Clinical trial NCT02240693
Conditions: Alzheimer Disease
Sponsor: Boehringer Ingelheim
Start date: 2015-01-15; Completion date: 2017-10-09
Enrollment: 128 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
The study is designed to compare the effects of 4 different doses of orally administered BI 409306 to placebo in patients with Alzheimers Disease

Detailed description:

Arms: arm 1: None arm 2: None arm 3: None arm 4: None arm 5: None
Interventions: intervention 1: BI 409306 intervention 2: Placebo intervention 3: BI 409306 intervention 4: Placebo intervention 5: Placebo intervention 6: BI 409306 intervention 7: BI 409306 intervention 8: Placebo intervention 9: Placebo
Intervention descriptions: intervention 1: None intervention 2: None intervention 3: None intervention 4: None intervention 5: None intervention 6: None intervention 7: None intervention 8: None intervention 9: None

Protocol documents:
Prot_000.pdf: 
Clinical Trial Protocol
Doc. No.: c01691934-10
EudraCT No.:
BI Trial No.:
2013-005031-24
1289.5
BI Investigational
Product:
BI 409306
Title:
A multi-centre, double-blind, parallel-group, randomized controlled 
study to investigate the efficacy, safety and tolerability of orally 
administered BI 409306 during a 12-week treatment period compared to 
placebo in patients with 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: 17 February 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:
17 Feb 2017
27 June 2014
1289.5
Title of trial:
A multi-centre, double-blind, parallel-group, randomized controlled study to 
investigate the efficacy, safety and tolerability of orally administered BI 409306 
during a 12-week treatment period compared to placebo in patients with Alzheimer’s
Disease.
Co-ordinating 
Investigator:
Phone: 
Fax: 
Trial site(s):
60
Clinical phase:
II
Objective(s):
To assess the efficacy, safety and tolerability of different doses of BI 409306 
compared to  placebo in treatment of prodromal AD
Methodology:
Placebo-controlled, double-blind, randomized parallel-design with 5 treatments over 
12 weeks of treatment duration
No. of patients: 
total entered:
288
each treatment:
96 for placebo group and 48 per treatment group
Diagnosis :
Patients with diagnosis of prodromal Alzheimer’s Disease according to criteria 
recommended by the International Working Group (IWG, Dubois et al., 2014)
Main criteria
for inclusion:
The study population will include male and female patients with AD who are at least 
55 years old and who have not received prescribed drugs for treatment of AD 
including acetyl cholinesterase inhibitors (donepezil, galantamine, rivastigmine, 
tacrine, phenserine) and memantine within three months prior to screening. A Mini-
Mental-State-Examination (MMSE) score of ≥24 and a global CDR score 0 or 0.5
combined with episodic memory dysfunction (demonstrated in the Free and Cued 
Selective Reminding Test (FCSRT) or the Wechsler Memory Visual Paired 
Associates test) and evidence of AD biomarker pathology based on measurements in 
CSF or on amyloid deposition in PET scan are required for inclusion.
Test product(s):
BI 409306
dose:
10mg QD, 25mg QD, 50mg QD, 25mg BID


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Doc. No.: c01691934-10
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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:
17 Feb 2017
27 June 2014
1289.5
mode of admin.:
Tablet, Oral
Comparator products:
Placebo to match BI 409306
dose:
NA
mode of admin.:
Tablet, Oral
Duration of treatment: 12 weeks
Criteria for efficacy:
Primary endpoint: 
-
Change in cognition as measured by change from baseline in 
Neuropsychological Test Battery (NTB) total score after 12-week treatment.
Secondary endpoints include: 
-
Change from baseline in ADCS-MCI-ADL total score after 12-week 
treatment 
-
Change from baseline in CDR-SB total score after 12-week treatment
-
Change from baseline in ADAS-cog11 (Alzheimer's Disease Assessment 
Scale-cognitive subscale) total score after 12-week treatment
Criteria for safety:
Adverse events, vital signs, 12-lead electrocardiograms (ECG) and routine 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 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
314
Baseline
4a12
4b12
4c12
5
6
EOT/ED11
FU
Studyweeks
-7
-2
1
2
3
4
8
12
16
Study-Day (or duration during 
screening/ run-in)
Dura-
tion 1-35
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
 
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
A-ß and tau-protein assessment in 
CSF or amyloid deposition in 
PET13
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
314
Baseline
4a12
4b12
4c12
5
6
EOT/ED11
FU
Studyweeks
-7
-2
1
2
3
4
8
12
16
Study-Day (or duration during 
screening/ run-in)
Dura-
tion 1-35
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
FCSRT
X
Wechsler Memory Paired
Associates15
X
CDR
X
CDR-SB
X14
X
X
NTB
X14
X
X
MCI-ADSC-ADL
X14
X
ADAS-cog11
X
X14
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 ( section 3.3.3) for further details.
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 and at 70-110 minutes post dose. Additional supine pulse rate 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 5.2.5.2 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 Lumbar puncture or PET scans should only be performed after general eligibility is most probably given based on medical status and 
results of neuropsychological screening assessments. Results from CSF sampling or PET scans must be available before start of visit 2
(run-in period). CSF samples collected in the past 4 months prior to informed consent can be considered for use in the study and for 
further details please refer to section 3.3.2, section 5.6.1 and appendix 10.2. Results of a PET scan performed in the past according to the 
recommendations in section 5.3.2.1can be used.
14 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.
15 Back-up test for patients that do not reach the required scores in FSCRT


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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...............................................................................................12
2.
RATIONALE, OBJECTIVES, AND BENEFIT - RISK 
ASSESSMENT ......................................................................................... 16
2.1
RATIONALE FOR PERFORMING THE TRIAL........................................16
2.2
TRIAL OBJECTIVES.......................................................................................16
2.3
BENEFIT - RISK ASSESSMENT ...................................................................17
3.
DESCRIPTION OF DESIGN AND TRIAL POPULATION.............. 18
3.1
OVERALL TRIAL DESIGN AND PLAN ......................................................18
3.1.1
Administrative structure of the trial...................................................19
3.2
DISCUSSION OF TRIAL DESIGN, INCLUDING THE CHOICE OF 
CONTROL GROUP(S).....................................................................................19
3.3
SELECTION OF TRIAL POPULATION ......................................................20
3.3.1
Main diagnosis for study entry............................................................21
3.3.2
Inclusion criteria...................................................................................21
3.3.3
Exclusion criteria ..................................................................................23
3.3.4
Removal of patients from therapy or assessments.............................26
3.3.4.1
Removal of individual patients................................................26
3.3.4.2
Discontinuation of the trial by the sponsor..............................27
4.
TREATMENTS........................................................................................ 28
4.1
TREATMENTS TO BE ADMINISTERED....................................................28
4.1.1
Identity of BI investigational product and comparator 
product(s)...............................................................................................29
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 un-blinding ...........................................31
4.1.5.1
Blinding....................................................................................31
4.1.5.2
Procedures for emergency unblinding .....................................32
4.1.6
Packaging, labelling, and re-supply ....................................................33
4.1.7
Storage conditions.................................................................................33


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4.1.8
Drug accountability ..............................................................................33
4.2
CONCOMITANT THERAPY, RESTRICTIONS, AND RESCUE 
TREATMENT....................................................................................................34
4.2.1
Rescue medication, emergency procedures, and additional 
treatment(s) ...........................................................................................34
4.2.2
Restrictions............................................................................................34
4.2.2.1
Restrictions regarding concomitant treatment .........................34
4.2.2.2
Restrictions on diet and life style.............................................35
4.3
TREATMENT COMPLIANCE.......................................................................35
5.
VARIABLES AND THEIR ASSESSMENT ......................................... 36
5.1
EFFICACY - CLINICAL PHARMACODYNAMICS...................................36
5.1.1
Endpoint(s) of efficacy..........................................................................36
5.1.2
Assessment of efficacy...........................................................................36
5.2
SAFETY..............................................................................................................38
5.2.1
Endpoint(s) of safety.............................................................................38
5.2.2
Assessment of adverse events...............................................................38
5.2.2.1
Definitions of adverse events...................................................38
5.2.2.2
Adverse event and serious adverse event reporting.................40
5.2.3
Assessment of safety laboratory parameters......................................41
5.2.4
Electrocardiogram................................................................................43
5.2.5
Assessment of other safety parameters...............................................43
5.2.5.1
Physical examination (PE) and Neurological Examination.....43
5.2.5.2
Vital signs (orthostatic blood pressure & pulse rate)...............43
5.2.5.3
Suicidal risk assessed by the C-SSRS......................................44
5.3
OTHER...............................................................................................................45
5.3.2
Imaging Assessment..............................................................................46
5.3.2.1 PET scan examination alternatively to CSF (where applicable) .
................................................................................................46
5.3.2.2
MRI / CCT...............................................................................46
5.4
APPROPRIATENESS OF MEASUREMENTS.............................................46
 
5.6
BIOMARKER(S) ...............................................................................................48
5.6.1
Methods of sample collection...............................................................48
5.6.2
Analytical determinations ....................................................................49


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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........................................................56
7.
STATISTICAL METHODS AND DETERMINATION OF
SAMPLE SIZE......................................................................................... 57
7.1
STATISTICAL DESIGN - MODEL................................................................57
7.2
NULL AND ALTERNATIVE HYPOTHESES ..............................................57
7.3
PLANNED ANALYSES....................................................................................59
7.3.1
Primary analyses...................................................................................59
7.3.2
Secondary analyses ...............................................................................59
7.3.3
Safety analyses.......................................................................................60
7.3.4
Interim analyses ....................................................................................60
7.4
HANDLING OF MISSING DATA ..................................................................61
7.5
RANDOMIZATION..........................................................................................61
7.6
DETERMINATION OF SAMPLE SIZE ........................................................61
8.
INFORMED CONSENT, DATA PROTECTION, TRIAL
RECORDS ................................................................................................ 63
8.1
STUDY APPROVAL, PATIENT INFORMATION, AND INFORMED 
CONSENT ..........................................................................................................63
8.2
DATA QUALITY ASSURANCE .....................................................................64
8.3
RECORDS..........................................................................................................64
8.3.1
Source documents .................................................................................64
8.3.2
Direct access to source data and documents.......................................65
8.4
LISTEDNESS AND EXPEDITED REPORTING OF ADVERSE 
EVENTS..............................................................................................................65
8.4.1
Listedness...............................................................................................65
8.4.2
Expedited reporting to health authorities and IECs/IRBs................65
8.5
STATEMENT OF CONFIDENTIALITY.......................................................65
8.6
COMPLETION OF TRIAL..............................................................................66
9.
REFERENCES......................................................................................... 67
9.1
PUBLISHED REFERENCES...........................................................................67
9.2
UNPUBLISHED REFERENCES.....................................................................68
10. APPENDICES .......................................................................................... 70


