Clinical trial NCT02337907
Conditions: Alzheimer Disease
Sponsor: Boehringer Ingelheim
Start date: 2015-01-21; Completion date: 2017-10-10
Enrollment: 329 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
The study is designed to compare the effects of BI 409306 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 arm 6: None
Interventions: intervention 1: Placebo intervention 2: Placebo intervention 3: BI 409306 intervention 4: Donepezil
Intervention descriptions: intervention 1: for blinding purposes intervention 2: None intervention 3: None intervention 4: None

Protocol documents:
Prot_001.pdf: 
Clinical Trial Protocol
Doc. No.: c02216748-08
EudraCT No.:
BI Trial No.:
2013-005040-28
1289.7
BI Investigational
Product:
BI 409306
Title:
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.
Clinical Phase:
II
Trial Clinical 
Monitor:
Phone: 
Fax: 
Co-ordinating 
Investigator:
Phone: 
Fax: 
Status:
Final Protocol (Revised Protocol based on global amendment No.4)
Version and Date:
Version:
5.0
         
Date: 23 Feb 2017
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TITLE PAGE


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CLINICAL TRIAL PROTOCOL SYNOPSIS
Name of company:
Tabulated
Trial Protocol
Boehringer Ingelheim
Name of finished product:
NA
Name of active ingredient:
BI 409306
Protocol date:
Trial number:
Revision date:
23 Feb 2017
17 Oct 2014
1289.7
Title of trial:
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
Co-ordinating 
Investigator:
Phone: 
Fax: 
Trial site(s):
60
Clinical phase:
II
Objective(s):
To assess safety, tolerability and efficacy of different doses of BI 409306 compared to 
placebo in treatment of cognitive impairment due to AD
Methodology:
Placebo -controlled, double-blind, randomised parallel-design comparison of 5 groups 
over 12 weeks of treatment.
No. of patients: 
total entered:
354
each treatment:
118 for placebo group and 59 for each treatment group
Diagnosis :
Patients with diagnosis of mild Alzheimer’s dementia according to the 
recommendations from the National Institute on Aging-Alzheimer’s Association 
workgroups on diagnostic guidelines for Alzheimer’s disease and ICD10 and DSM V 
criteria
Main criteria
for inclusion:
The population will include male and female patients at least 55 years old with mild 
Alzheimer’s dementia. A MMSE (Mini-Mental-State-Examination) score between 18-
26, an ADAS-cog11 score higher than 12 at screening, and a global CDR score of 1 or 
greater are required for inclusion. A caregiver has to be available for study site 
activities and on call by arrangement with the study site.
Test product(s):
BI 409306
dose:
10mg QD, 25mg QD, 50mg QD, 25mg BID
mode of admin.:
Tablet, Oral


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Name of company:
Tabulated
Trial Protocol
Boehringer Ingelheim
Name of finished product:
NA
Name of active ingredient:
BI 409306
Protocol date:
Trial number:
Revision date:
23 Feb 2017
17 Oct 2014
1289.7
Comparator products:
Donepezil (Aricept®; randomisation to this treatment stopped via amendment 2), 
Placebo
dose:
10mg QD (starting with 5 mg for the first 4 weeks)
mode of admin.:
Tablet, Oral
Duration of treatment: 12 weeks
Criteria for efficacy:
Primary endpoint:
1.
Cognition as measured by change from baseline in Neuropsychological Test
Battery (NTB) total z-score after 12-week treatment.
Secondary endpoints include: 
1. Change from baseline in ADCS-ADL total score after 12-week treatment 
2. Change from baseline in CDR-SB (Clinical Dementia Rating Scale Sum of
Boxes) total score after 12-week treatment
3. Change from baseline in ADAS-cog11 (Alzheimer’s Disease Assessment
Scale-cognitive subscale) total score after 12-week treatment 
Criteria for safety:
Adverse event reporting, vital signs, ECG (digital) and standard laboratory tests,
Columbia-Suicide Severity Rating Scale (C-SSRS).
Statistical methods:
Restricted Maximum Likelihood Estimation based Mixed-effects Model for Repeated 
Measures (MMRM) will be used to obtain adjusted means for the treatment effects. 
This model will include fixed, categorical effects of treatment, visit, current AChEI 
use (Yes, No) and treatment by visit interaction, as well as continuous fixed covariates 
of baseline and baseline-by-visit interaction. Patient will be considered as random 
effect. The unstructured covariance structure will be used as covariance structure for 
within-patient variation.
Descriptive statistics


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FLOW CHART
Trial Period
Screening
Placebo
Run-in
Period
Treatment Period
Follow-
up
Visit
1
2
3
Baseline
4a12
4b12
4c12
5
6
EOT/ED11
FU
Studyweeks
-3
-2
1
2
3
4
8
12
16
Study-Day (or duration during 
screening/ run-in)
Dura-
tion 1-7
days
Duration at least 
14 and at most 21 
days after 
screening period
1
8
15
22
29
57
85
EOT
+28
Visit window (in days)
±1
±1
±1
±3
±3
+3
±3
Patient information &               
informed consent signed
 
X
Register Patient in IRT
X
Randomisation (via IRT)
X
Demographics
X
Medical history / baseline 
conditions
X
In-/exclusion criteria 
X
X
X
Imaging of the Brain2
X
Concomitant medications
X
X
X
X
X
X
X
X
X
X
Height (screening only)/weight
X
X
X
Vital signs
X
X
X
X12
X12
X
X
X
X
Post Dose Heart Rate Procedure3
X
Physical examination
X
X
Neurological examination
X
X
Resting ECG (digital)
X
X
X
X12
X12
X
X
X
X
Adverse events
X
X
X
X
X12
X12
X
X
X
X
Dispense trial medication4
X
X
X
X
Collect study drug
X
X
X
X
Medication Compliance Check
X
X
X
X
Laboratory tests: Chemistry, 
haematology, urinanalysis
X
X
X
X
X
X
Blood Glucose (Onsite)5
X
X
X
X
 
 
Urine drug screen
X
X
Urine pregnancy test8
X
X
X
X
X
Vitamin B12 and folate
X
X
RPR (FTA, if RPR positive)
X
Prospective Suicidality 
Monitoring
C-SSRS
X9
X10
X10
X10
X10
X10
X10
X10
X10
X10


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Trial Period
Screening
Placebo
Run-in
Period
Treatment Period
Follow-
up
Visit
1
2
3
Baseline
4a12
4b12
4c12
5
6
EOT/ED11
FU
Studyweeks
-3
-2
1
2
3
4
8
12
16
Study-Day (or duration during 
screening/ run-in)
Dura-
tion 1-7
days
Duration at least 
14 and at most 21 
days after 
screening period
1
8
15
22
29
57
85
EOT
+28
Visit window (in days)
±1
±1
±1
±3
±3
+3
±3
Neuropsychological Rating 
Scales
MMSE
X
CDR
X
CDR-SB
X13
X
X
NTB
X13
X
X
ADCS-ADL
X13
X
ADAS-cog11
X
X13
X
1 Prior to any study related procedure
2 Results of a MRI or CCT-scan have to be available before visit 2. Please refer to exclusion #1 for further details. If a CCT or MRI cannot 
be obtained within the given visit window the duration of the screening period may be extended to a maximum of 21 days (if needed).
3 The baseline vital signs (supine pulse rate after 5 minutes of rest and systolic/diastolic blood pressure) will be measured before the first 
dose is taken. Additional vital signs assessments will be performed at the time points of post-dose PK sampling given in table 10.1.1:1
until 70-110 minutes post-dose (See section 5.2.5 and section 6.2 for details).
4 At all visits, the respective kit number has to be allocated to the patient via IRT
5 Only for patients with antidiabetic therapy (see section 6.2 for details).
 
8 Local urine pregnancy test (or blood test if required by local regulations) in women of child bearing potential. More frequent testing may 
be performed if required by local regulations.
9 Columbia Suicide Severity Rating Scale baseline/screening scale
10 Columbia Suicide Severity Rating Scale baseline since-last-visit scale
11 Also to be completed for patients who are withdrawn or who have discontinued the trial early: in case of early termination visit 7 should 
be performed no later than 7 days after the last study drug intake (visit FU four weeks later).
12 If the assessments at visit 4a do not show clinically relevant findings compared to baseline and if deemed clinically acceptable by the 
investigator then visits 4b and 4c may be performed as phone contacts. Attendance of the study partner is not necessarily required during 
visits 4 a-c. ECG and vital signs are only to be performed at clinic visits.
13 The neuropsychological assessments may be done on the day before the randomisation visit (last day of the screening period) 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.


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TABLE OF CONTENTS
TITLE PAGE ......................................................................................................1
CLINICAL TRIAL PROTOCOL SYNOPSIS ................................................2
FLOW CHART...................................................................................................4
TABLE OF CONTENTS ...................................................................................6
ABBREVIATIONS.......................................................................................... 10
1.
INTRODUCTION.................................................................................... 12
1.1
MEDICAL BACKGROUND............................................................................12
1.2
DRUG PROFILE...............................................................................................13
2.
RATIONALE, OBJECTIVES, AND BENEFIT – RISK 
ASSESSMENT ......................................................................................... 17
2.1
RATIONALE FOR PERFORMING THE TRIAL........................................17
2.2
TRIAL OBJECTIVES.......................................................................................17
2.3
BENEFIT – RISK ASSESSMENT...................................................................17
3.
DESCRIPTION OF DESIGN AND TRIAL POPULATION.............. 19
3.1
OVERALL TRIAL DESIGN AND PLAN ......................................................19
3.1.1
Administrative structure of the trial...................................................19
3.2
DISCUSSION OF TRIAL DESIGN, INCLUDING THE CHOICE OF 
CONTROL GROUP(S).....................................................................................20
3.3
SELECTION OF TRIAL POPULATION ......................................................21
3.3.1
Main diagnosis for study entry............................................................21
3.3.2
Inclusion criteria...................................................................................22
3.3.3
Exclusion criteria ..................................................................................22
3.3.4
Removal of patients from therapy or assessments.............................25
3.3.4.1
Removal of individual patients................................................25
3.3.4.2
Discontinuation of the trial by the sponsor..............................26
4.
TREATMENTS........................................................................................ 27
4.1
TREATMENTS TO BE ADMINISTERED....................................................27
4.1.1
Identity of BI investigational product and comparator 
product(s)...............................................................................................28
4.1.2
Method of assigning patients to treatment groups ............................30
4.1.3
Selection of doses in the trial................................................................30
4.1.4
Drug assignment and administration of doses for each patient .......31
4.1.5
Blinding and procedures for unblinding ............................................33
4.1.5.1
Blinding....................................................................................33
4.1.5.2
Procedures for emergency unblinding .....................................33
4.1.6
Packaging, labelling, and re-supply ....................................................34
4.1.7
Storage conditions.................................................................................34
4.1.8
Drug accountability ..............................................................................34


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4.2
CONCOMITANT THERAPY, RESTRICTIONS, AND RESCUE 
TREATMENT....................................................................................................35
4.2.1
Rescue medication, emergency procedures, and additional 
treatment(s) ...........................................................................................35
4.2.2
Restrictions............................................................................................35
4.2.2.1
Restrictions regarding concomitant treatment .........................35
4.2.2.2
Restrictions on diet and life style.............................................36
4.3
TREATMENT COMPLIANCE.......................................................................36
5.
VARIABLES AND THEIR ASSESSMENT ......................................... 37
5.1
EFFICACY – PHARMACODYNAMICS.......................................................37
5.1.1
Endpoint of efficacy..............................................................................37
5.1.2
Assessment of efficacy...........................................................................37
5.2
SAFETY..............................................................................................................39
5.2.1
Endpoint(s) of safety.............................................................................39
5.2.2
Assessment of adverse events...............................................................39
5.2.2.1
Definitions of adverse events...................................................39
5.2.2.2
Adverse event and serious adverse event reporting.................40
5.2.3
Assessment of safety laboratory parameters......................................42
5.2.4
Electrocardiogram................................................................................44
5.2.5
Assessment of other safety parameters...............................................45
5.2.5.1 Physical examination (PE) .........................................................45
5.2.5.2 Vital signs...................................................................................45
5.2.5.3
Suicidal risk assessed by the C-SSRS......................................46
5.4
APPROPRIATENESS OF MEASUREMENTS.............................................48
 
6.
INVESTIGATIONAL PLAN.................................................................. 50
6.1
VISIT SCHEDULE............................................................................................50
6.2
DETAILS OF TRIAL PROCEDURES AT SELECTED VISITS ................50
6.2.1
Screening and run-in period(s)............................................................51
6.2.2
Treatment period(s)..............................................................................52
6.2.3
End of trial and follow-up period........................................................55


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7.
STATISTICAL METHODS AND DETERMINATION OF
SAMPLE SIZE......................................................................................... 56
7.1
STATISTICAL DESIGN – MODEL ...............................................................56
7.1.1
Design.....................................................................................................56
7.2
NULL AND ALTERNATIVE HYPOTHESES ..............................................56
7.3
PLANNED ANALYSES....................................................................................57
7.3.1
Primary analyses...................................................................................58
7.3.2
Secondary analyses ...............................................................................58
7.3.3
Safety analyses.......................................................................................58
7.3.4
Interim analyses ....................................................................................59
7.4
HANDLING OF MISSING DATA ..................................................................60
7.5
RANDOMISATION ..........................................................................................60
7.6
DETERMINATION OF SAMPLE SIZE ........................................................61
8.
INFORMED CONSENT, DATA PROTECTION, TRIAL
RECORDS ................................................................................................ 62
8.1
STUDY APPROVAL, PATIENT INFORMATION, AND INFORMED 
CONSENT ..........................................................................................................62
8.2
DATA QUALITY ASSURANCE .....................................................................63
8.3
RECORDS..........................................................................................................63
8.3.1
Source documents .................................................................................63
8.3.2
Direct access to source data and documents.......................................63
8.4
LISTEDNESS AND EXPEDITED REPORTING OF ADVERSE 
EVENTS..............................................................................................................64
8.4.1
Listedness...............................................................................................64
8.4.2
Expedited reporting to health authorities and IECs/IRBs................64
8.5
STATEMENT OF CONFIDENTIALITY.......................................................64
8.6
COMPLETION OF TRIAL..............................................................................64
9.
REFERENCES......................................................................................... 65
9.1
PUBLISHED REFERENCES...........................................................................65
9.2
UNPUBLISHED REFERENCES.....................................................................66
10. APPENDICES .......................................................................................... 68
10.2
CLINICAL EVALUATION OF LIVER INJURY .........................................70
10.2.1 Introduction...........................................................................................70


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10.2.2 Procedures .............................................................................................70
11. DESCRIPTION OF GLOBAL AMENDMENT(S).............................. 72


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ABBREVIATIONS
ABCB1
ATP-binding cassette sub-family B member 1 (gene encoding for P-gp)
AChE-Is
Acetylcholine Esterase Inhibitor
AE
Adverse Event
AESI
Protocol-specified Adverse Event of Special Interest
AD
ADAS-cog
APOE
Alzheimer’s Disease
Alzheimer's Disease Assessment Scale-cognitive subscale
Apolipoprotein E
AUC
Area under the Curve
BCRP
breast cancer resistance protein
BDNF
Brain-derived neurotrophic factor
BPM
Beats per Minute
CDR-SB
Clinical Dementia Rating Scale–Sum of Boxes
CI
Confidence Interval
CML
Local Clinical Monitor 
CRA
Clinical Research Associate
CRF
CT
CCT
C-SSRS
Case Report Form
Computer Tomography
Cranial Computer Tomography
 
Columbia Suicide Severity Rating Scale
CTCAE
Common Terminology Criteria for Adverse Events
CTMF
Clinical Trial Master File
CTP
CTR
CYP
Clinical Trial Protocol
Clinical Trial Report
Cytochrome P450
DAT
Dementia of Alzheimer Type
DMC
DNA
Data Monitoring Committee
Deoxyribonucleic Acid
eCRF
Electronic Case Report Form
EDC
Electronic Data Capture
EM
EudraCT
Extensive metabolizer
European Clinical Trials Database
FAS
Full Analysis Set
FTA
Fluorescent treponemal antibody absorbent test
GCP
Good Clinical Practice
IB
Investigator’s Brochure
IEC
Independent Ethics Committee
IM
Intermediate metabolizer
IRB
Institutional Review Board
ISF
Investigator Site File
i.v.
Intravenous
IRT
Interactive Response Technology


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LTP
Long Term Potentation
MedDRA
Medical Dictionary for Drug Regulatory Activities
MNDA
Myeloid cell nuclear differentiation antigen
MMSE
Mini-Mental-State-Examination
MST
MRI
NMDA-R
Medical Subteam
Magnetic Resonance Imaging
N-methyl-D-aspartate receptor
NTB
Neuropsychological Test Battery
OPU
Operative Unit
p.o.
per os (oral)
P-gp
P-glycoprotein
PCC
PDE9
Protocol Challenge Committee
Phosphodiesterase-9
PM
Poor metabolizer
POC
Proof of Concept
RPR
Rapid Plasma Reagin
PTM
Placebo to Match
PK
Pharmacokinetic
PM
Poor metabolizers
RDC
Remote Data Capture
REP
Residual Effect Period
RNA
Ribonucleic Acid
q.d.
quaque die (once a day)
SAE
Serious Adverse Event
s.c.
Subcutaneous
SPC
STORM
Summary of Product Characteristics
Storage Conditions for Trial Medications
TCM
Trial Clinical Monitor
TDMAP
tmax,ss
Trial Data Management and Analysis PlanTime to maximum plasma 
concentration (at steady state)
TMM
Team Member Medicine
TMW
Trial Medical Writer
TSAP
Trial Statistical Analysis Plan
UM
Ultrarapid metabolizer


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1.
INTRODUCTION
1.1
MEDICAL BACKGROUND
Dementia of Alzheimer’s Type (DAT), 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 behavioral 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 purely symptomatic. 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 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. Upon 
activation, a cascade of intracellular, post-synaptic signaling 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. 


