Clinical trial NCT02788513
Conditions: Alzheimer Disease
Sponsor: Boehringer Ingelheim
Start date: 2016-08-11; Completion date: 2019-10-11
Enrollment: 611 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
The study is designed to compare the effects of BI 425809 compared to placebo in patients with cognitive impairment due to Alzheimer's Disease.

Detailed description:

Arms: arm 1: None arm 2: None arm 3: None arm 4: None arm 5: None
Interventions: intervention 1: BI 425809 dose 1 intervention 2: BI 425809 dose 2 intervention 3: BI 425809 dose 3 intervention 4: BI 425809 dose 4 intervention 5: Placebo
Intervention descriptions: intervention 1: None intervention 2: None intervention 3: None intervention 4: None intervention 5: None

Protocol documents:
Prot_000.pdf: 
001-MCS-40-106-RD-03 (12.0) / Saved on: 30 Jan 2015
CLINICAL TRIAL PROTOCOL
TITLE PAGE
Document Number:
c03632269-05
EudraCT No.:
   2015-005438-24
BI Trial No.:
1346.23
BI Investigational 
Product(s):
BI 425809
Title:
A multi-centre, double-blind, parallel-group, randomised 
controlled study to investigate efficacy and safety of orally 
administered BI 425809 during a 12-week treatment period 
compared to placebo in patients with cognitive impairment due 
to Alzheimer’s Disease.
Brief Title:
BI 425809 in patients with cognitive impairment due to 
Alzheimer’s Disease
Clinical Phase:
II
Trial Clinical 
Monitor:
Phone: 
, Fax: 
Coordinating 
Investigator:
Phone: 
          Fax: 
Status:
Final Protocol (Revised Protocol (based on global amendment No. 4))
Version and Date:
Version: 5.0
Date: 12 Jul 2018
Page 1 of 77
Proprietary confidential information.
2018 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.


Boehringer Ingelheim
12 Jul 2018
BI Trial No.: 1346.23
c03632269-05
Trial Protocol
Page 2 of 77
Proprietary confidential information © 2018 Boehringer Ingelheim International GmbH or one or more of its affiliated companies
001-MCS-40-106-RD-03 (12.0) / Saved on: 30 Jan 2015
CLINICAL TRIAL PROTOCOL SYNOPSIS
Name of company:
Boehringer Ingelheim 
Name of finished product:
NA
Name of active ingredient:
BI 425809
Protocol date:
14 Apr 2016
Trial number:
1346.23
Revision date:
12 Jul 2018
Title of trial:
A multi-centre, double-blind, parallel-group, randomised controlled study to 
investigate efficacy and safety of orally administered BI 425809 during a 12-week 
treatment period compared to placebo in patients with cognitive impairment due to 
Alzheimer’s Disease.
Coordinating
Investigator:
Phone: 
                                 
Trial site(s):
Multi-centre, multi-national trial
Clinical phase:
II
Objective(s):
To assess safety, tolerability and efficacy of different doses of BI 425809 
compared to placebo in treatment of cognitive impairment due to Alzheimer’s 
Disease
Methodology:
Placebo-controlled, double-blind, double-dummy, randomized, parallel-group 
design comparison of 5 treatment groups over 12 weeks of treatment
No. of patients: 
~950 enrolled
total entered:
~585
each treatment:
~117
Diagnosis :
Patients with diagnosis of mild-to moderate Alzheimer’s Disease Dementia 
according to the recommendations from the National Institute on Aging-
Alzheimer’s Association workgroups on diagnostic guidelines for Alzheimer’s 
disease 
Main criteria
for inclusion:
The population will include male and female patients at least 55 years old with 
mild-to-moderate Alzheimer’s Disease Dementia. A MMSE (Mini-Mental-
State-Examination) score between 15-26 is required for inclusion. A caregiver 


Boehringer Ingelheim
12 Jul 2018
BI Trial No.: 1346.23
c03632269-05
Trial Protocol
Page 3 of 77
Proprietary confidential information © 2018 Boehringer Ingelheim International GmbH or one or more of its affiliated companies
001-MCS-40-106-RD-03 (12.0) / Saved on: 30 Jan 2015
Name of company:
Boehringer Ingelheim 
Name of finished product:
NA
Name of active ingredient:
BI 425809
Protocol date:
14 Apr 2016
Trial number:
1346.23
Revision date:
12 Jul 2018
has to be available for study site activities and on call by arrangement with the 
study site
Test product(s):
BI 425809
dose:
2mg QD, 5mg QD, 10mg QD, 25mg QD 
mode of 
administration:
Tablet, oral
Comparator 
products:
Placebo matching BI 425809 1mg and 5mg
And Placebo matching BI 425809 25 mg
dose:
Not applicable
mode of 
administration:
Tablet, oral
Duration of treatment:
12 weeks
Endpoints:
Primary endpoint:
1.
Change from baseline in ADAS-cog11 (Alzheimer’s Disease Assessment 
Scale-cognitive subscale) total score after 12-week treatment 
Secondary endpoints include: 
2.
Change from baseline in ADCS-ADL (Alzheimer’s Disease Cooperative 
Study/Activities of Daily Living) total score after 12-week treatment 
3.
CIBIC Plus total score after 12-weeks treatment 
Safety criteria:
Adverse event reporting, vital signs, ECG (digital) and standard laboratory tests, 
Columbia-Suicide Severity Rating Scale (C-SSRS).
Statistical methods:
The primary objective is to define a suitable dose for BI 425809 regarding efficacy 
and safety for further pivotal testing in Phase III. For this purpose, a multiple 
comparison procedure with modelling (MCPmod) approach is considered. The 
primary endpoint is mean change from baseline in ADAS-Cog11 total score after 12 
weeks of treatment. Comparisons between treatment groups will be exploratory in 
nature and based on the numerical comparison of the respective treatment 
differences including confidence intervals when appropriate.


Boehringer Ingelheim
12 Jul 2018
BI Trial No.: 1346.23
c03632269-05
Trial Protocol
Page 4 of 77
Proprietary confidential information © 2018 Boehringer Ingelheim International GmbH or one or more of its affiliated companies
001-MCS-40-106-RD-03 (12.0) / Saved on: 30 Jan 2015
FLOW CHART
Trial Period
Screening
Treatment Period
Follow-up
Visit
012
1
2
Baseline
3a9
3b9
3c9
4
5
EOT/
ED8
FU111
FU2
Study-Day (or duration during 
screening/ run-in)
Duration 
14 days
1
8
15
22
29 
57
85
EOT
+7
EOT
+28
Study Week
-2
1
2
3
4
8
12
13
16
Visit window (in days)
+7 to      
- 2820
±2
±2
±2
±5
±5
+5
+2
+5
Patient information & informed 
consent signed (including informed 
consent for PGx)1
X
Register Patient in IRT
X17
Randomisation (via IRT)
X18
Register Patient’s End of Study Call  
in IRT
X
Demographics (of patient and study 
partner)
X
Medical history / baseline conditions
X
In-/exclusion criteria 
X
X
X
Imaging of the Brain2
X
Concomitant medications13
X
X
X
X
X
X
X
X
X
X
X
Height (screening only)/weight
X
X
X
Vital signs
X
X
X
X9
X9
X
X
X
X
Physical examination
X
X
Neurological examination
X
X
Resting ECG (digital)
X
X16
X9, 16
X9, 16
X16
X16
X16
Adverse events
X
X
X
X
X9
X9
X
X
X
X
X
Dispense trial medication3
X
X
X
Last dose of trial medication
X
Collect study drug
X
X
X
Medication Compliance Check
X
X
X
Laboratory tests: Chemistry, 
haematology, urine analysis
X14
X
X
X
X
X
Urine drug screen
X
X
Neuropsychological Rating Scales19
MMSE
X
ADAS-cog11
X
X10
X10
X10
CIBIS
X10
CIBIC+
X10
ADCS-ADL
X
X10
X10
Prospective Suicidality 
Monitoring19
C-SSRS
X6
X7
X7
X7
X7
X7
X7
X7
X7
X7


Boehringer Ingelheim
12 Jul 2018
BI Trial No.: 1346.23
c03632269-05
Trial Protocol
Page 5 of 77
Proprietary confidential information © 2018 Boehringer Ingelheim International GmbH or one or more of its affiliated companies
001-MCS-40-106-RD-03 (12.0) / Saved on: 30 Jan 2015
Trial Period
Screening
Treatment Period
Follow-up
Visit
012
1
2
Baseline
3a9
3b9
3c9
4
5
EOT/
ED8
FU111
FU2
Study-Day (or duration during 
screening/ run-in)
Duration 
14 days
1
8
15
22
29 
57
85
EOT
+7
EOT
+28
Study Week
-2
1
2
3
4
8
12
13
16
Visit window (in days)
+7 to      
- 2820
±2
±2
±2
±5
±5
+5
+2
+5
Completion of patient 
participation
X
Vital status collection15
X
1 Prior to any trial related procedures, including any pre-trial washout of medications and / or medication restrictions (for more 
details on medication restrictions refer to Section 4.2.2.1). 
2  Results of a MRI or CCT-scan have to be available prior to visit 2. Please refer to Exclusion #1 in Section 3.3.3 for further details. 
3 At all visits, the respective kit number has to be allocated to the patient via IRT
6  Columbia Suicide Severity Rating Scale baseline/screening version
7 Columbia Suicide Severity Rating Scale since-last-visit version
8 Also to be completed for permanently withdrawn patients or who have discontinued the trial prematurely not willing to come to 
remaining trial visits: in case of early termination visit FU1 should preferably be performed no later than 7 days after the last 
study drug intake (visit FU2 should follow four weeks later). 
9 If the assessments at visit 3a do not show clinically relevant findings compared to baseline and if deemed clinically acceptable by 
the investigator then visits 3b and 3c may be performed as phone contacts. Attendance of the study partner is not necessarily 
required during visits 3 a-c. ECG and vital signs are only to be performed at clinic visits. At any of visit 3 (i.e. visit 3a to 3b) 
the IMP may be taken at home.
10 The neuropsychological assessments may be performed one day before the actual clinic visit if agreed between site staff and 
patient. In any case it needs to be ensured that the recommendations for the conduct of the neuropsychological assessments 
(refer to Section 6.2 for details) are followed. Neuropsychological rating scales assessments need to be done in one day and 
may not be split in two individual days.
11 This visit can be done as phone or clinic visit
12 Visit 0 can be performed on the same day with Visit 1 (the Screening Visit) if there is no need to make these visits separate (e.g.
medication washouts, CCT or MRI scan availability)
13 Refer to section 4.2.2.1 to check for concomitant medication restrictions, requirements including any pre-trial washout of 
medications
14 Laboratory parameters: Haemoglobin, GFR, ALT, AST and alkaline phosphatase found abnormal at visit 1 may be re-tested twice
prior to Visit 2. If Vitamin B12 and/or folate are found below lower limit normal, please initiate the respective treatment to 
stabilise the condition. Vitamin B12 and/or folate re-test may be done twice prior to Visit 2. For possible extensions of 
screening period refer to Section 6.1.
15 Patients who prematurely discontinue from the trial and refuse to attend remaining trial visits will be contacted for vital status 
collection at week 12.
16 Perform the 12-lead ECG preferably within 3-5 hours post IMP dosing.
17 Patient needs to be registered in the IRT also if becoming a screen failure between V0 and V1.
18 Perform randomization call in the IRT preferably after the neuropsychological assessments are done.
19 All scales should be administered as the first procedure at the clinic visit in the order pre-set in the rater station (the order 
of the scales in the rater station is consistent with the protocol Flow Chart).
20 The screening period may be shorten to a minimum of 7 days if all screening procedures and results are available. At the 
same time the screening period may be extended by additional 4 weeks (28 days) for any reasons. For further details please 
refer to Section 6.1.


Boehringer Ingelheim
12 Jul 2018
BI Trial No.: 1346.23
c03632269-05
Trial Protocol
Page 6 of 77
Proprietary confidential information © 2018 Boehringer Ingelheim International GmbH or one or more of its affiliated companies
001-MCS-40-106-RD-03 (12.0) / Saved on: 30 Jan 2015
TABLE OF CONTENTS
TITLE PAGE ...........................................................................................................................1
CLINICAL TRIAL PROTOCOL SYNOPSIS .....................................................................2
FLOW CHART........................................................................................................................4
TABLE OF CONTENTS ........................................................................................................6
ABBREVIATIONS..................................................................................................................9
1.
INTRODUCTION...............................................................................................12
MEDICAL BACKGROUND.............................................................................12
1.1
DRUG PROFILE................................................................................................13
1.2
2.
RATIONALE, OBJECTIVES, AND BENEFIT - RISK ASSESSMENT .....15
RATIONALE FOR PERFORMING THE TRIAL.........................................15
2.1
TRIAL OBJECTIVES........................................................................................15
2.2
BENEFIT - RISK ASSESSMENT.....................................................................15
2.3
3.
DESCRIPTION OF DESIGN AND TRIAL POPULATION.........................17
OVERALL TRIAL DESIGN AND PLAN .......................................................17
3.1
3.1.1
Administrative structure of the trial .................................................................17
DISCUSSION OF TRIAL DESIGN, INCLUDING THE CHOICE OF 
3.2
CONTROL GROUP(S)......................................................................................18
SELECTION OF TRIAL POPULATION .......................................................19
3.3
3.3.1
Main diagnosis for trial entry ............................................................................19
3.3.2
Inclusion criteria .................................................................................................19
3.3.3
Exclusion criteria ................................................................................................20
3.3.4
Removal of patients from therapy or assessments...........................................22
3.3.4.1
Removal of individual patients ..........................................................................22
3.3.4.2
Discontinuation of the trial by the sponsor.......................................................23
4.
TREATMENTS...................................................................................................24
TREATMENTS TO BE ADMINISTERED.....................................................24
4.1
4.1.1
Identity of BI investigational product(s) and comparator product(s) ...........24
4.1.2
Method of assigning patients to treatment groups...........................................26
4.1.3
Selection of doses in the trial..............................................................................26
4.1.4
Drug assignment and administration of doses for each patient......................27
4.1.5
Blinding and procedures for unblinding...........................................................27
4.1.5.1
Blinding................................................................................................................27
4.1.5.2
Unblinding and breaking the code ....................................................................28
4.1.6
Packaging, labelling, and re-supply...................................................................28
4.1.7
Storage conditions...............................................................................................28
4.1.8
Drug accountability.............................................................................................28
CONCOMITANT THERAPY, RESTRICTIONS, AND RESCUE  
4.2
TREATMENT.....................................................................................................29


Boehringer Ingelheim
12 Jul 2018
BI Trial No.: 1346.23
c03632269-05
Trial Protocol
Page 7 of 77
Proprietary confidential information © 2018 Boehringer Ingelheim International GmbH or one or more of its affiliated companies
001-MCS-40-106-RD-03 (12.0) / Saved on: 30 Jan 2015
4.2.1
Rescue medication, emergency procedures, and additional treatment(s) .....29
4.2.2
Restrictions ..........................................................................................................29
4.2.2.1
Restrictions regarding concomitant treatment ................................................29
4.2.2.2
Restrictions on diet and life style.......................................................................34
TREATMENT COMPLIANCE........................................................................34
4.3
5.
VARIABLES AND THEIR ASSESSMENT ....................................................35
TRIAL ENDPOINTS..........................................................................................35
5.1
5.1.1
Primary Endpoint(s)...........................................................................................35
5.1.2
Secondary Endpoint(s) .......................................................................................35
ASSESSMENT OF EFFICACY........................................................................35
5.2
ASSESSMENT OF SAFETY.............................................................................37
5.3
5.3.1
Physical examination ..........................................................................................37
5.3.2
Vital Signs............................................................................................................37
5.3.3
Safety laboratory parameters ............................................................................37
5.3.4
Electrocardiogram ..............................................................................................39
5.3.5
Other safety parameters.....................................................................................40
5.3.5.1
Suicidal risk assessed by the C-SSRS................................................................40
5.3.6
Assessment of adverse events.............................................................................41
5.3.6.1
Definitions of AEs................................................................................................41
5.3.7
Adverse event collection and reporting.............................................................44
6.
INVESTIGATIONAL PLAN.............................................................................48
VISIT SCHEDULE.............................................................................................48
6.1
DETAILS OF TRIAL PROCEDURES AT SELECTED VISITS .................48
6.2
6.2.1
Screening and run-in period(s)..........................................................................49
6.2.2
Treatment period(s)............................................................................................49
6.2.3
Follow Up Period and Trial Completion...........................................................50
7.
STATISTICAL METHODS AND DETERMINATION OF SAMPLE SIZE
...............................................................................................................................52
STATISTICAL DESIGN – MODEL ................................................................52
7.1
NULL AND ALTERNATIVE HYPOTHESES ...............................................52
7.2
PLANNED ANALYSES.....................................................................................52
7.3
7.3.1
Primary endpoint analyses.................................................................................53


Boehringer Ingelheim
12 Jul 2018
BI Trial No.: 1346.23
c03632269-05
Trial Protocol
Page 8 of 77
Proprietary confidential information © 2018 Boehringer Ingelheim International GmbH or one or more of its affiliated companies
001-MCS-40-106-RD-03 (12.0) / Saved on: 30 Jan 2015
7.3.1.1
Primary analysis of the primary endpoint........................................................53
7.3.1.2
Secondary analyses of the primary endpoint ..................................................54
7.3.2
Secondary endpoint analyses .............................................................................55
7.3.4
Safety analyses.....................................................................................................56
INTERIM ANALYSES ......................................................................................57
7.4
HANDLING OF MISSING DATA ...................................................................57
7.5
RANDOMISATION ...........................................................................................57
7.6
DETERMINATION OF SAMPLE SIZE .........................................................58
7.7
8.
INFORMED CONSENT, DATA PROTECTION, TRIAL RECORDS........60
TRIAL APPROVAL, PATIENT INFORMATION, AND INFORMED 
8.1
CONSENT ...........................................................................................................60
DATA QUALITY ASSURANCE ......................................................................61
8.2
RECORDS...........................................................................................................61
8.3
8.3.1
Source documents ...............................................................................................61
8.3.2
Direct access to source data and documents.....................................................62
8.3.3
Storage period of records ...................................................................................62
LISTEDNESS AND EXPEDITED REPORTING OF ADVERSE EVENTS62
8.4
8.4.1
Listedness.............................................................................................................62
8.4.2
Expedited reporting of adverse events..............................................................62
STATEMENT OF CONFIDENTIALITY........................................................63
8.5
TRIAL MILESTONES.......................................................................................63
8.6
PROTOCOL VIOLATIONS .............................................................................63
8.7
COMPENSATION AVAILABLE TO THE PATIENT IN THE EVENT OF 
8.8
TRIAL RELATED INJURY..............................................................................64
9.
REFERENCES....................................................................................................65
PUBLISHED REFERENCES............................................................................65
9.1
UNPUBLISHED REFERENCES......................................................................67
9.2
11.
DESCRIPTION OF GLOBAL AMENDMENT(S) .........................................70


Boehringer Ingelheim
12 Jul 2018
BI Trial No.: 1346.23
c03632269-05
Trial Protocol
Page 9 of 77
Proprietary confidential information © 2018 Boehringer Ingelheim International GmbH or one or more of its affiliated companies
001-MCS-40-106-RD-03 (12.0) / Saved on: 30 Jan 2015
ABBREVIATIONS
ABCB1
ATP-binding cassette sub-family B member 1 (gene encoding for P-gp)
AChE-Is
Acetylcholine Esterase Inhibitors
AD
Alzheimer’s Disease
ADAS-cog
Alzheimer's Disease Assessment Scale-Cognitive subscale
ADCS-ADL
Alzheimer’s Disease Cooperative Study/Activities of Daily Living
AE
Adverse Event
AESI
Protocol-specified Adverse Event of Special Interest
AIC
Akaike Information Criterion
AUC
Area under the Curve
CCT
Cranial Computer Tomography
CI
CIBIC+
CIBIS
Confidence Interval
Clinician's Interview-Based Impression of Change
Clinical Interview-Based Impression of Severity
CML
Local Clinical Monitor 
CRA
Clinical Research Associate
CRF
Case Report Form
CSF
Cerebrospinal Fluid
C-SSRS
Columbia Suicide Severity Rating Scale
CT
Computer Tomography
CTCAE
Common Terminology Criteria for Adverse Events
CTMF
Clinical Trial Master File
CTP
Clinical Trial Protocol
CTR
Clinical Trial Report
CYP
Cytochrome P450
DEDP
Drug Exposure During Pregnancy
DMC
Data Monitoring Committee
eCRF
Electronic Case Report Form
ED
Early discontinuation
EDC
Electronic Data Capture
ERG
Electroretinogram
EudraCT
European Clinical Trials Database
FAS
Full Analysis Set
GCP
Good Clinical Practice
GlyT1
Glycin Transporter 1
HEENT
Head-Eyes-Ears-Nose-Throat
HPC
Human Pharmacology Centre
i.v.
Intravenous
IB
Investigator’s Brochure
IEC
Independent Ethics Committee
IM
Intermediate metabolizer


Boehringer Ingelheim
12 Jul 2018
BI Trial No.: 1346.23
c03632269-05
Trial Protocol
Page 10 of 77
Proprietary confidential information © 2018 Boehringer Ingelheim International GmbH or one or more of its affiliated companies
001-MCS-40-106-RD-03 (12.0) / Saved on: 30 Jan 2015
IRB
Institutional Review Board
IRT
Interactive Response Technology
ISF
Investigator Site File
LC-MS
Liquid Chromatography tandem Mass Spectrometry
LTP
Long Term Potentation
MCPmod
Multiple Comparison Procedures and modelling
MedDRA
Medical Dictionary for Drug Regulatory Activities
MMRM
Mixed Model Repeated Measures
MMSE
Mini-Mental-State-Examination
MRI
Magnetic Resonance Imaging
MST
Medical Subteam
NMDA-R
N-methyl-D-aspartate receptor
NOA
Not analyzed
NOP
No peak detectable
NOR
No valid result
NOS
No sample available
OPU
Operative Unit
p.o.
per os (oral)
PDE9
Phosphodiesterase-9
PG(x)
Pharmacogenomic(s)
P-gp
P-glycoprotein
PK
Pharmacokinetic
PM
Poor metabolizers
POC
Proof of Concept
PSA
Prostate Specific Antigen
PTM
Placebo to Match
q.d.
quaque die (once a day)
RDC
Remote Data Capture
REP
Residual Effect Period
RNA
Ribonucleic Acid
RPR
Rapid Plasma Reagin
s.c.
Subcutaneous
SAE
Serious Adverse Event
SP(1)
Spatial 
SPC
Summary of Product Characteristics
STORM
Storage Conditions for Trial Medications
SUSAR
Suspected Unexpected Serious Adverse Reactions
TCM
Trial Clinical Monitor
TDMAP
Trial Data Management and Analysis Plan
tmax,ss
Time to maximum plasma concentration (at steady state)
TMM
Team Member Medicine
TMW
Trial Medical Writer
TSAP
Trial Statistical Analysis Plan
UM
Ultrarapid metabolizer


Boehringer Ingelheim
12 Jul 2018
BI Trial No.: 1346.23
c03632269-05
Trial Protocol
Page 11 of 77
Proprietary confidential information © 2018 Boehringer Ingelheim International GmbH or one or more of its affiliated companies
001-MCS-40-106-RD-03 (12.0) / Saved on: 30 Jan 2015
UN
Unstructured