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10.2
LUMBAR PUNCTURE PROCEDURE AND CEREBROSPINAL FLUID 
(CSF) COLLECTION AND PROCESSING...................................................72
10.2.1 Positioning .............................................................................................72
10.2.2 Preparation............................................................................................73
10.2.3 Analgesia................................................................................................73
10.2.4 Lumbar puncture and CSF collection.................................................73
10.2.5 End of Procedure ..................................................................................73
10.2.6 CSF processing and shipment..............................................................73
 
10.4
CLINICAL EVALUATION OF LIVER INJURY .........................................74
10.4.1 Introduction...........................................................................................74
10.4.2 Procedures .............................................................................................75
11. DESCRIPTION OF GLOBAL AMENDMENT(S).............................. 77


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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
ADCS-MCI-
ADL
ANCOVA
Alzheimer’s Dementia
Alzheimer's Disease Assessment Scale-cognitive subscale
Alzheimer's Disease Cooperative Study/Activities of Daily Living scale 
adapted for MCI patients
Analysis of Covariance
AUC
BPM/bpm
BCRP
Area under the Curve
Beats per minute
breast cancer resistance protein
CDR-SB
Clinical Dementia Rating Scale–Sum of Boxes
CI
Confidence Interval
CIAS
Cognitive Impairment Associated with Schizophrenia
CML
Local Clinical Monitor 
CRA
Clinical Research Associate
CRF
CT
CCT
CSF
C-SSRS
Case Report Form
Computer Tomography
Cranial Computer Tomography
 
Cerebro-spinal Fluid
Columbia Suicide Severity Rating Scale
CTCAE
Common Terminology Criteria for Adverse Events
CTMF
Clinical Trial Master File
CTP
Clinical Trial Protocol
CTR
CYP
DAT
Clinical Trial Report
Cytochrome P450
Dementia of Alzheimer Type
DMC
DNA
Data Monitoring Committee
Deoxyribonucleic Acid
DSM
Diagnostic and Statistical Manual
eCRF
Electronic Case Report Form
ED
Early Discontinuation
EDC
EEG
EM
Electronic Data Capture
Electroencephalogram
Extensive Metabolizer
EOT
End Of Treatment
EudraCT
European Clinical Trials Database
FAS
Full Analysis Set


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FCSRT
FTA
Free and Cued Selective Reminding Test
Fluorescent treponemal antibody absorbent test
GCP
gMean
Good Clinical Practice
Geometric Mean
IB
Investigator’s Brochure
IEC
Independent Ethics Committee
IRB
IRT
Institutional Review Board
Interactive Response Technology
ISF
Investigator Site File
i.v.
intravenous
IWG
International Working Group
LTP
Long Term Potentation
MedDRA
MMSE
Medical Dictionary for Drug Regulatory Activities
Mini-Mental-State-Examination
MST
MRI
NTB
NDMA
Medical Subteam
Magnetic Resonance Imaging
Neuropsychological Test Battery
N-methyl-D-aspartate
OPU
Operative Unit
P-gp
P-glycoprotein
p.o.
Per os (oral)
PCC
PDE9A
Protocol Challenge Committee
Phosphodiesterase 9A
PET
Positron Emission Tomography
PK
PM
Pharmacokinetic
Poor Metabolizer
PTM
RDC
Placebo to Match
Remote Data Capture
RPR
Rapid Plasma Reagin
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
Trial Data Management and Analysis Plan
 
TMM
 
Team Member Medicine
TMW
TSAP
Trial Medical Writer
Trial Statistical Analysis Plan


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1.
INTRODUCTION
1.1
MEDICAL BACKGROUND
Alzheimer’s disease (AD), a chronic progressive mental disorder, 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 36 million people (R14-
0163) 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 
signs and symptoms (R10-5105).
In the prodromal stage of the disease, clinical symptoms may include impairment of episodic 
memory and/or other cognitive domains, like executive function, orientation and judgment. 
Patients with these prodromal clinical symptoms showed an increased risk of developing 
Alzheimer’s dementia with 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). Subsequently and in accordance with the 
further progression of the disease there is an increasing utilization of resources and medical 
care finally leading to the need for 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.
On the cellular level, AD is characterized by a progressive loss of synapses and neurons. 
Affected transmitter systems mainly include cholinergic and glutaminergic neurons. 
Glutamate as the major excitatory neurotransmitter in the human brain is most prominently 
associated with functions of memory formation and learning. Glutaminergic transmission is 
mediated by various receptors with the post-synaptic N-methyl-d-aspartate (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. 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 (AD) and cognitive impairment associated
with schizophrenia (CIAS).


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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.
For full details on drug profile, please refer to the latest version of the IB [U11-1079].
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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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 (such 
as sensation of flashing lights, altered color perception, photophobia / increased sensitivity to 
light or blurred vision) that occurred shortly after dosing and mostly resolved within 1 h, i.e., 
in close connection to maximum BI 409306 plasma concentrations as the concentration-time 
profile sharply and steeply peaks within the first 1-2 hours and then rapidly declines 
afterwards. 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.


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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 DAT and is considered as reference drug. This treatment isn’t approved for 
prodromal stages of the disease. 
Prodromal AD is described as a slight but noticeable and measurable decline in cognitive 
abilities, including memory and thinking skills. These declines of functional capabilities in 
patients with prodromal AD are not severe enough to allow the diagnosis of dementia
according to the current guidelines. However, those with prodromal AD have an increased 
risk of eventually developing Alzheimer's dementia. Therefore, a symptomatic treatment that 
delays the progress of these first symptoms caused by the underlying pathology might 
provide a substantial benefit to such patients.
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. 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.
The 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) because there is no approved treatment 
for prodromal AD available so far.
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 male and female patients at least 55 years of age with prodromal AD who 
have not received prescribed drugs for treatment of AD including acetyl cholinesterase 
inhibitors (donepezil, galantamine, rivastigmine, tacrine, phenserine) and memantine) within 
three months prior to screening. The criteria for inclusion of these patients will consist of an
MMSE score of 24 or higher, an CDR-score of 0 or 0.5, and an FCSRT score of 20 or lower 
for the free recall and of 42 or lower for the total recall and, if the FCSRT fails; performing
the Wechsler Memory Visual Paired Associates test. Evidence of A-ß and tau protein 
pathology in the brain is based on measurements in CSF or, alternatively, on amyloid 
deposition in PET scan. The study endpoints are listed in section 5.1.1.


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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. 
In summary, the toxicological profile of BI 409306 is characterised by cardiac effects which 
seem to be consistent with those described for phosphodiesterase inhibitors in general. All 
adverse effects were generally restricted to high dose levels and were reversible. It is 
recommended to carefully monitor cardiac function in clinical trials. 
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 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 patient
safety.
This is an experimental drug at an early stage of testing and therefore an individual benefit 
cannot be guaranteed. Only patients who have not received prescribed drugs for treatment of 
AD including acetyl cholinesterase inhibitors (donepezil, galantamine, rivastigmine, tacrine, 
phenserine) and memantine) within three months prior to screening will be included in this 
trial of short duration. Therefore, the assignment to the placebo arm is not associated with a 
higher risk for the patient. Also all study procedures (e.g. AD assessment, safety and 
suicidality monitoring etc.) may be a benefit for the patient e.g. intensive medical care, a 
potentially better knowledge of the underlying disease which may lead to a better handling of 
this disease. As stated above prodromal AD has an increased risk for developing into AD. 
AD 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 AD 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-center, randomized, double-blind, double dummy placebo 
controlled, parallel group study in patients with prodromal AD.
In total, 288 patients with prodromal AD who meet the entry criteria are planned to be 
randomized in this trial. The randomized treatment will be double blind. Each patient will 
receive active treatment with BI 409306 (each patient will receive one active treatment and 
placebos to match the alternative active treatment) or placebos (each patient will receive 
placebos to match each of the active treatments).
After obtaining informed consent, patients will undergo a screening period of a maximum of
5 weeks. All patients who successfully complete the screening period and are eligible for the 
study, then enter a minimum of 2 weeks of single blinded placebo run-in before 
randomization. 
Patients who successfully complete the single-blinded phase and who fulfil both the inclusion 
and exclusion criteria will be randomized to the 12-week double blind treatment period at 
visit 3 and will be assigned to one of the 5 treatment groups namely: once daily (QD) 10 mg, 
25 mg, or 50 mg BI 409306, or 25 mg BI 409306 twice daily (BID), or placebo.
Figure 3.1:1 Study design
After the end of the double-blind treatment period, patients will be followed up for an 
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.
Screen
2-week placebo run-in
Rando
TG1: BI 409306 10 mg QD
TG2: BI 409306 25 mg QD
TG3: BI 409306 50 mg QD
TG4: BI 409306 25 mg BID
TG5: Placebo
N=48
N=48
N=48
N=48
N=96


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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 
Procedures (SOPs), directing the clinical trial team in the preparation, conduct and reporting 
of the trial, order the materials as needed for the trial, ensures 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 a
service provider to support the following tasks related to the neuropsychological assessments: 
rater prequalification, rater training (online and at investigator meeting), provision of rater 
materials and central review of assessments (see section 5.1.2 and section 8.2 for details).
A central laboratory and central ECG service vendor 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 who will be 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 as defined in the 
monitoring manual, 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 successfully complete screening and are eligible for the study 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.


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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 cross-
over design.
To assess a comparative benefit/risk ratio treatment BI 409306 patients will randomly be 
allocated to one of 4 active doses or placebo only in a 1:1:1:1:2 ratio (for rationale of 
allocation of treatments refer to section 7.1 and for justification of doses refer to section 
4.1.3).
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).
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 also be sufficient to assess the efficacy, safety and 
tolerability of BI 409306 in prodromal stages of this disease.
The data collected in this double-blind, randomized, placebo-controlled trial are standard in 
diagnosed Alzheimer’s disease and therefore regarded to also provide important information 
in terms of efficacy, safety and tolerability on the use of BI 409306 maintenance treatment in 
patients with prodromal AD.
3.3
SELECTION OF TRIAL POPULATION
About 1000 patients will be screened for the study in approximately 12 countries. About 60 
study centres will be participating to ensure approximately 288 patients are randomised to 
study treatment.
Recruitment will be competitive and participating sites are expected to randomize at least 288
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 
section 6.2 and section 7.3 for details). Patients who discontinue following randomization 
may not be re-enrolled at a later date. A record is kept of all patients failing to complete all 
trial visits and their reasons for discontinuation. 
This trial (1289.5) investigates patients with cognitive impairment caused by the Alzheimer’s 
disease. In parallel BI is investigating the effect of BI 409306 in patients with mild 
Alzheimer’s dementia in the study 1289.7. It is expected that both trials share a high 
percentage of trial sites. The Mini Mental Stage Examination (MMSE) evaluates the severity 
of cognitive impairment and this assessment is used in both trials as part of the eligibility 
assessments with the following requirements:
1. 1289.5 – MMSE score ≥ 24
2. 1289.7 – MMSE score ≥ 18 - 26


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Patients who do not reach the required scores of ≥24 in MMSE and CDR total score 0 or 0.5
are not eligible for this study and must be registered as screen failure in IRT. If the result of 
the MMSE and CDR fulfill the requirements of the parallel trial 1289.7 and the patient and 
his study partner agree to alternatively participate in 1289.7 after giving a new consent then 
the results of the MMSE and CDR can be transferred into the database of 1289.7 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 1289.7 is no later than 7 
days after the MMSE/CDR for 1289.5 was performed. The patient will then be registered as a 
new patient in the IRT of 1289.7. This does not apply to sites participating in only one of the 
1289.5/1289.7 studies.
Permission to randomize more than 15 patients per site must be obtained in writing from the 
TCM at Boehringer Ingelheim. This will only be allowed after a careful review of the 
enrolment status.
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.
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 diagnosis of prodromal AD in accordance with the recommendation of the 
International Working Group (IWG), Dubois et al. 2014) [R14-2556]):

Symptoms noticed by the patients or informant

Cognitive testing confirming prodromal symptoms

Biomarker evidence of AD pathology

No evidence of other forms of dementia

No other concomitant illness or medication which could confound or prohibit 
completion in the trial by the patient
3.3.2
Inclusion criteria
Patients will be included in this study if they meet all of the following criteria:
1. Male and female patients with an age ≥ 55 years. 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.]) per investigators
judgement.
2. Body weight ≥ 50 kgs.