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LTP is regarded as a validated physiological model for cellular processes underlying learning 
and memory formation [R10-5109; R10-5092; R10-5102].
1.2
DRUG PROFILE
BI 409306 - a potent selective phosphodiesterase 9 (PDE9A) inhibitor –is being developed
for symptomatic treatment of Alzheimer’s disease and cognitive impairment associated with 
schizophrenia (CIAS). 
PDE9A inhibition is supposed to improve NMDA receptor signalling cascade by increasing 
cGMP levels 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. BI 409306 has 
demonstrated pro-cognitive properties in relevant animal models of learning and memory 
impairment. Therefore it is expected that treatment with BI 409306 will result in relevant 
cognition enhancing effects in AD and CIAS that are superior to currently available treatment 
options (if any).
For full details on drug profile, please refer to the latest version of the IB [c02101303].
 
 
 
 
 
 
 


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Clinical safety
In healthy volunteer trials [U12-1034-01, U13-1182-01, U12-2165-01, U13-1303-01, 
c02098989-02] , the most frequent drug related adverse events were visual side effects that 
occurred shortly after dosing and mostly resolved within 1 h. Overall, there were no relevant 
changes observed for laboratory, ECG recordings, and vital signs following treatment with BI 
409306 when compared to placebo. Only a rapid and short lasting increase in supine pulse 
rate of 12.9 ± 4.4 bpm was detected in Chinese CYP2C19 poor metabolizers subjects treated 
with BI 409306 (100 mg single dose) in study 1289.4 [c02098989-02]. Following this 
observation, pharmacometric analysis of all available human data revealed a BI 409306 
plasma concentration dependent increase in supine pulse rate reaching a maximum of 7-13 
bpm (median) at high exposure end in CYP2C19 poor metabolizers treated with BI409306 at 
100 mg. The maximum effects of BI 409306 on pulse rate were generally achieved at 
maximum BI 409306 plasma concentrations (20-30 minutes post dose) and disappeared 
rapidly with declining concentrations. Altogether, good to satisfactory safety and tolerability 
were observed in single doses of BI 409305 (up to 350mg in CYP2C19 extensive 
metabolizers (EM); up to 100mg in CYP2C19 poor metabolizers (PM)) in healthy young 
volunteers and multiple doses (14 days up to 100mg EM/50mg PM) of BI 409306 in healthy 
young and elderly subjects. None of the safety data presented a safety issue for further 
clinical trials.
Visual Side Effects
In healthy volunteer trials, the most frequent drug related adverse events were visual side 
effects (such as sensation of flashing lights, altered color perception, photophobia / increased 
sensitivity to light or blurred vision) that occurred shortly after dosing and resolved within 1 
h. These visual side effects are in close connection to maximum BI 409306 plasma 
concentrations which sharply and steeply peak within the first 1-2 hours and then rapidly 
decline afterwards.
Two preclinical studies have been conducted to elucidate these phenomena. Since no data 
were available on PDE9 protein expression in the retina, an immunhistochemical analysis 


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was performed in the first preclinical study in order to assess PDE9 expression in retina cells 
of rat and human tissue. This study demonstrated specific staining of PDE9 expression in rat 
and human retina tissue, confirmed via both positive tissue control (cerebellum and kidney) 
and via negative control (absence of primary antibody; isotype control). There was 
widespread distribution of PDE9 in the rat and human retina except the outer segment of the 
photoreceptor layer.
It is concluded from these experiments that PDE9 protein is expressed in retina and PDE9-
inhibition leads to changes in retina physiology (ERG and ganglion cell activity), providing a 
likely explanation for the transient visual effects noted in human.


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2.
RATIONALE, OBJECTIVES, AND BENEFIT – RISK 
ASSESSMENT
2.1
RATIONALE FOR PERFORMING THE TRIAL
Currently approved AD treatment is purely symptomatic. Registered symptomatic treatment 
consists of acetylcholinesterase inhibitors (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.
This study is designed to compare the effects of 4 different doses of orally administered BI
409306 to placebo (see section 3.2 for further details).
In addition to the ongoing efforts in the development of more effective symptomatic 
treatment options, new compounds with a disease-modifying potential are in the center of 
interest in the AD research field. However, no drug with a proven disease modifying potential 
is presently available, and its availability and use in the future will not reduce the medical 
need for symptomatic treatment. Furthermore, it cannot be expected that a putative disease-
modifying drug would have the potential to restore lost cognitive function. Therefore, a 
symptomatic treatment that proves to be more efficacious than the currently available 
compounds (AchE-Is, memantine) in improving both existing cognition deficits and the 
ability to better perform activities of daily living would provide a substantial benefit to 
patients.
2.2
TRIAL OBJECTIVES
The primary objective of this study is to assess efficacy and safety of BI 409306 at doses of 
10 mg, 25 mg and 50 mg once daily, 25 mg twice daily compared to placebo over a 12-week 
treatment period in patients with the following criteria: mild dementia of Alzheimer’s type 
aged at least 55 years, a MMSE between 18 and 26.
The study endpoints are listed in Section 5.1.1.
2.3
BENEFIT – RISK ASSESSMENT
The currently available safety data, including first results from a recently performed phase I 
trial with single doses orally administered up to 350 mg in healthy subjects, indicate that 
BI 409306 has a broad safety margin and is well tolerated. 
Consistent with the FDA draft guidance entitled "Suicidal Ideation and Behavior: Prospective 
Assessment of Occurrence in Clinical Trials", prospective assessment of suicidal ideation and 
behavior is included in this study using the C-SSRS.
Although rare, a potential risk for drug-induced liver injury is under constant surveillance by
sponsors and regulators. Therefore, this study requires timely detection, evaluation, and
follow-up of laboratory alterations of selected liver laboratory parameters to ensure patients´
safety.


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This is an experimental drug at an early stage of testing and therefore an individual benefit 
cannot be guaranteed. This is a trial of short duration. Therefore, the assignment to the 
placebo arm is not associated with a higher risk for the patient, and 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. 


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3.
DESCRIPTION OF DESIGN AND TRIAL POPULATION
3.1
OVERALL TRIAL DESIGN AND PLAN
This is a 12-week, multi-centre, randomised, double-blind, placebo controlled, parallel group 
comparison in patients with mild DAT.
In total, 354 patients with mild DAT who meet the entry criteria are planned to be 
randomised in this trial. The randomised treatment will be double blind. Each patient will be 
treated with one of the following forms of treatment: active treatment with BI 409306, or 
placebos (each patient will receive placebos to match each of the active treatments).
After obtaining informed consent, patients enter the screening period. All patients suitable 
after screening will undergo a 2-week single-blind placebo run-in period before
randomisation. Patients who successfully complete the single blinded phase and who still
meet the inclusion/exclusion criteria will be randomised to the 12-week double-blind 
treatment period at Visit 3 and will be assigned to one of the following 5treatment groups:
10 mg, 25 mg, 50 mg BI 409306, 25 mg BI 409306 twice daily (BID), or placebo.
After the end of the double-blind treatment period, patients will be followed up for additional 
4 weeks without study medication. Patients will be evaluated for efficacy at randomization, at 
visit 5 (week 4) and at visit EOT (week 12). 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.
Adverse events will be collected throughout the trial according to Section 5.2.2.2.
3.1.1
Administrative structure of the trial
The trial is sponsored by Boehringer Ingelheim (BI). Boehringer Ingelheim will appoint a 
Trial Clinical Monitor (TCM), responsible for coordinating the activities required in order to 
manage the trial in accordance with applicable regulations and internal Standard Operating 


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Procedures (SOPs), directing the clinical trial team in the preparation, conduct, and reporting 
of the trial, ordering the materials as needed for the trial, ensuring appropriate training and 
information of local clinical monitors (CMLs), CRAs, and investigators in participating 
countries. 
Data management and statistical evaluation will be done by BI according to BI SOPs. For 
these activities, a Trial Data Manager and a Trial Statistician will be appointed. Tasks and 
functions assigned in order to organize, manage, and evaluate the trial will be defined 
according to BI SOPs. A list of responsible persons will be given in the Clinical Trial Master 
File (CTMF) document.
 has been selected as 
service provider to support the following tasks related to the neuropsychological assessments: 
necessary rater prequalification, rater training (online and at investigator meeting), provision 
of rater materials and central review of assessments (see section 8.2 for details).
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 will be nominated to coordinate investigators at different sites 
participating in this multi-centre trial. Tasks and responsibilities for the Coordinating 
Investigator will be defined in a contract filed before initiation of the trial. Documents on 
participating (Principal) investigators and other important participants, especially their 
curricula vitae, will be filed in the CTMF.
The Investigator Site File (ISF) will be kept at the sites as far as required by local regulations 
and BI SOPs. A copy of the ISF documents will be kept as an electronic Clinical Trial Master
File.
3.2
DISCUSSION OF TRIAL DESIGN, INCLUDING THE CHOICE OF 
CONTROL GROUP(S)
All patients who are screening positive will undergo a single blinded placebo run-in phase in 
order to generally familiarize with the clinical setup of the neuropsychological tests as well as 
the regular intake of study drug to ensure compliance with study procedures.
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.
Treatment with BI 409306 will be compared to treatment with placebo. 


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In order to estimate the absolute drug effect on cognition and function, a double-blind 
comparison against placebo is included in this trial. With this approach we follow the EMA 
guideline on medical products for the treatment of Alzheimer’s disease and other dementias 
(CPMP/EWP/553/95 Rev. 1, 2008) [R11-5045].
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 409306.
The data collected in this double-blind, randomized, placebo-controlled trial are standard in 
this indication and will provide important information in terms of efficacy and safety on the 
use of BI 409306 maintenance treatment in patients with mild to moderate AD.
Independent raters for efficiency and AE are strongly recommended because the drug has 
known side effects which may inadvertently bias the trial team doctors who see the patients 
for visits. Please refer to section 6.2.
3.3
SELECTION OF TRIAL POPULATION
Untreated male and female patients, at least 55 years old, with diagnosis of mild Dementia of 
Alzheimers’ Type (DAT) will be randomised. Recruitment will be competitive and 
participating sites are expected to enter at least 354 patients.
Patients who fail to complete all assessments in terms of primary and secondary endpoints 
according to the study protocol will not be considered study completers (see Sections 6.2 and 
7.3 for details). Patients who discontinue following randomisation 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. Re-screening of not yet randomised patients can be allowed in 
exceptional cases but should be discussed on a case-by-case basis between the study site, 
Monitor staff and with the TCM.
Permission to randomise more than 15 patients per site must be obtained from the TCM at 
Boehringer Ingelheim. This will only be allowed after a careful review of the enrolment 
status.
A log of all patients included into the study (i.e. having given informed consent) will be 
maintained in the ISF at the investigational site irrespective of whether they have been treated
with investigational drug or not.
3.3.1
Main diagnosis for study entry
Patients with the diagnosis of mild Alzheimer’s 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 Dementia) will 
be included.


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3.3.2
Inclusion criteria
Patients are included in this study if they meet all of the following criteria:
1. Diagnosis of mild Alzheimer’s 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. Mini-Mental State Examination (MMSE) score of 18-26, an Alzheimer’s Disease 
Assessment Scale – cognitive subscale (ADAS-cog11) score > 12 and a 
global CDR score of 1 or greater at screening.
3. Patients must have given written informed consent in accordance with GCP and local 
legislation prior to any study procedures. All patients must be able to give informed 
consent personally and have capacity for such consent. An informed consent given by a 
legal representative will not be accepted.
4. Patients must have a reliable study partner (per investigator judgement 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 assessment 
of the ratings of the functional endpoints including CDR-SB 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.
5. 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.
6. Previous use of AD medications (AChEIs, memantine) is allowed up 3 month prior to 
screening. 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 currently taking memantine are excluded. .
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
Patients must be excluded from this study if they meet any of the following criteria:
1. Dementia secondary to other disorders (for example: neurosyphilis, craniocerebral 
trauma, small vessel disease) based on clinical data and/or current laboratory findings 
and/or a pre-existing MRI or CT of the brain. If previous cranial imaging is not available 
or older than 12 months prior to screening then a CCT or MRI needs to be performed at 
screening. Please check your local regulations if the use of radiations for a CCT scan is 


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allowed in your country. If performing of a CCT is not allowed in the frame of this trial 
(e.g. Germany, France, United Kingdom), a MRI must be performed.
2. Substantial concomitant cerebrovascular disease (defined by a history of a 
stroke/intracranial haemorrhage temporally related to the onset of worsening of cognitive 
impairment) (per investigator judgement).
3. Medical history of cancer (except for basal cell carcinoma) and/or treatment for cancer 
within the last 5 years.
4. History or diagnosis of the following symptomatic and unstable/uncontrolled conditions
(per investigator judgement):
a.
Uncontrolled cardiovascular illnesses such as chronic congestive heart failure 
(with or without oedema), tachycardia, arrhythmias, uncontrolled hypertension.
b. Significant ischemic heart disease, myocardial infarction within the last two years 
and/or with residual angina, orthopnea, conduction defects (ECG), or any other 
clinical significant heart disease classified as NYHA III or IV.
c.
Significant liver disease (for example cirrhosis, active hepatitis B and C, primary 
or metastatic liver neoplasm).
d. Significant gastrointestinal disorders (for example gastrointestinal bleeding within 
the last two years, malabsorption syndromes, post-gastrectomy, or active peptic 
ulcer disease).
e.
Uncontrolled endocrine disease such as uncontrolled diabetes mellitus or manifest 
hyperthyroidism.
f.
Unstable/uncontrolled major depression
g. Significant pulmonary disease predisposing to hypoxia.
h. Immunological disorder such as per investigator judgement clinically significant 
allergies, Lupus erythematodes, or scleroderma.
i.
Uncontrolled/Unstable haematological disease (regardless of cause) such as 
refractory anaemia or refractory myelosuppression.
j.
Systemic or multiple organ dysfunctions which, in the opinion of the investigator, 
would impact on the primary and secondary endpoints of the trial such as 
clinically relevant dehydration
5. Severe renal impairment defined as a GFR < 30 mL/min/1.73 m2 in the screening central 
lab report.
6. Neurological disease (other than DAT such as: Lewy body dementia – primary diagnosis, 
Huntington’s disease, Parkinson’s Disease, encephalitis, epilepsy, vascular or multi-
infarct dementia, stroke, congenital mental deficiency, multiple sclerosis) and psychiatric 
disorders such as schizophrenia, or mental retardation.
7. Any suicidal behaviour in the past 2 years (i.e. actual attempt, interrupted attempt, 
aborted attempt, or preparatory acts or behaviour).


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8. 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).
9.
Previous participation in investigational drug studies of mild cognitive impairment/DAT
within three months prior to screening. Having received active treatment in any other 
study targeting disease modification of AD like Aß immunization and tau therapies. 
Previous participation in studies with non-prescription medications, vitamins or other
nutritional formulations is allowed.
10. 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, or a positive urine drug screen for cocaine, heroin, 
or marijuana.
11. Known history of HIV infection.
12. Bodyweight < 50 kg.
13. Planned elective surgery requiring general anaesthesia, or hospitalisation for more than 
1 day (requiring an overnight stay) during the study period.
14. Pre-menopausal women (last menstruation ≤1 year prior to informed consent) who:

are nursing or pregnant or

are of child-bearing potential and are not practicing an acceptable method of birth 
control, or do not plan to continue using this method throughout the trial until 28 
days after the last treatment administration, and do not agree to submit to periodic 
pregnancy testing during participation in the trial. Acceptable methods of birth 
control include tubal ligation, vasectomized partner (and this has to be the patient's 
sole partner), transdermal patch, intra uterine devices/systems (IUDs/IUSs), 
combined estrogen-progestin oral contraceptives as well as implantable or 
injectable hormonal contraceptives unless they are a moderate to strong CYP1A2
inhibitor – see section 4.2.2.1. Complete sexual abstinence (if acceptable by local 
health authorities) is allowed when this is in line with the preferred and usual 
lifestyle of the subject. Periodic abstinence (e.g., calendar, ovulation, symptom-
thermal, post-ovulation methods) and withdrawal are not acceptable methods of 
contraception. Double barrier methods are permissible (if acceptable by local 
health authorities, note that this is not an acceptable method in EU countries).
15. For male patients: 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.
16. Use of any investigational drug or procedure within 3 months or 6 half-lives (whichever 
is longer) prior to randomisation.
17. The following drugs are prohibited for 3 months prior to randomisation and for the 
duration of the trial: 
a.
tricyclic antidepressants,
b. antidepressants that are monoamine oxidase inhibitors,


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c.
neuroleptics with moderate or greater anticholinergic potency (eg, 
chlorpromazine, fluphenazine, loxapine, perphenazine, thioridazine),
d. anticholinergic medications,
The following drugs may be given as needed if the total daily dose was stable 8 weeks 
prior to randomisation and is expected to be for the duration of the trial:
a.
neuroleptics listed in section 4.2.2.,
b. benzodiazepines and sedatives listed 4.2.2.
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
19. Any other clinical condition that, in the opinion of the investigator, would jeopardize
patient safety while participating in this clinical trial
20. Incompliance with study drug intake defined as a compliance <75% during the run-in 
phase
21. Clinically significant uncompensated hearing loss in the judgement of the investigator. 
Use of hearing aids is allowed.
22. Known hypersensitivity to the drug product excipients (gelantin, povidone K25, lactose 
monohydrate, microcrystalline cellulose, pregelatinized starch, hydroxypropylcellulose, 
croscarmellose sodium, magnesium stearate, hypromellose, propylene glycol, titanium 
dioxide, talc and iron oxide yellow).
3.3.4
Removal of patients from therapy or assessments
3.3.4.1
Removal of individual patients
An individual patient is to be withdrawn from the trial if:

The patient withdraws consent, without the need to justify the decision.

The patient needs to take concomitant drugs that interfere with the investigational
product or other study medications(s).

The patient is no longer able to participate for other medical reasons (e.g. surgery,
AEs, or other diseases).

If a patient becomes pregnant during the trial, the investigational drug will be stopped,
the patient will be discontinued from the trial and the patient will be followed up until
birth or otherwise termination of the pregnancy.

If the patient experiences sinus tachycardia (defined as resting heart rate >100 BPM 
measured in supine position after a minimum of 5 minutes rest) at any time point up 
to 90±20 minutes post-dose or if a pulse rate increase greater than 20 BPM over the 
pulse rate taken before the first dose administration (baseline) has persisted at 90±20
minutes post-dose. Heart rate is generally to be measured in a supine position after 5 
min rest. See also Section 5.2.5.