Boehringer Ingelheim
12 Jul 2018
BI Trial No.: 1346.23
c03632269-05
Trial Protocol
Page 12 of 77
Proprietary confidential information © 2018 Boehringer Ingelheim International GmbH or one or more of its affiliated companies
001-MCS-40-106-RD-03 (12.0) / Saved on: 30 Jan 2015
1.
INTRODUCTION
MEDICAL BACKGROUND
1.1
Alzheimer’s Disease Dementia, a chronic progressive mental disorder caused by Alzheimer’s 
Disease (AD), is the most common cause of dementia and accounts for 50 to 70% of all 
cases. AD is mainly a disorder of the elderly; however it can also affect patients below the 
age of 60. More than 25 million people in the world are currently affected by dementia, most 
of them suffering from AD, with around 5 million new cases occurring every year [R10-
5095; R10-5106]. The age-specific prevalence of AD almost doubles every 5 years after age 
65. Among developed nations, approximately 1 in 10 elderly people (65+ years) is affected 
by dementia to some degree, whereas more than one third of the very old people (85+ years) 
may have dementia-related symptoms and signs [R10-5105].
In the early stage of the clinical disease manifestation cardinal symptoms are characterized by 
an impairment of episodic memory and other cognitive domains, like executive function, 
orientation and judgment. This is followed by a progressive decline in the ability to perform 
activities of daily living and the appearance of behavioural changes and/or psychiatric 
symptoms (mood disturbances, hallucinations, personality changes). With progression of the 
disease there is an increasing utilization of resources and medical care finally leading to the 
need of full-time assisted living or nursing home care before death. The median time from 
onset of symptoms to death is estimated to be around 10 years.
The pattern of cognitive and functional decline is not uniform over the course of the disease 
and differs according to the measure in question and the scales used. Cognitive decline, for 
example, seems to be more rapid in the moderate and severe stages than in the mild and very 
severe stages, yielding a sigmoid curve of progression.
Currently approved AD treatment is used to treat the impairments in memory and function in 
patients with dementia. Registered symptomatic treatment is possible with 
acetylcholinesterase inhibitors (AChE-Is) and memantine. Donepezil, galantamine, and 
rivastigmine are the three widely registered AChE-Is for the treatment of mild to moderate 
AD. Donepezil is also approved for severe AD in the US and Canada. Memantine, an 
uncompetitive N-methyl-D-aspartate (NMDA) receptor antagonist, is registered in Europe 
and in the US for the treatment of moderate to severe AD. 
Currently, AChE-Is in general and donepezil in particular can be regarded as gold standard 
for treatment of mild-to-moderate AD.
On cellular level AD is characterized by a progressive loss of synapses and neurons. Affected 
transmitter systems mainly include cholinergic and glutamatergic neurons. Glutamate as the 
major excitatory neurotransmitter in the human brain is most prominently associated with 
functions of memory formation and learning. Glutamatergic transmission is mediated by 
various receptors with the post-synaptic NMDA receptor playing an essential role. GlyT1 
inhibition increases post-synaptic NMDA receptor signaling and BI 425809 increases 
learning and memory in rodent models. By GlyT1 inhibition a cascade of intracellular, post-


Boehringer Ingelheim
12 Jul 2018
BI Trial No.: 1346.23
c03632269-05
Trial Protocol
Page 13 of 77
Proprietary confidential information © 2018 Boehringer Ingelheim International GmbH or one or more of its affiliated companies
001-MCS-40-106-RD-03 (12.0) / Saved on: 30 Jan 2015
synaptic signalling events is triggered through elevation of second messengers such as cAMP 
and cGMP with subsequent activation of protein kinases and manifestation of long-term 
potentiation (LTP) and synaptic plasticity. LTP is regarded as a validated physiological 
model for cellular processes underlying learning and memory formation [R10-5109; R10-
5092; R10-5102].
DRUG PROFILE
1.2
BI 425809 is a GLYT1 inhibitor that is being developed for symptomatic treatment of AD 
and for symptomatic treatment of cognitive impairment in schizophrenia as adjunct to classic 
antipsychotic therapy.
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 
NMDA receptor hypofunction in cortical and hippocampal brain areas [R13-4518; R13-
4521]. 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 hypo-activation 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.
Based on in vitro data, at the highest proposed Phase 2 dose of 25 mg, BI 425809 may 
cause clinically relevant induction of CYP2B6. Based on a Phase I clinical study BI 
425809 is a mild CYP3A4 inducer at 25mg. Based on clinical DDI study BI with 
itraconazole and rifampicin BI 425809 is a sensitive CYP3A4 substrate and should not be 
given with moderate-to-strong inhibitors or inducers of CYP3A4.


Boehringer Ingelheim
12 Jul 2018
BI Trial No.: 1346.23
c03632269-05
Trial Protocol
Page 14 of 77
Proprietary confidential information © 2018 Boehringer Ingelheim International GmbH or one or more of its affiliated companies
001-MCS-40-106-RD-03 (12.0) / Saved on: 30 Jan 2015
Clinical Safety Pharmacology
In healthy volunteers, BI 425809 is generally well tolerated. The most frequent AEs were 
adverse CNS symptoms, most commonly headaches that showed a trend for dose 
dependency, were reversible and can be clinically monitored. In addition, BI 425809 may be 
associated with transient visual disturbances, and somnolence (drowsiness). These effects are 
understood to be mostly mild to moderate and transient. Decreased haemoglobin is a potential 
risk based on preclinical data and class effect; however, no clear decrease in haemoglobin 
was seen in BI 425809-treated subjects compared to placebo in phase I trials so far.
No serious safety concerns have been identified with administration of GLYT1 inhibitors in 
humans. The most frequent adverse events were CNS effects and visual effects. Visual 
effects are generally seen at higher doses and are transient in nature. Visual AEs and changes 
in Hb levels should be anticipated with GLYT1 inhibitors and are of special interest and 
should be closely monitored. Additionally, CNS effects should be anticipated and are 
expected to be dose-limiting.
For a more detailed description of the drug profile refer to the current Investigator’s Brochure
(IB) which is included in the Investigator Site File (ISF).


Boehringer Ingelheim
12 Jul 2018
BI Trial No.: 1346.23
c03632269-05
Trial Protocol
Page 15 of 77
Proprietary confidential information © 2018 Boehringer Ingelheim International GmbH or one or more of its affiliated companies
001-MCS-40-106-RD-03 (12.0) / Saved on: 30 Jan 2015
2.
RATIONALE, OBJECTIVES, AND BENEFIT - RISK 
ASSESSMENT
RATIONALE FOR PERFORMING THE TRIAL
2.1
Currently approved AD treatment is used to treat the impairment in memory and function in 
patients with dementia. Registered treatment mainly consists of AchE-Is and memantine. 
AchE-Is in general and donepezil in particular can be currently regarded as gold standard for 
treatment of mild-to-moderate AD.  However, there is still a high unmet medical need for 
additional symptomatic therapies able to improve cognition and function in patients with 
mild-to-moderate dementia of Alzheimer’s type.
This study is performed to define a suitable dose of BI 425809 regarding efficacy and safety 
for further pivotal testing in Phase III. The main rationale for this study is to provide proof of 
clinical concept and dose ranging data in patients with mild-to-moderate dementia of 
Alzheimer’s type aged at least 55 years at enrolment.
TRIAL OBJECTIVES
2.2
The proof of clinical concept will be achieved through primary endpoint comparison (mean 
change from baseline in ADAS-Cog11 total score at Week 12) of the four BI doses (2mg QD, 
5mg QD, 10mg QD and 25mg QD) and placebo.  A non-flat dose response relationship 
between the BI doses and placebo will be tested using the multiple comparison procedures 
and modelling (MCPmod) approach [R10-1424, R15-1961].
Other objectives of this study are safety
 of BI 
425809.
BENEFIT - RISK ASSESSMENT
2.3
The favorable benefit-risk ratio based on the so far acquired knowledge about BI 425809 is 
the rationale to conduct further studies with this molecule. Currently available data
comprising of six phase 1 trials results involved in total 229 healthy subjects treated with 
single or multiple doses of orally administered BI 425809 up to 150 mg per day. 
Based on non-clinical data, clinical data from other compounds in the same class, and 
subjects exposed in phase I trials; BI 425809 is assessed to be generally safe and well 
tolerated [c02155957-07].


Boehringer Ingelheim
12 Jul 2018
BI Trial No.: 1346.23
c03632269-05
Trial Protocol
Page 16 of 77
Proprietary confidential information © 2018 Boehringer Ingelheim International GmbH or one or more of its affiliated companies
001-MCS-40-106-RD-03 (12.0) / Saved on: 30 Jan 2015
Although rare, a potential for drug-induced liver injury 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 patients´ 
safety, see also Section 5.3.6.1.
This is newly developed drug at an early stage of testing and therefore an individual benefit 
cannot be guaranteed. 
This is a trial of short duration and the assignment to the placebo arm is not associated with a 
higher risk for the patient. 1 out of 5 patients will be randomised to the placebo arm. The 
study procedures (e.g. AD assessment, safety and suicidality monitoring etc.) may in fact 
benefit the patients e.g. intensive medical care, a potentially better knowledge of the 
underlying disease which may lead to a better handling of this disease. Also, this disease is 
not reversible and can last more than 20 years. Even if there is no direct benefit for the patient 
during participation in this trial, it can be assumed that the trial results may contribute to 
better drug development in future. In addition, due to the long duration of the disease the 
patient may directly benefit from the drug development based on the results of this trial. 


Boehringer Ingelheim
12 Jul 2018
BI Trial No.: 1346.23
c03632269-05
Trial Protocol
Page 17 of 77
Proprietary confidential information © 2018 Boehringer Ingelheim International GmbH or one or more of its affiliated companies
001-MCS-40-106-RD-03 (12.0) / Saved on: 30 Jan 2015
3.
DESCRIPTION OF DESIGN AND TRIAL POPULATION
OVERALL TRIAL DESIGN AND PLAN
3.1
This is a 12-week, multi-centre, multi-national, randomised, double-blind, double-dummy, 
placebo controlled, parallel group comparison in patients with mild-to-moderate Alzheimer’s 
Disease Dementia. In total, 585 patients with mild-to-moderate Alzheimer’s Disease 
Dementia who meet the entry criteria are planned to be randomised in this trial. The 
randomised treatment will be double blind. 
All patients suitable after screening will be randomised into 12-week double-blind treatment 
period at Visit 2 and will be assigned to one of the 4 treatment groups or placebo, refer to 
Figure 3.1: 1.
Figure 3.1: 1 Trial Design
After the end of the double-blind treatment period, patients will be followed up for additional 
4 weeks without study medication. Safety will be formally evaluated at each visit until end of 
the observational period which is 28 days after end of treatment or for an appropriately longer 
time in case of unresolved adverse events.
3.1.1
Administrative structure of the trial
Boehringer Ingelheim has appointed a Trial Clinical Monitor, responsible for coordinating all
required activities, in order to 

manage the trial in accordance with applicable regulations and internal SOPs,

direct the clinical trial team in the preparation, conduct, and reporting of the trial,

ensure appropriate training and information of local clinical monitors (CML), Clinical 
Research Associates (CRAs), and Investigators of participating countries.


Boehringer Ingelheim
12 Jul 2018
BI Trial No.: 1346.23
c03632269-05
Trial Protocol
Page 18 of 77
Proprietary confidential information © 2018 Boehringer Ingelheim International GmbH or one or more of its affiliated companies
001-MCS-40-106-RD-03 (12.0) / Saved on: 30 Jan 2015
Bracket Global has been selected as service provider to support tasks related to the 
neuropsychological assessments: necessary rater prequalification, rater training (online and at 
investigator meeting), provision of rater materials and central review of neuropsychological 
assessments (see Section 8.3.1 for details).
Data Management and Statistical Evaluation will be done by BI according to BI SOPs.
Tasks and functions assigned in order to organise, manage, and evaluate the trial will be 
defined according to BI SOPs. A list of responsible persons and relevant local information
can be found in the ISF.
Central laboratory and central ECG service vendors will be used for this trial. The 
organization of the trial in the participating countries will be done by the respective local BI 
organization (OPU) or by a Contract Research organization (CRO) with which the 
responsibilities and tasks have been agreed and a written contract has been filed before 
initiation of the clinical trial. In each local BI-organisation (OPU) participating in this study, 
a local clinical monitor (CML) will be appointed responsible for coordinating the activities 
required in order to manage the trial in accordance with applicable regulations and internal 
SOPs in the countries covered by the respective BI OPU.
A Coordinating Investigator has been nominated and will be responsible to coordinate 
Investigators at different centres participating in this multicentre trial. The Coordinating 
investigator was selected by the sponsor. 
 will review the trial protocol, any subsequent 
amendments to the protocol and the (draft) Clinical Trial Report (CTR). Relevant 
documentation on the participating (Principal) Investigators and other important trial staff 
shall be filed in the ISF.
DISCUSSION OF TRIAL DESIGN, INCLUDING THE CHOICE OF 
3.2
CONTROL GROUP(S)
A parallel group design is the appropriate design as the inherent within-patient variability and 
the progressive nature of the disease makes it difficult if not impossible to employ a 
crossover design.
In order to estimate the relative drug effect on cognition and function, a double-blind 
comparison against placebo is included in this trial. 
The current standard treatment of cognitive and functional impairment in AD shows 
substantial treatment effects during the first three months of treatment. Therefore, a 12-week 
treatment period is considered to be sufficient to assess the efficacy, tolerability and safety of 
BI 425809.
The data collected in this double-blind, randomised, and placebo-controlled trial are standard 
in this indication and will provide important information in terms of efficacy and safety on 
the use of BI 425809 in patients with mild-to-moderate AD.


Boehringer Ingelheim
12 Jul 2018
BI Trial No.: 1346.23
c03632269-05
Trial Protocol
Page 19 of 77
Proprietary confidential information © 2018 Boehringer Ingelheim International GmbH or one or more of its affiliated companies
001-MCS-40-106-RD-03 (12.0) / Saved on: 30 Jan 2015
SELECTION OF TRIAL POPULATION
3.3
Recruitment of the 585 patients will be competitive. Patients who discontinue following 
randomisation will not be replaced and may not be re-enrolled at a later date. A record is kept 
of all patients failing to complete all trial visits and their reasons for discontinuation. 
This trial aims to randomise approximately half of patients with mild Mini-Mental State 
Examination ((MMSE) 20-26) and half with moderate (MMSE 15-19) AD. The 
sponsor/study team will monitor recruitment closely and reserves the right to stop further 
enrollment of either mild or moderate patients in order to meet this goal. 
Permission to randomise more than 15 patients per site must be obtained from the TCM at 
Boehringer Ingelheim. This shall only be allowed after a careful review of the data quality 
and the performance of the site.
A log of all patients enrolled into the trial (i.e. who have signed informed consent) will be 
maintained in the ISF at the investigational site irrespective of whether they have been treated 
with investigational drug or not.
3.3.1
Main diagnosis for trial entry
Patients with the diagnosis of mild-to-moderate Alzheimer’s Disease Dementia (according to 
the Core Clinical Criteria of the recommendations from the National Institute on Aging-
Alzheimer’s Association workgroups [R13-4115] on diagnostic guidelines for Alzheimer’s 
Disease Dementia) will be included.
Please refer to Section 8.3.1 (Source Documents) for the documentation requirements 
pertaining to the in- and exclusion criteria.
3.3.2
Inclusion criteria
1. Diagnosis of mild-to-moderate Alzheimer’s Disease Dementia according to the 
recommendations from the National Institute on Aging-Alzheimer’s Association 
workgroups on diagnostic guidelines for Alzheimer’s disease (see Section 3.3.1).
2. MMSE score of 15-26 at screening (Visit 1).
3. Concomitant use of AChEIs is allowed but not required. Patients who are currently 
taking AChEIs are eligible as long as they have been using a stable dose for at least 3
months prior to screening and no change is foreseen for the duration of the study. This 
dose must be consistent with the product label in the concerned country. Patients who 
are not currently taking AChEIs but have taken them in the past are also eligible if 
AChEIs were stopped at least 3 months prior to screening.
4. All patients must sign and date an Informed Consent Form consistent with ICH-GCP
guidelines and local legislation prior to participation in the trial (i.e. prior to any trial 
related procedures, including any pre-trial washout of medications/medication 
restrictions, Section 4.2.2.1.) 


Boehringer Ingelheim
12 Jul 2018
BI Trial No.: 1346.23
c03632269-05
Trial Protocol
Page 20 of 77
Proprietary confidential information © 2018 Boehringer Ingelheim International GmbH or one or more of its affiliated companies
001-MCS-40-106-RD-03 (12.0) / Saved on: 30 Jan 2015
All patients must be able to give informed consent personally and have capacity for 
such consent. An informed consent given by a legal representative alone will not be 
accepted. 
5. Patients must have a reliable study partner (per investigator judgment, for instance a 
family member, partner etc., guardian (must be always the same person)) who is in close 
contact with the patient, available on call and who is able to contribute to the 
Neuropsychological Rating Scales at specific study visits as stated in the Flow Chart. 
This person will be able to communicate in the language in which the patient is being 
assessed and should also serve as a backup contact for the study site. The study partner 
must sign a separate informed consent form which describes their contributions during 
the study.
6. Patients must have at least 6 years of formal education and fluency in the test language 
as verbally confirmed by the patient and documented by the study investigator.
7. Male or female patients at least 55 years of age. Patients older than 85 years may be 
included based on an acceptable general health status, (e.g. concomitant diseases, 
physical capability to follow the required study procedures (visits etc.)) at discretion of 
the investigator. 
3.3.3
Exclusion criteria
1. Dementia secondary to disorders other than Alzheimer's Disease Dementia
(for example: Vitamin B12/Folate deficiency, neurosyphilis, craniocerebral trauma, 
small vessel disease). Lewy body dementia or vascular or multi-infarct dementia as
primary diagnosis is excluded. The above should be assessed based on clinical data, 
current laboratory findings, and a MRI or CT of the brain.
If previous cranial imaging is not available or older than 12 months prior to screening 
then a CT or MRI needs to be performed at screening. Local regulations need to be 
checked if use of radiation for a cranial CT scan is allowed in the concerned country. If 
performing of a cranial CT is not allowed (e.g. Germany, France), a MRI must be 
performed.
2. Any central nervous system disease other than AD which according to the investigator 
may be associated with worsening of cognition. Patients with epileptic seizure in last 2 
years should be excluded.
3. A disease or condition which in the opinion of the investigator are likely to interfere 
with trial testing procedures or put the patient at risk when participating in this trial. 
4. Any documented active or suspected malignancy or history of malignancy with need of 
concomitant treatment that interfere with the investigational product. 
5. Patients with life expectancy of less than 2 years are also excluded.


Boehringer Ingelheim
12 Jul 2018
BI Trial No.: 1346.23
c03632269-05
Trial Protocol
Page 21 of 77
Proprietary confidential information © 2018 Boehringer Ingelheim International GmbH or one or more of its affiliated companies
001-MCS-40-106-RD-03 (12.0) / Saved on: 30 Jan 2015
6. Any other clinical condition that, in the opinion of the investigator, would jeopardize 
patient safety while participating in this clinical trial.
7. Severe renal impairment defined as a GFR < 30 mL/min/1.73 m2 in the screening 
central lab report.
8. Haemoglobin less than 120 g/L (12g/dL) in men or 115g/L (11.5g/dL) in women in the 
screening lab report. History of haemoglobinopathy such as thalassemia major or sickle-
cell anaemia.
9. Clinically significant uncompensated hearing loss in the judgment of the investigator. 
Use of hearing aids is allowed.
10. Any suicidal behaviour in the past 2 years (i.e. actual attempt, interrupted attempt, 
aborted attempt, or preparatory acts or behaviour).
11. Any suicidal ideation of type 4 or 5 in the C-SSRS in the past 3 months (i.e. active 
suicidal thought with intent but without specific plan, or active suicidal thought with 
plan and intent).
12. Known history of HIV infection.
13. Significant history of drug dependence or abuse (including alcohol, as defined in 
Diagnostic and Statistical Manual of Mental Disorders [DSM-V] or in the opinion of the 
investigator) within the last two years.
14. Previous participation in investigational drug studies of dementia of Alzheimer’s Type
within three months prior to screening. Patients having received any active treatment 
in studies targeting disease modification of AD are excluded. Previous participation 
in studies with non-prescription medications, vitamins other nutritional formulations or 
non-pharmacological treatments is allowed.
15. Treatment with restricted medication (refer to Table 4.2.2.1:1) prior to Visit 1 and/or 
during the screening period.
16. Planned elective surgery requiring general anaesthesia, or hospitalisation for more than 
1 day (requiring an overnight stay) during the study period.
17. For females: Women who are of child bearing potential. Women not of childbearing 
potential are defined as: Women who are postmenopausal (12 months with no menses 
without an alternative medical cause) or who are permanently sterilized (e.g. 
hysterectomy, bilateral oophorectomy or bilateral salpingectomy).
For males: Men who are able to father a child, unwilling to be abstinent or to use an 
adequate form of effective contraception for the duration of study participation and for 
at least 28 days after treatment has ended.


Boehringer Ingelheim
12 Jul 2018
BI Trial No.: 1346.23
c03632269-05
Trial Protocol
Page 22 of 77
Proprietary confidential information © 2018 Boehringer Ingelheim International GmbH or one or more of its affiliated companies
001-MCS-40-106-RD-03 (12.0) / Saved on: 30 Jan 2015
18. Indication of liver disease, defined by serum levels of either ALT (SGPT), AST 
(SGOT), or alkaline phosphatase above 3 x upper limit of normal (ULN) as determined 
during screening.
3.3.4
Removal of patients from therapy or assessments
Removal of individual patients
3.3.4.1
It is important to distinguish between premature study drug discontinuation and premature 
study discontinuation. 
Patients can stop taking study drug for various reasons as described below; however, they 
should be encouraged to re-start study medication at the Investigator’s discretion when he/she 
considers it safe to do so.
After premature study drug discontinuation patients should be asked to further attend 
scheduled trial visits, follow-up visits and assessments until the end of the trial unless they 
withdraw consent to participate in the study. Should it not be possible to attend all visits, at 
least phone contacts should occur at the scheduled visit time points. It is vital to explain to
these patients the importance to continue trial participation.
Every effort should be made to collect data in all patients randomised. This includes 
randomised patients who never take study medications and patients that prematurely 
discontinue study drug.
Procedures to be followed for patients prematurely terminating the study drug and refusing to 
attend further trial visits are detailed in Section 6.2.3. Patients that withdraw from trial 
participation or study drug will not be replaced. The data for patients who discontinue trial 
treatment or completely withdraw from the trial after randomization must be documented and 
the reason for withdrawal and the date of last dose of study drug must be recorded in the 
(e)CRF. These data must be included in the trial database and must be reported.
An individual patient is to be discontinued from study drug if the following occurs:

The patient withdraws consent for study treatment, without the need to justify the 
decision.

The patient needs to take concomitant drugs that interfere with the investigational 
product or other trial medication (see Section 4.2.2 for details).

