Conditions: Schizophrenia Alzheimer Disease
Allocation: RANDOMIZED | Intervention model: PARALLEL
Enrollment: 61
Healthy volunteers: yes

Brief summary:
Single site, parallel-group, double-blind trial of low or high dose of BI 409306 to evaluate the ocular and systemic safety and pharmacokinetics during 14 day treatment period in patients with schizophrenia, Alzheimer's disease, or age comparable healthy volunteers.

Detailed description:

Arms:
arm 1: Alzheimer patients received once daily (QD) orally one tablet of 25 mg of BI 409306 and two 50 mg matching placebo tablets for 14 days. arm 2: Alzheimer patients received once daily (QD) orally 100 mg of BI 409306 (two 50 mg active tablets) and one 25 mg matching placebo tablet for 14 days. arm 3: Schizophrenia patients (cognitive impairment associated with schizophrenia) received once daily (QD) orally one tablet of 25 mg of BI 409306 and two 50 mg matching placebo tablets for 14 days. arm 4: Schizophrenia patients (cognitive impairment associated with schizophrenia) received once daily (QD) orally 100 mg of BI 409306 (two 50 mg active tablets) and one 25 mg matching placebo tablet for 14 days. arm 5: Age-comparable healthy volunteers received once daily (QD) orally one tablet of 25 mg of BI 409306 and two 50 mg matching placebo tablets for 14 days. arm 6: Age-comparable healthy volunteers received once daily (QD) 100 mg of BI 409306 (two 50 mg active tablets) and one 25 mg matching placebo tablet orally for 14 days.

Interventions: intervention 1: Placebo matching BI 409306 25 mg intervention 2: Placebo matching BI 409306 50 mg intervention 3: BI 409306 25 mg intervention 4: BI 409306 50 mg
Intervention descriptions: intervention 1: Film-coated tablet intervention 2: Film-coated tablet intervention 3: Film-coated tablet intervention 4: Film-coated tablet

Protocol document:
Prot_000.pdf: 
Clinical Trial Protocol
Doc. No.: c02218444-07
BI Trial No.:               
1289.27
BI Investigational
Product:
BI 409306
Title:
Randomised, parallel-group, double-blind study of systemic and ocular 
safety and pharmacokinetics of BI 409306 in patients with 
schizophrenia, Alzheimer’s disease, and age-comparable healthy 
volunteers
Clinical Phase:
1c
Trial Clinical 
Monitor:
Phone: 
Fax: 
Coordinating
Investigator:
Phone: 
Fax: 
E-mail:
Status:
Final Protocol (Revised Protocol based on global amendment No. 3)
Version and Date:
Version:
4.0
         
Date: 22 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:
N/A
Name of active ingredient:
BI 409306
Protocol date:
Trial number:
Revision date:
22 February 2017
05-Mar-2015
1289.27
Title of trial:
Randomised, parallel-group, double-blind study of systemic and ocular safety and 
pharmacokinetics of BI 409306 in patients with schizophrenia, Alzheimer’s disease, 
and age-comparable healthy volunteers
Coordinating 
Investigator:
Phone: 
Fax: 
Trial site:
Multi-center
Clinical phase:
Ic
Objectives:
To evaluate the ocular and systemic safety and pharmacokinetics during 14 day
treatment period in patients with schizophrenia, Alzheimer’s disease, or age-
comparable healthy volunteers treated with oral film-coated tablet of BI 409306 25 or 
100 mg 
Methodology:
Multi-center, parallel-group, double-blind trial of two doses of study medication in 
three groups treated for 14 days
No. of patients: 
total entered:
60 planned
each treatment:
30 planned for each treatment group (10 AD/10 CIAS/10 HV per group)
Diagnosis:
Patients with schizophrenia in stable clinical status and on stable antipsychotic 
treatment OR patients with diagnosis of mild Alzheimer’s disease currently treatment-
naïve or on stable treatment(s) OR age-comparable healthy volunteers.


