Conditions: Healthy
Allocation: RANDOMIZED | Intervention model: CROSSOVER
Enrollment: 32
Healthy volunteers: yes

Brief summary:
The main objective of Part 1of this trial is to investigate the effect of co-administration of multiple doses of donepezil on the single-dose pharmacokinetics of BI 425809 in healthy subjects. In Part 2 the main objective is the investigation of the effect of co-administration of multiple doses of BI 425809 on the single-dose pharmacokinetics of donepezil in healthy subjects.

Detailed description:

Arms:
arm 1: None arm 2: None

Interventions: intervention 1: BI 425809 intervention 2: Donepezil
Intervention descriptions: intervention 1: Film coated tablet intervention 2: Film coated tablet

Protocol document:
Prot_000.pdf: 
001-MCS-40-106-RD-13 (6.0) / Saved on: 13 Jun 2018
Clinical Trial Protocol
TITLE PAGE
Document Number:
c26441921-04
EudraCT No.
2018-004806-24
BI Trial No.
1346-0029
BI Investigational
Medicinal Product
BI 425809
Title
A study to investigate the effects of donepezil on the pharmacokinetics 
of BI 425809 and vice versa in healthy male and female subjects 
(Open-label, two-treatment, two-period, one fixed sequence cross-over 
design)
Lay Title
A study in healthy men and women to test which effects donepezil and 
BI 425809 have on each other
Clinical Phase
I
Clinical Trial Leader
Phone:
Fax:
Principal Investigator
Phone:
Fax:
Status
Final Protocol (Revised Protocol (based on global amendment 3))
Version and Date
Version: 4.0
Date: 29 May 2019
Page 1 of 80
Proprietary confidential information
© 2019 Boehringer Ingelheim International GmbH or one or more of its affiliated companies. All rights reserved.
This document may not - in full or in part - be passed on, reproduced, published or otherwise used without prior written permission


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CLINICAL TRIAL PROTOCOL SYNOPSIS
Company name
Boehringer Ingelheim
Protocol date
28 January 2019
Revision date
29 May 2019
BI trial number
1346-0029
Title of trial
A study to investigate the effects of donepezil on the pharmacokinetics of 
BI 425809 and vice versa in healthy male and female subjects (Open-label, 
two-treatment, two-period, one fixed sequence cross-over design)
Principal Investigator:
Trial site
Clinical phase
I
Trial rationale
Donepezil is a common medication used in patients diagnosed with Alzheimer’s 
Disease (AD). As BI 425809 is developed as a symptomatic treatment for AD it is 
very likely that it may be used on top of donepezil in clinical practice. Therefore it 
is crucial to investigate if there are any interactions between BI 425809 and 
donepezil when administered together before their concomitant use will be 
allowed in Phase 3 trials and later in clinical practice
Trial objectives
Part 1:
To investigate the effect of co-administration of multiple doses of donepezil on the
single-dose pharmacokinetics of BI 425809 in healthy subjects
Part 2:
To investigate the effect of co-administration of multiple doses of BI 425809 on 
the single-dose pharmacokinetics of donepezil in healthy subjects
Trial design
Part 1 + 2:
Open-label, two-treatment, two-period, one fixed sequence cross-over design
Trial endpoints:
Primary endpoints: 

Part 1: AUC0-and Cmax of BI 425809

Part 2: AUC0-and Cmax donepezil
Secondary endpoints: 

Part 1: AUC0-tz of BI 425809

Part 2: AUC0-tz of donepezil
Number of subjects
total entered
N = 32
each treatment
Part 1: N = 18
Part 2: N = 14
Diagnosis
Not applicable
Main criteria
for inclusion
Healthy male/female subjects, age of 18 to 50 years (inclusive), body mass index 
(BMI) of 18.5 to 29.9 kg/m2 (inclusive)


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Trial product 1:
BI 425809, film-coated tablet 
Strength:
25 mg
Mode of admin.:
Oral with 240 mL of water  
Trial product 2:
Donepezil-HCl-ratiopharm® 5 mg, film-coated tablets 
Strength:
5 mg 
Mode of admin.:
Oral administration with 240 mL of water. Donepezil dosing follows an up-
titration regime from 5 mg to 10 mg for tolerability reasons. 
Duration of treatment
Part 1*:
Treatment A (Reference 1):
Trial product 1: single dose of 25 mg BI 425809 on Day 1, Visit 2  
Treatment B (Test 1):
Trial product 1: single dose of 25 mg BI 425809 on Day 22, Visit 3 
Trial product 2: multiple doses of 5 mg donepezil q.d. on Days 1-7, Visit 3
multiple doses of 10 mg donepezil q.d. on Days 8-28, Visit 3
*There will be no wash-out period between treatment A and B.
Part 2**:
Treatment C (Reference 2): 
Trial product 2: single dose of 10 mg donepezil on Day 1, Visit 2
Treatment D (Test 2):
Trial product 2: single dose of 10 mg donepezil on Day 10, Visit 3
Trial product 1: multiple doses of 25 mg BI 425809 q.d. on Days 1-24, Visit 3
                                          
**There will be no wash-out period between treatment C and D
Statistical methods
The effects of donepezil on the pharmacokinetics of BI 425809 (Part 1) and the 
effects of BI 425809 on the pharmacokinetics of donepezil (Part 2) will be 
evaluated based on the point estimates of the intra-subject ratio (test to reference 
treatment) of the geometric means (gMeans) for the primary and secondary PK 
endpoints. 
Additionally, their two-sided 90% confidence intervals (CIs) will be provided. 
This method corresponds to the two one-sided t-tests procedure, each at the 5% 
significance level. 
Since the main focus is on estimation and not testing, an acceptance range was not 
specified. 
The statistical model will be a (mixed effects) ANOVA on the log-transformed
parameters, including effects for ‘subjects’ and ‘treatment’. CIs will be calculated 
based on the residual error from ANOVA.
Descriptive statistics will be calculated for all endpoints.


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FLOW CHART
Part 1
Visit*
Day
Planned time (relative to 
first drug administration 
[h:min]
Approximate clock time  of 
actual day [h:min]
Event and comment
Safety laboratory
PKplasma (BI 425809)
PKplasma Donepezil)
Safety assessments
12-lead ECG14
Vital signs (BP, PR)14
Questioning for AEs and 
concomitant therapy 6
1
-21 
to -1
n.a.
n.a.
Screening1
x10
x12,13
x
x
2 (Treatment A)
-3 to -1
-24:00
n.a.
x9
x
1
-10:00
08:00
Admission to trial site 
x15
x
x
x7
00:00
18:00
Drug administration, 25 mg BI 425809
x2
00:30
18:30
x
01:00
19:00
x
02:00
20:00
240ml fluid intake
x
03:00
21:00
x
03:30
21:30
x
04:00
22:00
240 mL fluid intake, Dinner, thereafter start 
of bed rest16 
x
x
x
x
04:30
22:30
x
05:00
23:00
x
2
06:00
00:00
x
08:00
02:00
x
10:00
04:00
x
12:00
06:00
End of bed rest16, Breakfast3
x
x
x
x
24:00
18:00
x
x
3
34:00
04:00
x
x
38:00
08:00
Discharge11
x
x
x
48:00
18:00
Ambulatory visit
x
x
4
72:00
18:00
Ambulatory visit
x
x
5
96:00
18:00
Ambulatory visit
x
x
x
6
120:00
18:00
Ambulatory visit
x
x
7
144:00
18:00
Ambulatory visit
x
x
8
168:00
18:00
Ambulatory visit
x10
x
x
3 (Treatment B)
1
-02:00
16:00
Admission to trial site
x15
x
00:00
18:00
Admin. 5 mg donepezil
x2
x2
x2
x2,7
2
14:00
08:00
Discharge11
x
x
x
24:00
18:00
Ambulatory visit11, admin. 5 mg donepezil
x2
x2
x2,7
3
48:00
18:00
Ambulatory visit11, admin. 5 mg donepezil
x2,7
4
72:00
18:00
Ambulatory visit11, admin. 5 mg donepezil
x10
x2
x2
x2,7
5
96:00
18:00
Ambulatory visit11, admin. 5 mg donepezil
x2,7
6
120:00
18:00
Ambulatory visit11, admin. 5 mg donepezil
x2
x2
x2,7
7
144:00
18:00
Ambulatory visit11, admin. 5 mg donepezil
x8
x2,7
8
168:00
18:00
Ambulatory visit11, admin. 10 mg donepezil
x10
x12
x2
x2
x2,7
9
192:00
18:00
Ambulatory visit11, admin. 10 mg donepezil
x2,7
10
216:00
18:00
Ambulatory visit11, admin. 10 mg donepezil
x2,7
11
240:00
18:00
Ambulatory visit11, admin. 10 mg donepezil
x2,7
12
264:00
18:00
Ambulatory visit11, admin. 10 mg donepezil
x10
x2
x2
x2,7
13
288:00
18:00
Ambulatory visit11, admin. 10 mg donepezil
x2,7
14
312:00
18:00
Ambulatory visit11, admin. 10 mg donepezil
x8
x2,7


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Visit
Day
Planned time (relative to 
first drug administration 
[h:min]
Approximate clock time of 
actual day [h:min]
Event and comment
Safety laboratory
PKplasma (BI 425809)
PKplasma Donepezil)
Safety assessments
12-lead ECG14
Vital signs (BP, PR)14
Questioning for AEs and 
concomitant therapy 6
3 (Treatment B)
15
336:00
18:00
Ambulatory visit11, admin. 10 mg donepezil
x2,7
16
360:00
18:00
Ambulatory visit11, admin. 10 mg donepezil
x10
x12
x2
x2
x2,7
17
384:00
18:00
Ambulatory visit11, admin. 10 mg donepezil
x2,7
18
408:00
18:00
Ambulatory visit11, admin. 10 mg donepezil
x2,7
19
432:00
18:00
Ambulatory visit11, admin. 10 mg donepezil
x10
x8
x2
x2
x2,7
20
456:00
18:00
Ambulatory visit11, admin. 10 mg donepezil
x8
x2,7
21
480:00
18:00
Ambulatory visit11, admin. 10 mg donepezil
x8
x2,7
22
494:00
08:00
Admission to trial site
x5,10
x12
x
x
x2,7
504:00
18:00
Drug administration,
25 mg BI 425809 + 10 mg donepezil
x8
x8
x2,7
504:30
18:30
x
505:00
19:00
x
506:00
20:00
240 ml fluid intake
x
507:00
21:00
x
507:30
21:30
x
508:00
22:00
240 mL fluid intake, Dinner, thereafter start 
of bed rest16
x
x
x
x
508:30
22:30
x
509:00
23:00
x
23
510:00
00:00
x
512:00
02:00
x
514:00
04:00
x
516:00
06:00
End of bed rest16, Breakfast3
x
x
x
x
528:00
18:00
Drug administration, 10 mg donepezil
x
x2
x2
x2,7
24
540:00
06:00
x
x2,7
542:00
08:00
Discharge11
x12
x
x
x7
552:00
18:00
Ambulatory visit11, admin. 10 mg donepezil
x8
x2,7
25
576:00
18:00
Ambulatory visit11, admin. 10 mg donepezil
x10
x8
x8
x2
x2
x2,7
26
600:00
18:00
Ambulatory visit11, admin. 10 mg donepezil
x8
x2,7
27
624:00
18:00
Ambulatory visit11, admin. 10 mg donepezil
x8
x2,7
28
648:00
18:00
Ambulatory visit11, admin. 10 mg donepezil
x8
x2,7
29
672:00
18:00
Ambulatory visit11
x10
x8
x2
x2
x2,7
4
44-49
n.a.
n.a.
End of trial examination4
x10
x12,13
x
x
x
1.
Screening includes subject information, informed consent, physical examination including neurological assessment, 
check of vital signs, visual tests, ECG, safety laboratory (including drug screening, alcohol breath test, urine pregnancy 
testing in females, and faecal occult blood 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 2 h prior to drug administration.
3.
If several actions are indicated at the same time point, the intake of meals will be the last action.
4.
End of trial examination includes physical examination including neurological assessment, vital signs, visual tests, 
ECG, safety laboratory, urine pregnancy testing in females, recording of AEs and concomitant therapies, faecal occult 
blood test. 
5.
Including urine drug screening and alcohol breath test and urine pregnancy testing in females
6.
AEs and concomitant therapies will be recorded throughout the trial, but will be specifically asked for at the time points 
indicated in the Flow Chart above.
7.
Includes questioning for ‘restrictions’


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8.
Pre-dose PK, i.e. within 10 min prior to the next drug administration
9.
Safety laboratory to be taken within 3 days prior to first trial drug administration of Visit 2 and 3. All results must be 
available and be checked by the investigator or his/her designee before trial drug administration. For Visit 3, the safety 
laboratory of day 8, Visit 2 will be used.
10. Includes immunochemical faecal occult blood (iFOB) test 
11. Discharge after confirmation of fitness by the investigator/designee
12. Neurological assessment (i.e. Romberg and Unterberger test, assessment of gait, further tests as needed) to be 
performed at the time points mentioned in the Flow Chart above and at any times CNS adverse events are reported
13. Colour discrimination, visual acuity testing, Amsler grid test: tests will be performed at screening, EOT and at any time 
visual adverse events are reported 
14. All blood pressure measurements, as well as pulse rate and ECG will be measured after at least 5 minutes of rest in the
supine position
15. Only urine drug screening and alcohol breath test and urine pregnancy testing in females 
16. Bed rest (except going to the toilet)
* There is no wash-out period between Visit 2 and Visit 3. Day 1 of Visit 3 follows directly after day 8 of Visit 2 but these 
are different days


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Part 2
Visit**
Day
Planned time (relative to 
first drug administration 
[h:min]
Approximate clock time  of 
actual day [h:min]
Event and comment
Safety laboratory
PKplasma (BI 425809)
PKplasma Donepezil)
Safety assessments
12-lead ECG14
Vital signs (BP, PR)14
Questioning for AEs and 
concomitant therapy6
1
-21 to -1
n.a.
n.a.
Screening 1
x5
x9,10,13
x
x
2 (Treatment C)
-3 to -1
-24:00
n.a.
Ambulatory visit
x12
x
-1
-12:00
20:00
Admission to trial site
x15
x
1
-02:00
06:00
x2
x2
x10,2
x2
x2
x2,7
00:00
08:00
Drug administration, 10 mg donepezil
01:00
09:00
x
02:00
10:00
240 mL fluid intake
x
03:00
11:00
x
04:00
12:00
240 mL fluid intake, Lunch3
x
x
x
x
06:00
14:00
x
08:00
16:00
x
10:00
18:00
Dinner3
x
12:00
20:00
x
x
x
x
2
18:00
02:00
x
24:00
08:00
x
x
x
x
x
3
48:00
08:00
x
x
4
72:00
08:00
x
x
x
72:30
08:30
Discharge11
x10
x
x
x
5
96:00
08:00
Ambulatory visit
x
x
x
x
6
120:00
08:00
Ambulatory visit
x
x
7
144:00
08:00
Ambulatory visit
x
x
8
168:00
08:00
Ambulatory visit
x
x
9
192:00
08:00
Ambulatory visit
x
x
10
216:00
08:00
Ambulatory visit
x
x
x10
x
x
x
11
240:00
08:00
Ambulatory visit
x
x
12
264:00
08:00
Ambulatory visit
x
x
13
288:00
08:00
Ambulatory visit
x
x
14
312:00
08:00
Ambulatory visit
x
x
15
336:00
08:00
Ambulatory visit
x
x
x