In the opinion of the Investigator, continuation on the study drug is not in the patient’s 
best interest, or if the patient fails to comply with the protocol (e.g. non-attendance at 
trial assessments, and reason to be recorded in the electronic eCRF)

The patient can no longer be treated with trial medication for other medical reasons 
(such as surgery, adverse events, other diseases, or pregnancy)

The patient’s disease/s and/or any concomitant condition significantly worsens, in 
clinical judgement of the Investigator


Boehringer Ingelheim
12 Jul 2018
BI Trial No.: 1346.23
c03632269-05
Trial Protocol
Page 23 of 77
Proprietary confidential information © 2018 Boehringer Ingelheim International GmbH or one or more of its affiliated companies
001-MCS-40-106-RD-03 (12.0) / Saved on: 30 Jan 2015

The patient 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)

Patient non-compliance with study drug administration (per Section 4.3)

Patient is unblinded to treatment by site staff

Decision by Boehringer Ingelheim to discontinue a specific patient (e.g. in case of 
SAEs).
If a patient becomes pregnant or a pregnancy is suspected during the trial the investigational 
drug will be stopped, the patient will be discontinued from treatment and the patient will be 
followed up through the end of the trial and until birth or otherwise termination of the 
pregnancy. For further information, including the process for follow-up on the outcome of the 
pregnancy please see Section 5.3.7.
Given the patient’s agreement, the patient will undergo the procedures for early treatment 
discontinuation and follow up as outlined in the Flow Chart and Section 6.2.3.
For all patients the reason for withdrawal (e.g. adverse events) must be recorded in the 
(e)CRF. These data will be included in the trial database and reported.
Discontinuation of the trial by the sponsor
3.3.4.2
Boehringer Ingelheim reserves the right to discontinue the trial overall or at a particular trial 
site at any time for the following reasons:
1. Failure to meet expected enrolment goals overall or at a particular trial site (this may 
include under-recruitment or risk of over-recruitment towards the end of the recruitment 
period)
2. Emergence of any efficacy/safety information invalidating the earlier positive benefit-
risk-assessment that could significantly affect the continuation of the trial
3. Violation of GCP, the CTP, or the contract disturbing the appropriate conduct of the trial
The Investigator / the trial site will be reimbursed for reasonable expenses incurred in case of 
trial termination (except in case of the third reason).


Boehringer Ingelheim
12 Jul 2018
BI Trial No.: 1346.23
c03632269-05
Trial Protocol
Page 24 of 77
Proprietary confidential information © 2018 Boehringer Ingelheim International GmbH or one or more of its affiliated companies
001-MCS-40-106-RD-03 (12.0) / Saved on: 30 Jan 2015
4.
TREATMENTS
TREATMENTS TO BE ADMINISTERED
4.1
Table 4.1: 1 
Treatment groups
Group
Treatment Regimen
Treatment
tbl./d
1
BI 425809 2mg QD
1mg
2-0-0
25mg PTM
1-0-0
2
BI 425809 5mg QD
5mg
1-0-0
1 and 5mg PTM
1-0-0
25mg PTM
1-0-0
3
BI 425809 10mg QD
5mg
2-0-0
25mg PTM
1-0-0
4
BI 425809 25mg QD
1 and 5mg PTM
2-0-0
25 mg
1-0-0
5
Placebo QD
1 and 5mg PTM
2-0-0
25 mg PTM
1-0-0
4.1.1
Identity of BI investigational product(s) and comparator product(s)
Table 4.1.1: 1
BI 425809, 2mg:
Substance:
BI 425809
Pharmaceutical formulation:
Tablet
Source:
Boehringer Ingelheim Pharma GmbH & Co KG
Birkendorfer Strasse 65
D-88397 Biberach a.d. Riss
Unit strength:
1 mg 
Daily Dose
2 mg QD (2-0-0) in Treatment Group 1
Posology
QD
Route of administration:
Per os


Boehringer Ingelheim
12 Jul 2018
BI Trial No.: 1346.23
c03632269-05
Trial Protocol
Page 25 of 77
Proprietary confidential information © 2018 Boehringer Ingelheim International GmbH or one or more of its affiliated companies
001-MCS-40-106-RD-03 (12.0) / Saved on: 30 Jan 2015
Table 4.1.1: 2
BI 425809, 5mg:
Substance:
BI 425809
Source:
Boehringer Ingelheim Pharma GmbH & Co KG
Birkendorfer Strasse 65
D-88397 Biberach a.d. Riss
Unit strength:
5 mg 
Daily Dose
5 mg QD (1-0-0) in Treatment Group 2
10 mg QD (2-0-0) in Treatment Group 3
Posology
QD
Route of administration:
Per os
Table 4.1.1: 3
BI 425809, 25mg:
Substance:
BI 425809
Pharmaceutical formulation:
Tablet
Source:
Boehringer Ingelheim Pharma GmbH & Co KG
Birkendorfer Strasse 65
D-88397 Biberach a.d. Riss
Daily Dose
25 mg QD (1-0-0) in Treatment Group 4
Unit strength:
25 mg
Posology
QD
Route of administration:
Per os


Boehringer Ingelheim
12 Jul 2018
BI Trial No.: 1346.23
c03632269-05
Trial Protocol
Page 26 of 77
Proprietary confidential information © 2018 Boehringer Ingelheim International GmbH or one or more of its affiliated companies
001-MCS-40-106-RD-03 (12.0) / Saved on: 30 Jan 2015
Table 4.1.1: 4
Placebo matching BI 425809, 1mg and 5mg:
Substance:
Placebo matching BI 425809
Pharmaceutical formulation:
Tablet
Source:
Boehringer Ingelheim Pharma GmbH & Co KG
Birkendorfer Strasse 65
D-88397 Biberach a.d. Riss
Unit strength:
n.a.
Daily Dose
n.a.
Posology
QD
Route of administration:
Per os
Table 4.1.1: 5
Placebo matching BI 425809, 25mg:
Substance:
Placebo matching BI 425809
Pharmaceutical formulation:
Tablet
Source:
Boehringer Ingelheim Pharma GmbH & Co KG
Birkendorfer Strasse 65
D-88397 Biberach a.d. Riss
Unit strength:
n.a.
Daily Dose
n.a.
Posology
QD
Route of administration:
Per os
4.1.2
Method of assigning patients to treatment groups
Patients are randomised to treatment groups at Visit 2. Note that the medication number is 
different from the patient number (the latter is assigned at trial entry). 
During Visit 2 and after the patient’s eligibility has been confirmed, the treatment will be 
assigned via Interactive Response Technology (IRT). To facilitate the use of the IRT, the 
Investigator will receive all necessary instructions.
4.1.3
Selection of doses in the trial
Efficacy in animal cognition tests is shown at doses that produce approximately 50% glycine 
increase in cerebrospinal fluid (CSF). These doses also result in CSF levels of BI 425809 of 
1x GLYT1 IC50. 


Boehringer Ingelheim
12 Jul 2018
BI Trial No.: 1346.23
c03632269-05
Trial Protocol
Page 27 of 77
Proprietary confidential information © 2018 Boehringer Ingelheim International GmbH or one or more of its affiliated companies
001-MCS-40-106-RD-03 (12.0) / Saved on: 30 Jan 2015
In a clinical phase I study (1346.3) [c03724403-01] a mean 50% glycine increase in CSF was 
achieved at a dose of 10mg QD. 
A mean CSF concentration of BI 425809 of 1xGLTY1 IC50 (5nM) was achieved at a dose of 
5 mg QD. Therefore, the target clinical dose is 5-10 mg QD.
4.1.4
Drug assignment and administration of doses for each patient
IRT will allocate medication kit numbers at Visit 2, 4, and 5. The amount of trial medication 
dispensed and returned will be recorded on drug accountability forms.
For blinding reasons all treatments will consist of three tablets verum or placebo to be taken 
in the morning depending on the treatment arm. This will not be changed during the entire 
study period (V2-EOT). 
For days without site visits, patients should be instructed to take the tablets orally with water 
in the morning at approximately the same time every day with or without food. If a dose is 
missed by more than 12hrs, that dose should be skipped and the next dose should be taken as 
scheduled. No double doses should be taken and dose reductions are not permitted. Patients 
should be instructed to bring all unused drug and empty study blister / bottles to the study 
site.
Patients should be instructed NOT to take their study medication on the morning of scheduled 
trial visits. The first dose of study medication will be taken in the end of visit 2 under 
supervision of the investigator or site staff. At all site visits the morning dose of the 
investigational drug will be taken during the visit under supervision of the investigator or 
relevant site staff after (if applicable) the blood samples were taken, the only exceptions are 
visits 3 a-c at which the IMP may also be taken at home. The last dose of study 
medication will be taken at EOT/ED visit (i.e. end of randomized treatment visit).
The actual visit date and time of study drug administration at the trial visit will be recorded 
in the eCRF at each visit. Patients are allowed to have a light breakfast/meal before the 
scheduled visit. Patients who erroneously take the morning dose of study medication before 
coming to the clinic at a visit with scheduled PK samples should have the visit rescheduled as 
soon as possible, ideally on the following day.
4.1.5
Blinding and procedures for unblinding
Blinding
4.1.5.1
Patients, Investigators and everyone involved in trial conduct or analysis or with any other
interest in this double-blind trial will remain blinded with regard to the randomised treatment 
assignments until after database lock.
The randomization code will be kept secret by Clinical Trial Support up to database lock.
The randomization codes will be provided to bioanalytics prior to last patient out to allow for 
the exclusion from the analyses of pharmacokinetic (PK) samples taken from placebo 
patients. Bioanalytics will not disclose the randomization code or the results of their 
measurements until the trial is officially unblinded.


Boehringer Ingelheim
12 Jul 2018
BI Trial No.: 1346.23
c03632269-05
Trial Protocol
Page 28 of 77
Proprietary confidential information © 2018 Boehringer Ingelheim International GmbH or one or more of its affiliated companies
001-MCS-40-106-RD-03 (12.0) / Saved on: 30 Jan 2015
Unblinding and breaking the code
4.1.5.2
Emergency unblinding will be available to the Investigator / Pharmacist / investigational drug 
storage manager via IRT. It must only be used in an emergency situation when the identity of 
the trial drug must be known to the Investigator in order to provide appropriate medical 
treatment or otherwise assure safety of trial participants. The reason for unblinding must be 
documented in the source documents and/or appropriate CRF page along with the date and 
the initials of the person who broke the code.
Due to the requirements to report Suspected Unexpected Serious Adverse Reactions 
(SUSARs), it may be necessary for a representative from Boehringer Ingelheim’s 
Pharmacovigilance group to access the randomisation code for individual patients during trial 
conduct. The access to the code will only be given to authorised Pharmacovigilance 
representatives and not be shared further.
For Japan only: In this blinded trial, an emergency code break will be available to the 
Investigator / the sub-Investigators via the IRT system. This code break may only be accessed 
in emergency situations when the identity of the trial drug must be known to the Investigator
/the sub-Investigators in order to provide appropriate medical treatment or if required to 
assure the safety of trial participants. Each site receives a manual from the IRT provider that 
contains instructions on how to unblind the treatment of a patient via the IRT (via 24-hour 
Emergency helpline). If the code break for a patient is accessed, the Sponsor must be 
informed immediately. The reason for accessing the code break, together with the date, must 
be documented on the appropriate eCRF page. In case third party needs to break the code, 
however, when the Investigator cannot be reached, the code can be opened by calling 
emergency code manager.
4.1.6
Packaging, labelling, and re-supply
For details of packaging and the description of the label, refer to the ISF.
4.1.7
Storage conditions
Drug supplies will be kept in their original packaging and in a secure limited access storage 
area according to the recommended storage conditions on the medication label. A
temperature log must be maintained for documentation.
If the storage conditions are found to be outside the specified range, the local clinical monitor 
(as provided in the list of contacts) must be contacted immediately.
4.1.8
Drug accountability
The Investigator / Pharmacist / investigational drug storage manager will receive the 
investigational drugs delivered by the Sponsor when the following requirements are fulfilled:

Approval of the trial protocol by the IRB / ethics committee, 

Availability of a signed and dated clinical trial contract between the Sponsor and the 
head of the investigational site,


Boehringer Ingelheim
12 Jul 2018
BI Trial No.: 1346.23
c03632269-05
Trial Protocol
Page 29 of 77
Proprietary confidential information © 2018 Boehringer Ingelheim International GmbH or one or more of its affiliated companies
001-MCS-40-106-RD-03 (12.0) / Saved on: 30 Jan 2015

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

Availability of the proof of a medical license for the principal Investigator

for USA availability of Form 1572
The Investigator / Pharmacist / investigational drug storage manager must maintain records of 
the product’s delivery to the trial site, the inventory at the site, the use by each patient, and 
the return to the Sponsor or alternative disposal of unused products. 
These records will include dates, quantities, batch / serial numbers, expiry (‘use- by’) dates, 
and the unique code numbers assigned to the investigational product and trial patients. The 
Investigator / Pharmacist / investigational drug storage manager will maintain records that
document adequately that the patients were provided the doses specified by the CTP and 
reconcile all investigational products received from the Sponsor. At the time of return to the 
Sponsor / appointed CRO, the Investigator / Pharmacist / investigational drug storage 
manager must verify that all unused or partially used drug supplies have been returned by the 
clinical trial patient and that no remaining supplies are in the Investigator’s possession.
CONCOMITANT THERAPY, RESTRICTIONS, AND RESCUE 
4.2
TREATMENT
4.2.1
Rescue medication, emergency procedures, and additional treatment(s)
There are no special emergency procedures to be followed.
4.2.2
Restrictions
Restrictions regarding concomitant treatment
4.2.2.1
For any chronic concomitant treatments stable dose and treatment regime should be 
maintained whenever possible during patient’s participation in the trial. In particular 
this would apply for antihypertensive drugs, lipid-lowering drugs, antidiabetic drugs 
and proton pump inhibitors.
Refer to Table 4.2.2.1:1 for relevant washout periods prior to cognitive testing during the 
study.


Boehringer Ingelheim
12 Jul 2018
BI Trial No.: 1346.23
c03632269-05
Trial Protocol
Page 30 of 77
Proprietary confidential information © 2018 Boehringer Ingelheim International GmbH or one or more of its affiliated companies
001-MCS-40-106-RD-03 (12.0) / Saved on: 30 Jan 2015
Table 4.2.2.1:1 Provides an overview of required, permitted and restricted medication. 
Study Period
Drug class
Sub-class
Prior to Visit 1
Visit 1 and 
Screening 
Period
Treatment 
Period
Follow-up 
Period
AD treatments
Cholinesterase 
inhibitors: eg 
Donepezil, 
rivastigmin, 
galantamine, 
tacrine, 
phenserine
Permitted if 
initiated and 
stable for at least 
3 months prior to 
Visit 1 and no 
change is 
foreseen during 
the study
Permitted if 
no dose and/or 
treatment 
regime change
Permitted if 
no dose and/or 
treatment 
regime change
Permitted if 
no dose 
and/or 
treatment 
regime 
change
memantine
NOT permitted 
for at least 3 
months prior to 
Visit 1
NOT 
permitted
NOT 
permitted
NOT 
permitted
Hypnotics/Sedatives
Benzodiazepines 
and 
Miscellaneous 
(eg H1 inhibitors, 
melatonine, 
herbal products 
etc.)1
Permitted if 
stable 8 weeks 
prior to V1
Permitted if 
no dose and/or 
treatment 
regime change
Permitted if 
no dose and/or 
treatment 
regime change
Permitted if 
no dose 
and/or 
treatment 
regime 
change
Barbiturates 
NOT permitted 
for at least 3 
months prior to 
Visit 1
NOT 
permitted
NOT 
permitted
NOT 
permitted


Boehringer Ingelheim
12 Jul 2018
BI Trial No.: 1346.23
c03632269-05
Trial Protocol
Page 31 of 77
Proprietary confidential information © 2018 Boehringer Ingelheim International GmbH or one or more of its affiliated companies
001-MCS-40-106-RD-03 (12.0) / Saved on: 30 Jan 2015
Table 4.2.2.1:1 Provides an overview of required, permitted and restricted medication. (cont.)
Study Period
Drug class
Sub-class
Prior to Visit 1
Visit 1 and 
Screening 
Period
Treatment 
Period
Follow-up 
Period
Antipsychotics 
(Neuroleptics)
Typical (1st
generation) and 
Atypical (2nd
generation)
Antipsychotics1
Permitted if stable 
at least 8 weeks 
prior to Visit 1
Permitted if no 
dose and/or 
treatment 
regime change
Permitted if no 
dose and/or 
treatment 
regime change
Permitted if 
no dose 
and/or 
treatment 
regime 
change
Antidepressants
Tricyclic, 
Tetracyclic, 
MAO inhibitors, 
SSRI, SNRI, 
SMSs, SARIS, 
NaSSA, NRIs  
and other 
mechanisms of 
action including 
herbal products1
Permitted if stable 
at least 8 weeks 
prior to Visit 1
Permitted if no 
dose and/or 
treatment 
regime change
Permitted if no 
dose and/or 
treatment 
regime change
Permitted if 
no dose 
and/or 
treatment 
regime 
change
Nootropics/       
Cognitive 
enhancers 
including 
Gingko and 
peripheral 
vasodilators 
Miscellaneous1
Permitted if 
initiated at least at 
Visit 1
Permitted if no 
dose and/or 
treatment 
regime change
Permitted if no 
dose and/or 
treatment 
regime change
Permitted if 
no dose 
and/or 
treatment 
regime 
change
Psychostimulants 
and 
Psychodyslectics
Miscellaneous1
Permitted if stable 
at least 3 months 
prior to Visit 1
Permitted if no 
dose and/or 
treatment 
regime change
Permitted if no 
dose and/or 
treatment 
regime change
Permitted if 
no dose 
and/or 
treatment 
regime 
change
Antiepileptics
Miscellaneous
Permitted if stable 
at least 3 months 
prior to Visit 1
Permitted if no 
dose and/or 
treatment 
regime change
Permitted if no 
dose and/or 
treatment 
regime change
Permitted if 
no dose 
and/or 
treatment 
regime 
change


Boehringer Ingelheim
12 Jul 2018
BI Trial No.: 1346.23
c03632269-05
Trial Protocol
Page 32 of 77
Proprietary confidential information © 2018 Boehringer Ingelheim International GmbH or one or more of its affiliated companies
001-MCS-40-106-RD-03 (12.0) / Saved on: 30 Jan 2015
Table 4.2.2.1:1 Provides an overview of required, permitted and restricted medication. (cont.)
Study Period
Drug class
Sub-class
Prior to Visit 1
Visit 1 and 
Screening 
Period
Treatment 
Period
Follow-up 
Period
Antiparkinsonics
Any 
Dopaminergics
and/or MAO-B 
inhibitors and/or 
COMT Inhibitors 
and/or 
Anticholinergics 
including 
Antihistaminines 
with 
anticholinergic 
effect 
Permitted if stable 
at least 3 months 
prior to Visit 1
Permitted if no 
dose and/or 
treatment 
regime change
Permitted if no 
dose and/or 
treatment 
regime change
Permitted if 
no dose 
and/or 
treatment 
regime 
change
Muscle relaxants
Central1
Permitted if stable 
at least 8 weeks 
prior to Visit 1
Permitted if no 
dose and/or 
treatment 
regime change
Permitted if no 
dose and/or 
treatment 
regime change
Permitted if 
no dose 
and/or 
treatment 
regime 
change
Antiemetics
Antihistamines, 
Benzamides, 5-
HT3 inhibitors1
Permitted if stable 
at least 8 weeks 
prior to Visit 1
Permitted if no 
dose and/or 
treatment 
regime change
Permitted if no 
dose and/or 
treatment 
regime change
Permitted if 
no dose 
and/or 
treatment 
regime 
change
Antimuscarinic 
drugs used for 
urinary 
incontinence 
treatment1
Permitted if stable 
at least 4 weeks 
prior to Visit 1
Permitted if no 
dose and/or 
treatment 
regime change
Permitted if no 
dose and/or 
treatment 
regime change
Permitted if 
no dose 
and/or 
treatment 
regime 
change
Central 
Analgesics
Opioid agonists1
Permitted if 
stable at least 4 
weeks prior to 
Visit 1
Permitted if no 
dose and/or 
treatment 
regime change
Permitted if no 
dose and/or 
treatment 
regime change
Permitted if 
no dose 
and/or 
treatment 
regime 
change


Boehringer Ingelheim
12 Jul 2018
BI Trial No.: 1346.23
c03632269-05
Trial Protocol
Page 33 of 77
Proprietary confidential information © 2018 Boehringer Ingelheim International GmbH or one or more of its affiliated companies
001-MCS-40-106-RD-03 (12.0) / Saved on: 30 Jan 2015
Table 4.2.2.1:1 Provides an overview of required, permitted and restricted medication. (cont.)
Study Period
Drug class
Sub-class
Prior to Visit 1
Visit 1 and 
Screening 
Period
Treatment 
Period
Follow-up 
Period
Strong and 
Moderate 
CYP3A4 
inhibitors and 
inducers2,3
NOT permitted 
for at least 8 
weeks prior to 
Visit 1
NOT permitted
NOT permitted
NOT 
permitted
CYP3A4 
sensitive drugs 
with narrow 
therapeutic 
index (e.g.
cyclosporine, 
fentanyl)2,3  
NOT permitted 
for at least 8 
weeks prior to 
Visit 1
NOT permitted
NOT permitted
NOT 
permitted
Grapefruit 
juice and St. 
John’s wort 
preparations
NOT permitted 
for at least 7 
days prior to 
Visit 2
NOT 
permitted
NOT
permitted
NOT 
permitted
Vitamin 
B12/Folate
Permitted in case 
of stable 
treatment prior 
to V1 or even if 
initiated either at 
Visit 1 or during 
screening period
Permitted 
Permitted 
Permitted
Nutritional 
Support of AD
Permitted in case 
of stable 
treatment prior 
to V1 or even if 
initiated either at 
Visit 1 or during 
screening period
Permitted if 
no dose and/or 
treatment 
regime change
Permitted if 
no dose and/or 
treatment 
regime change
Permitted if 
no dose 
and/or 
treatment 
regime 
change
Investigational 
Drugs 
NOT permitted 
for at least 3 
months or 6 half-
lives (whatever 
comes longer) 
prior to Visit 1
NOT permitted
NOT permitted
NOT 
permitted
1If these drugs are taken occasionally, i.e. on as needed bases, or if such treatment needs to be added and/or dose changed 
then dosing on the night prior to cognitive testing is not allowed. 


Boehringer Ingelheim
12 Jul 2018
BI Trial No.: 1346.23
c03632269-05
Trial Protocol
Page 34 of 77
Proprietary confidential information © 2018 Boehringer Ingelheim International GmbH or one or more of its affiliated companies
001-MCS-40-106-RD-03 (12.0) / Saved on: 30 Jan 2015
2For medication list, refer to the ISF
3If any of the listed drugs need to be added, then the IMP should be discontinued for at least the period of needed concurrent 
use. Once the use of either strong/moderate CYP3A4 inhibitors and inducers or CYP3A4 sensitive drugs with narrow 
therapeutic index is stopped, the re-introduction of the trial drug is possible as per investigator clinical judgement. The 
re-introduction details may be consulted with the clinical monitor local.
Please note: CYP3A4 and CYP2B6 sensitive drugs may have decreased levels of exposure 
when given concomitantly with BI 425809. Investigators should assess if dose adjustments 
and/or monitoring of the underlying disease is clinically required for patients who are taking 
such drugs. For a list of CYP3A4 and CYP2B6 sensitive drugs please refer to the list in the
ISF. 
BI 425809 may cause clinically relevant induction of CYP2B6. CYP2B6 sensitive drugs are 
not excluded but are to be given with caution. 
Restrictions on diet and life style
4.2.2.2
There are no other restrictions on diet, exercise, alcohol consume or smoking except that the 
patient’s usual habits, including nicotine and caffeine intake, should be within acceptable 
daily amounts in discretion of the investigator and not be drastically changed throughout the 
study conduct. The use of grapefruit juice (strong CYP3A4 inhibitor) and St. John’s 
wort preparations (strong CYP3A4 inducer) are restricted (see list of CYP3A4 
inhibitors in the ISF) starting 7 days before the first IMP administration until the end of 
treatment.
Considering the visual disturbances reported after drug administration and as a general 
precaution for CNS-active drugs, it is recommended that subjects should exercise caution
when driving or operating machinery after drug administration.
Dietary supplements and herbal remedies may impact the assessment of cognitive tests and 
therefore may be used only in line with Table 4.2.2.1:1.
TREATMENT COMPLIANCE
4.3
Patients are requested to bring all remaining trial medication including empty package 
material with them when attending visits.
Based on counts, treatment compliance will be calculated as the number of capsules taken, 
divided by the number of capsules which should have been taken according to the scheduled 
period, multiplied by 100. Compliance will be verified by the on-site monitor authorised by 
the Sponsor.
Treatment compliance (%) =
Number of tablets actually taken 100
     Number of tablets which should have been taken
If the number of doses taken is not between 80-120%, site staff will explain the patient the 
importance of treatment compliance.


