Conditions: Healthy
Allocation: NON_RANDOMIZED | Intervention model: SINGLE_GROUP
Enrollment: 16
Healthy volunteers: yes

Brief summary:
Investigate the effect of steady state exposures of memantine on the steady-state pharmacokinetics of BI 425809 and vice versa in healthy subjects.

Detailed description:

Arms:
arm 1: None

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

Protocol document:
Prot_001.pdf: 
001-MCS-40-106-RD-13 (6.0) / Saved on: 13 Jun 2018
Clinical Trial Protocol
TITLE PAGE
Document Number:
c26441810-03
EudraCT No.
2019-000468-36
BI Trial No.
1346-0039
BI Investigational
Medicinal Product
BI 425809
Title
A study to investigate the effects of memantine on the pharmacokinetics 
of BI 425809 and vice versa in healthy male and female subjects (non-
randomized, single-arm, open-label, three-period, one fixed sequence 
cross-over study)
Lay Title
A study in healthy men and women to test which effects memantine 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 2))
Version and Date
Version: 3.0
Date: 19 July 2019
Page 1 of 81
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
19 March 2019
Revision date
19 July 2019
BI trial number
1346-0039
Title of trial
A study to investigate the effects of memantine on the pharmacokinetics of 
BI 425809 and vice versa in healthy male and female subjects (non-randomized, 
single-arm, open-label, three-period, one fixed sequence cross-over study)
Principal Investigator: 
Trial site
Clinical phase
I
Trial rationale
Memantine is a common medication used in patients diagnosed with Alzheimer’s 
Disease (AD). Since BI 425809 is developed as a symptomatic treatment for AD it 
is very likely that it may be used on top of memantine in clinical practice. 
Therefore, it is crucial to investigate if there are any relevant pharmacokinetic
interactions between BI 425809 and memantine when administered together 
before their concomitant use could be allowed in Phase 3 trials and later in clinical 
practice.
Trial objectives
To investigate the effect of steady state exposure of memantine on the steady-state
pharmacokinetics of BI 425809 and vice versa in healthy subjects
Trial design
Non-randomized, single arm, open-label, three-period, one fixed sequence cross-
over design
Trial endpoints:
Primary endpoints:

AUCτ,ss and Cmax,ss of BI 425809 in blood

AUCτ,ss and Cmax,ss of memantine in blood
Number of subjects 
total entered
N = 16
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)
Trial product 1
BI 425809, film coated tablet
dose
25 mg
mode of admin.
Oral with 240 mL of water after an overnight fast of at least 10 h
Trial product 2
Memantine 
 film-coated tablets
dose
5 mg, 10 mg, 15 mg, 20 mg
mode of admin.
Oral administration with 240 mL of water. Memantine dosing follows an up-
titration regime from 5 mg to 20 mg for tolerability reasons


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Duration of treatment
Period 1 = Visit 2:    Treatment R1 (Reference 1 = BI 425809 alone) 
     Trial product 1:    Days 1-10:   multiple doses of 25 mg BI 425809 q.d.
Period 1 and 2 will be separated by a wash-out phase of at least 7 days between last treatment 
administration in Period 1 and first treatment administration in Period 2.
Period 2 = Visit 3:  Up-Titiration to R2 followed by Treatment R2 (Reference 2 =   
                                Memantine alone)           
     Trial product 2:    Up-titration regimen to Treatment R2, i.e.
Days 1-7:      multiple doses of 5 mg memantine q.d. 
Days 8-14:    multiple doses of 10 mg memantine q.d.
Days 15-21:  multiple doses of 15 mg memantine q.d
Days 22-28:  multiple doses of 20 mg memantine q.d
      Trial product 2:   Treatment R2, i.e.
Days 29-35:  multiple doses of 20 mg memantine q.d
Period 3 = Visit 4: Treatment T (Test = BI 425809 + Memantine) 
  Trial product 1:    Days 1-10 multiple doses of 25 mg BI 425809 q.d.
  Trial product 2:    Days 1-10 multiple doses of 20 mg memantine q.d.
Period 3 follow directly of period 2, i.e. the last day of period 2, is the calendar day before the first day 
of period 3.
Statistical methods
The effects of BI 425809 on the pharmacokinetics of memantine (T to R1) and the 
effects of memantine on the pharmacokinetics of BI 425809 (T to R2) will be 
evaluated based on the ratio (test to reference treatment) of the point estimates 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-test procedure, each at a 5% 
significance level. Since the main focus is on estimation and not testing, a formal 
hypothesis test and associated acceptance range is not specified. The statistical 
model will be an analysis of variance (ANOVA) on the logarithmic scale 
including effects for ‘subject’ and ‘treatment’. CIs will be calculated based on the 
residual error from the ANOVA.
Descriptive statistics will be calculated for all endpoints.


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FLOW CHART
Period
Visit
Day
Planned time (relative to first 
drug administration) 
[h:min]
Approximate clock time  of 
actual day [h:min]
Event and comment
Safety laboratory
Safety assessments
PK BI 425809 blood
PK memantine blood
PK urine memantine
C-SSRS
Vital signs (BP, PR) & 12-lead 
ECG
Questioning for AEs and 
concomitant therapy 6
SCR
1
-21 
to -1
Screening (SCR)1
x
x12,17
x
x
118
2
-1
-14:00
18 :00
Admission to trial site
x5
x12,17
x
x
1
-2:00
06:00
Allocation to subject 
numbers2
x2
x2
x2
x2
x2
0:00
08:00
Administration of 25 mg 
BI 425809
0:30
08:30
x
1:00
9:00
x
2:00
10:00
240 mL fluid intake
x
3:00
11:00
x
3:30
11:30
x
4:00
12:00
240 mL fluid intake, 
thereafter lunch3
x
x
x
4:30
12:30
x
5:00
13:00
x
6:00
14:00
x
7:00
15:00
x
8:00
16:00
Snack (voluntary)
x
10:00
18:00
x
11:00
19:00
Dinner3
x
x
12:00
20:00
x
2
24:00
08:00
Administration of 25 mg 
BI 425809
x
x8
x
25:00
09:00
Breakfast (voluntary),
discharge from trial site
x
x
3
48:00
08:00
Ambulatory visit, 
Administration of 25 mg 
BI 425809
x
4
72:00
08:00
Ambulatory visit, 
Administration of 25 mg 
BI 425809
x
5
96:00
08:00
Ambulatory visit, 
Administration of 25 mg 
BI 425809
x
x
6
120:00
08:00
Ambulatory visit, 
Administration of 25 mg 
BI 425809
x
7
144:00
08:00
Ambulatory visit, 
Administration of 25 mg 
BI 425809
x
8
168:00
08:00
Ambulatory visit, 
Administration of 25 mg 
BI 425809
x


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Period
Visit
Day
Planned time (relative to first 
drug administration) 
[h:min]
Approximate clock time  of 
actual day [h:min]
Event and comment
Safety laboratory
Safety assessments
PK BI 425809 blood
PK memantine blood
PK urine memantine
C-SSRS
Vital signs (BP, PR) & 12-lead 
ECG
Questioning for AEs and 
concomitant therapy 6
9
192:00
08:00
Ambulatory visit, 
Administration of 25 mg 
BI 425809
x
x
202:00
18:00
Admission to trial site
x5
x12
x
x
10
216:00
08:00
Administration of 25 mg 
BI 425809
x8
x2
x2
216:30
08:30
x
217:00
09:00
x
x
218:00
10:00
240 mL fluid intake
x
x
219:00
11:00
x
x
219:30
11:30
x
220:00
12:00
240 mL fluid intake, 
thereafter lunch3
x
x
x
220:30
12:30
x
221:00
13:00
x
222:00
14:00
x
x
223:00
15:00
x
224:00
16:00
Snack (voluntary)3
x
x
226:00
18:00
x
x
227:00
19:00
Dinner
228:00
20:00
x
x
x
11
240:00
08:00
Breakfast (voluntary)3,
discharge from trial site
x
x12
x
x
x
x
218
37
1
-2:00
06:00
Admission to trial site
x2,5
x2,12
x2
x
x2
x2
x2
0:00
08:00
Administration of 5 mg 
Memantine
┬13
│
0:30
08:30
x
│
1:00
09:00
x
│
x
2:00
10:00
240 mL fluid intake
x
│
x
3:00
11:00
x
│
x
3:30
11:30
x
│
4:00
12:00
240 mL fluid intake, 
thereafter lunch3
x
┼
│
x
x
4:30
12:30
x
│
5:00
13:00
x
│
6:00
14:00
x
│
x
7:00
15:00
x
│
8:00
16:00
Snack (voluntary)3
x
┼
x
x
10:00
18:00
x
│
x
11:00
19:00
Dinner
│
12:00
20:00
x
┼
x
x
2
24:00
08:00
Administration of 5 mg 
Memantine
x8
│
┴
x2
x2
25:00
09:00
Breakfast (voluntary)3,
discharge from trial site
x12
x
x
x
3 -7
48:0015
08:00
Ambulatory visit, 
Administration of 5 mg 
Memantine
x2,10
x2,9
x2,9


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Period
Visit
Day
Planned time (relative to first 
drug administration) 
[h:min]
Approximate clock time  of 
actual day [h:min]
Event and comment
Safety laboratory
Safety assessments
PK BI 425809 blood
PK memantine blood
PK urine memantine
C-SSRS
Vital signs (BP, PR) & 12-lead 
ECG
Questioning for AEs and 
concomitant therapy 6
8 -14
168:0015
08:00
Ambulatory visit, 
Administration of 10 mg 
Memantine
x2,10
x12,16
x8,16
x2,9
x2,9
15-21
336:0015
08:00
Ambulatory visit, 
Administration of 15 mg 
Memantine
x2,10
x12,16
x8,16
x2,9
x2,9
22-33
504:0015
08:00
Ambulatory visit, 
Administration of 20 mg 
Memantine
x2,14
x12,16
x8,11
x2,9
x2,9
34
792:00
08:00
Ambulatory visit, 
Administration of 20 mg 
Memantine
x8
x
x
802:00
18:00
Admission to trial site
x5
x12
x
x
35
816:00
08:00
Administration of 20 mg 
Memantine
x2
x8
┬13
│
x2
x2
816:30
08:30
x
│
817:00
09:00
x
│
x
818:00
10:00
240 mL fluid intake
x
│
x
819:00
11:00
x
│
x
819:30
11:30
x
│
820:00
12:00
240 mL fluid intake, 
thereafter lunch3
x
┼
│
x
820:30
12:30
x
│
821:00
13:00
x
│
822:00
14:00
x
│
x
823:00
15:00
x
│
824:00
16:00
Snack (voluntary)3
x
┼
x
826:00
18:00
x
│
x
827:00
19:00
Dinner
│
828:00
20:00
x
┼
x
x
3
47
1
0:00
08:00
Administration of 25 mg 
BI 425809 and 20 mg 
Memantine
x
x8
x8
│
┴
x2
x2
1:00
09:00
Snack (voluntary)3
2:00
10:00
4:00
12:00
lunch3
x
x
6:00
14:00
8:00
16:00
Snack (voluntary)3
x
x
10:00
18:00
11:00
19:00
Dinner
12:00
20:00
x
x
2
24:00
08:00
Administration of 25 mg 
BI 425809 and 20 mg 
Memantine
x2
x
3
48:00
08:00
Administration of 25 mg 
BI 425809 and 20 mg 
Memantine
x2
x2
49:00
09:00
Breakfast (voluntary)3,
discharge from trial site
x12
x
x
x