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Name of company:
Tabulated
Trial Protocol
Boehringer Ingelheim
Name of finished product:
N/A
Name of active ingredient:
BI 409306
Protocol date:
Trial number:
Revision date:
22 February 2017
05-Mar-2015
1289.27
Main criteria
for inclusion:
Schizophrenia patients age 18-55 years with established diagnoses of schizophrenia 
(per Diagnostic and Statistical Manual of Mental Disorders version V (DSM-V)) with 
the following clinical features:
i.
Clinically stable and are in the residual (non-acute) phase of their illness for 
at least 8 weeks prior to randomisation
ii.
Current antipsychotic and concomitant psychotropic medications must meet 
the criteria below: 
ii)-1. Maintained on current atypical (second generation) antipsychotic            
medications (in any approved dosage form) other than Clozapine and on 
current dose for at least 8 weeks prior to randomisation, and/or 
ii)-2. Maintained on current typical (first generation) antipsychotic 
medications and on current dose for at least 6 months, optionally combined 
with anticholinergics if treated with a stable dose for at least 6 months prior 
to randomisation, and/or
ii)-3. Maintained on current concomitant psychotropic medications other 
than anticholinergics, antiepileptics and lithium, and on current dose for at 
least 8 weeks prior to randomisation. Antiepileptics and lithium are allowed 
if initiated at least 6 months prior to randomisation. 
iii.
Have no more than a ‘‘moderate’’ severity rating on 
hallucinations and delusions (Positive and Negative Syndrome 
Scale (PANSS)–positive syndrome Hallucinatory Behavior 
item score ≤ 4 and Delusions item score ≤ 4)
iv.
Have no more than a ‘‘moderate’’ severity rating on positive 
formal thought disorder (PANSS–positive syndrome 
Conceptual Disorganization item score ≤ 4)
v.
Have a minimal level of extrapyramidal symptoms (Simpson-
Angus Scale total score < 6) and depressive symptoms 
(PANSS–general psychopathology syndrome Depression item 
score ≤ 4)
OR
Patients with diagnosis of mild Alzheimer’s Dementia according to the 
recommendations from the National Institute on Aging-Alzheimer’s Association 
workgroups on diagnostic guidelines for Alzheimer’s disease, who are currently 
treatment-naïve or on stable treatment of acetyl cholinesterase inhibitors and/or
memantine for at least 3 months before randomization. A MMSE (Mini-Mental-State-
Examination) score between 18-26, and age 55 - 85 years with availability of pre-
existing brain CCT or MRI compatible with diagnosis of Alzheimer’s disease.


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Name of company:
Tabulated
Trial Protocol
Boehringer Ingelheim
Name of finished product:
N/A
Name of active ingredient:
BI 409306
Protocol date:
Trial number:
Revision date:
22 February 2017
05-Mar-2015
1289.27
Main criteria
for inclusion:
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.
OR
Age-comparable healthy volunteers age 18 to 85 years. Healthy volunteers 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.
Test products:
BI 409306
dose:
25 mg q.d. or 100 mg q.d.
mode of admin.:
Tablet, Oral
Comparator products:
N/A
dose:
mode of admin.:
Duration of treatment: 14 days
Criteria for
Pharmacokinetics:
Secondary: Cmax,ss, tmax,ss of BI 409306
Criteria for safety:
Primary endpoint:

The number (%) of subjects with AEs, coded to the MedDRA-SOC ‘Eye 
disorders’, as determined by the investigator at End of Trial
Secondary endpoint:

The number (%) of subjects with drug-related AEs as determined by the 
investigator at End of Trial
Statistical methods:
Analyses of adverse events will be performed in accordance with BI statistical 
standards, essentially, tabulations of frequencies/proportions will be displayed.  
Descriptive statistics will be provided for PK endpoints.


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FLOW CHART
Screen
-ing1
Base-
line2
Treatment
End of 
Trial10
Visit
1
2
3
4** 5** 6**
7
8**
9
10** 11** 12** 13** 14** 15
16
EOT
Day
-28 to  
-3
-2 to 
-1
1
2
3
4
5
6
7
8
9
10
11
12
13
14 21 to 28
Informed Consent
X
Demographics
X
Medical History
X
Physical Examination
X
X
X
X
Vital Signs3,4
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
12-lead ECG4
X
X
X
X
X
Eligibility Criteria 
X1
Randomization
X
 
X1
Laboratory 
X
X
X
X
X
Urinalysis
X
X
X
Drug Screen
X
Pregnancy Test5
X
X
X
X
PK Blood Sample4*
X7*
X7*
X
Drug Administration
X7
X
X
X
X
X
X
X
X
X
X
X
X
X7
 
 
 
 
 
 
 