Boehringer Ingelheim
12 Jul 2018
BI Trial No.: 1346.23
c03632269-05
Trial Protocol
Page 35 of 77
Proprietary confidential information © 2018 Boehringer Ingelheim International GmbH or one or more of its affiliated companies
001-MCS-40-106-RD-03 (12.0) / Saved on: 30 Jan 2015
5.
VARIABLES AND THEIR ASSESSMENT 
TRIAL ENDPOINTS
5.1
The following efficacy measures are completed at the times shown in Section 6.2 and the 
Flow Chart:
5.1.1
Primary Endpoint(s)

The change from baseline in ADAS-Cog11 (Alzheimer’s Disease Assessment Scale-
Cognitive subscale 11 item) total score after 12 weeks of treatment
5.1.2
Secondary Endpoint(s)

Change from baseline in the ADCS-ADL (Alzheimer’s Disease Cooperative 
Study/Activities of Daily Living) score after 12weeks of treatment

CIBIC+ (Clinician's Interview-Based Impression of Change) score after 12 weeks of
treatment
ASSESSMENT OF EFFICACY
5.2
Established neuropsychological assessments will be used to capture individual changes in 
memory, cognitive function and activities of daily living. Detailed instructions how to 
administer the assessments can be found in the respective user manuals which will be filed in 
the ISF.
ADAS-Cog11 is an 11-item cognitive subscale that objectively measures memory, language, 
orientation and praxis with a total score range of 0 to 70, with lower scores indicating less 
severe impairment.  A negative change indicates an improvement from baseline [R96-2608].


Boehringer Ingelheim
12 Jul 2018
BI Trial No.: 1346.23
c03632269-05
Trial Protocol
Page 36 of 77
Proprietary confidential information © 2018 Boehringer Ingelheim International GmbH or one or more of its affiliated companies
001-MCS-40-106-RD-03 (12.0) / Saved on: 30 Jan 2015
ADCS-ADL is a rating scale used to assess basic and instrumental activities of daily living. 
In the full version of the scale, 23 items are rated by the investigator using information 
supplied by the caregiver. Each item has a score range varying from 0-3 to 0-5. The sum 
score could range from 0 to 78, with higher scores indicating less severe impairment.  A 
positive change indicates an improvement from baseline [R97-3207].
CIBIS and CIBIC+ (Clinician's Interview-Based Impression of Change) scales are based on 
semi- structured interview covering domains of function and cognition. They additionally 
require the assessment of psychiatric signs and symptoms.  The patient and their caregiver are 
interviewed and questioned by the clinician [R17-3992].  


Boehringer Ingelheim
12 Jul 2018
BI Trial No.: 1346.23
c03632269-05
Trial Protocol
Page 37 of 77
Proprietary confidential information © 2018 Boehringer Ingelheim International GmbH or one or more of its affiliated companies
001-MCS-40-106-RD-03 (12.0) / Saved on: 30 Jan 2015
ASSESSMENT OF SAFETY
5.3
5.3.1
Physical examination
A full physical examination will be performed at the visits indicated in the Flow Chart. This 
should be performed according to medical standards and usually includes (but is not 
necessarily limited to) a review of the following organ systems: General appearance 
(including Skin), Head-Eyes-Ears-Nose-Throat (HEENT), Chest (including Pulmonary and 
Heart), Abdomen, Extremities, Urogenital  and neurological assessment (basic mental status, 
cranial nerves, motor system, sensation, cerebellum/coordination). Clinically relevant 
abnormal findings documented after inclusion will be reported as (S)AEs.
5.3.2
Vital Signs
Systolic and diastolic blood pressure (BP) and pulse rate (PR) will be measured after the 
patient has rested for at least 5 min in the sitting position. The measured vital signs will be 
documented in the source documents and recorded in the eCRF.
5.3.3
Safety laboratory parameters
Parameters that will be determined during the trial conduct are listed in Table 5.3.3: 1 and 
Table 5.3.3: 2. All analyses will be performed by a central laboratory. Patients don’t have to 
be fasted for the blood sampling for the safety laboratory. The respective reference ranges 
and details about sample handling and shipment will be provided in the ISF (Lab Manual).
Haemoglobin, GFR, ALT, AST and alkaline phosphatase found abnormal at Visit 1 
may be re-tested twice prior to Visit 2.
The following lab parameters will not be determined at each study visit:

TSH at screening only

Vitamin B12 and folate at screening and EOT only; if at Screening visit (Visit 1) 
Vitamin B12 and folate lab results are found abnormal (below lower limit normal) an 
appropriate treatment may be initiated. Two re-tests can be done prior to Visit 2. The 
patient can be randomised only if Vitamin B12 and folate lab results are within 
normal reference ranges. Refer to section 6.1 for further information on visit 
scheduling. 


Boehringer Ingelheim
12 Jul 2018
BI Trial No.: 1346.23
c03632269-05
Trial Protocol
Page 38 of 77
Proprietary confidential information © 2018 Boehringer Ingelheim International GmbH or one or more of its affiliated companies
001-MCS-40-106-RD-03 (12.0) / Saved on: 30 Jan 2015
Table 5.3.3: 1
Safety laboratory parameters – whole blood, serum or plasma
Hematology

Haematocrit

Haemoglobin

MCV, MCH, RDW, MCHC

Reticulocyte Count and Index
(reflex test if Hb outside normal 
range or decreased >2g/dL 
compared to baseline)

Red Blood Cells (RBC) / 
Erythrocytes

WBC / Leukocytes

Platelet Count / Thrombocytes

Differential Automatic (relative and 
absolute count): 
Neutrophils, Eosinophils, Basophils, 
Monocytes,  Lymphocytes
Clinical chemistry

Albumin 

Alkaline phosphatase
- -GT (gamma-glutamyl 
transferase) reflex test triggered by
elevated alkaline phosphatase on 
two sequential measures

ALT (alanine aminotransaminase, 
SGPT)

AST (aspartate 
aminotransaminase, SGOT) 

Bicarbonate

Bilirubin total, fractionated if 
increased 

Calcium 

Chloride 

Creatinine 

Vitamin B12

Ferritin, serum iron, transferrin 
and TIBC as reflex if Hb outside 
normal range or decreased >2g/dL 
compared to baseline

Creatine kinase (CK)

CK-MB, troponin (reflex tests if CK is 
elevated)

Lactate dehydrogenase (LDH)

Lipase

Magnesium 

Phosphate 

Potassium

Protein total 

Sodium

Urea (BUN)

LDL/HDL and total cholesterol

Triglycerides

TSH

Folate


Boehringer Ingelheim
12 Jul 2018
BI Trial No.: 1346.23
c03632269-05
Trial Protocol
Page 39 of 77
Proprietary confidential information © 2018 Boehringer Ingelheim International GmbH or one or more of its affiliated companies
001-MCS-40-106-RD-03 (12.0) / Saved on: 30 Jan 2015
Table 5.3.3: 2
Safety laboratory parameters – urine
Urinalysis 
Semi quantitative

Nitrite

Protein

Glucose

Hemoglobin

Ketone

Urine pH

Leukocyte esterase (for 
WBC)
Urine Drug Screen

Cannabis 

Cocaine

Benzodiazepine

Amphetamines

Barbiturates

Methadone

Opiates

Phencyclidine (PCP)
Human urine chorionic 
gonadotropin (HCG)*
*Pregnancy testing (HCG, urine) will only be performed if required by local regulations. It may also be done more
frequently or in plasma instead of urine if required (please note: this trial will include no patients of child-bearing 
potential)
5.3.4
Electrocardiogram
A12-lead ECGs (I, II, III, aVR, aVL, aVF, V1 – V6) will be performed as scheduled in the 
Flow Chart using the equipment provided by the central ECG vendor. The ECGs will be 
recorded for at least 10 second duration after the subjects have rested for at least 5 minutes in 
a supine position. Electrode placement will be performed according to the method of 
Einthoven/Goldberger (ankles and wrists). Single ECGs will be recorded at the time points 
indicated in the Flow Chart.  At visits 3, 4 and EOT the ECGs will be performed preferably 
within 3-5 hours post IMP dosing to correlate with the cmax of the BI 425809. ECG 
recordings at planned time points may be repeated for quality reasons like alternating current 
artefacts, muscle movements and electrode dislocation. In this case the repeated ECG 
recordings will be used if quality was better.
The investigator or a designee should evaluate whether the ECG is normal or abnormal and 
whether it is clinically significant, if abnormal. The electronic version of the ECG is regarded 


Boehringer Ingelheim
12 Jul 2018
BI Trial No.: 1346.23
c03632269-05
Trial Protocol
Page 40 of 77
Proprietary confidential information © 2018 Boehringer Ingelheim International GmbH or one or more of its affiliated companies
001-MCS-40-106-RD-03 (12.0) / Saved on: 30 Jan 2015
as source data. Dated and signed printouts will be stored in the patient’s medical file if there 
is no validated and certified e-medical record for ECG data.
Additional ECGs may be collected by the investigator for safety reasons. Clinically relevant 
findings noticed at baseline assessment should be reported as baseline condition. Clinically 
relevant abnormal findings noticed after baseline assessment will be reported as adverse 
events and followed up and/or treated locally until normal or stable condition.
All ECGs will be transmitted electronically to the central ECG vendor to perform a 
centralized and independent analysis. Abnormalities detected during this centralized ECG 
evaluation will not necessarily qualify as AEs.
Central evaluation on individual ECGs will be performed by the vendor and a report will be 
provided to the site. Decisions on patient’s eligibility, treatment or further follow-up of any 
ECG related findings are the responsibility of the investigator. 
5.3.5
Other safety parameters
Suicidal risk assessed by the C-SSRS 
5.3.5.1
Consistent with the FDA draft guidance entitled "Suicidal Ideation and Behaviour: 
Prospective Assessment of Occurrence in Clinical Trials", prospective assessment of suicidal 
ideation and behaviour is included in this study using the C-SSRS (paper version; shall be 
administered via Bracket rater-station). 
The C-SSRS is a semi-structured, investigator-rated interview, developed by clinical experts 
in cooperation with the FDA, assessing both suicidal behaviour and suicidal ideation. It does 
not give a global score, but provides some categorical and some severity information 
specifically for behaviour and ideation.
The C-SSRS interview may be administered by any type of physician, psychologist, clinical 
social worker, mental health counsellor, 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 behaviour, 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 
behaviour 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 behaviour 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.


Boehringer Ingelheim
12 Jul 2018
BI Trial No.: 1346.23
c03632269-05
Trial Protocol
Page 41 of 77
Proprietary confidential information © 2018 Boehringer Ingelheim International GmbH or one or more of its affiliated companies
001-MCS-40-106-RD-03 (12.0) / Saved on: 30 Jan 2015
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.
5.3.6
Assessment of adverse events
Definitions of AEs 
5.3.6.1
Adverse event
An adverse event (AE) is defined as any untoward medical occurrence in a patient or clinical 
investigation subject administered a medicinal product and which does not necessarily have 
to have a causal relationship with this treatment.
An AE can therefore be any unfavourable and unintended sign (including an abnormal 
laboratory finding), symptom, or disease temporally associated with the use of a medicinal 
product, whether or not considered related to the medicinal product.
Adverse reaction
An adverse reaction is defined as a response to a medicinal product which is noxious and 
unintended. Response in this context means that a causal relationship between a medicinal 
product and an adverse event is at least a reasonable possibility. Adverse reactions may arise 
from use of the product within or outside the terms of the marketing authorisation or from 
occupational exposure. Conditions of use outside the marketing authorization include off 
label use, overdose, misuse, abuse and medication errors.
Serious adverse event
A serious adverse event (SAE) is defined as any AE which:

results in death,

is life-threatening,

requires inpatient hospitalisation or prolongation of existing hospitalisation,

results in persistent or significant disability or incapacity,

is a congenital anomaly/birth defect,
or

is to be deemed serious for any other reason if it is an important medical event when 
based upon appropriate medical judgment which may jeopardize the patient and may 
require medical or surgical intervention to prevent one of the other outcomes listed in 
the above definitions.
Life-threatening in this context 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. All reports of suicidal ideation type 4 or 5 and all reports of suicidal behavior 


Boehringer Ingelheim
12 Jul 2018
BI Trial No.: 1346.23
c03632269-05
Trial Protocol
Page 42 of 77
Proprietary confidential information © 2018 Boehringer Ingelheim International GmbH or one or more of its affiliated companies
001-MCS-40-106-RD-03 (12.0) / Saved on: 30 Jan 2015
from prospective monitoring in C-SSRS (see Section 5.3.5.1 for details) are also considered 
to be life-threatening and must be reported as SAEs by the investigator.
For Japan only: The following events will be handled as “deemed serious for any other 
reason”. An AE which possibly leads to disability will be reported as an SAE.
AEs considered “Always Serious”
In accordance with the European Medicines Agency initiative on Important Medical Events, 
Boehringer Ingelheim has set up a list of AEs, which by their nature, can always be 
considered to be “serious” even though they may not have met the criteria of an SAE as given 
above.
The latest list of “Always Serious AEs” can be found in the RDC. These events should 
always be reported as SAEs as described in Section 5.3.7.
Cancers of new histology and exacerbations of existing cancer must be reported as a serious 
event regardless of the duration between discontinuation of the drug and the occurrence of the 
cancer.
Adverse events of special interest (AESIs)
The term AESI relates to any specific AE that has been identified at the project level as being 
of particular concern for prospective safety monitoring and safety assessment within this trial, 
e.g. the potential for AEs based on knowledge from other compounds in the same class. AESI 
need to be reported to the Sponsor’s Pharmacovigilance Department within the same 
timeframe that applies to SAE, see Section 5.3.7.
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 and/or ALT >3 fold ULN combined with an elevation of total 
bilirubin >2 fold ULN measured in the same blood draw sample, and/or

marked peak aminotransferase (ALT, and/or AST) elevations ≥10 fold ULN
These lab findings constitute a hepatic injury alert and the patients showing these lab 
abnormalities need to be followed up according to the “DILI checklist” provided via the 
RDC-system.
In case of clinical symptoms of hepatic injury (icterus, unexplained encephalopathy, 
unexplained coagulopathy, right upper quadrant abdominal pain, etc.) without lab results 
(ALT, AST, total bilirubin) available, the investigator should make sure these parameters are 
analysed, if necessary in an unscheduled blood test. Should the results meet the criteria of 
hepatic injury alert, the procedures described in the DILI checklist should be followed.
No further AESIs have been defined for this trial.


Boehringer Ingelheim
12 Jul 2018
BI Trial No.: 1346.23
c03632269-05
Trial Protocol
Page 43 of 77
Proprietary confidential information © 2018 Boehringer Ingelheim International GmbH or one or more of its affiliated companies
001-MCS-40-106-RD-03 (12.0) / Saved on: 30 Jan 2015
Intensity of AEs
The intensity of the AE should be judged based on the following:
Mild:
Awareness of sign(s) or symptom(s) that is/are easily tolerated
Moderate:
Enough discomfort to cause interference with usual activity
Severe:
Incapacitating or causing inability to work or to perform usual activities
Causal relationship of AEs
The definition of an adverse reaction implies at least a reasonable possibility of a causal 
relationship between a suspected medicinal product and an adverse event. An adverse 
reaction, in contrast to an adverse event, is characterised by the fact that a causal relationship 
between a medicinal product and an occurrence is suspected.
Medical judgment should be used to determine the relationship, considering all relevant 
factors, including pattern of reaction, temporal relationship, de-challenge or re-challenge, 
confounding factors such as concomitant medication, concomitant diseases and relevant
history.
Arguments that may suggest that there is a reasonable possibility of a causal relationship 
could be:

The event is consistent with the known pharmacology of the drug

The event is known to be caused by or attributed to the drug class.

A plausible time to onset of the event relative to the time of drug exposure.

Evidence that the event is reproducible when the drug is re-introduced

No medically sound alternative aetiologies that could explain the event (e.g. 
preexisting or concomitant diseases, or co-medications).

The event is typically drug-related and infrequent in the general population not 
exposed to drugs (e.g. Stevens-Johnson syndrome).

An indication of dose-response (i.e. greater effect size if the dose is increased, smaller 
effect size if dose is diminished).
Arguments that may suggest that there is no reasonable possibility of a causal relationship 
could be:

No plausible time to onset of the event relative to the time of drug exposure is evident
(e.g. pre-treatment cases, diagnosis of cancer or chronic disease within days / weeks of 
drug administration; an allergic reaction weeks after discontinuation of the drug
concerned)

Continuation of the event despite the withdrawal of the medication, taking into 
account the pharmacological properties of the compound (e.g. after 5 half-lives).
Of note, this criterion may not be applicable to events whose time course is prolonged
despite removing the original trigger.

Additional arguments amongst those stated before, like alternative explanation (e.g. 
situations where other drugs or underlying diseases appear to provide a more likely 
explanation for the observed event than the drug concerned).

Disappearance of the event even though the study drug treatment continues or remains 
unchanged.


Boehringer Ingelheim
12 Jul 2018
BI Trial No.: 1346.23
c03632269-05
Trial Protocol
Page 44 of 77
Proprietary confidential information © 2018 Boehringer Ingelheim International GmbH or one or more of its affiliated companies
001-MCS-40-106-RD-03 (12.0) / Saved on: 30 Jan 2015
For Japan only: the reason for the decision on causal relationship for unlisted AEs needs to be
provided in the CRF.
5.3.7
Adverse event collection and reporting
AE Collection
The following must be collected and documented on the appropriate eCRF by the 
Investigator:

From signing the informed consent onwards through the Residual Effect Period 
(REP), until individual patient’s end of trial:
- all AEs (serious and non-serious) and all AESIs.

After the individual patient’s end of trial: 
- the investigator does not need to actively monitor the patient for AEs but should 
only report relevant SAEs and relevant AESIs of which the investigator may become 
aware of.
Figure 5.3.7: 1  
Collection and reporting of AEs/SAEs during the study
If a patient reports a change in visual perception or any vision-related AE, site staff must 
record the patient’s verbatim description in the source documents to be reported in the eCRF
and SAE form, if applicable. A local ophthalmology assessment will be required for any 
visual AE that is rated as moderate or severe by the subject or at the discretion of the PI. The 
ophthalmologist will act as a consultant to the Investigator and may offer advice on the 
proper management and treatment for the reaction.
The REP is defined as 11 days after the last trial medication application. All AEs which 
occurred through the treatment phase and throughout the REP will be considered as on 
treatment please see Section 7.3.4. Events which occurred after the REP will be considered as 
post treatment events.


Boehringer Ingelheim
12 Jul 2018
BI Trial No.: 1346.23
c03632269-05
Trial Protocol
Page 45 of 77
Proprietary confidential information © 2018 Boehringer Ingelheim International GmbH or one or more of its affiliated companies
001-MCS-40-106-RD-03 (12.0) / Saved on: 30 Jan 2015
AE reporting to sponsor and timelines
The Investigator must report SAEs, AESIs, and non-serious AEs which are relevant for the 
reported SAE or AESI, on the BI SAE form via fax immediately (within 24 hours ) to the 
Sponsor’s unique entry point (country specific contact details will be provided in the ISF). 
The same timeline applies if follow-up information becomes available. In specific occasions 
the Investigator could inform the Sponsor upfront via telephone. This does not replace the 
requirement to complete and fax the BI SAE form.
For Japan only : All SAEs and AESIs must be reported immediately to the head of the trial 
site.
With receipt of any further information to these events, a follow-up SAE form has to be 
provided. For follow-up information the same rules and timeline apply as for initial 
information.
Information required
For each AE, the Investigator should provide the information requested on the appropriate 
(e)CRF pages and the BI SAE form. The Investigator should determine the causal 
relationship to the trial medication.
The following should also be recorded as an (S)AE in the (e)CRF and SAE form (if 
applicable):

Worsening of the underlying disease or of other pre-existing conditions

Changes in vital signs, ECG, physical examination and laboratory test results, if they 
are judged clinically relevant by the Investigator.
If such abnormalities already pre-exist prior trial inclusion they will be considered as 
baseline conditions.
All (S)AEs, including those persisting after individual patient’s end of trial must be followed 
up until they have resolved, have been sufficiently characterized, or no further information 
can be obtained.
Pregnancy
In rare cases pregnancy may occur in a clinical trial. Once a patient has been enrolled into 
this clinical trial and has taken trial medication, the Investigator must report immediately 
(within 24 hours) any potential drug exposure during pregnancy (DEDP) to the sponsor’s 
unique entry point (country-specific contact details will be provided in the ISF). The
Pregnancy Monitoring Form for Clinical Trials (Part A) should be used.
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 B).


Boehringer Ingelheim
12 Jul 2018
BI Trial No.: 1346.23
c03632269-05
Trial Protocol
Page 46 of 77
Proprietary confidential information © 2018 Boehringer Ingelheim International GmbH or one or more of its affiliated companies
001-MCS-40-106-RD-03 (12.0) / Saved on: 30 Jan 2015
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.


Boehringer Ingelheim
12 Jul 2018
BI Trial No.: 1346.23
c03632269-05
Trial Protocol
Page 47 of 77
Proprietary confidential information © 2018 Boehringer Ingelheim International GmbH or one or more of its affiliated companies
001-MCS-40-106-RD-03 (12.0) / Saved on: 30 Jan 2015


Boehringer Ingelheim
12 Jul 2018
BI Trial No.: 1346.23
c03632269-05
Trial Protocol
Page 48 of 77
Proprietary confidential information © 2018 Boehringer Ingelheim International GmbH or one or more of its affiliated companies
001-MCS-40-106-RD-03 (12.0) / Saved on: 30 Jan 2015
6.
INVESTIGATIONAL PLAN
VISIT SCHEDULE
6.1
All trial visits should be initiated preferentially in the morning starting before 9:00 AM and 
as consistently as possible throughout the entire trial. Patients should be instructed to 
avoid intake of the morning dose of the study medication at home at scheduled visit days as 
they will be dosed whilst at the study site under site staff supervision.
All patient visits should be scheduled according to the Flow Chart. All visit procedures 
should preferably be completed on one day. If necessary (preferred), all planned 
neuropsychological rating scales (as per Flow Chart) from Visit 1 (screening) to Visit 6 (end 
of treatment) can be performed one day prior to the planned clinic visit. Sites should make 
every attempt to adhere to the protocol time windows as close as possible. The screening 
period may be shorten to a minimum of 7 days if all screening procedures and results 
are available. At the same time the screening period (i.e. period between Visit 1 and Visit 
2) may be extended by additional 4 weeks (i.e. 42 days in total) for any reason (e.g. 
administrative reasons, lab re-tests, concomitant medication adherence, adverse event, etc.). 
If screening period needs to be extended any further, the clinical monitor should be contacted
to discuss further steps. If any visit after the randomisation has to be rescheduled, subsequent 
visits should follow the original visit schedule with the goal to reach 85+5 days treatment 
period. The trial medication packs contain sufficient medication to allow for these time 
windows.
If the reason for removal of a patient from the treatment is an adverse event or an abnormal 
laboratory test result, the patient must be followed until complete resolution or stabilization
of the event or until follow-up is agreed adequate by the Investigator and BI Clinical Monitor.
DETAILS OF TRIAL PROCEDURES AT SELECTED VISITS
6.2
The following requirements for the conduct of the neuropsychological assessments need to be
followed: 

The assessments should be administered in the same sequence found in the flowchart 
and approximately at the same time of the day at every applicable visit. 

