: BI 894416 Reference Formulation intervention 2: BI 894416 Formulation A2 intervention 3: BI 894416 Formulation C2 intervention 4: BI 894416 Formulation D2 intervention 5: BI 894416 Formulation F2
Intervention descriptions: intervention 1: R1 - 60 milligram (6 x 10 milligram tablets) BI 894416 Reference Formulation, immediate release (IR) tablets taken orally with 240 mL of water after an overnight fast of at least 10 hours. intervention 2: T1 - One single dose of 62.5 milligram (1 tablet) BI 894416 Formulation A2, extended release (ER) tablet (fast release rate, FRR) taken orally with 240 mL of water after an overnight fast of at least 10 hours. intervention 3: T2 - One single dose of 62.5 milligram (1 tablet) BI 894416 Formulation C2, extended release (ER) tablet (slow release rate, SRR) taken orally with 240 mL of water after an overnight fast of at least 10 hours.

and T5 - One single dose of 62.5 milligram (1 tablet) BI 894416 Formulation C2, extended release (ER) tablet (slow release rate, SRR) taken orally with 240 mL of water following a high-fat high-calorie breakfast. intervention 4: T3 - One single dose of 62.5 milligram (1 capsule) BI 894416 Formulation D2, extended release (ER) capsule (fast release rate, FRR) taken orally with 240 mL of water after an overnight fast of at least 10 hours. intervention 5: T4 - One single dose of 62.5 milligram (1 capsule) BI 894416 Formulation F2, extended release (ER) capsule (slow release rate, SRR) taken orally with 240 mL of water after an overnight fast of at least 10 hours.

and T6 - One single dose of 62.5 milligram (1 capsule) BI 894416 Formulation F2, extended release (ER) capsule (slow release rate, SRR) taken orally with 240 mL of water following a high-fat high-calorie breakfast.

Protocol documents:
Prot_000.pdf: 
001-MCS-40-106-RD-13 (6.0) / Saved on: 13 Jun 2018
Clinical Trial Protocol
TITLE PAGE
Document Number:
c28590127-04
EudraCT No.
2019-003424-21
BI Trial No.
1371-0022
BI Investigational
Medicinal Product
BI 894416
Title
Formulation selection and subsequent optimization of two 
different oral formulations of BI 894416 in healthy male subjects 
(open-label, randomised, single-dose study in two parts; trial part 
1: five-period crossover design with an additional sixth period in
a fixed sequence; trial part 2: three-period crossover followed by 
a two-period crossover design)
Lay Title
A study in healthy men to find the best formulation of BI 894416 
and to test how this is taken up in the body
Clinical Phase
I
Clinical Trial Leader
Phone:
Fax: 
Principal 
Investigator
Tel: 
 (day)
Tel: 
 (out of hours emergency)
Status
Final Protocol (Revised Protocol (based on global amendment 1))
Version and Date
Version: 2.0
Date: 22 July 2020
Page 1 of 77
Proprietary confidential information
© 2020 Boehringer Ingelheim International GmbH or one or more of its affiliated companies. All rights reserved.
This document may not - in full or in part - be passed on, reproduced, published or otherwise used without prior written permission


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BI Trial No.: 1371-0022
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Trial Protocol
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CLINICAL TRIAL PROTOCOL SYNOPSIS
Company name
Boehringer Ingelheim
Protocol date
16 December 2019
Revision date
22 July 2020
BI trial number
1371-0022
Title of trial
Formulation selection and subsequent optimization of two different oral
formulations of BI 894416 in healthy male subjects (open-label, randomised, single-
dose study in two parts; trial part 1: five-period crossover design with an additional 
sixth period in a fixed sequence; trial part 2: three-period crossover followed by a 
two-period crossover design)
Principal Investigator:
Trial site
Clinical phase
I
Trial rationale
To optimize the oral formulation of BI 894416 in healthy subjects
Trial objective
To select a formulation principle (tablet vs. capsule) and to optimize the identified 
formulation of BI894416, if needed.
Trial design
Open-label, randomised, single-dose study in two parts; trial part 1: five-period 
crossover design with an additional sixth period in a fixed sequence; trial part 2: 
three-period crossover followed by a two-period crossover design
Trial endpoints:
Primary endpoint: AUC0-of BI 894416
Secondary endpoint: AUC0-tz of BI 894416
Number of subjects 
total entered
42
each treatment
Trial part 1: 24
Trial part 2: 18
Diagnosis
Not applicable
Main criteria
for inclusion
Healthy male subjects, age of 18 to 55 years (inclusive), body mass index (BMI) of 
18.5 to 29.9 kg/m2 (inclusive)


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Test product 1
BI 894416 Prototype Formulation A2
dose
62.5 mg (1 tablet)
mode of admin.
Oral with 240 mL of water after an overnight fast of at least 10 h
Test product 2
BI 894416 Prototype Formulation C2
dose
62.5 mg (1 tablet)
mode of admin.
-
Oral with 240 mL of water after an overnight fast of at least 10 h or
-
Oral with 240 mL of water following a high-fat high-calorie breakfast
Test product 3
BI 894416 Prototype Formulation D2
dose
62.5 mg (1 capsule)
mode of admin.
Oral with 240 mL of water after an overnight fast of at least 10 h
Test product 4
BI 894416 Prototype Formulation F2
dose
62.5 mg (1 capsule)
mode of admin.
-
Oral with 240 mL of water after an overnight fast of at least 10 h or
-
Oral with 240 mL of water following a high-fat high-calorie breakfast
Test product 5
BI 894416 Prototype Formulations G or I
dose
50 to 75 mg (1 tablet or capsule)
mode of admin.
-
Oral with 240 mL of water after an overnight fast of at least 10 h or
-
Oral with 240 mL of water following a high-fat high-calorie breakfast
Test product 6
BI 894416 Prototype Formulations H or K
dose
50 to 75 mg (1 tablet or capsule)
mode of admin.
-
Oral with 240 mL of water after an overnight fast of at least 10 h or
-
Oral with 240 mL of water following a high-fat high-calorie breakfast
Ref. product 1 & 2
BI 894416 Reference Formulation
dose
60 mg (6 x 10 mg tablets)
mode of admin.
Oral with 240 mL of water after an overnight fast of at least 10 h


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Duration of treatment
One day (single dose) for each treatment
Trial part 1

R1 - Reference 1: 60 mg BI 894416, fasted (n=24)

T1 - Formulation A2: 62.5 mg BI 894416, fasted (n=24)

T2 - Formulation C2: 62.5 mg BI 894416, fasted (n=24)

T3 - Formulation D2: 62.5 mg BI 894416, fasted (n=24)

T4 - Formulation F2: 62.5 mg BI 894416, fasted (n=24)
At least 10 subjects of part 1 (fixed sequence part)

T5 - Formulation C2: 62.5 mg BI 894416, after high-fat, high-calorie
breakfast (n≥10)
At least 10 of the other subjects of part 1 (fixed sequence part)

T6 - Formulation F2: 62.5 mg BI 894416, after high-fat, high-calorie
breakfast (n≥10)
Decision point: either (a) stop here or (b) proceed to trial part 2A with one of 
the optimised formulations, G or I.
Trial part 2 (optional)
Trial part 2A (only one, either G or I will be tested in the fasted and fed state)

R2 - Reference 2: 60 mg BI 894416, fasted (n=18)

T7 - Formulation G or I: 50-75 mg BI 894416, fasted (n=18)

T8 - Formulation G or I): 50-75 mg BI 894416, after high-fat, high-calorie
breakfast (n=18)
Decision point: either (a) stop here or (b) proceed to trial part 2B with one of 
the optimised formulations, H or K
Trial part 2B (only one, either H or K will be tested in the fasted and fed state)

T9 - Formulation H or K: 50-75 mg BI 894416, fasted (n=18)

T10 - Formulation H or K: 50-75 mg BI 894416, after high-fat, high-
calorie breakfast (n=18)
There will be a washout period of at least 4 days between treatments, i.e. the dose in 
the preceding treatment period and the dose in the following treatment period will 
be separated by at least 4 days.
Statistical methods
Preliminary pharmacokinetic analyses and simulations will be performed between 
trial part 1 and trial part 2A as, well as between part 2A and 2B, if appropriate.
Relative bioavailability will be estimated by the ratios of the geometric means (test/
reference) for primary, secondary and further selected endpoints. Additionally, their 
two-sided 90% confidence intervals (CIs) will be provided. This method 
corresponds to the two one-sided t-test procedure, each at a 5% significance level. 
Since the main focus is on estimation and not testing, a formal hypothesis test and 
associated acceptance range is not specified. The statistical model will be an 
analysis of variance (ANOVA) on the logarithmic scale.
CIs will be calculated based on the residual error from the ANOVA.
Descriptive statistics will be calculated for all endpoints.


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FLOW CHART – TRIAL PART 1
Period
Visit
Day
Planned time (relative to 
drug administration) 
[h:min]
Approximate clock time of 
actual day [h:min]
Event and comment
Safety laboratory7
PK blood
Neurological examination8
12-lead ECG
Vital signs (BP, PR)
Questioning for AEs and 
concomitant therapy 6
SCR
1
-28 to -1
Screening (SCR)1
A
x
x
x
1/2/3/4/5/6 (six periods separated by a wash-out of at least 4 days)
2/3/4/5/6/7
-1
-12:00
20:00
Admission to trial site(visit 2 
only)
x5
x
-11:30
20:30
Snack (voluntary)
1
-1:30
06:30
Allocation to treatment2 (visit 2 
only)
B2/9
x2
x2
x2
x2
-0:30
07:30
High fat, high calorie breakfast
(Treatment T5 & T6 only)
0:00
08:00
Drug administration (with 
240 mL fluid intake)
0:20
08:20
x
x
0:40
08:40
x
x
1:00
09:00
x
x
x
x
2:00
10:00
240 mL fluid intake
x
x
x
x
3:00
11:00
x
x
4:00
12:00
240 mL fluid intake, thereafter 
lunch3
x
x
x
x
5:00
13:00
x
x
6:00
14:00
x
x
8:00
16:00
Snack (voluntary)3
x
x
x
x
10:00
18:00
x
x
11:00
19:00
Dinner
12:00
20:00
x
x
14:00
22:00
x
x
16:00
24:00
x
x
2
24:00
08:00
B
x
x
x
x
34:00
18:00
x
x
3
48:00
08:00
x
x
58:00
18:00
x
x
4
72:00
08:00
Breakfast (voluntary)
Discharge from trial site(visit 
7 only)
B10
x
x
x
x
EoT
8
8 to 15
End of trial (EoT) examination4
A
x
x
x
x
1.
Subject must be informed and written informed consent obtained prior to starting any screening procedures. Screening 
procedures include physical examination, check of vital signs, ECG, safety laboratory (including drug screening,
alcohol breath- and urine cotinine test), demographics (including determination of body height and weight, smoking 
status and alcohol history), relevant medical history, concomitant therapy and review of inclusion/exclusion criteria.
2.
The time is approximate; the procedure is to be performed and completed within the 3 h prior to drug administration.
3.
If several actions are indicated at the same time, the intake of meals will be the last action.
4.
At the end of trial visit the EoT examination includes physical examination, vital signs, ECG, safety laboratory, 
recording of AEs and concomitant therapies.
5.
Only urine drug screening and alcohol breath test will be done at this time.
6.
AEs and concomitant therapies will be recorded throughout the trial, but will be specifically asked for at the times
indicated in the Flow Chart above.
7.
A and B define different sets of safety laboratory examinations (see Section 5.2.3)


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8.
Unscheduled neurological examinations may be added at any time during the trial for individual volunteers or the whole 
treatment group, e.g., in case of neurological adverse events, if assessed as necessary by the investigator.
9.
Pharmacogenetic samples will be collected at Day 1 prior to first drug administration in period 1.
10. Only to be taken before discharge from the trial site


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FLOW CHART – TRIAL PARTS 2A & 2B (OPTIONAL)
Period
Visit
Day
Planned time (relative to 
drug administration) 
[h:min]
Approximate clock time of 
actual day [h:min]
Event and comment
Safety laboratory7
PK blood
Neurological examination8
12-lead ECG
Vital signs (BP, PR)
Questioning for AEs and 
concomitant therapy 6
SCR
1
-28 to -1
Screening (SCR)1
A
x
x
x
1/2/3/4/5 (five identical periods separated by a wash-out of at least 4 days – preliminary 
PK analysis between periods 3 and 4)
2/3/4/5/6
-1
-12:00
20:00
Admission to trial site(visit 2 
only)
x5
x
-11:30
20:30
Snack (voluntary)
1
-1:30
06:30
Allocation to treatment2 (visit 2 
only)
B2/9
x2
x2
x2
x2
-0:30
07:30
High fat, high calorie breakfast
(Treatments T8 & T10 only)
0:00
08:00
Drug administration (with 240 
mL fluid intake)
0:20
08:20
x
x
0:40
08:40
x
x
1:00
09:00
x
x
x
x
2:00
10:00
240 mL fluid intake
x
x
x
x
3:00
11:00
x
x
4:00
12:00
240 mL fluid intake, thereafter 
lunch3
x
x
x
x
5:00
13:00
x
x
6:00
14:00
x
x
8:00
16:00
Snack (voluntary)3
x
x
x
x
10:00
18:00
x
x
11:00
19:00
Dinner
12:00
20:00
x
x
14:00
22:00
x
x
16:00
24:00
x
x
2
24:00
08:00
B
x
x
x
x
34:00
18:00
x
x
3
48:00
08:00
x
x
58:00
18:00
x
x
4
72:00
08:00
Breakfast (voluntary)
Discharge from trial site(visits 4 
and/ or 6 only)
B10
x
x
x
x
EoT
8
8 to 15
End of trial (EoT) examination4
A
x
x
x
x
1.
Subject must be informed and written informed consent obtained prior to starting any screening procedures. Screening 
procedures include physical examination, check of vital signs, ECG, safety laboratory (including drug screening, 
alcohol breath, and urine cotinine test), demographics (including determination of body height and weight, smoking 
status and alcohol history), relevant medical history, concomitant therapy and review of inclusion/ exclusion criteria.
2.
The time is approximate; the procedure is to be performed and completed within the 3 h prior to drug administration.
3.
If several actions are indicated at the same time, the intake of meals will be the last action.
4.
At the end of trial part 2A (Visit 4) and/ or 2B (Visit 6), the EoT examination includes physical examination, vital signs, 
ECG, safety laboratory, recording of AEs and concomitant therapies. Should trial part 2B follow within 28 days after 
EoT examination of part 2A, no additional safety laboratory examination is needed.
5.
Only urine drug screening and alcohol breath test will be done at this time.
6.
AEs and concomitant therapies will be recorded throughout the trial, but will be specifically asked for at the times
indicated in the Flow Chart above.
7.
A and B define different sets of safety laboratory examinations (see Section 5.2.3)


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8.
Unscheduled neurological examinations may be added at any time during the trial for individual volunteers or the whole 
treatment group, e.g., in case of neurological adverse events, if assessed as necessary by the investigator.
9.
Pharmacogenetic samples will be collected at Day 1 prior to first drug administration in period 1.
10. Only to be taken before discharge from the trial site


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TABLE OF CONTENTS
TITLE PAGE ......................................................................................................1
CLINICAL TRIAL PROTOCOL SYNOPSIS ................................................2
FLOW CHART – TRIAL PART 1 ...................................................................5
FLOW CHART – TRIAL PARTS 2A & 2B (OPTIONAL)...........................7
TABLE OF CONTENTS ...................................................................................9
ABBREVIATIONS.......................................................................................... 13
1.
INTRODUCTION.................................................................................... 16
1.1
MEDICAL BACKGROUND............................................................................16
1.2
DRUG PROFILE...............................................................................................16
1.2.2
Comparator ...........................................................................................19
1.3
RATIONALE FOR PERFORMING THE TRIAL........................................19
1.4
BENEFIT - RISK ASSESSMENT ...................................................................20
1.4.1
Expected benefit to the target population...........................................20
1.4.2
Procedure-related risks ........................................................................20
1.4.3
Risks related to BI 894416 and safety measures ................................21
1.4.4
Drug-induced liver injury ....................................................................24
1.4.5
Overall assessment of benefit-risk ratio..............................................24
2.
TRIAL OBJECTIVES AND ENDPOINTS........................................... 26
2.1
MAIN OBJECTIVES, PRIMARY AND SECONDARY ENDPOINTS ......26
2.1.1
Main objectives......................................................................................26
2.1.2
Primary endpoint..................................................................................26
2.1.3
Secondary endpoint ..............................................................................26
2.2.2.2
Safety and tolerability..............................................................27
3.
DESCRIPTION OF DESIGN AND TRIAL POPULATION.............. 28
3.1
OVERALL TRIAL DESIGN AND PLAN ......................................................28
3.2
DISCUSSION OF TRIAL DESIGN, INCLUDING THE CHOICE OF 
CONTROL GROUPS........................................................................................31
3.2.1
Discussion of study design....................................................................31
3.2.2
Rational for decision rules....................................................................31
3.3
SELECTION OF TRIAL POPULATION ......................................................31
3.3.1
Main diagnosis for trial entry..............................................................32


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3.3.2
Inclusion criteria...................................................................................32
3.3.3
Exclusion criteria ..................................................................................33
3.3.4
Withdrawal of subjects from treatment or assessments ...................34
3.3.4.1
Discontinuation of trial treatment............................................35
3.3.4.2
Withdrawal of consent to trial participation ............................35
3.3.4.3
Discontinuation of the trial by the sponsor..............................35
3.3.5
Replacement of subjects .......................................................................36
4.
TREATMENTS........................................................................................ 37
4.1
INVESTIGATIONAL TREATMENTS ..........................................................37
4.1.1
Identity of the Investigational Medicinal Products ...........................37
4.1.2
Selection of doses in the trial and dose modifications........................40
4.1.3
Method of assigning subjects to treatment groups ............................40
4.1.4
Drug assignment and administration of doses for each subject .......40
4.1.5
Blinding and procedures for unblinding ............................................43
4.1.6
Packaging, labelling, and re-supply ....................................................44
4.1.7
Storage conditions.................................................................................44
4.1.8
Drug accountability ..............................................................................44
4.2
OTHER TREATMENTS, EMERGENCY PROCEDURES, 
RESTRICTIONS ...............................................................................................45
4.2.1
Other treatments and emergency procedures....................................45
4.2.2
Restrictions............................................................................................45
4.2.2.1
Restrictions regarding concomitant treatment .........................45
4.2.2.2
Restrictions on diet and life style.............................................45
4.3
TREATMENT COMPLIANCE.......................................................................46
5.
ASSESSMENTS....................................................................................... 47
5.1
ASSESSMENT OF EFFICACY.......................................................................47
5.2
ASSESSMENT OF SAFETY............................................................................47
5.2.1
Physical examination ............................................................................47
5.2.2
Vital signs...............................................................................................47
5.2.3
Safety laboratory parameters..............................................................47
5.2.4
Electrocardiogram................................................................................49
5.2.5
Other safety parameters.......................................................................50
5.2.5.1
Neurological examination........................................................50
5.2.6
Assessment of adverse events...............................................................50
5.2.6.1
Definitions of adverse events...................................................50
Adverse event ............................................................50
5.2.6.1.1
Serious adverse event ................................................51
5.2.6.1.2
AEs considered ‘Always Serious’.............................51
5.2.6.1.3
Adverse events of special interest .............................52
5.2.6.1.4
Intensity (severity) of AEs.........................................52
5.2.6.1.5
Causal relationship of AEs ........................................52
5.2.6.1.6
5.2.6.2
Adverse event collection and reporting ...................................53