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Visit**
Day
Planned time (relative to 
first drug administration 
[h:min]
Approximate clock time  of 
actual day [h:min]
Event and comment
Safety laboratory
PKplasma (BI 425809)
PKplasma Donepezil)
Safety assessments
12-lead ECG14
Vital signs (BP, PR)14
Questioning for AEs and 
concomitant therapy 6
3 (Treatment D)
1
00:00
08:00
Ambulatory visit11, admin. 25mg BI 425809
x2,15
x2
x2
x2,9,10
x2
x2
x2,7
2
24:00
08:00
Ambulatory visit11, admin. 25mg BI 425809
x2,7
3
48:00
08:00
Ambulatory visit11, admin. 25mg BI 425809
x2,7
4
72:00
08:00
Ambulatory visit11, admin. 25mg BI 425809
x8
x2,7
5
96:00
08:00
Ambulatory visit11, admin. 25mg BI 425809
x
x10
x
x
x2,7
6
120:00
08:00
Ambulatory visit11, admin. 25mg BI 425809
x2,7
7
144:00
08:00
Ambulatory visit11, admin. 25mg BI 425809
x2,7
8
168:00
08:00
Ambulatory visit11, admin. 25mg BI 425809
x8
x2,7
9
192:00
08:00
Ambulatory visit11, admin. 25mg BI 425809
x
x8
x2,7
204:00
20:00
Admission to trial site
x15
x7
10
214:00
06:00
x10,2
x2
x2
x2
216:00
08:00
Administration of 10 mg donepezil                  
+ 25 mg BI 425809
x8
x8
217:00
09:00
x
218:00
10:00
240 mL fluid intake
x
219:00
11:00
x
220:00
12:00
240 mL fluid intake, Lunch3
x
x
x
x
222:00
14:00
x
224:00
16:00
x
226:00
18:00
Dinner3
x
228:00
20:00
x
x
x
x
11
234:00
02:00
x
240:00
08:00
Administration of 25mg BI 425809
x
x8
x8
x10
x
x
x2,7
12
264:00
08:00
Administration of 25mg BI 425809
x8
x2,7
13
288:00
08:00
Administration of 25mg BI 425809
x8
x2,7
288:30
08:30
Discharge11
x
x
x
14
312:00
08:00
Ambulatory visit11, admin. 25mg BI 425809
x8
x2,7
15
336:00
08:00
Ambulatory visit11, admin. 25mg BI 425809
x
x8
x8
x10
x
x
x2,7
16
360:00
08:00
Ambulatory visit11, admin. 25mg BI 425809
x8
x2,7
17
384:00
08:00
Ambulatory visit11, admin. 25mg BI 425809
x8
x2,7
18
408:00
08:00
Ambulatory visit11, admin. 25mg BI 425809
x8
x2,7
19
432:00
08:00
Ambulatory visit11, admin. 25mg BI 425809
x8
x2,7
20
456:00
08:00
Ambulatory visit11, admin. 25mg BI 425809
x
x8
x8
x10
x
x
x2,7
21
480:00
08:00
Ambulatory visit11, admin. 25mg BI 425809
x8
x2,7
22
504:00
08:00
Ambulatory visit11, admin. 25mg BI 425809
x8
x2,7
23
528:00
08:00
Ambulatory visit11, admin. 25mg BI 425809
x8
x2,7
24
552:00
08:00
Ambulatory visit11, admin. 25mg BI 425809
x8
x8
x10
x2,7
25
576:00
08:00
Ambulatory visit11
x
x
x
x
x
4
36-40
n.a.
n.a.
End of trial examination4
x5
x9,10,13
x
x
x
1.
Screening includes subject information, informed consent, physical examination including neurological assessment, 
check of vital signs, ECG, safety laboratory (including drug screening, alcohol breath test, pregnancy testing in females,
and faecal occult blood test), demographics (including determination of body height and weight, smoking status and 
alcohol history), visual tests, C-SSRS, 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 2 h prior to drug administration.
3.
If several actions are indicated at the same time point, the intake of meals will be the last action.
4.
End of trial examination includes physical examination, vital signs, ECG, safety laboratory including pregnancy testing 
in females, recording of AEs and concomitant therapies, faecal occult blood test, C-SSRS and visual tests.
5.
Includes immunochemical faecal occult blood (iFOB) test
6.
AEs and concomitant therapies will be recorded throughout the trial, but will be specifically asked for at the time points 
indicated in the Flow Chart above.


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7.
Includes questioning for ‘restrictions’
8.
Pre-dose PK., i.e. within 10 min prior to the next drug administration
9.
C-SSRS 
10. Neurological assessment (i.e. Romberg and Unterberger test, assessment of gait, further tests as needed) to be performed 
at the time points mentioned in the Flow Chart above and at any times CNS adverse events are reported
11. Discharge after confirmation of fitness by the investigator/designee
12. Safety laboratory to be taken within 3 days prior to first trial drug administration of Visit 2 and 3. All results must be 
available and be checked by the investigator or his/her designee before trial drug administration.
13. Colour discrimination, visual acuity testing, Amsler grid test: tests will be performed at screening, EOT and at any time 
visual adverse events are reported 
14. All blood pressure measurements, as well as pulse rate and ECG will be measured after at least 5 minutes of rest in the
supine position
15. Only urine drug screen and alcohol breath test and urine pregnancy testing (female subjects), no safety lab
** There is no wash-out period between Visit 2 and Visit 3. Day 1 of Visit 3 follows directly after day 15 of Visit 2 but these 
are different days


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TABLE OF CONTENTS
TITLE PAGE ......................................................................................................1
CLINICAL TRIAL PROTOCOL SYNOPSIS ................................................2
FLOW CHART...................................................................................................4
TABLE OF CONTENTS ................................................................................ 10
ABBREVIATIONS.......................................................................................... 14
1.
INTRODUCTION.................................................................................... 17
1.1
MEDICAL BACKGROUND............................................................................17
1.2
DRUG PROFILE...............................................................................................17
1.2.1
BI 425809 ...............................................................................................17
1.2.1.1
Non-clinical pharmacokinetics ................................................17
1.2.1.2
Non-clinical safety pharmacology and toxicology ..................18
1.2.1.3
Clinical experience in humans.................................................18
1.2.1.4
Clinical pharmacokinetics........................................................19
1.2.2
Donepezil................................................................................................20
1.2.3
Residual Effect Period..........................................................................23
1.3
RATIONALE FOR PERFORMING THE TRIAL........................................23
1.4
BENEFIT - RISK ASSESSMENT ...................................................................23
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 endpoints ................................................................................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 GROUP..........................................................................................28
3.3
SELECTION OF TRIAL POPULATION ......................................................29
3.3.1
Main diagnosis for trial entry..............................................................29
3.3.2
Inclusion criteria...................................................................................29
3.3.3
Exclusion criteria ..................................................................................29
3.3.4
Withdrawal of subjects from treatment or assessments ...................31
3.3.4.1
Discontinuation of trial treatment............................................32


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3.3.4.2
Withdrawal of consent to trial participation ............................33
3.3.4.3
Discontinuation of the trial by the sponsor..............................33
3.3.5
Replacement of subjects .......................................................................33
4.
TREATMENTS........................................................................................ 34
4.1
INVESTIGATIONAL TREATMENTS ..........................................................34
4.1.1
Identity of the Investigational Medicinal Products ...........................34
4.1.2
Selection of doses in the trial................................................................34
4.1.3
Method of assigning subjects to treatment groups ............................35
4.1.4
Drug assignment and administration of doses for each subject .......35
4.1.5
Blinding and procedures for unblinding ............................................36
4.1.6
Packaging, labelling, and re-supply ....................................................37
4.1.7
Storage conditions.................................................................................37
4.1.8
Drug accountability ..............................................................................38
4.2
OTHER TREATMENTS, EMERGENCY PROCEDURES, 
RESTRICTIONS ...............................................................................................38
4.2.1
Other treatments and emergency procedures....................................38
4.2.2
Restrictions............................................................................................39
4.2.2.1
Restrictions regarding concomitant treatment .........................39
4.2.2.2
Restrictions on diet and life style.............................................39
4.3
TREATMENT COMPLIANCE.......................................................................40
5.
ASSESSMENTS....................................................................................... 42
5.1
ASSESSMENT OF EFFICACY.......................................................................42
5.2
ASSESSMENT OF SAFETY............................................................................42
5.2.1
Physical examination ............................................................................42
5.2.2
Vital signs...............................................................................................42
5.2.3
Visual tests.............................................................................................42
5.2.3.1
Color discrimination test..........................................................42
5.2.3.2
Visual acuity test (near visual acuity)......................................43
5.2.3.3
Amsler grid test........................................................................43
5.2.4
Suicidality monitoring (Part 2 only)....................................................44
5.2.5
Safety laboratory parameters..............................................................44
5.2.6
Electrocardiogram................................................................................47
5.2.7
Assessment of adverse events...............................................................48
5.2.7.1
Definitions of adverse events...................................................48
Adverse event ............................................................48
5.2.7.1.1
Serious adverse event ................................................48
5.2.7.1.2
AEs considered ‘Always Serious’.............................49
5.2.7.1.3
Adverse events of special interest .............................49
5.2.7.1.4
Intensity (severity) of AEs.........................................50
5.2.7.1.5
Causal relationship of AEs ........................................50
5.2.7.1.6
5.2.7.2
Adverse event collection and reporting ...................................51


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AE collection.............................................................51
5.2.7.2.1
AE reporting to the sponsor and timelines ................52
5.2.7.2.2
Information required..................................................52
5.2.7.2.3
Pregnancy ..................................................................52
5.2.7.2.4
5.3
DRUG CONCENTRATION MEASUREMENTS AND 
PHARMACOKINETICS..................................................................................52
5.3.1
Assessment of pharmacokinetics .........................................................52
5.3.2
Methods of sample collection...............................................................53
5.3.2.1
Blood sampling for pharmacokinetic analysis.........................53
5.3.3
Analytical determinations ....................................................................54
5.3.3.1
Analytical determination of analyte plasma concentration......54
5.6
APPROPRIATENESS OF MEASUREMENTS.............................................54
6.
INVESTIGATIONAL PLAN.................................................................. 55
6.1
VISIT SCHEDULE............................................................................................55
6.2
DETAILS OF TRIAL PROCEDURES AT SELECTED VISITS ................55
6.2.1
Screening period....................................................................................55
6.2.2
Treatment period ..................................................................................55
6.2.3
Follow-up period and trial completion ...............................................56
7.
STATISTICAL METHODS AND DETERMINATION OF
SAMPLE SIZE......................................................................................... 57
7.1
STATISTICAL DESIGN – MODEL ...............................................................57
7.2
NULL AND ALTERNATIVE HYPOTHESES ..............................................57
7.3
PLANNED ANALYSES....................................................................................57
7.3.1
Primary endpoint analyses...................................................................59
7.3.2
Secondary endpoint analyses ...............................................................59
7.3.4
Safety analyses.......................................................................................60
7.4
INTERIM ANALYSES .....................................................................................61
7.5
HANDLING OF MISSING DATA ..................................................................61
7.5.1
Safety......................................................................................................61
7.5.2
Pharmacokinetics..................................................................................61
7.6
RANDOMISATION ..........................................................................................61
7.7
DETERMINATION OF SAMPLE SIZE ........................................................61
8.
INFORMED CONSENT, TRIAL RECORDS, DATA 
PROTECTION, PUBLICATION POLICY, AND 
ADMINISTRATIVE STRUCTURE...................................................... 63


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8.1
TRIAL APPROVAL, SUBJECT INFORMATION, INFORMED 
CONSENT ..........................................................................................................63
8.2
DATA QUALITY ASSURANCE .....................................................................64
8.3
RECORDS..........................................................................................................64
8.3.1
Source documents .................................................................................64
8.3.2
Direct access to source data and documents.......................................65
8.3.3
Storage period of records.....................................................................65
8.4
EXPEDITED REPORTING OF ADVERSE EVENTS .................................65
8.5
STATEMENT OF CONFIDENTIALITY AND SUBJECT PRIVACY.......65
8.5.1
Collection, storage and future use of biological samples and 
corresponding data ...............................................................................66
8.6
TRIAL MILESTONES .....................................................................................66
8.7
ADMINISTRATIVE STRUCTURE OF THE TRIAL ..................................66
9.
REFERENCES......................................................................................... 68
9.1
PUBLISHED REFERENCES...........................................................................68
9.2
UNPUBLISHED REFERENCES.....................................................................69
10. APPENDICES .......................................................................................... 71
10.1
COLUMBIA-SUICIDE SEVERITY RATING SCALE ................................71
11. DESCRIPTION OF GLOBAL AMENDMENT(S).............................. 77
11.1
GLOBAL AMENDMENT 1 .............................................................................77
11.2
GLOBAL AMENDMENT 2 .............................................................................79
11.3
GLOBAL AMENDMENT 3 .............................................................................80


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ABBREVIATIONS
AD
Alzheimer’s Disease
AE
Adverse event
AESI
Adverse events of special interest
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-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
C-SSRS
Blood pressure
Columbia Suicide Severity Rating Scale
CA
Competent authority
CI
Confidence interval
CIAS
Cognitive impairment associated with schizophrenia
CL
Total clearance of the analyte in plasma after intravascular administration
 
Cmax
Maximum measured concentration of the analyte in plasma
CNS
Central nervous system
CRF
Case Report Form, paper or electronic (sometimes referred to as ‘eCRF’)
CRO
Contract Research Organisation
CTM
Clinical Trial Manager
CTP
Clinical trial protocol
CTR
Clinical trial report
CV
Arithmetic coefficient of variation
DDI
Drug-drug-interaction
DILI
Drug induced liver injury
eECG
Electrocardiogram
eCRF
Electronic case report form
eDC
Electronic data capture
EDTA
Ethylenediaminetetraacetic acid


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EOT/EoTrial
End of trial
EudraCT
European Clinical Trials Database
FDA
Food and Drug Administration
FU
Follow-up
GCP
Good Clinical Practice
gCV
Geometric coefficient of variation
GI
Gastrointestinal
GlyT1
Glycine transporter 1
gMean
Geometric mean
iFOB
Immunochemical Faecal occult blood test
IB
Investigator’s brochure
IEC
Independent Ethics Committee
IMP
Investigational Medical Product
IPD
Important protocol deviations
IRB
Institutional Review Board
ISF
Investigator site file
LC-MS/MS
Liquid chromatography with tandem mass spectrometry
MDA
Methylenedioxyamphetamine
MDMA
Methylenedioxymethamphetamine
MedDRA
Medical Dictionary for Regulatory Activities
MRT
Mean residence time of the analyte in the body after intravenous bolus 
administration
NMDA
N-methyl-D-aspartate
PK
Pharmacokinetic(s)
PKS
Pharmacokinetic set
PR
Pulse rate
QT
Time between start of the Q-wave and the end of the T-wave in an 
electrocardiogram
QTc
QT interval corrected for heart rate using the method of Fridericia (QTcF) 
or Bazett (QTcB)
R
Reference treatment
REP
Residual effect period
SAE
Serious adverse event
SCR
Screening
SmPC
Summary of Product Characteristics
SOP
Standard operating procedure


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ss
(at) steady state
SUSAR
Suspected unexpected serious adverse reaction
T
Test product or treatment
TMF
Trial master file
 
TS
Treated set
TSAP
Trial statistical analysis plan
ULN
Upper limit of normal
 
XTC
Ecstasy 


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1.
INTRODUCTION
BI 425809 is a glycine transporter 1 (GlyT1) inhibitor that is being developed for 
symptomatic treatment of Alzheimer’s Disease (AD) and cognitive impairment associated 
with schizophrenia (CIAS)
1.1
MEDICAL BACKGROUND
Schizophrenia and AD are chronic, severe, and disabling brain disorders affecting both men 
and women. Both disorders are characterized by abnormalities in glutamatergic pathways 
related to N-methyl-D-aspartate (NMDA) receptor hypofunction in cortical and hippocampal 
brain areas. These abnormalities are hypothesized to lead to negative symptoms and cognitive 
impairment in schizophrenia and cognitive impairment in AD. Inhibition of GlyT1 aims at 
improving NMDA receptor hypoactivation in patients with schizophrenia and AD by 
increasing the concentration of the NMDA receptor co-activator glycine in the synaptic cleft, 
thereby leading to improvement of negative and cognitive symptoms in patients with 
schizophrenia (as add-on therapy to antipsychotics) as well as to cognitive improvement in 
AD patients (as add-on therapy to acetylcholinesterase inhibitors).
BI 425809 is a potent and selective inhibitor of GlyT1 and does not show species selectivity 
regarding inhibition of human, rat and pig GlyT1. In vivo proof-of-mechanism (i.e. target 
engagement in brain) is demonstrated by a dose dependent increase of glycine in rat 
cerebrospinal fluid. Results from pre-clinical studies with BI 425809 have demonstrated pro-
cognitive properties in relevant animal models of learning and memory impairment. 
Therefore it is expected that treatment with BI 425809 has the potential to improve cognitive 
functioning in patients with AD and CIAS.
BI 425809 has been administered to healthy volunteers in so far 8 Phase 1 trials and 2 Phase 
2 trials in patients are currently ongoing.  In addition, BI 425809 is not a first in class 
compound. Other GLYT1 inhibitors (e.g. Bitopertin and sarcosine) have been tested in 
clinical trials before [R13-4447, R13-4508].
1.2
DRUG PROFILE
1.2.1
BI 425809
1.2.1.1
Non-clinical pharmacokinetics
 
 
Based 
on in vitro data, at the highest proposed Phase II dose of 25 mg, BI 425809 and BI 758790 
may cause clinically relevant induction of CYP2B6.