AEs/CTs
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Trial Termination
X
* Refer to table below for timing of intensive PK sampling for Days 1 and 14.
**Home visits may be conducted for these visits in lieu of study center visits (cf. Section 6.1).
Treatment Day 1 and 14: Blood Sampling for Pharmacokinetic and Vital Signs
Planned Time 
(h:min)
-2:00
0:00
0:20
0:30
0:45
1:00
1:30
2:00
4:00
6:00
Clock Time
(h:min)
Pre-dose
8:00
(dosing)
8:20
8:30
8:45
9:00
9:30
10:00
12:00
14:00
PK Sample
X
X
X
X
X
X
X
X
X
Vital Signs13
(Day 1 only)
X13
X13
X13
X13
X13


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Footnotes:
1.
Screening to be performed within 3-28 days before drug administration, including body weight, height, 
smoking and alcohol history, and also an abbreviated visual exam per exclusion criteria (cf. Section 3.3.3).
2.
In-patient stay is optional. If feasible for in-patient stay, the following procedures would apply: eligible 
study participants will be admitted to the study center in-patient facility for overnight stays.  All CIAS 
subjects will remain in-patient for the duration of the treatment period, starting on Day -2 and will be 
allowed to leave after the last study procedure and after their fitness has been confirmed by the investigator 
on Day 14. AD subjects and healthy volunteers will check into clinic on Day -2 and remain in-patient till 
Day 1, return for daily visits till Day 12,  and check into clinic again on Day 13 to Day 14. If there is a need 
that required AD subjects to remain in-patient, then the CIAS schedule plan may be utilized, per 
investigator discretion.
3.
Vital signs will be collected via orthostatic measurements of systolic/diastolic blood pressure and pulse rate 
supine after 5 minutes rest, immediately after standing up and again after 3 minutes standing (cf. Section 
5.2.6).
4.
Vital signs and ECGs should be completed before dosing (pre-dose) and PK blood draws. Pre-dose is 
within 2 hours before the dose is given.
5.
Serum pregnancy tests will be performed at specified study visits on female subjects of child-bearing 
potential – except for CIAS subjects staying in-patient. In addition, urine (dipstick) pregnancy tests will be 
performed at Visit 2. Only those female subjects with a negative urine pregnancy test will receive study 
medication at Visit 3 (Day 1).
6.
 
 
 
7.
Time of last meal before drug administration will be recorded on PK blood draw Days 1 and 14.
8.
 
9.
 
 
10. End-of-Trial examination (EOT) to be performed 7 to 14 days after last drug administration. Subjects who 
discontinue treatment early due to any reason (cf. Section 3.3.4.1) must complete an early EOT visit within 
7 days of last drug administration, with all the procedures performed. 
11.
 
 
12.
 
13. Only on Day 1 PK, pulse rate is to be measured in a supine position after at least 5 minutes of rest pre-dose 
and at the time points of post-dose PK sampling until 110 mins post-dose (20 ±5 min, 30 ±5 min, 45 ±10 
min and 90 ±20 min). 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 at pre-dose and 
at 70~110 minutes post dose.


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TABLE OF CONTENTS
TITLE PAGE ......................................................................................................1
CLINICAL TRIAL PROTOCOL SYNOPSIS ................................................2
FLOW CHART...................................................................................................5
TABLE OF CONTENTS ...................................................................................7
ABBREVIATIONS.......................................................................................... 11
1.
INTRODUCTION.................................................................................... 14
1.1
MEDICAL BACKGROUND............................................................................14
1.2
DRUG PROFILE...............................................................................................16
1.2.1
Drug substance......................................................................................16
1.2.2
Toxicology..............................................................................................18
1.2.3
Clinical Study ........................................................................................19
1.2.4
Pharmacokinetic profile in humans ....................................................20
2.
RATIONALE, OBJECTIVES, AND BENEFIT - RISK 
ASSESSMENT ......................................................................................... 21
2.1
RATIONALE FOR PERFORMING THE TRIAL........................................21
2.2
TRIAL OBJECTIVES.......................................................................................22
2.3
BENEFIT - RISK ASSESSMENT ...................................................................23
3.
DESCRIPTION OF DESIGN AND TRIAL POPULATION.............. 25
3.1
OVERALL TRIAL DESIGN AND PLAN ......................................................25
3.1.1
Administrative structure of the trial...................................................26
3.2
DISCUSSION OF TRIAL DESIGN, INCLUDING THE CHOICE OF 
CONTROL GROUP..........................................................................................26
3.3
SELECTION OF TRIAL POPULATION ......................................................27
3.3.1
Main diagnosis for study entry............................................................27
3.3.2
Inclusion criteria...................................................................................27
3.3.3
Exclusion criteria ..................................................................................29
3.3.4
Removal of subjects from therapy or assessments.............................32
3.3.4.1
Removal of individual subjects................................................32
3.3.4.2
Discontinuation of the trial by the sponsor..............................33
4.
TREATMENTS........................................................................................ 34
4.1
TREATMENTS TO BE ADMINISTERED....................................................34
4.1.1
Identity of BI investigational product and comparator product......34
4.1.2
Method of assigning subjects to treatment groups ............................35
4.1.3
Selection of doses in the trial................................................................35