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Period
Visit
Day
Planned time (relative to first 
drug administration) 
[h:min]
Approximate clock time  of 
actual day [h:min]
Event and comment
Safety laboratory
Safety assessments
PK BI 425809 blood
PK memantine blood
PK urine memantine
C-SSRS
Vital signs (BP, PR) & 12-lead 
ECG
Questioning for AEs and 
concomitant therapy 6
4
72:00
08:00
Ambulatory Visit:
Administration of 25 mg 
BI 425809 and 20 mg 
Memantine
x
x2
x2
5
96:00
08:00
Ambulatory Visit:
Administration of 25 mg 
BI 425809 and 20 mg 
Memantine
x8
x8
x2
x2
6
120:00
08:00
Ambulatory Visit:
Administration of 25 mg 
BI 425809 and 20 mg 
Memantine
x8
x8
x2
x2
7
144:00
08:00
Ambulatory Visit:
Administration of 25 mg 
BI 425809 and 20 mg 
Memantine
x2
8
168:00
08:00
Ambulatory Visit:
Administration of 25 mg 
BI 425809 and 20 mg 
Memantine
x2
9
192:00
08:00
Ambulatory Visit:
Administration of 25 mg 
BI 425809 and 20 mg 
Memantine
x8
x8
x2
x2
202:00
18:00
Admission to trial site
x5
x12
x
x
10
216:00
08:00
Administration of 25 mg 
BI 425809 and 20 mg 
Memantine
x2
x8
x8
┬13
│
│
x2
x2
216:30
08:30
x
x
│
217:00
09:00
x
x
│
x
218:00
10:00
240 mL fluid intake
x
x
│
x
219:00
11:00
x
x
│
x
219:30
11:30
x
x
│
220:00
12:00
240 mL fluid intake, 
thereafter lunch3
x
x
┼
│
x
220:30
12:30
x
x
│
221:00
13:00
x
x
│
222:00
14:00
x
x
│
x
223:00
15:00
x
x
│
224:00
16:00
Snack (voluntary)3
x
x
┼
x
226:00
18:00
x
x
│
x
227:00
19:00
Dinner
│
228:00
20:00
x
x
┼
x
11
240:00
08:00
Breakfast (voluntary)3,
discharge from trial site
x12
x
x
┴
x
x
x
18
Phone call
x
FU
5
32 -37
End of trial (EoTrial) 
examination4
x
x12,17
x
x
x


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1.
Subject must be informed and written informed consent obtained prior to starting any screening procedures. Screening 
procedures include physical examination, check of vital signs, visual tests, C-SSRS assessment, ECG, safety laboratory 
(including drug screening and alcohol breath test), demographics (including determination of body height and weight, 
smoking status and alcohol history), relevant medical history, concomitant therapy and review of inclusion/exclusion 
criteria
2.
The time is approximate; the procedure is to be performed and completed within the 2 h prior to drug administration.
3.
If several actions are indicated at the same time, the intake of meals will be the last action.
4.
End of trial examination includes physical examination including neurological assessment, vital signs, visual tests, 
C-SSRS assessment, ECG, safety laboratory, recording of AEs and concomitant therapies,.
5.
Only urine drug screening and alcohol breath test as well as pregnancy test in women will be done at this time
6.
AEs and concomitant therapies will be recorded throughout the trial, but will be specifically asked for at the times 
indicated in the Flow Chart above.
7.
There will be no further wash-out period between visit 3 and 4, i.e. Day 1 of Visit 4 the following calendar day of 
Day 35 visit 3
8.
The sample is to be taken within 10 min prior to next dosing
9.
During the up-titration phase to steady state vital signs, ECG and AE/CT questioning is performed on each day prior to
memantine medication
10. During the up-titration phase to steady state safety lab is taken at the last day of each memantine dose level
11. Only on day 22 and 33
12. Neurological assessment for details refer to Section 5.2.1
13. A blank urine sample (x) is to be obtained prior to administration of trial medication. Other urine samples are to be
collected over the stated post-dose intervals as indicated above. For technical reasons the planned stop time of the urine 
sample obtained starting visit 3, 828:00, will be 840:00.
14. Only on day 28
15. The column “planned time” only includes start time of the first day of the respective interval of days
16. To be done on the first day of each dose level
17. Visual tests, for details refer to Section 5.2.3
18. Period 1 and 2 will be separated by a wash-out phase of at least 7 days between last treatment administration in Period 1 
and first treatment administration in Period 2


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TABLE OF CONTENTS
TITLE PAGE ......................................................................................................1
CLINICAL TRIAL PROTOCOL SYNOPSIS ................................................2
FLOW CHART...................................................................................................4
TABLE OF CONTENTS ...................................................................................9
ABBREVIATIONS.......................................................................................... 13
1.
INTRODUCTION.................................................................................... 16
1.1
MEDICAL BACKGROUND............................................................................16
1.2
DRUG PROFILE...............................................................................................16
1.2.1
BI 425809 ...............................................................................................16
1.2.1.1
Non-clinical pharmacokinetics ................................................16
1.2.1.2
Non-clinical safety pharmacology and toxicology ..................17
1.2.1.3
Clinical experience in humans.................................................18
1.2.1.4
Clinical pharmacokinetics........................................................18
1.2.2
Memantine.............................................................................................19
1.2.2.1
Drug product ............................................................................19
1.2.2.2
Clinical experience in humans.................................................19
1.2.2.3
Clinical pharmacokinetics........................................................21
1.2.3
Residual Effect Period..........................................................................22
1.3
RATIONALE FOR PERFORMING THE TRIAL........................................22
1.4
BENEFIT - RISK ASSESSMENT ...................................................................22
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 ......................................................28
3.3.1
Main diagnosis for trial entry..............................................................29
3.3.2
Inclusion criteria...................................................................................29


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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
3.3.4.2
Withdrawal of consent to trial participation ............................32
3.3.4.3
Discontinuation of the trial by the sponsor..............................32
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................................................................35
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....................................................................................... 41
5.1
ASSESSMENT OF EFFICACY.......................................................................41
5.2
ASSESSMENT OF SAFETY............................................................................41
5.2.1
Physical examination ............................................................................41
5.2.2
Vital signs...............................................................................................41
5.2.3
Visual tests.............................................................................................41
5.2.3.1
Color discrimination test..........................................................42
5.2.3.2
Visual acuity test (near visual acuity)......................................42
5.2.3.3
Amsler grid test........................................................................42
5.2.4
Suicidality monitoring ..........................................................................42
5.2.5
Safety laboratory parameters..............................................................43
5.2.6
Electrocardiogram................................................................................46
5.2.7
Other safety parameters.......................................................................47
5.2.8
Assessment of adverse events...............................................................47
5.2.8.1
Definitions of adverse events...................................................47


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Adverse event ............................................................47
5.2.8.1.1
Serious adverse event ................................................47
5.2.8.1.2
AEs considered ‘Always Serious’.............................48
5.2.8.1.3
Adverse events of special interest .............................48
5.2.8.1.4
Intensity (severity) of AEs.........................................49
5.2.8.1.5
Causal relationship of AEs ........................................49
5.2.8.1.6
Suicidal risk assessed by the C-SSRS .......................50
5.2.8.1.7
5.2.8.2
Adverse event collection and reporting ...................................50
AE collection.............................................................50
5.2.8.2.1
AE reporting to the sponsor and timelines ................51
5.2.8.2.2
Information required..................................................51
5.2.8.2.3
Pregnancy ..................................................................52
5.2.8.2.4
5.3
DRUG CONCENTRATION MEASUREMENTS AND 
PHARMACOKINETICS..................................................................................52
5.3.1
Assessment of pharmacokinetics .........................................................52
5.3.2
Methods of sample collection...............................................................52
5.3.2.1
Blood sampling for pharmacokinetic analysis of BI 425809...52
5.3.2.2
Blood sampling for pharmacokinetic analysis of memantine..53
5.3.2.3
Urine sampling for pharmacokinetic analysis of memantine ..53
5.3.3
Analytical determinations ....................................................................54
5.3.3.1
Analytical determination of BI 425809 and memantine plasma 
concentration............................................................................54
5.3.3.2
Analytical determination of memantine urine concentration...54
5.3.4
Pharmacokinetic - pharmacodynamic relationship...........................54
5.4
ASSESSMENT OF BIOMARKER..................................................................54
5.5
BIOBANKING ...................................................................................................54
5.6
APPROPRIATENESS OF MEASUREMENTS.............................................54
6.
INVESTIGATIONAL PLAN.................................................................. 56
6.1
VISIT SCHEDULE............................................................................................56
6.2
DETAILS OF TRIAL PROCEDURES AT SELECTED VISITS ................56
6.2.1
Screening period....................................................................................56
6.2.2
Treatment periods.................................................................................56
6.2.3
Follow-up period and trial completion ...............................................57
7.
STATISTICAL METHODS AND DETERMINATION OF
SAMPLE SIZE......................................................................................... 58
7.1
STATISTICAL DESIGN – MODEL ...............................................................58
7.2
NULL AND ALTERNATIVE HYPOTHESES ..............................................58
7.3
PLANNED ANALYSES....................................................................................58
7.3.1
Primary endpoint analyses...................................................................60
7.3.2
Secondary endpoint analyses ...............................................................60


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7.3.4
Safety analyses.......................................................................................61
7.4
INTERIM ANALYSES .....................................................................................62
7.5
HANDLING OF MISSING DATA ..................................................................62
7.5.1
Safety......................................................................................................62
7.5.2
Pharmacokinetics..................................................................................62
7.6
RANDOMISATION ..........................................................................................62
7.7
DETERMINATION OF SAMPLE SIZE ........................................................62
8.
INFORMED CONSENT, TRIAL RECORDS, DATA 
PROTECTION, PUBLICATION POLICY, AND 
ADMINISTRATIVE STRUCTURE...................................................... 64
8.1
TRIAL APPROVAL, SUBJECT INFORMATION, INFORMED 
CONSENT ..........................................................................................................64
8.2
DATA QUALITY ASSURANCE .....................................................................65
8.3
RECORDS..........................................................................................................65
8.3.1
Source documents .................................................................................65
8.3.2
Direct access to source data and documents.......................................66
8.3.3
Storage period of records.....................................................................66
8.4
EXPEDITED REPORTING OF ADVERSE EVENTS .................................66
8.5
STATEMENT OF CONFIDENTIALITY AND SUBJECT PRIVACY.......67
8.5.1
Collection, storage and future use of biological samples and 
corresponding data ...............................................................................67
8.6
TRIAL MILESTONES .....................................................................................67
8.7
ADMINISTRATIVE STRUCTURE OF THE TRIAL ..................................68
9.
REFERENCES......................................................................................... 69
9.1
PUBLISHED REFERENCES...........................................................................69
10. APPENDICES .......................................................................................... 73
10.1
COLUMBIA-SUICIDE SEVERITY RATING SCALE ................................73
11. DESCRIPTION OF GLOBAL AMENDMENTS................................. 79
11.1
GLOBAL AMENDMENT 1 .............................................................................79
11.2
GLOBAL AMENDMENT 2 .............................................................................81


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ABBREVIATIONS
AE
Adverse event
AESI
Adverse events of special interest
ALT
Alanine transaminase
ANOVA
Analysis of variance
AST
Aspartate transaminase
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
AUCτ,ss
Area under the concentration-time curve of the analyte in plasma at 
steady state over a uniform dosing interval τ
BA
Bioavailability
BI
Boehringer Ingelheim
BMI
Body mass index (weight divided by height squared)
BP
Blood pressure
C-SSRS
Columbia Suicide Severity Rating Scale
CA
Competent authority
CI
CIAS
Confidence interval
Cognitive impairment associated with schizophrenia
Cmax
Maximum measured concentration of the analyte in plasma
CNS
Central nervous system
CRA
Clinical Research Associates
CRF
CRO
CTL
Case Report Form, paper or electronic (sometimes referred to as ‘eCRF’)
Contract Research Organisation
Clinical Trial Leader
CTP
Clinical trial protocol
CTR
Clinical trial report
DILI
Drug induced liver injury
ECG
Electrocardiogram
eCRF
Electronic case report form
eDC
Electronic data capture


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EDTA
Ethylenediaminetetraacetic acid
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
Gastro-intestinal
GlyT1
Glycine transporter 1
gMean
Geometric mean
IB
Investigator’s brochure
ICH
International Conference on Harmonization
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
NMDAR
NMDA receptor 
PE
Polyethylene
PK
Pharmacokinetic(s)
PKS
Pharmacokinetic set
PP
Polypropylene
PR
Pulse rate
q.d.
quaque die (once a day)
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
RTA
Renal tubular acidosis
SAE
Serious adverse event
SCR
Screening


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SmPC
Summary of Product Characteristics
SOP
Standard operating procedure
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, one Phase 1 
trial in healthy volunteers 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
Elimination of BI 425809 in preclinical species and humans primarily occurs through 
oxidation. CYP3A is predicted to contribute to >90% of the hepatic metabolism of BI 425809 
which is consistent with a 6-fold increase in BI 425809 AUC0-∞with co-administration of 
itraconazole, a specific CYP3A inhibitor [c03355329].