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1.2.1.2
Non-clinical safety pharmacology and toxicology
 
 
 
 
 
 
 
For a more detailed description of the BI 425809 profile, please refer to the current 
Investigator’s Brochure (IB) [c02155957].
1.2.1.3
Clinical experience in humans
At the time of preparation of this clinical trial protocol, BI 425809 has been investigated in 
eight Phase 1 trials (7 of them already reported; one trial (1346-0016 [c11975084]) clinically 
completed, data on file). Two Phase 2 trials (1346-0009 [c03559983] and 1346-0023
[c03632269]) and one Phase 1 trial (1346-0015 [c21363182]) are ongoing.
More than of 245 healthy subjects have received one or more doses of BI 425809 (single 
doses of 0.5 mg to 150 mg and multiple doses of 5 mg to 75 mg bid (150 mg/day)), including 
18 subjects aged 65 years or older (for details please refer to Investigator’s Brochure, 
Table 6.1: 1 [c02155957]).
Altogether, BI 425809 was generally well tolerated in young and elderly healthy male and 
female volunteers. No deaths or serious adverse events (SAEs) and no AEs of special interest 
(AESI) were reported. Across all BI 425809 treatment groups, there were 3 subjects with 
severe, but self-limiting AEs. Overall, drug-related AEs have been seen more frequently in 
the subjects treated with BI 425809 (33.5% vs 26.9% on placebo). Across all BI 425809 
treatment groups, 3 subjects discontinued treatment due to an AE (2x nausea and vomiting, 
1x procedural headache), all subjects recovered (for details please refer to Investigator’s 
Brochure, Table 6.3.1.1: 3 [c02155957]).


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The most frequent AEs for BI 425809 were nervous system disorders (25.3%), with headache 
being the most common (18.0%). These AEs appear to be dose-related, with a tendency for 
greater frequency at higher doses and can be clinically monitored.
In addition, transient visual disturbances (at doses ≥ 25 mg BI 425809 qd, mainly blurred 
vision) and somnolence (drowsiness) were observed. These effects are mostly mild to 
moderate and transient. 
In general, there were no clinically relevant findings in the clinical laboratory evaluation, 
12-lead ECG, vital signs. No suicidal ideation or behaviour was observed. No notable 
decrease in haemoglobin or haematocrit was noted in the BI 425809 treatment groups 
compared with placebo.
For a more detailed list of observed AEs and safety measures please refer to the current 
Investigator’s Brochure, section 6 [c02155957].
1.2.1.4
Clinical pharmacokinetics
 
As BI 425809 is a substrate of CYP3A4, co-administration of weak, moderate and strong
CYP3A4 inhibitors and inducers is not permitted.
Due to a mild induction potential for CYP3A4 [c08949593], BI 425809 should be 
administered with caution in presence of sensitive substrates of these enzymes, and sensitive 
CYP3A4 substrates with a narrow therapeutic index are not permitted. BI 425809 had no 
relevant effect on CYP2C9, CYP2C19, and P-gp substrates.
 
 
 
 
For a more detailed description of the BI 425809 profile please refer to the current 
Investigator’s Brochure [c02155957].


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1.2.2
Donepezil 
Donepezil is a specific and reversible inhibitor of acetylcholinesterase, the predominant
cholinesterase in the brain. Current theories on the pathogenesis of the cognitive signs and 
symptoms of Alzheimer’s disease attribute some of them to a deficiency of cholinergic 
neurotransmission [R15-4794]. Donepezil is indicated for the symptomatic treatment of mild 
to moderate dementia of the Alzheimer’s type and commonly used in this patient population
[R18-3913].
In mild to moderate AD the dosing recommendation is a daily dose of 5 mg q.d. which might 
be increased to a maximum dose of 10 mg q.d.. For tolerability reasons, it is recommended to 
administer donepezil in the evening and to use an up-titration scheme starting with 5 mg 
donepezil q.d. and increasing to 10 mg q.d. if needed and well tolerated.
Maximum plasma levels after administration of 10 mg donepezil are reached approximately 
3 - 4 hours after oral administration [R15-4794, R18-3913].
The terminal disposition half-life is approximately 70 hours. Following multiple dose 
administration, steady state is reached within ~3 weeks. Donepezil is mainly excreted (57%) 
in the urine, both intact (17%) and metabolized, and also via faeces (14.5%). It is extensively 
metabolized to four major metabolites, of which one, 6-O-Desmethyl-Donepezil has a 
comparable activity to donepezil, and a number of minor metabolites, of which not all have 
been identified [R18-3913].
In vitro studies have shown that CYP3A4 and to a minor extent CYP2D6 are involved in the 
metabolism of donepezil. In a study in healthy volunteers, ketoconazole increased mean 
donepezil concentrations by about 30 %. In patients with mild – moderate hepatic impairment 
steady state exposures of donepezil were increased (AUC up to ~ 48%, Cmax up to ~39%) 
[R18-3913].
Enzyme inducers such as rifampicin, phenytoin, carbamazepine and alcohol may reduce the 
levels of donepezil [R15-4794].
In human liver microsomes CYP-450 enzymes 1A2, 2C9, 2C19, 2D6 and 3A4 were inhibited 
by donepezil with IC50 values > 100 μm. In addition, the mean ki values for CYP-3A4 and 
CYP-2D6 were calculated to be 131 μm and 47 μm, respectively. Clinical studies have shown 
that the steady-state Cmax for the 10 mg dose of donepezil is approximately 164 nm. Since it 
is anticipated that therapeutic concentrations of donepezil are more than 280-fold lower than 
the lowest ki value obtained with CYP-2D6 and almost 800-fold lower than the ki observed 
with CYP-3A4, it is expected that donepezil will not inhibit the metabolism of other drugs 
metabolized by these or any other CYP-450 isoenzymes [R18-3919].
Data from clinical trials in healthy volunteers indicate a good safety profile for daily doses up 
to 10 mg and an acceptable safety profile for a daily dose of 23 mg. This is in accordance 
with the sponsor’s own experience of a trial in healthy volunteers that received multiple doses 
of donepezil [c09564954]


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
A randomized, double-blind, multiple dose study was investigating the 
pharmacokinetic and pharmacodynamics profile of donepezil, clinical trials with 
healthy volunteers. Single daily doses of donepezil (5 and 10 mg) each evening were 
administered on 28 consecutive days. 
8 subjects received 5 mg donepezil for 28 days, 8 subjects started with 5 mg donepezil 
and switched thereafter to a daily dose of 10 mg for the remaining 21 days. 
Donepezil was well tolerated by all subjects. The most frequently reported adverse 
events were headache, gastrointestinal upset, sleep disturbance and lethargy. All were 
transient, mild and resolved during continued treatment without the need for 
adjunctive therapy [R05-0853].

An open-label, randomized, single-dose, two-period crossover study was investigating 
the bioequivalence of two extended-release tablets of donepezil 23 mg under fasting 
(n=74) and fed (n= 93) conditions.  
In the fasting study, a total of 154 AEs were reported by 52 subjects. Of all AEs, two 
(increased neutrophil count and oral herpes) were unexpected and possibly related to 
the administration of the product. In the fed study, 81 subjects experienced a total of 
305 AEs. Of all AEs, four (mydriasis, oral herpes, photophobia, and pupils unequal) 
were unexpected and possibly related to the administration of the (test or reference) 
products. 
No subject was withdrawn from the study for safety reasons. There were no deaths or 
serious adverse events reported. All of the observed AEs were considered to be
resolved. Given this information, the study drugs appeared to be well-tolerated and 
there were no safety concerns observed [R15-4356].

A study to investigate the pharmacokinetic drug-drug interaction following oral 
administration of BI 409306 and donepezil in 32 healthy male (n = 17) and female 
(n = 15) subjects. Part 1 of this trial was performed as a one fixed sequence, open-
label trial, in which single doses of BI 409306 and multiple doses of donepezil (5 mg 
qd for 7 days followed by 10 mg qd for 14 days) were administered, Part 2of this trial 
was a randomised, open-label, 2-way crossover design, in which single doses of 
donepezil and multiple doses of BI 409306 were given.
In Part 1of the trial, i.,e. after multiple doses of donepezil, 16 out of 18 subjects 
(88.9%) were reported with at least 1 AE that was assessed as drug-related. The most 
frequently reported drug-related AEs were dizziness and nausea (both 55.6% of 
subjects), followed by headache and fatigue (both 22.2%). Dizziness was only 
observed after administration of donepezil alone, whereas nausea and headache were 
observed after administration of donepezil alone and in combination with BI 409306. 
As expected visual brightness a known AE of BI 409306 was only observed after 
BI 409306 administration. Fatigue was observed in all 3 treatment phases.
All subjects completed the trial except for 1 subject in Part 1 who withdrew during the 
second treatment period (donepezil administration) because of AEs that were 
considered not to be drug-related (lower abdominal pain, haematochezia, and ruptured 
ovarian cyst) [c09564954].


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According to [R15-4794, R18-3913], the safety profile mainly results from the cholinergic 
activity of donepezil, resulting in

Gastrointestinal symptoms (e.g. nausea, diarrhea, vomiting, abdominal pain, gastric 
and duodenal ulcers and gastrointestinal hemorrhage)

Cardiac symptoms (e.g. syncopes, bradycardia, sino-atrial block, atrioventricular 
block)

Central-nervous symptoms (e.g. syncopes, dizziness, insomnia, seizures, 
extrapyramidal symptoms and neuroleptic malignant syndrome)
Further undesirable effects of donepezil include common cold, anorexia, hallucinations, 
agitations, aggressive behavior, abnormal dreams and nightmares, livery dysfunction 
including hepatitis, minor increase in serum concentration of muscle creatine kinase,
rhabdomyolisis, rash pruritus, muscle cramps, urinary incontinence, headache, fatigue, pain, 
and accident.
Donepezil

Is likely to exaggerate succinylcholine-type muscle relaxation during anesthesia

Should not be co-administered with other cholinergic agonists or antagonists

Has minor or moderate influence on the ability to drive and use machines

May have vagotonic effects on the sinoatrial and atrioventricular nodes manifesting as 
bradycardia or heart block 

As a cholinomimetic may cause bladder outflow obstruction although this was not 
observed in clinical trials with marketed Aricept (tradename of donepezil in the US)

As a cholinomimetic may have the potential to cause seizures

Should be used with care in patients with history of asthma or COPD as 
cholinomimetics may cause bronchoconstriction 
Neuroleptic Malignant Syndrome (NMS):
NMS, a potentially life-threatening condition characterized by hyperthermia, muscle rigidity, 
autonomic instability, altered consciousness and elevated serum creatine phosphokinase 
levels, has been reported to occur very rarely in association with donepezil, particularly in 
patients also receiving concomitant antipsychotics. Additional signs may include 
myoglobinuria (rhabdomyolysis) and acute renal failure.
Cholinergic crisis:
Donepezil overdose can result in cholinergic crisis characterized by severe nausea, vomiting, 
salivation, sweating, bradycardia, hypotension, respiratory depression, collapse and 
convulsions.  Increasing muscle weakness is possible and may result in death if respiratory 
muscles are involved.
For a more detailed description of the profile of BI 425809, please refer to the current 
Investigator’s Brochure [c02155957] and for donepezil to the SmPC [R18-3913].


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1.2.3
Residual Effect Period
The Residual Effect Period (REP) of BI 425809 is 11 days, the REP for donepezil 15 days. 
This is the period after the last dose with measurable drug levels and/or pharmacodynamic 
effects is still likely to be present.
1.3
RATIONALE FOR PERFORMING THE TRIAL
BI 425809 is being developed for the symptomatic treatment of AD. Donepezil is a specific 
and reversible inhibitor of acetylcholinesterase and is frequently used for the symptomatic
treatment of AD.
Both, BI 425809 as well as donepezil are metabolized via CYP3A4. Clinical data show that 
BI 425809 is a weak inducer of CYP3A4 and at the same time a sensitive CYP3A4 substrate 
[c02155957]. As donepezil is a commonly used medication in the target population of 
BI 425809 the potential and relevance of possible drug-drug interaction shall be investigated 
with this trial to ensure a safe use in upcoming clinical trials as well as in later clinical use in 
the target population.
1.4
BENEFIT - RISK ASSESSMENT
Participation in this study is without any (therapeutic) benefit for healthy subjects. Their 
participation in the study, however, is of major importance to the development of BI 425809. 
The assessment of the drug-drug-interaction (DDI) potential of BI 425809 and donepezil will 
contribute to a safe clinical use of this GlyT1-inhibitor in patients with Alzheimer`s disease 
that are also treated with donepezil.
The subjects are exposed to the risks of the study procedures and the risks related to the 
exposure to the trial medication.
Procedure-related risks
The use of an indwelling venous catheter for the purpose of blood sampling may be 
accompanied by mild bruising and also, in rare cases, by transient inflammation of the wall of 
the vein. In addition, in rare cases a nerve might be injured while inserting the venous 
catheter, potentially resulting in paresthesia, reduced sensibility, and/or pain for an indefinite 
period. The same risks apply to veinipuncture for blood sampling.
The total volume of blood withdrawn during the entire study per subject will not exceed the 
volume of a normal blood donation (500 mL). No health-related risk to healthy subjects is 
expected from this blood withdrawal.
Drug-related risks and safety measures
Risks related to BI 425809 administration
In Part 2 of this trial, a dose of 25 mg BI 425809 q.d. will be administered over a period of 
24 days. Multiple oral doses of 25 mg BI 425809 have already been administered in trial 


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1346.2 [c02958024] (12 days) and 1346.3 [c03724403] (14 days) and considered safe and 
well tolerated (for details please refer to Section 1.2.1.3). Further, two Phase II trials, one in 
patients with Alzheimer’s disease (1346.23) and one in patients with CIAS (1346.9), are 
currently ongoing in which patients receive up to 25 mg BI 425809 q.d. in an ambulatory 
setting over a period of 12 weeks with no safety issues reported so far.
Based on its mechanism of action, its preclinical profile and the data obtained from ongoing 
and completed Phase I/II studies so far, there is no indication that BI 425809 should be 
regarded as a high risk compound. 
The main dose-limiting AEs observed so far, were expected based on its mode of action. 
These adverse CNS symptoms, including dizziness, headache, and visual effects showed a 
trend towards dose dependency and were monitorable and reversible after treatment 
discontinuation. The reported adverse events were mostly of mild to moderate intensity and 
did not jeopardize the subject’s wellbeing. Adequate safety monitoring including 
neurological examinations, vital signs/ECG, visual tests, safety laboratory, suicidality 
assessment and adverse events monitoring has been implemented. Though the trial is 
designed in parts in an ambulatory fashion, if the investigator has any clinical concern the 
safety of the subject will be paramount and the inpatient stay will be extended or initiated.
Risks related to donepezil administration
Multiple doses of donepezil up to 10 mg were well tolerated in healthy volunteer trials 
[R15-4355, R05-0853, c09564954]. With single doses up to 23 mg donepezil, the safety 
profile was still summarized as “well tolerated” and did not raise safety concerns 
[R15-4356].The safety profile of donepezil is mainly driven by cholinergic effects that in 
case of overdose may lead to a cholinergic crisis (see Section 1.2.2). Symptoms resulting 
from the cholinergic effects of donepezil are monitorable and can be adequately treated
(see Section 4.2.1).
Risks related to the combined administration of BI 425809 and donepezil 
BI 425809 and M530 were determined to be mild in vitro irreversible inhibitors of CYP3A;
however, once daily oral administration of BI 425809 (25mg) did not inhibit CYP3A-
mediated elimination of midazolam in humans (1346.22 [c08949593]. Mild in vitro 
reversible inhibition of CYP2D6 (IC50 >100 μM) by M530 is not expected to be of clinical 
impact based on exposures associated with 25 mg qd (Cmax 25 mg 278 nmol/L, AUC0-inf
12700nmol*h/L [c02155957] and the minor contribution of CYP2D6 to donepezil
metabolism compared to CYP3A4. Therefore an increase of donepezil exposure after BI 
425809 administration is not to be expected. 
On the opposite, as BI 425809 has been shown clinically to be a weak inducer of CYP3A4 
and may therefore reduce levels of donepezil as it has been shown for other enzyme inducers 
such as rifampicin, phenytoin, carbamazepine and alcohol [R15-4794].
Regarding donepezil, no inhibition of the metabolism of drugs metabolized by CYP-450 
isoenzymes is expected at therapeutic doses of donepezil (Section 1.2.2).


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In summary, a clinically relevant pharmacokinetic interaction causing elevated exposures of 
donepezil or BI 425809 is considered unlikely.
Safety measures

Close monitoring of 
o
Adverse events
o
Safety lab (special focus on hepatic parameters, markers of GI bleeding (CRP, 
haematology, iFOB), CK)
o
ECG (focus on possible vagotonic action of donepezil) 
o
Vital signs

Prohibition to use drugs as concomitant therapy that are known to also trigger 
gastrointestinal ulcers/hemorrhage, e.g. NSAIDs (Section 4.2.2)

Availability of rescue medication (atropine) in case of signs and symptoms of 
cholinergic crisis (see Section 4.2.1).