Assessment of the Neuropsychological Rating Scales should preferentially be done by 
the same member of the site staff for a given patient throughout the study period.

CIBIS/CIBIC+ rater should not perform other ratings and further procedures such as 
laboratory procedures, dispensing of IMP, or monitoring of AEs and ASEs. The study 
partner contributing to the functional assessments should not change during the study. 
If that cannot be avoided this is to be recorded in the source data and as a protocol 
violation. 
The members of the site staff performing the assessment have to be properly trained (either at 
the investigator training or individually) and training documentation has to be filed in the 
ISF. The training standards and standards for the conduct of the assessments will be defined 
for each assessment individually and can be found in the ISF. It is the responsibility of the 


Boehringer Ingelheim
12 Jul 2018
BI Trial No.: 1346.23
c03632269-05
Trial Protocol
Page 49 of 77
Proprietary confidential information © 2018 Boehringer Ingelheim International GmbH or one or more of its affiliated companies
001-MCS-40-106-RD-03 (12.0) / Saved on: 30 Jan 2015
Principal Investigator at the site to ensure proper training of all members of the site staff 
involved in the neuropsychological assessments.
6.2.1
Screening and run-in period(s)
Screening Period
Informed Consent prior to trial participation
All patients must sign an Informed Consent consistent with ICH-GCP guidelines prior to any 
study specific procedures. Please refer to Section 8.1 for details. 
Particular procedures
The screening visit (see Flow Chart for full details) will include the following 
procedures/assessments: check of signed Informed Consent, demographics, review of 
relevant medical history/baseline conditions at the discretion of the Investigator, relevant 
medication history and review of concomitant therapy, inclusion/exclusion criteria, physical 
exam, body weight and height, vital signs (blood pressure and pulse rate), ECG, safety 
laboratory tests. Neuropsychological assessments and suicidality monitoring will be done.
6.2.2
Treatment period(s)
The procedures of the visits in the treatment phase will be performed as outlined in the Flow 
Chart. 
Visit 2 (Baseline)
As soon as eligibility of a screened patient is confirmed, the patient may enter the study and 
Visit 2 can be conducted. This visit includes the assessment of the endpoints and 
randomisation via IRT. IRT should preferably be called after the patient has completed the 
assessments of the neuropsychological endpoints.
At the start of Visit 2 it should be ensured that all Visit 1 procedures have been successfully 
completed and eligibility has been confirmed (including results of the neuropsychological 
rating scales performed at Visit 1). 
Neuropsychological assessments will be done. Similarly suicidality monitoring shall be 
performed and eligibility criteria shall be re-assessed.
Study medication should be taken at the end of the visit at the site and study drug kits will be 
dispensed for home administration. Intake of study drug and handling of the blisters needs to 
be trained with the patient and the study partner.
Visit 3a
This visit will be a mandatory clinic visit. Study procedures have to be completed according 
to the Flow Chart.
Visit 3b and 3c:
These visits may be phone contacts with the patient if (in discretion of the investigator) no 
clinically relevant changes in vital signs are observed at Visit 3a. Study procedures have to be 
completed according to the Flow Chart.


Boehringer Ingelheim
12 Jul 2018
BI Trial No.: 1346.23
c03632269-05
Trial Protocol
Page 50 of 77
Proprietary confidential information © 2018 Boehringer Ingelheim International GmbH or one or more of its affiliated companies
001-MCS-40-106-RD-03 (12.0) / Saved on: 30 Jan 2015
The attendance of the study partner is not required for Visits 3a-c. The IMP may be taken at 
home at visits 3 a-c.
Visits 4, 5 and EOT
These visits are part of the treatment period. Procedures are to be performed according to the 
flowchart. The recommendations for the performance of the neuropsychological assessments 
should be noted and followed.
Unscheduled visits will be possible at the discretion of the investigator at any time in order to 
check the safety of the patient.
6.2.3
Follow Up Period and Trial Completion
All randomised patients should be followed up until the end of study at week 16. 
End of Treatment (EOT) Visit:
If the regular end of the treatment period at week 12 is reached or if the patient withdraws 
consent for further participation in the trial the EOT Visit will be completed. The overall 
duration of the treatment period (randomisation to EOT) should not be less than 85 days.
It is important to distinguish between premature study drug discontinuation and complete 
withdrawal of consent to participate in further study procedures. Patients not willing to 
continue study drug intake should be asked to further attend scheduled trial visits, follow-up 
visits and assessments until the end of the trial unless they withdraw consent to participate in 
the study. Should it not be possible to attend all visits, at least phone contacts should occur at 
the scheduled visits time points. For patients not attending remaining trial visits or not being 
available for phone contacts replacing the remaining clinic visits any attempt will be made to 
get information on vital status at Week 12 (refer to Flow Chart). Patients will be asked to 
agree to be contacted by the site personnel, which could be by telephone calls (in person visit 
would be preferred), to allow collection of this information. If death occurs, the investigator 
will review the circumstances, including the relevant medical records to ascertain the most 
likely primary and secondary causes of death. Collection of vital status will be performed in 
accordance with national ethical and regulatory guidelines. The need for vital status 
information will be explained to patients prior to their participation in the trial.
It is vital to explain to these patients the importance to continue trial participation (please see 
Section 3.3.4 for further details).
All unused study medication will be collected and study drug diary will be checked. 
Procedures are to be performed according to the Flow Chart.
Follow-up (FU) 1:
This follow-up visit will preferentially be performed as a phone contact one week after EOT 
for all patients who had at least one dose of trial medication (see Flow Chart for procedures 
to be performed). 
Follow-up (FU2) 2:


Boehringer Ingelheim
12 Jul 2018
BI Trial No.: 1346.23
c03632269-05
Trial Protocol
Page 51 of 77
Proprietary confidential information © 2018 Boehringer Ingelheim International GmbH or one or more of its affiliated companies
001-MCS-40-106-RD-03 (12.0) / Saved on: 30 Jan 2015
This visit is a clinic visit and need to performed 28±3 day after EOT (see Flow Chart for 
procedures to be performed).


Boehringer Ingelheim
12 Jul 2018
BI Trial No.: 1346.23
c03632269-05
Trial Protocol
Page 52 of 77
Proprietary confidential information © 2018 Boehringer Ingelheim International GmbH or one or more of its affiliated companies
001-MCS-40-106-RD-03 (12.0) / Saved on: 30 Jan 2015
7.
STATISTICAL METHODS AND DETERMINATION OF
SAMPLE SIZE
STATISTICAL DESIGN – MODEL
7.1
See Section 3.1 for details on the design of the study.
See Section 2.2 for details on the objective of the study.
A multiple comparison procedure with modelling (MCPMod) approach is considered for
proof-of-concept.  Further details are included in Section 7.3.1.1.
The treatment comparisons for the primary continuous endpoint will be conducted using a 
restricted maximum likelihood estimation based on mixed model repeated measures analysis. 
Further details are included in Section 7.3.1.2.
NULL AND ALTERNATIVE HYPOTHESES
7.2
The primary endpoint is mean change from baseline in ADAS-Cog11 total score after 12 
weeks of treatment. Baseline refers to the last observed measurement prior to administration 
of any randomised study medication.
The null hypothesis is that there is a flat dose response pattern across placebo and any dose of 
BI 425809 within the tested dose range (0-25mg) on mean change in ADAS-Cog11 total score 
from baseline to treatment week 12. 
The alternative hypothesis is that there is a non-flat dose response pattern indicating a benefit 
of BI 425809 compared to placebo.
The MCPmod procedure allows for the simultaneous evaluation of different potential dose 
response patterns, whilst protecting the overall probability of type I error (one-sided alpha of 
0.05). The pre-specified models and their parameters used for this test are outlined in Section
7.3.1 and Section 7.7.
PLANNED ANALYSES
7.3
Analysis set
The statistical analyses will be based on the following patient populations:

Treated Set 
The treated set (TS) is defined as all patients treated with at least one dose of study 
medication. Patients in the treated set will be analyzed based on the actual treatment received 
at the randomization. The TS will be used for safety analyses.

Full Analysis Set
The full analysis set (FAS) will consist of all randomised patients who were treated with at 
least one dose of study drug and had a baseline and at least one post-baseline on treatment 
efficacy assessment. Patients in the FAS will be analyzed based on the intent-to-treat 


Boehringer Ingelheim
12 Jul 2018
BI Trial No.: 1346.23
c03632269-05
Trial Protocol
Page 53 of 77
Proprietary confidential information © 2018 Boehringer Ingelheim International GmbH or one or more of its affiliated companies
001-MCS-40-106-RD-03 (12.0) / Saved on: 30 Jan 2015
principle (i.e., patients in the FAS will be analyzed based on the planned treatment assigned 
at randomization). The FAS will be used for efficacy analyses.
Data from subjects who are screened but not randomised will be listed but not included in any 
summary statistics or inferential statistics. Specifications of important protocol violations will 
be provided in the TSAP.
7.3.1
Primary endpoint analyses
7.3.1.1
Primary analysis of the primary endpoint
The analyses for PoC and dose-finding will be done using multiple comparison procedures 
and modelling (MCPmod) techniques [R10-1424] for mixed model repeated measures 
(MMRM) [R15-4293], whereby several possible dose response models (patterns) will be 
evaluated (while keeping full control of the type I error of 5%, 1-sided) to identify the best-
fitting model or subset of models.  The MMRM model as described in Section 7.3.1.2 will be 
fitted for MCPmod.
For the PoC testing and for the sample size calculation, the basic shape of each of the models 
to be tested must be pre-defined.  Six different models will be tested in the analysis:  
betamod, emax, sigEmax, linear, linear logistic and logistic. Except in the model ‘betamod’, 
the maximum effect is assumed to be achieved at the maximum dose being tested.  For the 
sample size calculation, the maximum standardized effect size is assumed to be 0.35. Further 
details are given in Section 7.7.
The active BI 425809 doses are 2 mg, 5 mg, 10 mg, and 25 mg daily.  The following model 
assumptions and resulting graphs (Figure 7.3.1.1: 1) have been selected to cover both 
plausible and a diverse range of dose response patterns:  

Betamod:          
75% of the maximum effect is achieved at 2 mg
                         
87.5% of the maximum effect is achieved at 5 mg
                        
25% of the maximum effect is achieved at 25 mg
                                  
Maximum effect achieved at 10 mg
    
Scalar parameter = 26

Emax1:              
20% of the maximum effect is achieved at 2 mg

sigEmax:            
25% of the maximum effect is achieved at 5 mg
                            75% of the maximum effect is achieved at 10 mg

Linear:                 
no assumptions needed

Linear logisticno assumptions needed

Logistic:
    
10% of the maximum effect is achieved at 5 mg 
                           50% of the maximum effect is achieved at 10 mg 
PoC is established if at least one model is significant, rejecting the null hypothesis of a flat 
dose-response relation over 12 weeks for the primary endpoint (mean change from baseline 
in ADAS-Cog11 total score) jointly for each of the candidate dose-response models with a 
contrast test controlled for the family-wise error rate (α = 0.05 1-sided).


Boehringer Ingelheim
12 Jul 2018
BI Trial No.: 1346.23
c03632269-05
Trial Protocol
Page 54 of 77
Proprietary confidential information © 2018 Boehringer Ingelheim International GmbH or one or more of its affiliated companies
001-MCS-40-106-RD-03 (12.0) / Saved on: 30 Jan 2015
If PoC is established, the best-fitting model from the above set of six models can be refitted 
to the data without any parameter assumptions to generate new estimates of the model 
parameters from the data. The target dose will be obtained via model averaging across the 
significant models based on Akaike Information Criterion (AIC) (the smaller the AIC value 
the better the model fit). The target dose(s) can then be determined from that model by 
incorporating information on the minimum clinically relevant effect as well as safety 
information. The target dose to be chosen should show a delta of at least 2 points in the mean 
change from baseline ADAS-Cog11 total score at week 12 compared to placebo. This will be 
measured on the modelled efficacy and only doses within the dose range investigated (0mg-
25mg) will be considered although the actual modelling will be performed on a broader range 
of doses including extrapolation.
Figure 7.3.1.1: 1:  
Shape of the models within the candidate set
7.3.1.2
Secondary analyses of the primary endpoint
If considered necessary and for the purpose of further model refinement MCPmod might be 
repeated on the primary endpoint but with an extended set of shapes including the original 
candidates. Additionally to that covariates may be taken into account in a sensitivity analysis. 
The primary endpoint will also be analysed using a restricted maximum likelihood estimation 
based on MMRM for the change from baseline in ADAS-Cog11 total score after 12 weeks of 


Boehringer Ingelheim
12 Jul 2018
BI Trial No.: 1346.23
c03632269-05
Trial Protocol
Page 55 of 77
Proprietary confidential information © 2018 Boehringer Ingelheim International GmbH or one or more of its affiliated companies
001-MCS-40-106-RD-03 (12.0) / Saved on: 30 Jan 2015
treatment. The model will include fixed, categorical covariates of treatment, visit, baseline 
MMSE (> 20, < 20) and treatment by visit interaction, as well as the continuous fixed 
covariates of baseline and baseline-by-visit interaction. Patient will be considered as random 
effect. The unstructured covariance structure will be used to model the within patient 
measurements. 
The first model to converge will be used as the primary analysis. The Kenward-Roger 
approximation will be used to estimate denominator degrees of freedom. Significance tests 
will be based on least-squares means using a two-sided α = 0.05 (two-sided 95% confidence 
intervals). ). Analyses will be implemented using SAS (version 9.4) PROC MIXED. 
Procedures to follow if the analysis fails to converge will be described in the TSAP.
The primary treatment comparisons will be between the placebo and the different doses of BI 
425809 with respect to the mean change from baseline in the ADAS-Cog11 total score after 
12 weeks of treatment. Adjusted mean change from baseline as well as treatment contrasts 
will be presented together with the 95% confidence intervals. The primary treatment 
comparisons will be the contrast between treatments at the endpoint visit. 
Comparisons between treatment groups will be exploratory in nature and based on the 
numerical comparison of the respective treatment means.
7.3.2
Secondary endpoint analyses
If considered necessary a MCPmod approach will also be applied to the secondary endpoints.
Comparisons between treatment groups will be exploratory in nature and based on the 
numerical comparison of the respective treatment means.
More details on the analyses of the secondary endpoints will be included in the TSAP.


Boehringer Ingelheim
12 Jul 2018
BI Trial No.: 1346.23
c03632269-05
Trial Protocol
Page 56 of 77
Proprietary confidential information © 2018 Boehringer Ingelheim International GmbH or one or more of its affiliated companies
001-MCS-40-106-RD-03 (12.0) / Saved on: 30 Jan 2015
7.3.4
Safety analyses
Adverse events will be coded using the Medical Dictionary for Regulatory Activities
(MedDRA) coding dictionary. Standard BI summary tables and listings will be produced. All 
adverse events with an onset between start of treatment and end of the residual effect period 
(REP), a period of 11 days after the last dose of trial medication, will be assigned to the 
treatment period for evaluation.
All treated patients will be included in the safety analysis and will be summarized under the 
actual trial medication received at randomization. In general, safety analyses will be 
descriptive in nature and will be based on BI standards. No hypothesis testing is planned.
Statistical analysis and reporting of adverse events will concentrate on treatment-emergent 
adverse events. To this end, all adverse events occurring between start of treatment and end 
of the residual effect period will be considered ‘treatment-emergent’. The residual effect 
period is defined as 11 days after the last drug intake.Adverse events that start before first 
drug intake and deteriorate under treatment will also be considered as ‘treatment-emergent’.
Frequency, severity, and causal relationship of adverse events will be tabulated by system 
organ class and preferred term after coding according to the current version of the Medical 
Dictionary for Drug Regulatory Activities (MedDRA). Frequency tables for all adverse 
events, protocol-specified AESI, serious adverse event (SAE), adverse event leading to death, 
adverse event leading to discontinuation, investigator assessed drug-related adverse event and 
serious adverse event will be generated for treatment-emergent adverse events. In addition, 
summary statistics and descriptive analyses will be conducted for other safety parameters 
including suicidality as assessed by C-SSRS.
Laboratory data will be analysed both quantitatively as well as qualitatively. The latter will 
be done via comparison of laboratory data to their reference ranges. Values outside the 
reference range as well as values defined as clinically relevant will be highlighted in the 
listings. Treatment groups will be compared descriptively with regard to distribution 
parameters as well as with regard to frequency and percentage of patients with abnormal 
values or clinically relevant abnormal values.
Vital signs, physical examinations, or other safety-relevant data observed at screening, 
baseline, during the course of the trial and at the end-of-trial evaluation will be assessed with 
regard to possible changes compared to findings before start of treatment.


Boehringer Ingelheim
12 Jul 2018
BI Trial No.: 1346.23
c03632269-05
Trial Protocol
Page 57 of 77
Proprietary confidential information © 2018 Boehringer Ingelheim International GmbH or one or more of its affiliated companies
001-MCS-40-106-RD-03 (12.0) / Saved on: 30 Jan 2015
INTERIM ANALYSES
7.4
No interim analysis is planned.
HANDLING OF MISSING DATA
7.5
Every effort will be made to collect complete data at the specified time points.
If a patient misses a visit, the missing data will not be imputed. The mixed effect model will 
handle missing data based on a likelihood method under the "missing at random” assumption.  
Additional details on the imputation of missing data will be specified in the Trial Statistical 
Analysis Plan (TSAP) prior to unblinding.
RANDOMISATION
7.6
Eligible patients will be randomly assigned to one of the 5 treatment groups, with an 
allocation of 1:1:1:1:1 respectively for BI 425809 2 mg once daily: BI 425809 5 mg once 
daily: BI 425809 10 mg once daily: BI 425809 25 mg once daily: placebo once daily. 
The randomisation will be stratified by baseline MMSE (> 20, < 20). The randomisation will 
be done in blocks to achieve balanced allocation.
The randomisation of patients to the treatment groups will be performed via an interactive 
response technology (IRT). BI will arrange for the randomization and the packaging and 
labelling of trial medication. The randomization list will be generated using a validated 
system, which involves a pseudo-random number generator so that the resulting treatment 
will be both reproducible and non-predictable. The block size will be documented in the 
CTR. Access to the codes will be controlled and documented.


Boehringer Ingelheim
12 Jul 2018
BI Trial No.: 1346.23
c03632269-05
Trial Protocol
Page 58 of 77
Proprietary confidential information © 2018 Boehringer Ingelheim International GmbH or one or more of its affiliated companies
001-MCS-40-106-RD-03 (12.0) / Saved on: 30 Jan 2015
DETERMINATION OF SAMPLE SIZE
7.7
The sample size calculation is based on an assumed maximum effect size of BI 425809 vs. 
placebo of 0.35 for the primary endpoint, as well as on the pre-specified model parameters 
listed in Section 7.3.1.1. The assumed standardized effect size of 0.35 is based on the 
expectation that BI 425809 has somewhat better efficacy than AChEIs, for which results are 
summarized in Table 7.7:1.
Table 7.7: 1 
Effect sizes for Acetyl Cholinesterase Inhibitors (AChEI)
K Rockwood (2004) [R15-5201]
Donepezil 
Galantamine 
Rivastigmine 
AChEI Effect size (ES): Median (range)
Low Dose ES
= 0.15 (0.03-0.22) 
Medium Dose ES = 0.23 (0.12-0.29)
High Dose ES
= 0.28 (0.01-0.31)
For the PoC analysis of the four BI 425809 dose groups vs. placebo using the MCPmod
approach with the parameters as listed in Section 7.3.1, a sample size of 95 evaluable patients 
per group is needed to establish PoC with 80% average power (one-sided 5% alpha level).  
An additional 10% of Japanese patients will be added, bringing the total to 105 evaluable 
patients.  The primary analysis will be conducted on all patients, while an internal decision 
making analysis will be conducted excluding the Japanese patients.
Assuming that 10% of the randomised patients withdraw early without providing useful 
information, then 117 randomised patients per group are required. With 5 treatment groups, a 
total of 585 patients are required. Table 7.7: 2 below gives the sample size calculations under 
different standardized effect sizes using 1-sided type I error rate of 0.05 and 80% power. The 
calculations for the PoC step have been performed using Dose Finding in the R-package 
[R15-2001] released on 28 SEP 2014 (depends on R version ≥ 2.15.0). The R codes for the 
sample size calculations as well as the analyses using the MCPmod approach will be 
provided in the TSAP.


Boehringer Ingelheim
12 Jul 2018
BI Trial No.: 1346.23
c03632269-05
Trial Protocol
Page 59 of 77
Proprietary confidential information © 2018 Boehringer Ingelheim International GmbH or one or more of its affiliated companies
001-MCS-40-106-RD-03 (12.0) / Saved on: 30 Jan 2015
Table 7.7: 2
Sample size calculation under different standardized effect sizes for 
the ADAS-Cog11 total score change from baseline with 80% power 
and one-sided alpha of 0.05
Standardized Effect size
0.3
0.325
0.35
0.375
0.4
Power = 80%
   N for each active treatment arm
126
107
95
81
71
   N including 10% Japanese patients1
139
119
105
90
78
   Total
695
595
525
450
390
   Adjusting for 10% dropout
      N for each treatment arm2
154
132
117
100
87
      Total
772
660
585
500
433
1 Power = 85%
2 Power = 88%
The sample size calculations in Table 7.7: 3 consider a range of standardized effect sizes and 
power for a direct comparison between BI 425809 doses and the placebo. Two-sample t-test 
is used for these exploratory treatment comparisons without adjustment for multiplicity.
Table 7.7: 3
Sample size calculations under different standardized effect sizes and 
power for the ADAS-Cog11 total score change from baseline with 
one-sided alpha of 0.05
Standardized Effect size
0.3
0.325
0.35
0.375
0.4
Power = 85%
N for each active treatment arm
161
137
119
103
91
Power = 80%
N for each active treatment arm
139
118
102
89
78
Power = 75%
N for each treatment arm
121
103
89
78
68
The two-sample t-test method with equal n’s in nQuery Advisor 6.01 was used for the 
calculation.


Boehringer Ingelheim
12 Jul 2018
BI Trial No.: 1346.23
c03632269-05
Trial Protocol
Page 60 of 77
Proprietary confidential information © 2018 Boehringer Ingelheim International GmbH or one or more of its affiliated companies
001-MCS-40-106-RD-03 (12.0) / Saved on: 30 Jan 2015
8.
INFORMED CONSENT, DATA PROTECTION, TRIAL
RECORDS
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 Tripartite Guideline 
for Good Clinical Practice (GCP), relevant BI Standard Operating Procedures (SOPs), the 
Japanese GCP regulations (Ministry of Health and Welfare Ordinance No. 28, March 27, 
1997), and relevant regulations.
Standard medical care (prophylactic, diagnostic and therapeutic procedures) remains in the 
responsibility of the treating physician of the patient.
The Investigator will inform the Sponsor immediately of any urgent safety measures taken to 
protect the trial subjects against any immediate hazard, and also of any serious breaches of 
the protocol or of ICH GCP and the Japanese GCP regulations (Ministry of Health and 
Welfare Ordinance No. 28, March 27, 1997).
The Boehringer Ingelheim transparency and publication policy can be found on the following 
web page: trials.boehringer-ingelheim.com. The rights of the Investigator and of the sponsor 
with regard to publication of the results of this trial are described in the Investigator contract.
As a rule, no trial results should be published prior to finalization of the Clinical Trial Report.
For Japan only: The rights of the investigator / trial site and of the sponsor with regard to 
publication of the results of this trial are described in the investigator contract / trial site’s 
contract. As a general rule, no trial results should be published prior to finalisation of the 
Clinical Trial Report.
The certificate of insurance cover is made available to the Investigator and the patients, and is
stored in the ISF (Investigator Site File).
TRIAL APPROVAL, PATIENT INFORMATION, AND INFORMED 
8.1
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 patient participation in the trial, written informed consent must be obtained from each 
patient (or the patient’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 patient-
information form retained by the Investigator as part of the trial records. A signed copy of the 
informed consent and any additional patient information must be given to each patient or the 
patient’s legally accepted representative.