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4.1.4
Drug assignment and administration of doses for each patient .......35
4.1.5
Blinding and procedures for unblinding ............................................36
4.1.5.1
Blinding....................................................................................36
4.1.5.2
Procedures for emergency unblinding .....................................36
4.1.6
Packaging, labelling, and re-supply ....................................................36
4.1.7
Storage conditions.................................................................................37
4.1.8
Drug accountability ..............................................................................37
4.2
CONCOMITANT THERAPY, RESTRICTIONS, AND RESCUE 
TREATMENT....................................................................................................38
4.2.1
Rescue medication, emergency procedures, and additional 
treatment................................................................................................38
4.2.2
Restrictions............................................................................................38
4.2.2.1
Restrictions regarding concomitant treatment .........................38
4.2.2.2
Restrictions on diet and life style.............................................40
4.3
TREATMENT COMPLIANCE.......................................................................40
5.
VARIABLES AND THEIR ASSESSMENT ......................................... 41
5.1
EFFICACY - CLINICAL PHARMACODYNAMICS...................................41
5.1.1
Endpoints of efficacy.............................................................................41
5.1.2
Assessment of efficacy...........................................................................41
5.2
SAFETY..............................................................................................................41
5.2.1
Endpoints of safety................................................................................41
5.2.2
Assessment of adverse events...............................................................42
5.2.2.1
Definitions of adverse events...................................................42
5.2.2.2
Adverse event collection and reporting ...................................44
5.2.3
Assessment of safety laboratory parameters......................................45
5.2.4
Electrocardiogram................................................................................47
5.2.5
Physical examination ............................................................................47
5.2.6
Vital signs...............................................................................................48
5.2.7
24-hour holter monitoring....................................................................48
5.4
APPROPRIATENESS OF MEASUREMENTS.............................................54


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5.5
DRUG CONCENTRATION MEASUREMENTS AND 
PHARMACOKINETICS..................................................................................55
5.5.1
Pharmacokinetic endpoints..................................................................55
5.5.2
Methods of sample collection...............................................................55
5.5.3
Analytical determinations ....................................................................56
5.6
BIOMARKER....................................................................................................56
5.7
PHARMACODYNAMICS................................................................................56
5.8
PHARMACOKINETIC - PHARMACODYNAMIC RELATIONSHIP .....56
6.
INVESTIGATIONAL PLAN.................................................................. 57
6.1
VISIT SCHEDULE............................................................................................57
6.2
DETAILS OF TRIAL PROCEDURES AT SELECTED VISITS ................58
6.2.1
Screening and baseline period .............................................................58
6.2.2
Treatment periods.................................................................................58
6.2.3
End of trial and follow-up period........................................................59
7.
STATISTICAL METHODS AND DETERMINATION OF
SAMPLE SIZE......................................................................................... 60
7.1
STATISTICAL DESIGN - MODEL................................................................60
7.2
NULL AND ALTERNATIVE HYPOTHESES ..............................................61
7.3
PLANNED ANALYSES....................................................................................61
7.3.1
Primary analyses...................................................................................61
7.3.2
Secondary analyses ...............................................................................62
7.3.3
Safety analyses.......................................................................................62
7.3.4
Interim analyses ....................................................................................63
7.3.5
Pharmacokinetic analyses ....................................................................63
7.3.6
Pharmacogenomic analyses..................................................................64
7.4
HANDLING OF MISSING DATA ..................................................................64
7.5
RANDOMISATION ..........................................................................................64
7.6
DETERMINATION OF SAMPLE SIZE ........................................................64
8.
INFORMED CONSENT, DATA PROTECTION, TRIAL
RECORDS ................................................................................................ 65
8.1
STUDY APPROVAL, PATIENT INFORMATION, AND INFORMED 
CONSENT ..........................................................................................................65
8.2
DATA QUALITY ASSURANCE .....................................................................65
8.3
RECORDS..........................................................................................................66
8.3.1
Source documents .................................................................................66
8.3.2
Direct access to source data and documents.......................................67
8.4
LISTEDNESS AND EXPEDITED REPORTING OF ADVERSE 
EVENTS..............................................................................................................67