Subjects will receive a trial specific emergency card with information for 
anesthesiologists about the donepezil intake in case of unplanned surgery and 
potential use of succinylcholine

As donepezil may impact the ability to operate vehicles and/or machines, subjects 
participating in Part 1of this trial subjects are not allowed to drive a vehicle or operate 
machines during Visit 3

Although only healthy subjects are allowed to enter this trial per se the investigator 
has to specifically ask subject’s for any life-time history of asthma or seizure resulting 
in exclusion of the subject
Although rare, a potential for drug-induced liver injury is under constant surveillance by
sponsors and regulators. Therefore, this study requires timely detection, evaluation, and
follow-up of alterations in selected liver laboratory parameters to ensure subjects´ safety.
Overall assessment
Considering the good safety profile of BI 425809 observed so far in healthy subjects, and the 
safety and tolerability of donepezil up to single doses of 23 mg in healthy volunteers, the 
unlikelihood of increased drug exposures due to a donepezil-BI 425809 interaction and taking 
into account the safety measures described in this chapter, the benefit of a successful clinical 
development of BI 425809 for the treatment of Alzheimer’s disease or CIAS is assessed to 
outweigh the potential risks to healthy subjects participating in this trial that are further 
considered to be low and acceptable.


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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 Part 1of this trial is to investigate the effect of co-administration of 
multiple doses of donepezil on the single-dose pharmacokinetics of BI 425809 in healthy 
subjects. In Part 2 the main objective is the investigation of the effect of co-administration of 
multiple doses of BI 425809 on the single-dose pharmacokinetics of donepezil in healthy 
subjects.
2.1.2
Primary endpoints
Part 1:
The following pharmacokinetic parameters will be determined for BI 425809:

AUC0-∞(area under the concentration-time curve of the analyte in plasma over the 
time interval from 0 extrapolated to infinity)

Cmax (maximum measured concentration of the analyte in plasma)
Part 2:
The following pharmacokinetic parameters will be determined for donepezil:

AUC0-∞(area under the concentration-time curve of the analyte in plasma over the 
time interval from 0 extrapolated to infinity)

Cmax (maximum measured concentration of the analyte in plasma)
2.1.3
Secondary endpoint
Part 1:
The following pharmacokinetic parameters will be determined for BI 425809:

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)
Part 2:
The following pharmacokinetic parameters will be determined for donepezil:

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 425809 will be assessed based on:  

Adverse events (including clinically relevant findings from the physical and 
neurological examination)

Safety laboratory tests, including faecal occult blood test

12-lead ECG

Visual tests

Vital signs (blood pressure, pulse rate)

Suicidality assessment (C-SSRS, only Part 2)


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3.
DESCRIPTION OF DESIGN AND TRIAL POPULATION
3.1
OVERALL TRIAL DESIGN AND PLAN
The study will consist of two parts and will be performed in healthy male and female 
subjects. Each subject does only participate in one part of the trial. Both parts are designed as 
open-label, two-treatment, two-period, one fixed sequence cross-over to investigate the 
effects of donepezil as perpetrator (Part 1) and as victim (Part 2) in relation to BI 425809.
Part 1 and part 2 are independent from each other as they investigate different 
pharmacokinetic objectives and endpoints of part 1 would not alter the rationale for part 2. 
Therefore completion of part 1 is not required to allow start of part 2. This of course does not 
apply for any safety issues as defined in the stopping criteria (ref Section 3.3.4).
Considering the well-known safety profiles of the selected dose of BI 425809 and donepezil, 
the unlikelihood of increased drug exposures due to a donepezil-BI 425809 interaction and 
the already implemented safety measures (ref Section 1.4) treatment of all subjects in one 
cohort per trial part, i.e. one cohort of 18 subjects in part 1 and one cohort of 14 subjects in 
part 2, respectively, is not considered to be an undue risk for enrolled subjects. However, 
treatment in cohorts for logistical reasons is possible. In this case, the cohorts should be of 
about the same size and be treated not too wide apart in terms of time for better comparability 
and reducing any possible factors influencing the readout.
In both parts there will be no washout period between treatments.
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 GROUP
Open-label design
Both parts (Part 1 and Part 2) are conducted open-label. Blinding is not possible because the 
treatments are distinguishable. The open-label treatment is not expected to bias results, since 
the study endpoints are derived from measurement of plasma concentrations of the analyte 
provided by a bioanalytical laboratory which is blinded to treatment allocation.
Fixed sequence design
A fixed sequence design was selected due to the long half-life of both, donepezil and 
BI 425809. The fixed-sequence design is not expected to lead to systematic errors in the 
estimation of the treatment effects, because the trial duration is short enough so that 
nonspecific time-effects are not expected.
In both part, dosing durations are long enough to achieve steady-state drug exposures of the 
perpetrator drugs (Part 1: donepezil, Part 2: BI 425809) reliably and to exclude any transient 
effects. Actually, dosing duration of BI 425809 with 10 days exceeds the time needed to 


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achieve steady state (after 6 days of dosing) to allow for maximum induction of CYP3A
which is delayed compared to achievement of steady state.
3.3
SELECTION OF TRIAL POPULATION
It is planned that 18 (Part 1) and 14 (Part 2) healthy male or female subjects will enter the 
study. They will be recruited from the volunteer’s pool of the trial site.
A log of all subjects enrolled into the trial (i.e. who have signed informed consent) will be 
maintained in the ISF irrespective of whether they have been treated with investigational drug 
or not.
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 or female 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 50 years (inclusive) 
3.
BMI of 18.5 to 29.9 kg/m2 (inclusive) 
4.
Signed and dated written informed consent prior to admission to the study, in accordance 
with GCP and local legislation
5.
Male subjects, or female subjects who meet any of the following criteria from the first 
administration of trial medication until 30 days after trial completion:
-
Use of adequate contraception that does not contain hormones, i.e. non-hormonal 
intrauterine device plus condom 
-
Sexually abstinent
-
A vasectomised sexual partner (vasectomy at least 1 year prior to enrolment)
-
Surgically sterilised (including hysterectomy)
-
Postmenopausal, defined as at least 1 year of spontaneous amenorrhea (in 
questionable cases a blood sample with levels of FSH above 40 U/L and estradiol 
below 30 ng/L is confirmatory)
3.3.3
Exclusion criteria
Subjects will not be allowed to participate, if any of the following general criteria apply:
1.
Any finding in the medical examination (including BP, PR or ECG) 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 50 to 90 mmHg, or pulse rate outside the 
range of 50 to 90 bpm


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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) 
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 60 days of planned  
administration of investigational drug in the current trial, or concurrent participation in 
another clinical trial in which investigational drug is administered
13. Smoker (more than 10 cigarettes or 3 cigars or 3 pipes per day)
14. Inability to refrain from smoking on specified trial days
15. Alcohol abuse (consumption of more than 20 g per day for females and 30 g per day for
males)
16. Drug abuse or positive drug screening
17. Blood donation of more than 100 mL within 30 days of planned administration of trial 
medication or intended blood donation during the trial
18. Intention to perform excessive physical activities within one week prior to the 
administration of trial medication or during the trial
19. Inability to comply with the dietary regimen of the trial site
20. A marked baseline prolongation of QT/QTc interval (such as QTc intervals that are 
repeatedly greater than 450 ms in males or repeatedly greater than 470 ms in females) or 
any other relevant ECG finding at screening
21. A history of additional risk factors for Torsade de Pointes (such as heart failure, 
hypokalaemia, or family history of Long QT Syndrome)
22. Subject is assessed as unsuitable for inclusion by the investigator, for instance, because 
the subject is not considered able to understand and comply with study requirements, or 
has a condition that would not allow safe participation in the study 


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Female subjects will not be allowed to participate, if any of the following apply:
23. Positive pregnancy test, pregnancy, or plans to become pregnant within 30 days after 
study completion
24. Lactation
In addition, the following trial-specific exclusion criteria apply:
25. History of asthma or obstructive pulmonary disease
26. Clinically relevant cardiac conduction disorders such as sinoatrial or higher degree 
atrioventricular block and sick sinus syndrome. 
27. Bladder outflow obstruction
28. Subjects with increased risk for developing gastrointestinal ulcers (e.g. those with a 
history of ulcer disease or frequent use of non-steroidal anti-inflammatory drugs)
29. History of macular degeneration or any abnormal finding in visual tests (Amsler grid 
test, colour discrimination test) at screening
30. Subjects with known hypersensitivity to piperidine derivatives (e.g. astemizol, loratadin, 
pethidin, loperamid, haloperidol, domperidon)
31. Liver tests (ALT, AST, GGT, AP), Total Bilirubin or Creatinine outside the normal 
range at the screening examination
Specifically for Part 2:
32. Any suicidal ideation of type 2 to 5 on the C-SSRS in the past 12 months (i.e. active 
suicidal thought, active suicidal thought with method, active suicidal thought with intent 
but without specific plan, or active suicidal thought with plan and intent)
33. Any lifetime history of suicidal behaviour (i.e. actual attempt, interrupted attempt,
aborted attempt, or preparatory acts or behaviour).
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; please see 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 
discontinuation, a complete end of trial examination will be performed, if possible, and the 
information will be recorded in the CRF. If the discontinuation occurs before the end of the 
REP (see Section 1.2.3), the discontinued subject should if possible be questioned for AEs 
and concomitant therapies at or after the end of the REP in order to ensure collection of AEs 


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and concomitant therapies throughout the REP, if not contrary to any consent withdrawal of 
the subject.
If it is known that a subject becomes pregnant during the trial, administration of the trial 
medication is to be stopped immediately, and the subject is to be removed from the trial. The 
subject is to be followed until she has given birth or until the end of the pregnancy. The 
subject’s data are to be collected until the end of the trial (last visit of last subject) and 
reported in the CTR. For reporting of pregnancy and associated events, refer to Section 
5.2.7.2.4.
3.3.4.1
Discontinuation of trial treatment
An individual subject will discontinue trial treatment if:

The subject wants to discontinue trial treatment, without the need to justify the 
decision

The subject has repeatedly shown to be non-compliant with important trial 
procedures and, in the opinion of both, the investigator and sponsor 
representative, is not willing or able to adhere to the trial requirements in the 
future.

The subject needs to take concomitant medication that interferes with the 
investigational medicinal product or other trial treatment

The subject can no longer receive trial treatment for medical reasons (such as 
pregnancy, surgery, adverse events [AEs], or diseases)

The subject has an elevation of AST and/or ALT ≥3-fold ULN OR 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

The subject shows signs and symptoms of cholinergic crisis or neuroleptic 
malignant syndrome (see Section 1.2.2).

The subject exhibits serious suicidality, in the clinical judgment of the 
investigator or according to the following criteria:
- any suicidal behaviour (i.e. actual attempt, interrupted attempt, aborted attempt, 
or preparatory acts or behaviour)
- any suicidal ideation of type 4 or 5 in the C-SSRS (i.e. active suicidal thought 
with intent but without specific plan, or active suicidal thought with plan and 
intent)
In addition to these criteria, the investigator may discontinue subjects at any time based on 
his or her clinical judgment.
Even if the trial treatment is discontinued, the subject remains in the trial and, given his/her 
agreement, will undergo the procedures for early treatment discontinuation and follow up as 
outlined in the Flow Chart and Section 6.2.3.


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3.3.4.2
Withdrawal of consent to trial participation
Subjects may withdraw their consent to trial participation at any time without the need to 
justify the decision. If a subject wants to withdraw consent, the investigator should be 
involved in the discussion with the subject and explain the difference between trial treatment 
discontinuation and withdrawal of consent to trial participation, as well as explain the options 
for continued follow up after trial treatment discontinuation, please see Section 3.3.4.1 above
3.3.4.3
Discontinuation of the trial by the sponsor
Boehringer Ingelheim reserves the right to discontinue the trial at any time for any of the 
following reasons:

Failure to meet expected enrolment goals overall or at a particular trial site

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

Violation of GCP, or the CTP, or the contract with BI impairing the appropriate 
conduct of the trial

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).
3.3.5
Replacement of subjects
In case more than 2 subjects per Part discontinue treatment, the Clinical Trial Leader together 
with the Trial Pharmacokineticist and the Trial Statistician are to decide, if and how many 
subjects will be replaced. A replacement subject will be assigned a unique trial subject 
number, and will be assigned to the same treatment as the subject he or she replaces.


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4.
TREATMENTS
4.1
INVESTIGATIONAL TREATMENTS
The investigational products have been manufactured by BI Pharma GmbH & Co. KG 
(BI 425809) and by Ratiopharm GmbH, Germany (donepezil).
4.1.1
Identity of the Investigational Medicinal Products
The characteristics of the trial products are given below:
Trial product 1:
Substance:
BI 425809
Pharmaceutical formulation:
Film coated tablet
Source:
BI Pharma GmbH & Co. KG, Germany
Unit strength:
25 mg
Posology:
Part 1: 0-0-1
Part 2: 1-0-0
Route of administration:
Oral
Duration of use:
Part 1: single dose on Day 1, Visit 2, and on Day 22, Visit 3
Part 2: multiple doses on days 1-24, Visit 3
Trial product 2:
Name:
Donepezil-HCl-ratiopharm®
Substance:
Donepezil
Pharmaceutical formulation:
Film-coated tablet
Source:
Ratiopharm GmbH, Germany
Unit strength:
5 mg
Posology:
Part 1: 0-0-1 (Days 1-7, Visit 3) and
0-0-2 (Days 8-28, Visit 3)
Part 2: 2-0-0
Route of administration:
Oral
Duration of use:
Part 1: multiple doses on days 1-28, Visit 3
Part 2: single dose on Day 1, Visit 2 and on Day 10, Visit 3
4.1.2
Selection of doses in the trial
The donepezil dose selected for this trial is the standard clinical dose [R18-3913] and the 
chosen up-titration scheme is recommended to improve tolerability. The dose selected for 


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BI 425809 is the highest dose to be tested in the ongoing Phase 2 and presumably in the 
following Phase 3 trials.
4.1.3
Method of assigning subjects to treatment groups
Both parts of the trial are designed as open-label, fixed sequence. All subjects participating in 
one Part will receive the same treatment sequence. 
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.
All subjects may be treated in one cohort, i.e. all subjects may receive treatment on the same 
calendar day. In case this is not feasible (e.g., due to logistical or recruitment reasons), the
group may be split into several cohorts as required. 
The following procedure regarding reserve subjects applies:
Reserve subjects will attend the Screening Visit and follow all trial procedures up to
treatment allocation on Day 1, but will not be dosed unless they replace a subject who does
not fulfill the requirements of the trial before administration of the IMP, i.e. they will remain
at the trial site until all intended subjects have been allocated to treatment. They will be
informed that they will be reserve subjects.
4.1.4
Drug assignment and administration of doses for each subject
This trial consists of two parts: 
Part 1 is an open-label, two-treatment, two-period, one fixed sequence cross-over trial, in 
which all subjects will first receive BI 425809 (treatment A = Reference 1) alone and then
again after multiple doses of donepezil (treatment B = Test 1). 
The treatments to be evaluated in Part 1 are outlined in Table 4.1.4: 1 below.
Table 4.1.4: 1
Part 1: Dosage and treatment schedule
Treatment
Substance
Formulation
Unit strength
Dosage
Total dose
A 
(Reference 1)
BI 425809
Tablet
25 mg
1 tablet (Day 1, Visit 2)
25 mg
B
(Test 1)
Donepezil
BI 425809
Tablet 
Tablet
5 mg
25 mg
1 tablet (Day 1-7, Visit 3) q.d.
2 tablets (Day 8-28, Visit 3) q.d.
1 tablet (Day 22, Visit 3)
245 mg
25 mg
Part 2 has an open-label two-treatment, two-period, one fixed-sequence cross-over design. In
Part 2 all subjects will first receive donepezil (treatment C = Reference 2) alone and then 
again after multiple doses of BI 425809 (treatment D = Test 2).
The treatments to be evaluated in Part 2 are outlined in Table 4.1.4: 2 below.


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Table 4.1.4: 2
Part 2: Dosage and treatment schedule
Treatment
Substance
Formulation
Unit strength
Dosage
Total dose
C 
(Reference 2)
Donepezil
Tablet
5 mg
2 tablets (Day 1, Visit 2)
10 mg
D
(Test 2)
Donepezil
BI 425809
Tablet 
Tablet
5 mg
25 mg
2 tablets (Day 10, Visit 3)
1 tablet (Days 1-24, Visit 3) q.d.
10 mg
600  mg
Trial medication will be administered to fasted subjects only (for fasting periods please refer 
to Section 4.2.2.2). The investigator (or authorised designee) will administer the trial 
medication as an oral dose together with about 240 mL of water to subjects who are 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 Part 1, subjects will be kept under close medical surveillance until 38 h following 
administration of BI 425809 on Day 1, Visit 2 and on Day 22 Visit 3. In addition subjects 
will remain under medical supervision for about 14 h following the first dose of donepezil on 
Day 1 Visit 3. This in-house surveillance period can be extended anytime if deemed 
necessary based on the medical judgement of the investigator.
In Part 2, subjects will be kept under close medical surveillance until at least 72 h following 
administration of donepezil on Day 1(Visit 2) and Day 10 (Visit 3). 
There will be no wash-out period between treatments A/C and B/D in Part 1 and 2, 
respectively as the extended blood sampling phase already covers a sufficiently long wash-
out between the drug administration of treatment A/C and the first drug administration in 
treatment B/D. Therefore the first day of treatment B/D, i.e. Visit 3, follows immediately 
after the last day of treatment A/C, i.e. Visit 2, but these two days are not the same day.
For restrictions with regard to diet see Section 4.2.2.2.
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.
PK samples will be labelled in such a way that treatment allocation cannot be derived by the 
analytical site.