Boehringer Ingelheim
12 Jul 2018
BI Trial No.: 1346.23
c03632269-05
Trial Protocol
Page 61 of 77
Proprietary confidential information © 2018 Boehringer Ingelheim International GmbH or one or more of its affiliated companies
001-MCS-40-106-RD-03 (12.0) / Saved on: 30 Jan 2015
The Investigator must give a full explanation to trial patients by using the patient information 
form, which is prepared avoiding the use of technical terms and expressions. The patient is 
given sufficient time to consider participation in the trial. The Investigator obtains written 
consent of the patient’s own free will with the informed consent form after confirming that 
the patient understands the contents. The Investigator 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.
DATA QUALITY ASSURANCE
8.2
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.
RECORDS
8.3
Case Report Forms (CRF) / (e)CRF for individual patients will be provided by the Sponsor.
See Section 4.1.5.2 for rules about emergency code breaks. For drug accountability, refer to 
Section 4.1.8.
8.3.1
Source documents
Source documents provide evidence for the existence of the patient and substantiate the 
integrity of the data collected. Source documents are filed at the Investigator’s site.
Data reported on the CRF must be consistent with the source data or the discrepancies must 
be explained. The Investigator may need to request previous medical records or transfer 
records, depending on the trial; current medical records must also be available.
Neuropsychological rating scales data entered into the Rater Station will be regarded as 
source data. These will be centrally reviewed and may be further analysed by the delegated 
third party vendor. 
For eCRFs all data must be derived from source documents.
For the paper CRF, the following data need to be derived from source documents:

Patient identification: gender, date or year of birth (in accordance with local laws and 
regulations)

Patient participation in the trial (substance, trial number, patient number, date patient 
was informed)

Dates of Patient’s visits, including dispensing of trial medication

Medical history (including trial indication and concomitant diseases, if applicable)

Medication history

Adverse events and outcome events (onset date (mandatory), and end date (if 
available))


Boehringer Ingelheim
12 Jul 2018
BI Trial No.: 1346.23
c03632269-05
Trial Protocol
Page 62 of 77
Proprietary confidential information © 2018 Boehringer Ingelheim International GmbH or one or more of its affiliated companies
001-MCS-40-106-RD-03 (12.0) / Saved on: 30 Jan 2015

Serious adverse events (onset date (mandatory), and end date (if available))

Concomitant therapy (start date, changes)

Originals or copies of laboratory results (in validated electronic format, if available)

Completion of Patient’s Participation in the trial” (end date; in case of premature 
discontinuation document the reason for it).

Prior to allocation of a patient 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 or testing conducted specific for a protocol) to support 
inclusion/exclusion criteria does not make the patient eligible for the clinical trial.
8.3.2
Direct access to source data and documents
The Investigator / institution will permit trial-related monitoring, audits, IRB / IEC review 
and regulatory inspection, providing direct access to all related source data / documents. 
CRF/eCRF and all source documents, including progress notes and copies of laboratory and 
medical test results must be available at all times for review by the Sponsor’s clinical trial 
monitor, auditor and inspection by health authorities (e.g. FDA). The Clinical Research 
Associate (CRA) / on site monitor and auditor may review all CRF / eCRF, and written 
informed consents. The accuracy of the data will be verified by reviewing the documents
described in Section 8.3.1.
8.3.3
Storage period of records
Trial site(s):
The trial site(s) must retain the source documents and essential documents for a period 
defined by the Japanese GCP regulation and trial site’s contract with the sponsor.
Sponsor:
The Sponsor must retain the essential documents according to the Sponsor’s SOPs.
LISTEDNESS AND EXPEDITED REPORTING OF ADVERSE EVENTS
8.4
8.4.1
Listedness
To fulfil the regulatory requirements for expedited safety reporting, the Sponsor evaluates 
whether a particular adverse event is "listed", i.e. is a known side effect of the drug or not. 
Therefore, a unique reference document for the evaluation of listedness needs to be provided.
For the BI 425809 this is the current version of the IB [c02155957-07].
8.4.2
Expedited reporting of adverse events
BI is responsible to fulfil their legal regulatory reporting obligation and in accordance to the 
requirements defined in this CTP.


Boehringer Ingelheim
12 Jul 2018
BI Trial No.: 1346.23
c03632269-05
Trial Protocol
Page 63 of 77
Proprietary confidential information © 2018 Boehringer Ingelheim International GmbH or one or more of its affiliated companies
001-MCS-40-106-RD-03 (12.0) / Saved on: 30 Jan 2015
STATEMENT OF CONFIDENTIALITY
8.5
Individual patient medical information obtained as a result of this trial is considered 
confidential and disclosure to third parties is prohibited with the exceptions noted below. 
Patient confidentiality will be ensured by using patient identification code numbers.
Treatment data may be given to the patient’s personal physician or to other appropriate 
medical personnel responsible for the patient’s welfare. Data generated as a result of the trial 
need to be available for inspection on request by the participating physicians, the Sponsor’s 
representatives, by the IRB / IEC and the regulatory authorities.
TRIAL MILESTONES
8.6
The start of the trial is defined as the date of the enrolment pf the first patient in the whole 
trial.
The end of the trial is defined as the date of the last visit of the last patient in the whole trial
(“Last Patient Out”).
The “Last Patient Drug Discontinuation” (LPDD) date is defined as the date on which the 
last patient at an individual trial site ends trial medication (as scheduled per protocol or 
prematurely). Individual Investigators will be notified of SUSARs occurring with the trial 
medication until 30 days after LPDD at their site.
Early termination of the trial is defined as the premature termination of the trial due to any 
reason before the end of the trial as specified in this protocol.
Temporary halt of the trial is defined as any unplanned interruption of the trial by the 
sponsor with the intention to resume it.
Suspension of the trial is defined as an interruption of the trial based on a Health Authority 
request.
The IEC / competent authority in each participating EU member state will be notified about 
the trial milestones according to the respective laws.
A final report of the clinical trial data will be written only after all patients have completed 
the trial in all countries (EU or non-EU) to incorporate and consider all data 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, regardless of the country of the last patient 
(EU or non-EU).
For Japan only: when the trial is completed, the Investigator should inform the head of the 
trial site of the completion in writing, and the head of the trial site should promptly inform the 
IRB and sponsor of the completion in writing.
PROTOCOL VIOLATIONS
8.7
For Japan only: The investigator should document any deviation from the protocol regardless 
of their reasons. Only when the protocol was not followed in order to avoid an immediate 
hazard to trial subjects or for other medically compelling reason, the principal investigator 
should prepare and submit the records explaining the reasons thereof to the sponsor, and 
retain a copy of the records.


Boehringer Ingelheim
12 Jul 2018
BI Trial No.: 1346.23
c03632269-05
Trial Protocol
Page 64 of 77
Proprietary confidential information © 2018 Boehringer Ingelheim International GmbH or one or more of its affiliated companies
001-MCS-40-106-RD-03 (12.0) / Saved on: 30 Jan 2015
COMPENSATION AVAILABLE TO THE PATIENT IN THE EVENT OF 
8.8
TRIAL RELATED INJURY
For Japan only: In the event of health injury associated with this trial, the Sponsor is 
responsible for compensation based on the contract signed by the trial site.


Boehringer Ingelheim
12 Jul 2018
BI Trial No.: 1346.23
c03632269-05
Trial Protocol
Page 65 of 77
Proprietary confidential information © 2018 Boehringer Ingelheim International GmbH or one or more of its affiliated companies
001-MCS-40-106-RD-03 (12.0) / Saved on: 30 Jan 2015
9.
REFERENCES
PUBLISHED REFERENCES
9.1
R03-0748
Berg L. Clinical dementia rating (CDR). Psychopharmacol Bull 1988. 
24(4):637-639.
R10-1424
Pinheiro J, Bornkamp B, Bretz F. Design and analysis of dose-finding 
studies combining multiple comparisons and modeling procedures. J 
Biopharm Stat 2006. 16(5):639-656.
R10-5092
Cooke SF, Bliss TVP. Plasticity in the human central nervous system. Brain 
2006. 129:1659-1673.
R10-5095
Ferri CP, Prince M, Brayne C, Brodaty H, Fratiglioni L, Ganguli M, et al. 
Global prevalence of dementia: a Delphi consensus study. Lancet 2005. 
366:2112-2117.
R10-5102
Reymann KG, Frey JU. The late maintenance of hippocampal LTP: 
requirements, phases, 'synaptic tagging', 'late-associativity' and 
implications. Neuropharmacology 2007. 52:24-40.
R10-5105
Strauss E von, Viitanen M, Ronchi D de, Winblad B, Fratiglioni L. Aging 
and the occurrence of dementia: findings from a population-based cohort 
with a large sample of nonagenarians. Arch Neurol 1999. 56:587-592.
R10-5106
Wimo A, Winblad B, Aguero-Torres H, Strauss E von. The magnitude of 
dementia occurrence in the world. Alzheimer Dis Assoc Disord 2003. 
17(2):63-67.
R10-5109
Bliss TVP, Collingridge GL. A synaptic model of memory: long-term 
potentiation in the hippocampus. Nature 1993. 361:31-39.
R13-4518
Hu NW, Ondrejcak T, Rowan MJ. Glutamate receptors in preclinical 
research on Alzheimer's disease: update on recent advances. Pharmacol 
Biochem Behav 2012. 100:855-862.
R13-4115
McKhann GM, Knopman DS, Chertkow H, Hyman BT, Jack CR, Kawas 
CH, et al. The diagnosis of dementia due to Alzheimer's disease: 
recommendations from the National Institute on Aging-Alzheimer's 
Association workgroups on diagnostic guidelines for Alzheimer's disease. 
Alzheimers Dement 2011. 7:263-269.


Boehringer Ingelheim
12 Jul 2018
BI Trial No.: 1346.23
c03632269-05
Trial Protocol
Page 66 of 77
Proprietary confidential information © 2018 Boehringer Ingelheim International GmbH or one or more of its affiliated companies
001-MCS-40-106-RD-03 (12.0) / Saved on: 30 Jan 2015
R13-4521
Lin CH, Lane HY, Tsai GE. Glutamate signaling in the pathophysiology 
and therapy of schizophrenia. Pharmacol Biochem Behav 2012. 100:665-
677.
R15-1961
European Medicines Agency (EMA). Committee for Medicinal Products 
for Human Use (CHMP): qualification opinion of MCP-Mod as an efficient 
statistical methodology for model-based design and analysis of phase II 
dose finding studies under model uncertainty (23 January 2014, 
EMA/CHMP/SAWP/757052/2013). 
http://www.ema.europa.eu/docs/en_GB/document_library/Regulatory_and_
procedural_g uideline/2014/02/WC500161027.pdf (access date: 28 April 
2015) ; London: European Medicines Agency (EMA) 2014.
R15-2001
Bornkamp B, Pinheiro J, Bretz F. Package 'DoseFinding' (February 19, 
2015). http://cran.r-
project.org/web/packages/DoseFinding/DoseFinding.pdf (access date: 28 
April 2015) ; Comprehensive R Archive Network 2015
R15-4293
Pinheiro J, Bornkamp B, Glimm E, Bretz F. Model-based dose finding 
under model uncertainty using general parametric models. Stat Med 2014. 
33(10):1646-1661.
R15-5201
Rockwood K. Size of the treatment effect on cognition of cholinesterase 
inhibition in Alzheimer's disease. J Neurol Neurosurg Psychiatry 2004. 
75(5):677-685.
R17-3992 
Lezak MD, Howieson DB, Loring DW, Hannay HJ, Fischer JS, editors 
Neuropsychological assessment. 4th ed. New York: Oxford University 
Press (2004)
R96-2608 
Rosen WG, Mohs RC, Davis KL. A new rating scale for Alzheimer’s 
disease. Am J Psychiatry 1984; 141(11): 1356-1364.
R97-3207
Galasko D, Bennett D, Sano M, Ernesto C, Thomas R, Grundman M, et al. 
An inventory to assess activities of daily living for clinical trials in 
alzheimer's disease. Alzheimer Dis Assoc Disord 1997. 11(2):S33-S39.


Boehringer Ingelheim
12 Jul 2018
BI Trial No.: 1346.23
c03632269-05
Trial Protocol
Page 67 of 77
Proprietary confidential information © 2018 Boehringer Ingelheim International GmbH or one or more of its affiliated companies
001-MCS-40-106-RD-03 (12.0) / Saved on: 30 Jan 2015
UNPUBLISHED REFERENCES
9.2
c02155957-07
BI 425809 Investigator‘s Brochure. 04 Dec 2017
c02820512-01
. Safety, toleratility, and 
pharmacokinetics of single rising oral doses of BI 425809 in healthy male 
subjects (partially randomised, single-blind, placebo-controlled) and 
investigation of relative bioavailability and food effect of BI 425809 (open-
label, randomised, three-way cross-over). 1346.1. 05 May 2015.
c03724403-01
. Nonrandomised, open label, 
sequential-group study to assess the pharmacokinetics and 
pharmacodynamic effect of different multiple oral doses of BI 425809 in 
healthy male volunteers. 1346.3. 01 Feb2016.
001-MCS-36-472 
Boehringer Ingelheim SOP: „Standart Operation Procedure“, current
version, IDEA for CON


Boehringer Ingelheim
12 Jul 2018
BI Trial No.: 1346.23
c03632269-05
Trial Protocol
Page 68 of 77
Proprietary confidential information © 2018 Boehringer Ingelheim International GmbH or one or more of its affiliated companies
001-MCS-40-106-RD-03 (12.0) / Saved on: 30 Jan 2015


Boehringer Ingelheim
12 Jul 2018
BI Trial No.: 1346.23
c03632269-05
Trial Protocol
Page 69 of 77
Proprietary confidential information © 2018 Boehringer Ingelheim International GmbH or one or more of its affiliated companies
001-MCS-40-106-RD-03 (12.0) / Saved on: 30 Jan 2015


Boehringer Ingelheim
12 Jul 2018
BI Trial No.: 1346.23
c03632269-05
Trial Protocol
Page 70 of 77
Proprietary confidential information © 2018 Boehringer Ingelheim International GmbH or one or more of its affiliated companies
001-MCS-40-106-RD-03 (12.0) / Saved on: 30 Jan 2015
11.
DESCRIPTION OF GLOBAL AMENDMENT(S)
Number of global amendment
1
Date of CTP revision
14 Mar 2016
EudraCT number
2015-005438-24
BI Trial number
1346.23
BI Investigational Product(s)
BI 425809
Title of protocol
A multi-centre, double-blind, parallel-group, 
randomised controlled study to investigate efficacy, 
safety and tolerability of orally administered 
BI 409306 during a 12-week treatment period 
compared to placebo in patients with cognitive 
impairment due to Alzheimer’s Disease.
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
Flowchart, 5.3.5.1
Description of change
The eC-SSRS (electronic version) was replaced by 
the C-SSRS (paper version).
Rationale for change
The eC-SSRS is an always self-administered 
questionnaire and not available in a rater-
completed version. In the mild-to-moderate 
dementia population studied in this protocol the 
rater-completed C-SSRS is the appropriate tool to 
monitor suicidality.


Boehringer Ingelheim
12 Jul 2018
BI Trial No.: 1346.23
c03632269-05
Trial Protocol
Page 71 of 77
Proprietary confidential information © 2018 Boehringer Ingelheim International GmbH or one or more of its affiliated companies
001-MCS-40-106-RD-03 (12.0) / Saved on: 30 Jan 2015
Number of global amendment
2
Date of CTP revision
14 Apr 2016
EudraCT number
2015-005438-24
BI Trial number
1346.23
BI Investigational Product(s)
BI 425809
Title of protocol
A multi-centre, double-blind, parallel-group, 
randomised controlled study to investigate efficacy, 
safety and tolerability of orally administered 
BI 409306 during a 12-week treatment period 
compared to placebo in patients with cognitive 
impairment due to Alzheimer’s Disease.
To be implemented only after 
approval of the IRB / IEC / 
Competent Authorities
To be implemented immediately 
in order to eliminate hazard –
IRB / IEC / Competent 
Authority to be notified of 
change with request for 
approval
Can be implemented without 
IRB / IEC / Competent 
Authority approval as changes 
involve logistical or 
administrative aspects only
Section to be changed
1.2
Description of change
A typo was corrected and information on CYP2b6 
induction was added.
Rationale for change
New information was added.
Section to be changed
2.1
Description of change
Rationale for change
New information was added.
Section to be changed
3.3.3, 4.2.2.1, and 4.2.2.2
Description of change
A new exclusion and restrictions on herbal 
medications were added.
Rationale for change
Herbal medications that may potentially interfere 
with efficacy assessments were excluded
Section to be changed
5.4.1
Description of change
Recording of food intake with study drug was 
added
Rationale for change
Information will be required to study impact of 
food intake on exposure
Section to be changed
7.3.3
Description of change
Genes related to PDE9 pathways were removed 


Boehringer Ingelheim
12 Jul 2018
BI Trial No.: 1346.23
c03632269-05
Trial Protocol
Page 72 of 77
Proprietary confidential information © 2018 Boehringer Ingelheim International GmbH or one or more of its affiliated companies
001-MCS-40-106-RD-03 (12.0) / Saved on: 30 Jan 2015
from the planned pharmacogenomic analysis.
Rationale for change
A typo was corrected
Number of global amendment
3
Date of CTP revision
12 Dec 2017
EudraCT number
2015-005438-24
BI Trial number
1346.23
BI Investigational Product(s)
BI 425809
Title of protocol
A multi-centre, double-blind, parallel-group, 
randomised controlled study to investigate efficacy, 
safety and tolerability of orally administered 
BI 409306 during a 12-week treatment period 
compared to placebo in patients with cognitive 
impairment due to Alzheimer’s Disease.
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
Title page
Description of change
Update in Trial Clinical Monitor
Rationale for change
Updated information.
Section to be changed
Synopsis
Description of change

Deletion of CDR from Main criteria 
inclusion 

Primary Endpoint ADAS-cog13
(Alzheimer’s Disease Assessment Scale-
cognitive subscale) was changed to ADAS-
cog11 (Alzheimer’s Disease Assessment 
Scale-cognitive subscale)

CDR SB (Clinical Dementia Rating Sum of 
Boxes) was deleted from Secondary 
Endpoints

CIBIS and CIBIC+ were added among 
Secondary Endpoints


Boehringer Ingelheim
12 Jul 2018
BI Trial No.: 1346.23
c03632269-05
Trial Protocol
Page 73 of 77
Proprietary confidential information © 2018 Boehringer Ingelheim International GmbH or one or more of its affiliated companies
001-MCS-40-106-RD-03 (12.0) / Saved on: 30 Jan 2015

Further editorial changes
Rationale for change
New concept to detect efficacy signal in executive 
function and memory of the heterogenous AD 
patient population which will be included in this 
trial.
Section to be changed
Flow Chart
Description of change

Visit 0 was added to allow comfortable 
time window for imaging, review of In/Ex 
Criteria and concomitant medications 

Changes to the structure of 
Neuropsychological Rating Scales (ADAS-
cog13 (Alzheimer’s Disease Assessment 
Scale-cognitive subscale) changed to 
ADAS-cog11, CDR SB (Clinical Dementia 
Rating Sum of Boxes) was deleted,  CIBIS, 
CIBIC+  
 
were added

Further editorial changes
Rationale for change

New concept to detect efficacy signal in 
executive function and memory of the 
heterogenous AD patient population which 
will be included in this trial.

Increase clarity on performance of trial 
related procedures
Section to be changed
1.2
Description of change
Sentences Updated “Based on in vitro data, at the 
highest proposed Phase 2 dose of 25 mg, BI 
425809 may cause clinically relevant induction of 
CYP2B6. Based on Phase I clinical studies BI 
425809 is a mild CYP3A4 inducer at 25mg” 
Rationale for change
Section updated to be in line with current version 
of the IB dated 04 Dec 2017 
Section to be changed
2.3
Description of change
Information on further completed phase 1 trials 
added
Rationale for change
New information added
Section to be changed
3.3.2
Description of change
CDR deleted from inclusion criteria 
Rationale for change
CDR shall not be used as an endpoint therefore this 
complicated and long scale was deleted from 
Inclusion Criteria
Section to be changed
3.3.3
Description of change

Change in haemoglobin cut-off value, less 


Boehringer Ingelheim
12 Jul 2018
BI Trial No.: 1346.23
c03632269-05
Trial Protocol
Page 74 of 77
Proprietary confidential information © 2018 Boehringer Ingelheim International GmbH or one or more of its affiliated companies
001-MCS-40-106-RD-03 (12.0) / Saved on: 30 Jan 2015
strict requirement

Editorial changes
Rationale for change

Reflect negligible Hb lowering effect of 
drug on Hb levels therefore allow lower HB 
levels for inclusion

Changes to ease reading and understanding
Section to be changed
3.3.4
Description of change
Editorial changes
Rationale for change
Increase clarity of the text
Section to be changed
4.2.2
Description of change

Added sentence 

Previous text information on concomitant 
treatments converted into table and 
elaborated further  
Rationale for change
Increase clarity on concomitant treatments, 
emphasize necessity of stable background 
treatments throughout the trial participation as any 
changes may have direct or indirect impact on 
cognition and the diagnosis under scrutiny   
Section to be changed
5.1
Description of change
Changes aligned with protocol synopsis and Flow 
Chart, description of newly added 
neuropsychological tests added, pharmacokinetic 
endpoint previously not mentioned were added
Rationale for change
New concept to detect efficacy signal in executive 
function and memory of the heterogenous AD 
patient population which will be included in this 
trial.
Section to be changed
5.3.3
Description of change
Possibility to introduce Vitamin B12 and folate 
treatments if values are found abnormal (below 
lower limit normal) at Visit 1.
Rationale for change
To allow such patient to participate in the trial, to 
reduce SF rate
Section to be changed
5.3.4
Description of change
Text on central and independent analysis of ECGs 
added 
Rationale for change
To increase objective assessment of ECGs in the 
trial
Section to be changed
5.4.
Description of change
Editorial changes  
 
Rationale for change
Simplification of the section
 
Section to be changed
6.1


Boehringer Ingelheim
12 Jul 2018
BI Trial No.: 1346.23
c03632269-05
Trial Protocol
Page 75 of 77
Proprietary confidential information © 2018 Boehringer Ingelheim International GmbH or one or more of its affiliated companies
001-MCS-40-106-RD-03 (12.0) / Saved on: 30 Jan 2015
Description of change
Editorial and operational changes, more 
explanation on trial conduct and visit planning
Rationale for change
Increase understanding and allow more flexibility 
for patient and the site staff in the trial
Section to be changed
6.2.3
Description of change
Procedure for Vital status collection and 
management of patient withdrawn from the trial 
added
Rationale for change
Increase understanding and add more guidance 
how to proceed with above mentioned patient 
Section to be changed
7
Description of change
Small editorial changes 
Rationale for change
To be aligned with the rest of the protocol text
Section to be changed
8.3.1
Description of change
Explanatory text added 
Rationale for change
Increase clarity of the text
Section to be changed
Appendix 10.1
Description of change
Editorial changes
Rationale for change
Text simplified, redundant sections deleted
Number of global amendment
4
Date of CTP revision
12 Jul 2018
EudraCT number
2015-005438-24
BI Trial number
1346.23
BI Investigational Product(s)
BI 425809
Title of protocol
A multi-centre, double-blind, parallel-group, 
randomised controlled study to investigate efficacy, 
safety and tolerability of orally administered 
BI 409306 during a 12-week treatment period 
compared to placebo in patients with cognitive 
impairment due to Alzheimer’s Disease.
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