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AE collection.............................................................53
5.2.6.2.1
AE reporting to the sponsor and timelines ................54
5.2.6.2.2
Information required..................................................54
5.2.6.2.3
5.2.6.2.4 Pregnancy ..................................................................54
5.3
DRUG CONCENTRATION MEASUREMENTS AND 
PHARMACOKINETICS..................................................................................55
5.3.1
Assessment of pharmacokinetics .........................................................55
5.3.2
Methods of sample collection...............................................................55
5.3.2.1
Blood sampling for pharmacokinetic analysis.........................55
5.6
APPROPRIATENESS OF MEASUREMENTS.............................................56
6.
INVESTIGATIONAL PLAN.................................................................. 57
6.1
VISIT SCHEDULE............................................................................................57
6.2
DETAILS OF TRIAL PROCEDURES AT SELECTED VISITS ................57
6.2.1
Screening period....................................................................................57
6.2.2
Treatment periods.................................................................................58
6.2.3
Follow-up period and trial completion ...............................................60
7.
STATISTICAL METHODS AND DETERMINATION OF
SAMPLE SIZE......................................................................................... 61
7.1
STATISTICAL DESIGN – MODEL ...............................................................61
7.2
NULL AND ALTERNATIVE HYPOTHESES ..............................................61
7.3
PLANNED ANALYSES....................................................................................61
7.3.1
Primary endpoint analyses...................................................................62
7.3.2
Secondary endpoint analyses ...............................................................64
7.3.3
Further endpoint analyses....................................................................64
7.3.3.1
Pharmacokinetic analyses........................................................64
7.3.4
Safety analyses.......................................................................................64
7.4
INTERIM ANALYSES .....................................................................................65
7.5
HANDLING OF MISSING DATA ..................................................................66
7.5.1
Safety......................................................................................................66
7.5.2
Pharmacokinetics..................................................................................66
7.6
RANDOMISATION ..........................................................................................66
7.7
DETERMINATION OF SAMPLE SIZE ........................................................67
8.
INFORMED CONSENT, TRIAL RECORDS, DATA 
PROTECTION, PUBLICATION POLICY, AND 
ADMINISTRATIVE STRUCTURE...................................................... 68


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8.1
TRIAL APPROVAL, SUBJECT INFORMATION, INFORMED 
CONSENT ..........................................................................................................68
8.2
DATA QUALITY ASSURANCE .....................................................................69
8.3
RECORDS..........................................................................................................69
8.3.1
Source documents .................................................................................69
8.3.2
Direct access to source data and documents.......................................70
8.3.3
Storage period of records.....................................................................70
8.4
EXPEDITED REPORTING OF ADVERSE EVENTS .................................70
8.5
STATEMENT OF CONFIDENTIALITY AND SUBJECT PRIVACY.......70
8.5.1
Collection, storage and future use of biological samples and 
corresponding data ...............................................................................71
8.6
TRIAL MILESTONES .....................................................................................71
8.7
ADMINISTRATIVE STRUCTURE OF THE TRIAL ..................................72
9.
REFERENCES......................................................................................... 73
9.1
PUBLISHED REFERENCES...........................................................................73
9.2
UNPUBLISHED REFERENCES.....................................................................74
10. APPENDICES .......................................................................................... 75
11. DESCRIPTION OF GLOBAL AMENDMENT(S).............................. 76
11.1
GLOBAL AMENDMENT 1 .............................................................................76
11.2
GLOBAL AMENDMENT 2 .............................................................................77


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ABBREVIATIONS
ADME
Absorption, distribution, metabolism, and excretion
ADP
Adenosine diphosphate
AE
Adverse event
AESI
Adverse events of special interest
ALCOA
Attributable, legible, contemporaneous, original, and accurate
ANOVA
Analysis of variance
AUC0-∞
Area under the concentration-time curve of the analyte in plasma over the 
time interval from 0 extrapolated to infinity
AUC0-24
Area under the concentration-time curve of the analyte in plasma over the 
time interval from 0 to 24 h
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
BA
Bioavailability
BI
Boehringer Ingelheim
BMI
Body mass index (weight divided by height squared)
BP
Blood pressure
CA
Competent authority
CI
Confidence interval
CL
Total clearance of the analyte in plasma after intravascular administration
CRF
Case Report Form, paper or electronic (sometimes referred to as ‘eCRF’)
CTM
Clinical Trial Manager
CTP
Clinical trial protocol
CTR
Clinical trial report
CYP3A
Cytochrome P450 subfamily 3A
DILI
Drug induced liver injury
DNA
Deoxyribonucleic acid
EC
Ethics Committee
ECG
Electrocardiogram
eCRF
Electronic case report form
eDC
Electronic data capture 


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EDTA
Ethylenediaminetetraacetic acid
EEG
Electroencephalography
EoT
End of trial
ER
Extended release
EudraCT
European Clinical Trials Database
F
Absolute bioavailability factor
FDA
Food and Drug Administration
FOB
Faecal occult blood
GCP
Good Clinical Practice
GI
Gastro-intestinal
gMean
Geometric mean
IB
Investigator’s brochure
ICF
Informed Consent Form
IEC
Independent Ethics Committee
IMPD
Investigational Medicinal Product Documentation
IPD
Important protocol Deviation
IQRMP
Integrated Quality and Risk Management Plan
IR
Immediate release
IRB
Institutional Review Board
ISF
Investigator site file
z
Terminal rate constant of the analyte in plasma
LC-MS/MS
Liquid chromatography with tandem mass spectrometry
LLOQ
Lower limit of quantification
MDA
Methylenedioxyamphetamine
MDMA
Methylenedioxymethamphetamine
MedDRA
Medical Dictionary for Regulatory Activities
MRD
Multiple-rising dose
NK
Natural killer
PfOS
Powder for reconstitution of an oral solution
PK
Pharmacokinetic(s)
PKS
Pharmacokinetic set
PP
Polypropylene
PR
Pulse rate
QT
Time between start of the Q-wave and the end of the T-wave in an 
electrocardiogram
QTc
QT interval corrected for heart rate using the method of Fridericia (QTcF) 
or Bazett (QTcB)


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R
Reference treatment
REP
Residual effect period
SAE
Serious adverse event
SCR
Screening
SOP
Standard operating procedure
SRD
Single-rising dose
SUSAR
Suspected unexpected serious adverse reaction
SYK
Spleen tyrosine kinase
T
Test product or treatment
TDMAP
Trial Data Management and Analysis Plan
TMF
Trial master file
TS
Treated set
TSAP
Trial statistical analysis plan
tz
Time of last measurable concentration of the analyte in plasma
ULN
Upper limit of normal
UV
Ultraviolet
WHO
World Health Organization
WOCBP
Woman of child bearing potential
Vz
Apparent volume of distribution during the terminal phase after 
intravascular administration
XTC
Ecstasy
ZAP70
Zeta-chain-associated protein kinase of 70 kDa


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1.
INTRODUCTION
BI 894416 is an oral, selective, spleen tyrosine kinase (SYK) inhibitor being developed for 
the indication of uncontrolled, severe, and persistent asthma.
This trial will be performed to select one formulation principle (extended release (ER) tablet
vs. ER capsule) and to optimize the selected ER formulation.
1.1
MEDICAL BACKGROUND
Asthma is a heterogenous disease, characterized by a chronic inflammatory process of the 
airways and driven by both, the innate and adaptive immune pathways [R14-4230, 
P08-01263]. In severe asthma, the T type 2 inflammation (T2) -high and T2-low, and the 
non-T2 pathways are involved associated with a mixed pattern of inflammation involving 
eosinophil-, basophil-, mast-, neutrophil-, innate lymphoid- and dendritic cells [R15-5888, 
R16-0945].
SYK is a non-receptor cytoplasmic tyrosine kinase that is predominantly expressed in cells of 
hematopoietic lineage, including B cells, T cells, monocytes, NK cells, mast cells, basophils, 
and neutrophils [R15-5470]. SYK is a key component of the signal transduction associated 
with the T2-high and T2-low, and non-T2 asthma pathways that is activated through 
interaction with allergens and a number of innate and adaptive immune receptors, including 
Fc receptors on basophil-, mast-, B- and T cells. SYK is essential for the FcεR1-mediated 
activation and degranulation of mast- and basophil cells. SYK is also important in the signal 
propagation of the dectin family of innate receptors, present on macrophages, dendritic cells 
and neutrophils. Furthermore, SYK has important roles in B- and T cell development, with 
partially redundant functions with Zeta-chain-associated protein kinase of 70 kDa (ZAP70) 
[R15-5470, R16-5298].
For more details on medical background, refer to the most recent version of the Investigator’s 
Brochure (IB) [c03536505].
1.2
DRUG PROFILE


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Table 1.2.1: 1
Study 1371-0008 –Adverse event (preliminary) listing of a single
75 mg dose of BI 894416
Subject
Term
Outcome
Severity
Relationship
Seriousness
Comment
Pressure 
sensation left 
parasternal; 
short episodes 
(10 seconds) 
for 30 minutes
Recovered/ 
Resolved
Mild
No
No
Nosebleed
Recovered/ 
Resolved
Mild
No
No
The subject 
had a 
nosebleed at 
home; not 
longer than 1 
to 2 minutes
Elevated serum 
CK
Not 
Recovered/ 
Not 
Resolved
Mild
No
No
Elevated serum 
[GOT/] GPT
Not 
Recovered/ 
Not 
Resolved
Mild
No
No
Elevated serum 
[GOT/] GPT
Not 
Recovered/ 
Not 
Resolved
Mild
No
No
Anemia 
(normochromic, 
normocytic)
Recovered/ 
Resolved
Mild
No
No
Headache
Recovered/ 
Resolved
Moderate
No
No
Headache
Recovered/ 
Resolved
Mild
No
No
Tension 
headache
Recovered/ 
Resolved
Mild
Yes
No
Orthostatic 
dysregulation
Recovered/ 
Resolved
Moderate
No
No
Orthostatic 
dysregulation 
during blood 
sampling prior 
to drug 
administration
Headache
Recovered/ 
Resolved
Mild
Yes
No
Diarrhea
Recovered/ 
Resolved
Mild
Yes
No
No SAEs and no AESI were observed in this dose group. Patient 
 with elevated liver and 
CK- values received placebo. All other adverse events as well as changes from base line of 
laboratory, ECG and vital sign parameters were of minor clinical relevance.
The corresponding pharmacokinetic geometric mean parameters were 2330 nM for Cmax and 
15100 nM*h for AUC0-24. These values were slightly higher than those in the first-in-man 
study 1371-0001 after a single 70 mg dose of BI 894416 with a geometric mean Cmax of 
2,130 nM and a geometric mean AUC0-24 of 11,100 nM*h.
In conclusion, a single 75 mg dose of BI 894416 was well tolerated and safe. The systemic 
and peak exposure was similar to that seen in study 1371-0001 after a single dose of 70 mg.


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1.2.2
Comparator
Not applicable
1.3
RATIONALE FOR PERFORMING THE TRIAL
Preclinical pharmacokinetic/ pharmacodynamic modelling showed that
 
 
 
 is necessary to achieve full clinical efficacy in humans.
Based on data from trial 1371-0001, thrice daily administration of an immediate release 
formulation (IR) would be necessary to achieve this goal.
With an ER formulation a twice daily dosing regimen is expected to result in BI 894416 
plasma concentrations corresponding to an 
 with a lower total daily 
systemic exposure compared to that of the IR formulation. Twice daily dosing might also be 
associated with higher patient convenience and compliance.
In trial part 1, oral ER tablet and capsule formulations, based on different release principles,
will be tested, to identify the formulation that would most reliably lead to a therapeutically 
relevant exposure (i.e. concentrations corresponding to an
when single 
dose pharmacokinetics is simulated to steady state under fasted and fed conditions.
If necessary, the formulation selected in trial part 1 would be further optimized in trial part 2 
with regards to dose and drug release. This could either result in (i) an increased
for 
better target inhibition and/ or (ii) a lower potential food effect to achieve a more stable target 
inhibition and/ or (iii) a reduced variability of the pharmacokinetics for a more consistent 
target inhibition in the study population.


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The Clinical Trial Authorisation (CTA) application for this study describes a flexible protocol 
design using the concept of formulation design space /a bracketed dose approach to allow 
decision-making in response to interim pharmacokinetic observations. The principles of a 
flexible protocol were discussed and agreed with the Medicines and Healthcare products 
Regulatory Agency (MHRA) at a Scientific Advice Meeting between the MHRA and 
 (formerly 
).
Based upon the concept of formulation design space/ a bracketed dose approach, specific 
IMPs are not detailed within the Investigational Medicinal Product Dossier (IMPD) but rather
a defined dose range of formulation inputs and corresponding performance outputs are 
described and justified based on in vitro studies. The chosen formulation from within the 
approved design space for the first prototype to be dosed will be documented in a File Note 
and approved by the sponsor and a 
 representative ahead of 
manufacture.
1.4
BENEFIT - RISK ASSESSMENT
Participation in this clinical trial is without any (therapeutic) benefit for healthy subjects. 
Their participation, however, is of major importance for the development of BI 894416. 
Subjects are exposed to risks of study procedures and risks related to the exposure to the trial 
medication.
1.4.1
Expected benefit to the target population
Asthma is a heterogeneous disease that is driven by the innate and adaptive immune pathway. 
In severe asthma, both the T2-high and T2-low, and the non-T2 inflammation pathways are 
involved, and associated with a mixed pattern of inflammation involving eosinophil-, 
basophil-, mast-, neutrophil-, innate lymphoid- and dendritic cells. Up to 50% of severe 
asthma is driven by the non T2 and/ or T2-low alone or in combination with the T2-high 
pathway. This non-T2/T2-low component represents an area of unmet medical need that does 
not respond to high dose inhaled corticosteroids or other current controller therapy, and is 
unlikely to respond to the T2-high monoclonal antibodies targeted therapies.
SYK is a key component of signal transduction associated with the T2-high and T2-low, and 
non-T2 asthma pathways that is activated through interaction with allergens and a number of 
innate and adaptive immune receptors including Fc receptors on basophils, mast, B and T 
cells. SYK is also important in the signal propagation of the dectin family of innate receptors, 
present on macrophages, dendritic cells and neutrophils.
Such a therapy would meet a substantial unmet medical need for severe asthma patients, 
especially those with a non T2 and/ or T2-low component, whether early/ late-onset or steroid 
resistant, and could become a safe and effective alternative to high dose inhaled 
corticosteroids, oral systemic corticosteroids or T2-high biological monoclonal antibodies.
1.4.2
Procedure-related risks
The use of an indwelling venous catheter or venepuncture for e.g. blood sampling may result 
in mild bruising, and in rare cases, in transient inflammation of the wall of the vein, or nerve 


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injury, potentially resulting in paraesthesia, reduced sensibility, and/ or pain for an indefinite 
period.
The total volume of blood withdrawn per subject during the entire study will not exceed the 
volume of a normal blood donation (500 mL). No health-related risk to healthy subjects is 
expected from withdrawal of this volume of blood.
Electrocardiogram stickers on the subjects' chests and limbs may cause some local irritation 
and may be uncomfortable to remove but subjects will be closely monitored to ensure any 
local irritation does not persist.
1.4.3
Risks related to BI 894416 and safety measures
Potential effects on immune cells
SYK is involved in the function of basophil-, mast-, neutrophil- and dendritic cells. 
Moreover, SYK is implicated in the development and function of both, T- and B cells. For 
further details, refer to the most recent IB [c03536505].
The risk for healthy volunteers due to effects of BI 894416 on immune cells is expected to be 
minimal, for the following reasons:

Inhibition of SYK is not expected to have a negative effect with regards to the 
immune response of innate immune cells to viral or bacterial infections due to 
redundancy in the infection-immune response. The key neutrophil- and dendritic cell 
functions most likely will be triggered by alternative pathways.

Safety and tolerability data of trial 1371-0001 are not suggestive of an increased risk 
of infectious adverse events or of any relevant BI 894416-related findings in WBC, 
differential blood count, immunoglobulins, or lymphocyte subpopulations after single 
doses up to 70 mg BI 894416. For further details, refer also to the most recent 
IB [c03536505]).

Due to the reversible mode of action of BI 894416 with regard to SYK inhibition, any 
potential effects on immune cells are expected to be of transient nature.
Risk mitigation and monitoring: Subjects with a history or diagnosis of relevant 
immunological disease will be excluded from trial participation (refer to Section 3.3.3,).
Adverse events will be monitored for an increase in infectious adverse events. Safety 
laboratory will contain WBC, differential blood count, and CRP.
Tumour biology and carcinogenicity
The SYK pathway has been hypothesized to act as both, a tumour suppressor and a tumour 
promoter in different types of human cancers [R16-4459]. An increased risk of carcinogenic/
metastatic potential in epithelial cancers has been reported in the literature related to SYK 
knock-out mice, but not related to SYK inhibition. Allelic deletion of SYK has been 
associated with breast adenocarcinoma [R15-4770]. However, there is no evidence that 


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pharmacologic inhibition of SYK will increase carcinogenicity or metastatic risk. Preclinical 
data with a potent and selective tool SYK inhibitor, BI 1002494, are in line with an absence 
of a carcinogenic effect due to inhibition of SYK enzymatic function [n00243171].
Risk mitigation and monitoring: Only male subjects will be included in this trial. In view of 
the extended time necessary to induce a carcinogenic effect, a maximum of 6 single doses of 
BI 894416 are not considered to be a relevant carcinogenic risk to male subjects, participating 
in this study. Accordingly, no further measures of risk mitigation are thought to be required 
in this study.
Platelet aggregation and bleeding risk
A role of SYK in platelet function has been demonstrated in the literature [R15-5470].
Several platelet functions rely on SYK signalling (e.g. collagen receptor GPVI) but others are 
independent of SYK [R16-5240]. In vitro studies using human platelets demonstrated that at 
concentrations up to 100 μM, BI 894416 had no effect on extrinsic or intrinsic coagulation 
pathways. Also, BI 894416 did not inhibit ADP-induced platelet aggregation up to 100 μM. 
However, BI 894416 inhibited collagen- and arachidonic acid-induced platelet aggregation at 
3 μM and 5 μM, respectively. In general, platelet function, as measured by bleeding time,
should not be affected by a drug after the administration of a single dose. Therefore, the risk 
for bleeding is considered to be low with regard to platelet inhibition, unless a subject is also 
on other antiplatelet drugs that block other pathways. In line with this conclusion, data of 
previous trial 1371-0001 did not indicate any signs of an increased risk of bleeding.
Risk mitigation and monitoring: Use of any other concomitant drugs that could reasonably 
inhibit platelet aggregation or coagulation (e.g. acetylsalicylic acid) will be prohibited in this 
trial (refer also to Sections 3.3.3 and 4.2.2.1). Adverse events will be monitored for any signs
of bleeding or bleeding-related adverse events.
Bone density
SYK is reported to be involved in osteoclast differentiation, development and function. For 
details, refer to the most recent version of the IB [c03536505]. In this trial, each subject is 
treated with a maximum of 6 single doses of BI 894416. Due to comparatively slow turnover 
of bone tissue, no relevant effect on bone is expected, and no specific monitoring of bone 
density is necessary or reasonable in this trial.
Mortality/ morbidity in preclinical studies
Due to overt morbidity that occurred in toxicological studies with CByB6F1 non-transgenic 
mice and in Wistar Han rats, some animals died or had to be sacrificed. Clinical signs 
preceding morbidity were similar in both rodent species and included respiratory changes 
(rapid, shallow, and/ or laboured breathing), decreased motor activity, ruffled fur, hunched or 
prostrate posture, eye changes (squinting, discharge) and/ or hypothermia. These findings
occurred at exposures of ≥723,000 nM*h which is equivalent to 20-fold of the human 
exposure cap. One dog of the 3-day escalation study was sacrificed due to overt 
neurotoxicity. For details, refer to the most recent IB [c03536505].


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Risk mitigation and monitoring: Data of trial 1371-0001 indicate good safety and tolerability 
of BI 894416 at all investigated doses (single oral doses of up to 70 mg). Doses of BI 894416,
given in trial 1371-0022 and expected plasma exposures are about the same as those
previously given to and seen in healthy volunteers, respectively. Moreover, subjects will be 
in-house at the trial site and under close medical observation for 24 h after administration of 
BI 894416. Vital signs and ECGs will be recorded during the trial. Subjects will be instructed 
to report AEs spontaneously and will be asked at pre-defined time points for AEs. In case of 
AEs in need of treatment, the investigator can authorise symptomatic therapy and, if required, 
subjects will be kept under supervision at the trial site or transferred to a hospital, until all 
monitored results will have returned to an acceptable level.
Neurotoxicity
In dog toxicology studies, acute adverse neurological effects with tremor and movement 
disorder, assessed as dyskinesia (paresis/ rigidity), were observed at high exposures (for 
further detail, refer also to most recent IB [c03536505]). One dog was euthanized due to 
overt neurotoxicity in 3-day escalation study at 90 mg/kg/day [n00235423]. In another dose 
escalation study [n00245394], all clinical signs of neurotoxicity were reversible with the 
cessation of dosing. No structural changes were observed in histopathology. Peripheral nerve 
conduction velocity and EEG were unchanged. No specific mechanism causing these
neurological effects in dogs was identified. Although it has not been determined whether or 
not these neurological changes are dog specific, an external expert review considered these 
findings most likely to be a channelopathy specific to dog and not likely to occur in man. For 
more detail, refer also to the most recent IB [c03536505].
Risk mitigation and monitoring: Subjects with relevant neurological disorder in the medical 
history will be excluded from trial participation (refer to Section 3.3.3). Neurological 
examinations, as described in Section 5.2.5.1, will be performed at screening, and subjects 
with clinically relevant findings in this neurological examination will be excluded from study 
participation (refer to Section 3.3.3). If necessary (investigator decision), unscheduled
neurological examinations may be performed at any time during the trial. Relevant findings 
in the neurological examination during the trial will be reported as AEs. If necessary, subjects 
may be sent for further, more specific evaluation and treatment to a local neurologist.
Genotoxicity, reproductive and developmental toxicity
Genetic toxicology results by weight of evidence indicate that BI 894416 is not mutagenic or 
clastogenic. In the 2-week repeat dose range finding study in male rats [n00240179],
degeneration of spermatids of the testes was observed which is considered a secondary effect, 
related to overt toxicity and morbidity.
It is unknown whether BI 894416 or its metabolites are distributed into male semen. 
Theoretically, there is a risk for exposure of a trial subject’s female partner who is a woman 
of child bearing potential (WOCBP) to subtherapeutic exposures of BI 894416 or its 
metabolites via male semen. Developmental and reproductive studies have not yet been 
conducted. Therefore, the effect of subtherapeutic concentrations of BI 894416 or its 
metabolites with regards to embryofetal risk has not been explored so far.