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 however, once daily, oral 
administration of BI 425809 (25 mg) resulted in mild induction of CYP3A-mediated 
elimination of the sensitive CYP3A substrate, midazolam, in humans [c08949593].
 In vitro inhibition of P-gp by 
BI 425809 did not translate into a clinically relevant exposure change of digoxin (a selective 
P-gp substrate) in humans [c08949593]. 
1.2.1.2
Non-clinical safety pharmacology and toxicology
A comprehensive package of safety pharmacology, genetic toxicology, embryo-foetal
development and general toxicology studies have been conducted that support repeated 
administration of BI 425809 to adult human subjects for up to 13 weeks duration, including
women of child-bearing potential with a medically acceptable method of contraception. As 
preclinical studies to assess pre- and post-natal development have not been performed yet 
BI 425809 may not be administered to women who are, or who may be, breastfeeding.
In summary, there were no effects on blood pressure, heart rate, or electroretinogram in
safety pharmacology studies. Adverse findings were mainly on-target effects or secondary to 
CNS depressant effects on the central nervous system (CNS) at doses higher than the 
anticipated maximum therapeutic dose of 25 mg BI 425809. Haematology changes including 
a decrease in haemoglobin and red blood cells and associated histopathology changes like 
splenic extramedullary haematopoiesis were mild and occurred in rats at human equivalent 
doses higher than planned for clinical studies.
Two major human metabolites of BI 425809, BI 758790 and BI 761036 have been identified 
and their toxicity evaluated with no evidence of pharmacological activity, genotoxicity, feto-
toxicity or teratogenicity, or adverse effects in repeat-dose toxicity in studies in animals up to 
15 weeks duration.


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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. Two Phase 2 trials (1346-0009 and 1346-0023) and one Phase 1 trial 
(1346-0015) are ongoing.
More than 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 IB, 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 IB, Table 6.3.1.1:3
[c02155957]).
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
After administration of BI 425809 tablets, maximum plasma concentrations of BI 425809 
occurred around 3 to 5 h after dosing. The terminal half-life was independent of the 
administered dose and ranged from 37 to 59h. Exposure increased in the tested dose range of 
5 to 75 mg but with a trend to a less than dose proportional behaviour for doses of 50 mg and 
above. Food increased drug exposure (fed/fast ratio for Cmax: 142%, for AUC0-tz: 126%).
Steady state was reached after 6 days of BI 425809 dosing with accumulation ratios for Cmax 
ranging from 1.96 to 2.63 and for AUC from 2.31 to 3.21. No exposure difference between 


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young and elderly healthy subjects was observed. Furthermore, pharmacokinetics in Japanese 
and Chinese subjects were comparable with Caucasians.
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.
In plasma from young and elderly healthy volunteers administered single or multiple oral 
doses of BI 425809 (10, 25 and 50 mg) (trials 1346.1 and 1346.2), four oxidative metabolites, 
M526, M528, BI 758790, and M544 and two metabolites resulting from hydrolysis of the 
amide bond, BI 761036 and M312 (IN00079211), were identified. BI 761036 was with 54% 
the main contributor to plasma drug-related exposure, BI 758790 occurs at plasma exposures 
similar to parent, each made up around 20% of total drug-related exposure.
For a more detailed description of the BI 425809 profile please refer to the current 
Investigator’s Brochure [c02155957].
1.2.2
Memantine 
Memantine is a voltage-dependent, moderate-affinity uncompetitive NMDA-receptor 
antagonist. It modulates the effects of pathologically elevated tonic levels of glutamate that 
may lead to neuronal dysfunction. There is increasing evidence that malfunctioning of 
glutamatergic neurotransmission, in particular at NMDA-receptors, contributes to both 
expression of symptoms and disease progression in neurodegenerative dementia [R18-3740, 
R18-3739].
1.2.2.1
Drug product
Film-coated tablet in dose strengths of 5, 10, 15, and 20 mg are commercially available. For 
the therapy of patients, the recommended maximum daily dose is 20 mg per day. To reduce 
the risk of undesirable effects, the maintenance dose shall be achieved by upward titration of 
5 mg per week over the first 3 weeks [R18-3740, R18-3739].
1.2.2.2
Clinical experience in humans

In a clinical trial, potential drug-drug interactions were investigated between 
memantine and dextromethorphan in healthy male volunteers. The trial was 
conducted in an open-label, randomized, parallel-group design [P13-15942].
In one group (N=23), subjects were administered memantine in an up-titration scheme 
from 5 mg to 20 mg (10 mg bid) to steady state, similar to the dosing regimen in the 
planned trial 1346-0039. Therefore, the safety profile from this group is described in 
more detail: The adverse events observed after the up-titration phase under during 
memantine monotherapy (10 mg bid for 11 days) included headache, somnolence, 


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decreased appetite, and dry mouth. All AEs were mild to moderate, no severe AEs, no 
deaths or serious adverse events were reported. Clinically significant increased ALT
values ranged from 50 to 156 U/L.
One subject was withdrawn from the trial during the upitration phase due to adverse 
events. The subject experienced nine central nervous system (CNS) and 
gastrointestinal AEs after 10 days of memantine monotherapy (i.e. 2 days after 
starting with 5 mg bid);These AEs included lightheadedness, dizziness, insomnia, 
constipation, abdominal pain,nausea, and loose stools, as well as emotional lability.

A double-blind, fixed-dose study in 78 patients with moderate to severe AD assessed 
the safety and tolerability of a memantine 20 mg once-daily regimen compared with a 
10 mg dose taken twice daily. Further, a 1-step once-daily dose titration schedule was 
compared with the standard 3-step up-titration schedule. Safety analysis suggest that 
once-daily dosing of memantine is as well tolerated as twice-daily dosing and that the 
standard 3-step up-titration schema may be better tolerated than a 1-step up-titration 
regimen. These results are in alignment with the current dosing recommendation 
provided by the SmPC [R18-3740, R18-3739] and are reflected in the design of this 
trial.
According to the current summary of product characteristics (SmPC) [R18-3740, R18-3739]
common side effects of memantine are somnolence, dizziness, headache, balance disorders, 
dyspnea, constipation, hypertension, elevated liver function tests, and drug hypersensitivity.
Uncommon side effects of memantine include fungal infection, confusion, hallucinations 
(mainly observed in patients with severe Alzheimer´s disease), abnormal gait, venous 
thrombosis/thromboembolism, vomiting, fatigue and cardiac failure.
Seizures are described as very rare side effects.
From post-marketing experience there were reports of psychotic reactions, pancreatitis, and
hepatitis in the context of memantine use. The frequency of these events is not known.
Further In post-marketing experience depression, suicidal ideation and suicide have been 
reported in patients treated with Memantine. However, Alzheimer’s disease has been 
associated with these events, too.
Memantine has minor or moderate influence on the ability to drive and use machines such
that subjects should be warned to take special care.
Overdose
Relative large overdoses (200 mg and 105 mg/day for 3 days, respectively) have been 
associated with either only symptoms of tiredness, weakness and/or diarrhoea or no 
symptoms. In the overdose cases below 140 mg or unknown dose the patients revealed 
symptoms from central nervous system (confusion, drowsiness, somnolence, vertigo, 
agitation, aggression, hallucination, and gait disturbance) and/or gastrointestinal origin 
(vomiting and diarrhoea).


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In the most extreme case of overdose, the patient survived the oral intake of a total of 
2000 mg memantine with effects on the central nervous system (coma for 10 days, and later 
diplopia and agitation). The patient received symptomatic treatment and plasmapheresis. The 
patient recovered without permanent sequelae.
In another case of a large overdose, the patient also survived and recovered. The patient had 
received 400 mg memantine orally. The patient experienced central nervous system 
symptoms such as restlessness, psychosis, visual hallucinations, proconvulsiveness, 
somnolence, stupor, and unconsciousness.
In the event of overdose, treatment should be symptomatic. No specific antidote for 
intoxication or overdose is available. Standard clinical procedures to remove active substance 
material, e.g. gastric lavage, carbo medicinalis (interruption of potential entero-hepatic 
recirculation), acidification of urine, forced diuresis should be used as appropriate. 
In case of signs and symptoms of general central nervous system (CNS) overstimulation, 
careful symptomatic clinical treatment should be considered [R18-3740, R18-3739]
1.2.2.3
Clinical pharmacokinetics
After oral administration in humans, memantine is completely absorbed with an absolute
bioavailability of approximately 100%. There is no indication that food influences the 
absorption of memantine. Tmax is between 3 and 8 hours and memantine has demonstrated 
linear pharmacokinetics in the dose range of 10 to 40 mg in healthy volunteers [R18-3740, 
R18-3739].
Daily doses of 20 mg lead to steady-state plasma concentrations of memantine ranging from 
70 to 150 ng/ml (0.5 - 1 μmol/L) with large interindividual variations. When daily doses of 5 
to 30 mg were administered, a mean cerebrospinal fluid (CSF)/serum ratio of 0.52 was 
calculated. The volume of distribution is around 10 l/kg. About 45% of memantine is bound 
to plasma-proteins. 
In humans, about 80% of the circulating memantine-related material is present as the parent 
compound. Main human metabolites are N-3,5-dimethyl-gludantan, the isomeric mixture of 
4- and 6-hydroxy-memantine, and 1-nitroso-3,5-dimethyl-adamantane. None of these 
metabolites exhibit NMDA-antagonistic activity. No cytochrome P450-catalysed metabolism 
has been detected in vitro and memantine did not inhibit CYP1A2, 2A6, 2C9, 2D6, 2E1, 3A, 
Flavin-containing monooxygenase, epoxide hydrolase or sulphation in vitro. [R18-3740, 
R18-3739]
Unchanged memantine is mainly excreted renally with a terminal t½ of 60 to 100 hours. 
Tubular secretion as well as tubular reabsorption are involved in its renal elimination. In vitro 
data suggest a potential role of MATE1 and OCT2 for renal secretion of memantine 
[R17-3276, R15-0935] and also indicate that both, MATE1 and to an even higher extent 
OCT2, are inhibited by memantine, albeit with reported IC50 values that exceed unbound 
plasma concentrations expected during therapy [R17-3276]. The renal elimination rate of 
memantine under alkaline urine conditions may be reduced by a factor of up to 7 to 9. 
Alkalisation of urine may result from drastic changes in diet, e.g. from a carnivore to a 
vegetarian diet. Therefore, concomitant use of drugs that have an alkalizing effect on the 
urinary pH, e.g. massive ingestion of alkalising gastric buffers, or that compete at / inhibit the
transporters of the renal cation transporter system (OCT2, MATE1) may theoretically lead to 