The patient exhibits serious suicidality, in the clinical judgement of the investigator or 
according to criteria below: 


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
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)
A patient can be discontinued after discussion between sponsor and investigator if eligibility 
criteria are being violated, or if the patient fails to comply with the protocol (e.g. 
nonattendance at study assessments).
Patients who drop out during screening or during placebo run-in phase prior to randomisation 
(Visit 3) will be considered as screening failures. Data will be collected for signed IC for the 
study 
 demographics, AE, concomitant 
medications and randomisation and will be recorded in the eCRFs. No further follow-up is 
required. 
Patients who discontinue or withdraw from the study after randomisation (Visit 3) will be 
considered as “early discontinuations” and the reason for premature discontinuation must be 
recorded in the eCRFs. The data will be included in the trial database and will be reported. 
Patients who drop out during screening or during placebo run-in phase prior to randomisation
(Visit 3) will be considered a screening failure. They must be recorded as screening failures
in eCRFs and no further follow-up is required.
Patients who withdraw or discontinue from the trial after randomisation will not be replaced.
3.3.4.2
Discontinuation of the trial by the sponsor
Boehringer Ingelheim reserves the right to discontinue the trial overall or at a particular trial 
site at any time for the following reasons:

Failure to meet expected enrolment goals overall or at a particular trial site,

Emergence of any efficacy/safety information that could significantly affect 
continuation of the trial and/or invalidate the earlier positive benefit-risk-assessment,

Violation of GCP, the CTP, or the contract by a trial site or investigator, 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).


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4.
TREATMENTS
4.1
TREATMENTS TO BE ADMINISTERED
The trial medication will be provided by Boehringer Ingelheim. Following an initial 
screening visit and a single blind 2-week placebo run-in-period, patients who qualify 
according to inclusion and exclusion criteria will be randomised to one of the five following 
treatment groups of investigational drugs:
Table 4.1:1 Treatment groups
Group
Treatment Regimen
Treatment
tbl./d
1
BI 409306 10 mg QD
BI 10 mg
1-0-0
BI 25/50 mg PTM
1-0-1
Donepezil 5/10mg PTM
0-0-1
2
BI 409306 25 mg QD
BI 25 mg
1-0-0
BI 10 mg PTM
1-0-0
BI 25/50 mg PTM
0-0-1
Donepezil 5/10mg PTM
0-0-1
3
BI 409306 50 mg QD
BI 50 mg
1-0-0
BI 10 mg PTM
1-0-0
BI 25/50 mg PTM
0-0-1
Donepezil 5/10mg PTM
0-0-1
4
BI 409306 25 mg BID 
BI 25 mg
1-0-1
BI 10 mg PTM
1-0-0
Donepezil 5/10mg PTM
0-0-1


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Table 4.1:1 Treatment groups (continued)
5
Placebo
BI 10 mg PTM
1-0-0
BI 25/50 mg PTM
1-0-1
Donepezil 5/10mg PTM
0-0-1
4.1.1
Identity of BI investigational product and comparator product(s)
Table 4.1.1: 1
BI 409306, 10mg
Substance:
BI 409306
Pharmaceutical form:
Tablet
Source:
Boehringer Ingelheim Pharma GmbH & Co. KG
Unit Strength:
10 mg
Daily Dose:
10 mg QD (1-0-0) in Treatment Group 1, 
Route of administration:
Per os
Posology: 
QD
Duration of use:
12 weeks
Table 4.1.1: 2
BI 409306, 25mg and 50mg
Substance:
BI 409306
Pharmaceutical form:
Tablet
Source:
Boehringer Ingelheim Pharma GmbH & Co. KG
Unit Strength:
25 mg, 50 mg
Daily Dose:
25 mg QD (1-0-0) in Treatment Group 2, 
50 mg QD (1-0-0) in Treatment Group 3, 
25 mg BID (1-0-1) in Treatment Group 4
Route of administration:
Per os
Posology: 
QD or BID
Duration of use:
12 weeks


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Table 4.1.1: 3
Placebo matching BI 409306, 10mg
Substance:
Placebo matching BI 409306
Pharmaceutical form:
Tablet
Source:
Boehringer Ingelheim Pharma GmbH & Co. KG
Unit Strength:
n.a.
Daily Dose:
n.a.
Route of administration:
Per os
Posology: 
QD
Duration of use:
12 weeks
Table 4.1.1: 4
Placebo matching BI 409306, 25mg and 50mg
Substance:
Placebo matching BI 409306
Pharmaceutical form:
Tablet
Source:
Boehringer Ingelheim Pharma GmbH & Co. KG
Unit Strength:
n.a.
Daily Dose:
n.a.
Route of administration:
Per os
Posology: 
QD or BID
Duration of use:
12 weeks
Table 4.1.1: 5
Placebo matching Donepezil 5mg and 10mg
Substance:
Placebo matching Donepezil HCl (Aricept®)
Pharmaceutical form:
Overcapsuled Tablet(s)
Source:
Boehringer Ingelheim Pharma GmbH & Co. KG
Unit Strength:
5 mg, 10 mg
Daily Dose:
5 mg (week 1-4), 
10 mg (week 5-12) in Treatment Group 6
Route of administration:
Per os
Posology:
QD (0-0-1)
Duration of use:
12 weeks
Patients that have been randomised into the study prior to this protocol version being 
implemented, have a chance of being randomised to treatment with the formerly used active 


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comparator donepezil. These patients will continue in the study. Please refer to table 4.1.1:6 
for further details on Donepezil.
Table 4.1.1: 6
Donepezil 5mg and 10mg
Substance:
Donepezil HCl (Aricept®)
Pharmaceutical form:
Overcapsulated Tablet(s)
Source:
ESAI UK/EISAI 
Unit Strength:
5 mg, 10 mg
Daily Dose:
5 mg (week 1-4), 
10 mg (week 5-12)
Route of administration:
Per os
Posology:
QD (0-0-1)
Duration of use:
12 weeks
4.1.2
Method of assigning patients to treatment groups
Patients eligible for the trial will be assigned at random to one of the five treatment groups at 
Visit 3 by Interactive Response Technology (IRT). Details on randomisation are provided in 
Section 7.5. Assignment and drug supply management of study drug will be done via IRT. 
Note that the medication numbers assigned to the patient by the IRT are different from the 
patient number; each medication box has a different medication number. The patient number 
is assigned at study entry, i.e. signing informed consent at Visit 1.
To facilitate the use of IRT, each study site will receive an information manual describing the 
steps to randomise a patient, to obtain a medication kit assignment and to acknowledge 
receipt of study medication. The manual will be part of the ISF. Medication kits (including 
single blinded placebo run-in kits) will be assigned at Visits 2, 3, 5 and 6 for each patient. 
The access to the randomization codes will be controlled, documented and limited to a pre-
specified group of users in order to ensure the blinding of the treatment groups.
4.1.3
Selection of doses in the trial
BI409306 has been tested in animal models to assess cognitive effects. On the basis of the 
described mode of action and the presented experimental efficacy in these animal memory 
tests, peak levels of BI 409306 in CSF in the range of 1x PDE9 IC50 need to be targeted for 
memory enhancing efficacy in humans. In a PoC study in healthy volunteers [U12-2165-01], 
it was shown that BI 409306 is able to cross the human blood-CSF barrier (plasma to CSF) 
with a concentration corresponding to IC 50 (65 nmol/L) in CSF reached at 25 mg in 2 out of 
4 subjects and exceeded IC 50 in all subjects at the higher doses. CSF exposure to BI 409306 
increased with increasing dose and the CSF to plasma ratio for BI 409306 Cmax in humans is 
comparable to the one observed in rats and is constant over the entire dose range tested. CSF 
concentration-time profiles of BI 409306 peak approximately 0.5 to 1 hour later than in 
plasma and decline monoexponentially and roughly in parallel to plasma concentrations 
afterwards with BI 409306 concentrations in CSF decreasing beyond the quantification limit 
(0.5 nmol/L) after 8 to 14 hours post dosing. Therefore, the 25mg dose is anticipated to be the 


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effective dose and will be tested once daily (QD) and twice daily (BID). To study the dose-
response relationship, a lower dose (10mg) and a higher dose (50mg) will also be tested. For 
further details to the preclinical data as well to the human proof of mechanism study, please 
refer to the current version of the IB.
Following the run-in period patients will be randomised (Visit 3) to one of the 5 treatment 
arms.
Patients who qualify will be randomised to one of five treatment groups as follows:

BI 409306 10mg QD (Treatment Group 1)

BI 409306 25mg QD (Treatment Group 2)

BI 409306 50mg QD (Treatment Group 3)

BI 409306 25mg BID (Treatment Group 4)

Placebo (Treatment Group 5)
Patients that have been randomised into the study prior to this protocol version being 
implemented, have a chance of being randomised to treatment with the formerly used active 
comparator donepezil. Donepezil belongs to the class of AChEIs and represents the current 
standard of care for mild Alzheimer’s Dementia. Therefore, we consider it to be safe and 
justifiable that these patients will stay on this treatment until end of the planned treatment 
duration. The double-blind treatment used in this trial will contain placebo for donepezil to 
keep the blind.
Medication will be dispensed in a double-blind manner. All patients will take 2 tablets in the 
morning and 1 tablet and 1 capsule in the evening.
Patients should be instructed not to take their trial medication on the morning of visits 
because they will receive trial medication during the visits. Patients who, by mistake, took 
medication on the morning of the visit should have the visit rescheduled as soon as possible, 
ideally on the following day.
Visits should preferentially be scheduled in the morning, at approximately the same time of 
the day. The actual visit date and time of study drug administration at the trial visit will be 
recorded in the eCRF.
4.1.4
Drug assignment and administration of doses for each patient
At Visit 2, 3, 5 and 6 study medication will be provided to the patient. At each of these visits, 
medication assignment will be provided through IRT. The assigned medication number must 
be entered in the eCRF, and the corresponding medication kit must be given to the patient. 
The amount of trial medication dispensed and returned will be recorded on drug 
accountability forms.


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All patients who meet inclusion criteria will be assigned a placebo run-in kit at the beginning 
of the run-in period (Visit 2), and dispensing will occur just once. During the run-in period 
patients will take 4 placebo tablets/capsules daily (2 tablets in the morning and 1 tablet and 1 
capsule in the evening) to mimic the dosing schedule during treatment period. At beginning 
of the run-in period (V2), patients should be instructed to take their trial medication twice 
daily with water. The first dose of study medication will be taken at the end of visit 2 under 
supervision of the investigator or site staff. At all following visits the investigational drug
will be taken during the visit under supervision of the investigator or relevant site staff 
always after the blood samples were taken as described in Section 5.2.3, 5.2.5. 
Medication should be taken with or without food in the morning (except for visit days with 
neuropsychological assessments) and in the evening at approximately the same time every 
day. If a dose is missed by more than 4hrs, 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. Run-in medication assignment will be done through IRT. 
Following the run-in period patients will be randomised (Visit 3) to one of the 5 treatment 
arms. IRT will allocate medication kit numbers at Visit 3, 5 and 6. The amount of trial 
medication dispensed and returned will be recorded on drug accountability forms. 
For blinding reasons all treatments will consist of two tablets verum or placebo for the 
morning dose and one placebo capsule and one tablet verum or placebo for the evening dose 
depending on the treatment arm. This will not be changed during the entire study.
The actual visit date and time of study drug administration at the trial visit will be recorded in 
the eCRF at each visit.
Patients should be instructed to take the tablets orally with water at approximately the same 
time every day in the morning with or without food. If a dose is missed by more than 4hrs, 
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. 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 visit 6 should have the visit rescheduled as soon as possible, ideally on the following 
day (
. The actual date and time of administration of the 
medication at the trial visit will be recorded in the eCRF.
The oral basic treatment with donepezil will be similar to the other treatments but will start 
with 5 mg once daily for the first 4 weeks of the trial. After then the dose will change to 
10 mg once daily. Once this protocol version is implemented, no additional patients will be 
randomized to the Donepezil arm but patients already randomised to Donepezil will continue 
in the study.
Enrolment of patients currently on AChEIs can only be initiated after the IRT system has 
been re-programmed and activated accordingly. Sites will be notified by the CMLs. 


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4.1.5
Blinding and procedures for unblinding
4.1.5.1
Blinding
Administration of the placebo run-in will be single blinded, meaning patients will not know 
during which period of the trial they will be receiving placebo.
Study medications will be administered double blinded. In order to maintain blinding in 
regard to each treatment, each dose will contain 3 tablets and 1 capsule daily in a double-
dummy design, as shown in Table 4.1:1. Placebo tablets / capsules are identical in the size 
and appearance to the corresponding active tablet / capsule and are combined with active 
drug tablets as needed in each treatment group to maintain the blinding.
After randomisation at Visit 3, patients, investigators and everyone involved in analysing or 
with an interest in this double-blind trial will remain blinded with regard to the randomised 
treatment assignments until after database lock. However, due to the requirements to report 
Serious Unexpected Suspected Adverse Reactions (SUSARs), it may be necessary for a 
representative from BI’s drug safety group to access the randomisation code for individual 
patients during trial conduct. In such cases, access to the code will only be permitted by 
authorised drug safety representatives. Access to the code will be via the IRT system.
The randomisation code will be kept secret by Clinical Trial Support at BI up to database 
lock. The access to randomization codes will be controlled, documented and limited to a 
prespecified group of users who are not involved into capturing, processing and evaluation of 
the clinical data unless defined differently or in case of an emergency in order to ensure the 
blinding of the treatments. Please refer to Section 4.1.5.2 for the rules regarding breaking the 
code for an individual or for all patients in emergency situations. The random code will be 
transferred to the trial data manager only after the Blinded Report Planning Meeting, and 
after locking of the trial database.
The randomisation codes will be provided to bioanalytics prior to last patient out to allow
them to perform appropriate pharmacokinetic analytical determination. Bioanalytics will not 
disclose the randomisation code or the results of their measurements until the study is 
officially unblinded. Prior to unblinding of the trial database, any pharmacokinetic results or 
data may only be communicated in a way that does not provide any direct or indirect link 
between patient number and treatment.
4.1.5.2
Procedures for emergency unblinding
For blinded trials an emergency code break will be available to the investigator / pharmacist / 
investigational drug storage manager. This code break may only be opened in emergency 
situations when the identity of the trial drug must be known to the investigator in order to 
provide appropriate medical treatment or if required to assure safety of trial participants.  If 
the code break for a patient is opened, the sponsor must be informed immediately. The reason 
for opening the code break must be documented on the envelope and appropriate CRF page 
along with the date and the initials of the person who broke the code. 


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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
Study medication (BI 409306, Donepezil or placebo) will be stored in a secure, locked 
compartment under the supervision of the site staff. Store tablets in the original package in 
order to protect them from moisture and light. For storage conditions refer to the locally 
approved medication label and the STORM document in the ISF.
4.1.8
Drug accountability
Drug supplies, which will be provided by the sponsor, must be kept in a secure, limited 
access storage area under the storage conditions defined by the sponsor. Where necessary, a 
temperature log must be maintained to make certain that the drug supplies are stored at the 
correct temperature.
The investigator / pharmacist/ investigational drug storage manager will receive the 
investigational drugs delivered by the sponsor when the following requirements are fulfilled:

approval of the study protocol by the IRB / ethics committee,

availability of a signed and dated clinical trial contract between the sponsor and the 
Head of Trial Centre,

approval/notification of the regulatory authority, e.g. competent authority,

availability of the curriculum vitae of the principal investigator,

availability of a signed and dated clinical trial protocol or immediately imminent 
signing of the clinical trial protocol, <in exceptional cases, medication could already 
be sent to the site, before its activation via IVRS>

if applicable, availability of the proof of a medical licence for the principal 
investigator, 

for the USA availability of the 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 disposition of unused product(s).
These records will include dates, quantities, batch/serial numbers, expiry (‘use by’) dates, and 
the unique code numbers assigned to the investigational product(s) 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 product(s) received from the sponsor. At the time of return to the 
sponsor, 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.


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4.2
CONCOMITANT THERAPY, RESTRICTIONS, AND RESCUE 
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
4.2.2.1
Restrictions regarding concomitant treatment
Intake of the following medications with the mentioned exceptions is prohibited during the 
entire duration of the trial including follow-up:
a.
Tricyclic antidepressants, other drugs which are active on the central nervous 
system (CNS) i.e. psychotropics (tricyclic antidepressants and monoamine
oxidase inhibitors, mood stabilisers, neuroleptics, atypical antipsychotics, 
antiepileptics, benzodiazepines, other hypnotics or sedatives (including sedative 
antihistamines), muscle relaxants, or central analgesics, e.g., opioids. 
Note: Zolpidem (10 mg/day), chloral hydrate (1 g/day), triazolam, quetiapine, 
temazepam and oxazepam if needed for sleep are allowed as needed. Olanzapine 
or risperidone are allowed as needed for occasional intake in case of psychotic 
symptoms. If these above substances are taken occasionally, then dosing on the 
night prior to cognitive testing is not allowed. 
b. Agents having central dopamine antagonist activity, i.e. reserpine, methyldopa, 
antiemetic’s etc. However, the serotonin and combined 
serotonin/norepihnephrine Re-Uptake Inhibitors (SSRIs/SNRIs) like fluoxetin, 
es-citalopram, citalopram, sertalin, venlafaxin, duloxetin are allowed, but 
paroxetine is excluded. Other antidepressant drugs without anticholinergic 
effects may be given as needed if the total daily dose was stable 8 weeks prior to 
randomization and is expected to be maintained for the duration of the trial.
c.
Intake of other phospodiesterase inhibitors (for example theophylline, 
roflumilast, sildenafil, tadalafil, vardenafil, avanafil). 
d. Intake of St. Johns wort, Carbamazepine, extracts from Gingko, artemisinin, 
enzalutamide, efavirenz, lopinavir, ritonavir, tipranavir, rifampicin as they are 
relevant CYP2C19 inducers
e.
Use of medications that are known to be moderate or strong CYP1A2 inhibitors 
is not permitted. (For a list of moderate or strong CYP1A2 inhibitors, please 
consult the ISF Section 11 “Safety Information”).
Non-prescription drugs or vitamins including medical nutrition formulations that have been 
initiated before Visit 1 can be continued concomitantly during the study. However initiation 
of such medication and of other prescribed treatment for AD after visit 1 is prohibited.