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3. Patients with a confirmed diagnosis of prodromal AD on neuropsychological testing 
defined as:

Mini-Mental State Examination (MMSE) score: ≥ 24
and

a global CDR-score of 0 or 0.5 
and

Free and Cued Selective Recall Reminding Test (FCSRT) score:
o
free recall test: ≤ 20 (out of 48) and
o
total recall test: ≤ 42 (out of 48) 
Patients who do not reach the required score in FCSRT will additionally perform the 
Wechsler Memory Visual Paired Associates test. If the Wechsler Memory Visual Paired 
Associates test shows a cognitive deficit worse than 1 standard deviation to the mean 
(compared to the reference values of age and educational norms for inclusion), then the 
patients can be considered to be eligible for the study. [R14-4676]
4. Confirmation of abnormal markers of AD pathology either via a), or alternatively b)
mentioned below:*
a) Presence in cerebrospinal fluid of (samples taken within past 4 months may be 
eligible, refer to section 5.6.1 and appendix 10.2 for full details):

low Aβ1-42 concentrations (< 640 pg/mL) and increased total tau 
concentrations (>375 pg/ml), 
or / and

low Aβ1-42 concentrations (< 640 pg/mL) and increased phospho-tau 
concentrations (> 52 pg/mL in cerebrospinal fluid),
or
b) Abnormal amyloid deposition in a cerebral PET scan. Scans performed in the past 
according to the recommendations in section 5.3.2.1 are acceptable.
* Note – CSF or PET could be the procedure of choice as per local regulations or IRBs/ 
IECs or site practices (as applicable).
5. Patients who have not received prescribed drugs for treatment of AD (including acetyl 
cholinesterase inhibitors (donepezil, galantamine, rivastigmine, tacrine, phenserine) and 
Memantine) within three months prior to screening.
6. Patients must have at least 6 years of formal education and fluency in the test language as 
verbally confirmed by the patient and documented by the study investigator. 


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7. 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.
8. Patients must have a reliable study partner (per investigator judgement, for instance a 
family member, partner etc., guardian). This person should be in close contact with the 
patient and agree to accompany the patient on all scheduled visits. The person should also 
agree to be reachable by phone and should be able to contribute to the neuropsychological 
assessments of the patient, wherever necessary. This person should be able to 
communicate in the language in which the patient is being assessed and should also serve 
as a back-up contact for the study site. This person must sign a separate informed consent 
form which describes their contribution during the study.
3.3.3
Exclusion criteria
Patients must be excluded from this study if they meet any of the following criteria:
1.
Mild cognitive impairment with any etiology other than prodromal AD (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 (CCT). 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 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 haemorrhagia) 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. Medical history or diagnosis of any 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 New York Heart Association 
(NYHA) III or IV.
c.
Significant liver disease (for example cirrhosis, active hepatitis B and C, primary 
or metastatic liver neoplasm).


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d.
Significant gastrointestinal disorders as per investigator’s judgement (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 
hyperthyroidism.
f.
Unstable/Uncontrolled major depression.
g.
Significant pulmonary disease predisposing to hypoxia.
h.
Immunological disorders such as clinically significant allergies, Lupus 
erythematosus, or scleroderma.
i.
Unstable/uncontrolled haematological disease (regardless of etiology) 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 with a GFR < 30ml/min/1.73m2 in the screening central 
lab report.
6. Any other psychiatric disorders such as schizophrenia, or mental retardation.
7. Any suicidal actions in the past 2 years (per investigator judgement i.e. actual attempt, 
interrupted attempt, aborted attempt, or preparatory acts or behaviour).
8. Any suicidal ideation of type 4 or 5 in the Columbia Suicide Severity Rating Scale (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 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 however these should be captured in the eCRF.
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. Any planned surgeries requiring general anaesthesia, or hospitalisation for more than 
1 day during the study period.
13. 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 


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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).
14. 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.
15. Use of any investigational drug or procedure for other indications within 3 months or 6 
half-lives (whichever is longer) prior to randomization.
16. Intake of the following medications within 3 months prior to randomization and intended 
to be initiated during the duration of the trial:
a.
tricyclic antidepressants,
b. antidepressants that are monoamine oxidase inhibitors,
c.
neuroleptics with moderate or greater anticholinergic potency (e.g.
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.
17. 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 
visit 1.
18. Any other clinical condition that, in the opinion of the Investigator, would jeopardize 
patient safety whilst participating in this clinical trial.
19. Non-compliance with study drug intake during placebo run-in phase defined as 
compliance < 75 %.
20. Clinically significant uncompensated hearing loss in the judgment of the investigator. Use 
of hearing aids is allowed.
21. Known hypersensitivity to the drug product excipients (lactose monohydrate, 
microcrystalline cellulose, pregelatinized starch, hydroxypropylcellulose, croscarmellose 
sodium, magnesium stearate, hypromellose, propylene glycol, titanium dioxide, talc and 
iron oxide yellow).


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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), refer to section 4.2.2.

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.

At visit 3, if the patient experiences sinus tachycardia (defined as resting pulse 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. Pulse rate is generally to be measured in a 
supine position after 5 min rest. See also section 5.2.5.2, and section 6.2.2.

The patient exhibits serious suicidality, in the clinical judgement of the investigator or 
according to criteria below: 

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 have been violated, or if the patient fails to comply with the protocol (e.g. non-
attendance at study assessments).
Patients who drop out during screening or during placebo run-in phase prior to randomization 
(Visit 3) will be considered as screening failure. For patients that screen fail, data will be 
collected for signed IC, demographics, AE, concomitant medications and randomization and 
recorded in the eCRFs. No further follow-up is required. 
Patients who discontinue or withdraw from the study after randomization (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 withdraw or discontinue from the trial after randomization will not be replaced.


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If a female patient is suspected to be or becomes pregnant during treatment, the patient must 
inform the investigator immediately and stop taking all study drugs. For the reporting, follow 
up and documentation of pregnancy cases refer to section 5.2.2.2. 
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:
1. Failure to meet expected enrolment goals overall or at a particular trial site,
2. Emergence of any efficacy/safety information that could significantly affect 
continuation of the trial and/or invalidate the earlier positive benefit-risk-assessment,
3. 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 blinded 2-week placebo run-in period, patients who qualify 
according to in- and exclusion criteria will be randomized to one of the five following 
treatment groups of investigational drugs:
Table 4.1:1 Treatment groups
Group
Treatment Regimen
Treatment
tbl./d
1
10 mg BI 409306 QD
BI 10 mg
1-0-0
BI 25/50 mg PTM
1-0-1
2
25 mg BI 409306 QD
BI 25 mg
1-0-0
BI 10 mg PTM
1-0-0
BI 25/50 mg PTM
0-0-1
3
50 mg BI 409306 QD
BI 50 mg
1-0-0
BI 10 mg PTM
1-0-0
BI 25/50 mg PTM
0-0-1
4
25 mg BI 409306 BID 
BI 25 mg
1-0-1
BI 10 mg PTM
1-0-0
5
PTM BI 409306
BI 10 mg PTM
1-0-0
BI 25/50 mg PTM
1-0-1
(PTM = Placebo to Match)
Note: The 25mg and 50 mg tablets active drug and PTM are visibly identical.


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4.1.1
Identity of BI investigational product and comparator product(s)
Table 4.1.1: 1
BI 409306
Substance:
BI 409306
Pharmaceutical form:
Tablet
Source:
Boehringer Ingelheim Pharma GmbH & Co KG
Unit Strength:
10 mg, 25 mg, 50 mg
Daily Dose:
10 mg QD (1-0-0) in Gr.1, 
25 mg QD (1-0-0) in Gr.2, 
50 mg QD (1-0-0) in Gr.3, 
25 mg BID (1-0-1) in Gr.4
Route of administration:
Per os
Posology: 
QD or BID
Duration of use:
12 weeks
Table 4.1.1: 2
Placebo matching BI 409306, 10 mg tablet
Substance:
Placebo matching BI 409306, 10 mg tablet
Pharmaceutical form:
Tablet
Source:
Boehringer Ingelheim Pharma GmbH & Co KG
Unit Strength:
-
Daily Dose:
n.a
Route of administration:
Per os
Posology:
QD (1-0-0) in Gr.2, 3, 4, 5 and run-in
Duration of use:
12 weeks
Table 4.1.1: 3
Placebo matching BI 409306, 25 mg or 50 mg tablet
Substance:
Placebo matching BI 409306, 25 mg or 50 mg 
tablet
Pharmaceutical form:
Tablet
Source:
Boehringer Ingelheim Pharma GmbH & Co KG
Unit Strength:
-
Daily Dose:
n.a
Route of administration:
Per os
Posology:
QD (0-0-1) in Gr. 2 and 3; BID (1-0-1) in Gr.1, 
5 and run-in
Duration of use:
12 weeks


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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 randomization 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 randomize 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 treatments 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-brain 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 approx. 0.5 to 1 hour later than in plasma and 
decline mono-exponentially 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 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 [U11-
1079].
Patients will be randomized to one of five treatment groups as follows during the treatment 
period:

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)


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4.1.4
Drug assignment and administration of doses for each patient
All patients who fulfil both inclusion and exclusion criteria until visit 2 will be assigned to a 
single blinded placebo run-in kit at the beginning of the run-in period (Visit 2).
The 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. 
IRT will allocate medication kit numbers at Visit 2, 3, 5 and 6. 
For blinding reasons all treatments will consist of two tablets of active drug or placebo for the 
morning dose and one tablet of active drug or placebo for the evening dose depending on the 
treatment arm. This will not be changed during the entire study.
During the run-in period patients will take 3 placebo tablets daily (2 tablets in the morning 
and 1 tablet in the evening) to mimic the dosing schedule during the treatment period.
Following the run-in period patients will be randomized (Visit 3) to one of the 5 treatment 
arms as outlined in figure 3.1:1
The first dose of the study medication will be taken at visit 2 under supervision of the 
investigator or site staff. At all applicable clinic visits the investigational drug will be taken 
during the visit under supervision of the investigator or relevant site staff. The actual visit 
date and time of study drug administration at the trial visit will be recorded in the eCRF.
Patients should be instructed to take the tablets orally with water at approximately the same 
time every day in the morning and in the evening 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 visit days. 
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.
4.1.5
Blinding and procedures for un-blinding
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.