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Risk mitigation: In order to address the risk of exposure of a subject’s female WOCBP 
partner to BI 894416 or its metabolites via the subject’s seminal fluid, subjects need to use 
barrier contraception (condom) or abstinence (refer also to Section 3.3.3).
Phototoxicity
Subjects will be advised to avoid direct exposure to sun and UV light during the entire trial
(refer to Section 4.2.2.2). Further protective measures would not be necessary, given the low 
phototoxic potential of BI 894416.
Potential effects on QT interval
Preclinical studies suggested no pro-arrhythmic potential or cardiovascular liability with 
BI 894416. However, statistical results of first-in-man trial 1371-0001 showed a most-likely 
dose- and concentration-dependent increase of QTcF interval. At gMean Cmax of the 70 mg 
dose group, placebo- and baseline-corrected predicted mean QTcF increase was 5.9 ms (upper 
limit of the 90%-CI was 10.5 ms). In this study, the risk of QT prolongation may need 
differential considerations: While the risk might be similar after the administration of 60 mg 
of the IR reference formulation as compared to the trial 1371-0001 in which a single dose of
70 mg was administered, the risk might be lower after the administration of the ER 
formulations, due to the Cmax of BI 894416 which is expected to be lower. Also, in trial 1371-
0008 after a single dose of 75 mg, no ECG changes were noted.
Risk mitigation and monitoring: Subjects with cardiovascular disorders (refer also to 
Section 3.3.3), subjects who have been using drugs that cause QT/QTc prolongation (refer 
also to Section 3.3.3), subjects who show a marked baseline prolongation of QT/QTc interval 
or any other relevant ECG finding at screening (refer also to Section 3.3.3), and subjects with 
a history of additional risk factors for Torsade de Pointes arrhythmia (refer also to 
Section 3.3.3) will be excluded from trial participation. Moreover, subjects will be in-house
under close observation for 72 h following drug administration, and ECGs are registered pre-
and post-dose at the time points given in the Flow Chart. Considering these risk-mitigating
measures, the risk to subjects participating in this trial due to potential effects on the QT 
interval are considered minimal.
1.4.4
Drug-induced liver injury
Although rare, a potential for drug-induced liver injury (DILI) is under constant surveillance 
by sponsors and regulators. Therefore, this trial requires timely detection, evaluation, and 
follow-up of laboratory alterations in selected liver laboratory parameters to ensure subjects´ 
safety. For further information, refer to Section 5.2.6.1.4, adverse events of special interest.
1.4.5
Overall assessment of benefit-risk ratio
BI 894416 is a highly specific SYK inhibitor that has been adequately characterised in pre-
clinical studies. The non-clinical safety package supports administration of BI 894416 of up 
to 4 weeks duration to man.


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Data of previous trials 1371-0001 and 1371-0008 indicate good safety and tolerability of 
single oral doses of BI 894416 at all dose levels up to 70 mg and 75 mg, respectively. In 
addition, data from oral administration of three SYK inhibitors are available and provide 
additional information on safety and tolerability of this class of drug in man. Published data 
indicate acceptable safety and tolerability of these three SYK inhibitors in healthy volunteers. 
For details, refer to the most recent IB [c03536505]).
BI 894416 plasma exposures in this trial are expected to be within the range of those values 
that were observed in the first-in-man trial 1371-0001 and that were associated with good 
safety and tolerability.
Considering the medical need for a better treatment in severe asthma and taking into account 
the (so far) known safety profile of BI 894416, characterised in trials 1371-0001 (single 
rising dose, first in man), 1371-0021 (food interaction), 1371-0004 (itraconazole interaction)
and the ongoing 1371-0008, the expected benefit is likely to outweigh the potential risks and 
justifies exposure of healthy volunteers.


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2.
TRIAL OBJECTIVES AND ENDPOINTS
2.1
MAIN OBJECTIVES, PRIMARY AND SECONDARY ENDPOINTS
2.1.1
Main objectives
The main objective of this trial is to select a formulation principle (tablet vs. capsule) and to 
optimize the identified extended release formulation of BI894416, if needed.
2.1.2
Primary endpoint
The following pharmacokinetic parameters will be determined for BI 894416:

AUC0-∞(area under the concentration-time curve of the analyte in plasma over the 
time interval from 0 extrapolated to infinity)
2.1.3
Secondary endpoint
The following pharmacokinetic parameter will be determined for BI 894416:

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)


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2.2.2.2
Safety and tolerability
Safety and tolerability of BI 894416 will be assessed based on:

Adverse events (including clinically relevant findings from the physical examination)

Safety laboratory tests

12-lead ECG

Vital signs (blood pressure, pulse rate)


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3.
DESCRIPTION OF DESIGN AND TRIAL POPULATION
3.1
OVERALL TRIAL DESIGN AND PLAN
The study will be performed in healthy male subjects as an open-label, randomised, single-
dose study in two parts. For a depiction of the overall study design, refer to Figure 3.1: 1.
Figure 3.1: 1
Example of the overall study design
Trial part 1 (n=24) will be performed as a five-period crossover design in order to compare
test treatments T1 to T4 to the reference treatment R1. These treatments will be administered 
under fasted conditions and in one of the following 5 sequences, T3-R1-T1-T4-T2, T2-T1-
T3-R1-T4, T4-T3-R1-T2-T1, T1-T4-T2-T3-R1, R1-T2-T4-T1-T3. Test treatments T5 or T6 
will be added as the sixth treatment period. These treatments will be administered under fed
conditions.
Trial part 2 (n=18) is optional and will be split in two parts. Trial part 2A will be performed 
as a three-period crossover design, with sequences T7-T8-R2, R2-T7-T8 and T8-R2-T7, to 
compare treatments T7 and T8 to the reference treatment R2. If appropriate, trial part 2B will 
follow as a two-period crossover design, with sequences T9-T10 and T10-T9, in order to 
compare test treatments T9 and T10.
A single dose of each treatment will be administered as follows:
Trial part 1

R1-Reference Formulation 1: 60 mg BI 894416, fasted (n=24)

T1-Prototype Formulation A2: 62.5 mg BI 894416, fasted (n=24)

T2- Prototype Formulation C2: 62.5 mg BI 894416, fasted (n=24)

T3- Prototype Formulation D2: 62.5 mg BI 894416, fasted (n=24)

T4- Prototype Formulation F2: 62.5 mg BI 894416, fasted (n=24)
At least 10 subjects of part 1 (fixed sequence part)

T5- Prototype Formulation C2: 62.5 mg BI 894416, after high-fat, high-calorie 
breakfast (n≥10)
R1
T1
T2
T3
T4
T4
T2
T3
T1
R1
T5/6
T5/6
T5/6
T5/6
T5/6
R2
T7
T8
T7
T8
R2
T9
T10
T10
T9
Trial Part 1
Trial Part 2A
Trial Part 2B
Stop or Optimise
Stop or Optimise
Note: Depicted sequences are examples only


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At least 10 of the other subjects of part 1 (fixed sequence part)

T6- Prototype Formulation F2: 62.5 mg BI 894416, after high-fat, high-calorie 
breakfast (n≥10)
Decision point: either (a) stop here or (b) proceed to trial part 2A with either optimised 
formulations G (tablet) or I (capsule), as T7 under fasted conditions and T8 after a high-fat, 
high-calorie breakfast.
Decision rules:
The decision will be based on data of a minimum of 16 evaluable subjects and will include
the assessment of (i) safety parameters (e.g. AE’ ECG, vital signs and safety laboratory data)
up to 72 h post-dose, (ii) preliminary pharmacokinetic analysis up to 58h post-dose, and (iii) 
pharmacokinetic simulations, using an existing model which was based on pharmacokinetic 
data of Phase I studies.
Criteria to stop after trial part 1 will be:

Pharmacokinetic simulations to steady state demonstrate a Cmin
 under 
fasted and fed conditions and further optimization of the formulation with regards to 
dose and drug release is not expected to improve pharmacokinetic properties.

Pharmacokinetic simulations to steady state indicate that Cmin
 cannot 
be achieved under fasted and/ or fed conditions even considering dose and drug 
release optimization.
For additional discontinuation criteria, refer to Section 3.3.4.3.
Criteria to continue after trial part 1 will be:

Pharmacokinetic simulations to steady state demonstrate a Cmin ≥ 
 under 
fasted and/ or fed conditions and further optimization of formulation with regards to 
dose and drug release is expected to improve pharmacokinetic properties

Pharmacokinetic simulations to steady state demonstrate a Cmin
 under 
fasted and/ or fed conditions and further optimization of formulation with regards to 
dose and drug release is expected to improve to a Cmin
Improved pharmacokinetic properties would be (i) a reduced food effect, (ii) a higher 
at 
a similar or even reduced dose, (iii) a smaller peak to trough ratio at simulated steady state 
pharmacokinetics, (iv) possibly reduced variability of pharmacokinetic parameters. The 
optimization would be guided by (i) the formulation principle (ER tablet vs. ER capsule), (ii) 
the release rate (and profile) and (iii) the dose.
If optimization is considered possible, formulations G (ER tablet) or I (ER capsule) will be 
developed and further tested in trial part 2A.
In case, both ER tablet formulation or ER capsule formulation would qualify for 
optimization, a decision will be made based on available data.
Trial part 2 (optional)
Trial part 2A (only one, either G or I will be tested in the fasted and fed state)

R2-Reference Formulation 2: 60 mg BI 894416, fasted (n=18)


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
T7- Prototype Formulation G or I: 50-75 mg BI 894416, fasted (n=18)

T8- Prototype Formulation G or I: 50-75 mg BI 894416, after high-fat, high-calorie 
breakfast (n=18)
Decision point: either (i) stop here or (ii) proceed to trial part 2B with either optimised 
formulations H (tablet) or K (capsule), as T9 under fasted conditions and T10 after a high-fat, 
high-calorie breakfast.
Decision rules:
The decision will be based on data of a minimum of 12 evaluable subjects and will include 
the assessment of (i) safety parameters (e.g. AE’ ECG, vital signs and safety laboratory data)
up to 72 h post-dose, (ii) preliminary pharmacokinetic analysis up to 58h post-dose, and (iii) 
pharmacokinetic simulations, using an existing model which was based on pharmacokinetic 
data of Phase I studies.
Criteria to stop after trial part 2A will be:

Pharmacokinetic simulations to steady state demonstrate a
 under 
fasted and fed conditions and further optimization of the formulation with regards to 
dose and drug release is not expected to improve pharmacokinetic properties.

Pharmacokinetic simulations to steady state indicate that 
 cannot 
be achieved under fasted and/ or fed conditions even considering dose and drug 
release optimization.
For additional discontinuation criteria, refer to Section 3.3.4.3.
Criteria to continue after trial part 2A will be:

Pharmacokinetic simulations to steady state demonstrate a
 under 
fasted and/ or fed conditions and further optimization of formulation with regards to 
dose and drug release is expected to improve pharmacokinetic properties

Pharmacokinetic simulations to steady state demonstrate a 
D63 under 
fasted and/ or fed conditions and further optimization of formulation with regards to 
dose and drug release is expected to improve to a 
Improved pharmacokinetic properties would be (i) a reduced food effect, (ii) a higher 
at 
a similar or even reduced dose, (iii) a smaller peak to trough ratio at simulated steady state 
pharmacokinetics, (iv) possibly reduced variability of pharmacokinetic parameters. The 
optimization would be guided by (i) the release rate (and profile) and (ii) the dose.
If optimization is considered possible, formulations H (ER tablet) or K (ER capsule) will be 
developed and further tested in trial part 2B.
Trial part 2B (only one, either H or K will be tested in the fasted and fed state)

T9- Prototype Formulation H or K : 50-75 mg BI 894416, fasted (n=18)

T10- Prototype Formulation H or K : 50-75 mg BI 894416, after high-fat, high-calorie 
breakfast (n=18)
For details on decision making and procedures between trial parts, refer to Section 6.2.2.


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There will be a washout period of at least 4 days between the treatments, i.e. the dose in the 
preceding treatment period and the dose in the following treatment period are separated by at 
least 4 days.
Subjects will be randomly allocated to the different treatment sequences. For details, refer to 
Section 4.1.
An overview of all relevant trial activities is provided in the Flow Chart. For visit schedule 
and details of trial procedures at selected visits, refer to Sections 6.1 and 6.2, respectively.
3.2
DISCUSSION OF TRIAL DESIGN, INCLUDING THE CHOICE OF 
CONTROL GROUPS
3.2.1
Discussion of study design
All trial parts
The open-label treatment is not expected to bias results, since the study endpoints are derived 
from measurement of plasma concentrations of the analyte which are provided by a 
bioanalytical laboratory that is blinded to treatment allocation.
For relative bioavailability trials, the crossover design is preferred because of its efficiency: 
since each subject serves as his own control, the comparison between formulations is based 
on an intra-subject comparison, thus removing inter-subject variability from the comparison 
between formulations [R94-1529].
Period 6 of trial part 1 (fixed sequence)
A fixed-sequence design was selected in which BI 894416 Formulation C2 (T5) or 
Formulation F2 (T6) was administered in the sixth study period after a high-fat, high-calorie 
breakfast. The fixed-sequence design is not expected to lead to systematic errors in the 
estimation of the treatment effects since nonspecific time-effects are unlikely due to the short 
trial duration.
3.2.2
Rational for decision rules
The rational for performing this trial is to identify an ER formulation that results in 
therapeutically relevant exposures after twice daily dosing.
Rules, described in Section 3.1, allow to make a decision whether one of the tested
formulations meets the requirements after trial part 1, or whether it can be improved within 
this trial in part 2A and/ or part 2B. Rules would also guide the termination of the process,
either after trial part 1 or trial part 2A, if no successful formulation was to be achieved.
3.3
SELECTION OF TRIAL POPULATION
It is planned that a total of 42 healthy male subjects will enter the trial, 24 in trial part 1 and 
18 in trial part 2. They will be recruited from the volunteers' pool of the trial site.


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 must have a full medical history from each subject’s general practitioner 
(GP) within the last 12 months, prior to enrolment in the study. Before subjects are admitted 
to the clinical unit, The Over Volunteering Prevention System (TOPS) will be checked to 
ensure that each subject has not participated in a study at another site within at least 90 days 
of the dosing date.
Only male subjects will be included in the study because no data on reproductive toxicology 
are available at this time and because, until availability of data from the 26-week Tg.rasH2 
carcinogenicity study, study populations are restricted to male volunteers or patients (refer 
also to the most recent IB [c03536505]).
A log of all subjects enrolled into the trial (i.e. who have signed informed consent) will be 
maintained in the ISF irrespective of whether they have been treated with investigational drug 
or not.
3.3.1
Main diagnosis for trial entry
The study will be performed in healthy subjects.
3.3.2
Inclusion criteria
Subjects will only be included in the trial if they meet the following criteria:
1. Healthy male subjects according to the assessment of the investigator, as 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 55 years (inclusive) at the time of signing informed consent
3. BMI of 18.5 to 29.9 kg/m2 (inclusive) as measured at screening
4. Signed and dated written informed consent prior to admission to the study, in accordance 
with GCP and local legislation
5. Subjects who are sexually active must use, with their partner, highly effective 
contraception from the time of administration of trial medication until 30 days after 
administration of trial medication. Adequate methods are:

Condoms plus use of hormonal contraception by the female partner that started at 
least 2 months prior to administration of trial medication (e.g., implants, injectables, 
combined oral or vaginal contraceptives, intrauterine device) or

Condoms plus surgical sterilization (vasectomy at least 1 year prior to enrolment) or

Condoms plus surgically sterilised partner (including hysterectomy) or

Condoms plus intrauterine device or

Condoms plus partner of non-childbearing potential (including homosexual men)
Subjects are required to use condoms to prevent unintended exposure of the partner (both,
male and female) to the study drug via seminal fluid. Male subjects should use a condom 
throughout the study and for 30 days after last IMP administration. Alternatively, true 
abstinence is acceptable when it is in line with the subject’s preferred and usual lifestyle. 


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If a subject is usually not sexually active but becomes active, with their partner, they must 
comply with the contraceptive requirements detailed above
Male subjects should not donate sperm for the duration of the study and for at least 30 days
after last IMP administration
3.3.3
Exclusion criteria
Subjects will not be allowed to participate, if any of the following general criteria apply:
1. Any finding in the medical examination (including BP, PR, ECG, physical and 
neurological examination) deviating from normal and assessed 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 40 to 90 mmHg, or pulse rate outside the 
range of 40 to 100 bpm at screening and pre-dose of first period
3. Any laboratory value outside the reference range that the investigator considers to be of 
clinical relevance
4. Any evidence of a concomitant disease assessed as clinically relevant by the investigator
5. Gastrointestinal, hepatic, renal, respiratory, cardiovascular, metabolic, immunological or 
hormonal disorders
6. Cholecystectomy or other surgery of the gastrointestinal tract that could interfere with the 
pharmacokinetics of the trial medication (except appendectomy or simple hernia repair)
7. Diseases of the central nervous system (including but not limited to any kind of seizures 
or stroke), and other relevant neurological or psychiatric disorders
8. History of relevant orthostatic hypotension, fainting spells, or blackouts
9. Chronic or relevant acute infections
10. History of relevant allergy or hypersensitivity (including allergy to the trial medication or 
its excipients). Inactive hayfever is permitted
11. Use of drugs within 30 days of planned administration of trial medication that might 
reasonably influence the results of the trial (including drugs that cause QT/QTc interval
prolongation)
12. Intake of an investigational drug in another clinical trial within 90 days of planned first 
administration of investigational drug in the current trial, or concurrent participation in 
another clinical trial in which investigational drug is administered
13. Smoker (unless the subject quit smoking for at least 3 months prior to first planned 
administration of trial medication) as demonstrated by a positive urine cotinine test; this 
includes also the use of e-cigarettes and nicotine replacement products
14. Alcohol abuse (consumption of more than 21 units per week) or positive alcohol breath 
test
15. Drug abuse or positive drug screening
16. Blood donation of more than 100 mL within 30 days of planned administration of trial 
medication or intended blood donation during the trial
17. Intention to perform excessive physical activities within one week prior to the 
administration of trial medication or during the trial