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4.2.2.2 Restrictions on diet and life style
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.
4.3
TREATMENT COMPLIANCE
Patients will be asked to bring all trial medication containers (with or without any remaining 
tablets/capsules) with them to each trial visit. The tablets /capsules will be counted and 
compliance will be calculated according to the formula:
Compliance during the placebo run-in period should be between 75% and 120%. If 
compliance is outside this range, the patient should be carefully interviewed and, if necessary, 
re-informed about the purpose and the conduct of the trial. Unreliable patients should not be 
randomised at the discretion of the investigator.
Compliance during the randomised treatment period should be between 80% and 120%. 
Patients who are not compliant according to this definition should be carefully interviewed 
and re-informed about the purpose and the conduct of the trial. 
%
100
period
same
in the
been taken
have
should
 which 
 tablets
of
Number 
count
t 
last table
since
aken 
actually t
 tablets
of
Number 
(%)
Compliance




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5.
VARIABLES AND THEIR ASSESSMENT
5.1
EFFICACY – PHARMACODYNAMICS
5.1.1
Endpoint of efficacy
The following efficacy measures are completed at the times shown in Section 6.2 and the
flow chart:

Primary endpoint:

The primary endpoint is Neuropsychological Test Battery (NTB) response, defined as 
change from baseline in total z-score after 12-week treatment.  
Secondary endpoints: 

Change from baseline in the ADCS-ADL (Alzheimer’s Disease Cooperative 
Study/Activities of Daily Living) score after 12-week treatment.

Change from baseline CDR-SB (Clinical Dementia Rating – Sum of Boxes) after 12-
week treatment

Change from baseline in ADAS-Cog11 (Alzheimer’s Disease Assessment Scale-
cognitive subscale) total score after 12-week treatment.
5.1.2
Assessment of efficacy
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.
Neuropsychological Test Battery (NTB)
The NTB consists of 9 validated components:

Wechsler Memory Scale visual immediate (score range, 0-18)

Wechsler Memory Scale verbal immediate (score range, 0-24)

Rey Auditory Verbal Learning Test (RAVLT) immediate (score range, 0-105)

Wechsler Memory Digit Span (score range, 0-24)

Controlled Word Association Test (COWAT)


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
Category Fluency Test (CFT)

Wechsler Memory Scale visual delayed (score range, 0-6)

Wechsler Memory Scale verbal delayed (score range, 0-8)

RAVLT delayed (score range, 0-30). The RAVLT delayed measure is composed of 
delayed recall and recognition performance components that are summed to yield a 
score ranging from 0 to 30.
Raw scores on each of the 9 NTB tests will be converted to z-scores using the baseline means 
and standard deviations (SDs) for each test. The resultant z-scores will be averaged to obtain 
a total z-score, incorporating all 9 NTB tests [R13-2645].
ADCS-ADL
This 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. Higher scores indicate better function [R97-3207].
CDR-SB is obtained through semi structured interviews of patients and informants, and 
cognitive functioning is rated in 6 domains of functioning: memory, orientation, judgment 
and problem solving, community affairs, home and hobbies, and personal care. Each domain 
is rated on a 5-point scale of functioning as follows: 0, no impairment; 0.5, questionable 
impairment; 1, mild impairment; 2, moderate impairment; and 3, severe impairment (personal 
care is scored on a 4-point scale without a 0.5 rating available). The CDR-SB score is 
computed [R03-0748].
ADAS-cog/11 is an 11-item cognitive subscale that objectively measures memory, language, 
orientation and praxis with a total score range of 0 to 70 [R96-2608].
) has been selected as
service provider to support tasks related to the neuropsychological assessments.
The services of 
 include:
Necessary Rater prequalification
Central Rater training for neuropsychological assessments used as primary and
secondary endpoints (online and at investigator meeting)
Provision of Rater materials
Central Quality Review of Assessments
Details of rater prequalifications, Rater Training, Rater Materials (including Assessments)
and of the Central review procedures will be available in a separate document filed in the
ISF.
These members of the site staff conducting the neuropsychological assessments have to be
adequately trained (either at the investigator training or individually) and training


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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 Principal Investigator at the site to ensure proper training of
all members of the site staff involved in the neuropsychological assessments.
5.2
SAFETY
5.2.1
Endpoint(s) of safety
No additional study specific important safety endpoints will be assessed in this study. 
5.2.2
Assessment of adverse events
5.2.2.1
Definitions of adverse events
Adverse event
An adverse event (AE) is defined as any untoward medical occurrence, including an 
exacerbation of a pre-existing condition, in a patient in a clinical investigation who received a 
pharmaceutical product. The event does not necessarily have to have a causal relationship 
with this treatment.
Serious adverse event
A serious adverse event (SAE) is defined as any AE which results in death, is immediately 
life-threatening, results in persistent or significant disability / incapacity, requires or prolongs 
patient hospitalisation, 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 
judgement which may jeopardise the patient and may require medical or surgical intervention 
to prevent one of the other outcomes listed in the above definitions.
Intensity of adverse event
The intensity of the AE should be judged based on the following:
Mild:
Awareness of sign(s) or symptom(s) which 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 adverse event
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. Assessment of causal relationship should be recorded in the case report forms. 


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Yes:
There is a reasonable causal relationship between the investigational product 
administered and the AE. 
No:
There is no reasonable causal relationship between the investigational product 
administered and the AE. 
If a SAE is reported from a still blinded trial, the causal relationship must be provided by the 
investigator for all potential trial drugs, i.e. the BI trial drug and for all other trial drugs (i.e. 
any active comparator or placebo according to the trial design).
Worsening of underlying disease or other pre-existing conditions 
Worsening of underlying disease or other pre-existing conditions will be recorded as an 
(S)AE in the eCRF.
Changes in vital signs, ECG, physical examination, and laboratory test results
Changes in vital signs, ECG, physical examination and laboratory test results will be 
recorded as an (S)AE in the eCRF , if they are judged clinically relevant by the investigator.
Protocol-specified Adverse Events of Special Interest (AESI)
The following are considered as AESIs:
Hepatic injury defined by the following alterations of liver parameters: 
o
For patients with normal liver function at baseline:
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.
Patients showing these lab abnormalities need to be followed up according to section 10.2 of 
this clinical trial protocol and the “DILI checklist” provided in the ISF.
Adverse Events of Special Interest are to be reported in an expedited manner similar to 
Serious Adverse Events, even if they do not meet any of the seriousness criteria – for details 
please see chapter 5.2.2.2.
5.2.2.2
Adverse event and serious adverse event reporting
All adverse events, serious and non-serious, occurring during the course of the clinical trial 
(i.e., from signing the informed consent onwards through the follow-up-period) will be 
collected, documented and reported to the sponsor by the investigator on the appropriate 
CRF(s) / eCRFs / SAE reporting forms. Reporting will be done according to the specific 
definitions and instructions detailed in the ‘Adverse Event Reporting’ section of the 
Investigator Site File.
For each adverse event, the investigator will provide the onset date, end date, intensity, 
treatment required, outcome, seriousness, and action taken with the investigational drug. The 
investigator will determine the relationship of the investigational drug to all AEs as defined in 
Section 5.2.2.1. 


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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. 
A local ophthalmology assessment will be required if 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 residual effect period (REP) for BI 409306 is 7 days. Therefore, all events reported 
within 7 days after the last trial medication will be considered on drug. All adverse events 
will be reported up until the last per protocol visit (follow-up visit) which is 28 days after the 
last dose of trial medication. The investigator does not need to actively monitor patients for 
adverse events once the clinical trial has ended. However, if the investigator becomes aware 
of an SAE(s) that occurred after the patient has completed the clinical trial (including any 
protocol required REP and / or follow-up), it should be reported by the investigator to the 
sponsor if considered relevant.
If not stipulated differently in the ISF, the investigator must report the following events 1) if 
using paper process SAE form via telephone/fax or 2) if available for the trial, using the 
electronic submission process (RDC) immediately (within 24 hours) to the sponsor: SAEs 
and non-serious AEs relevant to the SAE(s), and Adverse Events of Special Interest.
BI has set up a list of AEs which are defined to be always serious. In order to support the 
investigator with the identification of these “always serious adverse events”, if a non-serious 
AE is identified to be serious per BI definition, a query will be raised. The investigator must 
verify the description and seriousness of the event. If the event description is correct, the item 
“serious” needs to be ticked and an SAE has to be reported in expedited fashion following the 
same procedure as above.
The list of these adverse events can be found via the RDC-system.
The SAE form is to be forwarded to the defined unique entry point identified for the BI OPU 
(country-specific contact details will be provided in the Investigator Site File) or by using the 
electronic submission process. This immediate report is required irrespective of whether the 
investigational product has been administered or not and irrespective of causal relationship. It 
also applies if new information to existing SAEs or Adverse Events of Special Interest
becomes available. 
Pregnancy
In rare cases, pregnancy might occur in clinical trials. Once a female subject has been 
enrolled into the clinical trial, after having taken study medication, the investigator must 
report immediately any drug exposure during pregnancy to the sponsor. Drug exposure 
during pregnancy has to be reported immediately (within 24 hours) to the defined unique 
entry point for SAE forms of the respective BI OPU (country-specific contact details will be 
provided in the Investigator Site File). The outcome of the pregnancy associated with the 
drug exposure during pregnancy must be followed up. In the absence of an (S)AE, only the 


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Pregnancy Monitoring Form for Clinical Trials and not the SAE form is to be completed. The 
ISF will contain the Pregnancy Monitoring Form for Clinical Trials (Part A and Part B).
5.2.3
Assessment of safety laboratory parameters
All safety parameters that will be determined during the trial conduct are listed in Table 
5.2.3: 1. 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).
The following lab parameters will not be determined at each study visit:

TSH, HIV and syphilis testing: at screening only

Vitamin B12 and folate at screening and EOT only

Urine drug screen at screening and EOT only 


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Table 5.2.3: 1
Safety laboratory parameters – whole blood, serum or plasma
Haematology
Haematocrit
Haemoglobin
- Reticulocyte Count (reflex test if Hb 
outside normal range)
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
Creatine kinase (CK)
CK-MB, troponin (reflex tests if CK is 
elevated)
Lactate dehydrogenase (LDH)
Lipase
Magnesium 
Phosphate 
Potassium
Protein total 
Sodium
Urea (BUN)
TSH
Folate
Serology
HIV-antibody and Syphilis testing (Rapid 
plasma reagin (RPR), if RPR positive, then 
performing Fluorescent Treponemal 
Antibody test (FTA))


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Table 5.2.3: 2
Safety laboratory parameters – urine
Urinalysis 
Semi quantitative
Nitrite
Protein
Glucose
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 be performed in female patients of child bearing
potential only according to the time points indicated in the Flow Chart or if required by local 
regulations more frequently or in plasma instead of urine 
5.2.4
Electrocardiogram
ECG-recordings will be made at the time points described in the Flow Chart. Twelve-lead 
ECGs (I, II, III, aVR, aVL, aVF, V1 – V6) will be recorded using equipment provided by a 
central ECG vendor. The ECGs will be recorded for at least a 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). At all time-
points, indicated in the Flow Chart, single ECGs will be recorded. 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.
All locally printed ECGs will be evaluated by the investigator or a designee. Additional 
(unscheduled) ECGs can be recorded for safety reasons at any time based on the judgment of 
the investigator. Clinically relevant abnormal findings will be reported as baseline conditions 
or adverse events. Any ECG abnormalities will be carefully monitored and if necessary the 
subject will be removed from the trial and medically treated.


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All ECGs will be transmitted electronically to the central ECG vendor in order to enable a 
centralized and independent re-evaluation of all 12-lead ECGs (This will only be done if 
requested by the sponsor. Abnormalities detected during this centralised ECG evaluation will 
not necessarily qualify as AE.).
5.2.5
Assessment of other safety parameters
5.2.5.1 Physical examination (PE)
A physical examination will be carried out as described in the Flow Chart.  
A physical examination including, but not limited to, general appearance, skin, neck, eyes, 
ears, nose, throat, breast, lungs, heart, abdomen, back, lymph nodes, extremities, and nervous 
system will be performed. The physical examination will include examination of known and 
suspected sites of disease. 
Clinically relevant abnormal findings noticed after randomisation will be reported as (S)AEs.
5.2.5.2 Vital signs
Vital signs (systolic/diastolic blood pressure (including orthostatic measurement as outlined 
below), supine pulse rate after 5 minutes rest) will be recorded at all the study visits as
described in the Flow Chart, including the early End of Treatment Visit and the Follow-up
Visit (4 weeks after the end of treatment). Body weight will be measured at the visits 
indicated in the flow chart and the same scale has to be used for all measurements. The height
is measured only at visit 1 (screening).
Measuring Orthostatic Blood Pressure 
1.
Have the patient lie down for 5 minutes. 
2.
Measure blood pressure and pulse rate. 
3.
Have the patient stand. 
4.
Repeat blood pressure and pulse rate measurements after standing 1 and 3 minutes.
Only at visit 3 the following additional vital signs measurements need to be performed which 
include: 

pulse rate is to be measured in a supine position after 5 minutes of rest pre-dose 
and at the time points of post-dose PK sampling until 90±20 minutes post-dose.
Pulse rate should be taken before the respective blood for PK sampling is drawn. 

Systolic/diastolic blood pressure (including orthostatic measurement) is to be done 
at baseline and at 90±20 minutes post dose. 
This procedure is to be performed in a quiet environment and unexpected disturbances have 
to be avoided. In case of an unexpected disturbance (for example slamming door) this 
measurement may be repeated.


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If there is a finding which meets any withdrawal criterion (See Section 3.3.4.1), the subject 
should be removed from study participation. The investigator may repeat the additional post-
dose pulse rate assessment at any other visit at the timepoints described for Visit 3 if deemed 
clinically necessary for any reason.
Clinically relevant abnormal findings noticed after baseline assessment will be reported as 
(S)AEs.
5.2.5.3 Suicidal risk assessed by the C-SSRS 
The C-SSRS®, developed by leading experts in cooperation with the FDA, is a questionnaire 
assessing both suicidal behaviour and suicidal ideation. The medical qualified clinician 
administered interview with the questionnaire has a typical administration time of five 
minutes, can be easily coupled with evaluation of inclusion/exclusion criteria and causes only 
a low burden on patients and the assessing medical qualified clinician. The interview consists 
of five questions related to suicidal behaviour and five questions related to suicidal ideation, 
evaluated as either present or not. Patients presenting with any suicidal behaviour or suicidal 
ideation will be excluded from participation in the trial. The C-SSRS® has been widely used 
in large multinational clinical trials in the past four years and it is available in over 20 
languages. The C-SSRS® will be administered by the medical qualified clinician or expert 
clinician and will be assessed at the screening visit with the aim to exclude patients with 
active moderate or severe symptomatology prior to the Screen Visit, or recent (or current) 
suicidal or suicide attempt according to the C-SSRS® (baseline/screening version). 
Subsequently, the C-SSRS® “since last visit” assessment will be performed at each clinic 
visit after visit 3 and as shown in the Flow Chart. If there is a positive response of suicide 
attempt or suicidal ideation by the patient during the administration of the C-SSRS® during 
the treatment period, the medical qualified clinician is to immediately interview the patient 
during the clinic visit and determine if the patient will be discontinued from the trial and 
appropriate actions for the patient’s safety have to be initiated by the investigator. For 
assessment of the C-SSRS® paper forms will be used and results will be transcribed into the 
e-CRF.
 
 
 


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5.4
APPROPRIATENESS OF MEASUREMENTS
All measurements performed during this trial are standard measurements and will be 
performed in order to monitor safety aspects and to determine pharmacokinetics of BI
409306 in an appropriate way.
The scheduled measurements are appropriate to see drug induced changes in vital signs, 
standard laboratory values, and ECG. The primary and secondary endpoints are widely 
accepted assessments of function and cognition in Alzheimer’s Disease. They have been
widely used in previous phase II and phase III studies in this indication.
 
 
 
 
 
 
 
 
 
 
 
 
 


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6.
INVESTIGATIONAL PLAN
6.1
VISIT SCHEDULE
All trial visits should preferentially take place in the morning starting before 9:00 AM. 
Patients should be instructed not take trial medication on the morning of a clinic visit before 
attending the clinic. 
All patients are to adhere to the visit schedule as specified in the Flow Chart (with time 
window for rescheduling). 
If any visit has to be rescheduled, subsequent visits should follow the original visit date 
schedule. The trial medication packs contain sufficient medication to allow for these time 
windows.
The end of the trial is defined as “last patient out”, i.e. last visit completed by the last patient.
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.
6.2
DETAILS OF TRIAL PROCEDURES AT SELECTED VISITS
Study procedures to be performed at each visit are listed in the Flow Chart. Additional details 
regarding visit procedures are provided below. 
The following section describes recommendations for the conduct of the neuropsychological 
assessments. 

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.

It is strongly recommended that a member only performs independent tests (meaning 
that different assessments of cognition should be performed by different members of 
the team). 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 adverse events should be evaluated by a team member that is not directly 
involved in the neuropsychological and functional assessments (NTB, CDR, , ADCS-
ADL and ADAS-cog11) to prevent partial unblinding. 
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 


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Principal Investigator at the site to ensure proper training of all members of the site staff 
involved in the neuropsychological assessments.
This trial (1289.7) investigates patients with mild Alzheimer’s dementia. In parallel BI is 
investigating the effect of BI 409306 in patients with cognitive impairment caused by the 
Alzheimer’s disease in study 1289.5. It is expected that both trials share a high percentage of 
trial sites. One of the medically well-established non-invasive neurological assessments is the 
Mini Mental Stage Examination (MMSE) which evaluates the severity of cognitive 
impairment. This assessment is used in both trials as part of the eligibility assessments. 
Patients who do not reach the required scores of <27 in MMSE or CDR total score of greater 
than 1 are not eligible for this study and must be registered as screen failure in IRT. If the 
result of the MMSE and CDR would fulfill the requirements of the parallel trial 1289.5 and 
the patient and his study partner agree to alternatively participate in 1289.5 after giving a new 
consent then the results of the MMSE and CDR can be transferred into the database of 1289.5 
without repeated performance of the MMSE and CDR and vice versa. This prevents the risk 
of unwanted learning effects which would be a consequence of repeating the MMSE and 
CDR in the same patient. This rule only applies if the screening visit for 1289.5 is no later 
than 7 days after the MMSE for 1289.7 was performed. The patient will then be registered as 
a new patient in the IRT of 1289.5. This does not apply to sites participating in only one of 
the 1289.5/1289.7 studies.
6.2.1
Screening and run-in period(s)
Visit 1 (screening)

Patients must sign Informed Consent (
 before 
any study related procedures are performed.