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memantine accumulation [P17-09169, R17-3276]. In patients with moderate renal 
impairment (creatinine clearance 30 - 49 ml/min), daily dose of memantine should be 10 mg 
per day that may be increased to 20 mg/day if well tolerated. In patients with severe renal 
impairment (creatinine clearance 5 – 29 ml/min) daily dose should be reduced to 10 mg per 
day.
For a more detailed description of the memantine profile please refer to the current SmPC
[R18-3740, R18-3739]
1.2.3
Residual Effect Period
The Residual Effect Period (REP) of BI 425809 
 and of Memantine 21 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
Memantine is a common medication used in patients diagnosed with Alzheimer’s Disease 
(AD). Since BI 425809 is developed as a symptomatic treatment for AD it is very likely that 
it may be used on top of memantine in clinical practice. Therefore, it is crucial to investigate 
if there are any interactions between BI 425809 and memantine when administered together 
before their concomitant use could be allowed in Phase 3 trials and later in clinical practice.
1.4
BENEFIT - RISK ASSESSMENT
Participation in this clinical trial is without any (therapeutic) benefit for healthy subjects. 
Their participation, however, is of major importance for the development of BI 425809. The 
assessment of the drug-drug-interaction potential of BI 425809 will contribute to a safe 
clinical use of this GlyT1 inhibitor in patients with AD who often have to use multiple co-
medications Subjects are exposed to risks of study procedures and risks related to the 
exposure to the trial medication.
Procedure-related risks
The use of an indwelling venous catheter or venepuncture for e.g. blood sampling may result 
in mild bruising, and in rare cases, in transient inflammation of the wall of the vein, or nerve 
injury, potentially resulting in paraesthesia, reduced sensibility, and/or pain for an indefinite 
period.
The total volume of blood withdrawn per subject during the entire study will not exceed the 
volume of a normal blood donation (500 mL). No health-related risk to healthy subjects is 
expected from withdrawal of this volume of blood.
Drug-related risks and safety measures
Risks related to BI 425809 administration


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In this trial, a dose of 25 mg BI 425809 q.d. will be administered over two periods of 10 days 
each, once alone and once in combination with memantine. Multiple oral doses of 25 mg 
BI 425809 have already been administered in trial 1346.2 (12 days) and 1346.3 (14 days) and 
are 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 
qd 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 memantine administration
Memantine can cause a variety of side effects that can range from mild to severe and serious 
(see Section 1.2.2). Many of these have been reported from clinical trials in patients with AD, 
i.e. in patients with considerable comorbidities.
Data from clinical trials with memantine administration in healthy volunteers indicate good 
tolerability in general. Dizziness, headache, somnolence, decreased appetite were observed
adverse events and increased ALT values were seen in the safety lab. These AEs were mild to 
moderate, they are monitorable and will be reflected in the safety measures.
Risks related to the combined administration of BI 425809 and Memantine
Based on available data (see Section 1.2), a clinically relevant pharmacokinetic or
pharmacodynamic interaction between memantine and BI 425809 is considered unlikely
based on the following considerations:
Pharmacokinetic interaction:
Memantine selectively inhibits CYP2B6 activity at clinically relevant concentrations, 
whereas inhibition of other CYPs during memantine therapy is unlikely, i.e. it is not expected 
to affect BI 425809 metabolism that is mostly CYP3A4 mediated (see Section 1.2.1.1)
[P04-11747]. In vitro memantine also inhibits OCT2 and to a lesser extent MATE. BI 425809 
is not a substrate of OCT2, regarding MATE there are no in vitro data available. However, as 
the gMean fractional renal excretion of BI 425809 is low (around 5% over all dose groups),
the impact of a potential interaction via MATE inhibition should be minor (see Section 
1.2.1.1).


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For memantine, no cytochrome P450-catalysed metabolism has been detected in vitro. An 
interaction based on the mild induction potential of BI 425809 on CYP3A4 is therefore 
considered unlikely. The renal transporters OCT2 and MATE1 may be involved in the 
tubular secretion of memantine [R17-3276]. In in vitro studies, BI 425809 did not inhibit the 
organic cation transporter OCT2 and was found to only inhibit MATE1 and MATE2K 
transporters with IC50 values between 30 and 100 uM [n00241265, n00263124]. Based on 
exposures associated with the current highest dose of BI 425809 (25 mg qd) and DDI 
prediction approaches outlined in regulatory guidelines [P14-08681, P12-05791], clinically-
relevant inhibition of memantine renal secretion is considered unlikely. No trend towards an 
alkalization of urine by BI 425809 has been observed after multiple doses of BI 425809
(CTR 1346.2, Listing 1.1 [c02958024]).
Pharmacodynamic interaction:
Both drugs, BI 425809 and memantine, are targeting the NMDA receptor (NMDAR). 
However, the mode of action of both drugs is different.
Memantine is a moderate-affinity uncompetitive NMDAR antagonist. The NMDAR is a 
voltage-sensitive, glutamate-gated ion channel that, after activation, allows entry of calcium 
into the neuron. One hypothesis is that chronic overactivity at the NMDAR, allows excessive 
calcium influx and may via subsequnt synaptic or dendritic damage, necrosis or apoptosis, 
play a role in the progression of AD, especially at later stages of the disease (moderate-to-
severe). At rest, the NMDAR channel is blocked by a magnesium ion. Memantine binds at, or 
near, the magnesium-binding site and thereby blocks calcium entry into the cell at times of 
partial neuronal depolarization, but allows entry during full neuronal depolarization. This 
allows normal physiologic signal transmission during times of learning or recall, along with 
inhibiting pathologic, tonic overactivation [P18-12042, R18-3925].
BI 425809 inhibits GlyT1 leading to increased glycine concentrations in the synaptic cleft. 
Glycine is a physiological co-activator of the NMDAR. The physiological NMDAR function 
is critical for learning and memory and cognitive performance. It has been shown that mice 
with point mutations in the NMDAR glycine binding site display greatly reduced NMDAR 
function and show severe deficits in learning and memory performance. These deficits can be 
rescued by administration of the NMDA receptor glycine site agonist D-serine [R18-3925].
BI 425809 is hypothesized to reduce NMDAR hypofunction in regard to disturbed 
physiological signal transmission required for learning and memory. On the other hand 
memantine is thought to inhibit the overactivation of the NMDAR in late stage Alzheimer’s 
disease patients, while at the same time it does not affect at therapeutic exposure levels 
(approximately 50% occupancy of the NMDAR) the physiological signal transmission 
needed for cognitive function.
Therefore, in conclusion, a pharmacodynamic interaction of BI 425809 and mementine by 
counteracting the effects of the other drug is not expected.


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Drug-induced liver injury
Although rare, a potential for drug-induced liver injury (DILI) is under constant surveillance 
by sponsors and regulators. Therefore, this trial requires timely detection, evaluation, and 
follow-up of laboratory alterations in selected liver laboratory parameters to ensure subjects´ 
safety; see also Section 5.2.8.1.4, adverse events of special interest.
Safety measures:

A thorough screening examination will ensure that only suitable healthy subjects will
enter the study, for example subjects with
o
with high liver enzymes or history of or current liver disease
o
GFR < 80 ml/min
o
medical conditions or nutrition habits that may cause urine alkalization
will be excluded from study participation.

Close monitoring of 
o
Adverse events 
o
Safety lab (special focus on hepatic parameters, eGFR)
o
ECG and Vital signs (focus on blood pressure)
o
C-SSRS

Prohibition to use drugs that may cause urine alkalization (Section 4.2.2)

Drugs, medical conditions or nutrition habits that may cause urine alkalization are not 
allowed

As memantine may impact the ability to operate vehicles and/or machines, subjects 
are not allowed to drive a vehicle or operate machines during Visit 3 and 4

Close medical surveillance for at least 25 hours post-dose on the day of first 
administration of BI 425809 and memantine, respectively, and for up to 49 hours 
post-dose after combined administration of BI 425809 and memantine


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2.
TRIAL OBJECTIVES AND ENDPOINTS
2.1
MAIN OBJECTIVES, PRIMARY AND SECONDARY ENDPOINTS
2.1.1
Main objectives
To investigate the effect of steady state exposures of memantine on the steady-state 
pharmacokinetics of BI 425809 and vice versa in healthy subjects.
2.1.2
Primary endpoints
The following pharmacokinetic parameters will be determined for BI 425809 and for 
memantine:

AUCτ,ss (area under the concentration-time curve of the analyte in plasma at steady 
state over a uniform dosing interval τ)

Cmax,ss (maximum measured concentration of the analyte in plasma at steady state over 
a uniform dosing interval τ)
2.1.3
Secondary endpoint
Not applicable.


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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

12-lead ECG (only abnormal findings will be reported as AE)

Visual tests (only abnormal findings will be reported as AE)

Vital signs (blood pressure, pulse rate)

Suicidality assessment (C-SSRS)


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3.
DESCRIPTION OF DESIGN AND TRIAL POPULATION
3.1
OVERALL TRIAL DESIGN AND PLAN
The study will be performed in healthy male and female subjects and is designed non-
randomized, single-arm, open-label, three-period, one fixed sequence cross-over to 
investigate the effects of steady state exposures of memantine on steady state 
pharmacokinetics of BI 425809 and vice versa.
Considering the well-known safety profiles of the selected dose of BI 425809 and 
memantine, the unlikelihood of increased drug exposures due to a pharmacokinetic 
memantine-BI 425809 interaction and the already implemented safety measures (ref 
Section 1.4) treatment of all 16 subjects in one cohort in this trial 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, e.g. two cohorts of 8 
subjects, and be treated not too wide apart in terms of time for better comparability and 
reducing any possible factors influencing the readout.
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
This trial is 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 analytes 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, memantine and 
BI 425809. The fixed-sequence design enables intra-individual comparisons and 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.
Dosing durations are long enough to achieve steady-state drug exposures of both drugs 
reliably and to exclude any transient effects.
3.3
SELECTION OF TRIAL POPULATION
It is planned that 16 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.


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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
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)


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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 
14. Alcohol abuse (consumption of more than 12 g per day for females and 24 g per 
day for males)
15. Drug abuse or positive drug screening
16. Blood donation of more than 100 mL within 30 days of planned administration of 
trial medication or intended blood donation during the trial
17. Intention to perform excessive physical activities within one week prior to the 
administration of trial medication or during the trial
18. Inability to comply with the dietary regimen of the trial site
19. A marked baseline prolongation of QT/QTc interval (such as QTc intervals that 
are repeatedly greater than 450 ms in males or repeatedly greater than 470 ms in 
females) or any other relevant ECG finding at screening
20. A history of additional risk factors for Torsade de Pointes (such as heart failure, 
hypokalaemia, or family history of Long QT Syndrome)
21. Subject is assessed as unsuitable for inclusion by the investigator, for instance,
because the subject is not considered able to understand and comply with study 
requirements, or has a condition that would not allow safe participation in the 
study 
Female subjects will not be allowed to participate, if any of the following apply:
22. Positive pregnancy test, pregnancy, or plans to become pregnant within 30 days
after study completion
23. Lactation
In addition, the following trial-specific exclusion criteria apply:
24. Any lifetime history of suicidal behaviour (i.e. actual attempt, interrupted 
attempt, aborted attempt, or preparatory acts or behaviour)
25. Any suicidal ideation of type 2 to 5 on the C-SSRS in the past 12 months (i.e. 
active suicidal thought without method, intent or plan; active suicidal thought 
with method but without intent or plan; active suicidal thought with method and 


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intent but without specific plan; or active suicidal thought with method, intent 
and plan)
26. eGFR (CKD-EPI equation) < 80ml/min at screening
27. Liver tests (ALT, AST, GGT, AP), total bilirubin and creatinine outside the 
normal range at the screening examination 
28. History of relevant liver diseases such as disturbance of liver function, jaundice, 
drug induced liver injury, Dubin-Johnson syndrome, Rotor syndrome, or liver 
tumors
29. Any presence or history of a condition linked with significantly elevated urine 
pH, including but not limited to renal tubular acidosis (RTA), severe infections of 
the urinary tract with Proteus bacteria.
30. Concomitant use of hormonal replacement therapy or hormonal contraceptives
31. Vegetarian diet or the purpose to switch from carnivore to vegetarian diet is not 
allowed during this trial due to potential urine alkalization.
32. History of macular degeneration or any abnormal finding in visual tests (Amsler 
grid test, colour discrimination test) at screening
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 
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 
5.2.8.2.4.