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18. Inability to comply with the dietary regimen of the trial site
19. A marked baseline prolongation of QT/QTc interval (such as QTc intervals that are 
repeatedly greater than 450 ms) or any other relevant ECG finding at screening and pre-
dose
20. A history of additional risk factors for Torsade de Pointes (such as heart failure, 
hypokalaemia, or family history of Long QT Syndrome)
21. Subject is assessed as unsuitable for inclusion by the investigator, for instance, because 
the subject is not considered able to understand and comply with study requirements, or 
has a condition that would not allow safe participation in the study 
In addition, the following trial-specific exclusion criteria apply:
22. History of relevant neurological disorder affecting the peripheral or central nervous 
system (this includes but is not limited to: stroke, epilepsy, inflammatory or atrophic 
diseases affecting the nervous system, cluster headache or any cancer of the nervous 
system). Febrile seizures in childhood or adolescence, recovered carpal tunnel syndrome, 
recovered uncomplicated meningitis, recovered herpes zoster, tension headache, 
occasional benign tics (e.g. due to stress) or minor par- or dysesthesia (e.g. as a side effect 
of prior blood withdrawal) do not constitute a history of relevant neurological disorder.
23. History of immunological disease, except allergy not relevant to the trial (such as mild 
hay fever or dust mite allergy) and except asthma in childhood or adolescence
24. History of cancer (other than successfully treated basal cell carcinoma)
25. Liver enzymes (ALT, AST, GGT, AP) above upper limit of normal at the screening 
examination
26. Within 10 days prior to administration of trial medication, use of any drug that could 
reasonably inhibit platelet aggregation or coagulation (e.g., acetylsalicylic acid)
27. Male subjects with WOCBP partner who are unwilling to use male contraception 
(condom or sexual abstinence) from time point of first administration of trial medication 
until 30 days after the last administration of trial medication
28. Subjects with pregnant or lactating partners
For study restrictions, refer to Section 4.2.2.
3.3.4
Withdrawal of subjects from treatment or assessments
Subjects may discontinue trial treatment or withdraw consent to trial participation as a whole 
(‘withdrawal of consent’) with very different implications. For details, refer to 
Sections 3.3.4.1 and 3.3.4.2 below.
If a subject is removed from or withdraws from the trial prior to the first administration of 
trial medication, the data of this subject will not be entered in the case report form (CRF) and 
will not be reported in the clinical trial report (CTR). If a subject is removed from or 
withdraws from the trial after the first administration of trial medication, this will be 
documented and the reason for discontinuation must be recorded in the CRF; in addition, the 
data will be included in the CRF and will be reported in the CTR. At the time of 


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discontinuation, a complete end of trial examination will be performed, if possible, and the 
information will be recorded in the CRF.
3.3.4.1
Discontinuation of trial treatment
An individual subject will discontinue trial treatment, if:
1. The subject wants to discontinue trial treatment, without the need to justify the decision
2. The subject has repeatedly shown to be non-compliant with important trial procedures 
and, in the opinion of both, the investigator and sponsor representative, is not willing or 
able to adhere to the trial requirements in the future
3. The subject needs to take concomitant medication that interferes with the investigational 
medicinal product or other trial treatment
4. The subject can no longer receive trial treatment for medical reasons (such as surgery, 
adverse events [AEs], or diseases)
5. The subject has an elevation of AST and/ or ALT ≥3-fold ULN and an elevation of total 
bilirubin ≥2-fold ULN (measured in the same blood sample) and/ or needs to be followed 
up according to the DILI checklist provided in the ISF
6. The subject experiences a drug-related AE of severe intensity or a serious AE including 
but not limited to:
Corrected QT interval by Fridericia’s formula (QTcF) interval of >500 msec or increase 
in QTcF interval of >60 msec from baseline (confirmed following a repeat ECG) 
In addition to these criteria, the investigator may discontinue subjects at any time based on 
his or her clinical judgment.
Even if the trial treatment is discontinued, the subject remains in the trial and, given his 
agreement, will undergo the procedures for early treatment discontinuation and follow up as 
outlined in the Flow Chart, and Section 6.2.3.
3.3.4.2
Withdrawal of consent to trial participation
Subjects may withdraw their consent to trial participation at any time without the need to 
justify the decision. If a subject wants to withdraw consent, the investigator should be 
involved in the discussion with the subject and explain the difference between trial treatment 
discontinuation and withdrawal of consent to trial participation, as well as explain the options 
for continued follow up after trial treatment discontinuation. Refer also to Section 3.3.4.1
above.
3.3.4.3
Discontinuation of the trial by the sponsor
Boehringer Ingelheim reserves the right to discontinue the trial at any time for any of the 
following reasons:
1. Failure to meet expected enrolment goals overall or at a particular trial site


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2. New toxicological findings, serious adverse events, or any safety information invalidating
the earlier positive benefit-risk-assessment. More specifically, the trial will be terminated,
if more than 50% of the subjects have drug-related and clinically relevant adverse events 
of moderate or severe intensity, or if at least 1 drug-related serious adverse event is 
reported
3. Violation of GCP or the CTP or the contract with BI impairing the appropriate conduct of 
the trial
4. The sponsor decides to discontinue the further development of the investigational product
The investigator/ trial site will be reimbursed for reasonable expenses incurred in case of trial 
termination (except, if item 3 applies).
Stopping Criteria
The study will be halted, and the risk to other subjects evaluated, if any of the following 
criteria are met:

A serious adverse reaction (i.e., a serious AE considered at least possibly related to the 
IMP administration) in one subject.

Severe non-serious adverse reactions (i.e., severe non-serious AE considered as, at least 
possibly related to the IMP administration) in two subjects in the same cohort ( cohort 
refers to subjects receiving the same treatment), independent of within or not within the
same system organ class.
3.3.5
Replacement of subjects
In case of more than 4 subjects in trial part 1 and 4 subjects in trial part 2 do not complete the 
trial, the Clinical Trial Leader together with the Trial Pharmacokineticist and the Trial 
Statistician are to decide, if and how many subjects will be replaced and which regimens they 
are required to complete. A total of maximum 8 subjects will be replaced in the whole trial. A 
replacement subject will be assigned a unique trial subject number, and will be assigned to 
the same treatment as the subject he replaces.
In trial part 1, up to 8 replacement subjects may be enrolled into the study. The maximum 
number of replacement subjects that may be dosed is 4.
In trial part 2, up to 8 replacement subjects may be enrolled into the study. The maximum 
number of replacement subjects that may be dosed is 4.
Subjects withdrawn due to an IMP-related AE or termination of the study will not be 
replaced.
Subjects who are withdrawn for other reasons may be replaced at the discretion of the 
investigator and sponsor to ensure sufficient evaluable subjects.
For trial part1 and 2, replacement subjects will complete the entire sequence.


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4.
TREATMENTS
4.1
INVESTIGATIONAL TREATMENTS
The investigational products are manufactured by two different manufacturers:

IR reference tablet: 

ER tablet and ER capsule: 
BI 894416 doses will be calculated and administered as a free base, so the conversion factor 
is 1. The molecular weight of BI 894416 is 382.46 g/mol.
4.1.1
Identity of the Investigational Medicinal Products
Trial part 1
The characteristics of the test product are given below:
Name:
T1- Prototype Formulation A2 (ER tablet - fast release rate)
Substance:
BI 894416
Pharmaceutical formulation: Tablet
Source:
Unit strength:
62.5 mg
Posology:
1-0-0
Route of administration:
Oral with 240 mL of water after an overnight fast of at least 
10 h
Duration of use:
One day (single dose) for each treatment
Name:
T2 & T5/ Prototype Formulation C2(ER tablet – slow release 
rate)
Substance:
BI 894416
Pharmaceutical formulation: Tablet
Source:
Unit strength:
62.5 mg
Posology:
1-0-0
Route of administration:
Oral with 240 mL of water after an overnight fast of at least 
10 h or (T2)
Oral with 240 mL of water following a high-fat high-calorie
breakfast (T5)
Duration of use:
One day (single dose) for each treatment


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Name:
T3- Prototype Formulation D2(ER capsule – fast release rate)
Substance:
BI 894416
Pharmaceutical formulation: Capsule
Source:
Unit strength:
62.5 mg
Posology:
1-0-0
Route of administration:
Oral with 240 mL of water after an overnight fast of at least 
10 h
Duration of use:
One day (single dose) for each treatment
Name:
T4 & T6- Prototype Formulation F2 (ER capsule – slow
release rate)
Substance:
BI 894416
Pharmaceutical formulation: Capsule
Source:
Unit strength:
62.5 mg
Posology:
1-0-0
Route of administration:
Oral with 240 mL of water after an overnight fast of at least 
10 h or
Oral with 240 mL of water following a high-fat high-calorie
breakfast
Duration of use:
One day (single dose) for each treatment
The characteristics of the reference product are given below:
Name:
R1-Reference Formulation 1 (IR tablet)
Substance:
BI 894416
Pharmaceutical formulation: Tablet
Source:
Unit strength:
10 mg
Posology:
6-0-0
Route of administration:
Oral with 240 mL of water after an overnight fast of at least 
10 h
Duration of use:
One day (single dose) for each treatment


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Trial part 2 (optional)
Name:
T7 & T8/ Prototype Formulation G or I(optimized ER tablet 
or ER capsule formulation)
Substance:
BI 894416
Pharmaceutical formulation: Tablet (Formulation G) or Capsule (Formulation I)
Source:
Unit strength:
50 to 75 mg
Posology:
1-0-0
Route of administration:
Oral with 240 mL of water after an overnight fast of at least 
10 h or (T7)
Oral with 240 mL of water following a high-fat high-calorie
breakfast (T8)
Duration of use:
One day (single dose) for each treatment
Name:
T9 & T10/ Prototype Formulation H or K(optimized ER tablet 
or ER capsule formulation
Substance:
BI 894416
Pharmaceutical formulation: Tablet (Formulation H) or Capsule (Formulation K)
Source:
Unit strength:
50 to 75 mg
Posology:
1-0-0
Route of administration:
Oral with 240 mL of water after an overnight fast of at least 
10 h or (T9)
Oral with 240 mL of water following a high-fat high-calorie
breakfast (T10)
Duration of use:
One day (single dose) for each treatment
The characteristics of the reference product are given below:
Name:
R2- Reference Formulation 2 (IR tablet)
Substance:
BI 894416
Pharmaceutical formulation: Tablet
Source:


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Unit strength:
10 mg
Posology:
6-0-0
Route of administration:
Oral with 240 mL of water after an overnight fast of at least 
10 h
Duration of use:
One day (single dose) for each treatment
4.1.2
Selection of doses in the trial and dose modifications
The doses selected for the ER tablet or ER capsule are expected to result in clinically relevant 
BI 894416 exposures. Dose modification within a defined range would become necessary, if 
the extent of absorption from a ER formulation differed from that of the IR formulation.
4.1.3
Method of assigning subjects to treatment groups
The randomisation list will be provided to the trial site in advance.
According to the planned sample size of trial part 1(n=24), 2 cohorts (12 subjects each) are 
planned. Each subject will be allocated to one of 10 treatment sequences (R1, T1 to T4 and 
T5, or R1, T1 to T4 and T6). For details, refer to Section 7.6.
According to the planned sample size of trial part 2 (n=18), each subject will be allocated to 
one of five treatment sequence (R2, T7 to T10). For details, refer to Section 7.6.
Prior to the start of the study, subjects willing to participate will be recruited to cohorts 
according to their temporal availability. In the morning of Day 1 (Visit 2), subjects will be 
allocated to treatment sequences prior to the first administration of trial medication. For this 
purpose, numbers of the randomisation list will be allocated to the subjects sequentially just 
prior to first dosing by using the method ‘first come, first served’. Subjects are then assigned 
to a treatment sequence according to the randomisation list. Hence, no bias is introduced 
when providing the randomization list in advance to the site. Reference and test treatments 
will be administered in the sequence specified in the Flow Chart.
Once a subject number has been assigned, it cannot be reassigned to any other subject.
The randomisation procedure is described in Section 7.6.
4.1.4
Drug assignment and administration of doses for each subject
This trial is an open-label, randomised, single-dose study in two parts.
All 24 subjects of trial part 1 will receive six treatments in randomised order as a five-period 
crossover design with an additional sixth period as a fixed sequence.
All 18 subjects of trial part 2 will receive in randomised order first three treatments in a three-
period crossover design, followed by two treatments in a two-period crossover design (if 
appropriate).
Trial part 1
The treatments to be evaluated in trial part 1 are outlined in Table 4.1.4: 1 below.


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Table 4.1.4: 1
Dosage and treatment schedule – trial part 1
Treatment
Substance
Formulation
Unit 
strength
Dosage
Total dose
Trial part 1
T1 (Test 1)
BI 894416
Tablet/ Formulation A2,
fasted (n=24)
62.5 mg
1 Tablet SD
62.5 mg
T2 (Test 2)
BI 894416
Tablet/ Formulation C2,
fasted (n=24)
62.5 mg
1 Tablet SD
62.5 mg
T3 (Test 3)
BI 894416
Capsule/ Formulation D2,
fasted (n=24)
62.5 mg
1 Capsule SD
62.5 mg
T4 (Test 4)
BI 894416
Capsule/ Formulation F2,
fasted (n=24)
62.5 mg
1 Capsule SD
62.5 mg
T5 (Test 5)
BI 894416
Tablet/ Formulation C2,
fed (n≥10)
62.5 mg
1 Tablet SD
62.5 mg
T6 (Test 6)
BI 894416
Capsule/ Formulation F2,
fed (n≥10)
62.5 mg
1 Capsule SD
62.5 mg
R1 (Reference 1)
BI 894416
Tablet/ Reference Formulation 1,
fasted (n=24)
10 mg
6 Tablets SD
60 mg
In trial part 1, in the first five periods, administration of trial medication will be performed 
after all 24 subjects have fasted overnight. Fasting is to start no later than 10 h before the 
scheduled dosing. In the sixth period (T5 and T6), administration of trial medication will be 
performed under fed condition. A high-fat, high-calorie meal (for details, refer to Table
4.1.4: 3) will be served 30 min before drug administration. At least 10 subjects (n≥10) will 
receive treatment 5, at least 10 of the other subjects (n≥10) will receive treatment 6.
The investigator (or authorised designee) will administer the trial medication as an oral dose 
together with about 240 mL of water to subjects in a standing position. For drug 
administration, the so-called four-eye principle (two-person rule) should be applied. For this, 
one authorised employee of the trial site should witness the administration of trial medication, 
and – if applicable – its preparation (e.g. reconstitution), if correct dosage cannot be ensured 
otherwise.
Trial part 2 (optional)
The treatments to be evaluated are outlined in Table 4.1.4: 2 below.


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Table 4.1.4: 2
Dosage and treatment schedule – trial part 2 A & B (optional)
Treatment
Substance
Formulation
Unit 
strength
Dosage
Total dose
Trial part 2A
T7 (Test 7)
BI 894416
Tablet or Capsule/
Formulation G or I,
fasted (n=18)
50 to 75 mg
1 Tablet SD
50 to 75 mg
T8 (Test 8)
BI 894416
Tablet or Capsule/
Formulation G or I, 
fed (n=18)
50 to 75 mg
1 Tablet SD
50 to 75 mg
R2 (Reference 2)
BI 894416
Tablet/
Reference Formulation 2,
fasted (n=18)
10 mg
6 Tablets SD
60 mg
Trial part 2B
T9 (Test 9)
BI 894416
Tablet or Capsule/
Formulation H or K,
fasted (n=18)
50 to 75 mg
1 Tablet SD
50 to 75 mg
T10 (Test 10)
BI 894416
Tablet or Capsule/
Formulation H or K,
fed (n=18)
50 to 75 mg
1 Tablet SD
50 to 75 mg
In trial part 2A, administration of trial medication will be performed under fasted and fed 
conditions. Fasting is to start no later than 10 h before the scheduled dosing. Fed condition 
are defined as having completely consumed a high-fat, high-calorie meal (for details, refer to 
Table 4.1.4: 3 which will be served 30 min before drug administration. The administration of 
the reference formulation medication will be performed only under fasted conditions.
The investigator (or authorised designee) will administer the trial medication as an oral dose 
together with about 240 mL of water to subjects in a standing position. For drug 
administration, the so-called four-eye principle (two-person rule) should be applied. For this, 
one authorised employee of the trial site should witness the administration of trial medication, 
and – if applicable – its preparation (e.g. reconstitution), if correct dosage cannot be ensured 
otherwise.
In trial part 2B, administration of trial medication will be performed under fasted and fed 
conditions. Fasting is to start no later than 10 h before the scheduled dosing. Fed condition 
are defined as having completely consumed a high-fat, high-calorie meal (for details, refer to 
Table 4.1.4: 3) which will be served 30 min before drug administration.
The investigator (or authorised designee) will administer the trial medication as an oral dose 
together with about 240 mL of water to subjects in a standing position. For drug 
administration, the so-called four-eye principle (two-person rule) should be applied. For this, 
one authorised employee of the trial site should witness the administration of trial medication, 


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and – if applicable – its preparation (e.g. reconstitution), if correct dosage cannot be ensured 
otherwise.
Trial part 1 and 2
In certain treatment periods, as stipulated above, a high-fat, high-calorie meal will be served 
30 min before drug administration. The subjects must completely consume the meal prior to 
drug intake. The composition of the standard high-fat, high-calorie meal is detailed in 
Table 4.1.4: 3; this meal is in compliance with the FDA guidance ‘Food-Effect
Bioavailability and Fed Bioequivalence Studies’ [R03-2269]. For restrictions with regard to 
diet, refer to Section 4.2.2.2.
Table 4.1.4: 3
Composition of the high-fat, high-calorie meal
Ingredients
1 chicken eggs (whole content) for fried eggs
10 g butter for frying eggs
2 slices grilled bacon
2 toasted slices of white bread
20 g butter for buttering toast slices
1 hash brown 
240 mL whole milk (3.5% fat)
Sum1: 910 kcal
1
The total caloric content was supplied approximately as following: 144 kcal as protein, 280 kcal 
as carbohydrate, and 486 kcal as fat.
Subjects will be kept under close medical surveillance until 72 h after drug administration.
During the first 2 h after drug administration, subjects are not allowed to lie down (i.e. no 
declination of the upper body of more than 45 degrees from upright posture, except medical 
examination and assessments).
The treatments will be separated by a wash-out phase of at least 4 days.
4.1.5
Blinding and procedures for unblinding
This Phase I trial will be handled in an open fashion throughout (that is, during the conduct,
including data cleaning and preparation of the analysis). This is considered acceptable 
because the potential for bias seems to be low and does not outweigh practical considerations.
Emergency envelopes will not be provided, because the dose of trial medication is known to 
investigators and subjects.


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4.1.6
Packaging, labelling, and re-supply
The investigational medicinal products will be provided either by BI or by 
, as 
described in Section 4.1.1. They will be packaged and labelled in accordance with local law
and the principles of Good Manufacturing Practice.
For details of packing and the description of the label, refer to the ISF.
The name, address and telephone number of the trial site are provided in the subject 
information form. The EudraCT number is indicated on the title page of this protocol as well 
as on the subject information and informed consent forms.
No 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 in accordance with the recommended (labelled) storage conditions. If 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 (for BI manufactured products) or the Qualified Person (for 
 
manufactured products as provided in the list of contacts) is to be contacted immediately.
4.1.8
Drug accountability
The investigator or designee will receive the investigational drugs delivered from the sponsor
or 
 team, if the following requirements are fulfilled:

Approval of the clinical trial protocol by the IRB/ ethics committee

Availability of a signed and dated clinical trial contract between the sponsor and the 
investigational site

Approval/ notification of the regulatory authority, e.g. competent authority

Availability of the curriculum vitae of the Principal Investigator

Availability of a signed and dated clinical trial protocol
Only authorised personnel documented in the form 'Trial Staff List' may dispense medication 
to trial subjects. The trial medication must be administered in the manner specified in the 
CTP.
The investigator or designee must maintain records of the product’s delivery to the trial site, 
the inventory at the site, the use by each subject, and the 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 medicinal product and trial subjects. The 
investigator or designee will maintain records that document adequately that the subjects 
were provided the doses specified by the CTP and reconcile all investigational medicinal 
products received from the sponsor. At the time of disposal of remaining trial medication, the 
investigator or designee must verify that no remaining supplies are in the investigator’s 
possession.