Boehringer Ingelheim
12 Jul 2018
BI Trial No.: 1346.23
c03632269-05
Trial Protocol
Page 76 of 77
Proprietary confidential information © 2018 Boehringer Ingelheim International GmbH or one or more of its affiliated companies
001-MCS-40-106-RD-03 (12.0) / Saved on: 30 Jan 2015
Section to be changed
Flow Chart
Description of change

Correction of typo in visit window of 
screening period and IRT registration call in 
thus aligning this information  with section 
6.1

Added End of Study IRT call abnd last dose 
of trial medication information to the Flow 
Chart (previously if different sections of the 
protocol)

Correction of typo in IRT patient 
registration call (must be at V1 as only at 
V1 we may enter the MMSE score to the 
IRT)

Putting the order of neuropsychological 
rating scales in line with the rater station 
device the sites are using 

Enable 2 laboratory re-tests (if needed) in 
screening period to ease operational 
conduct 

Added footnotes 17-20

Correction of further minor typos
Rationale for change
Editorial changes to increase clarity of the text and 
align with further sections of the protocol
Section to be changed
1.2
Description of change
Correction of typos (Cyp →CYP; itroconazole →
itraconazole)
Rationale for change
Corrections of typos
Section to be changed
3.3.2
Description of change
Deletion of duplicated sentence in In. Crit. #4
Rationale for change
Editorial change  
Section to be changed
3.3.3
Description of change
Rewording of Ex. Crit. #14
Rationale for change
Increase clarity due to too many questions being 
raised for this Ex. Crit.  
Section to be changed
4.1.4
Description of change

Dose missed by more than 12 hours should 
be skipped, original text 4 hours (this was a 
typo from previous bid posology)  

Added information on drug administration 
during visits 3a-c and the last trial drug 
administration. 
Rationale for change
Typo correction and added information to increase 
clarity of the text and align with further sections of 
the protocol


Boehringer Ingelheim
12 Jul 2018
BI Trial No.: 1346.23
c03632269-05
Trial Protocol
Page 77 of 77
Proprietary confidential information © 2018 Boehringer Ingelheim International GmbH or one or more of its affiliated companies
001-MCS-40-106-RD-03 (12.0) / Saved on: 30 Jan 2015
Section to be changed
4.2.2.1
Description of change
Correction of typos in table 4.2.2.1.1 Central 
Analgesics and Vitamin B12/Folate 
Addition text on Nutritional Support in AD and 
grapefruit juice and St. John’s Wort preparations
Rationale for change
Added text to increase clarity and editorial changes  
Section to be changed
4.2.2
Description of change
Rewording of dietary supplements restrictions to be 
aligned with section 4.2.2.1
Rationale for change
Editorial changes to increase clarity of the protocol
Section to be changed
5.2
Description of change
Deletion of inconsistent sentence (coding 
administration time 90 seconds was deleted)   
Rationale for change
Inconsistent sentence deleted
Section to be changed
5.3.1
Description of change
Added text to enable proper reporting of abnormal 
findings resulting from physical examinations. 
Rationale for change
Added text to increase clarity and top be in line 
with section 5.3.7 of the protocol
Section to be changed
5.3.3; 5.3.4; 5.3.5.1 and 5.3.7
Description of change
Added text to align with Protocol Flow Chart and 
editorial changes
Rationale for change
Added text and editorial changes to increase clarity  
Section to be changed
6.1 and 6.2.2
Description of change
Modified text to increase clarity and ease 
operational conduct of the trial   
Rationale for change
Editorial changes
Section to be changed
7.3.5
Description of change
Typo corrections   
Rationale for change
Editorial changes 


 
 
 
 
APPROVAL / SIGNATURE PAGE 
 
Document Number: 
 
Technical Version Number:
 
Document Name: 
 
 
 
                                                                                                                 
 
Title: 
 
 
 
 
                                                                                                                   
 
Signatures (obtained electronically) 
 
Meaning of Signature  
Signed by 
Date Signed 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
c03632269
5.0
clinical-trial-protocol-version-05
A multi-centre, double-blind, parallel-group, randomised controlled study to
investigate efficacy and safety of orally administered BI425809 during a 12-week
treatment period compared to placebo in patients with cognitive impairment due to
Alzheimer’s Disease.
Author-Trial Clinical Monitor
13 Jul 2018 11:01 CEST
Author-Trial Clinical
Pharmacokineticist
13 Jul 2018 11:38 CEST
Author-Trial Statistician
16 Jul 2018 22:00 CEST
Approval-Therapeutic Area 
17 Jul 2018 08:40 CEST
Approval-Team Member Medicine
17 Jul 2018 18:23 CEST


Boehringer Ingelheim 
Page 2 of 2
Document Number: 
 Technical Version Number:
 
 
 
(Continued) Signatures (obtained electronically) 
 
Meaning of Signature  
Signed by 
Date Signed 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
c03632269
5.0

SAP_001.pdf: 
TITLE PAGE
Trial Statistical Analysis Plan
c28812145 -01
BI Trial No.:
1346.23
Title:
A multi-centre, double-blind, parallel-group, randomized controlled
study to investigate efficacy and safety of orally administered BI 
425809 during a 12-week treatment period compared to placebo in 
patients with cognitive impairment due to Alzheimer’s Disease.
Including Protocol Amendment 1, 2, 3 and 4 [c03632269-05]. 
Investigational
Product(s):
BI 425809
Responsible trial 
statistician(s):
Telephone: 
Date of statistical 
analysis plan:
4 OCT 2019 Signed
Version:
Revised
Page 1 of 33
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.


Boehringer Ingelheim
TSAP for BI Trial No.: 1346.23                                                                    Page 2 of 33
Proprietary confidential information © 2019 Boehringer Ingelheim International GmbH or one or more of its affiliated companies
1.      TABLE OF CONTENTS
TITLE PAGE ...........................................................................................................................1
1.
TABLE OF CONTENTS .........................................................................................2
LIST OF TABLES...................................................................................................................4
2.           LIST OF ABBREVIATIONS ...................................................................................5
3.           INTRODUCTION......................................................................................................6
4.           CHANGE IN THE PLANNED ANALYSIS OF THE STUDY.............................6
5.           ENDPOINTS ..............................................................................................................6
5.1          PRIMARY ENDPOINT ......................................................................................6
5.2          SECONDARY ENDPOINTS ..............................................................................7
5.2.1       Key secondary endpoint..................................................................................7
5.2.2       Secondary endpoints .......................................................................................7
6.          GENERAL ANALYSIS DEFINITIONS..................................................................8
6.1         TREATMENTS.....................................................................................................8
6.2          IMPORTANT PROTOCOL DEVIATIONS.....................................................9
6.3          SUBJECT SETS ANALYSED..........................................................................13
          
6.5          POOLING OF CENTRES ................................................................................14
6.6          HANDLING OF MISSING DATA AND OUTLIERS ...................................14
6.6.1       Missing efficacy data.....................................................................................14
6.6.2       Missing safety data and other data ..............................................................16
6.6.3       Missing AE dates and times..........................................................................16
6.7         BASELINE, TIME WINDOWS AND CALCULATED VISITS ...................16
7.          PLANNED ANALYSIS............................................................................................17
7.1         DEMOGRAPHICS AND OTHER BASELINE CHARACTERISTICS.......17
7.2         CONCOMITANT DISEASES AND MEDICATION......................................18
7.3         TREATMENT COMPLIANCE ........................................................................18
7.4         PRIMARY ENDPOINT .....................................................................................18
7.4.1       Primary analysis of the primary endpoint ..................................................18
7.4.2
Secondary Analysis........................................................................................20
7.4.3
Sensitivity analyses 
of the primary endpoint.......20
7.5          SECONDARY ENDPOINTS ............................................................................20
7.5.1       Key secondary endpoints ..............................................................................20
7.7          EXTENT OF EXPOSURE................................................................................22
7.8          SAFETY ANALYSIS.........................................................................................22
7.8.1        Adverse events ..............................................................................................22
7.8.2        Laboratory data............................................................................................24


Boehringer Ingelheim
TSAP for BI Trial No.: 1346.23                                                                    Page 3 of 33
Proprietary confidential information © 2019 Boehringer Ingelheim International GmbH or one or more of its affiliated companies
7.8.3       Vital signs .......................................................................................................24
7.8.4       ECG ................................................................................................................24
7.8.5
Others .............................................................................................................24
7.8.5.2       C-SSRS....................................................................................................24
8.          REFERENCES..........................................................................................................25
10          HISTORY TABLE...................................................................................................33


Boehringer Ingelheim
TSAP for BI Trial No.: 1346.23                                                                    Page 4 of 33
Proprietary confidential information © 2019 Boehringer Ingelheim International GmbH or one or more of its affiliated companies
LIST OF TABLES
Table 6.1: 1       Treatment descriptions.....................................................................................8
Table 6.1: 2       Analysing treatment periods (same for all treatment groups) .........................9
Table 6.2: 1       Handling of iPDs ...........................................................................................10
Table 6.3: 1       Subject sets analyzed .....................................................................................13
Table 6.7: 1       Time windows for on-treatment efficacy measurements scheduled for each 
on-treatment visit .............................................................................................................16
Table 7.4.1: 1       Optimal contrast coefficients......................................................................19
Table 10: 1       History table....................................................................................................33


Boehringer Ingelheim
TSAP for BI Trial No.: 1346.23                                                                    Page 5 of 33
Proprietary confidential information © 2019 Boehringer Ingelheim International GmbH or one or more of its affiliated companies
2.           LIST OF ABBREVIATIONS
Term
Definition / description
AChE-Is
Acetylcholine Esterase Inhibitors     
AD
Alzheimer’s Disease 
ADAS-Cog
Alzheimer's Disease Assessment Scale-Cognitive Subscale
ADCS-ADL             Alzheimer’s Disease Cooperative Study/Activities of Daily Living
AE
Adverse Event
AESI
BADLs
Adverse Event of Special Interest
Basic Activities of Daily Living
CI
Confidence Interval
CIBIC+
Clinician’s Interview-Based Impression of Change
CIBIS
Clinical Interview-Based Impression of Severity
COWAT
The Controlled Oral Word Associate Test
CT
Concomitant Therapy
C-SSRS
Columbia Suicide Severity Rating Scale
eCRF
Electronic Case Report Form
EudraCT
European Clinical Trials Database
IADLs
Instrumental Activities of Daily Living
MCPMod
Multiple Comparison & Modelling
MedDRA
Medical Dictionary for Drug Regulatory Activities
MMRM
Mixed Model Repeated Measures
MMSE
Mini-Mental-State-Examination
NPI
Neuropsychiatric Scale
OC
Observed Cases
OR
Original Result
PD               
Pharmacodynamics
PK
Pharmacokinetic
PG(x)
Pharmacogenomic(s)
SD
Standard Deviation
SE
Standard Error
SOC
System Organ Class
TS
Treated Set
VFT
Verbal Fluency Test


Boehringer Ingelheim
TSAP for BI Trial No.: 1346.23                                                                    Page 6 of 33
Proprietary confidential information © 2019 Boehringer Ingelheim International GmbH or one or more of its affiliated companies
3.           INTRODUCTION
As per International Conference on Harmonization (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 protocol, and to include detailed procedures for executing the 
statistical analysis of the primary and secondary variables and other data.
This TSAP assumes familiarity with the Clinical Trial Protocol (CTP), including Protocol
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, randomization.
R Version 3.3.2 with “DoseFinding” package (R15-2001) will be used for analyses based on 
Multiple Comparison Procedures and Modelling (MCPMod) and SAS Version 9.4 will be 
used for all other analyses.
4.           CHANGE IN THE PLANNED ANALYSIS OF THE STUDY
For detailed description of the analyses, please see Sections 7.4.2
5.           ENDPOINTS
The primary objectives of this trial are to establish proof-of-clinical-concept with respect to a 
non-flat dose-response curve and to define one or more suitable doses for BI 425809 
regarding efficacy and safety for further investigation in Phase III trials. 
5.1          PRIMARY ENDPOINT
The primary efficacy endpoint is:
The change from baseline in the ADAS-Cog11 (Alzheimer's Disease Assessment Scale-
Cognitive Subscale: 11-item variant) total score (see Section 9.1 for details) after 12 weeks of 


Boehringer Ingelheim
TSAP for BI Trial No.: 1346.23                                                                    Page 7 of 33
Proprietary confidential information © 2019 Boehringer Ingelheim International GmbH or one or more of its affiliated companies
treatment. The sum of the 11 subscale scores would be the ADAS-Cog11 total score. For 
details of the derivation of the ADAS-Cog11 total score and its subscales, please refer to 
Section 6.6.1 and Section 9.1. The ADAS-Cog11 is measured at screening (Visit 1), baseline 
(Visit 2), week 4 (Visit 4) and week 12 (EOT), with a smaller score indicating better 
cognition. 
5.2          SECONDARY ENDPOINTS
5.2.1       Key secondary endpoint
This section is not applicable as no key secondary endpoint has been specified in the 
protocol.
5.2.2       Secondary endpoints
The secondary efficacy endpoints include: 
Change from baseline in the Alzheimer’s Disease Cooperative Study/Activities of Daily 
Living (ADCS-ADL) score after 12 weeks of treatment. The ADCS-ADL is a 23 item scale 
ranging from 0-78, that is consisted of 6 BADLs items (items 1-6, ranging from 0-22) and 17 
IADLs items (items 7-23, ranging from 0-56). A smaller score indicates more severity.
ADCS-ADL is measured at screening (Visit 1), baseline (Visit 2) and week 12 (EOT).
Clinician's Interview-Based Impression of Change (CIBIC+) score after 12 weeks of
treatment. CIBIC+ is measured at week 12 (EOT). A smaller score indicates better general 
condition (except for 0, which means not assessed).


Boehringer Ingelheim
TSAP for BI Trial No.: 1346.23                                                                    Page 8 of 33
Proprietary confidential information © 2019 Boehringer Ingelheim International GmbH or one or more of its affiliated companies
6.          GENERAL ANALYSIS DEFINITIONS
6.1         TREATMENTS
For regimen and administration details please refer to Sections 3.1 and 4.1 of the CTP.
Table 6.1: 1       Treatment descriptions
Long Name
Short Name
Placebo QD
Placebo QD
BI 425809 2 mg QD
BI 2mg QD
BI 425809 5 mg QD
BI 5mg QD
BI 425809 10 mg QD
BI 10mg QD
BI 425809 25 mg QD
BI 25mg QD


Boehringer Ingelheim
TSAP for BI Trial No.: 1346.23                                                                    Page 9 of 33
Proprietary confidential information © 2019 Boehringer Ingelheim International GmbH or one or more of its affiliated companies
Table 6.1: 2       Analysing treatment periods (same for all treatment groups)
Analysing Treatment Period Start Date
End Date
Screening
Date of informed consent
Date of first treatment 
administration 
Treatment
Date of first treatment 
administration 
Date of last treatment 
administration + REP + 1 
day
Follow-up
Date of last treatment 
administration + REP +1 
day
End of study date
                   REP is the residual effect period which is defined as 11 days after the last dose of trial treatment.
6.2          IMPORTANT PROTOCOL DEVIATIONS
Important protocol deviations (iPDs) affecting subjects’ rights will be identified separately 
from those affecting analysis sets in the study report. Patients with iPDs that could potentially 
impact efficacy endpoints will be excluded from the PPS (Refer to Section 6.3). 
The iPDs are listed in Table 6.2: 1 below. They will be reviewed at Trial Oversight Meeting 
(TOM) conducted periodically based on data accumulated during the trial. A list of protocol 
deviations will be discussed at the report planning meeting (RPM).
If the data show other iPDs, this table will be supplemented accordingly at TOMs or RPMs or 
through team review of the manual PD log. The decision whether a patient will be excluded 
from the analysis will be made at the final RPM prior to data unblinding.


Boehringer Ingelheim
TSAP for BI Trial No.: 1346.23                                                                    Page 10 of 33
Proprietary confidential information © 2019 Boehringer Ingelheim International GmbH or one or more of its affiliated companies
Table 6.2: 1       Handling of iPDs
Category/
iPD Code
Description
Example/Comment
Excluded from
A
Entrance criteria not met
A1
Inclusion criteria not met
A1.1
Patient younger than 
55 years of age
Inclusion criteria 7 not met as specified in the 
protocol.
PPS
A1.2
Diagnosis of mild to 
moderate 
Alzheimer's Disease 
Dementia not met
Inclusion criteria 1 not met as specified in the 
protocol.
PPS, FAS
A1.3
MMSE score 
beyond range
Inclusion criteria 2 not met as specified in the 
protocol.
PPS
A1.4
Previous or current 
use of ACHE-Is 
medication 
requirement not met.
Inclusion criteria 3 not met as specified in the 
protocol.
PPS
A1.5
Inadequate 
education and 
language 
Inclusion criteria 6 not met as specified in the 
protocol.
PPS
A1.6
Inadequate study 
partner reliability
Inclusion criteria 5 not met as specified in the 
protocol.
PPS
A2
Exclusion criteria met
A2.1
Secondary disorder 
other than 
Alzheimer's Disease 
Dementia confirmed
Exclusion criteria 1 met as specified in the 
protocol.
PPS
A2.2
Substantial 
concomitant 
cerebrovascular 
disease
Exclusion criteria 2 met as specified in the 
protocol.
PPS
A2.3
Patients with 
conditions that may 
interfere with the 
trial testing 
procedures
Exclusion criteria 3 met as specified in the 
protocol.
PPS
A2.4
Medical history of 
primary or recurrent 
malignant disease
Exclusion criteria 4 met as specified in the 
protocol.
PPS
A2.5
Condition with life 
expectancy less than 
2 years confirmed
Exclusion criteria 5 met as specified in the 
protocol.
PPS
A2.6
Any suicidal 
behavior in the past 
2 years
Exclusion criteria 10 met as specified in the 
protocol.
None


Boehringer Ingelheim
TSAP for BI Trial No.: 1346.23                                                                    Page 11 of 33
Proprietary confidential information © 2019 Boehringer Ingelheim International GmbH or one or more of its affiliated companies
Table 6.2: 1       Handling of iPDs cont
Category/
iPD Code
Description
Example/Comment
Excluded from
A
Entrance criteria not met
A2
Exclusion criteria met
A2.7
Any suicidal 
ideation of type 4 or 
5 in the C-SSRS in 
the past 3 months
Exclusion criteria 11 met as specified in the 
protocol.
None
A2.8
Participation in AD 
study less than 3 
months from 
screening, treatment 
for disease 
modification 
Exclusion criteria 14 met as specified in the 
protocol.
PPS
A2.9
Known history of 
HIV infection
Exclusion criteria 12 met as specified in the 
protocol.
PPS
A2.10
Prohibited drugs 
prior to visit 1 
and/or during the 
screening period
Exclusion criteria 15 met as specified in the 
protocol.
PPS
A2.11
Uncompensated 
hearing loss
Exclusion criteria 9 met as specified in the 
protocol.
PPS
B
                              Informed consent not available/not done
B1
Informed consent 
not available/not 
done
Informed consent date missing; no signature on 
ICF
All
B2
Informed consent 
too late
Inclusion criteria 4. 
Check if informed consent date (actual consent 
date) was prior or on Visit 1.
Applicable to all informed consents. Check if 
date of informed consent was after the date of 
any study-related procedure.
If patient signed the wrong version of ICF and 
then signed the correct version of ICF with the 
date after screening, it is still deemed as iPD
None


Boehringer Ingelheim
TSAP for BI Trial No.: 1346.23                                                                    Page 12 of 33
Proprietary confidential information © 2019 Boehringer Ingelheim International GmbH or one or more of its affiliated companies
Table 6.2: 1       Handling of iPDs cont
Category/
iPD Code
Description
Example/Comment
Excluded from
C
Trial medication and randomization
C1
Incorrect trial medication taken
C1.1
Incorrect trial 
medication taken 
during study
Any deviation. Check whether the medication 
packages dispensed (med. Numbers entered 
into EDC) has the correct content (to be seen 
from the med. number list that was the basis for 
packaging). If content was correct, the 
deviation will only be noted. Otherwise, the 
cases will be described individually and 
possibly excluded.
In addition, check whether the dispensed 
packages match the randomized treatment of 
the patient (IRT assignment). If not, and if 
treated consistently throughout the trial, 
analyze as treated.
PPS
C2
Randomization order not followed
C2.1
Error by the vendor 
who implemented 
the randomization 
scheme
E.g., the same randomization number was 
given to different patients or the assignment of 
duplicate medication numbers or incorrect 
medication numbers.
Verify by comparing the medication numbers 
and randomization numbers from IRT.
If a patient actually receives the correct 
medication despite the wrong kit, they will not 
be excluded from the PPS.
Vendor to check before unblinding.
PPS
C3
Non-compliance with study medication
C3.1
Non-compliance 
with study
medication
Compliance < 80% or >120 %
PPS if <80%
D
Concomitant medication
D1
Prohibited 
medication use 
before the treatment 
period of the trial
To be determined on a case by case basis.
PPS
D2
Prohibited 
medication use 
during the conduct 
of the trial
To be determined on a case by case basis.
PPS
KEY:
PPS – Per Protocol Set


Boehringer Ingelheim
TSAP for BI Trial No.: 1346.23                                                                    Page 13 of 33
Proprietary confidential information © 2019 Boehringer Ingelheim International GmbH or one or more of its affiliated companies
6.3          SUBJECT SETS ANALYSED
SCR - Screened set: All patients screened for the trial, with informed consent given and 
signed and who completed at least one screening procedure at Visit 1.
RS- Randomized set: This patient set includes all patients who signed the informed consent 
form and were also randomized, regardless whether the patient was treated with trial 
medication or not.
TS-Treated set: All patients who were randomized and treated with at least one dose of study 
medication.
FAS- Full analysis set: The full analysis set (FAS) will consist of all randomized patients 
who were treated with at least one dose of study drug and had a baseline and at least one 
corresponding post baseline on treatment measurement for any efficacy endpoints. In 
particular, for the secondary endpoint CIBIC+, CIBIS is considered its’ corresponding 
baseline measurement.
PPS- Per protocol set: All patients in the FAS without important protocol deviations that 
impact efficacy assessments. PPS analyses will be conducted if more than 10% of patients in 
FAS have an iPD.
The SCR, RS and TS will be used to populate patient disposition and the TS will be used for 
demographics, baseline characteristics, treatment exposure, and safety analyses (including 
adverse events, laboratory measurements, vital signs, and ECG). Safety analyses will assign 
patients to the treatment group based on the treatment received. 
Table 6.3: 1       Subject sets analyzed
                                                              Subject set
Analysis
SCR
RS
TS
FAS
PPS
Primary endpoint  
OC
OC3
Secondary endpoints
OC
Safety variables 
OR
Disposition
OR1
OR1
OR1
Demographics
OR2
OR     
Baseline cognitive 
assessments
OC
Disclosure tables
OR
OR
1)
Disposition table requires multiple patient sets to populate
2)
Additional table for clinical trial disclosure requirements
3)
PPS analyses only conducted if more than 10% of patients in FAS have an iPD
Note: For definitions of OC (Observed Case), OR (Original Results) refer to Section 6.6.