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This trial incorporates a double-blind, double-dummy trial design, meaning that treatments 
are indistinguishable according to the scheme as shown in Table 4.1:1. Placebo tablets are 
identical in the size and appearance to the corresponding active tablet and are combined with 
active drug tablets as needed in each treatment group to maintain the blinding.
After randomization at visit 3, patients, investigators and everyone involved in analysing or 
with a potential interest in this double-blind trial will remain blinded with regard to the 
randomized 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 randomization 
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 randomization 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 pre-
specified group of users who are not involved into the 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. For details of the rules of breaking the codes in case of an 
emergency refer to section 4.1.5.2. The random code will be transferred to the trial data 
manager only after the Blinded Report Planning Meeting (BRPM) and after locking of the 
trial database.
The randomization codes will be provided to the sponsor’s bioanalytic department prior to 
last patient out to allow them to perform appropriate pharmacokinetic analytical 
determination. Bioanalytics’ will not disclose the randomization 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
The IRT will be available for the unblinding of patients by the investigator in an emergency 
situation.
Detailed information on the IRT un-blinding procedures is described in the IRT manual that 
will be provided to the sites. The code break may only be performed in emergency situations 
when the identity of the trial medication must be known to the investigator in order to provide 
appropriate medical treatment or if required to assure the safety of trial participants.
The reason for un-blinding must be documented on the appropriate e-CRF page and in the 
patient source data.
If possible, the monitor must be contacted and informed prior to the site un-blinding a
patient's treatment. 


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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 Investigator Site File 
(ISF).
4.1.7
Storage conditions
Study medication (BI 409306 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, 

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)
No rescue medication, emergency procedure or additional treatments are foreseen for this 
study.
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 is allowed. If they 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/noradrenalin 
Re-Uptake Inhibitors (SSRIs/SNRIs) like fluoxetin, es-citalopram, citalopram, 
sertalin, venlafaxin, duloxetin are allowed, but paroxetine is excluded. Other 
antidepressant drugs without anticholinergic and without dopaminergic 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 theophyllin, 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. Intake of prescribed drugs for treatment of AD including acetyl cholinesterase 
inhibitors (donepezil, galantamine, rivastigmine, tacrine, phenserine) and 
memantine)
f. 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”). 
The drugs listed below may be used as needed:


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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 after visit 1 is prohibited.
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.
Drastic weight-loss dieting during the study is not permitted.
4.3
TREATMENT COMPLIANCE
Patients will be asked to bring all trial medication containers (with or without any remaining 
tablets) with them to each trial visit. The tablets 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%.
Compliance during the randomized 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 - CLINICAL PHARMACODYNAMICS
5.1.1
Endpoint(s) 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-MCI-ADL (Alzheimer's Disease Cooperative 
Study/Activities of Daily Living for mild cognitive impairment) 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.
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-MCI-ADL
This is a functional scale based on the information provided by an informant/caregiver that 
describes the performance of patients in several activities of daily living for MCI patients.  
This is a 24 item scale with 6 items related to complex abilities.  The sum score could range 
from 0 to 69.  Higher scores indicate better function [R13-2647].
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


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
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 
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


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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. 
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 the underlying disease or other pre-existing conditions (except worsening of 
suicidal ideation and behavior)
Worsening of the underlying disease or of other pre-existing conditions will be recorded as an 
(S)AE in the (e)CRF.
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 (e)CRF, 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 alterations of liver parameters as defined below: 
o
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 Appendix 10.4
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 section 5.2.2.2.


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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 REP/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. 
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 and hence the time period for which 
adverse events will still be considered on-treatment, is 7 days following last intake of trial 
medication. 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 


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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 or next business day 
whichever is shorter) 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 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
The laboratory tests listed in Table 5.2.3:1 will be performed at the central laboratory service 
provider. Patients don’t have to be fasted for the blood sampling for the safety laboratory. 
Instructions on collection, handling/ processing, and shipping of the samples will be provided 
in the investigator site file by the central laboratory. For time points of laboratory sampling 
refer to the Flow Chart.
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

Human urine chorionic gonadotropin for women of child bearing potential only


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Table 5.2.3: 1
Safety laboratory parameters
Category
Test name
Haematology  
Hematocrit (Hct)
Hemoglobin (Hb) (Reticulocyte Count (reflex test  if Hb outside normal ranges)
Red Blood Cells (RBC) Erythrocytes
Reticulocyte Count
White Blood Cells / Leukocytes
Platelet Count/ Thrombocytes
Diff. Automatic 
(manual if diff. automatic is abnormal)
- Neutrophils
- Eosinophils
- Basophils
- Monocytes
- Lymphocytes
Chemistry
AST(GOT)
Bicarbonate
ALT(GPT)
Creatinine
Alkaline Phosphatase (AP)
- -GT (gamma-glutamyl transferase) 
reflex test triggered by elevated alkaline 
phosphatase on two sequential measures
Phosphate
Albumin
Urea (BUN)
Creatine Kinase (CK)
Bilirubin Total (if increased:)
CK-MB, troponin (reflex tests if CK is 
elevated)
Bilirubin Direct
Lactic Dehydrogenase (LDH)
Bilirubin Indirect
Calcium
Lipase
Sodium
Magnesium
Potassium
Potassium
Chloride
Protein, Total
Vitamin B12
TSH
Folate
Serology
HIV testing and Syphilis testing (Rapid plasma reagin (RPR), if RPR positive, then 
performing Fluorescent Treponemal Antibody test (FTA)
Urine Pregnancy test  
Human urine chorionic gonadotropin
Urinalysis 
Urine Nitrite
Urine Ketone
Urine Protein
Urine WBC/ Leukocytes
Urine Glucose
Urine pH
Urine-Sediment 
(microscopic 
examination), (only if 
urine analysis 
abnormal)
Urine Sediment Bacteria
Urine Sediment RBC/ Erythrocytes
Urine Cast in Sediment
Urine Sediment WBC/ Leucocytes
Urine Squamous Epith Cells
Drug screening 
(urine)
Cannabis
Cocaine
Benzodiazepine
Amphetamines
Barbiturates
Methadone
Opiates
Phencyclidine (PCP)


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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 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. 
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. Any ECG abnormalities will be carefully monitored and if necessary the 
subject will be removed from the trial and medically treated.
All ECGs will be transmitted electronically to the central ECG vendor in order to enable a 
centralized re-evaluation of all 12-lead ECGs by an independent ECG laboratory (only if 
needed). Abnormalities detected during this centralized ECG evaluation will not necessarily 
qualify as AE.
5.2.5
Assessment of other safety parameters
5.2.5.1
Physical examination (PE) and Neurological Examination
A standard 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 and extremities will be 
performed. The physical examination will include examination of known and suspected sites 
of disease. 
A standard neurological examination will be carried out as described in the Flow Chart.
A neurological examination including, but not limited to, mental status, cranial nerves, 
reflexes, motor strength and coordination will be performed. The neurological examination 
will include examination of known and suspected sites of disease. 
Clinically relevant abnormal findings noticed after baseline assessment will be reported as 
(S)AEs.
5.2.5.2
Vital signs (orthostatic blood pressure & pulse rate)
Vital signs (orthostatic measurements of systolic/diastolic blood pressure and pulse rate) 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. 


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2.
Measure blood pressure and pulse rate. 
3.
Have the patient stand and immediately measure blood pressure and pulse rate. 
4.
Repeat blood pressure and pulse rate measurements after 3 minutes of standing.
Only at visit 3 the following additional 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 mins post-dose. Pulse 
rate should be taken before the respective blood for PK sampling is drawn. 

Orthostatic measurements of systolic/diastolic blood pressure and pulse rate are to 
be done pre-dose 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.
If there is a finding which meets any withdrawal criterion (See section 3.3.4.1), the subject 
should be removed from study participation. 
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 behavior 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 behavior and five questions related to suicidal ideation, 
evaluated as either present or not. Patients presenting with any suicidal behavior 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 screening 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 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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5.3
OTHER


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5.3.2
Imaging Assessment
5.3.2.1 PET scan examination alternatively to CSF (where applicable)
Pattern for β-amyloid pathology on functional neuroimaging with PET (evaluation of β -
amyloid positivity for tracers should be performed according to the prescribing information 
for display and interpretation provided in the label of the used tracer). Local PET scan 
specialists who assess the PET scans must have been trained by the manufacturer of the used 
A-ß tracer. A tracer specific training certificate should have been available for review, which 
confirms this individual training with name of the rater and when the training was performed.
5.3.2.2
MRI / CCT
Performance and assessment of brain MRI or CT images of the brain (not older than 12 
months prior to randomization) to rule out other reasons for dementia should be performed by
qualified readers according to radiological standards.
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.


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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 used 
in previous phase II and phase III studies in this indication.
 
 
 
 
 
 
 
 


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5.6
BIOMARKER(S)
The following biomarker samples will be collected:
1. CSF samples collected to determine a positive amyloid signature at baseline via 
evaluation of CSF Aß1-42 and Tau levels (see also section 3.3.2) which is mandatory 
for all sites and patients that decide for confirmation of diagnosis using CSF. CSF 
sample aliquots that were not used for the assessment of Aβ1-42, total-Tau and 
phospho-Tau181 will be destroyed after the final study report is archived at the latest. 
 
 
.
2.
 
 
 
 
 
The CSF collection processes is also described here and for details on the timing of 
collection, please refer to the Flow Chart.
5.6.1
Methods of sample collection
Patients for whom the CSF amyloid signature will be acquired as part of the screening 
procedure for inclusion will undergo a single lumbar puncture (visit 1, see Flow Chart; 
approximately 8 mL per individual) and collected CSF will be analysed for Aβ1-42, total-Tau 
and phospho-Tau181.
Detailed instructions for obtaining, handling and shipping of CSF samples are provided in 
Appendix 10.2.)
 


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5.6.2
Analytical determinations
CSF samples will be analysed for Aβ1-42, total-Tau and phospho-Tau181 using validated 
immunoassays. 
 