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All unused medication will be disposed of locally by the trial site upon written authorisation 
of the trial clinical monitor. Receipt, usage and disposal of trial medication must be 
documented on the appropriate forms. Account must be given for any discrepancies.
4.2
OTHER TREATMENTS, EMERGENCY PROCEDURES,
RESTRICTIONS
4.2.1
Other treatments and emergency procedures
There are no special emergency procedures to be followed. No additional treatment is 
planned. However, if adverse events require treatment, the investigator can authorise 
symptomatic therapy. In those cases, subjects will be treated as necessary and, if required, 
kept under supervision at the trial site or transferred to a hospital until all results of medical 
evaluations are acceptable.
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.
Acetylsalicylic acid or other drugs that may inhibit platelet aggregation or coagulation should 
be avoided during the entire study.
Known inhibitors/ inducers of CYP3A and P-glycoprotein should be avoided during the 
entire study.
If needed, ibuprofen or paracetamol may be given to treat adverse events, e.g. headache.
4.2.2.2
Restrictions on diet and life style
Poppy-seeds containing foods should not be consumed starting 3 days before screening and
the first drug administration in the first treatment period until after the last pharmacokinetic
sample in the last period in order to avoid false-positive results in the drug screen.
While admitted to the trial site, the subjects will be instructed not to consume any foods or 
drinks other than those provided by the staff. Standardised meals will be served at the times
indicated in the Flow Chart. No food is allowed for at least 10 h before and 4 h after drug
intake.
On Day 1 of each treatment period, from 1 h before drug intake until lunch, fluid intake is 
restricted to the milk served with breakfast (refer to Table 4.1.4: 3), the water administered
with the drug, and an additional 240 mL of water at 2 h and 4 h post-dose (mandatory for all 
subjects). From lunch until 24 h post-dose, total fluid intake is not restricted.
Grapefruits, Seville oranges (sour or bitter oranges) and their juices, and dietary supplements 
and products containing St. John's wort (Hypericum perforatum) are not permitted from 


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7 days before the first administration of trial medication until after the last pharmacokinetic 
sample in the last treatment period is collected.
Alcoholic beverages are not permitted from 2 days before screening and the first 
administration of trial medication in the first period until discharge from the unit at each 
study period (where applicable).
Smoking is not allowed 3 months prior to screening and during the trial.
Barbecued meat and broccoli should be avoided during the trial.
Methylxanthine-containing drinks or foods (such as coffee, tea, cola, energy drinks, or 
chocolate) are not allowed from 10 h before until 24 h after each administration of 
BI 894416.
Excessive physical activity (such as competitive sport) should be avoided from 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.
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 
of trial medication will provide additional confirmation of compliance.
Mouth and hand checks will be conducted after dosing to ensure the tablet(s)/ capsule has 
been swallowed.
The date and time that each subject is dosed will be recorded in the subject’s source data. 
Any violation of compliance will require evaluation by the investigator and sponsor to 
determine if the subject can continue in the study.
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, refer to Section 3.3.4.1).


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5.
ASSESSMENTS
5.1
ASSESSMENT OF EFFICACY
Not applicable.
5.2
ASSESSMENT OF SAFETY
5.2.1
Physical examination
At screening, the medical examination will include demographics, height and body weight, 
smoking and alcohol history (alcohol history results are not mandatory to be entered into
CRF or to be reported), 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 including a 
neurological examination.
5.2.2
Vital signs
Systolic and diastolic blood pressures (BP) as well as pulse rate (PR) or heart rate (heart rate 
is considered to be equal to pulse rate) will be measured by a blood pressure monitor (DASH 
4000) at the times indicated in the Flow Chart, after subjects have rested for at least 5 min in
a supine position. All recordings should be made using the same type of blood pressure 
recording instrument on the same arm, if possible.
5.2.3
Safety laboratory parameters
For the assessment of laboratory parameters, blood and urine samples will be collected by the 
trial site at the times indicated in the Flow Chart. For all safety laboratory sets A and B,
subjects should be fasted for at least 10 h. For retests, at the discretion of the investigator or 
designee, overnight fasting is not required.
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
BI test name [comment/ abbreviation]
A
B
Haematology
Haematocrit
Haemoglobin
Red Blood Cell Count/ Erythrocytes
White Blood Cells/ Leucocytes
Platelet Count/ Thrombocytes (quant)
X
X
X
X
X
X
X
X
X
X
Automatic WBC 
differential, relative
Neutrophils; Eosinophils; Basophils; Monocytes; 
Lymphocytes
X
X
Automatic WBC 
differential, absolute 
Neutrophil, absol.; Eosinophils, absol.; Basophils, absol.; 
Monocytes, absol.; Lymphocytes, absol.
X
X
Manual differential 
WBC (if automatic
differential WBC is 
abnormal and 
clinically relevant in 
the opinion of the 
investigator)
Neut. Poly (segs); Neut. Poly (segs), absol.; Neutrophils 
Bands; Neutrophils Bands, absol.; Eosinophils/ Leukocytes; 
Eosinophils, absol.; Basophils/ Leukocytes; Basophils, absol.; 
Monocytes/ Leukocytes; Monocytes, absol.; Lymphocytes/
Leukocytes; Lymphocytes, absol.
Coagulation
Activated Partial Thromboplastin Time
Prothrombin Time – INR (International Normalization Ratio)
X
X
X
X
Enzymes
AST [Aspartate transaminase]/ GOT, SGOT
ALT [Alanine transaminase]/ GPT, SGPT
Alkaline Phosphatase
Gamma-Glutamyl Transferase
X
X
X
X
X
X
X
X
Hormones
Thyroid Stimulating Hormone
X
--
Substrates
Glucose (Plasma)
Creatinine
Bilirubin, Total
Bilirubin, Direct (only if bilirubin above upper limit normal)
Protein, Total
C-Reactive Protein (Quant)
X
X
X
X
X
X
X
X
X
X
X
X
Electrolytes
Sodium
Potassium
Calcium
Chloride
X
X
X
X
X
X
X
X
Urinalysis (Stix)
Urine Nitrite (qual)
Urine Protein (qual)
Urine Glucose (qual)
Urine Ketone (qual)
Urobilinogen (qual)
Urine Bilirubin (qual)
Urine RBC/ Erythrocytes (qual)
Urine WBC/ Leucocytes (qual)
Urine pH
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Urine sediment 
(microscopic 
examination if 
erythrocytes, 
leukocytes nitrite or 
protein are abnormal 
in urine)
Only positive findings will be reported (for instance, the 
presence of sediment bacteria, casts in sediment, squamous 
epithelial cells, erythrocytes, leukocytes)
X
X
A and B, are different sets of laboratory examinations. Flow Chart detail at which time point the respective set is
performed


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The tests listed in Table 5.2.3: 2 are exclusionary laboratory tests that may be repeated as 
required. The results will not be entered in the CRF/ database and will not be reported in the 
CTR. Except for drug screening, it is planned to perform these tests during screening only. 
Drug screening will be performed at screening and prior to each treatment period.
Table 5.2.3: 2
Exclusionary laboratory tests
Functional lab group
Test name 
Drug screening (urine)
Amphetamine/ MDA
Barbiturates
Benzodiazepine
Cannabis
Cocaine
Methadone
Methamphetamines/ MDMA/XTC
Opiates
Phencyclidine
Tricyclic antidepressants
Urine cotinine
Infectious serology (blood)
Hepatitis B surface antigen (qualitative)
Hepatitis B core antibody (qualitative)
Hepatitis C antibodies (qualitative)
HIV-1 and HIV-2 antibody (qualitative)
To encourage compliance with alcoholic restrictions, a breath alcohol test (
 Alcolmeter 
S-D2) will be performed prior to each treatment period, and may be repeated at any time 
during the study at the discretion of an investigator or designee. The results will not be 
included in the CTR. The urine cotinine test is only performed at screening.
The laboratory tests listed in Tables 5.2.3: 1 and 5.2.3: 2 will be performed at ‘
 
, with the exception 
of drug screening and urine cotinine test. These tests will be performed at the trial site using 
an 
Drug Screen Test Cup or comparable test systems.
5.2.4
Electrocardiogram
Twelve-lead ECGs (I, II, III, aVR, aVL, aVF, V1 - V6) will be recorded using a 
computerised electrocardiograph (
 ELI 250) at the times provided in the Flow Chart.
To achieve a stable heart rate at rest and to assure high quality recordings, the site personnel 
will be instructed to assure a relaxed and quiet environment so that all subjects are at
complete rest.
All ECGs will be recorded for a 10 sec duration after subjects have rested for at least 5 min in 
a supine position. ECG assessment will always precede all other study procedures scheduled 
for the same time to avoid compromising ECG quality.
All ECGs will be stored as paper copies. Electrode placement will be performed according to 
the method of Wilson, Goldberger and Einthoven modified by Mason and Likar (hips and 
shoulders instead of ankles and wrists). Precise electrode placement will be marked with an 
indelible mark on the skin to allow reproducible placement throughout the study.


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All locally printed ECGs will be evaluated by the investigator or a designee. Abnormal 
findings will be reported as AEs (during the trial) or baseline conditions (at screening) if 
assessed to be clinically relevant by the investigator. Any ECG abnormalities will be 
carefully monitored and, if necessary, the subject will be removed from the trial and will 
receive the appropriate medical treatment.
ECGs may be repeated for quality reasons (for instance, due to alternating current artefacts, 
muscle movements, or electrode dislocation) and the repeated ECG will be used for analysis. 
Additional (unscheduled) ECGs may be collected by the investigator for safety reasons.
5.2.5
Other safety parameters
5.2.5.1
Neurological examination
At Screening and at EoT examination, a physical neurological examination will be 
performed. Upon investigator judgment, additional neurological examinations may be added 
at any time during the trial, for individual subjects or for the whole treatment group.
The neurological examination will include the following assessments:

Eye movement

Pupil size and pupil reactivity

Reflexes

Assessment of muscle strength

Gait

Romberg test

Tremor

Point-to-point movements

Sensitivity
Documentation, Assessment, and Reporting
Results will be documented in source data at the clinical trial site and assessed for clinical 
relevance by an investigator, deputy investigator or sub-investigator. Clinically relevant 
findings of the neurological examination will be reported as Adverse Events (during the trial) 
or as baseline conditions (at screening). Case narratives may be written, if necessary.
5.2.6
Assessment of adverse events
5.2.6.1
Definitions of adverse events
Adverse event
5.2.6.1.1
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.


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The following should also be recorded as an AE in the CRF and BI SAE form (if applicable):

Worsening of the underlying disease or of other pre-existing conditions 

Changes in vital signs, ECG, physical examination, and laboratory test results, if they 
are judged clinically relevant by the investigator
If such abnormalities already pre-exist prior to trial inclusion, they will be considered as 
baseline conditions and should be collected in the eCRF only.
Serious adverse event
5.2.6.1.2
A serious adverse event (SAE) is defined as any AE which fulfils at least one of the 
following criteria:

Results in death 

Is life-threatening, which refers to an event in which the patient was at risk of death 
at the time of the event; it does not refer to an event that hypothetically might have 
caused death if more severe

Requires inpatient hospitalisation

Requires prolongation of existing hospitalisation

Results in persistent or significant disability or incapacity

Is a congenital anomaly/ birth defect

Is deemed serious for any other reason if it is an important medical event when based 
upon appropriate medical judgment which may jeopardize the patient and may 
require medical or surgical intervention to prevent one of the other outcomes listed in 
the above definitions. Examples of such events are intensive treatment in an 
emergency room or at home for allergic bronchospasm, blood dyscrasias or 
convulsions that do not result in hospitalization or development of dependency or 
abuse
AEs considered ‘Always Serious’
5.2.6.1.3
Cancers of new histology and exacerbations of existing cancer must be classified as a serious 
event regardless of the time since discontinuation of the trial medication and must be reported 
as described in Section 5.2.6.2, subsections ‘AE Collection’ and ‘AE reporting to sponsor
and timelines’.
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 
defined above.
The latest list of ‘Always Serious AEs’ can be found in the eDC system, an electronic data 
capture system which allows the entry of trial data at the trial site. These events should 
always be reported as SAEs as described above.


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Adverse events of special interest
5.2.6.1.4
The term adverse events of special interest (AESI) relates to any specific AE that has been 
identified at the project level as being of particular concern for prospective safety monitoring 
and safety assessment within this trial, e.g. the potential for AEs based on knowledge from 
other compounds in the same class. AESIs need to be reported to the sponsor’s 
Pharmacovigilance Department within the same timeframe that applies to SAEs, refer to 
Section 5.2.6.2.2.
The following are considered as AESIs:

Hepatic injury
A hepatic injury is defined by the following alterations of hepatic laboratory 
parameters:
o
An elevation of AST (aspartate transaminase) and/ or ALT (alanine transaminase)
≥3-fold ULN combined with an elevation of total bilirubin ≥2-fold ULN measured 
in the same blood sample, or
o
Aminotransferase (ALT, and/ or AST) elevations ≥10 fold ULN
These lab findings constitute a hepatic injury alert and the subjects showing these lab 
abnormalities need to be followed up according to the ‘DILI checklist’ provided in the 
ISF or eDC system, as applicable. In case of clinical symptoms of hepatic injury 
(icterus, unexplained encephalopathy, unexplained coagulopathy, right upper quadrant 
abdominal pain, etc.) without lab results (ALT, AST, total bilirubin) available, the 
Investigator should make sure that these parameters are analysed, if necessary in an 
unscheduled blood test. Should the results meet the criteria of hepatic injury alert, the 
procedures described in the DILI checklist should be followed.
Intensity (severity) of AEs
5.2.6.1.5
The intensity (severity) of the AE should be judged based on the following:
Mild:
Awareness of sign(s) or symptom(s) that is/ are easily tolerated
Moderate:
Sufficient discomfort to cause interference with usual activity
Severe:
Incapacitating or causing inability to work or to perform usual activities
Causal relationship of AEs
5.2.6.1.6
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


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
Evidence that the event is reproducible when the drug is re-introduced

No medically sound alternative aetiologies that could explain the event (e.g. pre-
existing or concomitant diseases, or co-medications)

The event is typically drug-related and infrequent in the general population not 
exposed to drugs (e.g. Stevens-Johnson syndrome)

An indication of dose-response (i.e. greater effect size if the dose is increased, smaller 
effect size if dose is reduced)
Arguments that may suggest that there is no reasonable possibility of a causal relationship 
could be:

No plausible time to onset of the event relative to the time of drug exposure is evident 
(e.g. pre-treatment cases, diagnosis of cancer or chronic disease within days/ weeks of 
drug administration; an allergic reaction weeks after discontinuation of the drug 
concerned)

Continuation of the event despite the withdrawal of the medication, taking into 
account the pharmacological properties of the compound (e.g. after 5 half-lives). Of 
note, this criterion may not be applicable to events whose time course is prolonged 
despite removing the original trigger

Additional arguments amongst those stated before, like alternative explanation (e.g. 
situations where other drugs or underlying diseases appear to provide a more likely 
explanation for the observed event than the drug concerned)

Disappearance of the event even though the trial drug treatment continues or remains 
unchanged
5.2.6.2
Adverse event collection and reporting
AE collection
5.2.6.2.1
Upon enrolment into a trial, i.e. signature of the informed consent form, 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
time, and intensity of these events. In addition, each subject will be regularly assessed by the 
medical staff throughout the clinical trial and whenever the investigator deems necessary. As 
a minimum, subjects will be questioned for AEs (and concomitant therapies) at the time
points indicated in the Flow Chart. Assessment will be made using non-specific questions
such as ‘How do you feel?’. Specific questions will be asked wherever necessary in order to 
more precisely describe an AE.
A carefully 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, intensity of the event, and 
any treatment or action required for the event and its outcome.
The following must be collected and documented on the appropriate CRF(s) by the 
investigator:

From signing the informed consent onwards until an individual subject’s end of trial: 


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o
All AEs (serious and non-serious) and all AESIs 
o
The only exception to this rule are AEs (serious and non-serious) and AESIs in 
Phase I trials in healthy volunteers, when subjects discontinue from the trial due to 
screening failures prior to administration of any trial medication. In these cases, 
the subjects’ data must be collected at trial site but will not be entered in the CRF 
or trial database and will not be reported in the CTR.

After the individual subject’s end of trial:
o
The investigator does not need to actively monitor the subject for AEs but should 
only report any occurrence of cancer and related SAEs and related AESIs of 
which the investigator may become aware of by any means of communication, 
e.g. phone call. Those AEs should, however, not be reported in the CRF.
AE reporting to the sponsor and timelines
5.2.6.2.2
The Investigator must report SAEs, AESIs, and non-serious AEs which are relevant for the 
reported SAE or AESI, on the BI SAE form immediately (within 24 hours) to the sponsor’s 
unique entry point (country specific reporting process 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 send 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
5.2.6.2.3
All (S)AEs, including those persisting after the individual subject’s end of trial, must be 
followed up until they have resolved, have been sufficiently assessed as ‘chronic’ or ‘stable’, 
or no further information can be obtained.
5.2.6.2.4
Pregnancy
Once the male subject has been enrolled in the clinical trial and has taken trial medication, 
and if a partner of the male trial participant becomes pregnant, the investigator must report 
any drug exposure during pregnancy in a partner of the male trial participant immediately 
(within 24 hours) by means of Part A of the Pregnancy Monitoring Form to the sponsor’s 
unique entry point, after a written consent of the pregnant partner. The outcome of the 
pregnancy associated with the drug exposure during pregnancy must be followed up and 
reported to the sponsor’s unique entry point on the Pregnancy Monitoring Form for Clinical 
Trials (Part B).
The ISF will contain the Pregnancy Monitoring Form for Clinical Trials (Part A and Part B) 
as well as non-trial specific information and consent for the pregnant partner. As pregnancy 
itself is not to be reported as an AE, in the absence of an accompanying SAE and/ or AESI, 
only the Pregnancy Monitoring Form for Clinical Trials and not the SAE form is to be 


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completed. If there is an SAE and/or AESI associated with the pregnancy, an SAE form must 
be completed in addition.
5.3
DRUG CONCENTRATION MEASUREMENTS AND 
PHARMACOKINETICS
5.3.1
Assessment of pharmacokinetics
For the assessment of pharmacokinetics, samples will be collected at the time points indicated 
in the Flow Chart. The actual sampling times will be recorded and used for determination of 
pharmacokinetic parameters.
5.3.2
Methods of sample collection
5.3.2.1
Blood sampling for pharmacokinetic analysis
BI 894416
For quantification of BI 894416 concentrations in plasma, approximately 2.0 mL of blood 
will be drawn from an antecubital or forearm vein into a 
 
 blood drawing tube at the times indicated in 
the Flow Chart. Blood will be withdrawn by means of either an indwelling venous catheter or 
by venepuncture with a metal needle.
At a minimum, the sample tube labels should list BI trial number, subject number, visit, and 
planned sampling time. Further information such as matrix may also be provided.
Further use of samples
After the completion of BI 894416-quantification in plasma aliquots, the left-over and/ or 
back-up aliquots may be used for further methodological investigations (e.g. for stability 
testing or assessment of metabolites. However, only data related to the analyte and/ or its 
metabolite(s), including anti-drug antibodies (if applicable), will be generated by these 
additional investigations. The study samples will be discarded after completion of the 
additional investigations but not later than 5 years after the CTR is archived.
Results of any further investigations are not planned to be part of the CTR but can be 
included into the CTR, if necessary.


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5.6
APPROPRIATENESS OF MEASUREMENTS
All measurements performed during this trial are standard measurements and will be 
performed in order to monitor subjects’ safety and to determine pharmacokinetic parameters 
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 5.3,
2.1.2, 2.1.3, and 2.2.2.1 are generally used assessments of drug exposure.
Due to reversible neurologic effects observed in dog studies at high exposures, a neurological 
examination is performed at Screening to ensure that no subject with a clinically relevant 
finding in the neurological examination is included into the trial. Upon investigator judgment, 
additional neurological examinations may be added at any time during the trial, for individual 
subjects or for the whole treatment group.


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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 the end of trial examination are provided in 
Flow Chart.
Study measurements and assessments scheduled to occur ‘before’ trial medication 
administration on Day 1 are to be performed and completed within a 3 h-period prior to the 
trial drug administration.
The acceptable deviation from the scheduled time for vital signs, ECG, and safety laboratory 
tests will be ± 30 min within 4 hours after administration and ±60 min thereafter.
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 venepuncture are scheduled for the same time, venepuncture should be the last of 
the measurements due to its inconvenience to the subject and possible influence on 
physiological parameters.
For planned blood 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 
the determination of pharmacokinetic parameters.
Starting from 48 hours after BI 894416 administration a time window of ± 60 min will be 
allowed for PK samples.
If a subject misses an appointment, it will be rescheduled, if possible. The relevance of 
measurements outside the permitted time windows will be assessed no later than at the Report 
Planning Meeting.
6.2
DETAILS OF TRIAL PROCEDURES AT SELECTED VISITS
6.2.1
Screening period
After having been informed about the trial, all subjects will provide 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, physical- and neurological examination, refer to Sections 5.2.1 to 5.2.5.
This study permits the re-screening of a subject who has discontinued the study as a pre-
treatment failure (i.e., subject has not been randomised/ has not been treated); the reason for 
failure must be temporary and expected to resolve. If re-screened, the subject must be re-
consented.
The identity of the subjects will be confirmed at admission and pre-dose. The subjects will be 
admitted to the clinical unit on the evening before dosing (Day -1). The admission and pre-
dose procedures are presented in Flow Chart. In addition, the ongoing eligibility of subjects 
will be re-assessed at admission/ pre-dose, as described in Flow Chart.