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8.4.1
Listedness...............................................................................................67
8.4.2
Expedited reporting to health authorities and IECs/IRBs................67
8.5
STATEMENT OF CONFIDENTIALITY.......................................................67
8.6
END OF TRIAL.................................................................................................67
9.
REFERENCES......................................................................................... 68
9.1
PUBLISHED REFERENCES...........................................................................68
9.2
UNPUBLISHED REFERENCES.....................................................................72
10. APPENDICES .......................................................................................... 75
10.1
PHARMACOKINETIC METHODS...............................................................75
10.1.1 Evaluation of Pharmacokinetic Parameter ........................................75
10.1.2 Handling of missing data......................................................................76
10.1.2.1 Plasma concentration - time profiles........................................76
10.1.2.2 Pharmacokinetic parameters....................................................76
11. DESCRIPTION OF GLOBAL AMENDMENTS................................. 78


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ABBREVIATIONS
AChE-Is
Acetylcholinesterase Inhibitors
AD
Alzheimer’s Disease / Alzheimer’s Dementia
AE
Adverse Event
AESI
Adverse Events of Special Interest
ALT (SGPT)
Alanine Aminotransferase (Serum Glutamic-Pyruvic Transaminase)
AST (SGOP)
Aspartate Aminotransferase (Serum Glutamic-Oxaloacetic Transaminase)
 
 
 
 
BI
Boehringer Ingelheim
BP
Blood Pressure
BLQ
Below the Limit of Quantification
bpm
beats per minute
BRPM
Blinded Report Planning Meeting
 
cf.
Consult
CA
Competent Authority
CI
Confidence Interval
CIAS
Cognitive Impairment Associated with Schizophrenia
Cmax
 
Maximum concentration of the analyte in plasma
 
 
CLCR
Creatine Clearance (calculation)
CML
Local Clinical Monitor 
CNS
Central Nervous System
CRA
Clinical Research Associate
CRF
Case Report Form
CSF
Cerebrospinal Fluid
CT
 Concomitant Therapy
CTP
Clinical Trial Protocol
CTR
CYP
Clinical Trial Report
Cytochrome P450
DDI
Drug-Drug Interaction
DEDP
Drug Exposure During Pregnancy
DILI
Drug-Induced Liver Injury
DNA
Deoxyribonucleic Acid


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DSM-V
Diagnostic and Statistical Manual of Mental Disorders, Version V
ECG
Electrocardiogram
eCRF
Electronic Case Report Form
EM
Extensive Metabolizers
EOT
End of Trial
EudraCT
European Clinical Trials Database
FDA
Food and Drug Administration
gCV
Geometric coefficient of variation
gMean
Geometric Mean
GCP
Good Clinical Practice
h
hour
HV
Healthy Volunteers
IB
Investigator’s Brochure
ICH
International Conference on Harmonization
IEC
Independent Ethics Committee
IRB
Institutional Review Board
ISF
Investigator Site File
IUDs/IUSs
Intra Uterine Devices/Systems
LC-MS/MS
Liquid Chromatography Tandem Mass Spectrometry
MedDRA
Medical Dictionary for Drug Regulatory Activities
MRI
Magnetic Resonance Imaging
NC
Not Calculated
NCE
New Chemical Entity
NOA
Not Analyzed
NIMP
Non-Investigational Medicinal Product
NOAEL
No Observed Adverse Effect Level
NOP
No Peak Detectable
NOR
Novel Object Recognition
NOS
No Sample available
PBO
Placebo
PCP
Phencyclidine
p.o.
per os (oral)