 
 
 
 
 


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6.
INVESTIGATIONAL PLAN
6.1
VISIT SCHEDULE
All trial visits should be initiated preferentially in the morning starting before 9:00 AM. 
Patients should be instructed to avoid intake of the morning dose of the study medication at 
home at scheduled visit days as they will be dosed whilst at the study site.
All patient visits should be scheduled according to the Flow Chart.
If any visit has to be rescheduled, subsequent visits should follow the original visit 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 to be adequate by the Investigator and BI CML.
Blood samples for the optional pharmacogenomics evaluation should be collected only after 
obtaining separate informed consent. 
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, MCI-
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.
6.2.1
Screening and run-in period(s)
Visit 1 (screening)

No trial procedures should be done unless the patient and study partner have consented to 
taking part in the trial.

Once the patient has consented, the patient is considered to be enrolled in the trial and has 
started screening. The patient should be recorded on the enrolment log and be registered 
in the IRT as a screened patient. 

Informed consent for optional pharmacogenomics sampling, if applicable should be 
obtained.

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

The following screening procedures must however be performed in the order of the Flow
Chart: MMSE, FCSRT, (Wechsler Memory Visual Paired Associates test, if applicable),
CDR, ADAS-cog11, MRI/CCT and PET/ CSF sampling (whichever applicable) to ensure 
that undesirable, invasive screening procedures are deferred until necessary.

If the patient fails screening due to the results of the MMSE and/or the CDR then an 
alternative participation in study 1289.7 might be considered, where applicable.

Administration of C-SSRS (baseline/screening scale)

Collection of urine and blood for safety laboratory testing including testing for HIV, 
Syphilis and vitamin B12 and folate levels.

Collection of blood samples for optional soluble biomarker evaluation from patients who 
consent.

If patient does not meet inclusion/exclusion criteria at visit 1 then the patient must be 
recorded in IRT and CRFs as a screen failure. 

If the patient is eligible according to inclusion/exclusion criteria available at visit 1, the 
run-in visit (visit 2) should be scheduled. Patient should be reminded to come for visit 2
in the morning.

Patients are allowed to have a light breakfast/ meal before coming to the study site. 

Patients should be reminded not to take occasionally used sleeping aids (see section 
4.2.2.1) in the evening prior to visit 2.

Patient should be reminded to inform the study site in case of adverse events. 
Visit 2 (Run-in period) 

It is recommended to perform study procedures in the order as listed in the Flow Chart.


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
Results pending for assessments done at visit 1 for inclusion/ exclusion criteria should be 
evaluated and if the patient is deemed ineligible, the patient must be recorded in IRT and 
CRFs as a screen failure.

If patient does not meet inclusion/exclusion criteria available on visit 2 the patient must 
be recorded in IRT and CRFs as a screen failure. 

Informed consent for optional pharmacogenomics sampling, if applicable should be 
obtained

Administration of C-SSRS (since last visit scale).

The intake of trial medication and handling of medication blisters should be discussed 
with the patient and the study partner. The first dose of the trial medication should be 
taken by the patient under the supervision of the study. Patients should be advised to take 
the trial medication as per the drug label till the next scheduled visit. The importance of 
compliance to the study drug intake should be emphasized to the study partner as well.

Patients should be reminded to get all used and un-used medication including the 
medication packaging back at visit 3.

Patients should be reminded not to take occasionally used sleeping aids (see section 
4.2.2.1) in the evening prior to visit 3. 

Patients should be reminded to NOT take any study medication on the morning of visit 3.

Patients are allowed to have a light breakfast/ meal before coming to the study site. 

Patient should be reminded to inform the study site in case of adverse events. 
6.2.2
Treatment period(s)
Visit 3 (Randomization visit)
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.

It is recommended to perform study procedures in the order as listed in the Flow Chart.

Study medication provided at visit 2 and returned should be collected and compliance 
check performed.

Beginning with Visit 3 until end of treatment (EOT/ ED respectively) the 
neuropsychological assessments should always be performed approximately at the same 
time (in the morning) in the order as stated in the Flow Chart

Eligible patients should be randomised using IRT. If patient does not meet 
inclusion/exclusion criteria at visit 3 the patient must be recorded in IRT and CRFs as a 
screen failure. 

Informed consent for optional pharmacogenomics sampling, if applicable should be 
obtained

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 


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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

Administer the neuropsychological assessments in the following order :

CDR-SB

NTB

ADCS-MCI-ADL

ADAS-cog11

Administration of C-SSRS (since last visit scale).

Pre-dose vital signs (orthostatic measurements of systolic/diastolic blood pressure and 
pulse rate). Please see section 5.2.5.2.

 
 

Collection of urine and blood for safety laboratory testing.

 

New medication kits should be dispensed and the intake of trial medication and handling 
of medication blisters should be discussed with the patient and the study partner. 

The first dose of the study medication from the new kit should be taken under the 
supervision of the study staff.

 

Post Dose Vital Signs (orthostatic measurements of systolic/diastolic blood pressure and 
pulse rate) at 70-110 minutes should be performed. Please see section 5.2.5.2.

Patients should be advised to take the trial medication as per the drug label till the next 
scheduled visit. The importance of compliance to the study drug intake should be 
emphasized to the study partner as well. Patients should be reminded to return all used 
and un-used medication including the medication packaging back to the clinic at visit 5.

Patients should be reminded not to take occasionally used sleeping aids (see section 
4.2.2.1) in the evening prior to visit 5

Patient should be reminded to NOT take any study medication on the morning of visits 4
and 5.

Patients are allowed to have a light breakfast/ meal before coming to the study site. 

Patient should be reminded to inform the study site in case of adverse events.
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.


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
The attendance of the study partner is not necessarily required during the visits 4a-c.

Patients should be advised to take the trial medication as per the drug label till the next 
scheduled visit. The importance of compliance to the study drug intake should be 
emphasized

Administration of C-SSRS (since last visit scale).

Patients should be reminded to return all used and un-used medication including the 
medication packaging back to the clinic at visit 5.

Patient should be reminded to NOT take any study medication on the morning of visit 5.

Patients are allowed to have a light breakfast/ meal before coming to the study site.

Patients should be reminded not to take occasionally used sleeping aids (see section 
4.2.2.1) in the evening prior to visit 5. 

Patient should be reminded to inform the study site in case of adverse events.
Visit 5

It is recommended to perform study procedures in the order as listed in the Flow Chart. 

Study medication provided at visit 3 and returned should be collected and compliance 
check performed.

Neuropsychological assessments should always be performed approximately at the same 
time (in the morning) in the order as stated in the Flow Chart. 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). 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

Administer the neuropsychological assessments in the following order:

CDR-SB 

NTB 

Administration of C-SSRS (since last visit scale).

New medication kits should be dispensed and the intake of trial medication and handling 
of medication blisters should be discussed with the patient and the study partner. 

The first dose of the study medication from the new kit should be taken under the 
supervision of the study staff.

Patients should be advised to take the trial medication as per the drug label till visit 6. The 
importance of compliance to the study drug intake should be emphasized to the study 
partner as well. 

Patients should be reminded to get all used and un-used medication including the 
medication packaging back at visit 6.

Patient should be reminded to NOT take any study medication on the morning of visit 6.

Patients are allowed to have a light breakfast/ meal before coming to the study site.

Patients should be reminded not to take occasionally used sleeping aids (see section 
4.2.2.1) in the evening prior to visit 6.

Patient should be reminded to inform the study site in case of adverse events.


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Visits 6

It is recommended to perform study procedures in the order as listed in the Flow Chart.

Study medication provided at visit 5 and returned should be collected and compliance 
check performed.

Collection of urine and blood for safety laboratory testing 

C-SSRS (since last visit scale)

New medication kits should be dispensed and the intake of trial medication and handling 
of medication blisters should be discussed with the patient and the study partner. 

 

The first dose of the study medication from the new kit should be taken under the 
supervision of the study staff.


Patients should be advised to take the trial medication as per the drug label till visit EOT. 
The importance of compliance to the study drug intake should be emphasized to the study 
partner as well. 

Patients should be reminded to return all used and un-used medication including the 
medication packaging back to the clinic at visit EOT.

Patient should be reminded to NOT take any study medication on the morning of visit 
EOT.

Patients are allowed to have a light breakfast/ meal before coming to the study site.

Patients should be reminded not to take occasionally used sleeping aids (see section 
4.2.2.1) in the evening prior to visit EOT. 

Patient should be reminded to inform the study site in case of adverse events.
Visits 7 (End of Treatment/ Early Discontinuation visit)

It is recommended to perform study procedures in the order as listed in the Flow Chart.

Study medication provided at visit 6 and returned should be collected and compliance 
check performed. 

Neuropsychological assessments should always be performed approximately at the same 
time (in the morning) in the order as stated in the Flow Chart.

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

Administer the following neuropsychological assessments in the following order:

CDR-SB 

NTB 

ADCS-MCI-ADL

ADAS-cog11 


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
C-SSRS (since last visit scale)

Collection of urine and blood for safety laboratory testing.

 

Visit EOT is the end of treatment visit. Study medication will not be taken at Visit EOT.
6.2.3
End of trial and follow-up period
For all patients completing the study according to protocol, a follow-up contact (Visit FU) 
will be performed at the end of the follow-up phase of 28 days.


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7.
STATISTICAL METHODS AND DETERMINATION OF 
SAMPLE SIZE
7.1
STATISTICAL DESIGN - MODEL
This is a phase II multi-centre, double-blind, parallel-group, randomized, placebo-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 
prodromal Alzheimer’s Disease. The primary endpoint is Neuropsychological Test Battery 
(NTB) response, defined as change from baseline in total z-score after 12-week treatment.
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).
Another design aspect is the randomization allocation ratio of 1:1:1:1:2 of 10 mg, 25 mg, 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 randomization 
allocation ratio is modified from a traditional equal ratio where only about 17 % 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 (Visit 3) 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 response for pooled doses of 10 mg QD, 25 mg QD, 25 mg BID and 50 mg 
QD ≠Mean NTB response of placebo
If the null hypothesis H1-0  is rejected in favour of H1-a, then the proof of concept is 
established. 


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
Step 2 for dose response finding: 
A regression model will be fitted first as the following functional form.
μ(d) = β + βd + βd
,
where μ(d) denotes the mean response of NTB of the dose level i group, d denotes for dose 
levels i, for i = 1, 2,..,5 and β’s are the coefficients. The dose d 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 favour 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 peak response in the respective model Mean NTB response = 
Mean NTB response of placebo.
H4-a: The dose group with peak response in the 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
For the secondary endpoint, all calculated p-values should be considered as descriptive for 
the analysis of secondary endpoint. Therefore, no alpha correction will be carried out.


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7.3
PLANNED ANALYSES
Analysis set
Treated set (TS): All patients who were randomized and treated with at least one dose of 
study medication.
Full analysis set (FAS): 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 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 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 [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 score after 
12 weeks of treatment. The model will include fixed, categorical effects of treatment, visit 
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-MCI-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. 