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4.1.6
Packaging, labelling, and re-supply
BI 425809 tablets will be provided by BI. They will be packaged and labelled in accordance 
with local law and the principles of Good Manufacturing Practice. 
For details of packing and the description of the label, refer to the ISF.
The telephone number of the sponsor and the name, address and telephone number of the trial 
site are provided in the subject information form. The EudraCT number is indicated on the 
title page of this protocol as well as on the subject information and informed consent forms.
For donepezil, the commercially available product will be supplied by a public pharmacy. 
Transport and storage are under the responsibility of the investigator and must comply with 
the pertinent information in the SmPC of the drug product used in the clinical trial
[R18-3913].
Documentation on the commercial drug product, containing at least the following 
information, must be available on-site in the ISF:

Clinical trial number

Investigator name

Trade name of drug product

Substance International non-proprietary name (INN)

Holder of marketing authorization

Dosage form

Quantity

Unit strength

Batch/lot number

Use-by date

Point of purchase

Date of receipt

Recipient (name and function)
In addition, documentation of drug purchase, including identification of drug product and 
quantity, must be available at the clinical site and filed in the ISF.
Also, if required according to the SmPC of the drug product, documentation of temperature 
monitoring during shipment/transport must be available at the clinical site and filed in the ISF 
(e.g. for commercial drug products required to be stored cooled or frozen).
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 (as provided in the list of contacts) is to be contacted immediately.


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4.1.8
Drug accountability
The investigator or designee will receive the investigational drugs delivered from the sponsor
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, as 
applicable. 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.
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
No specific rescue medication is foreseen for BI 425809.
In case of a donepezil overdose, general supportive measures should be utilised. Tertiary 
anticholinergics such as atropine may be used as an antidote for donepezil overdosage. 
Intravenous atropine sulphate titrated to effect is recommended. An initial dose of 1.0 to 
2.0 mg i.v. with subsequent doses based upon clinical response. 
No additional treatment is planned. However, in case of adverse events in need of treatment, 
the investigator can authorise symptomatic therapy. In those cases, subjects will be treated as 
necessary and, if required, kept under supervision at the trial site or transferred to a hospital 
until all medical evaluation results have returned to an acceptable level.


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4.2.2
Restrictions
4.2.2.1
Restrictions regarding concomitant treatment
In principle, no concomitant therapy is allowed, including hormonal contraceptives or ovary 
hormone replacement.
However in case there are AEs needing treatment special care is to be taken that the 
following concomitant medications should be avoided:

The use of weak, moderate or strong CYP3A4 inhibitors and inducers is not 
permitted. CYP3A4 sensitive drugs with narrow therapeutic range are not permitted 
during the trial period. 

Drugs that are known to trigger gastrointestinal bleeding/ulcers, e.g. NSAIDs or 
corticosteroids, are not allowed in Part 2.

Paracetamol and diclofenac must be avoided as symptomatic therapy of AEs due to its 
potential liver toxicity.

The concomitant use of other inhibitors of acetycholinesterase, agonists or antagonists 
of the cholinergic system is also not allowed. An exception is the use of tertiary 
anticholinergics such as atropine in case of overdose (see Section 4.2.1).
All concomitant or rescue therapies will be recorded (including time of intake on study days) 
on the appropriate pages of the CRF.
4.2.2.2
Restrictions on diet and life style
While admitted to the trial site the subjects are restricted from consuming any other foods or 
drinks than those provided by the staff. Standardised meals will be served at the time points 
described in the Flow Chart.
Part 1:
On all dosing days of Part 1, with the exception of PK profile days, the trial medication will 
be administered after a fasting period of at least 2 h prior and keeping a post-administration 
fasting period of at least 1 h. Fluid intake is not allowed from 1 h predose until 
administration.
On PK profile days (Day 1, Visit 2 and Day 22, Visit 3) subjects will remain fasted for at 
least 4 hours before administration until 4 hours after and their fluid intake is restricted to the 
water administered with the drug and an additional 240 mL of water served at 2 h and 4 h 
post-dose (mandatory for all subjects) from 1 hour before drug intake until 4 hours post dose.
On PK profile days (Day 1, Visit 2 and Day 22, Visit 3) subjects are requested to go to bed 
after dinner, lie down (i.e. no declination of the upper body of less than 45 degrees from 
upright posture except for medical examination or if they need to go to the toilet) and try to 
sleep. For details regarding post-dose bed resting period see Flow Chart.


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Part 2:
In Part 2, administration will be performed following an overnight fast starting no later than 
10 h before scheduled dosing. On PK profile days (Day 1, treatment C and Day 10, treatment 
D), no food is allowed for at least 4 h; from 1 h before drug intake until lunch, fluid intake is 
restricted to the water administered with the drug, and an additional 240 mL of water served 
at 2 h and 4 h post-dose (mandatory for all subjects). From lunch until 24 h post-dose, total 
fluid intake is restricted to 3000 mL. On the remaining days, food is not allowed for at least 1 
h after drug administration and fluid intake is not allowed from 1 hour predose until
administration.
On PK profile days (Day 1, Visit 2 and Day 10, Visit 3) subjects are not allowed to lie down, 
i.e. no declination of the upper body of more than 45 degrees from upright posture, except for 
ECG and blood pressure measurements, during the first 4 h after drug administration.
Part 1 + 2:
On all other in-house days food will be served at standard times if not indicated otherwise in 
the Flow chart.
Alcoholic beverages, grapefruits, Seville oranges (sour or bitter oranges) and their juices, and 
dietary supplements and products including St. John's wort (Hypericum perforatum) are not 
permitted starting 7 days before the first administration of trial medication until after the last 
PK sample of each study period is collected.
Smoking is not allowed during in-house confinement at the trial site.
Methylxanthine-containing drinks or foods (such as coffee, tea, cola, energy drinks, and 
chocolate) are not allowed from 24 h before until 24 h after each administration of trial 
medication.
Excessive physical activity (such as competitive sport) should be avoided starting 7 days 
before the first administration of trial medication until the end of trial examination.
Direct exposure to the sun or exposure to solarium radiation should be avoided during the 
entire study.
If female subjects of child-bearing potential are included in the trial, adequate contraception 
is to be maintained throughout the course of the trial (see Section 3.3.2 for the definition of 
adequate measures). Hormonal contraception is not allowed.
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.


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Subjects who are non-compliant (for instance, who do not appear for scheduled visits or 
violate trial restrictions) may be removed from the trial and the CRF will be completed 
accordingly (for further procedures, please see Section 3.3.4.1).


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5.
ASSESSMENTS
5.1
ASSESSMENT OF EFFICACY
Not applicable.
5.2
ASSESSMENT OF SAFETY
5.2.1
Physical examination
At the screening visit, the medical examination will include documentation of subject 
information, informed consent, demographics including height and body weight, smoking 
and alcohol history, relevant medical history and concomitant therapy, review of inclusion 
and exclusion criteria, visual tests, C-SSRS assessment (only for Part 2), review of vital signs 
(BP, PR), 12-lead ECG, laboratory tests, and a physical examination (including a 
neurological examination consisting of Romberg and Unterberger test, assessment of gait, 
further tests as needed). At the end of trial examination, it will include review of vital signs, 
12-lead ECG, laboratory tests, C-SSRS assessment, visual tests and a physical examination 
with a neurological assessment (i.e. Romberg and Unterberger test, assessment of gait, further 
tests as needed). During the treatment period neurological examination (i.e. Romberg and 
Unterberger test, assessment of gait, further tests as needed) will be performed at the time 
points indicated in the Flow Chart. In addition, neurological examinations are to be 
performed at any times CNS adverse events are reported. The occurrence of headache, 
however, does not require the performance of neurological assessments (except upon 
discretion of the investigator). The reason for this is that headaches are in most cases
unspecific symptoms without clear causative CNS involvement that occur frequently in 
clinical trials in healthy volunteers. Abnormal findings in the neurological and physical 
examination will be reported as AEs 
5.2.2
Vital signs
Systolic and diastolic blood pressures (BP) as well as pulse rate (PR) will be measured by a 
blood pressure monitor (Dinamap, GE Medical Systems, Freiburg, Germany) 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
Visual tests
Visual tests will be performed at screening, EOT and any time the subject reports visual 
adverse events or if it is deemed necessary by the investigator or 
 designee.
5.2.3.1
Color discrimination test
Color vision will be tested using the Ishihara test for color deficiency.


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The test consists of a number of colored plates, called Ishihara plates, each of which contains
a circle of dots appearing randomized in color and size. Within the pattern are dots which
form a number visible to those with normal color vision and invisible, or difficult to see, for
those with a color vision deficiency.
Examination of color vision will be carried out at the times indicated in the Flow Chart and
any time the subject reports visual adverse events or if it is deemed necessary by the 
investigator or 
 designee.
Two plates will be randomly selected for each time point as well as a plate with a positive
(the plate number must be recognized by all subjects) and a negative control (the plate
number should not be recognized by any subject).
Subjects will be instructed to recognize and report the numbers seen on the plates. Test
results will be reviewed by investigator or his/her designee for correctness.
All test results will be documented in the source documents and entered in eCRF. Any 
abnormal findings detected in this test during the screening examination will lead to the
exclusion of the subject. Any deterioration occurring during the study will be documented as
an AE and an additional ophthalmologic examination should be considered.
5.2.3.2
Visual acuity test (near visual acuity)
Near vision cards (e.g. Jaeger Eye Chart) will be used to measure visual acuity. The smallest 
line that a subject can read at a distance of 35 centimeter will be recorded.
If the subject uses glasses, then the test should be performed using them.
Visual acuity testing will be carried out at the times indicated in the Flow Chart and any time 
the subject reports visual adverse events or if it is deemed necessary by the investigator or 
 
designee.
All test results will be documented in the source documents and entered in eCRF.
Tests results will be reviewed by investigator or his/her designee for correctness and 
deteriorations from the baseline will be documented as an AE (narratives will be written).
The test results will be documented, and during the course of the study, each post-dose result
obtained in a particular subject will be compared to the baseline result.
5.2.3.3
Amsler grid test
The Amsler grid is a grid of horizontal and vertical lines used to monitor a person's central 
visual field. It is a diagnostic tool that aids in the detection of visual disturbances caused by 
changes in the retina, particularly the macula (e.g. macular degeneration, epiretinal 
membrane), as well as the optic nerve and the visual pathway to the brain.


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If the subject uses glasses, then the test should be performed using them. Subjects should 
hold the Grid at a normal reading distance about 35 cm away from the face using only one 
eye (another eye closed) and look at the dot in the center of the grid. If any of the lines in the 
grid look distorted, blurry, or missing, this will be documented in the source documents as 
AE (narratives will be written).
Any abnormal findings detected in this test during the screening examination will lead to the 
exclusion of the subject. Any deterioration that occurred during the study will be documented 
as an AE and an additional ophthalmologic examination should be considered.
All test results will be documented in the source documents and entered in eCRF.
5.2.4
Suicidality monitoring (Part 2 only)
Based on the FDA guidance on prospective assessment of suicidality [R12-4395] suicidal 
ideation and behaviour should be assessed as part of the evaluation of any drug being 
developed for a psychiatric condition. This recommendation also refers to clinical trials in 
healthy volunteers with multiple dose administration of the IMP.
In Part 2 of this trial, with multiple doses of BI 425809, suicidal thoughts and behaviour will 
be assessed by C-SSRS [R08-1147]. The original Columbia Suicidal Severity Rating scale is 
shown in Appendix 10.1.
5.2.5
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 after the subjects have fasted for at least 10 h
in Part 2 and for at least 4 h in Part 1. 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 5.2.5: 1 and 5.2.5: 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.
Fecal occult blood testing will be performed at the trial site using an immunochemical test kit 
for hemoglobin (e.g. the PreventID CC test by Preventis GmbH or similar). As subjects may 
not be able to defecate at the trial site, they may collect the specimen at home and bring the 
test specimen to the trial site.


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Table 5.2.5: 1
Routine laboratory tests
Functional lab group
BI test name [comment/abbreviation]
A
B
C
D
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
X
X
X
X
X
X
X
X
X
X
Automatic WBC 
differential, relative
and absolute
Neutrophils/Leukocytes; Eosinophils/Leukocytes; Basophils/ 
Leukocytes; Monocytes/Leukocytes; 
Lymphocytes/Leukocytes 
X
X
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)
Fibrinogen
X
X
X
X
X
X
X
X
X
X
X
X
Enzymes
AST [Aspartate transaminase] /GOT, SGOT 
ALT [Alanine transaminase] /GPT, SGPT
Alkaline Phosphatase
Gamma-Glutamyl Transferase 
Glutamate Dehydrogenase (GLDH)
Creatine Kinase [CK]
Creatine Kinase Isoenzyme MB [only if CK is elevated] 
Lactic Dehydrogenase
Lipase
Amylase
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
--
--
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Hormones
Thyroid Stimulating Hormone 
Free T3 - Triiodothyronine  
Free T4 – Thyroxine 
X
X
X
--
--
--
--
--
--
X
X
X
Substrates
Glucose (Plasma)
Creatinine 
Bilirubin, Total 
Bilirubin, Direct
Protein, Total
Albumin
C-Reactive Protein (Quant)  
Uric Acid 
Cholesterol, total 
Triglyceride
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
--
--
--
X
X
X
X
X
X
X
--
--
--
X
X
X
X
X
X
X
X
X
X


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Table 5.2.5: 1
Routine laboratory tests (cont.)
Functional lab group
BI test name [comment/abbreviation]
A
B
C
D
Electrolytes
Sodium
Potassium
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
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)
A: parameters to be determined at Visit 1 of Part 1 and 2 (screening examination) 
B: parameters to be determined at Visit 2 and 3 of Part 1 as indicated in the Flow Chart
C: parameters to be determined at Visit 2 and 3 of Part 2 as indicated in the Flow Chart)
D: parameters to be determined at Visit 4 (end of trial examination)
The tests listed in Table 5.2.5: 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 pregnancy tests and drug screening, it is planned to perform these tests 
during screening only. Pregnancy testing in women will be performed at screening, prior to 
each treatment period, and as part of the end of trial examination. Drug screening will be 
performed at screening and prior to each treatment period.


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Table 5.2.5: 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
Infectious serology (blood)
Hepatitis B surface antigen (qualitative)
Hepatitis B core antibody (qualitative)
Hepatitis C antibodies (qualitative)
HIV-1 and HIV-2 antibody (qualitative)
Pregnancy test (urine)
Beta human chorionic gonadotropin (beta-HCG)
To encourage compliance with alcoholic restrictions, a breath alcohol test (e.g. Alcotest®
7410, Dräger AG, Lübeck, Germany) will be performed as indicated in the Flow Chart, 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 laboratory tests listed in Tables 5.2.5: 1 and 5.2.5: 2 will be performed at Medizinisches
Versorgungszentrum Dr. Klein Dr. Schmitt & Partner, Kaiserslautern, Germany with the 
exception of the iFOB and the drug screening and pregnancy tests. Thelater ones will be 
performed at the trial site using Multidrogen Pipettiertest (Diagnostik Nord GmbH, 
Schwerin) and Alere TestPack+Plus hCG Urine Test, respectively, or comparable test 
systems.
Laboratory data will be transmitted electronically from the laboratory to the trial site.  
5.2.6
Electrocardiogram
Twelve-lead ECGs (I, II, III, aVR, aVL, aVF, V1 - V6) will be recorded using a 
computerised electrocardiograph (CardioSoft EKG System, GE Medical Systems, Freiburg, 
Germany) 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 electronically on the Muse CV Cardiology System (GE Medical 
Systems, Freiburg, Germany). 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).


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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.
5.2.7
Assessment of adverse events
5.2.7.1
Definitions of adverse events
Adverse event
5.2.7.1.1
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.
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
5.2.7.1.2
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 jeopardise the patient and may 


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require medical or surgical intervention to prevent one of the other outcomes listed in 
the above definitions. Examples of such events are intensive treatment in an 
emergency room or at home for allergic bronchospasm, blood dyscrasias or 
convulsions that do not result in hospitalisation or development of dependency or 
abuse
AEs considered ‘Always Serious’
5.2.7.1.3
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 5.2.7.2, 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.
Adverse events of special interest
5.2.7.1.4
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, please see 
Section 5.2.7.2.2.
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 
eDC system. 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.


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Intensity (severity) of AEs
5.2.7.1.5
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
5.2.7.1.6
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

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


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5.2.7.2
Adverse event collection and reporting
AE collection
5.2.7.2.1
Upon enrolment into a trial, the subject’s baseline condition is assessed (for instance, by 
documentation of medical history/concomitant diagnoses), and relevant changes from 
baseline are noted subsequently. 
Subjects will be required to report spontaneously any AEs as well as the time of onset, end
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: 
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.