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PK
Pharmacokinetics
PM
Poor Metabolizers
PR
Pulse Rate
q.d.
quaque die (once a day)
RBC
Red Blood Cell
RDC
Remote Data Capture
REP
Residual Effect Period, after the last dose of medication with measureable 
drug levels or pharmacodynamic effects still likely to be present
SAE
Serious Adverse Event
SOP
Standard Operating Procedures
SSRIs/SNRIs
Serotonin/Norepihnephrine Re-Uptake Inhibitors
SUSARs
Suspected Unexpected Serious Adverse Reactions
TCM
Trial Clinical Monitor
TDM
Trial Data Management
TDMAP
Trial Data Management and Analysis Plan
TMF
Trial Master File
TSAP
Trial Statistical Analysis Plan
TSTAT
Trial Statistician
 
tmax,ss
Time from (last) dosing to the maximum measured concentration of the 
analyte in plasma at steady state
ULN
Upper Limit of Normal
Vz/F
Apparent volume of distribution following an extravascular administration
WBC
White Blood Cell


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1.
INTRODUCTION
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).
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 25 million people in the 
world are currently affected by dementia, most of them suffering from AD, with around 5 
million new cases occurring every year (R10-5095; R10-5106). The age-specific prevalence 
of AD almost doubles every 5 years after age 65. Among developed nations, approximately 1 
in 10 elderly people (65+ years) is affected by dementia to some degree, whereas more than 
one third of the very old people (85+ years) may have dementia-related symptoms and signs 
(R10-5105).
AD is characterized, in the early stage, by an impairment of episodic memory and other 
cognitive domains, like executive function, orientation and judgment. 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. This is followed by a progressive 
decline in the ability to perform activities of daily living and the appearance of behavioral 
changes and/or psychiatric symptoms (mood disturbances, hallucinations, personality 
changes).
Schizophrenia is a chronic, severe, and disabling brain disorder affecting about one percent of 
the world´s general population. The symptoms of schizophrenia fall into three broad 
categories:

Positive symptoms, such as delusions, hallucinations, and disordered thoughts.

Negative symptoms, such as restricted affect and drive.

Cognitive symptoms, such as poor executive functioning, trouble focusing or paying             
attention, impairment of working memory, verbal and visual learning and memory.
Cognitive impairment is a core feature of schizophrenia. There is substantial evidence that 
cognitive deficits are a major determinant of functional recovery in schizophrenia. Around 
20-60% of the variance in functional outcome in schizophrenia is explained by cognitive 
performance.
On cellular level, AD is characterized by a progressive loss of synapses and neurons. 
Affected transmitter systems mainly include cholinergic and glutamatergic neurons. 
Cognitive dysfunction in schizophrenia is caused by an impaired functioning of glutamatergic 
pathways in (pre-) frontal cortical but also limbic areas of the brain (R10-5098; R10-5113;
R10-5103). Glutamate as the major excitatory neurotransmitter in the human brain is most 
prominently associated with functions of memory formation and learning. Glutamatergic 
transmission is mediated by various receptors with the post-synaptic NMDA receptor playing 
an essential role. Upon activation, a cascade of intracellular, post-synaptic signaling events is 