The patient should be recorded on the enrolment log and be registered in the IRT as a 
screened patient.

Study procedures have to be completed according to the Flow Chart.

Demographics include age, educational level, current or past professional experience

ECG and vital sign measurement will be performed.

For diabetic patients with antidiabetic therapy: exclusion of hypoglycemia for the 
period of the neuropsychological assessment (documented plasma glucose 
concentration ≥ 90 mg/dl (5mmol/l) at the beginning and directly after the 
assessment). If glucose is too low patients need to eat a snack and then be retested to 
confirm that the blood sugar value is above 90 mg/dl before the tests are started

Blood pressure must always be measured before taking any blood sample.

A complete physical examination and neurological examination.

Laboratory samples will be collected as described in the flow chart.

Assessment for MRI (if no pre-existing MRI or CT of the brain is already available 
(please refer to inclusion criteria for details)) must be scheduled in order that results 
are available prior to Visit 2

Administer the following neuropsychological assessments in the following order:


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
MMSE

CDR

ADAS-cog11

Administration of C-SSRS (baseline/screening scale)

Once Visit 1 procedures are complete and laboratory results are received, 
inclusion/exclusion criteria must be reviewed again. If the patient is still eligible 
according to inclusion/exclusion criteria, the patient should be contacted to schedule 
next visit.

If a patient does not meet inclusion/exclusion criteria the patient must be recorded in 
CRFs as a screen failure. Patient must be registered as screen failure in IRT.
Visit 2 (Run-in period) 

Study procedures have to be completed according to the Flow Chart.

Blood pressure must always be measured before taking any blood sample.

Contact IRT to obtain run-in medication kit number and dispense the medication to 
the patient

Administration of C-SSRS (baseline since last visit scale)

The intake of trial medication and handling of medication blisters should be discussed 
and trained with the patient and the caregiver. The first dose of trial medication should 
be taken by the patient after the neuropsychological assessments have been 
administered. The first dose of the study medication should be taken under the 
supervision of the study staff.

Patients who fail the run-in period following Visit 2 procedures should be registered 
as a screen failure in the IRT.
6.2.2
Treatment period(s)
Visit 3
Visit 3 is the baseline/randomisation visit and marks the beginning of the treatment period. 
The neuropsychological assessments may be done on the day before the randomisation visit 
(last day of the screening period) 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.

Study procedures have to be completed according to the Flow Chart.

Collect returned run-in medication.

Re-assessment of in/exclusion criteria including assessment of compliance of study 
drug intake.

Neuropsychological assessments and collection of urine and blood for laboratory 
testing must be performed prior to administration of study medication.

Blood pressure must always be measured before taking any blood sample.

ECG will be performed

Laboratory samples will be collected as described in Flow Chart.


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
For diabetic patients with anti-diabetic therapy: exclusion of hypoglyemia for the 
period of the neuropsychological assessment (documented plasma glucose 
concentration ≥ 90 mg/dl (5mmol/l) at the beginning and directly after the 
assessment).

Administer the following neuropsychological assessments in the following order:

CDR-SB

NTB

ADCS-ADL

ADAS-cog11

Administration of C-SSRS (baseline since last visit scale)

The intake of trial medication and handling of medication blisters should be discussed 
and (if deemed necessary) re-trained with the patient and the caregiver. The dose of 
trial medication should be taken by the patient after the neuropsychological 
assessments have been administered.

Contact IRT to randomise patient and obtain medication kit numbers and dispense the
medication to the patient (if neuropsychological testing was not performed according 
to the protocol patients should not be randomized, please refer to inclusion criteria,
#6).


Post dose vital signs assessment: Pulse rate is to be measured in a supine position after 
5 minutes of rest pre-dose and at the time points of post-dose PK sampling until 110 
mins post-dose (15-25 mins, 25-35 mins, 35-55 mins, 70-110 mins post-dose). Pulse 
rate should be taken before the respective blood for PK sampling is drawn. 
Systolic/diastolic blood pressure (including orthostatic measurement) is to be done at 
baseline and at 70-110 minutes post dose. This procedure is to be performed in a quiet 
environment and unexpected disturbances have to be avoided. In case of an 
unexpected disturbance (for example slamming door) this measurement may be 
repeated.

Instruct patient NOT to take study medication on the morning of trial visits.
Visits 4, 5, 6 and EOT/ED
Visits 4, 5, 6 and EOT/ED are part of the treatment period. 
Visit 4 a, b, c

Visit 4a is a mandatory clinic visit. Visits 4b and Visit 4c may be a phone contact with 
the patient if (in discretion of the investigator) no clinically relevant abnormalities in 
ECG and vital signs are observed at visit 4a. Study procedures have to be completed 
according to the Flow Chart.
ECG and vital signs are only to be performed at clinic visits.

Administration of C-SSRS (baseline since last visit scale)

The attendance of the study partner is not necessarily required during the visits 4a-c.

Instruct patient NOT to take study medication on the morning of trial visits 5 and 6.


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Visits 5, 6 and EOT/ED

Study procedures have to be completed according to the Flow Chart.

Collect returned medication at every visit prior to dispensing new medication

Neuropsychological assessments and collection of urine and blood for laboratory 
testing 
must be performed prior to administration 
of study medication

For diabetic patients with antidiabetic therapy: exclusion of hypoglycemia for the 
period of the neuropsychological assessment (documented plasma glucose 
concentration ≥ 90 mg/dl (5mmol/l) at the beginning and directly after the 
assessment).

Administer the following neuropsychological assessments in the following order:

CDR-SB (V5 and EOT)

NTB (V5 and EOT)

ADCS-ADL (EOT)

ADAS-cog11 (EOT)

Administration of C-SSRS (baseline since last visit scale)

The intake of trial medication and handling of medication blisters should be discussed 
and (if deemed necessary) re-trained with the patient and the caregiver. The dose of 
trial medication should be taken by the patient after the neuropsychological 
assessments have been administered. 


Blood pressure must always be measured before taking any blood sample

Laboratory samples will be collected as described in Flow chart.

New medication kit must be dispensed at Visits 5 and Visit 6 and IRT must be 
contacted at those visits to obtain medication kit numbers to be dispensed.

Instruct patient NOT to take study medication on the morning of next trial visits.

Visit EOT/ED is the end of treatment visit. Study medication will not be taken at Visit 
EOT/ED.
End of Treatment
End Of Treatment Visit will need to be performed for any patients who discontinue study 
medication, i.e. both for patients who complete the full 12-week treatment period and for 
patients who discontinue study medication early. 
Patients who discontinue study medication early should be registered as withdrawn in the 
IRT, and patients who complete the full 12-week treatment period should be registered as 
completed in the IRT.
Assessments should be performed as mentioned in Flow Chart and the respective protocol
sections.


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6.2.3
End of trial and follow-up period
For all patients completing the study according to protocol, a follow-up contact (Visit 8) with 
the patient should be done by the investigator at the end of the follow-up phase of 28 days. 
The attendance of the study partner is not necessarily required during the FU visit.
In case of premature discontinuation from the 12-week treatment period however, a Visit 7 /
End of Treatment Visit should be performed within 7 days of last intake of study drug (if this 
visit occurs within the time window of a scheduled visit, the Visit 7 / End Of Treatment Visit 
will replace the scheduled visit) and the patient should return to Visit 8 (28 days after End Of 
Treatment Visit).


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7.
STATISTICAL METHODS AND DETERMINATION OF
SAMPLE SIZE
7.1
STATISTICAL DESIGN – MODEL
7.1.1
Design
This phase II trial is a multi-centre, double-blind, parallel-group, randomised, placebo- and 
active- controlled study to investigate efficacy, safety and tolerability of orally administered 
BI 409306 once or twice daily during a 12-week treatment period compared to placebo in 
patients with mild Alzheimer’s Dementia. The primary endpoint is Neuropsychological Test 
Battery (NTB) response, defined as change from baseline in total z-score after 12-week 
treatment. Further analysis details are provided in Section 7.3 (Planned Analyses).
The primary analysis is the restricted maximum likelihood based mixed model repeated 
measurement (MMRM) comparing the change from baseline of NTB total z-score after 12-
week treatment. Further analysis details are provided in Section 7.3 (Planned Analyses).
The randomisation allocation ratio is 1:1:1:1: 2 of 10 mg, 25mg, 50 mg, 25 mg BID of BI 
409306 and placebo. Since the literature suggests that higher placebo response is related to 
the probability of patients receiving trial medication, the randomisation allocation ratio is 
modified from a traditional equal ratio where only about 14% of patients would receive 
placebo to an allocation ratio of 1:1:1:1: 2 where 33% of patients would receive placebo 
[P10-10921]. This is further elaborated in the Section 7.5 and the impact on sample size 
calculation is provided in Section 7.6.
7.2
NULL AND ALTERNATIVE HYPOTHESES
The objective of this exploratory trial is to demonstrate proof-of-concept and also explore the 
dose response of BI 409306 in NTB total score change from baseline (Visit3) after 12 weeks 
treatment. The hypotheses testing will be carried in the following steps. No multiplicity 
adjustment will be made; hence all the p-values will be descriptive. All tests will be tested at 
a two-sided alpha 0.05. 

Step 1 for Proof-of-Concept:
H1-0: Mean NTB response of pooled doses of 10 mg QD, 25 mg QD, 25 mg BID and 50 mg 
QD = Mean NTB response of placebo
H1-a : Mean NTB of pooled doses of 10 mg QD, 25 mg QD, 25 mg BID and 50 mg QD ≠ 
Mean NTB of placebo
If the null hypothesis H1-0 is rejected in favor of H1-a, then the proof of concept is established. 

Step 2 for dose response finding: 
A regression model will be fitted first as the following functional form.
() = 
 + 
 + 

,


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where () denotes the mean response of NTB of the dose level i group,  denotes for dose 
levels i, for i = 1, 2,..,4 and 
’s are the coefficients. The dose  will be treated as continuous 
variable.   
Testing for linear dose response curve 
H2-0: β1 = 0, β2 =0
H2-a: β1 ≠0, β2=0
If the null hypothesis H2-0 is rejected in favor of H2-a, then the following test will be tested for 
quadratic dose response curve. 
H3-0: β2 = 0
H3-a: β2 ≠0

Step 3: 
Once the dose response curve is determined from Step 2, the dose group with peak 
response in the selected model will be tested as follows: 
H4-0: The dose group with the peak response in respective model Mean NTB response = 
Mean NTB response of placebo
H4-a : The dose group with the peak response in respective model Mean NTB response ≠
Mean NTB response of placebo
In addition to the 3 steps above, the confidence intervals of difference in treatment effect 
against placebo will be presented for efficacy evaluation. 
Note Step 1 and Step 3 the testing will be based on the adjusted means of NTB response from 
the primary model as described in Section 7.3
The data for patients on donepezil will be analysed using descriptive statistics.  
All calculated p-values should be considered descriptive for the analysis.  Therefore, no alpha 
correction will be carried out.
For secondary endpoints, all calculated p-values should be considered descriptive for the 
analyses of the secondary endpoints. Therefore, no alpha correction will be carried out.
7.3
PLANNED ANALYSES
Analysis set
Treated Set
The treated set (TS) will consist of all patients who were randomised and treated with at least 
one dose of study drug.
Full Analysis Set


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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 post baseline on treatment 
primary endpoint NTB assessment. The FAS will be used for the primary analyses.
7.3.1
Primary analyses
Derivation of primary endpoint
The primary endpoint NTB total score will be analysed as change from baseline (Visit 3)
after 12 weeks of treatment. The NTB includes 9 tests as described in Section 5.1. For each 
patient, raw scores on each of the 9 NTB tests will be converted to the standardized z-score 
using the baseline means and standard deviations (SDs) for each test. The baseline means and 
SDs will be calculated using all randomised patients. The resultant z-scores will be averaged 
to obtain a total z-score, incorporating all 9 NTB tests. Change from baseline will be 
calculated as the post-baseline composite z-score minus the pre-treatment z-score, such that a 
positive change indicates an improvement from baseline [R13-2645].
Primary analysis model
The restricted maximum likelihood (REML) based mixed effects model with repeated 
measurements (MMRM) will be used for the change from baseline in NTB total z-score after 
12 weeks of treatment. The model will include fixed, categorical effects of treatment, visit, 
current AChEI use (Yes, No) 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 
errors. If this analysis fails to converge, compound symmetry covariance structure might be 
used. The Kenward-Roger approximation will be used to estimate denominator degrees of 
freedom. Analyses will be implemented using SAS PROC MIXED. The primary treatment 
comparisons will be the contrast between treatments after 12 weeks of treatment. Adjusted 
mean values as well as treatment contrasts will be presented together with the 95% 
confidence intervals.
7.3.2
Secondary analyses
The REML model as described for the primary endpoint will be performed for the secondary 
endpoint CDR-SB. An ANCOVA model similar to the primary endpoint model will be 
performed for the ADAS-Cog11 and ADCS-ADL secondary endpoints.  Further details will 
be provided in the TSAP.  . The adjusted mean values as well as the treatment contrasts will 
be presented together with the 95% confidence intervals. 
7.3.3
Safety analyses
Standard safety analyses will be performed on the TS.
All safety data will be displayed and analyzed using descriptive statistical methods. No 
formal inferential analysis is planned for safety comparison.


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Statistical analysis and reporting of adverse events will concentrate on treatment-emergent
adverse events. To this end, all adverse events occurring between first drug intake and end of 
the residual effect period after last treatment administration will be considered ‘treatment-
emergent’.
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).
Descriptive statistics of laboratory values over time and for the difference from baseline will 
be provided. Frequency tables of changes with respect to the reference range between 
baseline and last value on treatment will also be presented.
Vital signs, ECG and other safety parameters at screening/run-in/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.
The responses to the C-SSRS will be summarized through descriptive statistics. 
More details of these analyses will be included in the TSAP.
7.3.4
Interim analyses
There is no interim analysis planned for this study.


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7.4
HANDLING OF MISSING DATA
Every effort will be made to collect complete data at the specified time points. 
In general, completely missing visits will be handled through the statistical model.
NTB measurements

For NTB, if more than 3 out of 9 items are missing, the total z-
score will not be derived and it will be set to missing [R13-
2645]. 

If all data from a visit is missing at random (i.e. the patient 
withdraw for any reason or a visit is missed but the patient has 
not withdrawn), the likelihood based repeated measures mixed 
effects model described in Section 7.3.1 will handle missing 
data.
Additional details on the imputation of missing data will be specified in the Trial Statistical 
Analysis Plan (TSAP) prior to unblinding.
7.5
RANDOMISATION
Eligible patients will be randomly assigned to one of the 5 treatment groups, with an 
allocation of 1:1:1:1: 2 respectively for BI 409306 10 mg once daily: BI 409306 25 mg once
daily: BI 409306 50 mg once daily: BI 409306 25 mg twice daily: 10mg once daily: placebo. 
The randomisation will be stratified by current AChEI use (Yes,No).
The randomisation of patients to the treatment groups will be performed via an interactive 
response technology (IRT). BI will arrange for the randomisation as well as packaging and 
labeling of study medication. The randomisation list will be generated using a validated 
system, which involves a pseudo-random number generator and a supplied seed number so 
that the resulting allocation of medication numbers to treatment is both reproducible and non-
predictable. The access to the randomisation codes will be controlled and documented.


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7.6
DETERMINATION OF SAMPLE SIZE
The primary efficacy hypothesis will be tested by comparing the dose group of BI 409306
with the peak response in the fitted regression model to the placebo group on the primary
endpoint, the change from baseline (Visit 3) in NTB total z-score after 12-week treatment. 
(See section 7.2 for the details of hypothesis testing.)As previously mentioned, the 
randomisation allocation ratio of 1:1:1:1: 2 of 10 mg, 25mg, 50 mg, 25 mg BID of BI 409306 
and placebo is used so that 33% of patients will be randomised to placebo. Since these results 
in an unequal allocation of treatment to placebo, the sample size required for the active 
treatment and placebo for various effect sizes are displayed separately. The sample size 
calculations in Table 7.6:1 displays the range of effect sizes considered for this trial under 
these assumptions using a 2-sided alpha of 0.05 with 80% power. The two-sample t-test 
method with unequal n’s in nQuery Advisor 6.01 was used for the calculation.
Table 7.6: 1 Sample size calculations 
Standardized effect size 
0.45
0.475
0.50
0.55
0.6
0.65
Power
80%
80%
80%
80%
80%
80%
n for each active treatment arm
59
53
48
40
34
29
n for placebo arm 
118
106
96
80
68
58
Total 
354
318
288
240
204
174
Based on the calculations provided in Table 7.6:1 and recent data for trials using 
adjunct therapy, a sample size of 59 per active treatment arm and 118 for placebo arm 
was selected as adequate for this phase II proof of concept trial. This sample size would 
allow us to detect an effect size of 0.45 with 80% power, 2 sided alpha .05. 
Assuming a 10% dropout rate, this sample size would allow us to detect an effect size of 
0.475 with 80% power and assuming a 20% dropout rate, this sample size would allow 
us to detect an effect size of 0.5 with 80% power, 2-sided alpha at 0.05.