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6.2.2
Treatment periods
Samples for genotyping will be taken from all subjects prior to first drug administration in
period 1 (for details, refer to Section 5.5.1).
Trial part 1
Each subject is expected to participate in 6 treatment periods. At least 4 days will separate 
drug administrations between treatment periods.
On Day -1 of the first treatment period, study participants will be admitted to the trial site and 
kept under close medical surveillance for at least 72 h following the last drug administration. 
Subjects will then be allowed to leave the trial site after formal assessment and confirmation 
of their fitness.
For details on time points and procedures for collection of plasma samples for 
pharmacokinetic analysis, refer to Flow Chart and Section 5.3.2.
The safety measurements performed during the treatment period are specified in Section 5.2, 
their sampling time points are in Flow Chart. For details on times of 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.
Decision making and procedures after trial part 1
After completion of trial part 1, a preliminary pharmacokinetic analysis will be performed
(for details, refer to Section 7.4). On the basis of these data and supported by 
pharmacokinetic simulations, the sponsor will decide on whether (i) at least one formulation 
will meet the requirements for use in future clinical studies, or (ii) no formulation will meet 
the requirements and an improvement is not possible, or (iii) a formulation principle can be 
improved and needs to be further optimized. In case of (i) and (ii) the trial will be stopped. In 
case of (iii) the trial will be continued with trial part 2A. For details on decision rules, refer to 
Section 3.1. Should the study be continued, a batch of modified study medication will be 
produced and provided by 
 This medication will then be used in trial part 2A.
A formal and documented formulation selection review will take place after trial part 1.
The review can be conducted face-to-face or by video/ telephone conference. The Clinical 
Trial Leader is responsible for the organisation and minutes of the reviews. Minutes will be 
signed off by the Principal Investigator (or an authorised deputy) and Clinical Trial Leader 
(or an authorised deputy), and will be filed in the ISF and TMF.
In addition and depending on the findings, suitable experts from the sponsor or external 
institutions may be consulted on an as needed basis. In these cases expert recommendations 
will be documented in the minutes of the review and considered for the decision making. 
Continuation to trial part 2A will only be permitted, if no safety concerns exist neither in the 
opinion of the Principal Investigator (or an authorised deputy) nor the Clinical Trial Leader 
(or an authorised deputy).
The data set will consist of the following:

BI 894416 plasma concentrations of up to at least 58 h after dosing


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
Preliminary pharmacokinetic parameter estimates (for details, refer to Section 7.4)

Safety data of up to at least 72h after dosing, e.g. adverse events, 12-lead ECG, vital 
signs and clinical laboratory tests
Trial part 2A (optional)
Each subject is expected to participate in 3 treatment periods (Day 1 in each period), if 
applicable. At least 4 days will separate drug administrations between treatment periods.
On Day -1 of each treatment period, study participants will be admitted to the trial site and 
kept under close medical surveillance for at least 72 h following drug administration. 
Subjects will then be allowed to leave the trial site after formal assessment and confirmation 
of their fitness.
For details on time points and procedures for collection of plasma samples for 
pharmacokinetic analysis, refer to Flow Chart and Section 5.3.2. 
The safety measurements performed during the treatment period are specified in Section 5.3
of this protocol and in the Flow Chart . For details on times of 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.
Decision making and procedures after trial part 2A
After completion of trial part 2A, a preliminary pharmacokinetic analysis will be performed 
(for details, refer to Section 7.4). On the basis of these data and supported by 
pharmacokinetic simulations, the sponsor will decide on whether (i) the formulation will 
meet the requirements for use in future clinical studies, or (ii) the formulation will not meet 
the requirements and an improvement is not possible, or (iii) a formulation can be improved 
and needs to be further optimized. In case of (i) and (ii) the trial will be stopped. In case of 
(iii) the trial will be continued with trial part 2B. For details on decision rules, refer to 
Section 3.1. Should the study be continued, a batch of modified study medication will be
produced and provided by 
 This medication will then be used in trial part 2B.
A formal and documented formulation review will take place after trial part 2B.
The review can be conducted face-to-face or by video/ telephone conference. The Clinical 
Trial Leader is responsible for the organisation and minutes of the reviews. Minutes will be 
signed off by the Principal Investigator (or an authorised deputy) and Clinical Trial Leader
(or an authorised deputy), and will be filed in the ISF and TMF.
In addition and depending on the findings, suitable experts from the sponsor or external 
institutions may be consulted on an as needed basis. In these cases expert recommendations 
will be documented in the minutes of the review and considered for the decision making. 
Continuation to trial 2B will only be permitted if no safety concerns exist neither in the 
opinion of the Principal Investigator (or an authorised deputy) nor the Clinical Trial Leader 
(or an authorised deputy).


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The data set will consist of the following:

BI 894416 plasma concentrations of up to at least 58 h after dosing

Preliminary pharmacokinetic parameter estimates (for details, refer to Section 7.4)

Safety data of up to at least 72h after dosing, e.g. adverse events, 12-lead ECG, vital 
signs and clinical laboratory tests
In the event the result of any particular part of the study is inconclusive, additional subjects 
may be recruited and enrolled to permit a scheduled group to be repeated once. For the repeat 
group, formulation may be adjusted within the design space of the IMPD to establish 
conditions that optimize the bioavailability of the oral formulation.
Trial part 2B (optional)
Each subject of trial part 2A is expected to participate in 2 further treatment periods (Day 1 in 
each period), if applicable. At least 4 days will separate drug administrations in the first and 
second treatment periods.
On Day -1 of each treatment period, study participants will be admitted to the trial site and
kept under close medical surveillance for at least 72 h following drug administration. The 
subjects will then be allowed to leave the trial site after formal assessment and confirmation 
of their fitness.
For details on time points and procedures for collection of plasma samples for 
pharmacokinetic analysis, refer to Flow Chart and Section 5.3.2.
The safety measurements performed during the treatment period are specified in Section 5.3
of this protocol and in the Flow Chart. For details on times of 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.
Each subject will receive a card stating the telephone number of the investigator and subjects 
will be kept under close medical surveillance until 72 h after drug administration. A
physician will be responsible for the clinical aspects of the study and will be available at all 
times during the study.
6.2.3
Follow-up period and trial completion
For AE assessment, laboratory tests, recording of ECG and vital signs, and physical- and 
neurological examination during the follow-up period, refer to Sections 5.2.1 to 5.2.5.
Subjects who discontinue treatment before the end of the planned treatment period should 
undergo the EoT Visit.
All abnormal values (including laboratory parameters) that are assessed as clinically relevant 
by the investigator will be monitored using the appropriate tests until a return to a medically 
acceptable level is achieved. (S)AEs persisting after a subject’s EoT Visit must be followed 
until they have resolved, have been sufficiently characterised, or no further information can 
be obtained.


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7.
STATISTICAL METHODS AND DETERMINATION OF
SAMPLE SIZE
7.1
STATISTICAL DESIGN – MODEL
The main objective of this trial is to investigate the relative bioavailability of extended release 
formulations compared with the immediate release formulation, following oral administration
under fasted and fed conditions on the basis of the primary and secondary pharmacokinetic 
endpoints, as listed in Sections 2.1.2 and 2.1.3.
In addition relative bioavailability between selected extended release formulations will be 
investigated. The trial is designed to allow intra-subject comparisons and will be evaluated 
statistically by use of a linear model for logarithmically transformed pharmacokinetic 
endpoints.
A further objective is to evaluate and compare further pharmacokinetic parameters between 
the treatments.
In addition the assessment of safety will be evaluated for the parameters specified in 
Section 2.2.2.2.
All parameters will be assessed descriptively.
7.2
NULL AND ALTERNATIVE HYPOTHESES
The relative bioavailability of the reference formulation will be compared with the test 
formulations, the ratios of the geometric means (test/ reference), and their corresponding
2-sided 90% confidence intervals (CIs) will be provided. In addition, relative bioavailability 
between selected extended release formulations will be investigated in the same way as 
between test and reference. Since the main focus is on estimation and not testing, a formal 
hypothesis test and associated acceptance range is not specified.
7.3
PLANNED ANALYSES
Analysis sets
Statistical analyses will be based on the following analysis sets:

Treated set (TS): The treated set includes all subjects who were randomized and 
treated with at least one dose of study drug. The treated set will be used for safety 
analyses.

Pharmacokinetic parameter analysis set (PKS): This set includes all subjects in the 
treated set (TS) who provide at least one pharmacokinetic endpoint that was defined 
as primary or secondary and was not excluded due to a protocol violation relevant to 
the evaluation of pharmacokinetics or due to pharmacokinetic non-evaluability (as 
specified in the following subsection ‘Pharmacokinetics’). Descriptive and model 
based analyses of pharmacokinetic parameters will be based on the PKS.


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Adherence to the protocol will be assessed by the trial team. Important protocol deviations
(IPD) categories will be described in the IQRMP, IPDs will be identified no later than in the 
Report Planning Meeting, and the IPD categories will be updated as needed.
Pharmacokinetics
The pharmacokinetic parameters listed in Section 2.1 for drug BI 894416 will be calculated
according to the relevant BI SOP ‘Standards and processes for analyses performed within 
Clinical Pharmacokinetics/ Pharmacodynamics’ [001-MCS-36-472].
Plasma concentration data and parameters of a subject will be included in the statistical 
pharmacokinetic analyses if they are not flagged for exclusion due to a protocol violation 
relevant to the evaluation of pharmacokinetics (to be decided no later than in the Report 
Planning Meeting) or due to pharmacokinetic non-evaluability (as revealed during data 
analysis, based on the criteria specified below). Exclusion of a subject’s data will be 
documented in the CTR.
Relevant protocol deviations may be

Incorrect trial medication taken, i.e. the subject received at least one dose of trial
medication the subject was not assigned to

Incorrect dose of trial medication taken

Use of restricted medications
Plasma concentrations and/ or parameters of a subject will be considered as non-evaluable, if 
for example

The subject experienced emesis that occurred at or before two times median tmax of 
the respective treatment (median tmax is to be determined excluding the subjects 
experiencing emesis)

Missing samples/ concentration data at important phases of pharmacokinetic 
disposition curve
Plasma concentration data and parameters of a subject which is flagged for exclusion will be 
listed with its individual values but will not be included in the statistical analyses. Descriptive 
statistics of pharmacokinetic parameters will be based on the PKS.
Only concentration values within the validated concentration range and actual sampling times 
will be used for the calculation of pharmacokinetic parameters. Concentrations used in the 
pharmacokinetic calculations will be in the same format provided in the bioanalytical report, 
(that is, to the same number of decimal places provided in the bioanalytical report).
7.3.1
Primary endpoint analyses
Primary analyses
The statistical model used for the analysis of the primary endpoints will be an analysis of 
variance (ANOVA) model on the logarithmic scale. That is, the pharmacokinetic endpoints 
will be log-transformed (natural logarithm) prior to fitting the mixed model. 


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The pairwise comparisons of R1 with T1, T2, T3 and T4 will be analyzed in a five-way 
crossover model. This model will include effects accounting for the following sources of 
variation: sequence, subjects nested within sequences, period and treatment. The effect 
'subjects within sequences' will be considered as random, whereas the other effects will be 
considered as fixed. The model is described by the following equation:
yijkm = + i + sim + j + k + eijkm, where
yijkm = logarithm of response measured on subject m in sequence i receiving 
treatmentk in period j,
= the overall mean,
i = the ith sequence effect
sim = the effect associated with the mth subject in the ith sequence
j = the jth period effect
k = the kth treatment effect
eijkm = the random error associated with the mth subject in sequence i who received
treatment k in period j.
where sim ~ N	0,σB
2 i.i.d., eijkm ~ N	0,σW
2  i.i.d. and sim, eijkm are independent random 
variables.
The fasted vs fed comparisons (T2 - T5 and T4 - T6) will be analyzed as a two period fixed 
sequence cross-over model. The model used will include effects accounting for the following 
sources of variation: subjects and treatment. The effect ’subjects’ will be considered as 
random, whereas the effect ‘treatment’ will be considered as fixed. The model is described by 
the following equation:
ykm = + sm + k + ekm, where
           ykm = logarithm of response measured on subject m receiving treatment k,
           = the overall mean,
           sm = the effect associated with subject m
           k = the kth treatment effect
           ekm = the random error associated with subject m receiving treatment k.
where sm ~ N	0,σB
2 i.i.d., ekm ~ N	0,σW
2  i.i.d. and sm, ekm are independent random 
variables.


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Point estimates for the ratios of the geometric means (test/ reference) for the primary 
endpoints (refer to Section 2.1) and their two-sided 90% confidence intervals (CIs) will be 
provided.
The difference between the expected means for log(T)-log(R) will be estimated by the 
difference in the corresponding adjusted means (Least Squares Means). Additionally, their 
two-sided 90% confidence intervals will be calculated (which corresponds to the two one-
sided t-test procedure, each at a 5% significance level) based on the residual error from the 
ANOVA and will be back-transformed to the original scale to provide the point estimate and 
90% CIs for the ratio T/R.
Further exploratory analyses
The same statistical model as stated above will be repeated for the primary endpoints but with 
all sources of variation (‘sequence’, ‘subjects within sequences’, ‘period’, ‘treatment’) 
considered as fixed effects.
In addition to the model based approach all parameters will be calculated and analysed 
descriptively.
If an analysis model fails to converge or is not suitable, the model will be simplified.
7.3.2
Secondary endpoint analyses
The secondary endpoint (refer to Section 2.1.3) will be analysed in the same way as the 
primary endpoint.
7.3.3
Further endpoint analyses
7.3.3.1
Pharmacokinetic analyses
Further endpoints (refer to Section 2.2.2) will be analysed in the same way as the primary 
endpoint. 
7.3.4
Safety analyses
Safety will be analysed based on the assessments described in Section 2.2.2.2. All treated 
subjects (TS, refer to Section 7.2) will be included in the safety analysis. Safety analyses will 
be descriptive in nature and based on BI standards. No statistical comparison between 
treatment groups for safety data is planned, unless otherwise specified within the relevant 
section.
For all analyses, the treatment actually administered (= treatment at onset) to the subject will 
be used (any deviations from the randomised treatment will be discussed in the minutes of the 
Report Planning Meeting).
Treatments will be compared in a descriptive way. Tabulations of frequencies/ proportions 
will be used to evaluate categorical (qualitative) data, and tabulations of descriptive statistics 
will be used to analyse continuous (quantitative) data.


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Measurements (such as ECG, vital signs, or laboratory parameters) or AEs will be assigned to 
treatments (refer to 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 the screening period, those between first trial medication intake and end of 
REP (refer to Section 1.2.3) will be assigned to the treatment period. Events occurring after
the REP but prior to next intake or end of trial termination date will be assigned to ’follow-
up’. In case of two or more treatments, the follow-up will be summarized according to the 
previous treatment. These assignments including the corresponding time intervals will be 
defined in detail in the TSAP. Note that AEs occurring after the last per protocol contact but 
entered before final database lock will be reported to Pharmacovigilance only and will not be 
captured in the trial database.
Additionally, further treatment intervals (analysing treatments) may be defined in the TSAP 
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 follow-up 
intervals).
Adverse events will be coded using the Medical Dictionary for Regulatory Activities 
(MedDRA). Frequency, severity, and causal relationship of AEs will be tabulated by 
treatment, system organ class, and preferred term. SAEs, AESIs (refer to Section 5.2.6.1),
and other significant AEs (according to ICH E3) will be listed separately.
Previous and concomitant therapies will be presented per treatment group without 
consideration of time intervals and treatment periods.
Laboratory data will be compared to their reference ranges. Values outside the reference 
range as well as values defined as possibly clinically significant will be highlighted in the 
listings. Additionally, differences from baseline will be evaluated.
Vital signs or other safety-relevant data will be assessed with regard to possible on-treatment 
changes from baseline.
Relevant ECG findings will be reported as AEs.
7.4
INTERIM ANALYSES
No inferential statistical interim analysis is planned.
After trial part 1, a preliminary analysis of pharmacokinetic parameters e.g. AUC0-∞or AUC0-
tz, 
of BI 894416, provided as individual values and geometric means, will be 
performed for all tested formulations and modes of administration (fasted or fed). 
Pharmacokinetic simulations will be used as basis for prediction of steady state exposures. 
Further details will be described in a separate analysis plan. Similar analyses will be 
performed after trial part 2A, if appropriate.
In contrast to the final pharmacokinetic calculations, the preliminary analysis will be based 
on planned sampling times rather than on actual times, regardless of whether actual times 
were within the time windows. Therefore, minor deviations may occur between preliminary 
and final results. The preliminary results will be distributed to the investigator and the trial 


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team. The pharmacokinetic parameters will be calculated according to the BI SOP 'Standards 
and processes for analyses performed within Clinical Pharmacokinetics/ Pharmacodynamics' 
(001- MCS-36-472). A quality check of the preliminary data will be performed.
Depending on the results of available preliminary pharmacokinetic analyses, additional 
analyses may be performed, if requested by the Clinical Trial Leader, the Principal 
Investigator, or Trial Clinical Pharmacokineticist. Preliminary pharmacokinetic results will 
not be reported in the CTR.
7.5
HANDLING OF MISSING DATA
7.5.1
Safety
It is not planned to impute missing values for safety parameters.
7.5.2
Pharmacokinetics
Handling of missing pharmacokinetic data will be performed according to the relevant 
Corporate Procedure [001-MCS-36-472].
Pharmacokinetic parameters that cannot be reasonably calculated based on the available drug 
concentration-time data will not be imputed.
7.6
RANDOMISATION
Trial part 1
The patients are randomized to one of the following 10 treatment sequences, in a ratio of 
1:1:1:1:1:1:1:1:1:1:
-
T3-R1-T1-T4-T2-T5
T3-R1-T1-T4-T2-T6
-
T2-T1-T3-R1-T4-T5
T2-T1-T3-R1-T4-T6
-
T4-T3-R1-T2-T1-T5
T4-T3-R1-T2-T1-T6
-
T1-T4-T2-T3-R1-T5
T1-T4-T2-T3-R1-T6
-
R1-T2-T4-T1-T3-T5
R1-T2-T4-T1-T3-T6
The block size will be documented in the CTR.


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Trial part 2A (optional)
Subjects will be randomised to one of the 3 treatment sequences (T7-T8-R2, R2-T7-T8 and 
T8-R2-T7) in a 1:1:1 ratio. The block size will be documented in the CTR.
Trial part 2B (optional)
Subjects will be randomised to one of the 2 treatment sequences (T9-T10 and T10-T9) in a 
1:1 ratio. The block size will be documented in the CTR.
Randomization scheme, packaging and labelling
The sponsor will arrange for the randomisation which will be provided to 
 to allow 
them to conduct the manufacturing, packaging and labelling of trial medication. The 
randomisation list will be generated using a validated system that uses a pseudo-random 
number generator and a supplied seed number so that the resulting allocation is both 
reproducible and non-predictable.
The sponsor will provide the randomisation scheme to 
according to which 
 
will dispense the study medication.
The randomisation list will contain additional blocks to allow for subject replacement (refer 
to Section 3.3.5).
7.7
DETERMINATION OF SAMPLE SIZE
It is planned to enter a total of 24 subjects in trial part 1 and 18 subjects in trial part 2. The 
sample size determination is not based on a power calculation but is considered sufficient to 
achieve the aims of this exploratory trial.


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8.
INFORMED CONSENT, TRIAL RECORDS, DATA 
PROTECTION, PUBLICATION POLICY, AND
ADMINISTRATIVE STRUCTURE
The trial will be carried out in compliance with the protocol, the ethical principles laid down 
in the Declaration of Helsinki, in accordance with the ICH Harmonized Guideline for Good 
Clinical Practice (GCP), relevant BI Standard Operating Procedures (SOPs), the EU 
regulation 536/2014, and other relevant regulations. Investigators and site staff must adhere 
to these principles.
Standard medical care (prophylactic, diagnostic, and therapeutic procedures) remains the 
responsibility of the subject’s treating physician.
The investigator will inform the sponsor immediately of any urgent safety measures taken to 
protect the trial subjects against any immediate hazard, as well as of any serious breaches of 
the protocol or of ICH GCP.
The Boehringer Ingelheim transparency and publication policy can be found on the following 
web page: trials.boehringer-ingelheim.com. The rights of the investigator and of the sponsor 
with regard to publication of the results of this trial are described in the investigator contract. 
As a general rule, no trial results should be published prior to archiving of the CTR.
The terms and conditions of the insurance coverage are made available to investigator and 
subjects, and are stored in the ISF.
8.1
TRIAL APPROVAL, SUBJECT INFORMATION, INFORMED CONSENT
This trial will be initiated only after all required legal documentation has been reviewed and 
approved by the respective Institutional Review Board (IRB)/ Independent Ethics Committee 
(IEC) and competent authority (CA) according to national and international regulations. The 
same applies for the implementation of changes introduced by amendments.
Prior to a 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 retained by the investigator as part of the trial records. A signed copy of the 
informed consent and any additional subject information must be given to each subject or the 
subject’s legally accepted representative.
The subject must be given sufficient time to consider participation in the trial. The 
investigator or delegate obtains written consent of the subject’s own free will with the 
informed consent form after confirming that the subject understands the contents. The 
investigator or 
 delegate must sign (or place a seal on) and date the informed consent form. 
If a trial collaborator has given a supplementary explanation, the trial collaborator also signs 
(or places a seal on) and dates the informed consent.
Re-consenting may become necessary when new relevant information becomes available and 
should be conducted according to the sponsor’s instructions.