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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). Impaired 
NMDA receptor signalling and reduced levels of cGMP (R10-5110, P10-10289; R10-5097) 
have been shown in animal models of schizophrenia and in patients suffering from AD. 
Phosphodiesterase 9A (PDE9A) hydrolyses cGMP with the highest affinity of all PDEs and 
is highly expressed in the neocortex and hippocampus; therefore it is likely to be a significant 
determinant of intracellular basal cGMP levels in these brain regions.
PDE9A inhibitors should restore cGMP levels to physiological levels and give rise to 
memory improvement in patients via enhancing glutamatergic signalling, manifestation of 
long-term potentiation and strengthening of synaptic plasticity. BI 409306 showed 
convincing efficacy in two animal models of cognition enhancement addressing cognitive 
domains and brain regions known to be affected in AD and CIAS.
The pathophysiological mechanisms leading to deficits in cognition in schizophrenia and 
Alzheimer´s disease are largely unknown. Some of the deficits concern functions, such as 
working memory, attention, and perceptual organization, that have been proposed to involve 
synchronization of oscillatory activity in the high-frequency band (β and γ) (R14-3532). 
A substantial body of EEG studies supports the hypothesis that schizophrenia and AD are 
related to impaired neural synchrony and there is growing evidence that impaired sensory-
processing significantly contributes to the cognitive deficits in these disorders (R14-3419;
R14-3418; R14-3420). Sensory event-related potentials (ERPs) have also been widely used to 
examine basic neuronal activity in both normal brain function and in schizophrenia and 
Alzheimer´s disease, and have revealed abnormalities in the basic processing of both repeated 
and novel environmental stimuli (R14-3433) and may be used as biomarkers of the diseases 
(R14-3416; R14-3417).
Furthermore, visual acuity disturbances were the most common BI 409306 drug related 
adverse events, based on the phase I studies data.  Since the visual disturbances of the PDE5-
inhibitor sildenafil are known to be caused by its PDE6 off-target activity and PDE6 enzyme 
is expressed in photoreceptor cells of the retina, BI 409306 was evaluated for potential 
activity against recombinant human PDE6 isoforms revealing no relevant activity (i.e. IC50 > 
100 μM). Additionally, BI 409306 was tested for potential affinity to 95 off-target receptors 
at 10 μM using binding assays showing no relevant activity.
In summary, based on preclinical in vitro data, visual disturbances do not seem to be linked to 
PDE6 or other off-target activity of BI 409306. Two preclinical studies have been conducted 
to elucidate an explanation for these phenomena.
Since no data are available on PDE9 protein expression in the retina, an immunhistochemical 
analysis was performed in the first preclinical study in order to assess PDE9 expression in 
retina cells of rat and human tissue. This study demonstrated specific staining of PDE9 
expression in rat and human retina tissue, confirmed via both positive tissue control 
(cerebellum and kidney) and via negative control (absence of primary antibody; isotype 


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control). There was widespread distribution of PDE9 in the rat and human retina except the 
outer segment of the photoreceptor layer.
Subsequently, BI investigated in a second preclinical study the effects of PDE9- inhibitor BI 
409306 on rat retina in-vitro by measuring electro-retinogram (ERG) and ganglion cell 
activity using different concentrations and sildenafil, a PDE5-inhibitor with PDE6 off-target 
activity as an active control. Results show that the PDE9-inhibitor increased the amplitude of 
A-wave and B-wave of ERG, like the experimental control sildenafil. Field action potential 
analysis revealed that BI 409306, comparable to the experimental control sildenafil, enhanced 
spike activity of the retinal ganglion cells. The effects of BI 409306 and sildenafil on retinal 
activity (ERG and ganglion cell activity) were shown to be reversible.
As a conclusion from these experiments, PDE9 protein is expressed in retina and PDE9-
inhibition leads to changes in retina physiology (ERG and ganglion cell activity), providing a 
likely explanation for the transient visual effects noted in human.  
This study will utilize targeted ophthalmological assessments to further explain and 
characterize the effect of BI 409306 on ocular physiology.
1.2
DRUG PROFILE
1.2.1
Drug substance
BI 409306 is a new chemical entity (NCE) intended for oral administration. Film coated
immediate release tablets of 25 mg and 100 mg will be applied in this trial.
Pharmacology 
BI 409306 is a potent and selective PDE9A inhibitor. In vitro, BI 409306 inhibits the full-
length rat PDE9A with an IC50 of 168 nM and shows a long-lasting potentiation of 
hippocampal LTP in acute slices of rat brain (U10-2281; U10-2282; U10-2283; U10-2286).
In vivo, a dose-dependent increase of cGMP in brain and cerebrospinal fluid (CSF) was seen 
(U10-2288; U10-2287). In addition, BI 409306 reversed the memory impairment induced by 
the NMDA receptor antagonist MK-801 in T-maze spontaneous alternation test (T-maze) and 
novel object recognition test (U10-2472; U10-2284).
The results obtained with BI 409306 are well in line with the mode of action hypothesis of 
PDE9A inhibition, i e. targeting glutamatergic signalling pathway via increase of cGMP to 
strengthen LTP and synaptic plasticity leading to memory enhancement.
Preclinical Pharmacokinetics and Metabolism
The pharmacokinetics of BI 409306 in rats and dogs were characterized by rapid absorption 
and fast distribution into tissues. The volume of distribution was 0.8 l/kg in the rat and 1.4 
l/kg in the dog. Total plasma clearance was low in the rat (12.7 mL/min·kg) and in the dog 
(7.4 mL/min·kg). The absolute bioavailability accounted for 74% in rats and for 100% in 
dogs (C02101303).