Boehringer Ingelheim
TSAP for BI Trial No.: 1346.23                                                                    Page 14 of 33
Proprietary confidential information © 2019 Boehringer Ingelheim International GmbH or one or more of its affiliated companies
Note that the number of patients with available data for different endpoints may differ. For 
details, see Section 6.6 below. 
6.5          POOLING OF CENTRES
This section is not applicable because centre/country is not included in the statistical model.
6.6          HANDLING OF MISSING DATA AND OUTLIERS
Original result (OR) analysis
Original result analysis implies the analysis of data exactly as observed. OR analysis will be 
performed on variables that are not meaningful to apply any imputation rule on them for 
replacing the missing values.
6.6.1       Missing efficacy data
If a time point is entirely missing, it is handled via the MMRM model, and no other 
imputation rule will be applied. If some items’ scores of a questionnaire are missing, the 
imputation of the total scores will be based on the rules below.
Details on ADAS-Cog11 items and the derived composite endpoint items are described in 
Sections 9.1 and 9.2.
ADAS-Cog11
If a subscale score of ADAS-Cog11 is missing for a subject due to cognitive reasons, the 
worst possible score for that subscale will be given to the corresponding subject, if it is 
missing due to non-cognitive reasons, the corresponding subscale score will be treated as 
missing. 
If a patient has 3 or fewer missing ADAS-Cog11 subscale scores, the following algorithm will 
be used to impute the ADAS-Cog11 total score:
Total score = [(sum of scores from completed items) / (maximum possible sum of scores for 
completed items)]*(maximum total score [=70] for ADAS-Cog11)
If there are more than 3 missing ADAS-Cog11 items, ADAS-Cog11 score will be considered 
missing at that time point.


Boehringer Ingelheim
TSAP for BI Trial No.: 1346.23                                                                    Page 15 of 33
Proprietary confidential information © 2019 Boehringer Ingelheim International GmbH or one or more of its affiliated companies
The imputed number will be rounded to the nearest integer.  If the nearest integer is greater 
than the maximum possible score, the imputed score will be equal to the maximum possible 
score.
ADCS-ADL
For ADCS-ADL, if <30% of the items are missing, the total score will be imputed. The sum 
of the non-missing items will be prorated to the sum of total items.  The imputed number will 
be rounded to the nearest integer.  If the nearest integer is greater than the maximum possible 
score, the imputed score will be equal to the maximum possible score. If >30% of the items 
are missing, the total score at that visit will be considered missing. For example, total score = 
[(sum of scores from completed items) / (sum of maximum possible scores for completed 
items)]*(maximum total score [=78] for ADCS-ADL). Please refer to supplementary material 
(R14-0512) for details.
Observed cases (OC) analysis
For the analyses of all efficacy endpoints using MMRM analyses, it is planned to analyze 
only the available data that were observed or imputed per the imputation rules specified 
above while patients were on treatment, i.e., excluding the missing data. In other words, OC 
analysis will be performed and missing data in this analysis will not be replaced.
Last observation carried forward (LOCF) analysis
The last observation on-treatment need not necessarily be a value selected as a visit value if 
multiple measurements were performed within a time window for a visit. In this case the first


Boehringer Ingelheim
TSAP for BI Trial No.: 1346.23                                                                    Page 16 of 33
Proprietary confidential information © 2019 Boehringer Ingelheim International GmbH or one or more of its affiliated companies
on-treatment value or the value that was observed closest to the planned visit date within the 
last on-treatment time window will be carried forward.
Baseline observation carried forward (BOCF) analysis
As part of the LOCF technique, baseline values will be carried forward if no post-baseline 
value is available.
6.6.2       Missing safety data and other data
In general, missing data will not be imputed and only observed values will be analyzed. Data 
of patients who withdrew after the screening examination or were not treated will be only 
listed.
6.6.3       Missing AE dates and times
Missing or incomplete AE dates are imputed according to BI standards 
 
6.7         BASELINE, TIME WINDOWS AND CALCULATED VISITS
The baseline values are defined as the last pre-treatment observation at or prior to Visit 2. For 
laboratory safety measurements, the last value prior to the first drug administration will be 
considered as baseline values.
The midpoint between two on-treatment visits defines the end of a time window, with the 
midpoint being included in the time window of the preceding visit.
The time windows are defined based on the planned number of days as compare to the date of 
first administration of study drug, with the later date being day 1. 
Table 6.7: 1       Time windows for efficacy measurements scheduled for each visit
Time window
(actual days on treatment)
Visit number
Planned days
Start
End
1
-14
NA
Treatment - 1
2
1
1
1
4
29
2
57
EOT
85 
58
Date of last administration of trial treatment + 
8 days 


Boehringer Ingelheim
TSAP for BI Trial No.: 1346.23                                                                    Page 17 of 33
Proprietary confidential information © 2019 Boehringer Ingelheim International GmbH or one or more of its affiliated companies
Repeated and unscheduled efficacy measurements will be assigned to the nominal visits 
according to the time windows described above. 
For efficacy measurements, only one observation per time window will be selected for 
analysis at an on-treatment visit – the value will be selected which is the first one in the 
corresponding time window. If there are two observations which have the same difference in 
days to the planned day or if there are two observations on the same day, the first value will 
be used. If an observation is available on the last day of treatment, this observation will be 
preferably selected over any later observation that is still within the time window.
For safety measurements, collected visits numbers will be used.
For repeated and unscheduled safety measurements for the same visit on treatment, the worst 
of these will be selected for analysis. In case there is no standard reference direction for the 
safety parameter, the average of all values for the same visit will be used for analysis.
Note: for LOCF imputation, the last observed on-treatment value will be carried forward,
whether or not it was selected in the previous time window. For more details on LOCF refer
to Section 6.6.
7.          PLANNED ANALYSIS
The format of the listings and tables will follow the BI guideline 
 
The individual values of all subjects will be listed, sorted by dose group, subject number and 
visit. AE listings will be sorted by assigned treatment (see Section 7.8.1 below for details). 
The listings will be contained in Appendix of the CTR.
For End-Of-Text tables, the set of summary statistics is: N / Mean / Standard Deviation (SD)
/ Min / Median/ Max.
Disposition of the patient population participating in the trial will be analyzed by treatment 
and presented by the categories in the standard CRF groups and presented in the clinical trial 
report as a frequency-distribution.  
For tables that are provided for endpoints with some extreme data, median, quartiles and 
percentiles should be preferred to mean, standard deviation, minimum and maximum.
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 (unless otherwise specified, all patients in the respective patient 
set whether they have non-missing values or not). Percentages will be rounded to one decimal 
place. The category missing will be displayed only if there are actually missing values.
7.1         DEMOGRAPHICS AND OTHER BASELINE CHARACTERISTICS
Only descriptive statistics are planned for this section of the report.
The age categories for the demographic table are <65 and >=65.


Boehringer Ingelheim
TSAP for BI Trial No.: 1346.23                                                                    Page 18 of 33
Proprietary confidential information © 2019 Boehringer Ingelheim International GmbH or one or more of its affiliated companies
7.2        CONCOMITANT DISEASES AND MEDICATION
Only descriptive statistics are planned for this section of the report.
Concomitant medication use will be summarized by Anatomical-Therapeutic-Chemical 
classification 3 (ATC 3) and preferred name. AD related and non-AD related summaries will 
be presented for concomitant medications taken previously, taken during randomized 
treatment and those taken at baseline. A separate table presenting Non-Drug therapy will also 
be provided.
A summary of concomitant diseases will be provided by treatment group, System Organ 
Class (SOC) and Preferred Term (PT). The most current MedDRA version and WHO B3 
format on Sep. 2019 versions will be used. 
7.3         TREATMENT COMPLIANCE
Treatment compliance is calculated at week 4, 8, and 12/EOT based on protocol Section 4.3.
The cumulative treatment compliance during the entire treatment period is derived using the
following formulas:
For completers: if a subject’s observed treatment compliance rates are 85% at Week 4, 90%
at Week 8 and 100% at EOT, then the cumulative treatment compliance
rate = (0.85*4 + 0.90*4 + 1*4)/12 * 100% = 91.67%.
For early discontinued subject: if a subject’s observed treatment compliance rates are 85% at
Week 4, 100% at Week 8, 50% at EOT, then the cumulative treatment compliance rate =
(0.85*4 + 1*4 + 0.5*((EOT date – drug start date + 1)/7 – 8))/((EOT date – drug start date +
1)/7) * 100% = 89.7% if EOT date – drug start date + 1 = 60 days.
Only descriptive statistics are planned for this section of the report. Summary statistics of
compliance in the treated set will be given for the number of subjects as well as the
corresponding percentage with compliance in the categories <80%, 80% - 120%, >120%,
missing.
7.4         PRIMARY ENDPOINT
The primary analysis is at 12 weeks and will be performed on the full analysis set (FAS).
7.4.1       Primary analysis of the primary endpoint
The hypothesis testing and primary analysis are described in Sections 7.2 and 7.3.1 of the 
CTP, respectively.
The Multiple Comparison Procedures and Modeling (MCPMod) approach (R10-1424, R15-
4293) is implemented in two main steps: (1) trial design stage; (2) trial analysis stage. The 
procedures for the trial design stage, including the selection of candidate models covering a 
suitable range of dose-response shapes and sample size and power calculations, are provided 
in the CTP Sections 7.3.1 and 7.7. The procedures for the trial analysis stage are specified 
below.


Boehringer Ingelheim
TSAP for BI Trial No.: 1346.23                                                                    Page 19 of 33
Proprietary confidential information © 2019 Boehringer Ingelheim International GmbH or one or more of its affiliated companies
The change from baseline in ADAS-Cog11 at week 12 for each dose group as well as the 
corresponding variance-covariance matrix are estimated by an mixed effects model repeated 
measure including the fixed, categorical covariates of treatment, visit, baseline MMSE strata  
indicator (>=20, <20) and treatment-by-visit interaction, as well as the continuous fixed 
covariates of baseline ADAS-Cog11 value and baseline-by-visit interaction. Patient is
considered as random effect. The unstructured covariance matrix is used to estimate the 
within subject variability. The Kenward-Roger approximation will be used to estimate the 
denominator degrees of freedom. Analyses will be implemented using SAS 9.4 PROC 
MIXED. If the MMRM fails to converge, the compound symmetry covariance matrix may be 
considered.
The adjusted mean estimates of the doses and their estimated variance-covariance matrix 
from MMRM are used in the trial analysis stage. Then the multiple comparison procedure 
will be implemented using optimal contrast tests which control the family-wise type I error 
rate at one-sided α = 0.05. The optimal contrasts corresponding to the candidate models are 
calculated as in the trial design stage and shown in Table 7.4.1: 1 below. They will be 
updated using the expected model means from candidate set and the estimated variance-
covariance matrix from the data.
Table 7.4.1: 1       Optimal contrast coefficients
Proof of concept is established if at least one dose-response model is statistically significant, 
rejecting the null hypothesis of a flat dose-response curve, indicating a benefit of BI 425809 
over placebo.
Once the significance of a dose-response signal is established, the dose-response profile and 
the target dose can be estimated using the model averaging method. The selected dose-
response model(s) will be re-fitted to the data without any parameter assumptions to generate 
sets of new estimates of the model parameters from the data. The final dose-response model 
Contrast coefficients for dose
Model
Placebo
2mg
5mg
10mg
25mg
Linear
0.419
0.320
0.170
-0.080
-0.829
Linear 
Logistic
0.772
0.147
-0.094
-0.284
-0.541
Emax
0.641
0.303
-0.009
-0.297
-0.639
Sigmoid 
Emax
0.450
0.430
0.169
-0.394
-0.655
Logistic
0.372
0.352
0.269
-0.203
-0.790
Beta Model
0.656
-0.133
-0.392
-0.507
0.375


Boehringer Ingelheim
TSAP for BI Trial No.: 1346.23                                                                    Page 20 of 33
Proprietary confidential information © 2019 Boehringer Ingelheim International GmbH or one or more of its affiliated companies
will be obtained via weighted model averaging of the significant models based on Akaike 
Information Criterion (AIC) (the smaller the AIC value the better the model fit). Estimates 
for the target dose will be the smallest dose producing a delta greater than or equal to the 
target value of 2 points in the mean change from baseline in ADAS-Cog11 total score after 12
weeks of treatment, based on the final dose-response model, as well as considering safety 
information and other relevant information.
Figures and tables will be displayed for the MCPMod modelling. 
Test statistics and p-values will also be displayed for different dose-response models.
7.4.2
Secondary Analysis            
The secondary analysis of the primary endpoint will be done by fitting the same MMRM 
model that is used in the MCPMod analysis in Section 7.4.1.
The primary treatment comparisons will be between the placebo and the different doses of BI 
425809 with respect to the mean change from baseline in the ADAS-Cog11 total score after 
12 weeks of treatment. Adjusted mean change from baseline as well as the treatment 
contrasts will be presented together with the 95% confidence intervals. The primary treatment 
comparisons will be the contrast between treatments at week 12. 
Comparisons between placebo and different BI 425809 doses are exploratory in nature and 
based on the numerical comparison of the respective treatment means.
Figures that display the adjusted means from the MMRM approach on change from baseline 
in the ADAS-Cog11 total score for each dose level on each visit will also be presented.
7.4.3
Sensitivity analyses and subgroup analysis of the primary endpoint
The following sensitivity analyses will be done for the primary endpoint on FAS:
ANCOVA:
Analysis of covariance based on observed cases (OC) and LOCF will be used as sensitivity 
analyses for the primary endpoint, the model includes baseline value for the primary endpoint 
measure, MMSE stratification (>=20, <20) at baseline and treatment. 
7.5         SECONDARY ENDPOINTS
The analyses for the secondary endpoints are described in Section 7.3.2 of the CTP.  
7.5.1       Key secondary endpoints
This section is not applicable as no key secondary endpoint has been specified in the 
protocol.


Boehringer Ingelheim
TSAP for BI Trial No.: 1346.23                                                                    Page 21 of 33
Proprietary confidential information © 2019 Boehringer Ingelheim International GmbH or one or more of its affiliated companies
7.5.2       Secondary endpoints
The analyses of secondary endpoints are based on FAS. ANCOVA based on (OC) and BOCF 
will be used for the primary and sensitivity analyses of the secondary endpoints, respectively. 
The model will include the same corresponding variables as the ANCOVA model for the 
sensitivity analysis of the primary endpoint, i.e., baseline value for the corresponding 
secondary endpoints measures, MMSE stratification factor (>=20, <20) at baseline and 
treatment. For CIBIC+, CIBIS will be included as the baseline adjustment term. Comparisons 
between treatment groups will be considered exploratory in nature and based on the 
numerical comparison of the respective treatment means.


Boehringer Ingelheim
TSAP for BI Trial No.: 1346.23                                                                    Page 22 of 33
Proprietary confidential information © 2019 Boehringer Ingelheim International GmbH or one or more of its affiliated companies
7.7          EXTENT OF EXPOSURE
Extent of exposure will be calculated as the difference between last intake of study drug and 
the first administration of the study drug plus one day. Descriptive statistics will be provided 
for number of days of exposure for each treatment arm. In addition, cumulative exposure of 
number and percentage (N, %) of subjects will also be displayed as “1 to < 2 weeks”, “2 to 
<3 weeks”, “3 to <4 weeks”, “4 to <8 weeks”, “8 to <12 weeks”, “>=12 weeks” or “missing”.
7.8          SAFETY ANALYSIS
All safety analyses will be performed on the treated set. 
 
AEs will be coded based on the most current version of MedDRA®.
Analysis will be performed as defined in Section 7.3.4 of the CTP.
7.8.1        Adverse events
Unless otherwise specified, the analyses of adverse events will be descriptive in nature. All 
analyses of AEs will be based on the number of patients with AEs and NOT on the number of 
AEs.
For analysis of AE attributes such as duration, severity, etc. multiple AE occurrence data on 
the CRF will be collapsed into one AE event provided that all of the following applies:

All AE attributes are identical (LLT, intensity, action taken, therapy required, 
seriousness, reason for seriousness, relationship and outcome)

The occurrences were time-overlapping or time-adjacent (time-adjacency of 2 
occurrences is given if the second occurrence started on the same day or on the day
after the end of the first occurrence)
The analysis of adverse events will be based on the concept of treatment emergent adverse 
events. That means that all adverse events occurring between the date of the first drug intake 
till the date of the last drug intake + residual effect period will be assigned to the on-treatment
period. All adverse events occurring before first drug intake will be assigned to ‘screening’ 
and all adverse events occurring after the residual effect period but within 28 days afterwards 
will be assigned to ‘follow-up’ (for listings only). For details on the treatment definition, see 
Section 6.1.
Adverse events of special interest (AESIs)
A hepatic injury is defined by the following alterations of hepatic laboratory parameters:


Boehringer Ingelheim
TSAP for BI Trial No.: 1346.23                                                                    Page 23 of 33
Proprietary confidential information © 2019 Boehringer Ingelheim International GmbH or one or more of its affiliated companies

an elevation of AST and / or ALT ≥ 3 fold ULN combined with an elevation of total
            bilirubin ≥ 2 fold ULN measured in the same blood draw sample; and / or

marked peak aminotransferase (ALT and / or AST) elevations ≥ 10 fold ULN.
Refer to CTP Section 5.3.6.1 for details.
Analysis of other significant AEs
According to ICH E3 (12), AEs classified as ‘other significant’ needs to be reported and will 
include those non-serious and non-significant adverse events with 
(i) ‘action taken = discontinuation’ or ‘action taken = reduced’, or
(ii) Marked haematological and other lab abnormalities or lead to significant concomitant 
therapy as identified by the Clinical Monitor/Investigator at a Medical Quality Review 
Meeting (MQRM). 
AE summaries
An overall summary of adverse events will be presented. The frequency of patients with 
adverse events will be summarized by treatment, primary system organ class and preferred 
term according to MedDRA. Separate tables will be provided for patients with:

AEs occurring with incidence in preferred term greater than 2%

AEs occurring with incidence in preferred term greater than 5%

AEs leading to discontinuation

AEs leading to death

AESIs

Drug-related AEs

Serious adverse events

Series related AEs

Other significant adverse events according to ICH E3 (12)

Post-treatment AEs
The system organ classes will be sorted by default alphabetically, preferred terms will be 
sorted by frequency (within system organ class).


Boehringer Ingelheim
TSAP for BI Trial No.: 1346.23                                                                    Page 24 of 33
Proprietary confidential information © 2019 Boehringer Ingelheim International GmbH or one or more of its affiliated companies
7.8.2        Laboratory data
The analyses of laboratory data will be descriptive in nature and will be based on BI 
standards 
Baseline for safety laboratory parameters will be the last available measurement before the 
start of randomized study drug.
Laboratory measurements taken up to the residual effect period of 11 days after the last 
administration of randomized study drug will be considered as on-treatment.
Only patients with at least one available on-treatment value will be included in the analysis of 
an individual laboratory parameter. All individual data will be presented in listings.
Study visits will be presented by the Visit labels in Table 6.7.1.
7.8.3       Vital signs
Only descriptive statistics are planned for this section of the report. In case of multiple 
measurements including unscheduled visits, the value for the vital sign measurement will be 
the average of all the measurements for the corresponding visit. 
7.8.4       ECG
12-lead ECG measurements will be assessed as described in the CTP Flow Chart. ECG-
findings before first intake of trial drug will be considered as baseline condition. Any 
clinically significant new findings in the ECG measurement after the first ECG will be 
considered as AEs.
7.8.5
    Others
7.8.5.2       C-SSRS
The individual items and categories of suicidal ideation and behavior from the C-SSRS will 
be summarized through descriptive statistics according to Section 9.4
 


Boehringer Ingelheim
TSAP for BI Trial No.: 1346.23                                                                    Page 25 of 33
Proprietary confidential information © 2019 Boehringer Ingelheim International GmbH or one or more of its affiliated companies
8.          REFERENCES
1
CPMP/ICH/363/96: "Statistical Principles for Clinical Trials", ICH Guideline Topic 
E9, Note For Guidance on Statistical Principles for Clinical Trials, current version.
2
Bornkamp B, Pinheiro J, Bretz F. Package ‘DoseFinding’ (February 19, 2015). 
Comprehensive R Archive Network 2015; [R15-2001]
3
Doody RS, Thomas RG, Farlow M, et al. Phase 3 trials of solanezumab for mild-to-
moderate Alzheimer’s disease. N Engl J Med 2014; 370:311-21 [R14-0512]
4
Axovant Sciences Ltd: "Statistical Analysis Plan for Protocol RVT-101-3001", 
version: August 9, 2017 [R19-2720]
5
Jutten R, Harrison J, Jong F, et al. cohort composite measure of cognitive and 
functional progression in Alzheimer’s disease: Design of the Capturing Changes in 
Cognition study. Alzheimer’s & Dementia 2017; 130-138 [R19-2721]
9
Pinheiro J, Bomkamp B, Bretz F. Design and analysis of dose-finding studies 
combining multiple comparisons and modelling procedures. J Biopharm Stat 2006; 
16 (5): 639-656 [R10-1424]
10
Pinheiro J, Bomkamp B, Glimm E, et al. Model-based dose finding under model 
uncertainty using general parametric models. Stat Med 2014; 33 (10): 1646-1661 
[R15-4293]
12
CPMP/ICH/137/95: “Structure and Content of Clinical Study Reports”, ICH 
Guideline Topic E3; Note For Guidance on Structure and Content of Clinical Study 
Reports, current version.
15
Salloway S, Sperling R, Fox NC, et al. Two phase 3 trials of bapineuzumab in mild-
to-moderate Alzheimer’s disease. N Engl J Med 2014; 370: 322-33 [R14-0513]
16
Jutten R, Harrison J, Kjoe P, et al. Assessing cognition and function in early 
dementia using the cognitive-functional composite: findings from the Catch-Cog 
study cohort. Alzheimer’s Research & Therapy 2019; [R19-2722]


Boehringer Ingelheim
TSAP for BI Trial No.: 1346.23                                                                    Page 26 of 33
Proprietary confidential information © 2019 Boehringer Ingelheim International GmbH or one or more of its affiliated companies


Boehringer Ingelheim
TSAP for BI Trial No.: 1346.23                                                                    Page 27 of 33
Proprietary confidential information © 2019 Boehringer Ingelheim International GmbH or one or more of its affiliated companies


Boehringer Ingelheim
TSAP for BI Trial No.: 1346.23                                                                    Page 28 of 33
Proprietary confidential information © 2019 Boehringer Ingelheim International GmbH or one or more of its affiliated companies


Boehringer Ingelheim
TSAP for BI Trial No.: 1346.23       
Page 29 of 33
Proprietary confidential information © 2019 Boehringer Ingelheim International GmbH or one or more of its affiliated companies


Boehringer Ingelheim
TSAP for BI Trial No.: 1346.23                                                                    Page 30 of 33
Proprietary confidential information © 2019 Boehringer Ingelheim International GmbH or one or more of its affiliated companies


Boehringer Ingelheim
TSAP for BI Trial No.: 1346.23                                                                    Page 31 of 33
Proprietary confidential information © 2019 Boehringer Ingelheim International GmbH or one or more of its affiliated companies


Boehringer Ingelheim
TSAP for BI Trial No.: 1346.23                                                                    Page 32 of 33
Proprietary confidential information © 2019 Boehringer Ingelheim International GmbH or one or more of its affiliated companies


Boehringer Ingelheim
TSAP for BI Trial No.: 1346.23                                                                    Page 33 of 33
Proprietary confidential information © 2019 Boehringer Ingelheim International GmbH or one or more of its affiliated companies
10          HISTORY TABLE
Table 10: 1      History table
Version
Date
(DD-MMM-
YY)
Author
Sections 
changed
Brief description of change
1.0
5-AUG-19
All
This is the version 1.0 Core TSAP
1.9
4-OCT-19
Table 
6.7.1
This is the version 1.9 Core TSAP