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8.
INFORMED CONSENT, DATA PROTECTION, TRIAL 
RECORDS
The trial will be carried out in compliance with the protocol, the principles laid down in the 
Declaration of Helsinki, in accordance with the ICH Harmonised Tripartite Guideline for 
Good Clinical Practice (GCP) and relevant BI Standard Operating Procedures (SOPs). 
Standard medical care (prophylactic, diagnostic and therapeutic procedures) remains in the 
responsibility of the treating physician of the patient.
The investigator should inform the sponsor immediately of any urgent safety measures taken 
to protect the study subjects against any immediate hazard, and also of any serious breaches
of the protocol/ICH GCP and if located in Japan the Japanese GCP regulations (Ministry of 
Health and Welfare Ordinance No. 28, March 27, 1997).
The rights of the investigator and of the sponsor with regard to publication of the results of 
this trial are described in the investigator contract. As a general rule, no trial results should be 
published prior to finalisation of the Clinical Trial Report.
According to local requirements the terms and conditions of the insurance cover are made 
available to the investigator and the patients via documentation in the ISF (Investigator Site 
File).
8.1
STUDY APPROVAL, PATIENT INFORMATION, AND INFORMED 
CONSENT
This trial will be initiated only after all required legal documentation has been reviewed and 
approved by the respective Institutional Review Board (IRB) / Independent Ethics Committee 
(IEC) and competent authority (CA) according to national and international regulations. The 
same applies for the implementation of changes introduced by amendments.
Prior to patient participation in the trial, written informed consent must be obtained from each 
patient 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.
The patient must be informed that his/her personal trial-related data will be used by 
Boehringer Ingelheim in accordance with the local data protection law. The level of 
disclosure must also be explained to the patient.
The patient must be informed that his / her medical records may be examined by authorised 
monitors (CML/CRA) or Clinical Quality Assurance auditors appointed by Boehringer 
Ingelheim, by appropriate IRB / IEC members, and by inspectors from regulatory authorities.


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8.2
DATA QUALITY ASSURANCE
In order to achieve a high level of standardized processes, data collection of efficacy and 
safety endpoints is coordinated centrally: 
 
) has been selected as service provider to support tasks related to the 
neuropsychological assessments. A detailed description of services can be found in the 
vendor contract. The services of 
 include:
- Necessary Rater prequalification
- Central Rater training for neuropsychological assessments used as primary and secondary 
endpoints (online and at investigator meeting)
- Provision of Rater materials
- Central Quality Review of Assessments; for that purpose assessment procedures will be 
audio recorded
Details of rater prequalifications, Rater Training, Rater Materials (including assessments) and 
of the Central review procedures will be available in a separate document filed in the ISF.
Central lab analysis of safety lab
The data management procedures to ensure the quality of the data are described in detail in 
the trial data management and analysis plan (TDMAP) available in CTMF.
A quality assurance audit/inspection of this trial may be conducted by the sponsor or 
sponsor’s designees or by IRBs/IECs or by regulatory authorities. The quality assurance
auditor will have access to all medical records, the investigator’s trial-related files and 
correspondence, and the informed consent documentation of this clinical trial.
8.3
RECORDS
Case Report Forms (CRFs) for individual patients will be provided by the sponsor, either on 
paper or via remote data capture. 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 entered in the eCRFs that are transcribed from source documents must be consistent 
with the source documents or the discrepancies must be explained. The investigator may need 
to request previous medical records or transfer records, depending on the trial; also current 
medical records must be available.
For eCRFs all data must be derived from source documents.
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. 


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CRFs/eCRFs 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 CRFs/eCRFs, and written 
informed consents. The accuracy of the data will be verified by reviewing the documents
described in Section 8.3.1.
8.4
LISTEDNESS AND EXPEDITED REPORTING OF ADVERSE EVENTS
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 409306 this is the current version of the Investigator’s Brochure [c02101303]. The 
current versions of this reference document is to be provided in the ISF. No AEs are 
classified as listed for matching placebo, study design, or invasive procedures.
8.4.2
Expedited reporting to health authorities and IECs/IRBs
Expedited reporting of serious adverse events, e.g. suspected unexpected serious adverse 
reactions (SUSARs) to health authorities and IECs/IRBs, will be done according to local 
regulatory requirements. Further details regarding this reporting procedure are provided in the 
Investigator Site File.
8.5
STATEMENT OF CONFIDENTIALITY
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 , i.e. the CA.
8.6
COMPLETION OF TRIAL
The EC/competent authority in each participating EU member state needs to be notified about 
the end of the trial (last patient/patient out, unless specified differently in Section 6.2.3 of the 
CTP) or early termination of the trial. 


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9.
REFERENCES
9.1
PUBLISHED REFERENCES
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, Ferris 
S An inventory to assess activities of daily living for clinical trials in 
alzheimer’s disease. Alzheimer Dis Assoc Disord 11 (2), S33 – S39 (1997)
P10-10921 
Lidstone SC, Schulzer M, Dinelle K, Mak E, Sossi V, Ruth TJ, Fuente-
Fernandez R de la, Phillips AG, Stoessl A. Effects of expectation on 
placebo-induced dopamine release in Parkinson disease. Arch Gen 
Psychiatry 2010. 67(8):857-865
R03-0748 
Berg L. Clinical dementia rating (CDR). Psychopharmacol Bull 
1988. 24(4):637-639. 
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, Hall 
K, Hasegawa K, Hendrie H, Huang Y, Jorm A, Mathers C, Menezes PR, 
Rimmer E, Scazufca M, Alzheimer‘s Disease International, . 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. 
R11-5045
European Medicines Agency (EMEA), . Committee for Medicinal Products 
for Human Use (CHMP): guideline on medicinal products for the treatment 
of Alzheimer’s disease and other dementias (London, 24 July 2008, doc. 
Ref.CPMP/EWP/553/95, rev. 1). 
http://www.emea.europa.eu/docs/en_GB/document_library/Scientific_guide
line/2009/ 09/WC500003562.pdf (access date: 6 December 2011) 2008 
R13-2645
Harrison J, Minassian SL, Jenkins L, Black RS, Koller M, Grundman M, . 
A neuropsychological test battery for use in Alzheimer disease clinical 
trials. Arch Neurol 2007;64(9):1323-1329.


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R13-4115
McKhann GM, Knopman DS, Chertkow H, Hyman BT, Jack CR, Kawas 
CH, Klunk WE, Koroshetz WJ, Manly JJ, Mayeux R, Mohs RC, Morris JC, 
Rossor MN, Scheltens P, Carrillo MC, Thies B, Weintraub S, Phelps CH, . 
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. 
9.2
UNPUBLISHED REFERENCES
U10-2286-01
 Electrophysiological evaluation of the efficacy 
of a Boehringer Ingelheim compound at native targets using functional 
parameters: Investigation of the influence of 25004777 on glutamatergic 
synaptic transmission and synaptic long-term potentiation in hippocampus 
after strong tetanization. BI409306-Rosenbrock-1007-H. 17 Jul 2007.
U10-2789-01
. Effects of BI 409306 on 66ehavior assessed by observation in 
a modified IRWIN-test and on nocturnal activity in rats after oral
administration of 0.3, 1 and 3 mg/kg. GP2009/0096/0097/PH3. 10 Nov 2010.
U10-2801-01
, BI 409306: Mutagenicity study using 
micronucleus analysis of rat bone marrow - Part of the 4-week oral (gavage) 
toxicity study No. 10B040, international number 10B061, 10 Oct 2011
U10-2898-01
, BI 409306: Modified Irwin test in the 
rat, including body temperature and short-term locomotor activity by single 
oral (gavage) administration, 10B054; 7 Oct 2011
U10-2899-01
 BI 409306: Evaluation of respiratory 
parameters in the conscious male rat, using whole body bias flow 
plethysmography after single oral (gavage) administration,10B055, 29 Feb 
2012
U11-1173-01
,
BI 409306: 4-week oral (gavage) toxicity 
study in beagle dogs, 10B084, 10 Jan 2012
U12-1034-01
 A randomised, double-blind, placebo-
controlled (within dose groups) Phase I study to assess the safety, tolerability 
and pharmacokinetics of single rising doses 0.5 mg to 500 mg of BI 409306 
administered orally in healthy male volunteers. 1289.1. 19 Jan 2012
U12-2165-01
. Randomised, double-
blind, placebo-controlled, parallel-group proof of mechanism study to assess 
the pharmacokinetics and to evaluate the pharmacodynamic effect of 
different single oral doses of BI 409306 in healthy male volunteers. 1289.3. 
17 Sep 2012
U13-1182-01
 Safety, tolerability, 
pharmacokinetics, and pharmacodynamics of multiple-rising doses of BI 
409306 film-coated tablets given orally q.d. or bid for 14 days in young 


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healthy and elderly healthy male/female volunteers (randomised, 
doubleblind, placebo-controlled within dose groups Phase I study). 1289.2. 
20 Feb 2013
U13-1303-01
. Safety, tolerability, 
pharmacokinetics, and pharmacodynamics of multiple rising doses of BI 
409306 film-coated tablets given orally q.d. for 14 days in young and elderly 
healthy male/female volunteers (randomized, double-blind, placebo 
controlled within dose groups Phase I study). 1289.17. 22 Feb 2013
c02098989-02
. Safety, tolerability and 
pharmacokinetics of single oral doses of BI 409306 (tablet) in healthy 
Chinese and Japanese male volunteers and multiple oral doses of BI 409306 
(tablet) in healthy Japanese male volunteers (randomised, double-blind, 
placebocontrolled within dose groups). 1289.4. 13 Mar 2014
c02101303
Investigator’s Brochure: BI 409306 in Alzheimer’s Disease and Cognitive 
Impairment associated with Schizophrenia


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10.
APPENDICES


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10.2
CLINICAL EVALUATION OF LIVER INJURY
10.2.1
Introduction
Alterations of liver laboratory parameters, as described in Section 5.2.2.1 (Protocol-Specified 
Significant Events), are to be further evaluated using the following procedures: 
10.2.2
Procedures
Repeat the following laboratory tests: ALT, AST, and bilirubin (total and direct) - within 48 
to 72 hours and provide additional blood sample to the central laboratory for automatic reflex 
testing of the below listed laboratory parameters. Only in case whereby the central laboratory 
is not immediately available (e.g. if the logistics are such that the patient´s repeat specimen 
would not reach the central laboratory in a reasonable timeframe), ALT, AST, and bilirubin 
(total and direct) will be evaluated by local laboratory and results are made available to the 
investigator and to BI as soon as possible. If in such a case ALT and/or AST >3 fold ULN 
combined with an elevation of total bilirubin >2 fold ULN are confirmed, results of the 
laboratory parameters described below must be made available to the investigator and to BI 
as soon as possible.
In addition, 
o
obtain a detailed history of current symptoms and concurrent diagnoses and 
medical history according to the “DILI checklist” provided in the ISF 
o
obtain history of concomitant drug use (including non-prescription 
medications, herbal and dietary supplement preparations), alcohol use, 
recreational drug use, and special diets according to the “DILI checklist” 
provided in the ISF;
o
obtain a history of exposure to environmental chemical agents (consider home 
and work place exposure) according to the “DILI checklist” provided in the 
ISF;
and report these via the CRF.
Clinical chemistry
alkaline phosphatase, albumin, PT or INR, CK, CK-MB, coeruloplasmin, α-1 antitrypsin, 
transferin, amylase, lipase, fasting glucose, cholesterol, triglycerides
Serology
Hepatitis A (Anti-IgM, Total), Hepatitis B (HbsAg, DNA), Hepatitis C (Anti-HCV, RNA if 
Anti-HCV positive), Hepatitis D (Anti-IgM, Total), Hepatitis E (Anti-HEV, Anti-HEV IgM, 


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RNA if Anti-HEV IgM positive), Anti-Smooth Muscle antibody (titer), Anti-nuclear antibody 
(titer), Anti-LKM (liver-kidney microsomes) antibody, Anti-mitochondrial antibody, Epstein 
Barr Virus (VCA IgG, VCA IgM), cytomegalovirus (IgG, IgM), herpes simplex virus (IgG, 
IgM), varicella (IgG, IgM), parvovirus (IgG, IgM), toxoplasmosis (IgG, IgM)
Hormones, tumormarker
TSH
Haematology
Thrombocytes, eosinophils
o
Provide abdominal ultrasound to rule out biliary tract, pancreatic or 
intrahepatic pathology, e.g. bile duct stones or neoplasm.
o
Initiate close observation of subjects by repeat testing of ALT, AST, and total 
bilirubin (with fractionation by total and direct) at least weekly until the 
laboratory ALT and / or AST abnormalities stabilize or return to normal, then 
according to the protocol. Depending on further laboratory changes, additional 
parameters identified e.g. by reflex testing will be followed up based on 
medical judgement and Good Clinical Practices (GCP).


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11.
DESCRIPTION OF GLOBAL AMENDMENT(S)
Number of global amendment
1
Date of CTP revision
22 Dec 2014
EudraCT number
2013-005040-28
BI Trial number
1289.7
BI Investigational Product(s)
BI 409306
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 donepezil and 
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
4.1.1
Description of change
The source of IMP was corrected
Rationale for change
Correction
Section to be changed
4.1.4, 6.1, 6.2.1, 6.2.2, 6.2.3
Description of change
Requirements to take study drug fasted were
removed. Now drug can be taken with or without
food.
Rationale for change
Data from food interaction study (trial 1289.22)
show no clinically relevant food interaction with 
BI 409306


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Number of global amendment
1
Section to be changed
4.2.2.1
Description of change
Use of strong or moderate CYP3A4 inhibitors are
now mentioned to be prohibited
Rationale for change
Clarification that the use of strong or moderate 
CYP3A4 inhibitors is prohibited. While the 
contribution of CYP3A4 to the metabolism of BI 
409306 is minor, there is no data available 
regarding the potential effect of CYP3A4 
inhibitors on exposure of BI 409306. Therefore 
such medications could interfere with the 
investigational product as described in Section 
3.3.4.1.
Section to be changed
5.2.2
Description of change
Follow-up period changed to 28 days
Rationale for change
A typographical error was corrected
Section to be changed
6.2.1.
Description of change
The need for determination of blood glucose was 
removed from V2 description because no 
neuropsychological assessments will be done at 
V2
Rationale for change
Correction to align text with flowchart
Section to be changed
6.2.2.
Description of change
V5 was changed to V6
Rationale for change
A typographical error was corrected
Section to be changed
7.2
Description of change
The “highest dose group” was replaced by “the 
dose group with the peak response”
Rationale for change
A typo was corrected


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Number of global amendment
2
Date of CTP revision
27 Jul 2015
EudraCT number
2013-005040-28
BI Trial number
1289.7
BI Investigational Product(s)
BI 409306
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 donepezil and 
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, Clinical Trial Protocol Synopsis, Sections 
1.1, 2.1, 2.2, 3.1, 3.2, 3.3, 3.3.2, 3.3.3, 4.1, 4.1.1, 
4.1.2, 4.1.3, 4.1.4, 4.1.7, 5.1.1, 5.1.2, 7.1, 7.5, 7.6
Description of change
The donepezil arm was dropped from the study 
and therefore reference to donepezil was 
removed. Patient number and treatment groups, 
inclusion criteria, trial objectives and description 
of IRT and IMP were adapted accordingly.
Rationale for change
AChEIs (including donepezil) are the standard 
treatment in the indication under study. Therefore, 
the study design was changed to allow both 
treatment-naïve patients and patients on standard 
of care to enter the study. With this change it will 


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Number of global amendment
2
be possible to analyse the treatment effect in the 
expected target population for the compound 
under study.
Section to be changed
Clinical Trial Protocol Synopsis, Flowchart, 
sections 6.2, 6.2.2
Description of change
ADCS-MCI-ADL was removed from the study, 
MMSE was removed from V3, V5 and V7, 
ADAS-cog11 and ADCS-ADL were removed 
from V5
Rationale for change
The number of neuropsychological scales was 
reduced to reduce patient burden during the visits. 
As many of the items of the removed scales are 
part of the remaining assessment, the clinical 
validity of the primary and secondary analyses of 
the trial are not impacted.
Section to be changed
Clinical Trial Protocol Synopsis, Section 7.3.1, 
7.5
Description of change
Stratification factor current AChEI use (Yes, No) 
added to primary analysis model and 
randomisation.
Rationale for change
The study design was changed to allow treatment 
naïve and patients on the current standard of care 
to enter the study. This stratification factor was 
added to the randomization to ensure balance 
across treatment groups and added to the model to 
adjust for any potential treatment difference.
Section to be changed
Inclusion #8
Description of change
The criterion was deleted.
Rationale for change
The criterion contained only redundant 
information also mentioned in 
Exclusion criterion #1 (see below).
Section to be changed
Flowchart, 3.3.3, Exclusion criterion 1
Description of change
The use a CCT to exclude other disorders causing
dementia is now allowed if not prohibited by local 
regulations
Rationale for change
To allow patients with a contraindication for MRI 
to enter the study
Section to be changed
3.3.3, Exclusion criterion 9
Description of change
Clarifying the definition of previous participation 
in studies of mild cognitive impairment and
studies targeting Aß and tau therapies
Rationale for change
Clarification
Section to be changed
4.2.2.1
Description of change
The use of strong or moderate CYP3A4 inhibitors 
is now allowed.


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Number of global amendment
2
Rationale for change
Clinical data (trial 1289.23) did not show 
evidence for clinical significant changes in 
exposure to BI 409306 after CYP3A4 inhibition.
Section to be changed
Section 7.2
Description of change
10 mg QD arm added to step 1, Spelling of NTB 
fixed
Rationale for change
Typos corrected
Section to be changed
Section 7.3.2
Description of change
ANCOVA analysis added. Reference to TSAP.
Rationale for change
Clarification of analysis models for secondary 
endpoints with different number of data collection 
visits.
Section to be changed
10.2.2
Description of change
“fasting” was added to glucose
Rationale for change
A typo was corrected.


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Number of global amendment
3
Date of CTP revision
01 Sep 2016
EudraCT number
2013-005040-28
BI Trial number
1289.7
BI Investigational Product(s)
BI 409306
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 donepezil and 
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
Synopsis, 3.1, 3.3, 7.6
Description of change
Sample size was changed to a total of N=354 
allow to detect an effect size of 0.45 with 80% 
power, 2 sided alpha .05
Rationale for change
To power the study for a smaller effect size.