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AE reporting to the sponsor and timelines
5.2.7.2.2
The Investigator must report SAEs, AESIs, and non-serious AEs which are relevant for the 
reported SAE or AESI, on the BI SAE form via fax immediately (within 24 hours) to the 
sponsor’s unique entry point (country specific contact details will be provided in the ISF). 
The same timeline applies if follow-up information becomes available. In specific occasions 
the Investigator could inform the sponsor upfront via telephone. This does not replace the 
requirement to complete and fax the BI SAE form. 
With receipt of any further information to these events, a follow-up SAE form has to be 
provided. For follow-up information, the same rules and timeline apply as for initial 
information.
Information required
5.2.7.2.3
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.
Pregnancy
5.2.7.2.4
In rare cases, pregnancy might occur in a clinical trial. Once a subject has been enrolled in 
the clinical trial and has taken trial medication, the investigator must report any drug 
exposure during pregnancy in a trial participant immediately (within 24 hours) by means of 
Part A of the Pregnancy Monitoring Form to the sponsor’s unique entry point.
The outcome of the pregnancy associated with the drug exposure during pregnancy must be 
followed up and reported to the sponsor’s unique entry point on the Pregnancy Monitoring 
Form for Clinical Trials (Part B).
The ISF will contain the Pregnancy Monitoring Form for Clinical Trials (Part A and Part B) 
as 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 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, blood 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. 


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5.3.2
Methods of sample collection
5.3.2.1
Blood sampling for pharmacokinetic analysis
For quantification of BI 425809 concentrations in plasma, approximately 2.7 mL of blood
will be drawn from an antecubital or forearm vein into a K2-EDTA (dipotassium 
ethylenediaminetetraacetic acid)-anticoagulant blood drawing tube at the times indicated in 
the Flow Chart. Blood will be withdrawn by means of either an indwelling venous catheter or 
by venepuncture with a metal needle.
The EDTA-anticoagulated blood samples will be centrifuged for approximately 10 min at 
approximately 2000 g to 4000 g and at 4 to 8 °C. Two plasma aliquots will be obtained and 
stored in polypropylene tubes. The first aliquot should contain at least 0.5 mL of plasma. The 
process from blood collection until transfer of plasma aliquots into the freezer should be 
completed in less than 60 min, with interim storage of blood samples and aliquots on ice. The
time each aliquot was placed in the freezer will be documented. Until transfer on dry ice to 
the analytical laboratory, the aliquots will be stored upright at approximately -20°C or below 
at the trial site. The second aliquot will be transferred to the analytical laboratory after the 
bioanalyst has acknowledged safe arrival of the first aliquot. At the analytical laboratory, the 
plasma samples will be stored at approximately -20°C or below until analysis.
For quantification of donepezil plasma concentrations, approximately 2.7 mL of blood will be
taken from a forearm vein in a K2- EDTA-anticoagulant blood drawing tube at the time
points listed in the Flow Chart. The EDTA-anticoagulated blood samples will be centrifuged 
as soon as possible after collection. Centrifugation will last for about 10 minutes (at about 
2000 x g to 4000 x g) at 4-8°C. Two plasma aliquots will be prepared and stored in 
polypropylene tubes. The first aliquot should contain at least 0.5 mL plasma whereas the 
second aliquot should contain the remaining plasma. The process from blood collection until 
transfer of plasma aliquots into the freezer should be completed in less than 60 min, with 
interim storage of blood samples and aliquots on ice. The time each aliquot was placed in the 
freezer will be documented. Until shipment on dry ice to the analytical laboratory, plasma 
samples will be stored frozen in an upright position at about –20°C or below until transfer to 
the CRO.
At a minimum, the sample tube labels should list BI trial number, subject number, visit, and 
planned sampling time.
After completion of the trial, the plasma samples 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.


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5.3.3
Analytical determinations
5.3.3.1
Analytical determination of analyte plasma concentration
BI 425809 and donepezil concentrations in plasma will be determined by a validated 
LC-MS/MS (liquid chromatography tandem mass spectrometry) assay. All details of the 
analytical method will be available prior to the start of sample analysis.
During sample analysis, the bioanalyst will be blinded to subject allocation and will have no 
access to the randomisation code.
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 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 are generally used 
assessments of drug exposure. 
The C-SSRS is a validated tool to monitor for suicidality and recommended by the FDA 
[R12-4395]. The visual tests (Ishiara plates, Amsler grid test, and visual acuity test) are tests 
commonly used to assess and monitor the visual sense and have been implemented in 
previous clinical trials with BI 425809 [c02820512, c02958024].


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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 the 
Flow Chart.
Study measurements and assessments scheduled to occur ‘before’ trial medication 
administration on Day 1 are to be performed and completed within a 2 h-period prior to the
trial drug administration.
The acceptable deviation from the scheduled time for vital signs, C-SSRS and ECG will be 
be ± 1 h. For laboratory tests the acceptable deviation from the scheduled time will also be 
± 30 min, except for the iFOB where it will be ± 12 hours.
If scheduled in the Flow Chart at the same time as a meal, the following recordings have to 
be done first: 12-lead ECG recordings, vital signs, blood sampling, visual tests, C-SSRS. 
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.
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, visual tests, C-SSRS and physical examination, refer to Sections 5.2.1 to 5.2.7.
6.2.2
Treatment period
Each subject is expected to participate in 2 treatment periods, i.e. Visit 2 and 3. Subjects that 
take part in Part 1 cannot take part in Part 2 and vice versa.
Part 1
In the morning of Day 1 of Visit 2 and of Day 22 Visit 3, study participants will be admitted 
to the trial site and kept under close medical surveillance for at least 38 h following drug 
administration. In addition subjects will be admitted to the trial site prior to the first dose of 
donepezil (evening of Day 1 Visit 3) and remain under close medical surveillance until the 
following morning (Day 2, Visit 3). The subjects will then be allowed to leave the trial site 


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after formal assessment and confirmation of their fitness. On all other study days, subjects 
will be treated in an ambulatory fashion.
Part 2
Study participants will be admitted to the trial site in the evening of Day -1 of Visit 2 and of 
Day 9 Visit 3, and kept under close medical surveillance for at least 72 h following drug 
administration. After formal assessment and confirmation of their fitness, subjects will then 
be allowed to leave the trial site. On all other study days, subjects will be treated in an 
ambulatory fashion.
For details on time points and procedures for collection of plasma samples for PK 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.
6.2.3
Follow-up period and trial completion
For AE assessment, laboratory tests, recording of ECG and vital signs, and physical 
examination during the follow-up period, see Sections 5.2.1 to 5.2.7.
Subjects who discontinue treatment before the end of the planned treatment period should 
undergo the EoTrial Visit.
All abnormal values (including laboratory parameters) that are assessed as clinically relevant 
by the investigator will be monitored using the appropriate tests until a return to a medically 
acceptable level is achieved. (S)AEs persisting after a subject’s EoTrial Visit must be 
followed until they have resolved, have been sufficiently characterised, or no further 
information can be obtained.


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7.
STATISTICAL METHODS AND DETERMINATION OF
SAMPLE SIZE
7.1
STATISTICAL DESIGN – MODEL
The main objectives of this trial are to investigate the relative bioavailability of
Part 1:
25 mg (single dose) of BI 425809 when given alone (Test 1, T1) compared with 
co-administration with 10 mg (multiple doses) of donepezil (Reference 1, R1), and
Part 2:
10 mg (single dose) of donepezil when given alone (Test 2, T2) compared with 
co-administration with 25 mg (multiple doses) of BI 425809 (Reference 2, R2),
following oral administration on the basis of the primary and secondary pharmacokinetic 
endpoints, as listed in Section 2.1.2 and 2.1.3. The trial is designed to allow intra-subject 
comparisons and will be evaluated statistically by use of a linear model for logarithmically 
transformed PK endpoints.
 
.
The assessment of safety and tolerability is a further objective of this trial, and will be 
evaluated by descriptive statistics for the parameters specified in Section 2.2.2.2.
7.2
NULL AND ALTERNATIVE HYPOTHESES
The relative bioavailability of BI 425809 administered alone compared with co-
administration with donepezil (Part 1) and the relative bioavailability of donepezil 
administered alone compared with co-administration with BI 425809 (Part 2) will be 
estimated by the ratios of the geometric means (test/reference), and their corresponding 
2-sided 90% confidence intervals (CIs) will be provided. This method corresponds to the two 
one-sided t-test procedure, each at the 5% significance level. 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 PK endpoint that was defined as primary or 
secondary and was not excluded due to a protocol deviations relevant to the 
evaluation of PK or due to PK non-evaluability (as specified in the following 


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subsection ‘Pharmacokinetics’). Thus, a subject will be included in the PKS, even if 
he/she contributes only one PK parameter value for one period to the statistical 
assessment. Descriptive and model based analyses of PK parameters will be based on 
the PKS.
Adherence to the protocol will be assessed by the trial team. Important protocol deviations
(IPD) categories will be suggested in the IQRM plan. 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 425809 will be calculated 
according to the relevant SOP of the Sponsor (001-MCS-36-472).
Plasma concentration data and parameters of a subject will be included in the statistical 
pharmacokinetic (PK) analyses if they are not flagged for exclusion due to a protocol 
deviation relevant to the evaluation of PK (to be decided no later than in the Report Planning 
Meeting) or due to PK non-evaluability (as revealed during data analysis, based on the 
criteria specified below). Exclusion of a subject’s data will be documented in the CTR.
Relevant protocol violations may be

Incorrect trial medication taken, i.e. the subject received at least one dose of trial
medication the subject was not assigned to

Incorrect dose of trial medication taken

Use of restricted medications
Plasma concentrations and/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), 

The subject experiences emesis at any time during the labelled dosing interval

A predose concentration is >5% Cmax value of that subject

Missing samples/concentration data at important phases of PK disposition curve
Plasma concentration data and parameters of a subject which is flagged for exclusion will be 
reported with its individual values but will not be included in the statistical analyses. 
Descriptive and inferential statistics of PK 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).


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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 PK endpoints will be log-
transformed (natural logarithm) prior to fitting the ANOVA model. The model used in both 
Part 1 and Part 2 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 treatmentk,
= the overall mean,
sm = the effect associated with the mth subject, m = 1, 2, ..., n,
k = the kth treatment effect, k = 1, 2,
ekm = the random error associated with the mth subject in who received treatment k.
where s ~ N(0, σ
) i.i.d., e ~ N(0, σ
 ) i.i.d. and sm, ekm are independent random 
variables.
Point estimates for the ratios of the geometric means (test/reference) for the primary 
endpoints (see Section 2.1.2) and their two-sided 90% confidence intervals (CIs) will be 
provided.
For each endpoint, 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 based on the 
residual error from the ANOVA and quantiles from the t-distribution. These quantities will 
then be back-transformed to the original scale to provide the point estimate and 90% CIs for 
each endpoint.
 
 
7.3.2
Secondary endpoint analyses
The secondary endpoints (refer to Section 2.1.3) will be calculated according to the BI SOP 
‘Standards and processes for analyses performed within Clinical Pharmacokinetics/ 
Pharmacodynamics’ (001-MCS-36-472) and will be assessed statistically using the same 
methods as described for the primary endpoints.


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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 hypothesis testing is planned.
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.
Measurements (such as vital signs, or laboratory parameters) or AEs will be assigned to 
treatments (see Section 4.1) based on the actual treatment at the planned time of the 
measurement or on the recorded time of AE onset (concept of treatment emergent AEs). 
Therefore, measurements planned or AEs recorded prior to first intake of trial medication will 
be assigned to the screening period, those between first trial medication intake and end of 
REP (see 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 (see Section 5.2.7.1), 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.


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Vital signs or other safety-relevant data will be assessed with regard to possible on-treatment 
changes from baseline.
Relevant ECG and neurologic findings will be reported as AEs. Fecal occult blood testing 
results will be listed only.
Suicidality monitoring will be assessed by the C-SSRS questionnaire (Section 5.2.4). Results 
will be documented by means of an overall question (“Based on the C-SSRS, has the subject 
expressed any current suicide ideation or current/past suicide behaviour?” – yes/no) In case 
this overall question is answered with “yes”, the full questionnaire will be included in the 
clinical trial report. Findings will be reported as AEs, the completed forms will be stored at 
the site.
Details for the evaluation of visual tests will be described in the TSAP.
7.4
INTERIM ANALYSES
No interim analysis is planned.
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 PK data will be performed according to the relevant Corporate 
Procedure (001-MCS-36-472). PK parameters that cannot be reasonably calculated based on 
the available drug concentration-time data will not be imputed.
7.6
RANDOMISATION
No randomization is necessary (cf. Section 4.1.3).
7.7
DETERMINATION OF SAMPLE SIZE
It is planned to enter a total of 32 subjects in the trial (18 in Part 1 and 14 in Part 2), because 
this sample size 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 the investigator and 
the 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 trial 
conduct including monitoring approaches, vendor management and other processes focusing 
on areas of greatest risk. 
Continuous risk review and assessment may lead to adjustments in trial conduct, trial design 
or monitoring approaches. 
A quality assurance audit/inspection of this trial may be conducted by the sponsor, sponsor’s 
designees, or by IRB / IEC or by regulatory authorities. The quality assurance auditor will 
have access to all medical records, the investigator’s trial-related files and correspondence, 
and the informed consent documentation of this clinical trial..
8.3
RECORDS
CRFs for individual subjects will be provided by the sponsor. For drug accountability, refer 
to Section 4.1.8.
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(s) must retain the source and essential documents (including ISF) according to 
contract or the local requirements valid at the time of the end of the trial (whatever is longer).
Sponsor:
The sponsor must retain the essential documents according to the sponsor’s SOPs.
8.4
EXPEDITED REPORTING OF ADVERSE EVENTS
BI is responsible to fulfil their legal and regulatory reporting obligation in accordance with 
regulatory requirements.
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, biobanking and 
future use of biological samples and clinical data, in particular

Sample and data usage has to be in accordance with the separate biobanking informed 
consent

The BI-internal facilities storing biological samples from clinical trial participants as 
well as the external banking facility are qualified for the storage of biological samples 
collected in clinical trials.

An appropriate sample and data management system, incl. audit trail for clinical data 
and samples to identify and destroy such samples according to ICF is in place

A fit for the purpose documentation (biomarker proposal, analysis plan and report) 
ensures compliant usage

A fit for purpose approach will be used for assay/equipment validation depending on 
the intended use of the biomarker data
Samples and/or data may be transferred to third parties and other countries as specified in the 
biobanking ICF
8.6
TRIAL MILESTONES
The start of the trial is defined as the date 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 whole trial’ 
(‘Last Subject Completed’) or ‘end date of the last open AE’ or ‘date of the last follow-up 
test’ or ‘date of an AE has been decided as sufficiently followed-up’, whichever is latest.
Early termination of the trial is defined as the premature termination of the trial for any 
reason before the end of the trial as specified in this protocol.
Temporary halt of the trial is defined as any unplanned interruption of the trial by the 
sponsor with the intention to resume it.
Suspension of the trial is defined as an interruption of the trial based on a Health Authority 
request.
8.7
ADMINISTRATIVE STRUCTURE OF THE TRIAL
The trial is sponsored by Boehringer Ingelheim (BI).


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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 Clinical Trial 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 Clinical Trial Supplies Unit, BI Pharma GmbH 
& Co. KG, Biberach, Germany. Marketed donepezil will be sourced locally by the CRO.
Safety laboratory tests will be performed by the local laboratory of the trial site 
 
Analyses of BI 425809 concentrations in plasma samples will be performed at 
, 
.
Analyses of BI donepizil concentrations in plasma samples 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 by a CRO 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
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.
R05-0776
Rogers SL, Cooper NM, Sukovaty R, Pederson JE, Lee JN, Friedhoff LT. 
Pharmacokinetic and pharmacodynamic profile of donepezil HCI following 
multiple oral doses. Br J Clin Pharmacol 1998;46(Suppl 1):7-12.
R05-0853
Tiseo PJ, Rogers SL, Friedhoff LT. Pharmacokinetic and pharmacodynamic 
profile of donepezil HCl following evening administration. Br J Clin 
Pharmacol 1998;46 (Suppl 1):13-18.
R08-1147
Posner K. State of the science: measurement of suicidal adverse events and 
the Columbia Suicide Severity Rating Scale. 47th NCDEU Ann Mtg, Boca 
Raton, 11 - 14 Jun 2007. 2007:15.
R11-5230
Julious SA. Sample sizes for clinical trials. Boca Raton: Taylor & Francis 
Group; 2010.
R12-4395
Guidance for industry: suicidal ideation and behavior: prospective
assessment of occurrence in clinical trials (draft guidance, August 2012). 
http://www.fda.gov/downloads/Drugs/GuidanceRegulatoryInformation/
Guidances/UCM22 5130.pdf (access date: 5 October 2012); 2012.
R13-4447
Lane HY, Chang YC, Liu Y, Chiu CC, Tsai GE. Sarcosine or D-serine add-
on treatment for acute exacerbation of schizophrenia: a randomized, 
double-blind, placebo-controlled study. Arch Gen Psychiatry 
2005;62:1196-1204.
R13-4508
Martin-Facklam M, Patat A, Hofmann C, Boetsch C, Banken L, Biedinger
U, Boutouyrie-Dumont B. Safety, tolerability and pharmacokinetics of
bitopertin (RG1678), a novel glycine reuptake inhibitor after multiple doses 
in healthy volunteers. 3rd Biennial Conf of the Schizophrenia International 
Research Society (SIRS), Florence, 14 - 18 Apr 2012 (Poster). 2012.
R15-0511
Tiseo PJ, Perdomo CA, Friedhoff LT. Concurrent administration of
donepezil HCl and ketoconazole: assessment of pharmacokinetic changes
following single and multiple doses. Br J Clin Pharmacol 
1998;46(Suppl 1):30-34.
R15-1331
Elashoff JD. nQuery Advisor version 7.0 user's guide.
http://www.statsols.com/wp-content/uploads/2013/10/nQ70_
version2_manual.pdf (access date: 20 March 2015) ; Los Angeles: 
Statistical Solutions; 2007.