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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.
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 
residual effect period 7 day after last drug intake will be considered ‘treatment-related.
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, 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
No interim analysis is planned during the course of the 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 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 un-blinding.
7.5
RANDOMIZATION
Eligible patients will be randomly assigned to one of the 5 treatment groups, with an 
allocation of 2:1:1:1:1 respectively for placebo: BI 409306 10 mg once daily: BI 409306 
25 mg once daily: BI 409306 50 mg once daily once daily: BI 409306 25 mg twice daily.
The randomization will not be stratified.
The randomization of patients to the treatment groups will be performed via an interactive 
response technology (IRT). BI will arrange for the randomization as well as packaging and 
labeling of study medication. The randomization 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 randomization codes will be controlled and documented.
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 


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endpoint, the change from baseline in NTB total score after 12-week treatment. (See section 
7.2 for the details of hypothesis testing.)
As previously mentioned, the randomization allocation ratio of 1:1:1:1:2 of 10 mg, 25 mg, 
50 mg, 25 mg BID of BI 409306, and placebo is used so that 33 % of patients will be 
randomized 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 size 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
0.50
0.55
0.6
0.65
Power
80%
80%
80%
80%
80%
n for each active treatment arm
59
48
40
34
29
n for placebo arm 
118
96
80
68
58
Total 
354
288
240
204
174
Based on the calculations provided in Table 7.6:1, a sample size of 48 per active treatment 
arm and 96 for placebo arm was selected as adequate for a phase II proof of concept trial.
This sample size would allow us to detect an effect size of 0.5 with 80 % power or an effect 
size of 0.6 with 92 % power, 2-sided alpha at 0.05. 
Assuming a 10% dropout rate, this sample size would allow us to detect an effect size of 0.53 
with 80% power and assuming a 20% dropout rate, this sample size would allow us to detect 
an effect size of 0.56 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.
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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In this study each patient needs a dedicated study partner who will accompany the patient 
throughout the trial. The study partner also will actively contribute to specific 
neuropsychological assessments, which provide information about the patient’s cognitive 
status and activities of daily living. The study partner will join the informed consent process 
and read the patient information together with the patient. He/she will sign a separate 
informed consent form, which explains his role as a study partner and how the personal data 
he / she provided about themselves and about the patient will be used by Boehringer 
Ingelheim or the institutions as mentioned above.
8.2
DATA QUALITY ASSURANCE
In order to achieve a high level of standardised processes, data collection of efficacy and
safety endpoints are coordinated centrally:

Central rater pre-qualification, training, provisioning and quality review of 
neuropsychological assessments. Central quality review of assessments; for that 
purpose assessment procedures will be audio recorded. 
 
has been selected as service provider to 
support tasks related to the neuropsychological assessments.

Central lab analysis of efficacy endpoints, biomarkers and safety lab

Central ECG collection

Central IRT for randomisation and kit allocation
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 


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to request previous medical records or transfer records, depending on the trial; also current 
medical records must be available.
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. 
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 (U11-1079). The 
current version 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.


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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. For all other participating OPU’s local regulations will apply.


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9.
REFERENCES
9.1
PUBLISHED REFERENCES
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. 
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.
R13-2647
Pedrosa H, Sa A de, Guerreiro M, Maroco J, Simoes MR, Galasko D, 
Mendonca A de Functional evaluation distinguishes MCI patients from 
healthy elderly people - the ADCS/MCI/ADL scale. J Nutr Health Aging 14 
(8), 703 - 709 (2010)
R14-0163
Prince M, Bryce R, Albanese E, Wimo A, Ribeiro W, Ferri CP. The global 
prevalence of dementia: a systematic review and metaanalysis. Alzheimers 
Dement 2013. 9:63-75.
R14-2556
Dubois B, et al. Advancing research diagnostic criteria for Alzheimer's 
disease: the IWG-2 criteria. Lancet Neurol 13, 614 - 629 (2014)
R14-4676
C.M. Cullum et al. Normal Aging and Forgetting Rates on the Wechsler 
Memory Scale-Revised. Arch. Of Neuropsych., Vol. 5, pp.23-30, 1990
R96-2608
Rosen WG, Mohs RC, Davis KL, . A new rating scale for Alzheimer's 
disease. Am J Psychiatry 1984;141(11):1356-1364.
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 


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Psychiatry 2010. 67(8):857-865.
9.2
UNPUBLISHED REFERENCES
U10-2286-01
U10-2789-01
U10-2801-01
U10-2898-01
U10-2899-01
U11-1079
U11-1173-01
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
 Effects of BI 409306 on behaviour 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.
, 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
, 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
 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
, Investigator's Brochure: BI 409306 in Alzheimer's Disease and 
Cognitive Impairment associated with Schizophrenia, current version
, BI 409306: 4-week oral (gavage) toxicity 
study in beagle dogs, 10B084, 10 Jan 2012
U12-1034-01
U12-2165-01
. 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
 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


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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 
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, 
placebo-controlled within dose groups); BI409306; 6 June 2014


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10.
APPENDICES


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10.2
LUMBAR PUNCTURE PROCEDURE AND CEREBROSPINAL FLUID 
(CSF) COLLECTION AND PROCESSING
Evaluation of CSF amyloid is considered a gold standard to support a diagnosis of 
Alzheimer’s disease; it is highly likely that many potential patients would initially undergo 
CSF sampling before being considered for participation in this study. For the study it is 
necessary that the CSF sampling procedure is standardized and the evaluation of CSF 
amyloid as diagnostic inclusion criteria is performed at a central lab to ensure consistency of 
results. 
CSF sampling is an invasive procedure. To avoid repeated lumbar puncture for diagnosis and 
confirmation of eligibility, patients who initially underwent CSF sampling for diagnostic 
workup of cognitive impairment can be considered for inclusion if CSF was collected within 
the last 4 months prior to Informed Consent and if the sampling and storage was done 
according to the specifications set out in this protocol. The sampling of the CSF should be 
performed under the current medically accepted standards in the referring country (for 
instance: separate informed consent and considering potential contraindications like raised 
intracranial pressure, thrombocytopenia and other bleeding diathesis (including ongoing 
anticoagulant therapy) or suspected spinal epidural abscess. Aliquoting of samples as 
specified in the protocol is not necessary and it would be considered acceptable if the sites are 
able to provide at least 6ml of CSF as a single bulk sample or multiple aliquots. Multiple 
thawing of the samples once frozen is not allowed.
In the event the CSF sample provided is considered unacceptable for evaluation by the central 
lab, it is at the discretion of the investigator to consider taking an additional CSF sample for 
inclusion in the 1289.5 study or such patients would need to be screen failed or undergo PET 
for demonstration of amyloid pathology.
10.2.1
Positioning
The subject should assume a sitting position and arching “like a cat” with his or her back 
flexed to widen the gap between the spinous processes. The lumbar spine should be 
perpendicular to the bed. The point of insertion of the needle will be determined by palpation 
at the intersection of the midline and a line connecting the superior aspects of the iliac crests.
Deviations should be recorded in the source data as well as in the eCRF.
The needle will be inserted in the interspace between L3 and L4 or L4 and L5. The proper 
position will be indicated with a skin-marking pen.


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10.2.2
Preparation
The site should follow its local standard procedures for preparation of lumbar puncture. The 
further procedure will be performed in a sterile manner. 
10.2.3
Analgesia
Maximal 5 mL local anaesthetic (e.g. Xylocaïne® 2% with epinephrine) will be infiltrated 
subcutaneously.
10.2.4
Lumbar puncture and CSF collection
An (preferentially 25G) atraumatic needle with stylet in place will be inserted at the superior 
aspect of the inferior spinous process in the midline and approximately 15° cephalad. 
Advance the needle into the spinous ligament (increased resistance). Continue to advance the 
needle within the ligament until there is a fall in resistance. Remove the stylet. Collect the 
first 2 ml of CSF in collection tube 1 and further 6 ml in collection tube 2 (collection tubes to 
be used: Sarstedt, cat nr: 62.554.502).
10.2.5
End of Procedure
After all CSF has been collected, the needle will be removed, the site cleaned and a bandage 
applied.
10.2.6
CSF processing and shipment
Freshly collected CSF must be kept at room temperature (RT) but should be centrifuged 
within 1 hour of collection at 2000 xg, 10 min, RT. Immediately after centrifugation the 
respective supernatants should be transferred to fresh tubes (Sarstedt, cat nr: 62.554.502) and 
tubes inverted once. The CSF should then be divided into 500 µl aliquots (Sarstedt; tubes cat 
nr: 72.703, lids cat nr: 65.716) and immediately stored at approximately -80°C.
Coding of aliquots from collection tube 1: CT1_1, CT1_2, … 
Coding of aliquots from collection tube 2: CT2_1, CT2_2, …
The reason for splitting up the CSF at collection into 2 separate tubes is to ensure that the 
actual CSF sample to be analysed is not contaminated with tissue, blood, etc. So all analyses 
should be performed from the 2nd collection tube. Nevertheless, CSF from the 1st collection 
tube will still be kept as this might proof valuable for additional analyses. 
All aliquots (from collection tube 1 and 2) will be shipped on dry ice to the central laboratory, 
from where they will be shipped in batches to the biobank.


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10.4
CLINICAL EVALUATION OF LIVER INJURY
10.4.1
Introduction
Alterations of liver laboratory parameters, as described in section 5.2.2.1 (Adverse Events of 
Special Interest), are to be further evaluated using the following procedures: 


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10.4.2 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.
Assessment of additional lab parameters:
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, 
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


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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
14 Oct 2014
EudraCT number
2013-005031-24
BI Trial number
1289.5
BI Investigational Product(s)
BI 409306
Title of protocol
A multi-centre, double-blind, parallel-group, 
randomized controlled study to investigate the 
efficacy, safety and tolerability of orally 
administered BI 409306 during a 12-week 
treatment period compared to placebo in patients 
with 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
Description of change
Clarification of main criteria for inclusion
Rationale for change
To make synopsis consistent with changes and 
clarifications throughout the protocol.
Section to be changed
Flow Chart
Description of change
Flow Chart replaced for clarification and to 
include changes throughout the protocol. The 
neuropsychological assessment schedule was 
adapted.
Rationale for change
Clarifications and additional testing as well as 
changes in Visit Schedule as recommended by 
authority feedback.
Section to be changed
Abbreviations