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3.3.4.1
Discontinuation of trial treatment
An individual subject will discontinue trial treatment if:
1. The subject wants to discontinue trial treatment, without the need to justify the 
decision
2. The subject has repeatedly shown to be non-compliant with important trial 
procedures and, in the opinion of both, the investigator and sponsor representative, 
is not willing or able to adhere to the trial requirements in the future.
3. The subject needs to take concomitant medication that interferes with the 
investigational medicinal product or other trial treatment
4. The subject can no longer receive trial treatment for medical reasons (such as 
pregnancy, surgery, adverse events [AEs], or diseases)
5. 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
6. 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.
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:
1. Failure to meet expected enrolment goals overall or at a particular trial site
2. New toxicological findings, serious adverse events, or any safety information
invalidating the earlier positive benefit-risk-assessment. More specifically, the 


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trial will be terminated if more than 50% of the subjects have drug-related and 
clinically relevant adverse events of moderate or severe intensity, or if at least 1 
drug-related serious adverse event is reported
3. Violation of GCP, or the CTP, or the contract with BI impairing the appropriate 
conduct of the trial
4. The sponsor decides to discontinue the further development of the investigational 
product
The investigator / trial site will be reimbursed for reasonable expenses incurred in case of 
trial termination (except if item 3 applies).
3.3.5
Replacement of subjects
In case more than 2 subjects discontinue the trial, the Clinical Trial Leader together with the 
Trial Pharmacokineticist and the Trial Statistician are to decide, if and how many subjects 
will be replaced. 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 
(Memantine).
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:
1-0-0
Route of administration:
Oral
Duration of use:
Period 1 = Visit 2
Days 1-10: multiple doses of 25 mg BI 425809 q.d.
Period 3 = Visit 4
Days 1-10: multiple doses of 25 mg BI 425809 q.d.
Trial product 2:
Name:
Memantine 
(Startpackung and 20 mg Filmtabletten)
Substance:
Memantine
Pharmaceutical formulation:
Film coated tablet
Source:
Unit strength:
Memantine 
Startpackung
5 mg, 10 mg, 15 mg, 20 mg
Memantine 
20 mg Filmtabletten
20 mg
Posology:
1-0-0
Route of administration:
Oral
Duration of use:
Memantine 
Startpackung
Visit 3 = Period 2
Days 1-28:
During up-titration, 5 mg, 10 mg, 15 mg,
20 mg tablets will all be used as multiple
doses over 7 days 


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Memantine 
20 mg Filmtabletten
Days 29-35: Multiple doses of 20 mg tablets q.d.
Visit 4 = Period 3
Days 1-10:  Multiple doses of 20 mg tablets q.d.
4.1.2
Selection of doses in the trial
The memantine dose selected for this trial is the standard clinical dose [R18-3740, R18-3739]
and the chosen up-titration scheme is recommended to improve tolerability. The dose 
selected for 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
This is an open-label, three-period, fixed-sequence trial. All subjects 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 fulfil 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 is an open-label, three-period, one fixed sequence study. All subjects will receive 
the three treatments
The treatments to be evaluated are outlined in Table 4.1.4: 1 below.


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Table 4.1.4: 1
Dosage and treatment schedule
Treatment
Substance
Formulation
Unit strength
Dosage
Total
dose
R1 
(Reference 1)
BI 425809
Tablet
25 mg
1 tablet (Day 1-10/Visit 2) q.d.
250 mg
Up-titration 
to R2
Memantine
Tablet 
5 mg
1 tablet (Days 1-7/Visit 3) q.d.
35 mg
Memantine
Tablet 
10 mg
1 tablet (Days 8-14/Visit 3) q.d.
70 mg
Memantine
Tablet 
15 mg
1 tablet (Days 15-21/Visit 3) q.d.
105 mg
Memantine
Tablet 
20 mg
1 tablet (Days 22-28/Visit 3) q.d.
140 mg
R2
(Reference 2)
Memantine
Tablet 
20 mg
1 tablet (Days 29-35/Visit 3) q.d.
140 mg
T
(Test)
BI 425809
Tablet
25 mg
1 tablet (Day 1-10/Visit 4) q.d.
250 mg
Memantine
Tablet 
20 mg
1 tablet (Days 1-10/Visit 4) q.d.
200 mg
Administration of trial medication will be performed after subjects have fasted overnight; 
fasting is to start no later than 10 h before the scheduled dosing. 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.
Subjects will be kept under close medical surveillance until at least 25 h after administration
of BI 425809 alone and memantine alone on Day 1, Visit 2, and Day 1 Visit 3, respectively. 
Following the first combined administration of memantine and BI 425809 on Day 1 Visit 4, 
subjects will stay in the unit until at least 49 hours after administration.
The in-house surveillance period can be extended anytime if deemed necessary based on the 
medical judgement of the investigator.
During the first 4 h after drug administration on PK profile days (Day 1 and 10, Visit 2; Day 
1 and 35, Visit 3 and Day 10, Visit 4), subjects are not allowed to lie down (i.e. no 
declination of the upper body of more than 45 degrees from upright posture).
4.1.5
Blinding and procedures for unblinding
This Phase I trial will be handled in an open fashion throughout (that is, during the conduct,
including data cleaning and preparation of the analysis). This is considered acceptable 
because the potential for bias seems to be low and does not outweigh practical considerations.
Emergency envelopes will not be provided, because the dose of trial medication is known to 
investigators and subjects.


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4.1.6
Packaging, labelling, and re-supply
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 memantine, 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-
3740, R18-3739].
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 locally by the trial site upon written authorisation of 
the clinical trial leader. 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. There are no special emergency 
procedures to be followed. No additional treatment is planned. However, if adverse events 
require treatment, the investigator can authorise symptomatic therapy (for restrictions please 
refer to Section 4.2.2.1). In those cases, subjects will be treated as necessary and, if required, 
kept under supervision at the trial site or transferred to a hospital until all results of medical 
evaluations are acceptable.
In case of a memantine overdose, treatment should be symptomatic. No specific antidote for 
intoxication or overdose is available. Standard clinical procedures to remove active substance 
material, e.g. gastric lavage, carbo medicinalis (interruption of potential entero-hepatic 
recirculation), acidification of urine, forced diuresis should be used as appropriate [R18-3740, 
R18-3739].


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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:

Use of N-methyl-D-aspartate(NMDA)-antagonists such as amantadine, ketamine or 
dextromethorphan 

Active substances such as cimetidine, ranitidine, procainamide, quinidine, quinine and 
nicotine that use the same renal cationic transport system as amantadine 

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. 

Gastric buffers (such as sodium hydrogencarbonat) or other drugs which might result in 
urine alkalinization are not allowed in this trial. Urine alkalinization is known to reduce 
memantine elimination.

Paracetamol and diclofenac must be avoided as symptomatic therapy of AEs due to its 
potential liver toxicity.
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 will be instructed not to consume any foods or 
drinks other than those provided by the staff. Standardised meals will be served at standard 
times if not indicated otherwise in the Flow Chart.
On all dosing days, the trial medication will be administered after an overnight fast of at least 
10 h prior. Fluid intake is not allowed from 1 h pre-dose until drug administration.
On PK profile days (Day 1 and 10, Visit 2; Day 1 and 35, Visit 3 and Day 10, Visit 4) 
subjects will remain fasted until 4 hours after administration. 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.
From lunch until 24 h post-dose, subjects are advised that total fluid intake should be in the 
range of 2000 - 3000 mL.
On all other dosing days subjects have to remain fasted for 1 h after drug administration.


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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.
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.
A switch from carnivore to vegetarian diet is not allowed during this trial due to potential 
urine alkalinisation.
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 
and/or urinary excretion of trial medication will provide additional confirmation of 
compliance.
Subjects who are non-compliant (for instance, who do not appear for scheduled visits or 
violate trial restrictions) may be removed from the trial and the CRF will be completed 
accordingly (for further procedures, please see Section 3.3.4.1).


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5.
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 and informed consent, demographics including height and body weight, smoking 
and alcohol history (alcohol history will only be documented in the source documents),, 
relevant medical history and concomitant therapy, review of inclusion and exclusion criteria, 
visual tests, C-SSRS assessment, 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.
Only abnormal findings of the physical and neurological examination will be reported as 
AEs.
Results of neurological examinations will be kept in source data only, but not collected in the 
CRF.
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 
 
) 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 any time point 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.


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All test results will be documented in the source documents and entered into the 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.
5.2.3.1
Color discrimination test
Color vision will be tested using the Ishihara test for color deficiency.
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.
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.
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.
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).
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.
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).
5.2.4
Suicidality monitoring
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 


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developed for a psychiatric condition. This recommendation also refers to clinical trials in 
healthy volunteers with multiple dose administration of the IMP. 
The C-SSRS will be used as a monitoring tool as depression, suicidal ideation and suicide has 
been observed in Alzheimer patients treated with Memantine [R18-3740, R18-3739]. Further, 
with multiple doses of BI 425809, suicidal thoughts and behaviour will also be assessed by 
C-SSRS [R08-1147]. For details see Section 5.2.8.1.7. The original Columbia Suicidal 
Severity Rating scale is shown in Appendix 10.1.
C-SSRS will be performed at the times indicated in the Flow Chart.
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. 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. 
The eGFR based on the CDK-EPI creatinine equation [R13-3447] will be calculated at 
screening: 
eGFR 
= 141 x min(SCr/κ, 1)α x max(SCr /κ, 1)-1.209 x 0.993Age x 1.018 [if female] x 1.159 [if Black]
With 
eGFR (estimated glomerular filtration rate) = mL/min/1.73 m2
SCr (standardized serum creatinine) = mg/dL
κ = 0.7 (females) or 0.9 (males)
α = -0.329 (females) or -0.411 (males)
min = indicates the minimum of SCr/κ or 1
max = indicates the maximum of SCr/κ or 1
age = years


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Table 5.2.5: 1
Routine laboratory tests
Functional lab group
BI test name [comment/abbreviation]
A
B
C
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
Automatic WBC 
differential, relative 
Neutrophils/Leukocytes; Eosinophils/Leukocytes; Basophils/ 
Leukocytes; Monocytes/Leukocytes; 
Lymphocytes/Leukocytes 
X
X
X
Automatic WBC 
differential, absolute 
Neutrophil; Eosinophils; Basophils; Monocytes; 
Lymphocytes
X
X
X
Manual differential 
WBC (*if automatic
differential WBC is 
abnormal and seen 
as clinically relevant 
by 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.
X*
X*
X*
Coagulation
Activated Partial Thromboplastin Time 
Prothrombin time – INR (International Normalization Ratio)
Fibrinogen
X
X
X
X
X
X
X
X
X
Enzymes
AST [Aspartate transaminase] /GOT, SGOT 
ALT [Alanine transaminase] /GPT, SGPT
AP [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
Hormones
Thyroid Stimulating Hormone 
Free T3 - Triiodothyronine  
Free T4 – Thyroxine 
Estradiol (* if needed for confirmation of postmenopausal state)
FSH (* if needed for confirmation of postmenopausal state)
X
X
X
X*
X*
--
--
--
--
--
--
--
--
--
--
Substrates
Glucose (Plasma)
Creatinine 
eGFR 
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 


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Table 5.2.5: 1
Routine laboratory tests (cont.)
Functional lab group
BI test name [comment/abbreviation]
A
B
C
Electrolytes
Sodium
Potassium
Chloride
Calcium
X
X
X
X
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
Urine sediment 
(*microscopic 
examination if 
erythrocytes, 
leukocytes nitrite or 
protein are abnormal 
in urine)
Only positive findings will be reported (for instance, the 
presence of sediment bacteria, casts in sediment, squamous 
epithelial cells, erythrocytes, leukocytes)
X*
X*
X*
Pregnancy test (urine)
(*to be done as 
indicated by footnote 
5 in the Flow Chart)
Beta human chorionic gonadotropin (beta-HCG)
X
X*
X
A: parameters to be determined at Visit 1 (screening examination) 
B: parameters to be determined during Visit 2, Visit 3 and Visit 4 (for time points refer to Flow Chart)
C: parameters to be determined at Visit 5 (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 drug screening, it is planned to perform these tests during screening only. 
Drug screening will be performed at screening and prior to each admission to the unit.