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The consent and re-consenting process should be properly documented in the source 
documentation.
8.2
DATA QUALITY ASSURANCE
A risk-based approach is used for trial quality management. It is initiated by the assessment 
of critical data and processes for trial subject protection and reliability of the results as well as 
identification and assessment of associated risks. An Integrated Quality and Risk 
Management Plan documents the rationale and strategies for risk management during the trial 
conduct including monitoring approaches, vendor management and other processes focusing 
on areas of greatest risk.
Continuous risk review and assessment may lead to adjustments in the trial conduct, the trial 
design or monitoring approaches.
A quality assurance audit/ inspection of this trial may be conducted by the sponsor, sponsor’s 
designees, or by IRB/IEC or by regulatory authorities. The quality assurance auditor will 
have access to all medical records, the investigator’s trial-related files and correspondence, 
and the informed consent documentation of this clinical trial.
8.3
RECORDS
CRFs for individual subjects will be provided by the sponsor. For drug accountability, refer 
to Section 4.1.8.
8.3.1
Source documents
In accordance with regulatory requirements, the investigator should prepare and maintain 
adequate and accurate source documents and trial records for each trial subject that include 
all observations and other data pertinent to the investigation. Source data as well as reported 
data should follow the ‘ALCOA principles’ and be attributable, legible, contemporaneous, 
original, and accurate. Changes to the data should be traceable (audit trail).
Data reported on the CRF must be consistent with the source data or the discrepancies must 
be explained.
Before providing any copy of subjects’ source documents to the sponsor, the investigator 
must ensure that all subject identifiers (e.g., subject’s name, initials, address, phone number, 
and social security number) have properly been removed or redacted to ensure subject 
confidentiality.
If the subject is not compliant with the protocol, any corrective action (e.g. re-training) must 
be documented in the subject file.
For the CRF, data must be derived from source documents, for example:

Subject identification: sex, year of birth (in accordance with local laws and 
regulations)

Subject participation in the trial (substance, trial number, subject number, date subject 
was informed)

Dates of subject’s visits, including dispensing of trial medication


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
Medical history (including trial indication and concomitant diseases, if applicable)

Medication history

AEs and outcome events (onset date [mandatory], and end date [if available])

SAEs (onset date [mandatory], and end date [if available])

Concomitant therapy (start date, changes)

Originals or copies of laboratory results and other imaging or testing results, with 
proper documented medical evaluation (in validated electronic format, if available)

ECG results (original or copies of printouts)

Completion of subject’s participation in the trial (end date; in case of premature 
discontinuation, document the reason for it, if known)

Prior to allocation of a subject to a treatment into a clinical trial, there must be 
documented evidence in the source data (e.g. medical records) that the trial participant 
meets all inclusion criteria and does not meet any exclusion criteria. The absence of 
records (either medical records, verbal documented feedback of the subject or testing 
conducted specific for a protocol) to support inclusion/ exclusion criteria does not 
make the subject eligible for the clinical trial
8.3.2
Direct access to source data and documents
The investigator/ institution will allow site trial-related monitoring, audits, IRB/IEC review 
and regulatory inspections. Direct access must be provided to the CRF and all source 
documents/ data, including progress notes, copies of laboratory and medical test results which 
must be available at all times for review by the Clinical Research Associate, auditor and 
regulatory inspector (e.g. FDA). They may review all CRFs and informed consents. The 
accuracy of the data will be verified by direct comparison with the source documents 
described in Section 8.3.1. The sponsor will also monitor compliance with the protocol and 
GCP.
8.3.3
Storage period of records
Trial site:
The trial site must retain the source and essential documents (including ISF) according to 
contract or the local requirements valid at the time of the end of the trial (whatever is longer).
Sponsor:
The sponsor must retain the essential documents according to the sponsor’s SOPs.
8.4
EXPEDITED REPORTING OF ADVERSE EVENTS
BI is responsible to fulfil their legal and regulatory reporting obligation, including SUSAR 
reporting, in accordance with regulatory requirements in participating countries and regions.
8.5
STATEMENT OF CONFIDENTIALITY AND SUBJECT PRIVACY
Individual subject data obtained as a result of this trial is considered confidential and 
disclosure to third parties is prohibited with the exceptions noted in Section 8.7.


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Data protection and data security measures are implemented for the collection, storage and 
processing of patient data in accordance with the principles 6 and 12 of the WHO GCP 
handbook.
Personalised treatment data may be given to the subject’s personal physician or to other 
appropriate medical personnel responsible for the subject’s welfare. Data generated at the site 
as a result of the trial need to be available for inspection on request by the participating 
physicians, the sponsor’s representatives, by the IRB/IEC and the regulatory authorities.
8.5.1
Collection, storage and future use of biological samples and corresponding 
data
Measures are in place to comply with the applicable rules for the collection, storage and 
future use of biological samples and clinical data, in particular

Sample and data usage has to be in accordance with the informed consent

The BI-internal facilities storing biological samples from clinical trial participants as 
well as the external banking facility are qualified for the storage of biological samples 
collected in clinical trials

An appropriate sample and data management system, incl. audit trail for clinical data 
and samples to identify and destroy such samples according to ICF is in place

A fit for purpose documentation (e.g. biomarker proposal, analysis plan and report) 
ensures compliant usage

If applicable, a fit for purpose approach will be used for assay/ equipment validation 
depending on the intended use of the biomarker data
Samples and/ or data may be transferred to third parties and other countries as specified in the 
ICF.
8.6
TRIAL MILESTONES
The start of the trial is defined as the date of the enrolment of the first subject in the trial.
The end of the trial is defined as the ‘date of the last visit of the last subject in the whole 
trial’ (‘Last Subject Completed’) or ‘end date of the last open AE’ or ‘date of the last follow-
up test’ or ‘date of an AE has been decided as sufficiently followed-up’, whichever is latest.
Early termination of the trial is defined as the premature termination of the trial for any 
reason before the end of the trial as specified in this protocol.
Temporary halt of the trial is defined as any unplanned interruption of the trial by the 
sponsor with the intention to resume it.
Suspension of the trial is defined as an interruption of the trial based on a Health Authority 
request.
The EC/ competent authority in each participating EU member state will be notified about the 
trial milestones according to the laws of each member state.
A final report of the clinical trial data will be written only after all subjects have completed 
the trial in all countries (EU or non-EU), so that all data can be incorporated and considered 
in the report.


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The sponsor will submit to the EU database a summary of the final trial results within one 
year from the end of a clinical trial as a whole, regardless of the country of the last patient 
(EU or non-EU).
8.7
ADMINISTRATIVE STRUCTURE OF THE TRIAL
The trial is sponsored by Boehringer Ingelheim (BI).
The trial will be conducted at 
 
, under the supervision of the Principal Investigator. Relevant 
documentation on the participating (Principal) Investigators (e.g. their curricula vitae) will be 
filed in the ISF.
BI has appointed a Trial Clinical Leader, responsible for coordinating all required trial 
activities, in order to

Manage the trial in accordance with applicable regulations and internal SOPs

Direct the clinical trial team in the preparation, conduct, and reporting of the trial

Ensure appropriate training and information of local clinical trial managers (CTM), 
Clinical Research Associates, and investigators of participating trial sites
The trial medication will be provided by the 
 
(IR) and
(ER).
Safety laboratory tests will be performed by the local laboratory of the trial site 
 
.
Analyses of BI 894416 concentrations in plasma will be performed at 
 
On-site monitoring will be performed by BI or a contract research organisation appointed by 
BI.
Data management and statistical evaluation will be done by BI or a contract research
organization appointed 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.


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9.
REFERENCES
9.1
PUBLISHED REFERENCES
P08-01263
Expert panel report 3: guidelines for the diagnosis and management of
asthma: full report 2007 (NIH publication no. 07-4051, revised August 
2007). Website:.nhlbi.nih.gov ; Bethesda: U.S. Department of Health and 
Human Services, National Institutes of Health, National Heart, Lung and 
Blood. Institute; 2007.
R94-1529
Chow SC, Liu JP, editors. Design and analysis of bioavailability and 
bioequivalence studies. New York: Marcel Dekker Inc., 1992.
R03-2269
Guidance for industry: food-effect bioavailability and fed bioequivalence 
studies. In: U.S. Department of Health and Human Services, Food and Drug 
Administration, Center for Drug Evaluation and Research (CDER) 2002:1-
9.
R14-4230
Wenzel SE. Asthma phenotypes: the evolution from clinical to molecular
approaches. Nature Med 2012;18(5):716-725.
R15-4770
Blancato J, Graves A, Rashidi B, Moroni M, Tchobe L, Ozdemirli M, 
Kallakury B, Makambi KH, Marian C, Mueller SC. SYK allelic loss and 
the role of Syk-regulated genes in breast cancer survival. Plos One 
2014;9(2):e87610
R15-5470
Mocsai A, Ruland J, Tybulewicz VLJ. The SYK tyrosine kinase: a crucial 
player in diverse biological functions. Nat Rev Immunol 2010;10(6):387-
402.
R15-5888
Pelaia G, Vatrella A, Busceti MT, Gallelli L, Calabrese C, Terracciano R, 
Maselli R. Cellular mechanisms underlying eosinophilic and neutrophilic
airway inflammation in asthma. Mediators Inflamm 2015;2015:879783
R16-0945
Fahy JV. Type 2 inflammation in asthma - present in most, absent in many. 
Nat Rev Immunol 2015;15:57-65.
R16-4459
Krisenko MO, Geahlen RL. Calling in SYK: SYK's dual role as a tumor 
promoter and tumor suppressor in cancer. Biochim Biophys Acta Mol Cell 
Res 2015;1853(1 ):254-263.
R16-5240
Boylan B, Gao C, Rathore V, Gill JC, Newman DK, Newman PJ. 
Identification of FcgammaRIIa as the ITAM-bearing receptor mediating 
alphaIIbbeta3 outside-in integrin signaling in human platelets. Blood 
2008;112(7):2780-2786.
R16-5298
Alsadeq A, Hobeika E, Medgyesi D, Klaesener K, Reth M. The role of the
Syk/Shp-1 kinase-phosphatase equilibrium in B cell development and 
signaling. J Immunol 2014;193:268-276.


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9.2
UNPUBLISHED REFERENCES
001-MCS-36-472 Standards and processes for analyses performed within Clinical 
Pharmacokinetics/ Pharmacodynamics. Current version
c03536505
 Investigator Brochure: BI 
894416 Asthma. 
n00235423
 BI 894416: A dose escalation toxicokinetics and 
tolerability study in the Beagle dog. 14R137-pre-clinical-study-report. 
02 DEC 2014
n00240179
 BI 894416: 
Exploratory 15 day oral (gavage) toxicity study in male rats. 29 Jun 2015
n00243171
 Assessment of pro-proliferative effects of the 
SYK inhibitor BI 1002494 on human breast cancer cell lines and in silico 
genetic evaluation of SYK for tumour suppressor characteristics using data 
from breast cancer patient databases. Nonclinical Report. 2016-i-r-resp3-
report1. 11 July 2016.
n00245394
 BI 894416: Dose Escalation in Dogs with Assessment of 
Electroencephalography and Nerve Conduction Velocity. 15R160. 
21 February 2017.


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10.
APPENDICES
Not applicable.


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11.
DESCRIPTION OF GLOBAL AMENDMENT(S)
11.1
GLOBAL AMENDMENT 1
Date of amendment
22 July 2020
EudraCT number
EU number
2019-003424-21
BI Trial number
1371-0022
BI Investigational Medicinal 
Product(s)
BI 894416
Title of protocol
Formulation selection and subsequent optimization 
of two different oral formulations of BI 894416 in 
healthy male subjects (open-label, randomised, 
single-dose study in two parts; trial part 1: five-
period crossover design with an additional sixth 
period in a fixed sequence; trial part 2: three-period 
crossover followed by a two-period crossover 
design)
To be implemented only after approval of the IRB/IEC/Competent Authorities
To be implemented immediately in order to eliminate hazard –
IRB/IEC/Competent Authority to be notified of change with request for 
approval
Can be implemented without IRB/IEC/Competent Authority approval as 
changes involve logistical or administrative aspects only
Section to be changed
Synopsis, Section 3.1, Section 4.1.4
Section 7.3.1
Throughout the document
Description of change
Adaptation of the wording to the statistical scenarios
Minor editorial and formatting changes throughout 
the document
Rationale for change
Since block- and sample size do not match, an 
imbalances between treatment 5 and treatment 6 is 
anticipated. Therefore, the wording was adapted in 
the Synopsis, as well as in Sections 3.1 and 4.1.4 to 
rectify the wording and the statistical model was 
adapted in the Synopsis and Section 7.3.1.
Non-substantial’, because no major changes to the 
primary and secondary objectives were made
Minor editorial and formatting changes for
consistency reasons


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11.2
GLOBAL AMENDMENT 2
Date of amendment
EudraCT number
EU number
BI Trial number
BI Investigational Medicinal 
Product(s)
Title of protocol
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
Description of change
Rationale for change


 
 
 
 
APPROVAL / SIGNATURE PAGE 
 
Document Number: 
 
Technical Version Number:
 
Document Name: 
 
 
 
                                                                                                                 
 
Title: 
 
 
 
 
                                                                                                                   
 
Signatures (obtained electronically) 
 
Meaning of Signature  
Signed by 
Date Signed 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
c28590127
4.0
clinical-trial-protocol-version-02
Formulation selection and subsequent optimization of two different oral formulations
of BI 894416 in healthy male subjects (open-label, randomised, single-dose study in
two parts; trial part 1: five-period crossover design with an additional sixth period in
a fixed sequence; trial part 2: three-period crossover followed by a two-period
crossover design)
Author-Trial Statistician
22 Jul 2020 13:04 CEST
Approval-Therapeutic Area Head
22 Jul 2020 14:01 CEST
Author-Clinical Trial Leader
22 Jul 2020 17:09 CEST
Author-Trial Clinical
Pharmacokineticist
22 Jul 2020 17:48 CEST
Verification-Paper Signature
Completion
23 Jul 2020 12:47 CEST
Approval-Team Member Medicine
23 Jul 2020 15:07 CEST


Boehringer Ingelheim 
Page 2 of 2
Document Number: 
 Technical Version Number:
 
 
 
(Continued) Signatures (obtained electronically) 
 
Meaning of Signature  
Signed by 
Date Signed 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
c28590127
4.0

SAP_001.pdf: 
TITLE PAGE
TRIAL STATISTICAL ANALYSIS PLAN
c31606953-01
BI Trial No.:
1371-0022
Title:
Formulation selection and subsequent optimization of two different 
oral formulations of BI 894416 in healthy male subjects (open-
label, randomised, single-dose study in two parts; trial part 1: five-
period crossover design with an additional sixth period in a fixed 
sequence; trial part 2: three-period crossover followed by a two-
period crossover design)
Final protocol (including protocol revision 1 (c28590127-04))
Investigational
Product:
BI 894416
Responsible trial 
statistician:
Phone: 
Fax: 
Date of statistical 
analysis plan:
05 FEB 2021 SIGNED 
Version:
1
Page 1 of 24
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2021 Boehringer Ingelheim International GmbH or one or more of its affiliated companies. All rights reserved.
This document may not - in full or in part - be passed on, reproduced, published or otherwise used without prior written permission.


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1.
TABLE OF CONTENTS
TITLE PAGE............................................................................................................................1
1.
TABLE OF CONTENTS......................................................................................2
LIST OF TABLES ...................................................................................................................4
2.
LIST OF ABBREVIATIONS...............................................................................5
3.
INTRODUCTION.................................................................................................6
4.
CHANGES IN THE PLANNED ANALYSIS OF THE STUDY ......................7
5.
ENDPOINTS..........................................................................................................8
5.1
PRIMARY ENDPOINT........................................................................................8
5.2
SECONDARY ENDPOINT..................................................................................8
5.2.1
Key secondary endpoint........................................................................................8
5.2.2
Secondary endpoint...............................................................................................8
5.3
FURTHER ENDPOINTS.....................................................................................8
5.3.2
Safety parameters..................................................................................................8
5.4
OTHER VARIABLES ..........................................................................................8
5.4.1
Demographic and other baseline characteristics................................................8
5.4.2
Treatment compliance and treatment exposure.................................................9
6.
GENERAL ANALYSIS DEFINITIONS...........................................................10
6.1
TREATMENTS...................................................................................................10
6.2
IMPORTANT PROTOCOL DEVIATIONS....................................................12
6.3
SUBJECT SETS ANALYSED ...........................................................................13
6.4
SUBGROUPS.......................................................................................................14
6.5
POOLING OF CENTRES..................................................................................14
6.6
HANDLING OF MISSING DATA AND OUTLIERS ....................................14
6.7
BASELINE, TIME WINDOWS AND CALCULATED VISITS....................14
7.
PLANNED ANALYSIS ......................................................................................16
7.1
DEMOGRAPHIC AND OTHER BASELINE CHARACTERISTICS .........16
7.2
CONCOMITANT DISEASES AND MEDICATION......................................17
7.3
TREATMENT COMPLIANCE ........................................................................17
7.4
PRIMARY ENDPOINT......................................................................................17
7.4.1
Primary analysis of the primary endpoint........................................................17
7.4.2
Sensitivity analysis, subgroup analysis, exploratory analysis of the 
primary endpoint.................................................................................................18
7.5
SECONDARY ENDPOINT................................................................................18
7.5.1
Key secondary endpoint......................................................................................18
7.5.2
Secondary endpoint.............................................................................................18
7.6.2
Safety parameters................................................................................................19
7.7
EXTENT OF EXPOSURE .................................................................................19
7.8
SAFETY ANALYSIS..........................................................................................19
7.8.1
Adverse Events ....................................................................................................19


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7.8.2
Laboratory data...................................................................................................20
7.8.3
Vital signs.............................................................................................................21
7.8.4
ECG ......................................................................................................................21
7.8.5
Others ...................................................................................................................21
8.
REFERENCES ....................................................................................................22
9.
ADDITIONAL SECTIONS................................................................................23
10.
HISTORY TABLE..............................................................................................24


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LIST OF TABLES
Table 6.1: 1
Flow chart of analysis phases for statistical analyses of AEs...........................11
Table 6.1: 2
Overview of treatment sequences.....................................................................11
Table 6.2: 1
Handling of iPDs ..............................................................................................13
Table 6.3: 1
Subject sets analyzed........................................................................................14
Table 10: 1
History table .....................................................................................................24


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2.
LIST OF ABBREVIATIONS
Term
Definition / description
ALT
Alanine aminotransferase
ANOVA
Analysis of variance
AST
Aspartate aminotransferase
AUC0-tz
Area under the concentration-time curve of the analyte in plasma over the 
time interval from 0 the last quantifiable time point
AUC0-∞
Area under the concentration-time curve of the analyte in plasma over the 
time interval from 0 extrapolated to infinity
BI
Boehringer Ingelheim
BP
Blood pressure
CV
Arithmetic coefficient of variation
ER
Extended release
FRR
Fast release rate
gCV
Geometric coefficient of variation
gMean
Geometric mean
IQRMP
Integrated quality and risk management plan
IR
Immediate release
MedDRA
Medical Dictionary for Regulatory Activities
PKS
Pharmacokinetic parameter set
PR
Pulse rate
RAGe
Report appendix generator
SD
Standard Deviation
SOC
System Organ Class
SRR
Slow release rate
TS
Treated set
ULN
Upper limit of normal range


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3.
INTRODUCTION
As per ICH E9 (1) the purpose of this document is to provide a more technical and detailed 
elaboration of the principal features of the analysis described in the revised CTP, and to
include detailed procedures for executing the statistical analysis of the primary 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 as collected in the eCRF will be stored in a trial database within the RAVE EDC 
system. All study data also including external data will then be uploaded  to the CDR data 
warehouse.
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 Phoenix 6.3, 
Certara USA Inc., Princeton, NJ, USA).