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R15-4355
Nicholas T, Park Y, Choo HW, Plotka A, Martin W, Martin D, Schwam E.
Pharmacokinetic and safety interactions between a novel PDE9 inhibitor, 
PF-04447943, and donepezil in healthy volunteers. AAIC 2011, Int Conf of 
the Alzheimer's Association, Paris, 16 - 21 Jul 2011. Alzheimers Dement 
2011;7(4)(Suppl 1):S786.
R15-4356
Gadiko C, Tippabhotla SK, Thota S, Battula R, Khan SM, Vobalaboina V.
A randomized, crossover, single-dose bioequivalence study of two
extended-release tablets of donepezil 23 mg in healthy human volunteers 
under fasting and fed states. Sci Pharm 2013;81:777-791.
R15-4794
Aricept (donepezil hydrochloride) tablets (Eisai), Rx only (U.S. prescribing 
information, revised: January 2015). 2015.
R18-3913
Donepezil-HCl-ratiopharm 5 mg/10 mg Filmtabletten, Fachinformation, 
November 2015.
R18-3919
Tiseo PJ, Perdomo CA, Friedhoff LT. Concurrent administration of
donepezil HCl and cimetidine: assessment of pharmacokinetic changes
following single and multiple doses. Br J Clin Pharmacol 1998;46
(Suppl 1):25-29.
9.2
UNPUBLISHED REFERENCES
001-MCS-36-472 Standards and processes for analyses performed within Clinical 
Pharmacokinetics/Pharmacodynamics. Current version.
c02155957
Investigator`s Brochure BI 425809, Alzheimer’s Disease 
Cognitive Impairment Associated with Schizophrenia, 06 Jun 2018.
c02820512
, Safety, tolerability, and 
pharmacokinetics of single rising oral doses of BI 425809 in healthy male 
subjects (partially randomised, single-blind, placebo-controlled) and 
investigation of relative bioavailability and food effect of BI 425809 
(open-label, randomised, three-way crossover), 1346.1, 05 May 2015.
c02958024
, Safety, tolerability, and pharmacokinetics 
of multiple rising doses of BI 425809 tablets given orally once or twice 
daily for 12 days to young and elderly healthy male and female volunteers 
(randomised, double-blind, placebo-controlled within dose groups Phase I 
study) (Part 1) and comparison of pharmacokinetics of a single oral dose of 
BI 425809 after oral administration in the morning versus oral 
administration in the evening in young healthy male and female volunteers 
(randomised, twosequence, open, two period, two-way cross over) (Part 2),
1346.2, 01 Oct 2015.
c03355329
, Relative bioavailability of a 
single oral dose of BI 425809 when administered alone or in combination 
with multiple oral doses of itraconazole in healthy male subjects (an open-
label, two-period, fixed-sequence trial), 1346.10, 03 Dec 2015.


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c03559983
, A phase II randomised, double-blinded, placebo-controlled 
parallel group trial to examine the efficacy and safety of 4 oral doses of 
BI 425809 once daily over 12 week treatment period in patients with 
Schizophrenia, 1346.9, 13 Dec 2017.
c03632269
 A multi-centre, double-blind, parallel-group, randomised 
controlled study to investigate efficacy and safety of orally administered 
BI425809 during a 12-week treatment period compared to placebo in 
patients with cognitive impairment due to Alzheimer’s Disease, 1346.23, 
12 Jul 2018.
c03724403
Non-randomised, open label, 
sequential-group study to assess the pharmacokinetics and 
pharmacodynamic effect of different multiple oral doses of BI 425809 in 
healthy male volunteers, 1346.3, 01 Feb 2016.
c08949593
, A study to investigate 
the effects of multiple doses of BI 425809 on the single dose 
pharmacokinetics of cytochrome P450 substrates (midazolam, warfarin and 
omeprazole) and a P-glycoprotein substrate (digoxin) administered orally in 
an open-label, one-sequence trial in healthy male subjects, 1346.22, 
01 Aug 2016.
c09564954
 A study to investigate the 
pharmacokinetic drug-drug interaction following oral administration of 
BI 409306 and donepezil in healthy male and female subjects, 1289.24, 
29 Nov 2016.
c11975084
 Metabolism and pharmacokinetics of 
BI 425809 after administration of BI 425809 XX (C-14) as oral solution in 
healthy male volunteers, 1346.16, 25 Sep 2018.
c21363182
, Investigation of pharmacokinetics and 
absolute oral bioavailability of BI 425809 administered as an oral dose with 
an intravenous microtracer dose of [C-14]-BI 425809 in healthy male 
volunteers, 1346-0015, 07 Jan 2019.


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10.
APPENDICES
10.1
COLUMBIA-SUICIDE SEVERITY RATING SCALE


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11.
DESCRIPTION OF GLOBAL AMENDMENT(S)
11.1
GLOBAL AMENDMENT 1
Date of amendment
14 March 2019
EudraCT number
EU number
2018-004806-24
BI Trial number
1346-0029
BI Investigational Medicinal 
Product(s)
BI 425809
Title of protocol
A study to investigate the effects of donepezil on the 
pharmacokinetics of BI 425809 and vice versa in 
healthy male and female subjects (Open-label, two-
treatment, two-period, one fixed sequence cross-over
design)
To be implemented only after approval of the IRB / IEC / Competent 
Authorities
To be implemented immediately in order to eliminate hazard – IRB / IEC / 
Competent Authority to be notified of change with request for approval
Can be implemented without IRB / IEC / Competent Authority approval as 
changes involve logistical or administrative aspects only
Section to be changed
1. Section 3.1
2. Section 3.3.2
3. Section 3.3.3
4. Section 3.3.4.1
Description of change
1. Details on trial conduct added
2. Inclusion criterion 5 was corrected: The 
requirement to use adequate contraception for at 
least 30 days prior first drug administration was 
removed.
3. Exclusion criterion 31 (Normal liver function 
tests, total bilirubin and creatinine at screening) 
added
4. Treatment discontinuation in case of elevated 
liver parameters changed from of “…AST 
and/or ALT ≥3-fold ULN AND an elevation of 
total bilirubin ≥2-fold ULN…” to “…AST 
and/or ALT ≥3-fold ULN OR an elevation of 
total bilirubin ≥2-fold ULN…”
Rationale for change
1. Based on the feedback by BfArM, the respective 
recommendations were included in a revised 
protocol. This applies for all changes except of 
the change in section 1.3.2.


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2. The adaption of inclusion criterion 5 was based 
on EC feedback. EC raised concerns that the 
30 days pre-administration period as part of the 
contraception methods starts before the subjects 
had consented to trial participation. However, 
the requirement to use adequate contraception 
for at least 30 days prior first drug 
administration is only needed for oral 
contraceptives as incorrect use may affect the 
contraceptive effect. Since in this trial oral 
hormonal contraceptives are not allowed and the 
other recommended measures, e.g. non-
hormonal intra-uterine devices, are immediately
effective, a 30 day pre-administration period for 
the allowed contraceptive methods is not 
applicable and was deleted.
In addition a typo in the Flow Chart of part 2 was 
deleted.


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11.2
GLOBAL AMENDMENT 2
Date of amendment
13 May 2019
EudraCT number
EU number
2018-004806-24
BI Trial number
1346-0029
BI Investigational Medicinal 
Product(s)
BI 425809
Title of protocol
A study to investigate the effects of donepezil on the 
pharmacokinetics of BI 425809 and vice versa in 
healthy male and female subjects (Open-label, two-
treatment, two-period, one fixed sequence cross-over
design)
To be implemented only after approval of the IRB / IEC / Competent 
Authorities
To be implemented immediately in order to eliminate hazard – IRB / IEC / 
Competent Authority to be notified of change with request for approval
Can be implemented without IRB / IEC / Competent Authority approval as 
changes involve logistical or administrative aspects only
Section to be changed
1.
Synopsis
2.
Flow Chart
3.
Section 5.2.5
4.
Appendix 10.1
Description of change
1.
Trial Clinical Monitor changed to Clinical Trial 
Leader
2.
Alcohol breath test was added to footnote 15
3.
Visit 3 was added to footnote B
4.
The Screening Version of the C-SSRS was 
replaced by the Baseline/Screening Version of 
the C-SSRS
Rationale for change
1.
The naming of the function was changed within 
BI
2.
By mistake alcohol breath test as part of the 
drug screening procedure upon admission was 
not added. This was corrected
3.
An inconsistency between Flow Chart and 
Footnote B in Section 5.2.5 was corrected
4.
By mistake the wrong C-SSRS version for the 
screening assessment was included. This was 
corrected


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11.3
GLOBAL AMENDMENT 3
Date of amendment
29 May 2019
EudraCT number
EU number
2018-004806-24
BI Trial number
1346-0029
BI Investigational Medicinal 
Product(s)
BI 425809
Title of protocol
A study to investigate the effects of donepezil on the 
pharmacokinetics of BI 425809 and vice versa in 
healthy male and female subjects (Open-label, two-
treatment, two-period, one fixed sequence cross-over
design)
To be implemented only after approval of the IRB / IEC / Competent 
Authorities
To be implemented immediately in order to eliminate hazard – IRB / IEC / 
Competent Authority to be notified of change with request for approval
Can be implemented without IRB / IEC / Competent Authority approval as 
changes involve logistical or administrative aspects only
Section to be changed
1. Flow Chart
2. Section 5.3.2.1
Description of change
1. A typo in the planned times was corrected
2. The preparation instruction for donepezil samples 
did not mention that samples should be kept on 
ice and not longer than for 60 min. This was 
forgotten by mistake and now added
Rationale for change
A typo in the planned times was corrected and the 
preparation instruction for donepezil blood samples 
were clarified. 


 
 
 
 
APPROVAL / SIGNATURE PAGE 
 
Document Number: 
 
Technical Version Number:
 
Document Name: 
 
 
 
                                                                                                                 
 
Title: 
 
 
 
 
                                                                                                                   
 
Signatures (obtained electronically) 
 
Meaning of Signature  
Signed by 
Date Signed 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
c26441921
4.0
clinical-trial-protocol-revision-03
A study to investigate the effects of donepezil on the pharmacokinetics of BI 425809
and vice versa in healthy male and female subjects (Open label, two-treatment,
two-period, one fixed sequence cross-over design)
Approval-Team Member Medicine
29 May 2019 15:24 CEST
Approval-Therapeutic Area 
29 May 2019 15:29 CEST
Author-Trial Clinical
Pharmacokineticist
29 May 2019 17:50 CEST
Author-Clinical Trial Leader
03 Jun 2019 08:52 CEST
Author-Trial Statistician
03 Jun 2019 09:13 CEST
Verification-Paper Signature
Completion
03 Jun 2019 15:49 CEST


Boehringer Ingelheim 
Page 2 of 2
Document Number: 
 Technical Version Number:
 
 
 
(Continued) Signatures (obtained electronically) 
 
Meaning of Signature  
Signed by 
Date Signed 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
c26441921
4.0

SAP_001.pdf: 
TITLE PAGE
TRIAL STATISTICAL ANALYSIS PLAN
c29131491-01
BI Trial No.:
1346-0029
Title:
A study to investigate the effects of donepezil on the 
pharmacokinetics of BI 425809 and vice versa in healthy male and 
female subjects (Open-label, two-treatment, two-period, one fixed 
sequence cross-over design)
Including Protocol Amendment 3 [c26441921-04]
Investigational
Product:
BI 425809
Responsible trial 
statistician:
Phone: 
Fax: 
Date of statistical 
analysis plan:
20 SEP 2019 SIGNED
Version:
Final
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This document may not - in full or in part - be passed on, reproduced, published or otherwise used without prior written permission.


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1.
TABLE OF CONTENTS
TITLE PAGE ...........................................................................................................................1
1.
TABLE OF CONTENTS......................................................................................2
LIST OF TABLES...................................................................................................................4
2.
LIST OF ABBREVIATIONS ..............................................................................5
3.
INTRODUCTION.................................................................................................7
4.
CHANGES IN THE PLANNED ANALYSIS OF THE STUDY......................8
5.
ENDPOINTS .........................................................................................................9
5.1
PRIMARY ENDPOINTS.....................................................................................9
5.2
SECONDARY ENDPOINTS...............................................................................9
5.2.1
Key secondary endpoints......................................................................................9
5.2.2
Secondary endpoints.............................................................................................9
5.3.2
Safety parameters .................................................................................................9
5.4
OTHER VARIABLES........................................................................................10
5.4.1
Demographic and other baseline characteristics .............................................10
5.4.2
Treatment compliance and treatment exposure ..............................................10
6.
GENERAL ANALYSIS DEFINITIONS ..........................................................11
6.1
TREATMENTS...................................................................................................11
6.2
IMPORTANT PROTOCOL DEVIATIONS....................................................14
6.3
SUBJECT SETS ANALYSED...........................................................................15
6.5
POOLING OF CENTRES .................................................................................16
6.6
HANDLING OF MISSING DATA AND OUTLIERS....................................16
6.7
BASELINE, TIME WINDOWS AND CALCULATED VISITS ...................16
7.
PLANNED ANALYSIS......................................................................................17
7.1
DEMOGRAPHIC AND OTHER BASELINE CHARACTERISTICS.........17
7.2
CONCOMITANT DISEASES AND MEDICATION .....................................18
7.3
TREATMENT COMPLIANCE........................................................................18
7.4
PRIMARY ENDPOINTS...................................................................................18
7.4.1
Primary analysis of the primary endpoints......................................................18
 
7.5
SECONDARY ENDPOINTS.............................................................................19
7.5.1
Key secondary endpoints....................................................................................19
7.5.2
Secondary endpoints...........................................................................................19
7.6.2
Safety parameters ...............................................................................................20
7.7
EXTENT OF EXPOSURE.................................................................................20
7.8
SAFETY ANALYSIS..........................................................................................20


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7.8.1
Adverse Events ....................................................................................................20
7.8.2
Laboratory data ..................................................................................................21
7.8.3
Vital signs.............................................................................................................22
7.8.4
ECG......................................................................................................................22
7.8.5
Others...................................................................................................................22
10.
HISTORY TABLE..............................................................................................26


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LIST OF TABLES
Table 6.1: 1 Dosage and treatment schedule part 1..................................................................11
Table 6.1: 2 Dosage and treatment schedule part 2..................................................................11
Table 6.1: 3
Analysis phases for statistical analysis of AEs, vital signs, safety laboratory 
data and visual tests, part 1...............................................................................12
Table 6.1: 4
Analysis phases for statistical analysis of AEs, vital signs, safety laboratory 
data and visual tests, part 2...............................................................................13
Table 6.2: 1
Handling of IPDs..............................................................................................15
Table 6.3: 1
Subject sets analyzed........................................................................................15
Table 10: 1
History table .....................................................................................................26


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2.
LIST OF ABBREVIATIONS
Term
Definition / description
ADME
Absorption, Distribution, Metabolism and Excretion 
AE
Adverse Event
AESI
Adverse event of special interest
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 to the last quantifiable data point
AUC0-∞
Area under the concentration-time curve of the analyte in plasma over the
time interval from 0 extrapolated to infinity
BI 
Boehringer Ingelheim
BP
Blood pressure
Cmax
Maximum measured concentration of the analyte in plasma
CTP
Clinical Trial Protocol
CTR
Clinical Trial Report
CV
Arithmetic coefficient of variation
C-SSRS
Columbia Suicidal Severity Rating scale
ECG
Electrocardiogram
gCV
geometric coefficient of variation
gMean
Geometric mean
ICH
International Conference On Harmonisation
IPD
Important protocol deviations
IQRMP
Integrated quality and risk management plan
MedDRA
Medical Dictionary For Regulatory Activities
PK
Pharmacokinetics
PKS
Pharmacokinetic parameter set
PR
Pulse rate
RAGe
Report appendix generator
SAE
Serious adverse event
SD
Standard Deviation
SOC
System Organ Class


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Term
Definition / description
TS
Treated set
TSAP
Trial Statistical Analysis Plan
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 will be stored in a trial database within Medidata Rave system. 
The statistical analyses will be performed within the validated working environment CARE, 
including SASTM (current Version 9.4, by SAS Institute Inc., Cary, NC, USA), and a number 
of SASTM-based tools (e.g., macros for the analyses of AE data or laboratory data; Report 
Appendix Generator system (RAGe) for compilation/formatting of the CTR appendices). 
PK parameters will be calculated using Phoenix WinNonlinTM software (version Phoenix 6.3, 
Certara USA Inc., Princeton, NJ, USA).