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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)
To encourage compliance with alcoholic restrictions, a breath alcohol test (e.g. 
 
) will be performed at screening and at each admission to the 
trial site 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 
, with the 
exception of drug screening and pregnancy tests. These tests will be performed at the trial site 
using 
 and 
 
, 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 
 
) 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 
 
). 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). 
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 


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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). Additional (unscheduled) ECGs may be 
collected by the investigator for safety reasons.
5.2.7
Other safety parameters
Not applicable.
5.2.8
Assessment of adverse events
5.2.8.1
Definitions of adverse events
Adverse event
5.2.8.1.1
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
5.2.8.1.2
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 


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
Is deemed serious for any other reason if it is an important medical event when based 
upon appropriate medical judgment which may jeopardise the patient and may 
require medical or surgical intervention to prevent one of the other outcomes listed in 
the above definitions. Examples of such events are intensive treatment in an 
emergency room or at home for allergic bronchospasm, blood dyscrasias or 
convulsions that do not result in hospitalisation or development of dependency or 
abuse
AEs considered ‘Always Serious’
5.2.8.1.3
Cancers of new histology and exacerbations of existing cancer must be classified as a serious 
event regardless of the time since discontinuation of the trial medication and must be reported 
as described in Section 5.2.8.2, 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
5.2.8.1.4
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 5.2.8.2.2.
The following are considered as AESIs:

Hepatic injury
A hepatic injury is defined by the following alterations of hepatic laboratory 
parameters: 
o
An elevation of AST (aspartate transaminase) and/or ALT (alanine 
transaminase) ≥3-fold ULN combined with an elevation of total bilirubin 
≥2-fold ULN measured in the same blood sample, or
o
Aminotransferase (ALT, and/or AST) elevations ≥10 fold ULN
These lab findings constitute a hepatic injury alert and the subjects showing these lab 
abnormalities need to be followed up according to the ‘DILI checklist’ provided in the 
ISF. 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 


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test. Should the results meet the criteria of hepatic injury alert, the procedures 
described in the DILI checklist should be followed.
Intensity (severity) of AEs
5.2.8.1.5
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
5.2.8.1.6
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)


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
Disappearance of the event even though the trial drug treatment continues or remains 
unchanged
Suicidal risk assessed by the C-SSRS 
5.2.8.1.7
The C-SSRS is a semi-structured, investigator-rated interview, developed by clinical experts 
in cooperation with the FDA, assessing both suicidal behavior and suicidal ideation. It does 
not give a global score, but provides some categorical and some severity information 
specifically for behavior and ideation.
The C-SSRS interview may be administered by any type of physician, psychologist, clinical 
social worker, mental health counselor, nurse, or coordinator with C-SSRS training. It has a 
typical duration of five minutes, and causes only a low burden on subjects. At a minimum, 
the interview consists of 2 screening questions related to suicidal ideation and 4 related to 
suicidal behavior, and may be expanded to up to 17 items in case of positive responses. Free 
text entries are allowed for; the investigator has to directly evaluate the scale and write a 
report.
The C-SSRS has been widely used in large multinational clinical trials. The C-SSRS will be 
administered at the screening visit (using the ‘screening/baseline’ version) with the aim to 
exclude subjects with active moderate or severe symptomatology within a specified time 
prior to the screening or baseline visit. The life time history of suicidal ideation and behavior 
will also be recorded.
After the baseline visit the assessment ‘since last visit’ will be performed at each clinic or 
phone visit (‘since last visit’ version). The investigator is to review positive and negative 
reports for plausibility and clinical relevance. Doubtful reports may be repeated or reports
may be validated by a consulting psychiatrist. If there is a confirmed positive report of 
suicidal behavior or suicidal ideation type 4 or 5 after start of trial, the investigator is to 
immediately interview the subject during the clinic visit, and/or is to consult a psychiatrist. 
If the positive report is confirmed, appropriate actions for the subject’s safety have to be 
initiated.
All C-SSRS reports of suicidal ideation type 4 or 5 and all reports of suicidal behaviour must 
be reported as separate SAEs by the investigator. For ‘Self-injurious behaviour, no suicidal 
intent’ (Type 11) standard AE / SAE reporting rules are to be applied.
For each negative report (suicidal ideation type 1, 2 or 3) after start of the trial, the
investigator is to decide based on clinical judgment whether it represents an adverse event 
(AE) as defined in the protocol, and if it is considered an AE then it must be reported 
accordingly.
5.2.8.2
Adverse event collection and reporting
AE collection
5.2.8.2.1
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. 


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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.
AE reporting to the sponsor and timelines
5.2.8.2.2
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
5.2.8.2.3
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.


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Pregnancy
5.2.8.2.4
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.
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 and urine samples will be collected at the time 
points / time intervals indicated in the Flow Chart. The actual sampling times will be 
recorded and used for determination of pharmacokinetic parameters.
5.3.2
Methods of sample collection
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.
5.3.2.1
Blood sampling for pharmacokinetic analysis of BI 425809
For quantification of BI 425809 concentrations in plasma, 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 


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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.
5.3.2.2
Blood sampling for pharmacokinetic analysis of memantine
For quantification of memantine plasma concentrations, 2.7 mL of blood will be taken from 
an antecubital or forearm vein into a Li-Hep (Lithium-Heparin)-anticoagulant blood drawing 
tube at the times indicated in the Flow Chart. Blood will be withdrawn by means of either an 
indwelling venous catheter or by venipuncture with a metal needle. The Li-Hep-
anticoagulated blood samples will be centrifuged for about 10 min at about 2000 g to 4000 g 
and 4 to 8 °C. Two plasma aliquots containing at least 0.5 mL will be obtained and stored in 
polypropylene tubes. Within a maximum time of 2 hours after sampling at room temperature, 
the samples should be stored in a freezer. Plasma samples will be stored frozen in an upright 
position at about –20°C or below until shipment on dry ice to the analytical laboratory. At the 
analytical laboratory, the plasma samples will be stored at about –20°C or below until 
analysis.
5.3.2.3
Urine sampling for pharmacokinetic analysis of memantine
A blank urine sample will be collected before administration of trial medication (within 2 h 
before drug dosing) and two 0.5 mL aliquots will be retained to check for analytical 
interference by concomitant or rescue medication.
All urine voided during the sampling intervals indicated in the Flow Chart will be collected in
2 L polyethylene (PE) containers and stored at room temperature. Subjects are told to empty 
their bladders at the end of each sampling interval. In order to facilitate urine sampling, 
subjects will be advised to drink at least 100 mL water before the end of each urine sampling 
interval.
Due to the known adsorption of the drug (its metabolites) to the container wall, 10 mL of 
10% Tween 20 solution will be added to each 2 L PE collection container prior to the start of 
urine sampling. The weight of the empty container will be determined, thereafter 10 mL of 
10% Tween 20 will be added, and the weight of the container at the end of each sampling 
interval will be determined.
The urine weight/volume for each collection interval will be documented (however, no 
correction for the specific gravity of urine is done, i.e. 1 L is defined to be equal to 1 kg).
Two 0.5 mL aliquots will be stored in PP tubes for bioanalytical measurements. If more than 
one collection container is used in a sampling interval, the contents of all containers have to 
be mixed before aliquots are prepared. Mixing should be done by transferring the entire 
content of all collection containers into a single PE/PP or glass container, and stirring the 
mixed fractions for about 1 min (manually or using a stir bar or other stirring device made of 


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PE, PP, Teflon, or glass). Generally, the collection container should be shaken upon addition 
of every urine fraction to ensure proper distribution of Tween and urine.
At a minimum, the sample tube labels should list BI trial number, subject number, visit, and 
planned collection time.
Until transfer on dry ice to the analytical laboratory, the urine samples will be stored at
approximately -20C or below at the trial site. The second aliquot will be transferred after the 
bioanalyst has acknowledged safe arrival of the first aliquot. At the analytical laboratory, the 
urine samples will be stored at approximately -20°C or below until analysis.
After completion of the trial, the urine samples may be used for further methodological 
investigations, e.g. for stability testing, assessment of metabolites. However, only data related 
to the analyte and/or its metabolite(s) will be generated by these additional investigations. 
The study samples will be discarded after completion of the additional investigations but not 
later than 5 years after the CTR has been archived.
5.3.3
Analytical determinations
5.3.3.1
Analytical determination of BI 425809 and memantine plasma concentration
BI 425809 and memantine 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.
5.3.3.2
Analytical determination of memantine urine concentration
The memantine concentration PK urine study samples will be determined by validated liquid 
chromatography tandem mass spectrometry assays (LC-MS/MS) at a contracted laboratory 
with given authorization by BI. All details of the analytical method will be available prior to 
the start of sample analysis.
5.3.4
Pharmacokinetic - pharmacodynamic relationship
No analysis of the relationship between pharmacokinetic and pharmacodynamic parameters is 
planned for this trial.
5.4
ASSESSMENT OF BIOMARKER
Not applicable.
5.5
BIOBANKING
Not applicable.
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 


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laboratory values, and ECG parameters that might occur because 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, i.e. marked as “pre-dose” (footnote 2 in the Flow Chart) 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, ECG, and 
laboratory tests will be ± 30 min.
If scheduled in the Flow Chart at the same time as a meal, blood sampling, vital signs, visual 
tests, C-SSRS and 12-lead ECG recordings have to be done first. Furthermore, if several 
measurements including venepuncture are scheduled for the same time, venepuncture should 
be the last of the measurements due to its inconvenience to the subject and possible influence 
on physiological parameters.
For planned blood sampling times and urine collection intervals, 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 assessment and physical and neurological examination, refer to 
Sections 5.2.3 to 5.2.8.
6.2.2
Treatment periods
Each subject is expected to participate in 3 treatment periods (Visit 2 - 4).
In the evening of Day -1, and Day 9, Visit 2 study participants will be admitted to the trial 
site and kept under close medical surveillance until at least 24 h after drug administration on 
Day 1 and Day 10, respectively. 
During Visit 3, subjects will be admitted to the trial site on Day 1 in the morning and remain 
in-house up to 25 h after the first memantine administration on Day 1, Visit 3. In the evening 
of Day 34, Visit 3, subjects will again be admitted and stay under close medical surveillance 
until at least 49 h after the first combined administration of BI 425809 and memantine on 


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Day 1, Visit 4. They will be readmitted to the trial site in the evening of Day 9, Visit 4 and 
discharged not earlier than 24 h after the last drug administration of this trial.
At each discharge subjects will be allowed to leave the trial site after formal assessment and 
confirmation of their fitness. On all other study days, subjects will be treated in an 
ambulatory fashion.
The in-house surveillance period can be extended anytime if deemed necessary based on the 
medical judgement of the investigator. 
For details on time points and procedures for collection of plasma and urine 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.
On day 18 of Visit 4 (= Period 3) subjects will be contacted by phone and questioned about 
their well-being.
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 5.2.2 to 5.2.8.
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

25 mg of BI 425809 in Steady State when given alone (Reference 1, R1)
compared with co-administration of 25 mg of BI 425809 and 20 mg of 
memantine both in Steady State (Test, T),
and the relative bioavailability of 

20 mg of memantine in Steady State when given alone (Reference 2, R2)
compared with co-administration of 25 mg of BI 425809 and 20 mg of 
memantine both in Steady State (Test, T),
following oral administration on the basis of the primary 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. 
A further objective is to evaluate and compare further pharmacokinetic parameters between
the treatments. These pharmacokinetic parameters will be assessed by descriptive statistics.
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 memantine and the relative bioavailability of memantine administered 
alone compared with co-administration with BI 425809 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 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 and 
was not excluded due to a protocol deviations relevant to the evaluation of PK or due 


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to PK non-evaluability (as specified in the following 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 will 
include effects accounting for the following sources of variation: subjects and treatment. The 
effect ’subjects’ will be considered as random, whereas the effect ‘treatment’ will be 
considered as fixed. The model is described by the following equation:
ykm = + sm + k + ekm, where
ykm = logarithm of response measured on subject m receiving treatment k,
= the overall mean,
sm = the effect associated with 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) 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.
Further exploratory analyses
The same statistical models as stated above will be repeated for the primary endpoints but 
with all sources of variation (subjects, treatment) considered as fixed effects.
In addition to the model based approach all parameters will be calculated and analysed 
descriptively.
7.3.2
Secondary endpoint analyses
Not applicable.