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Number of global amendment
4
Date of CTP revision
23 Feb 2017
EudraCT number
2013-005040-28
BI Trial number
1289.7
BI Investigational Product(s)
BI 409306
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 donepezil and 
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
 replaced by 
Rationale for change
Change of responsibilities
Section to be changed
Section 1.2.
Description of change
Adding information that fluvoxamine, a strong
inhibitor of CYP2C19 and CYP1A2 increased
plasma exposure of BI 409306.
Rationale for change
Include results from clinical DDI study 1289.35
Section to be changed
Section 3.3.3 Exclusion criteria #14
Description of change
Removal of hormonal contraception, which are
moderate to strong CYP1A2 inhibitor, from the
samples of acceptable methods of contraception.
Rationale for change
Hormonal contraception may be a moderate
CYP1A2 inhibitor which can lead to a multifold
increased plasma exposure of BI409306 in poor


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Number of global amendment
4
metabolizer and therefore is excluded from
concomitant use.
Section to be changed
Section 4.2.2.1
Description of change
Moderate or strong CYP1A2 inhibitors added to
the list of restricted medications
Rationale for change
Moderate or strong CYP1A2 inhibitors may
significantly increase plasma exposure of BI
409306 in poor metabolizers


 
 
 
 
APPROVAL / SIGNATURE PAGE 
 
Document Number: 
 
Technical Version Number:
 
Document Name: 
 
 
 
                                                                                                                 
 
Title: 
 
 
 
 
                                                                                                                   
 
Signatures (obtained electronically) 
 
Meaning of Signature  
Signed by 
Date Signed 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
c02216748
8.0
clinical-trial-protocol-revision-04
A multi-centre, double-blind, parallel-group, randomised controlled study to
investigate efficacy, safety and tolerability of orally administered BI 409306 during a
12-weeks treatment period compared to placebo in patients with cognitive
impairment due to Alzheimer’s Disease.
Author-Trial Clinical Monitor
23 Feb 2017 17:01 CET
Author-Trial Statistician
23 Feb 2017 17:02 CET
Approval-Clinical Pharmacokinetics
23 Feb 2017 17:09 CET
Approval-Therapeutic Area 
24 Feb 2017 00:18 CET
Approval-Team Member Medicine
24 Feb 2017 18:29 CET
Verification-Paper Signature
Completion
03 Mar 2017 09:15 CET


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 Technical Version Number:
 
 
 
(Continued) Signatures (obtained electronically) 
 
Meaning of Signature  
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Date Signed 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
c02216748
8.0

SAP_000.pdf: 
TITLE PAGE
Trial Statistical Analysis Plan
c03164045 -01
BI Trial No.:
1289.7
Title:
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 donepezil and placebo in patients with cognitive 
impairment due to Alzheimer’s Disease.
Investigational
Product(s):
BI 409306
Responsible trial 
statistician(s):
Telephone: 
Fax: 
Date of statistical 
analysis plan:
13 JUN 2017 SIGNED 
Version:
Final
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1
TABLE OF CONTENTS
TITLE PAGE ......................................................................................................1
1
TABLE OF CONTENTS ......................................................................2
LIST OF TABLES ..............................................................................................4
2
LIST OF ABBREVIATIONS ...............................................................5
3
INTRODUCTION..................................................................................8
4
CHANGE IN THE PLANNED ANALYSIS OF THE STUDY.........9
5
ENDPOINT...........................................................................................10
5.1
PRIMARY ENDPOINT ....................................................................................10
5.2
SECONDARY ENDPOINTS............................................................................10
5.2.1
Key secondary endpoint................................................................................10
5.2.2
Other Secondary endpoints..........................................................................10
10
11
6
GENERAL ANALYSIS DEFINITIONS...........................................12
6.1
TREATMENTS..................................................................................................12
6.2
IMPORTANT PROTOCOL VIOLATIONS ..................................................14
6.3
PATIENT SETS ANALYSED..........................................................................18
...................................................................................................19
6.5
POOLING OF CENTRES ................................................................................19
6.6
HANDLING OF MISSING DATA AND OUTLIERS ...................................19
6.6.1
Missing efficacy data.....................................................................................19
6.6.2
Missing safety data and other data..............................................................21
6.6.3
Missing AE dates and times..........................................................................21
6.6.4
Missing plasma concentrations and pharmacokinetic parameters ..........21
6.7
BASELINE, TIME WINDOWS, AND CALCULATED VISITS .................21
7
PLANNED ANALYSIS.......................................................................23
7.1
DEMOGRAPHICS AND OTHER BASELINE CHARACTERISTICS......23
7.2
CONCOMITANT DISEASES AND MEDICATION ....................................23
7.3
TREATMENT COMPLIANCE .......................................................................23
7.4
PRIMARY ENDPOINT(S) ...............................................................................23
7.4.1
Primary efficacy analysis..............................................................................23
7.4.2
Sensitivity analyses - primary and MMRM endpoints..............................23
7.5
SECONDARY ENDPOINTS............................................................................24
7.5.1
Key secondary endpoint................................................................................24
7.5.2
Secondary endpoints .....................................................................................24
7.5.3
Sensitivity analyses - secondary endpoints..................................................24
..................................................................................24
7.7
EXTENT OF EXPOSURE................................................................................25
7.8
SAFETY ANALYSIS.........................................................................................25
7.8.1
Adverse events ...............................................................................................25
7.8.1.1
Assignment of AEs to treatment.................................................................25


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7.8.1.2
Analysis of other significant AEs...............................................................25
7.8.1.3
AE summaries.............................................................................................26
7.8.1.4
AE summaries for disclosure......................................................................26
7.8.2
Laboratory data.............................................................................................26
7.8.3
Vital signs.......................................................................................................26
7.8.4
ECG ................................................................................................................27
7.8.5
Others .............................................................................................................27
7.8.5.1
C-SSRS.......................................................................................................27
8
REFERENCES.....................................................................................28
9
ADDITIONAL SECTIONS ................................................................29
9.1
CALCULATION OF NTB TOTAL SCORE..................................................29
9.2
C-SSRS FDA CATEGORIES...........................................................................31
9.3
SAS CODE..........................................................................................................32
10
HISTORY TABLE...............................................................................33


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LIST OF TABLES
Table 6.1: 1
Treatment descriptions ....................................................................................12
Table 6.1: 2 
Definition of analyzing treatment period ........................................................13
Table 6.2: 1
important protocol violations ..........................................................................15
Table 6.3: 1
Patient sets analyzed........................................................................................19
Table 6.7: 1
Time windows for all pre/on-treatment safety visits.......................................21
Table 6.7: 2
Time windows for on-treatment efficacy measurement scheduled for each on 
treatment visit...................................................................................................................22
Table 9.1: 1
NTB description and scoring...........................................................................29
Table 9.2.1
CSSRS and FDA categories............................................................................31
Table 9.3.1
SAS Code for main analyses...........................................................................32
Table 10: 1
History table ....................................................................................................33


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2
LIST OF ABBREVIATIONS
Term
Definition / description
ABCB1
ATP-binding cassette sub-family B member 1 (gene encoding for P-gp)
ADCS-ADL
Alzheimer’s Disease Cooperative Study/Activities of Daily
ADCS-MCI-ADL
ADCS-ADL for mild cognitive impairment
AChE-Is
Acetylcholine Esterase Inhibitors
AD
ADAS-cog
Alzheimer’s Disease
Alzheimer's Disease Assessment Scale-cognitive subscale
AE
Adverse Event
AESI
Adverse Event of Special Interest
APOE
Apolipoprotein E
AUC
Area under the Curve
BCRP
Breast cancer resistance protein
BDNF
Brain-derived neurotrophic factor
b.i.d
bis in die (twice a day)
BPM
Beats per Minute
CDR-SB
Clinical Dementia Rating Scale–Sum of Boxes
BRPM
Blinded report planning meeting
CI
Confidence Interval
CRF
CT
Case Report Form
Concomitant therapy
CCT
Cranial Computer Tomography
CSF
Cerebrospinal fluid
Cmax,ss
Maximum measured concentration in plasma (at steady state)
C-SSRS
Columbia Suicide Severity Rating Scale
CTC
Common Terminology Criteria  
CTMF
Clinical Trial Master File
CTP
CTR
CYP
Clinical Trial Protocol
Clinical Trial Report
Cytochrome 
DAT
Dementia of Alzheimer Type
DMC
Data Monitoring Committee
DMG
Dictionary Maintenance Group
DNA
Deoxyribonucleic Acid
DM&SM
Boehringer Ingelheim Data Management and Statistics Manual
DRA
Drug Regulatory Affairs
eCRF
Electronic Case Report Form
EDC
Electronic Data Capture
EM
Extensive metabolizer
EMEA
European Agency for the Evaluation of Medicinal Products
EudraCT
European Clinical Trials Database
FAS
Full Analysis Set
FTA
Fluorescent treponemal antibody absorbent test
GCP
Good Clinical Practice
HPC
Human Pharmacology Centre


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HR
Heart Rate
IB
Investigator’s Brochure
ICF
Informed consent form
ICH
International Conference on Harmonisation
IEC
Independent Ethics Committee
IM
Intermediate metabolizer
IPV
Important protocol violation
IRB
Institutional Review Board
ISF
Investigator Site File
IRT
Interactive Response Technology
MCPMod
Multiple Comparisons & Modelling
MedDRA
Medical Dictionary for Drug Regulatory Activities
MI
Multiple Imputation
MNDA
Myeloid cell nuclear differentiation antigen
MMRM
Mixed model repeated measures
MMSE
Mini-Mental-State-Examination
MQRM
Medical Quality Review Meeting
MRI
Magnetic Resonance Imaging
MST
Medical Subteam
NMDA-R
N-methyl-D-aspartate receptor
NTB
Neuropsychological Test Battery
P-gp
P-glycoprotein
O*C
Oracle Clinical
OC
Observed cases
OR
Original result
PD 
Pharmacodynamics
PG(x)
Pharmacogenomic(s)
PM
Poor metabolizer
POC
Proof of Concept
PPS
Per protocol set
PSTAT
Project Statistician
PK
Pharmacokinetic
PM
Poor metabolizers
PV
Protocol violation
Q1
Lower quartile
Q3
Upper quartile
RDC
Remote Data Capture
REP
Residual Effect Period
RPR
Rapid Plasma Reagin
q.d.
quaque die (once a day)
SAE
Serious Adverse Event
SD
Standard Deviation
SE
Standard Error
SMQ
Standardised MedDRA query
SOC
System organ class


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SPC
Summary of Product Characteristics
TCM
Trial Clinical Monitor
TDMAP
tmax,ss
Trial Data Management and Analysis PlanTime to maximum plasma 
concentration (at steady state)
TESS
Treatment emergent signs and symptoms 
TMM
Team Member Medicine
TMW
Trial Medical Writer
TOC
Table of contents
TS
Treated Set
TSAP
Trial Statistical Analysis Plan
UM
Ultrarapid metabolizer


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3
INTRODUCTION
As per ICH E9, the purpose of this document is to provide a more technical and detailed 
elaboration of the principal features of the analysis described in the 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.
SAS Version 9.4 will be used for all analyses.


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4
CHANGE IN THE PLANNED ANALYSIS OF THE STUDY
The following changes were made:
 
The residual effect period (washout) is defined as 7 days, this is not mentioned in Section 
7.3.3 of the CTP, but is mentioned in section 5.2.2.2 of the CTP.
The data for patients entered prior to Amendment 2 will be handled as follows:

Donepezil data will be summarized descriptively

All treatment naïve patients will be assigned to the "No" stratum for concurrent use of 
AcHEI (Yes, No).

The data for assessments removed from the study completely, or for a specific visit 
due to the amendment will be summarized descriptively.


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5
ENDPOINT
5.1
PRIMARY ENDPOINT
The primary endpoint is:
The Neuropsychological Test Battery (NTB) response, defined as change from baseline in 
total z-score after 12 weeks of treatment.
For each patient's raw scores on each of the 9 NTB tests will be converted to the standardized 
z-score using the baseline means and standard deviations (SDs) for each test. The baseline 
means and SDs will be calculated using all randomized patients. The resultant z-scores will 
be averaged to obtain a total z-score, incorporating all 9 NTB tests. Change from baseline 
will be calculated as the post-baseline composite z-score minus the pre-treatment z-score, 
such that a positive change indicates an improvement from baseline. The measurements taken 
at Visit 3 will be considered as baseline values.  Further information can be found in section 
9.1.
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
Other Secondary endpoints
Secondary efficacy endpoints are the same as detailed in Section 5.1.1 of the protocol. 
Namely, they are the following:
Change from baseline in the ADCS-ADL (Alzheimer’s Disease Cooperative Study/Activities 
of Daily Living) score after 12 weeks of treatment.
Change from baseline CDR-SB (Clinical Dementia Rating – Sum of Boxes) after 12 weeks of 
treatment
Change from baseline in ADAS-Cog11 (Alzheimer’s Disease Assessment Scale cognitive 
subscale) total score after 12 weeks of treatment.


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6
GENERAL ANALYSIS DEFINITIONS
6.1
TREATMENTS
For regimen details refer to Section 3.1 of the CTP.
The treatments and treatment periods are defined as follows:
Table 6.1: 1
Treatment descriptions
TPATT
Long Name
Short Name
A
BI 409306 10 mg QD
BI 10mg QD
B
BI 409306 25 mg QD
BI 25mg QD
C
BI 409306 50 mg QD
BI 50mg QD
D
BI 409306 25 mg BID
BI 25mg BID
E
Placebo
Placebo
F
Donepezil 5mg/10mg QD
Donepezil


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Table 6.1: 2 
Definition of analyzing treatment period
Label
Interval
Start Date
Start time
Screening
Screening
Date of informed consent
00:00
Placebo Run-in (PBORI)
Run-in
Date of first administration of 
run-in medication
Time of first
administration of
run-in medication
12:00 if missing
BI 409306 10mg QD
BI 409306 25mg QD
BI 409306 50mg QD
BI 409306 25mg BID
Placebo
Donepezil 5mg/10mg QD
Treatment
Date of first administration of 
study drug
Time of first
administration of
study drug
12:00 if missing
Post-treatment
Post-treatment
Date of last intake of study 
drug + X+1 (see definition of 
X below)
00:00
Post-study 
Post-study 
Start date = Last contact
date, defined as the 
maximum of (Trial 
completion date, last study 
drug intake + X) +1
00:00
For safety analyses, data up to 7 days after last treatment intake will be considered as on 
treatment for AEs and for laboratory values. To clarify;

Screening:  starts from the date of informed consent to the date of first administration 
of run-in medication.

Placebo run in period: starts from the date of first administration of run-in medication 
to the date of first administration of randomised study drug.

On treatment: From the first intake of randomised study drug to last intake of 
randomised study drug + X days, where X=7 days for safety laboratory and AE.

Post-treatment: From end of on-treatment period until last contact. Last contact date is 
defined in Table 6.1: 1. Post treatment period is not applicable for patients with last 
contact equal to ‘last intake + X + 1 days’ where X is 7 days as previously specified.

Post study: From day after last contact defined in Table 6.1: 1. If period starts at end 
of on-treatment period then post-treatment period is not applicable.


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6.2
IMPORTANT PROTOCOL VIOLATIONS
Important protocol violations (IPV) affecting subjects’ rights will be identified separately 
from those affecting analysis sets in the study report. Patients with important PVs that could 
potentially impact efficacy endpoints will be excluded from the PPS (Refer to Section 6.3). 
The protocol violations are listed in the Table 6.2: 1 below. They will be reviewed at Medical 
Quality Review Meetings (MQRMs) conducted periodically based on data accumulated 
during the trial. A list of protocol deviations will be discussed at the blinded report planning 
meeting (BRPM).
If the data show other important PVs, this table will be supplemented accordingly at MQRMs 
or BRPMs or through team review of the manual PV log. The decision whether a patient will 
be excluded from the analysis will be made at the final BRPM prior to DBL.


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Table 6.2: 1
important protocol violations
Category/
Code
Description
Example/Comment
Excluded 
from PPS
Automatic
/Manual
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.
Yes
Automatic
A1.2
Diagnosis of mild Alzheimer's 
Dementia not met
Inclusion criteria 1 not met as 
specified in the protocol.
Yes
Automatic
A1.3
Inadequate MMSE or ADAS-
cog11 or CDR score
Inclusion criteria 2 not met as 
specified in the protocol.
Yes
Automatic
A1.4
Previous or current use of AD 
medication requirement not 
met.
Inclusion criteria 6 not met as 
specified in the protocol.
Yes
Automatic
A1.5
Inadequate education and 
language 
Inclusion criteria 5 not met as 
specified in the protocol.
Yes
Automatic
A1.6
Inadequate study partner 
reliability
Inclusion criteria 4 not met as 
specified in the protocol.
Yes
Automatic
A2
Exclusion criteria met
A2.1
Alzheimer's Dementia 
secondary disorder
Exclusion criteria 1 met as specified in 
the protocol.
Yes
Automatic
A2.2
Substantial concomitant 
cerebrovascular disease
Exclusion criteria 2 met as specified in 
the protocol.
Yes
Automatic
A2.3
Symptomatic and 
unstable/uncontrolled 
conditions
Exclusion criteria 4 met as specified in 
the protocol.
Yes
Automatic
A2.4
Neurological disease or other 
psychiatric disorder
Exclusion criteria 6 met as specified in 
the protocol.
Yes
Automatic
A2.5
Any suicidal behavior in the 
past 2 years
Exclusion criteria 7 met as specified in 
the protocol.
No
Automatic
A2.6
Any suicidal ideation of type 4 
or 5 in the C-SSRS in the past 
3 months
Exclusion criteria 8 met as specified in 
the protocol.
No
Automatic
A2.7
Participation in AD study less 
than 3 months from screening, 
treatment for disease 
modification or non-
prescription medications
Exclusion criteria 9 met as specified in 
the protocol.
Yes
Automatic
A2.8
Known history of HIV 
infection
Exclusion criteria 11 met as specified 
in the protocol.
Yes
Automatic
A2.9
Prohibited drugs within 3 
months prior to study 
participation
Exclusion criteria 17 met as specified 
in the protocol.
Yes
Automatic


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Table 6.2: 1 (continued)
important protocol violations
Category
/Code
Description
Example/Comment
Excluded 
from PPS
Automatic
/Manual
A2.10
Uncompensated hearing loss
Exclusion criteria 21 met as specified 
in the protocol.
Yes
Automatic
B
Informed consent not available/not done
B1
Informed consent not 
available/not done
Informed consent date missing; no 
signature on ICF
Exclude 
from All
Automatic
/Manual
B2
Informed consent too late
Check if informed consent date (actual 
consent date) was prior or on Visit 1.
Applicable to all informed consents. 
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 IPV
No
Automatic
/Manual
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 RDC) 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.
Yes
Automatic
C2
Randomization order not 
followed


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Table 6.2: 1 (continued)
important protocol violations
Category
/Code
Description
Example/Comment
Excluded 
from PPS
Automatic
/Manual
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.
Yes
Manual
C3
Non-compliance with study 
medication
C3.1
Non-compliance with study 
medication
Compliance < 80% or >120 %
Yes if 
<80%
Automatic
/Manual
D
Concomitant medication
D1
Prohibited medication use 
before the treatment period of 
the trial
To be determined on a case by case 
basis.
Yes
Automatic
/Manual
D2
Prohibited medication use 
during the conduct of the trial
To be determined on a case by case 
basis.
Yes
Automatic
/Manual
E
Trial specific protocol violations
E1
Negative pregnancy test result 
not obtained during the study 
participation
No
Automatic
E2
Treatment not discontinued due 
to HR elevation as described in 
CTP section 3.3.4.
No
Automatic
E3
Study partner change during 
study.
Yes
Automatic
E4
Assessments administered by 
unqualified rater
Yes
Manual
E5
C-SSRS not administered at 
every visit
No
Automatic


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Table 6.2: 1 (continued)
important protocol violations
Category
/Code
Description
Example/Comment
Excluded 
from PPS
Automatic
/Manual
F
Incorrect timing of endpoint measurements
F1
Incorrect timing -
assessments
F1.1
Assessment order not followed
NTB not administered in order 
specified in CTP
Yes
Automatic
F1.2
Rater switch on primary 
endpoint
NTB not administered by same rater
Yes
Manual
F2
Incorrect timing – times of 
measurements
F2.1
Assessment of NTB outside of 
window between visits
NTB assessment time >2 hour from 
Visit 3 NTB assessment time.
Yes
Automatic
KEY:
PPS – Per Protocol Set
6.3
PATIENT SETS ANALYSED
SCR - Screened set: All patients screened for the trial, with informed consent given 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 
drug.
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 post 
baseline on treatment primary endpoint NTB assessment (or secondary endpoint assessment). 
The FAS will be used for the primary analyses (and secondary analyses).
PPS- Per protocol set: All patients in the FAS without important protocol deviations that 
impact efficacy assessments. No analyses for the CTR are planned using the PPS set.
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. 
If a patient erroneously receives the wrong dose of study drug, the patient’s efficacy data will 
be analyzed in the randomized treatment group and the patient’s safety data will be analyzed 
in the actual treatment group. 
The efficacy analyses will follow the intention-to-treat (ITT) principle in assigning patients to 
treatment groups. I.e., efficacy analyses will be analyzed as randomized using the FAS.
If a patient receives a different study drug than randomized, this will be noted as an IPV.