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4.
CHANGES IN THE PLANNED ANALYSIS OF THE STUDY
The trial part 1 was performed according to the CTP and the trial was terminated before any 
subject in trial part 2 was treated. Therefore, the analysis described in this TSAP refers to trial 
part 1 only.
All analyses described in this TSAP are in accordance with the statistical methods described 
in the revised CTP.


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5.
ENDPOINTS
5.1
PRIMARY ENDPOINT
The primary endpoint is a PK endpoint of BI 894416, as defined in Section 2.1.2 of the CTP:

AUC0-∞(area under the concentration-time curve of the analyte in plasma over the
time interval from 0 extrapolated to infinity)
5.2
SECONDARY ENDPOINT
5.2.1
Key secondary endpoint
Not applicable
5.2.2
Secondary endpoint
The secondary endpoint is a PK endpoint of BI 894416, as defined in Section 2.1.2 of the 
CTP:

AUC0-tz (area under the concentration-time curve of the analyte in plasma over the
time interval from 0 the last quantifiable time point)
5.3
FURTHER ENDPOINTS
5.3.2
Safety parameters
Safety and tolerability of BI 894416 will be assessed based on further safety endpoint defined 
in Section 2.2.2.2 of the CTP:

Adverse events (including clinically relevant findings from the physical examination)

Safety laboratory tests

12-lead ECG 

Vital signs (blood pressure, pulse rate)
5.4
OTHER VARIABLES
5.4.1
Demographic and other baseline characteristics
CTP Section 5.2.1: At screening, the medical examination will include demographics, height 
and body weight, smoking and alcohol history (alcohol history results are not mandatory to 
be entered into CRF or to be reported), 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.


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Age (years) will be determined as the difference between year of birth and year of informed 
consent.
Body mass index will be calculated as weight (kg) / (height (m))2.
5.4.2
Treatment compliance and treatment exposure
Treatment compliance will not be analysed as a specific endpoint, cf. Section 4.3 of the CTP.
Since only single doses will be applied per treatment period, the date and time of drug 
administration along with measured drug plasma concentrations will ensure treatment 
exposure.


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6.
GENERAL ANALYSIS DEFINITIONS
6.1
TREATMENTS
For basic study information on treatments to be administered, assignment of treatment groups, 
and selection of doses, cf. Section 4 of the CTP.
The trial is divided into two parts but only trial part 1 was performed.
In trial part 1, each subject is planned to be treated in five subsequent treatment periods
(five-period cross-over) with one single dose in each treatment period followed by one single 
dose in a sixth treatment period in a fixed sequence.
Treatments in the five-period cross-over:

Reference treatment 1 (R1) – 60mg tab IR fasted:
60 mg of BI 894416, IR tablets under fasted conditions

Test treatment 1 (T1) – 62.5mg tab FRR fasted:
62.5 mg of BI 894416, ER tablet (fast release rate) under fasted conditions

Test treatment 2 (T2) – 62.5mg tab SRR fasted:
62.5 mg of BI 894416, ER tablet (slow release rate) under fasted conditions

Test treatment 3 (T3) – 62.5mg cap FRR fasted:
62.5 mg of BI 894416, ER capsule (fast release rate) under fasted conditions

Test treatment 4 (T4) – 62.5mg cap SRR fasted:
62.5 mg of BI 894416, ER capsule (slow release rate) under fasted conditions
Each subject is planned to be randomly allocated to one of five treatment sequences (T3-R1-
T1-T4-T2, T2-T1-T3-R1-T4, T4-T3-R1-T2-T1, T1-T4-T2-T3-R1 and R1-T2-T4-T1-T3, cf.
Table 6.1: 2).
Treatments in the fixed sequence:

Test treatment 5 (T5) – 62.5mg tab SRR fed:
62.5 mg of BI 894416 ER, tablet (slow release rate) after a high fat breakfast

Test treatment 6 (T6) – 62.5mg cap SRR fed:
62.5 mg BI 894416, capsule (slow release rate) after a high fat breakfast
Subject will be randomly allocated to either T5 or T6, stratified by sequence (cf. Table 6.1: 2
for an overview of the treatment sequences).


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For statistical analysis of AEs, safety laboratory data and vital signs, the following analysis 
phases are defined for each subject:
Table 6.1: 1
Flow chart of analysis phases for statistical analyses of AEs
Study 
analysis 
phase
Label
Start (inclusive)
End (exclusive)
Screening
Screening
Date of informed consent
Date/time of administration of 
BI 894416 in any formulation
On-treatment
BI 894416
respectively
Date/time of administration 
of BI 894416 in any 
formulation
Date/time of administration of 
BI 894416 in another 
formulation or 12:00 a.m. on 
day after subject's trial 
termination date, whichever 
occurs earlier
Analysis phases for statistical analysis of AEs are defined for each subject as described in the 
table above.
CTR Section 15, Appendix 16.1.13.1.8.2 and Appendix 16.1.13.1.8.3 AE displays will 
present results for the on-treatment phase only.
In disposition, demographics and baseline characteristics, all subjects will be analysed 
together (i.e., one “BI 894416” column). Exposure will be summarised by period and 
treatment formulation.
The statistical analyses of safety laboratory tests and vital signs will be performed including 
all subject together (i.e., one “BI 894416” column), with clear differentiation between 
baseline (cf. Section 6.7) and on-treatment measurements.
Table 6.1: 2
Overview of treatment sequences 
Trial part 1
T3-R1-T1-T4-T2-T5
T3-R1-T1-T4-T2-T6
T2-T1-T3-R1-T4-T5
T2-T1-T3-R1-T4-T6
T4-T3-R1-T2-T1-T5
T4-T3-R1-T2-T1-T6
T1-T4-T2-T3-R1-T5
T1-T4-T2-T3-R1-T6
R1-T2-T4-T1-T3-T5
R1-T2-T4-T1-T3-T6
More details on the technical implementation of these analyses are provided in the ADS Plan 
of this TSAP.


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6.2
IMPORTANT PROTOCOL DEVIATIONS
Consistency check listings (for identification of deviations from time windows) and a list of 
protocol deviations (e.g. deviations in drug administration, in blood sampling times, etc.) will 
be provided to be discussed at the Report Planning Meeting (RPM). At this meeting, it will be 
decided whether a discrepant data value can be used in the analyses or whether it must be 
corrected in the clinical database. Each protocol deviation must be assessed to determine 
whether it is an important protocol deviation (iPD). For definition of iPDs, and for the process 
of identification of these, refer to the BI reference document “Identify and Manage Important 
Protocol Deviations (iPD)” (2).
If any iPDs are identified, they are to be summarised into categories and will be captured in 
the decision log. Categories which are considered to be iPDs in this trial are defined in the 
integrated quality and risk management plan (IQRMP). If the data show other iPDs, the 
definition in the IQRMP and the table below will be supplemented accordingly by the time of 
the RPM. Additionally, all iPDs will be documented in the DV sheet.
iPDs will be summarized and listed. Table 6.2: 1 specifies which kind of iPDs could 
potentially lead to exclusion from which analysis set (cf. Section 6.3). The decision on 
exclusion of subjects from analysis sets will be made at the latest at the RPM, after discussion 
of exceptional cases and implications for analyses.


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Table 6.2: 1
Handling of iPDs
iPD code
iPD Category & Brief Description
Excluded from which 
analysis set
A1
Inclusion criteria not met
PKS
A2
Exclusion criteria violated
PKS
B1
Informed consent not available/not done
TS, PKS
B2
Informed consent too late
None
C1
Incorrect trial medication taken
PKS
C2
Randomisation not followed
PKS
C3
Non-compliance
PKS
C4
Medication code broken inappropriately
PKS
C5
Incorrect intake of trial medication
PKS
C6
Improper washout between treatments
PKS
D1
Prohibited medication use
PKS
D2
Mandatory medication not taken
PKS
D3
Improper washout of concomitant medication
PKS
E1
Certain violations of procedures used to 
measure primary or secondary data
PKS
F1
Certain violations of time schedule used to 
measure primary or secondary data
PKS
G1
Incorrect intake of meal
PKS
H1
PDs affecting efficacy, safety and rights
TS, PKS
6.3
SUBJECT SETS ANALYSED
Subject sets will be used as defined in the CTP, Section 7.3. 


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Table 6.3: 1
Subject sets analyzed
Subject set
Class of endpoint
TS
PKS
Disposition
X
iPDs
X
Primary PK endpoint
X
Secondary PK endpoint
X
Safety parameters & 
treatment exposure
X
Demographic/baseline 
endpoints
X
6.4
SUBGROUPS
A subgroup analysis is not planned.
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
Data of screened subjects who were withdrawn from the trial prior to first administration of 
any study drug will not be reported in the CTR.
Data of subjects who failed to complete all periods of the study (dropouts or withdrawals) will 
be reported in the CTR as far as their data are available. All withdrawals will be documented 
and the reason for withdrawal reported in the CTR.
CTP Section 7.5.1: It is not planned to impute missing values for safety parameters.
One exception where imputation might be necessary for safety evaluation are AE dates. 
Missing or incomplete AE dates are imputed according to BI standards (3).
Missing data and outliers of PK data are handled according to BI standards (4) and (5). CTP
Section 7.5.2: Pharmacokinetic parameters that cannot be reasonably calculated based on 
the available drug concentration-time data will not be imputed..
6.7
BASELINE, TIME WINDOWS AND CALCULATED VISITS
Baseline is defined as the last available value before any administration of BI 894416 (in any 
formulation). 


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Time windows are defined in Section 6.1 of the CTP. Adherence to time windows will be 
checked at the RPM.


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7.
PLANNED ANALYSIS
The format of the listings and tables will follow the BI guideline "Standards for Reporting of 
clinical trials and project summaries" (6).
The individual values of all subjects will be listed. Listings will be sorted by treatment 
sequence, subject number and visit (if visit is applicable in the respective listing). AE listings 
will be sorted by assigned treatment (see Section 7.8.1 below for details). The listings will be 
contained in Appendix 16.2 (SDL) of the CTR.
The following standard descriptive statistical parameters will be displayed in summary tables 
of continuous variables:
N 
number of non-missing observations
Mean 
arithmetic mean
SD 
standard deviation
Min 
minimum
Median 
median
Max 
maximum
For plasma concentrations as well as for all PK parameters the following descriptive statistics 
will additionally be calculated:
CV 
arithmetic coefficient of variation
gMean
geometric mean
gCV
geometric coefficient of variation
For PK parameters the following descriptive statistics will additionally be calculated:
P10
10th percentile
Q1
1st quartile
Q3
3rd quartile
P90
90th percentile
The data format for descriptive statistics of plasma concentrations will be identical with the 
data format of the respective concentrations. The descriptive statistics of PK parameters will 
be calculated using the individual values with the number of decimal places as provided by 
the evaluation program. Then the individual values as well as the descriptive statistics will be 
reported with three significant digits in the CTR.
Tabulations of frequencies for categorical data will include all possible categories and will 
display the number of observations in a category as well as the percentage (%) relative to the 
respective treatment group. Percentages will be rounded to one decimal place. The category 
missing will be displayed if and only if there 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.


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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. Concomitant non-drug therapies will be coded 
according to the most recent version of MedDRA.
A medication will be considered concomitant, if it

is ongoing at the time of first study drug administration, or

starts within the analysis phase of the respective treatment (see Section 6.1 for a definition 
of treatments and analysis phases).
The relevance of the concomitant therapies to the evaluation of PK will be decided no later 
than at the RPM.
Only descriptive statistics are planned for this section of the CTR.
7.3
TREATMENT COMPLIANCE
Treatment compliance will not be analyzed as a specific endpoint. Any deviations from 
complete intake will be addressed in the Report Planning Meeting (cf. Section 6.2) and 
described in the CTR.
7.4
PRIMARY ENDPOINT
7.4.1
Primary analysis of the primary endpoint
Primary analysis of the primary endpoint will be performed as defined in Section 7.3.1 of the 
CTP. The analysis will be based on the PKS.
To assess the relative bioavailability of extended release formulation compared with 
immediate release formulation on the PK of the treatment, the statistical model for the 
primary analysis defined in the CTP is an analysis of variance (ANOVA) model on the 
logarithmic scale including “sequence”, “period” and “treatment” (formulation) as fixed effect 
and “subject nested within sequence” as random effect. All formulation data are included in 
the model for each pairwise comparison. The formulations T1 (62.5mg tab FRR fasted), T2 
(62.5mg tab SRR fasted), T3 (62.5mg cap FRR fasted), and T4 (62.5mg cap SRR fasted) will 
be compared versus R1 (60mg tab IR fasted). 
To assess the relative bioavailability of BI fed compared with BI fasted, the statistical model 
for the primary analysis defined in the CTP is an ANOVA model on the logarithmic scale 
including “treatment” as fixed effect and “subject” as random effect. The model will be 
analysed as a two period fixed sequence cross-over model. The formulations T5 (62.5mg tab 
SRR fed) will be compared versus T2 (62.5mg tab SRR fasted) and T6 (62.5mg cap SRR fed) 
versus T4 (62.5mg cap SRR fasted).
The relative bioavailability will be estimated by the ratios of the geometric means of 
(test/reference) of the primary endpoint.


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Exclusion of plasma concentrations
The ADS ADPC (PK concentrations per time-point or per time-interval) contains column 
variables ACEXC or ACEXCO indicating inclusion/exclusion (ACEXC) of a concentration 
and an analysis flag comment (ACEXCO). Exclusion of a concentration depends on the 
analysis flag comment ACEXCO. For example, if ACEXCO is set to “ALL CALC”, the 
value will be excluded for all types of analyses based on concentrations. If ACEXCO is set to 
“DESC STATS” the value will be excluded from descriptive evaluations per planned time 
point/time interval. If ACEXCO contains the addition “TIME VIOLATION” or “TIME 
DEVIATION”, the value can be used for further analyses based on actual times. If ACEXCO 
is set to “HALF LIFE”, the value will be excluded from half-life calculation only; the value is 
included for all other analyses. Excluded concentration itself will be listed in the CTR 
associated with an appropriate flag.
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”.
Further details are given in “Noncompartmental Pharmacokinetic / Pharmacodynamic 
Analyses of Clinical Studies” (4) and “Description of Analytical Transfer Files and PK/PD 
Data Files” (5).
7.4.2
Sensitivity analysis, subgroup analysis, exploratory analysis of the primary 
endpoint
The same statistical model as used for the primary analysis for the comparison of 
formulations (Section 7.3.1 of the CTP) will be repeated for the primary endpoint but with all 
sources of variation (“sequence”, “subject within sequence”, “period” and “treatment”
(formulation)) considered as fixed effects.
Similarly, the model used for the primary analysis for the comparison of BI fed versus BI 
fasted will be repeated for the primary endpoint with “subject” and “treatment” as fixed 
effect.  
Furthermore, the primary PK endpoints will be assessed descriptively. The analysis of 
standard PK parameters is performed according to BI standards (4).
7.5
SECONDARY ENDPOINT
7.5.1
Key secondary endpoint
Not applicable.
7.5.2
Secondary endpoint
The analysis of secondary endpoints will be based on the PKS.


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The secondary endpoint will be statistically analysed in the same way as for the primary 
endpoint. The endpoint will also be assessed descriptively. The analysis of standard PK 
parameters is performed according to BI standards (4).
See Section 7.4 of this TSAP for details regarding exclusion of PK parameters and plasma 
concentrations.
7.6.2
Safety parameters
Safety endpoints and tolerability will be analysed as described in Section 7.8 of this TSAP.
7.7
EXTENT OF EXPOSURE
Descriptive statistics are planned for this section of the report.
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 further details on summarization of AE data, please refer to "Analysis and Presentation of 
Adverse Event Data from Clinical Trials" (7) and "Handling of missing and incomplete AE 
dates" (3). 
The analysis of AEs will be based on the concept of treatment emergent AEs. That means that 
all AEs will be assigned to screening or on-treatment phase as defined in Section 6.1. AEs 
will be analysed based on actual treatments, as defined in Table 6.1: 1.
An overall summary of AEs will be presented. This overall summary will comprise summary 
statistics for the class of AESIs.
CTP Section 5.2.6.1.4: The following are considered as AESIs:

Hepatic injury
A hepatic injury is defined by the following alterations of hepatic laboratory 
parameters:


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○
An elevation of AST (aspartate transaminase) and/ or ALT (alanine 
transaminase) ≥3-fold ULN combined with an elevation of total bilirubin ≥2-
fold ULN measured in the same blood sample, or 
○
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), in addition to deaths and SAEs, “other significant” AEs need to be 
listed in the clinical trial report. These will be any non-serious adverse event that led to an 
action taken with study drug (e.g. discontinuation or dose reduced or interrupted).
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 will be 
summarised separately. Separate tables will also be provided for subjects with SAEs and
subjects with AESIs. AEs will also be summarized by maximum intensity.
The SOCs and preferred terms within SOCs will be sorted by descending frequency over all 
treatment groups.
For disclosure of AE data on ClinicalTrials.gov, the frequency of subjects with non-serious 
AEs occurring with an incidence of greater than 5 % (in preferred terms) will be summarised 
by treatment, primary SOC and preferred term. The frequency of subjects with SAEs will also 
be summarised.
For disclosure of AE data in the EudraCT register, the frequency of AEs, the frequency of 
non-serious AEs with an incidence of greater than 5 % (in preferred terms) and the frequency 
of SAEs will be summarized.
For support of lay summaries, the frequency of subjects with drug-related SAEs will be 
summarized by treatment, primary SOC and preferred term.
7.8.2
Laboratory data
The analyses of laboratory data will be descriptive in nature and will be based on BI standards 
"Display and Analysis of Laboratory Data" (9).
Analyses will be based on normalised values, which mean transforming to a standard unit and 
a standard reference range. The original values will be analysed if the transformation into 
standard unit is not possible for a parameter.
Descriptive statistics of absolute values and change from baseline from laboratory parameters 
over time (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.
Unscheduled measurements of laboratory data will be assumed to be repeat measurements of 
the most recent scheduled measurement (e.g. for follow-up or confirmation of a particular 
value). Therefore, unscheduled measurements will be assigned to the planned time point of 
the previous scheduled measurement. Descriptive statistics will be calculated by planned time 
point based on the worst value of the subject at that planned time point (or assigned to that 
planned time point).


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Possibly clinically significant abnormal laboratory values are only those identified either in 
the Investigator's comments or at the RPM 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 (prior to 
first administration of study treatment) or as AEs (after first administration of study treatment) 
if judged clinically relevant by the investigator, and will be analyzed as such.
7.8.3
Vital signs
The analyses of vital signs (blood pressure and pulse rate) will be descriptive in nature. 
Descriptive statistics of absolute values and change from baseline from vital signs over time 
(see Section 6.7) will be provided.
Unscheduled measurements of vital signs will not be included in the descriptive statistics and 
will only be listed.
Clinically relevant findings in vital signs data will be reported as baseline conditions (prior to 
first administration of study treatment) or as AEs (after first administration of study treatment)
if judged clinically relevant by the investigator, and will be analyzed as such.
7.8.4
ECG
Abnormal findings in ECG 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.
7.8.5
Others
Physical examination findings will be reported as relevant medical history/ baseline condition 
(if a condition already exists before first administration of study treatment) or as AE (if 
condition emerges after first administration of study treatment) and will be summarized as 
such. No separate listing or analysis of physical examination findings will be prepared.


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8.
REFERENCES
1
CPMP/ICH/363/96: “Statistical Principles for Clinical Trials”, ICH Guideline 
Topic E9; Note For Guidance on Design, Conduct, Analysis and Evaluation of 
Clinical Trials, current version
2
001-MCS-40-413_1.0: “Identify and Manage Important Protocol Deviations 
(iPD)”, current version; IDEA for CON
3
KM Asset BI-KMED-BDS-HTG-0035: “Handling of missing and incomplete AE 
dates”, current version; KMED
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
KM Asset BI-KMED-BDS-HTG-0045: “Standards for Reporting of Clinical Trials 
and Project Summaries”, current version; KMED
7
KM Asset BI-KMED-BDS-HTG-0066: “Analysis and Presentation of Adverse 
Event Data from Clinical Trials”, current version; KMED
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
KM Asset BI-KMED-BDS-HTG-0042: “Display and Analysis of Laboratory Data”, 
current version; KMED


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9.
ADDITIONAL SECTIONS
Not applicable as no additional information is needed.


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