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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.
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 5.2.8.1), and 
other significant AEs (according to ICH E3) will be listed separately. 
Previous and concomitant therapies will be presented per treatment group without 
consideration of time intervals and treatment periods.
Laboratory data will be compared to their reference ranges. Values outside the reference 
range as well as values defined as possibly clinically significant will be highlighted in the 
listings. Additionally, differences from baseline will be evaluated.
Vital signs or other safety-relevant data will be assessed with regard to possible on-treatment 
changes from baseline.


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Relevant ECG findings will be reported as AEs.
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 AE, the completed forms will be stored at the 
site.
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 16 subjects in the trial, because this sample size is considered 
sufficient to achieve the aims of this exploratory trial. With this sample size, the following 
precision in estimating the ratio of geometric means (test/reference) can be expected with 
95% probability. Precision is defined as the ratio of upper CI limit to the relative BA 
estimate. Note that the precision is independent of the actual ratio of geometric means.
The observed intra-individual coefficient of variation (gCV) for BI 425809 in the DDI study 
with itraconazole [c03355329] was roughly 11% for Cmax and 24% for AUC. An intra-
individual variability of 7.7% was observed for memantine [R19-0656].
For various assumptions around the gCV of 24%, Table 7.7: 1 provides an overview of the 
achievable precision for estimating the ratio of geometric means (test/reference). For 
illustrative purposes, the expected 90% confidence intervals are displayed for different values 
of the ratios T/R of geometric means.


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Table 7.7: 1
Precision that can be expected with 95% probability and illustrative 
two-sided 90% confidence intervals around the ratios of geometric 
means (T/R) for different gCVs in a one fixed sequence design trial
Drug
gCV [%]
Sample Size
Precision**
Ratio [%]*
Lower CL [%]
Upper CL [%]
BI 425809
22.0
12
1.238
100
80.80
123.76
14
16
18
1.210
82.63
121.03
1.190
84.03
119.00
1.174
85.16
117.42
24.0
12
1.261
100
79.29
126.12
14
1.231
81.24
123.09
16
1.208 
82.75 
120.85 
18
1.191
83.96
119.10
26.0
12
1.285
100
77.82
128.50
14
1.252
79.89
125.17
16
1.227
81.49
122.71
18
1.208 
82.78 
120.80 
Memantine
7.7
12
1.078
100
92.74
107.83
14
1.070
93.47
106.98
16
1.063
94.03
106.34
18
1.058
94.48
105.84
* Ratio of geometric means (test/reference) for a PK endpoint is defined by exp(T)/exp(R).
**Defined as ratio of upper CL and relative BA estimate.
The expected 90% confidence interval limits in the table were derived by
CI limit, = exp(ln(θ) ± ω),
with θ being the ratio (T/R) on original scale and ω the distance from the estimate θ to either 
confidence interval limit on the log-scale, which was obtained from the achievable precision 
on the original scale.
The calculation was performed as described by Julious [R11-5230] using R Version 3.5.1.


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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. As a general rule, no trial results should be 
published prior to archiving of the CTR.
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. As treatment assignments will 
be known to investigators, rules about emergency code breaks are not applicable (see 
Section 4.1.5). 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)


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
Dates of subject’s visits, including dispensing of trial medication

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.


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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.
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 
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.


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The EC/competent authority will be notified about the trial milestones according to the laws 
of the member state.
A final report of the clinical trial data will be written only after all subjects have completed 
the trial, so that all data can be incorporated and considered in the report.
The sponsor will submit to the EU database a summary of the final trial results within one 
year from the end of a clinical trial as a whole.
8.7
ADMINISTRATIVE STRUCTURE OF THE TRIAL
The trial is sponsored by Boehringer Ingelheim (BI).
The trial will be conducted at 
under 
the supervision of the Principal Investigator. Relevant documentation on the participating 
(Principal) Investigators (e.g. their curricula vitae) will be filed in the ISF.
BI has appointed a Clinical trial leader (CTL), 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, Clinical Research Associates (CRA), 
and investigators of participating trial sites
BI 425809 will be provided by the Clinical Trial Supplies Unit, BI Pharma GmbH & Co. 
KG, Biberach, Germany. Marketed memantine will be sourced locally by the clinical trial 
site from public pharmacy.
Safety laboratory tests will be performed by the local laboratory of the trial site 
Analyses of BI 425809 in plasma and memantine concentrations in plasma and urine will be 
performed at the
On-site monitoring will be performed by BI or a contract research organisation appointed by 
BI.
Data management and statistical evaluation will be done by BI or a contract research 
organisation 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
P04-11747
Micuda S, Mundlova L, Anzenbacherova E, Anzenbacher P, Chladek J, Fuksa 
L, Martinkova J. Inhibitory effects of memantine on human cytochrome P450 
activities: prediction of in vivo drug interactions. Eur J Clin Pharmacol 2004. 
60(8):583-589.
P12-05791
Guidance for industry: drug interaction studies - study design, data analysis, 
implications for dosing, and labeling recommendations (draft guidance, 
February 2012 (this guidance document is being distributed for comment 
purposes only)). 
http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInform
ation/Guidances/ucm292362.pdf (access date: 14 May 2012) ; U.S. 
Department of Health and Human Services, Food and Drug Administration, 
Center for Drug Evaluation and Research (CDER); 2012.
P13-15942
Pope LE, Schoedel KA, Bartlett C, Sellers EM  A study of potential 
pharmacokinetic and pharmacodynamic interactions between 
dextromethorphan/quinidine and memantine in healthy volunteers. Clin Drug 
Invest 32 (8), e1 - e15 (2012).
P14-08681
European Medicines Agency (EMA). Committee for Human Medicinal 
Products (CHMP): guideline on the investigation of drug interactions, final 
(21 June 2012, CPMP/EWP/560/95/Rev. 1 Corr.) (this guideline replaces 
guideline CPMP/EWP/560/95). http://www.ema.europa.eu/docs/en 
_GB/document_library/Scientific_guideline/2012/0 7/WC500129606.pdf 
(access date: 4 June 2014) ; London: European Medicines Agency (EMA); 
2012.
P17-09169
Caraci F, Sultana J, Drago F, Spina E Clinically relevant drug interactions 
with anti-Alzheimer's drugs.CNS Neurol Disord Drug Targets 16 (4), 501 -
513 (2017).
P18-12042
Schmitt F, Ryan M, Cooper G.  A brief review of the pharmacologic and 
therapeutic aspects of memantine in Alzheimer's disease. Expert Opin Drug 
Metab Toxicol 2007;3(1):135-141.
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.


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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/Guida
nces/UCM22 5130.pdf (access date: 5 October 2012); 2012.
R13-3447
Levey AS, de Jong P, Coresh J, El Nahas M, Astor BC, Matsushita K, 
Gansevoort RT, Kasiske BL, Eckardt K. The definition, classification, and 
prognosis of chronic kidney disease: a KDIGO Controversies Conference 
report. Kidney International (2011) 80, 17–28.
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.
R15-0935
Busch AE, Karbach U, Miska D, Gorboulev V, Akhoundova A, Volk C, Arndt 
P, Ulzheimer JC, Sonders MS, Baumann C, Waldegger S, Lang F, Koepsell H. 
Human neurons express the polyspecific cation transporter hOCT2, which 
translocates monoamine neurotransmitters, amantadine, and memantine. Mol 
Pharmacol 1998;54(2):342-352.
R17-3276
Mueller F, Weitz D, Derdau V, Sandvoss M, Mertsch K, Koenig J, et al.  
Contribution of MATE1 to renal secretion of the NMDA receptor antagonist 
memantine. Mol Pharm 2017;14(9):2991-2998.
R18-0242
Guidance for industry: in vitro metabolism- and transporter-mediated drug-
drug interaction studies (draft guidance, this guidance document is being 
distributed for comment purposes only) (October 2017, clinical 
pharmacology). 
https://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInfor
mation/Guid ances/UCM581965.pdf (access date: 19 January 2018) ; U.S. 
Department of Health and Human Services, Food and Drug Administration, 
Center for Drug Evaluation and Research (CDER); 2017.
R18-3739
Memantine 
 20 mg, verschreibungspflichtig (Fachinformation, Stand der 
Information: 07/2017). 2017.
R18-3740
Memantine
Startpackung 
 verschreibungspflichtig 
(Fachinformation, Stand der Information: 07/2017). 2017.


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R18-3925
Moskal JR, Burch R, Burgdorf JS, Kroes RA, Stanton PK, Disterhoft JF, et al. 
GLYX-13, an NMDA receptor glycine site functional partial agonist enhances 
cognition and produces antidepressant effects without the psychotomimetic 
side effects of NMDA receptor antagonists. Expert Opin Invest Drugs 
2014;23(2):243-254.
R19-0656
Chladek J, Zaludek B, Sova P, Franc A, Sispera L, Martinkova J, et al. 
Steady-state bioequivalence studies of two memantine tablet and oral solution 
formulations in healthy volunteers. J Appl Biomed 2008;6:39-45.


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10.
APPENDICES
10.1
COLUMBIA-SUICIDE SEVERITY RATING SCALE


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11.
DESCRIPTION OF GLOBAL AMENDMENTS
11.1
GLOBAL AMENDMENT 1
Date of amendment
27 May 2019
EudraCT number
EU number
2019-000468-36
BI Trial number
1346-0039
BI Investigational Medicinal 
Product(s)
BI 425809
Title of protocol
A study to investigate the effects of memantine on 
the pharmacokinetics of BI 425809 and vice versa in 
healthy male and female subjects (non-randomized, 
single-arm, open-label, three-period, one fixed 
sequence cross-over study)
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 3.1
3. Section 5.2.8.1.7
4. Appendix 1.1
Description of change
1. a) Errors in the planned times and time points of 
    the C-SSRS assessments were corrected. 
b) By mistake, 3 memantine PK samples on day 
10, period 3, visit 4 at 219:30, 220:30 and 
221:00 were not entered in the Flow Chart of 
the CTP 1.0. This was corrected.
2. The size of possible cohorts was added and the 
risk assessment of this design was further 
specified.
3./4.The Screening version of the C-SSRS was 
    replaced by the Screening/Baseline version of the   
    C-SSRS as this is the correct version to be used.
Rationale for change
Based on EC feedback section 3.1 was revised as 
recommended.
3 PK samples of memantine were added that were by 
mistake not included in the original CTP. This 
correction was needed to align the sampling scheme 
for memantine in order to guarantee comparability of 


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profiles following administration of memantine 
alone and in combination with BI 425809.
In addition, some errors/typos were corrected.


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11.2
GLOBAL AMENDMENT 2
Date of amendment
19 July 2019
EudraCT number
EU number
2019-000468-36
BI Trial number
1346-0039
BI Investigational Medicinal 
Product(s)
BI 425809
Title of protocol
A study to investigate the effects of memantine on 
the pharmacokinetics of BI 425809 and vice versa in 
healthy male and female subjects (non-randomized, 
single-arm, open-label, three-period, one fixed 
sequence cross-over study)
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. Title page
2. Flow chart
3. Table 5.2.5: 1
4. Section 5.2.3
Description of change
1. Clinical Trial Leader was changed to
 new contact details were provided.
2. In the listing of SCR procedures under footnote 1, 
visual tests and C-SSRS were missing. Footnote 8 
was missing for the PK sample on Day 2, Visit 2. 
These were corrected.
3. A reference to the pregnancy test, indicating that
tests are to be done as per footnote 5 in the Flow 
Chart, was missing. This was corrected.
4. For visual tests, a reference to any time point as 
per the Flow Chart was added instead of SCR and 
EOT.
Rationale for change
1. The study has been handovered to
2./3. Addition of the missing data.
4. Correction of errors/typos.