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Table 6.3: 1
Patient sets analyzed
Patient set
Class of endpoint
SCR
RS
TS
FAS
Primary  
OC
Secondary 
OC
Further
OC
Safety endpoints 
OR
Disposition
OR1
OR1
OR1
Demographic
OR2
OR
Baseline endpoints
OC
Disclosure tables
OR
OR
1)
Disposition table requires multiple patient sets to populate
2)
Additional table for clinical trial disclosure requirements
Note: For definitions of OC (Observed Case) or OR (Original Results)) refer to section 6.6.
Note that the number of patients with available data for an endpoint may differ. For details, 
see section 6.6.
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 endpoints that are not meaningful to apply any imputation rule on them for 
replacing the missing values.
6.6.1
Missing efficacy data
NTB
Details on scoring with missing items are described in section 9.1.
ADAS-Cog11


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If a patient has 3 or fewer missing ADAS-Cog/11 items, the following algorithm will be used 
to compute the ADAS-Cog/11 total score:
Total score = [(total score from completed items) / (maximum total score for completed
items)]*(maximum total score[=70] for all items in the scale)
If there are more than 3 missing ADAS-Cog/11 items, ADAS-Cog/11 score will be 
considered missing at that time point.
ADCS-ADL
For ADCS-ADL, if <30% of the items are missing, the total score will be imputed.  The sum 
of the nonmissing items will be prorated to the sum of total items.  The imputed number will 
be rounded up to the nearest integer.  If the nearest integer is greater than the maximum 
possible score, the imputed score will be equal to the maximum score. If >30% of the items 
are missing, the total score at that visit will be considered missing. For e.g Total score = 
[(total score from completed items) / (maximum total score for completed items)]*(maximum 
total score[=78] for all items in the scale) Supplementary material for [8].
CDR-SB
If only 1 box (of 6) of the CDR is missing, the sum of the boxes will be imputed by prorating 
the sum from the other 5 boxes.  If the score from more than 1 box is not available, the CDR-
SB at that visit will be considered missing. For e.g Total score = [(total score from completed 
items) / (maximum total score for completed items)]*(maximum total score[=18] for all items 
in the scale) Supplementary material for [16].
Observed cases (OC) analysis
For all efficacy endpoints using MMRM analyses, it is planned to analyze only the available 
data that were observed 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.
The following imputation methods will be used if the rate of missing data is greater than 5%.
The method below will be used for the endpoints using ANCOVA analyses.
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 last 
on-treatment value within the time window will be carried forward, while the visit value can 
be the value that was observed closest to the planned visit date or the first value observed in
the time window. See Table 6.7: 2 for further details.
Baseline Observation Carried Forward (BOCF)
As part of the LOCF technique, baseline values will be carried forward if no post-baseline 
value is available.


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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 (see “Handling of 
missing and incomplete AE dates”) (2).
6.6.4
Missing plasma concentrations and pharmacokinetic parameters
Missing data and outliers of PK data are handled according to (1).
6.7
BASELINE, TIME WINDOWS, AND CALCULATED VISITS
For efficacy, the baseline is defined as the pre-treatment observation at Visit 3.  All other 
baseline variables will be observed from Visit 1.
For laboratory safety measurements, the last values prior to study 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.
Table 6.7: 1
Time windows for all pre/on-treatment safety visits 
Visit number
Visit label
Planned days
Interval (actual days on treatment)
1
Screening
-28
(-∞, PBORI-1]
2
Placebo Run-in period
-14
[PBORI ,TREATMENT-1]
3
Baseline
1
[NA, 1]
4a
Week 1
8
[2, 11]
4b
Week 2
15
[12, 18]
4c
Week 3
22
[19, 25]
5
Week 4
29
[26, 43]
6
Week 8
57
[44, 73]
EOT
Week 12
85
[74, 99]
FU
Follow-up
113
[100, Study drug stop date + 7 days]
These time windows are defined based on the planned number of days after the date of first 
administration of study drug. Reasons to base the time windows on the actual treatment start 
date rather than the randomisation date are: 

If first intake of study drug shows a large delay by e.g. more than one week after the 
date of randomisation, a measurement taken four weeks after randomisation rather 
reflects the drug effect after three weeks than after four weeks and thus may 
underestimate the treatment effect at this visit.


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
With large delays of the introduction of study drug after the randomisation, the time 
window for the first on-treatment visit could include times the patient was not yet on 
study drug. 
Table 6.7: 2
Time windows for on-treatment efficacy measurement scheduled for 
each on treatment visit
Time window
(actual days on treatment)
Visit Number
Visit label
Planned days
Start
EndA
3
Baseline
1
NA
1B
5
Week 4
29
2
57
EOT
Week 12
85
58
Study drug stop
date + 7 days
A In case of premature discontinuation of the study drug an EOT Visit has to be performed. If such an EOT Visit falls into 
the time window of a previous visit, measurements will be assigned to this previous visit and the visit value will be 
determined as described below. In this case the time window for the visit that includes EOT Visit will end 7 days after the 
study drug stop date, including Day 7.
B Only values taken prior to the start of treatment with randomised study drug can be considered baseline values. Time 
windows will be used for assignment of measurements to scheduled visits.
Repeated and unscheduled efficacy and safety measurements will be
assigned to the nominal visits and listed in the subject data listing (SDL) according to the 
time windows described above. 
If there are several safety laboratory values in one time window on treatment, the worst of 
these will be selected for the by-visit analyses. 
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 closest to the protocol 
planned visit day. 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. 
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.


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7
PLANNED ANALYSIS
For End-Of-Text (EoT) tables, the set of summary statistics is: N / Mean / SD / Min / Median
/ Max.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.
7.2
CONCOMITANT DISEASES AND MEDICATION
Only descriptive statistics are planned for this section of the report.
A summary of concomitant diseases will be provided by treatment group, System Organ
Class (SOC) and Preferred Term (PT).
7.3
TREATMENT COMPLIANCE
Only descriptive statistics are planned for this section of the report.
Overall compliance will be calculated as mentioned in CTP section 4.3
7.4
PRIMARY ENDPOINT(S)
The primary analysis is at 12 weeks and will be performed on the full analysis set (FAS).
Figures and tables will be displayed for the MMRM analysis results over time.
Assignment to stratum will be base on IRT and eCRF data.
7.4.1
Primary efficacy analysis
The primary analysis and hypothesis testing are described in section 7.3.1 of the CTP.
 
 


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7.5
SECONDARY ENDPOINTS
Figures and tables will be displayed for the MMRM and ANCOVA analyses results over 
time.
7.5.1
Key secondary endpoint
This section is not applicable as no key secondary endpoint has been specified in the 
protocol.
7.5.2
Secondary endpoints
The same primary analysis model will be performed for the secondary endpoint CDR-SB.
The secondary endpoints ADAS-Cog11 and ADCS-ADL will use the following model:
ANCOVA:
Analysis of covariance will be used for the change from baseline secondary endpoint score 
after 12 weeks of treatment; terms include baseline value for the secondary endpoint measure, 
treatment and stratification factor current AChE-I use.
 
 


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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. Cumulative exposure will be displayed 
by >=weeks displayed in the CTP flowchart.
7.8
SAFETY ANALYSIS
All safety analyses will be performed on the treated set. 
Analysis will be performed as defined in Section 7.3.3 of the CTP.
7.8.1
Adverse events
7.8.1.1
Assignment of AEs to treatment
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 multiple AE occurrence data on the CRF will be collapsed into an 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, 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)
For further details on summarization of AE data, please refer to (2, 3)
The analysis of adverse events will be based on the concept of treatment emergent adverse 
events. That means that all adverse events occurring between first drug intake till last drug 
intake + residual effect period will be assigned to the randomized treatment. All adverse 
events occurring before first drug intake will be assigned to ‘screening’ and all adverse events 
occurring after the residual effect period will be assigned to ‘post-treatment’ (for listings 
only). For details on the treatment definition, see section 6.1.
7.8.1.2
Analysis of other significant AEs
According to ICH E3 (11), 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


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(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. 
7.8.1.3
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 (mention MedDRA levels to be displayed in the 
tables). Separate tables will be provided for patients with other significant adverse events 
according to ICH E3 (4), for patients with significant non-serious adverse events (only if 
these are defined for the project) and for patients with serious adverse events, for patients 
with AEs leading to discontinuation, and for patients with drug-related AEs.
The system organ classes will be sorted by default alphabetically, preferred terms will be 
sorted by frequency (within system organ class).
7.8.1.4
AE summaries for disclosure
The following AE data is needed for disclosure on clinicaltrials.gov and EudraCT. This data 
will be included in section 16.1.9.2:

Number of patients with non-serious AEs > of 5 % 

Total number of deaths (all causes – entire study period) 

Total number of deaths resulting from drug-related adverse events

Total number of serious adverse events 

Total number of serious adverse events related to treatment

Total number of fatal adverse events 

Total number of fatal adverse events related to treatment 
7.8.2
Laboratory data
The analyses of laboratory data will be descriptive in nature and will be based on BI 
standards (5).
Baseline for safety laboratory parameters will be the last available measurement before the 
start of randomized study drug.
Laboratory measurements taken up to 7 days after the last administration of randomised 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.


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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 and analyzed as planned in section 7.8.1.
7.8.5
Others
7.8.5.1
C-SSRS
The individual items and categories of suicidal ideation and behaviour from the C-SSRS will 
be summarized through descriptive statistics according to section 9.2 and [9]. 


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8
REFERENCES
1
001 MCS 36-472: "Standards and processes for analyses performed within 
Clinical Pharmacokinetics/Pharmacodynamics", current version; IDEA for CON.
2
001-MCG-156_RD-01: "Handling of missing and incomplete AE dates", current 
version; IDEA for CON.
3
001-MCG-156: "Handling and summarization of adverse event data for clinical 
trial reports and integrated summaries", current version; IDEA for CON.
4
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
5
001-MCG-157: "Handling, Display and Analysis of Laboratory Data", current 
version; IDEA for CON.
6
Harrison J, Minassian SL, Jenkins L, Black RS, Koller M, Grundman M, . A 
neuropsychological test battery for use in Alzheimer disease clinical trials. Arch 
Neurol 2007;64(9):1323-1329. 
7
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.
8
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.
9
001-MCG-117: "Implementation at BI of the FDA guidance on prospective
assessment of suicidal ideation and behavior", current version; IDEA for CON


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9
ADDITIONAL SECTIONS
9.1
CALCULATION OF NTB TOTAL SCORE
Below is a description for the NTB along with detail on deriving the scores for the total 
scores and several subscales.  The derivations are based on [6] and the supplementary 
information from [7]. 
Table 9.1: 1
NTB description and scoring
The NTB is a cognitive assessment made up of the following 9 component tests:
1. Wechsler Memory Scale Visual Paired Associates–Immediate (WMVis-I), range 0 to 18;
2. Wechsler Memory Scale Verbal Paired Associates–Immediate (WMVer-I), range 0 to 24;
3. Rey Auditory Verbal Learning Test–Immediate (RAVL-I), range 0 to 105;
4. Wechsler Memory Scale–Digit Span (WMDS), range 0 to 24;
5. Controlled Word Association Test (COWAT);
6. Category Fluency Test (CFT);
7. Wechsler Memory Scale Visual Paired Associates–Delayed (WMVis-D), range 0 to 6;
8. Wechsler Memory Scale Verbal Paired Associates–Delayed (WMVer-D), range 0 to 8;
9. Rey Auditory Verbal Learning Test–Delayed (RAVL-D), range 0 to 30.
The first 3 tests assess immediate memory (WMVis-I, WMVer-I, RAVL-I), the second 3 assess executive function (WMDS, COWAT, CFT), 
and the last 3 assess delayed memory (WMVis-D,
WMVer-D, RAVL-D). Higher scores indicate better cognition on all tests.
First, a total score for each component test except the RAVL-D is calculated by summing all the scores. For the RAVL-D, the total score is 
calculated as:
total part 7 + total part 8 correct + (15 - total part 8 incorrect).
Then, a z-score for each component test is calculated as follows. For each subject j, at assessment time point t (with t = 0 denoting baseline), 
let yijt  denote subject j’s score at time t for the ith component test (i = 1, …, 9). Then the corresponding z-score, denoted zijt, is defined as:
zijt = (yijt –
i0 ) / si0  


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Where y i0 and s i0 denote the average and the standard deviation of the baseline scores on the ith component test across all study subjects in the 
FAS.
Finally, the NTB total score zjt for the jth subject at time t is calculated by averaging the 9
component test z-scores:
The NTB total z-score will be calculated only if scores for at least 6 of the 9 component tests are not missing [6].
In addition, the following subscales are defined:

NTB Immediate Memory z-score - average of the 3 immediate memory component test zscores;

NTB Delayed Memory z-score - average of the 3 delayed memory component test z-scores;

NTB All Memory z-score - average of all 6 memory component test z-scores;

NTB Executive Function z-score - average of the 3 executive function component test zscores.

The Immediate Memory, Delayed Memory, and Executive Function z-scores will be calculated only if at least 2 of the 3 components tests are 
not missing. The All Memory z-score will be calculated only if at least 4 of the 6 components tests are not missing.
The NTB total z-score (as well as NTB Immediate Memory, NTB Delayed Memory, NTB All Memory, and NTB Executive Function z-
scores) will be analyzed using the same MMRM as described for the primary analyses.  These analyses will be conducted for the FAS.


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9.2
C-SSRS FDA CATEGORIES
Eleven FDA categories and equivalent C-SSRS categories as the standard
for classifying suicidal ideation and behavior
Table 9.2.1
CSSRS and FDA categories
FDA Categories
Equivalent C-SSRS categories
Suicidal ideation:
1.  Passive
2.  Active: Nonspecific (no method, 
intent, or plan)
3.  Active: Method, but no intent or 
plan
4.  Active: Method and intent, but no 
plan
5.  Active: Method, intent, and plan
Suicidal behavior:
6.  Preparatory actions toward imminent 
suicidal behaviors
7.  Aborted attempt
8.  Interrupted attempt
9.  Suicide attempt
10. Completed suicide
11. Self-injurious behavior, no suicidal 
intent
Suicidal ideation:
1.  Wish to be dead
2.  Non-specific active suicidal 
thoughts
3.  Active suicidal ideation with any 
methods (not plan) without
intent to act
4.  Active suicidal ideation with some 
intent to act, without specific plan
5.  Active suicidal ideation with 
specific plan and intent
Suicidal behavior:
6.  Preparatory acts or behaviour
7.  Aborted attempt
8.  Interrupted attempt
9.  Non-fatal suicide attempt
10. Completed suicide
11. Self-injurious behavior without 
suicidal intent


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9.3
SAS CODE
The below table summarises the SAS code for the main analyses
Table 9.3.1
SAS Code for main analyses
Analysis
Code
Comments
Dose response
Test the following model:
PROC GLM DATA=one;
MODEL chgept = trt trt*trt;
RUN;
Treat BID dose as an in between dose = (QD + 2*QD)/2
Dose is treated as a continuous 
variable.  
denotes the mean 
response of dose level i.
MMRM
PROC MIXED DATA=dat cl method=reml ORDER=formatted;
CLASS trt visit patient  <ACHeI>;
MODEL chgept = trt baseline visit trt*visit baseline*visit 
<ACHeI>
/ ddfm=KR solution;
REPEATED visit / type=un subject=patient r rcorr ;
LSMEANS trt*visit / pdiff=all cl;
RUN ;
current AChEI use for 
1289.7
ANCOVA
PROC MIXED data=one METHOD=reml ORDER=formatted;
CLASS trt ;
MODEL chgept = baseline trt <ACHeI>;;
LSMEANS trt / CL DIFF OM ;
RUN;
current AChEI use for 
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10 HISTORY TABLE
Table 10: 1
History table
Version
Date
(DD-Mmm-YY)
Author
Sections 
changed
Brief description of change
Final
13-Jun-17
None
This is the final TSAP without any 
modification