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Number of global amendment
1
Description of change
Missing abbreviations were added
Rationale for change
To make section consistent the protocol
Section to be changed
2.3
Description of change
Rationale for suicidal monitoring was clarified 
Rationale for change
Clarification
Section to be changed
2.3
Description of change
“of short duration” was added 
Rationale for change
Clarification
Section to be changed
3.1 and 6.2.3
Description of change
Follow-up period was extended to 4 weeks
Rationale for change
To be aligned with project standards
Section to be changed
3.2
Description of change
The rationale for the choice of a placebo group 
was added
Rationale for change
Clarification
Section to be changed
3.3
Description of change
Re-screening was limited to exceptional cases on 
a case by case basis
Rationale for change
Clarification
Section to be changed
3.3
Description of change
The wording was adapted due to changes of 
MMSE and CDR cut-offs
Rationale for change
Clarification
Section to be changed
3.1.1
Description of change
Time frame for safety evaluation was specified
Rationale for change
Clarification
Section to be changed
3.3.1
Description of change
The reference to the IWG criteria was changed to 
the newest available version, the reference to 
DSM(V) was removed, “and/or informant” was 
added
Rationale for change
Update and clarification
Section to be changed
3.3.2
Description of change
The cut-off for the MMSE was changed and a 
cut-off for the global CDR-score was introduced
Rationale for change
Based on scientific advice from external experts 
the new cut-offs describe the target population 
(see section 3.3.1) more appropriately
Section to be changed
3.3.2
Description of change
The time period for confirmation of abnormal AD 
biomarker was added to the wording of the 
criterion.
Rationale for change
Clarification
Section to be changed
3.3.2 and 8.1


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Number of global amendment
1
Description of change
Inclusion Criterion #7 and #8 were changed. The 
option of consent by a legal representative was 
deleted throughout the CTP
Rationale for change
To be in accordance with ICH-GCP
Section to be changed
3.3.3
Description of change
The medical conditions listed in exclusion #4 
were clarified
Rationale for change
Clarification
Section to be changed
3.3.3
Description of change
The unit of GFR was changed from
ml/min to
ml/min/1.73m2
Rationale for change
A typographical error was corrected
Section to be changed
3.3.3
Description of change
Ex# 10 now includes DSM-V
Rationale for change
Clarification to meet project standards
Section to be changed
3.3.3
Description of change
Exclusion criterion #11 was reworded from
HIV infection confirmed by a central lab test
to
Known history of HIV infection.
Rationale for change
Clarification
Section to be changed
3.3.3
Description of change
Exclusion criterion #12 was removed
Rationale for change
Already covered by Exclusion criterion #1
Section to be changed
3.3.3
Description of change
Exclusion criterion #13: The acceptable methods 
for birth control for female patients of child-
bearing potential were changed
Rationale for change
Clarification based on authority feedback
Section to be changed
3.3.3.
Description of change
An additional exclusion criterion “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” was added.
Rationale for change
Based on authority feedback
Section to be changed
3.3.3
Description of change
“or dementia” was deleted from Exclusion #1
Rationale for change
Clarification
Section to be changed
3.3.3
Description of change
Exclusion #16: The list of medications prohibited 
3 months prior to randomisation was reworded


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Number of global amendment
1
Rationale for change
Clarification
Section to be changed
3.3.3
Description of change
Known hypersensitivity to drug product 
excipients was added
Rationale for change
Based on authority feedback
Section to be changed
3.3.4.1
Description of change
“if” was added
Rationale for change
A typographical error was corrected
Section to be changed
3.3.4.1
Description of change
“, for pre-specified PGx sampling” was deleted
Rationale for change
Clarification
Section to be changed
Table 4.1:1
Description of change
Run-in group was removed because it is not a 
treatment group
Rationale for change
Clarification
Section to be changed
Table 4.1.1:1
Description of change
Reference to run-in was removed
Rationale for change
Clarification
Section to be changed
4.1.4
Description of change
“at approximately the same time every day” was 
added and “because they will receive new 
medication kits during the visits” was removed
Rationale for change
Clarification
Section to be changed
4.1.7
Description of change
Storage conditions were updated to better match 
the STORM document
Rationale for change
Clarification
Section to be changed
4.2.2.1
Description of change
“Agonist”
Was changed to
“Antagonist”
Rationale for change
A typographical error was corrected
Section to be changed
4.2.2.1
Description of change
St. Johns wort, Carbamazepine, extracts from 
Ginko, artemisinin, enzalutamide, efavirenz, 
lopinavir, ritonavir, tipranavir, rifampicin were 
added to the list of prohibited medications 
Rationale for change
Relevant CYP2C19 inducers where excluded
Section to be changed
5.1.1 and 7.3.1
Description of change
NTB total score 
Was replaced by
NTB total z-score
Rationale for change
Clarification 
Section to be changed
5.1.1


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Number of global amendment
1
Description of change
Total CDR score was replaced by CDR-SB
Rationale for change
Clarification, a typo was corrected
Section to be changed
5.2.2.1
Description of change
The paragraph “Worsening of suicidal ideation 
and behaviour” was deleted
Rationale for change
Paragraph was included by error and contained 
misleading information
Section to be changed
5.2.2.2
Description of change
Wording on reporting of visual AEs moved from 
section 6.2.2 and changed to match project 
standards
Rationale for change
To be aligned with project standards
Section to be changed
5.2.5.2
Description of change
Section 10.1.1 was updated to project wording
Rationale for change
Clarification
Section to be changed
5.2.3
Description of change
Instructions for assessment of safety laboratory 
parameters were reworded to match project 
standards; Vitamin B12 and Folate were added to 
table 5.2.3: 1
Rationale for change
Clarification
Section to be changed
5.2.4
Description of change
ECGs will be transmitted to the vendor instead of 
being electronically stored at site only
Rationale for change
Changed to be aligned with project standards
Section to be changed
5.2.5.3
Description of change
Assessment of C-SSRS by paper was added
Rationale for change
Clarification
Section to be changed
5.3.1.1
Description of change
Sample handling instructions included in the lab 
manual were deleted
Rationale for change
Clarification to avoid contradicting statements
Section to be changed
5.6
Description of change
Instructions for handling/destruction of CSF and 
biomarker samples were updated
Rationale for change
Clarification
Section to be changed
5.6.1
Description of change
Duplicate text (instructions can be found in 
section 10.2) was deleted
Rationale for change
Clarification
Section to be changed
6.2
Description of change
Instructions for neuropsychological assessments 
were reworded to match project standards.
Rationale for change
Update of project standards


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Number of global amendment
1
Section to be changed
6.2.1
Description of change
CDR, ADAScog11, was added to the screening 
procedures
Rationale for change
Reflection of changes made to procedures
Section to be changed
6.2.1. and 6.2.2
Description of change
Recommendations for patients with antidiabetic 
therapy were added to visits with neurocognitive 
assessments
Rationale for change
Clarification
Section to be changed
6.2.2
Description of change
The option of doing the neuropsychological 
assessments on the last day of the screening 
period was added to the CTP
Rationale for change
To increase feasibility, change based on 
investigator feedback received 
Section to be changed
6.2.2
Description of change
Visit 4 was changed to be a clinic visit
Rationale for change
Based on authority feedback
Section to be changed
6.2.2
Description of change
Wording on visual adverse events was moved to 
section 5.2.2.2
Rationale for change
Update according to project standards
Section to be changed
6.2.2
Description of change
Various changes were made to reflect the changes 
made throughout the protocol
Rationale for change
Reflection of changes made to other sections of 
the protocol
Section to be changed
7.3
Description of change
The statement “No Per Protocol Set (PPS) 
analysis will be performed” was deleted.
Rationale for change
Changed to be aligned with project standards
Section to be changed
7.5
Description of change
Randomisation ratio was corrected
Rationale for change
Correction of a typographical error
Section to be changed
7.6
Description of change
!"# $%&'() *+ #',-. /$)"0,'/'-1 
*2 )"# 1)30. 
&*/#, /'1 '00#0
Rationale for change
Clarification
Section to be changed
8.7
Description of change
Section was removed 
Rationale for change
Section only to be included if trial is run in Japan 
according to CTP template
Section to be changed
10.2
Description of change
The instructions for CSF puncture and handling 


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Number of global amendment
1
were clarified
Rationale for change
Clarification
Section to be changed
10.4.2
Description of change
Serology was added and is to be done in case of 
reported liver injury and typos were corrected.
Rationale for change
To meet SOP requirements


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Number of global amendment
2
Date of CTP revision
22 Dec 2014
EudraCT number
2013-005031-24
BI Trial number
1289.5
BI Investigational Product(s)
BI 409306
Title of protocol
A multi-centre, double-blind, parallel-group, 
randomized controlled study to investigate the 
efficacy, safety and tolerability of orally 
administered BI 409306 during a 12-week 
treatment period compared to placebo in patients 
with 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
3.3.2
Description of change
Reference added
Rationale for change
Clarification
Section to be changed
Table 4.1.1: 1
Description of change
Source of IMP was corrected
Rationale for change
Clarification
Section to be changed
4.1.4, 6.2.1 - 6.2.3, 10.4.2
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
Section to be changed
4.2.2.1
Description of change
Use of strong or moderate CYP3A4 inhibitors are 


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Number of global amendment
2
also 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
5.2.2.2
Description of change
Follow-up period changed to 28 days
Rationale for change
Correct a typo
Section to be changed
Table 5.2.3: 1
Description of change
Additional routine safety lab parameters added
Rationale for change
Completeness of safety lab panel 
Section to be changed
6.2.1
Description of change
Removed: Recommendation to perform study 
procedures in the order as listed in the FC 
removed
Rationale for change
This applies only to the neuropsychological 
assessments and not in general to all procedures. 
Section to be changed
6.2.3 
Description of change
Follow-up visit is a mandatory clinic visit
Rationale for change
Correct typo
Section to be changed
7.2
Description of change
Specification of baseline visit added
Rationale for change
Clarification
Section to be changed
7.3.3
Description of change
Residual effect period is 7 days
Rationale for change
Correct typo
Section to be changed
10.2.6
Description of change
Samples will be shipped to the central lab and not 
directly to the analytical lab 
Rationale for change
Clarification - sample logistics adjusted
Section to be changed
Section 11, description of change for 3.3.3
Description of change
Adjust section with contraception of male patients
Rationale for change
Correct typo


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Number of global amendment
3
Date of CTP revision
03-Aug-2015
EudraCT number
2013-005031-24
BI Trial number
1289.5
BI Investigational Product(s)
BI 409306
Title of protocol
A multi-centre, double-blind, parallel-group, 
randomized controlled study to investigate the 
efficacy, safety and tolerability of orally 
administered BI 409306 during a 12-week 
treatment period compared to placebo in patients 
with 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; Sections 2.2; Section 2.3; Section 3.3.2. 
Description of change
Specifying the definition of eligible patients
Rationale for change
According to feedback from the investigators 
prodromal patients usually ask for treatment and 
sometimes take available AD medication despite 
the fact that there are no treatments registered for 
prodromal AD. In order to avoid unnecessary 
limitation to the recruitment we allow patients 
who previously took AD treatment to enter the 
trial.
Section to be changed
Synopsis;  Flowchart; Section 5.1; Section 6.2,
Section 9.1
Description of change
Removal of the following neuropsychological 
assessments
-
MMSE at Visit 3, 5 and EOT/ED
-
MCI-ADSC-ADL at visit 5