 
 
 
 
APPROVAL / SIGNATURE PAGE 
 
Document Number: 
 
Technical Version Number:
 
Document Name: 
 
 
 
                                                                                                                 
 
Title: 
 
 
 
 
                                                                                                                   
 
Signatures (obtained electronically) 
 
Meaning of Signature  
Signed by 
Date Signed 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
c26441810
3.0
clinical-trial-protocol-version-03
A study to investigate the effects of memantine on the pharmacokinetics of BI
425809 and vice versa in healthy male and female subjects (non-randomized,
single-arm, open-label, three-period, one fixed sequence cross-over study)
Author-Trial Clinical
Pharmacokineticist
19 Jul 2019 10:30 CEST
Author-Clinical Trial Leader
19 Jul 2019 10:32 CEST
Author-Trial Statistician
22 Jul 2019 09:49 CEST
Approval-Therapeutic Area
23 Jul 2019 11:26 CEST
Verification-Paper Signature
Completion
25 Jul 2019 11:26 CEST
Approval-Team Member Medicine
25 Jul 2019 16:34 CEST


Boehringer Ingelheim 
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Document Number: 
 Technical Version Number:
 
 
 
(Continued) Signatures (obtained electronically) 
 
Meaning of Signature  
Signed by 
Date Signed 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
c26441810
3.0

SAP_000.pdf: 
TITLE PAGE
TRIAL STATISTICAL ANALYSIS PLAN
c30114925-01
BI Trial No.:
1346-0039
Title:
A study to investigate the effects of memantine on the 
pharmacokinetics of BI 425809 and vice versa in healthy male and 
female subjects (nonrandomized, single-arm, open-label, three-
period, one fixed sequence cross-over study)
Including Protocol Amendment 2 [c26441810-02]
Investigational
Product:
BI 425809
Responsible trial 
statistician:
Phone: +
Fax: +
Date of statistical 
analysis plan:
22 NOV 2019 SIGNED
Version:
Final
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1.
TABLE OF CONTENTS
TITLE PAGE ...........................................................................................................................1
1.
TABLE OF CONTENTS......................................................................................2
LIST OF TABLES...................................................................................................................4
2.
LIST OF ABBREVIATIONS ..............................................................................5
3.
INTRODUCTION.................................................................................................7
4.
CHANGES IN THE PLANNED ANALYSIS OF THE STUDY......................8
5.
ENDPOINTS .........................................................................................................9
5.1
PRIMARY 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
6.
GENERAL ANALYSIS DEFINITIONS ..........................................................11
6.1
TREATMENTS...................................................................................................11
6.2
IMPORTANT PROTOCOL DEVIATIONS....................................................13
6.3
SUBJECT SETS ANALYSED...........................................................................14
6.5
POOLING OF CENTRES .................................................................................15
6.6
HANDLING OF MISSING DATA AND OUTLIERS....................................15
6.7
BASELINE, TIME WINDOWS AND CALCULATED VISITS ...................15
7.
PLANNED ANALYSIS......................................................................................16
7.1
DEMOGRAPHIC AND OTHER BASELINE CHARACTERISTICS.........16
7.2
CONCOMITANT DISEASES AND MEDICATION .....................................17
7.3
TREATMENT COMPLIANCE........................................................................17
7.4
PRIMARY ENDPOINTS...................................................................................17
7.4.1
Primary analysis of the primary endpoints......................................................17
7.4.2
Sensitivity analysis, subgroup analysis, exploratory analysis of the 
primary endpoint ................................................................................................18
7.5
SECONDARY ENDPOINTS.............................................................................18
7.5.1
Key secondary endpoints....................................................................................18
7.5.2
Secondary endpoints...........................................................................................18
7.6.2
Safety parameters ...............................................................................................18
7.7
EXTENT OF EXPOSURE.................................................................................18
7.8
SAFETY ANALYSIS..........................................................................................18


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7.8.1
Adverse Events ....................................................................................................18
7.8.2
Laboratory data ..................................................................................................20
7.8.3
Vital signs.............................................................................................................20
7.8.4
ECG......................................................................................................................21
7.8.5
Others...................................................................................................................21
10.
HISTORY TABLE..............................................................................................24


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LIST OF TABLES
Table 6.1: 1 Dosage and treatment schedule............................................................................11
Table 6.1: 2
Analysis phases for statistical analysis of AEs, vital signs and safety 
laboratory data ..................................................................................................12
Table 6.2: 1
Handling of IPDs..............................................................................................14
Table 6.3: 1
Subject sets analyzed........................................................................................14
Table 10: 1
History table .....................................................................................................24


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2.
LIST OF ABBREVIATIONS
Term
Definition / description
AE
Adverse Event
AESI
Adverse event of special interest
ALT
Alanine aminotransferase
ANOVA
Analysis of variance
AST
Aspartate aminotransferase
AUCτ,ss
area under the concentration-time curve of the analyte in plasma at steady
state over a uniform dosing interval τ
BI 
Boehringer Ingelheim
BP
Blood pressure
Cmax,ss
maximum measured concentration of the analyte in plasma at steady state 
over a uniform dosing interval τ
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
RPM
Report planning meeting
SAE
Serious adverse event
SD
Standard Deviation
SOC
System Organ Class
TS
Treated set
TSAP
Trial Statistical Analysis Plan


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Term
Definition / description
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 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 and memantine, as defined in Section 2.1.2 
of the CTP:

AUCτ,ss (area under the concentration-time curve of the analyte in plasma at steady
state over a uniform dosing interval τ)

Cmax,ss (maximum measured concentration of the analyte in plasma at steady state over
a uniform dosing interval τ)
5.2
SECONDARY ENDPOINTS
5.2.1
Key secondary endpoints
Not applicable.
5.2.2
Secondary endpoints
Not applicable.
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

12-lead ECG (only abnormal findings will be reported as AE)

Visual tests (only abnormal findings will be reported as AE)

Vital signs (blood pressure, pulse rate)

Suicidality assessment (C-SSRS)


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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 three subsequent treatment periods in a fixed sequence 
order. There will be a washout-period of at least 7 days between treatment period 1 and 2. 
Between treatment period 2 and 3 there will be no washout-period.
All subjects will receive multiple doses of BI 425809 alone in the first period, multiple doses 
of memantine alone in the second period and then multiple doses of BI 425809 and 
memantine combined in the third period.
Table 6.1: 1 Dosage and treatment schedule 
Treatment 
Substance
Formulation
Unit 
strength
Dosage
Total dose
R1 (Reference 1)
BI 425809
Tablet
25 mg
1 tablet (Day 1-10, Visit 2) q.d.
250 mg
Up-titration to R2
R2 (Reference 2)
Memantine
Tablet
5 mg
10 mg
15 mg
20 mg
20 mg
1 tablet (Day 1-7, Visit 3) q.d.
1 tablet (Day 8-14, Visit 3) q.d.
1 tablet (Day 15-21, Visit 3) q.d.
1 tablet (Day 22-28, Visit 3) q.d.
1 tablet (Day 29-35, Visit 3) q.d.
35 mg
70 mg
105 mg
140 mg
140 mg
T (Test)
BI 425809
Memantine
Tablet
Tablet
25 mg
20 mg
1 tablet (Day 1-10, Visit 4) q.d.
1 tablet (Day 1-10, Visit 4) q.d.
250 mg
200 mg
For statistical analyses of AEs, vital signs and safety laboratory data the following separate 
analysis phases will be defined for each subject:


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Table 6.1: 2
Analysis phases for statistical analysis of AEs, vital signs and safety laboratory
data
Study analysis 
phase
Label
Start
End
Screening
Screening
Date of informed consent
Date/time of first administration 
of BI 425809
On treatment 
BI 425809
BI
Date/time of first administration 
of BI 425809
Date/time of first administration 
of memantine
On treatment 
memantine
Mem
Combination of two phases:
First phase:
Date/time of last administration 
of BI 425809 alone + 
 
(i.e. REP of BI 425809 of
 
Second phase:
Date/time of last administration 
of BI 425809 + memantine 
 (i.e. REP of BI 
425809 
Combination of two phases:
First phase:
Date/time of first administration 
of BI 425809 + memantine
Second phase:
Date/time of last administration 
of BI 425809 + memantine 
+ 21*24h (i.e. REP of memantine 
of 21 days) or
00:00 a.m. on day after subject's 
trial termination date
whatever occurs earlier
On treatment 
BI 425809+
memantine
BI + Mem
Combination of two phases:
First phase:
Date/time of first administration 
of memantine
Second phase:
Date/time of first administration 
of BI 425809 + memantine
Combination of two phases:
First phase:
Date/time of last administration of 
BI 425809 alone 
 (i.e. 
REP of BI 425809 
Second phase:
Date/time of last administration 
of BI 425809 + memantine 
 (i.e. REP of BI 425809 
 
Follow-up
F/U
Date/time of last administration 
of BI 425809 + memantine 
+ 21*24h (i.e. REP of 
memantine of 21 days)
00:00 a.m. on day after subject's 
trial termination date
The planned duration of the analysis phase of BI 425809 is at least 17 days, of memantine it is 
41 days and of memantine + BI it is 25 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", defined as the total over all on-treatment phases

"Total BI", defined as the total over all on-treatment phases involving BI


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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 the analyses or whether it must be 
corrected in the clinical database. Each protocol deviation must be assessed to determine 
whether it is an important 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 which are considered to be IPDs in this trial are defined in the 
integrated quality and risk management plan (IQRMP). If the data show other IPDs, the 
definition in the IQRMP 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 Not Met
PKS
B1
Informed consent not available/not 
done
TS, PKS
B2
Informed consent too late
None
C1
Non-compliance
PKS
C2
Incorrect trial medication taken
PKS
C3
Incorrect intake of trial medication
PKS
C4
Improper washout between treatments
PKS
D1
Prohibited medication use
PKS
D2
Improper washout of concomitant 
medication
PKS
E1
Certain violations of procedures used to 
measure primary or secondary data
PKS
F1
Certain violations of time schedule used
to measure primary or secondary data
PKS
G1
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
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 study 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 sequence 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 of (T/R1) and (T/R2) 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".
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 


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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).
7.4.2
Sensitivity analysis, subgroup analysis, exploratory analysis of the primary 
endpoint
The same statistical model as used for the primary analysis (Sections 7.3.1 of the CTP) will be 
repeated for the primary endpoints but with all sources of variation ("subject", "treatment") 
considered as fixed effects.
Furthermore, primary PK endpoints will be assessed descriptively. The analysis of standard 
PK parameters is performed according to BI standards (4).
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
This section is not applicable as no secondary endpoint has been specified in the protocol.
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.


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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: 2
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.
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.


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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 laboratory values over time and for the difference from baseline (see 
Section 6.7) will be provided. Frequency tables of changes between baseline and last value on 
treatment with respect to the reference range will be presented.
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-
specific rules for flagging clinically significant values in an automated manner will not be 
applied in this study.
Clinically relevant findings in laboratory data will be reported as baseline conditions (prior to 
first administration of study treatment) or as AEs (after first administration of study treatment) 
if judged clinically relevant by the investigator, and will be analyzed as such.
7.8.3
Vital signs
The analyses of vital signs (blood pressure and pulse rate) will be descriptive in nature. 
Descriptive statistics of vital signs over time and for the difference from baseline (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 


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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 if 
applicable.
Visual test
Visual test will be performed as described in Section 5.2.3 of the CTP. 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 separately for colour discrimination test, visual 
acuity test and Amsler grid test and will also be summarized.
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 
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).


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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
22-NOV-19
None
This is the final TSAP