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4.
CHANGES IN THE PLANNED ANALYSIS OF THE STUDY
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 ENDPOINTS
Primary endpoints are PK endpoints of BI 425809 (part 1) and donepezil (part 2), 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)

Cmax (maximum measured concentration of the analyte in plasma)
5.2
SECONDARY ENDPOINTS
5.2.1
Key secondary endpoints
Not applicable.
5.2.2
Secondary endpoints
Secondary endpoints are PK endpoints of BI 425809 (part 1) and donepezil (part 2), as 
defined in Section 2.1.3 of the CTP:

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)
5.3.2
Safety parameters
Safety and tolerability of BI 425809 will be assessed based on further safety parameters
defined in Section 2.2.2.2 of the CTP:

Adverse events (including clinically relevant findings from the physical and neurological
examination)

Safety laboratory tests, including faecal occult blood test

12-lead ECG

Visual tests

Vital signs (blood pressure, pulse rate)

Suicidality assessment (C-SSRS, only part 2)


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5.4
OTHER VARIABLES
5.4.1
Demographic and other baseline characteristics
CTP: At the screening visit, the medical examination will include documentation of subject 
information, informed consent, demographics including height and body weight, smoking and 
alcohol history, relevant medical history and concomitant therapy, review of inclusion and 
exclusion criteria, visual tests, C-SSRS assessment (only for Part 2), review of vital signs (BP, 
PR), 12-lead ECG, laboratory tests, and a physical examination (including a neurological 
examination consisting of Romberg and Unterberger test, assessment of gait, further tests as 
needed).
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.
Treatment exposure is defined as the total dose and number of doses of BI 425809 and 
donepezil per subject.


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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.
Each subject is planned to be treated in two subsequent treatment periods in a fixed sequence 
order. There will be no washout-period between the two treatment periods.
Part 1:
All subjects will receive a single dose of BI 425809 alone in Visit 2 and a single dose of BI 
425809 after multiple dosing of donepezil in Visit 3.
Table 6.1: 1 Dosage and treatment schedule part 1
Treatment
Substance
Formulation
Unit 
strength
Dosage
Total dose
A (Reference 1)
BI 425809
Tablet
25 mg
1 tablet (Day 1, Visit 2)
25 mg
B (Test 1)
Donepezil  
BI 425809
Tablet
Tablet
5 mg
25 mg
1 tablet (Day 1-7, Visit 3) q.d.
2 tablets (Day 8-28, Visit 3) q.d.
1 tablet (Day 22, Visit 3)
245 mg
25 mg
Part 2:
All subjects will receive a single dose of donepezil alone in Visit 2 and then a single dose of 
donepezil after multiple dosing of BI 425809 in Visit 3.
Table 6.1: 2 Dosage and treatment schedule part 2
Treatment
Substance
Formulation
Unit 
strength
Dosage
Total dose
C (Reference 2)
Donepezil
Tablet
5 mg
2 tablets (Day 1, Visit 2)
10 mg
D (Test 2)
BI 425809  
Donepezil
Tablet
Tablet
25 mg
5 mg
1 tablet (Day 1-24, Visit 3) q.d.
2 tablets (Day 10, Visit 3)
600 mg
10 mg
For statistical analyses of AEs, vital signs, safety laboratory data and visual tests the 
following separate analysis phases will be defined for each subject:


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Table 6.1: 3
Analysis phases for statistical analysis of AEs, vital signs, safety laboratory
data and visual tests, part 1
Study analysis 
phase
Label
Start
End
Screening
Screening part 1
Date of informed consent
Date/time of first administration 
of BI 425809
On treatment 
BI 425809
BI part 1
Date/time of first administration 
of BI 425809
Date/time of first administration 
of donepezil
On treatment 
donepezil
Don part 1
Combination of two phases:
First phase:
Date/time of first administration 
of BI 425809 + 11*24h (i.e. 
REP of BI425809 of 11 days)
Second phase:
Date/time of second 
administration of BI 425809 + 
11*24h (i.e. REP of BI425809 
of 11 days)
Combination of two phases:
First phase:
Date/time of second 
administration of BI 425809
Second phase:
Date/time of last administration of 
donepezil + 15*24h (i.e. REP of 
donepezil of 15 days) or
00:00 a.m. on day after subject's 
trial termination date
whatever occurs earlier
On treatment 
BI 425809+
donepezil
Don + BI part 1
Combination of two phases:
First phase:
Date/time of first administration 
of donepezil
Second phase:
Date/time of second 
administration of BI 425809
Combination of two phases:
First phase:
Date/time of first administration 
of BI 425809 + 11*24h (i.e. REP 
of BI425809 of 11 days)
Second phase:
Date/time of second 
administration of BI 425809 + 
11*24h (i.e. REP of BI425809 of 
11 days) 
Follow-up
F/U part 1
Date/time of last administration 
of donepezil + 15*24h (i.e. REP 
of donepezil of 15 days)
00:00 a.m. on day after subject's 
trial termination date
The planned duration of the analysis phase of BI part 1 is 8 days, of Don part 1 it is 28 days
and of Don + BI part 1 it is 14 days.


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Table 6.1: 4
Analysis phases for statistical analysis of AEs, vital signs, safety laboratory
data and visual tests, part 2
Study analysis 
phase
Label
Start
End
Screening
Screening part 2
Date of informed consent
Date/time of first administration 
of Donepezil
On treatment 
donepezil
Don part 2
Date/time of first administration 
of donepezil
Date/time of first administration 
of donepezil + 15*24h (i.e. REP 
of donepezil of 15 days)
On treatment BI 
425809
BI part 2
Combination of two phases:
First phase:
Date/time of first administration 
of BI 425809
Second phase:
Date/time of second 
administration of donepezil + 
15*24h (i.e. REP of donepezil 
of 15 days)
Combination of two phases:
First phase:
Date/time of second 
administration of donepezil
Second phase:
Date/time of last administration of 
BI 425809 + 11*24h (i.e. REP of 
BI 425809 of 11 days) or
00:00 a.m. on day after subject's 
trial termination date
whatever occurs earlier
On treatment 
BI 425809+
donepezil
BI + Don part 2
Date/time of second 
administration of donepezil
Date/time of second 
administration of donepezil + 
15*24h (i.e. REP of donepezil of 
15 days) 
Follow-up
F/U part 2
Combination of two phases:
First phase:
Date/time of first administration 
of donepezil + 15*24h (i.e. REP 
of donepezil of 15 days)
Second phase:
Date/time of last administration 
of BI 425809 + 11*24h (i.e. 
REP of BI 425809 of 11 days)
Combination of two phases:
First phase:
Date/time of first administration 
of BI 425809
Second phase:
00:00 a.m. on day after subject's 
trial termination date
The planned duration of the analysis phase of Don part 2 is 15 days, of BI part 2 it is 19 days 
and of BI + Don part 2 it is 15 days.
AE displays in CTR Section 15.3, Appendix 16.1.13.1.8.2 and Appendix 16.1.13.1.8.3 will 
present results for the on-treatment phase only.
In AE tables in CTR Section 15.3 (but not in Appendix 16.1.13.1.8.2 and Appendix 
16.1.13.1.8.3 AE tables), the following total will be provided in addition: 

"Total on-trt part x", defined as the total over all on-treatment phases, x will be replaced 
with 1 or 2 for the respective part

"Total BI part x", defined as the total over all on-treatment phases involving BI, x will be 
replaced with 1 or 2 for the respective part


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CTR Appendix 16.1.13.1.8.1 displays will present results for the screening, on-treatment and 
follow-up phases.
Additionally to the total defined above, the following total will be provided in AE tables in 
CTR Section 16.1.13.1.8.1:

"Total part x", defined as the total over all study phases (screening + on-treatment + 
follow-up) , x will be replaced with 1 or 2 for the respective part
More details on the technical implementation of these analyses are provided in the ADS Plan 
of this TSAP.
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 analyses or whether it must be 
corrected in the clinical database. Each protocol deviation must be assessed to determine 
whether it is an important PD (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 that 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 will be supplemented accordingly by the time of the RPM.
IPDs will be summarized and listed. Table 6.2: 1 below specifies which kind of IPDs could 
potentially lead to exclusion from which analysis set. 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. If the data show other IPDs, this table will be supplemented 
accordingly by the time of the RPM.


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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
Non-compliance
PKS
C2
Incorrect intake of trial medication
PKS
C3
Incorrect trial medication taken
PKS
D1
Prohibited medication use
PKS
D2
Improper washout of prohibited
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
PDs affecting safety and rights of 
subjects
None
6.3
SUBJECT SETS ANALYSED
Subject sets will be used as defined in the CTP, Section 7.3.
Table 6.3: 1
Subject sets analyzed
Subject set
Class of endpoint
TS
PKS
Primary PK endpoints 
X
Secondary PK endpoints 
X
 
Safety parameters & 
treatment exposure
X
Demographic/baseline 
endpoints
X


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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: 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: PK 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 first drug administration.
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 "Reporting of clinical trials 
and project summaries" (6).
The individual values of all subjects will be listed. Listings will be sorted by treatment group
subject number and visit (if visit is applicable in the respective listing). AE listings will be 
sorted by assigned treatment (see Section 7.8.1 below for details). The listings will be 
contained in Appendix 16.2 (SDL) of the CTR.
The following standard descriptive statistical parameters will be displayed in summary tables 
of continuous variables:
N 
number of non-missing observations
Mean 
arithmetic mean
SD 
standard deviation
Min 
minimum
Median 
median
Max 
maximum
For plasma concentrations as well as for all PK parameters the following descriptive statistics 
will additionally be calculated:
CV 
arithmetic coefficient of variation
gMean
geometric mean
gCV
geometric coefficient of variation
For PK parameters the following descriptive statistics will additionally be calculated:
P10
10th percentile
Q1
1st quartile
Q3
3rd quartile
P90
90th percentile
The data format for descriptive statistics of plasma concentrations will be identical with the 
data format of the respective concentrations. The descriptive statistics of PK parameters will 
be calculated using the individual values with the number of decimal places as provided by 
the evaluation program. Then the individual values as well as the descriptive statistics will be
reported with three significant digits in the CTR.
Tabulations of frequencies for categorical data will include all possible categories and will 
display the number of observations in a category as well as the percentage (%) relative to the 
respective treatment group. Percentages will be rounded to one decimal place. The category 
missing will be displayed if and only if there 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 ENDPOINTS
7.4.1
Primary analysis of the primary endpoints
Primary analysis of the primary endpoints will be performed as defined in Sections 7.3.1 of 
the CTP.
The statistical model for the primary analysis defined in the CTP is an analysis of variance 
(ANOVA) model on the logarithmic scale including "treatment" as fixed effects and "subject" 
as random effect. Relative bioavailability of the study treatments will be estimated by the 
ratios of the geometric means

treatment B (Test 1)/treatment A (Reference 1) (part 1)

treatment D (Test 2)/treatment C (Reference 2) (part 2)
of the primary endpoints.
Exclusion of PK parameters
The ADS ADPP contains column variables APEXC and APEXCO indicating 
inclusion/exclusion (APEXC) of a PK parameter and an analysis flag comment (APEXCO). 
All analyses based on the PKS are based on PK parameter values which are not flagged for 
exclusion, i.e. with APEXC equal to "Included".


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Exclusion of plasma concentrations
The ADS ADPC (PK concentrations per time-point or per time-interval) contains column 
variables ACEXC or ACEXCO indicating inclusion/exclusion (ACEXC) of a concentration 
and an analysis flag comment (ACEXCO). Exclusion of a concentration depends on the 
analysis flag comment ACEXCO. For example, if ACEXCO is set to "ALL CALC", the value 
will be excluded for all types of analyses based on concentrations. If ACEXCO is set to 
"DESC STATS" the value will be excluded from descriptive evaluations per planned time 
point/time interval. If ACEXCO contains the addition "TIME VIOLATION" or "TIME 
DEVIATION", the value can be used for further analyses based on actual times. If ACEXCO 
is set to "HALF LIFE", the value will be excluded from half-life calculation only; the value is 
included for all other analyses. Excluded concentration itself will be listed in the CTR 
associated with an appropriate flag.
Further details are given in "Noncompartmental Pharmacokinetic / Pharmacodynamic 
Analyses of Clinical Studies" (4) and "Description of Analytical Transfer Files and PK/PD 
Data Files" (5).
7.5
SECONDARY ENDPOINTS
7.5.1
Key secondary endpoints
This section is not applicable as no key secondary endpoint has been specified in the protocol.
7.5.2
Secondary endpoints
The secondary endpoints will be statistically analysed in the same way as for the primary 
endpoints. The endpoints 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.


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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 analysis, multiple AE occurrence data on the eCRF will be collapsed into one event 
provided that all of the following applies:

All AE attributes are identical (lower level term, intensity, action taken, therapy required, 
seriousness, reason for seriousness, relationship, outcome, AESI)

The occurrences were time-overlapping or time-adjacent (time-adjacency of two 
occurrences is given if the second occurrence started at most 1 hour after the first 
occurrence ended)
For further details on summarization of AE data, please refer to "Analysis and Presentation of 
Adverse Event Data from Clinical Trials" (7) and "Handling of missing and incomplete AE 
dates" (3). 
The analysis of AEs will be based on the concept of treatment emergent AEs. That means that 
all AEs will be assigned to screening, on-treatment or follow-up phases as defined in 
Section 6.1. AEs will be analysed based on actual treatments, as defined in Table 6.1: 3 and 
Table 6.1: 4.
An overall summary of AEs will be presented. This overall summary will comprise summary 
statistics for the class of other significant AEs according to ICH E3 (8) and for the class of 
AESIs.
CTP: The following are considered as AESIs:

Hepatic injury
A hepatic injury is defined by the following alterations of hepatic laboratory 
parameters:
○
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.


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According to ICH E3 (8) AEs classified as "other significant" need to be reported and will 
include those non-serious and non-significant AEs
(i) which are marked haematological or other lab abnormalities, or
(ii) which were reported with "action taken = discontinuation" or "action taken = reduced", or
(iii) which lead to significant concomitant therapy as identified by the Clinical 
Monitor/Investigator at a Medical Quality Review Meeting. 
The frequency of subjects with AEs will be summarised by treatment, primary SOC and 
preferred term. AEs which were considered by the investigator to be drug related will be 
summarised separately. Separate tables will also be provided for subjects with SAEs, subjects 
with AESIs and subjects with other significant AEs (according to ICH E3 (8)). 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 means 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).
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-


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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.
Results from the fecal occult blood testing will be listed only.
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 be assigned to planned time points in the same 
way as described above for laboratory data. However, for vital signs, descriptive statistics will 
be calculated by planned time point based on the last value of the subject at that planned time 
point (or assigned to that planned time point).
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
Relevant ECG 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 ECG findings will be prepared.
7.8.5
Others
Physical and neurological 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 or neurological 
examination findings will be prepared.
Suicidality assessment
Suicidality monitoring will be performed as described in Section 5.2.4 of the CTP, results will
only be listed. No further analysis will be prepared. Findings will also be reported as AEs.
Visual test
Visual test will be performed as described in Section 5.2.3 of the CTP.
Unscheduled measurements of visual tests will be assigned to planned time points in the same 
way as described above for laboratory data. However, for visual tests, descriptive statistics 


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will be calculated by planned time point based on the last value of the subject at that planned 
time point (or assigned to that planned time point).
Colour discrimination test
Abnormal findings during the screening examination will lead to exclusion of the subject.
Any deterioration during the study compared to baseline will be reported as an AE. Results 
from all measurements will also be listed and summarized in a frequency table for each eye.
Visual acuity test
Any deterioration during the study compared to baseline will be reported as an AE. Results 
from all measurements will be listed and summarized including change from baseline
separately for each eye.
Amsler grid test
Abnormal findings during the screening examination will lead to exclusion of the subject.
Any deterioration during the study compared to baseline will be reported as an AE. Results 
from all measurements will also be listed and summarized for each eye.


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10.
HISTORY TABLE
Table 10: 1
History table
Version
Date
(DD-MMM-YY)
Author
Sections 
changed
Brief description of change
Final
20-SEP-2019
None
This is the final TSAP