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Number of global amendment
3
-
ADCS-ADL completely
-
ADAS-cog11 at Visit 5
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 is not impacted.
Section to be changed
Synopsis
Description of change
“disposition” replaced by “deposition”
Rationale for change
typo
Section to be changed
Flowchart; Section 3.3.3 (ex. #1); Section 
5.3.2.2.; Section 6.2.1
Description of change
The use of a CCT to exclude other disorders 
causing prodromal AD is now allowed if not 
prohibited by local regulations
Rationale for change
To allow patients with a contraindication for MRI 
(for instance pacemaker) to enter the study.
Section to be changed
Section 3.3.3 Exclusion criteria #9
Description of change
Amending 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
Section 4.2.2.1
Description of change
The use of strong or moderate CYP3A4 inhibitors 
is now allowed.
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 4.2.2.1
Description of change
Restrictions added for intake of drugs for 
treatment of AD during trial participation 
Rationale for change
To clarify that patients with previous treatment 
with AD drugs are not allowed to intake this 
drugs during this trial
Section to be changed
Table 5.2.3:1
Description of change
Deletion of “(Stix)” 
Rationale for change
Typo
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
Section 10.4.2


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Number of global amendment
3
Description of change
Clinical chemistry: “fasting” glucose added
Rationale for change
Typo


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Number of global amendment
4
Date of CTP revision
17-February 2017
EudraCT number
2013-005031-24
BI Trial number
1289.5
BI Investigational Product(s)
BI 409306
Title of protocol
A multi-centre, double-blind, parallel-group, 
randomized controlled study to investigate the 
efficacy, safety and tolerability of orally 
administered BI 409306 during a 12-week 
treatment period compared to placebo in patients 
with 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
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 #13
Description of change
Removal of hormonal contraception, which are
moderate to strong CYP1A2 inhibitors, 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 
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 


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Number of global amendment
4
the list of restricted medications
Rationale for change
Moderate or strong CYP1A2 inhibitors may
significantly increase plasma exposure of BI 
409306 in poor metabolizers
Section to be changed
6.2.2 
Description of change
Description of post dose Pk sampling added
Rationale for change
Clarification; Visit 3 description to be consistent 
with the descriptions at Visit 6


 
 
 
 
APPROVAL / SIGNATURE PAGE 
 
Document Number: 
 
Technical Version Number:
 
Document Name: 
 
 
 
                                                                                                                 
 
Title: 
 
 
 
 
                                                                                                                   
 
Signatures (obtained electronically) 
 
Meaning of Signature  
Signed by 
Date Signed 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
c01691934
10.0
clinical-trial-protocol-revision-4
A multi-centre, double-blind, parallel-group, randomized controlled study to
investigate the efficacy, safety and tolerability of orally administered BI 409306
during a 12-week treatment period compared to placebo in patients with Alzheimer’s
Disease.
Author-Trial Statistician
23 Feb 2017 16:52 CET
Author-Trial Clinical Monitor
23 Feb 2017 16:55 CET
Author-Clinical Pharmacokineticist
23 Feb 2017 16:56 CET
Approval-Therapeutic Area 
24 Feb 2017 00:21 CET
Approval-Team Member Medicine
24 Feb 2017 18:33 CET
Verification-Paper Signature
Completion
02 Mar 2017 11:51 CET


Boehringer Ingelheim 
Page 2 of 2
Document Number: 
 Technical Version Number:
 
 
 
(Continued) Signatures (obtained electronically) 
 
Meaning of Signature  
Signed by 
Date Signed 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
c01691934
10.0

SAP_001.pdf: 
TITLE PAGE
Trial Statistical Analysis Plan
c03164258 -01
BI Trial No.:
1289.5
Title:
   A multi-centre, double-blind, parallel-group, randomized controlled
   study to investigate the efficacy, safety and tolerability of orally
   administered BI 409306 during a 12-week treatment period compared to
   placebo in patients with 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 ..................................................13
6.3
PATIENT SETS ANALYSED..........................................................................17
 
18
6.5
POOLING OF CENTRES ................................................................................18
6.6
HANDLING OF MISSING DATA AND OUTLIERS ...................................18
6.6.1
Missing efficacy data.....................................................................................18
6.6.2
Missing safety data and other data..............................................................19
6.6.3
Missing AE dates and times..........................................................................20
6.6.4
Missing plasma concentrations and pharmacokinetic parameters ..........20
6.7
BASELINE, TIME WINDOWS, AND CALCULATED VISITS .................20
7
PLANNED ANALYSIS.......................................................................22
7.1
DEMOGRAPHICS AND OTHER BASELINE CHARACTERISTICS......22
7.2
CONCOMITANT DISEASES AND MEDICATION ....................................22
7.3
TREATMENT COMPLIANCE .......................................................................22
7.4
PRIMARY ENDPOINT ....................................................................................22
7.4.1
Primary efficacy analysis..............................................................................22
7.5
SECONDARY ENDPOINTS............................................................................23
7.5.1
Key secondary endpoint................................................................................23
7.5.2
Other Secondary endpoints..........................................................................23
7.7
EXTENT OF EXPOSURE................................................................................24
7.8
SAFETY ANALYSIS.........................................................................................24
7.8.1
Adverse events ...............................................................................................24


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7.8.1.1
Assignment of AEs to treatment.................................................................24
7.8.1.2
Analysis of other significant AEs...............................................................24
7.8.1.3
AE summaries.............................................................................................25
7.8.1.4
AE summaries for disclosure......................................................................25
7.8.2
Laboratory data.............................................................................................25
7.8.3
Vital signs.......................................................................................................25
7.8.4
ECG ................................................................................................................26
7.8.5
Others .............................................................................................................26
7.8.5.1
C-SSRS.......................................................................................................26
8
REFERENCES.....................................................................................27
9
ADDITIONAL SECTIONS ................................................................28
9.1
CALCULATION OF NTB TOTAL SCORE..................................................28
9.2
C-SSRS FDA CATEGORIES...........................................................................30
9.3
SAS CODE..........................................................................................................31
10
HISTORY TABLE...............................................................................32


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LIST OF TABLES
....11
Table 6.1: 1 
Treatment descriptions ....................................................................................12
Table 6.1: 2 
Definition of analyzing treatment period ........................................................12
Table 6.2: 1
important protocol violations ..........................................................................14
Table 6.3: 1
Patient sets analyzed........................................................................................18
Table 6.7: 1
Time windows for all pre/on-treatment safety visits.......................................20
Table 6.7: 2
Time windows for on-treatment efficacy measurement scheduled for each on 
treatment visit...................................................................................................................21
Table 9.1: 1
NTB description and scoring...........................................................................28
Table 9.2.1
CSSRS and FDA categories............................................................................30
Table 9.3.1
SAS Code for main analyses...........................................................................31
Table 10: 1
History table ....................................................................................................32


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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
AUC
Area under the Curve
BCRP
Breast cancer resistance protein
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
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


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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
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
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
Trial Data Management and Analysis 
 
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 data for patients entered prior to Amendment 3 will be handled as follows:

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
Efficacy, safety and tolerability of different doses of BI 409306 compared to placebo in 
patients with prodromal AD are the objectives of this trial.
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-MCI-ADL (Alzheimer’s Disease Cooperative 
Study/Activities of Daily Living for mild cognitive impairment) 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
10mg QD
B
BI 409306 25 mg QD
25mg QD
C
BI 409306 50 mg QD
50mg QD
D
BI 409306 25 mg BID
25mg BID
E
Placebo
Placebo
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
Treatment
Date of first administration of 
study medication
Time of first
administration of
study medication
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


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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 randomized study drug.

On treatment: From the first intake of randomized study drug to last intake of 
randomized 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.
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 1 not met as 
specified in the protocol.
Yes
Automatic
A1.2
No confirmed diagnosis of 
prodromal AD on 
neuropsychological testing
Inclusion criteria 3 not met as 
specified in the protocol.
Yes
Automatic
A1.3
No confirmation of abnormal 
markers of AD pathology
Inclusion criteria 4 not met as 
specified in the protocol.
Yes
Automatic
A1.4
Received drugs for treatment of 
AD within three months of 
screening
Inclusion criteria 5 not met as 
specified in the protocol.
Yes
Automatic
A1.5
Inadequate education and 
language 
Inclusion criteria 6 not met as 
specified in the protocol.
Yes
Automatic
A1.6
Inadequate study partner 
reliability
Inclusion criteria 8 not met as 
specified in the protocol.
Yes
Automatic
A2
Exclusion criteria met
A2.1
Mild cognitive impairment
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
Any 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


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Table 6.2: 1 (continued)
important protocol violations
Category
/Code
Description
Example/Comment
Excluded 
from 
PPS
Automatic/
Manual
A2
Exclusion criteria met
A2.9
Prohibited drugs within 3 months 
prior to study participation
Exclusion criteria 16 met as 
specified in the protocol.
Yes
Automatic
A2.10
Uncompensated hearing loss
Exclusion criteria 20 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 
(IVRS assignment). If not, and if 
treated consistently throughout the 
trial, analyze as treated.
Yes
Automatic


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Table 6.2: 1 (continued)
important protocol violations
Category
/Code
Description
Example/Comment
Excluded 
from PPS
Automatic
/Manual
C2
Randomisation order not 
followed
C2.1
Error by the vendor who 
implemented the randomization 
scheme
E.g., the same randomization number 
was given to different patients or the 
assignment of
duplicate medication numbers or 
incorrect medication numbers.
Verify by comparing the medication 
numbers and randomization numbers 
from IVRS.
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
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)


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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-MCI
For ADCS-ADL-MCI, 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[=69] 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.
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.


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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 randomization date are: 

If first intake of study drug shows a large delay by e.g. more than one week after the 
date of randomization, a measurement taken four weeks after randomization rather 
reflects the drug effect after three weeks than after four weeks and thus may 
underestimate the treatment effect at this visit.

With large delays of the introduction of study drug after the randomization, the time 
window for the first on-treatment visit could include times the patient was not yet on 
study drug. 


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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 randomized 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
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.
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
Other Secondary endpoints
The same primary analysis model will be performed for the secondary endpoint CDR-SB.
The secondary endpoints ADAS-Cog11 and ADCS-ADL-MCI 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 secondary endpoint measure and 
treatment.
 
 


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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
(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. 


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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 randomized
study drug will be considered as on-treatment.
Only patients with at least one available on-treatment value will be included in the analysis of 
an individual laboratory parameter. All individual data will be presented in listings.
Study visits will be presented by the Visit labels in Table 6.7.1,
7.8.3
Vital signs
Only descriptive statistics are planned for this section of the report.


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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 study 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 summarizes 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 ;
MODEL chgept = trt baseline visit trt*visit baseline
/ ddfm=KR solution;
REPEATED visit / type=un subject=patient r rcorr ;
LSMEANS trt*visit / pdiff=all cl;
RUN ;
ANCOVA
PROC MIXED data=one METHOD=reml ORDER=formatted;
CLASS trt ;
MODEL chgept = baseline trt ;
LSMEANS trt / CL DIFF OM ;
RUN;


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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