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After oral administration of [14C] labeled BI 409306 to rats, 26.2% of the administered dose 
was recovered in feces and 64.5% was recovered in urine until 48 h post dose (C02101303).
BI 409306 is extensively metabolized, and two major Phase I metabolites are likely formed in 
humans (U10-2959; U10-2646). In vitro investigations with human hepatocytes and human 
liver microsomes demonstrated that BI 409306 oxidative metabolism is mainly dependent on 
cytochrome P450 (CYP) isoenzyme 2C19 (U10-2646). In human liver microsomes of 
CYP2C19 poor metabolisers, BI 409306 metabolism was low and mediated by CYP 3A4/5, 
though a contribution of further enzymes cannot be excluded (U11-2807).
The in vitro plasma protein binding of BI 409306 in humans is low (27%) and consistent over 
other species with no observed gender difference. BI 409306 showed a high intrinsic passive 
permeability in investigations with Caco-2 cells. BI 409306 was not a substrate of P-gp, 
BCRP and SLC. The drug was identified as weak inhibitor of P-gp, BCRP, OAT3 and other 
SLC-transporters with IC50’s of >500 μM, 100 - 500 μM, 26 μM and >200 μM, respectively.
An affinity to melanin containing tissues, i.e. skin and eye was observed; however, as BI
409306 does not significantly absorb light in the relevant wavelength of 290 – 700 nm, no 
phototoxic potential is expected. After single intravenous and oral administration to rats, BI 
409306 was extensively metabolised.
Drug-drug interactions based on inhibition or induction of cytochrome P450 enzymes by BI 
409306 are unlikely to occur. In vitro investigations with human hepatocytes and human liver 
microsomes demonstrated that BI 409306 metabolism is mainly CYP 2C19 dependent.
Safety Pharmacology (other than ocular)
Central nervous system
There was no effect of BI 409306 in the Irwin test in rats and on nocturnal motility in rats up 
to dose of 45 mg/kg. Reduced body weight gain (24 h post dose but reversible until Day 7), 
slight to moderate decrease in body temperature (15 min post dose) and slight decrease in 
locomotor activity (15 min post dose) were limited to the maximum dose tested (750 mg/kg) 
(C02101303).
Cardiovascular function
BI 409306 did not induce any effects on ECG and blood pressure in dogs (telemetry) up to 
the dose of 5 mg/kg. Dose dependent increase of contractility, heart rate with cases of sinus 
tachycardia and systolic ventricular pressure in the dose levels of 9 and 20 mg/kg were 
observed. Additionally, decrease in systolic pressure and reduction of RR/ PR/ QT intervals 
were limited to the highest dose level of 20 mg/kg (C02101303).
Respiratory function
No physiologically relevant findings up to the maximum dose tested (750 mg/kg).


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Gastrointestinal
BI 409306 had no effects on Gastrointestinal function in rats up to the maximum tested dose
1.2.2
Toxicology
Target organs identified after repeat-dose toxicity testing were liver (rats), adrenal glands
(rats), ovaries (rats), spleen (rats) and the cardiovascular system (rats and dogs) (R05-2282; 
U10-2597; U10-4089; U11-1173). Adverse effects in rats were mainly limited to the highest 
doses tested. Cardiovascular effects in dogs occurred also at lower dosages but were 
considered monitorable.
The No Observed Effect Levels (NOEL) after oral administration of BI 409306 for 13 weeks 
was 9 mg/kg (corresponding to Cmax) of 9090/7880 nmol/L, and AUC0-24h of 24600/13500 
nmol·h/L in males/females) in the rat. After oral administration of BI 409306 for 4 weeks the 
No Observed Adverse Effect Level (NOAEL) was 9 mg/kg (corresponding to C(max) of 
11900/13000 nmol/L, and AUC0-24h of 26900/30800 nmol·h/L in males/females) in the dog.
The overall assessment of genotoxicity testing in vitro and in vivo revealed that BI 409306 is 
not genotoxic.
Data from the dose range finding studies in mice and rats indicate a low potential of BI 
409306 for acute toxic effects (estimated LD50: > 750 mg/kg in mice; around 1000 mg/kg in 
rats; > 50 mg/kg in dogs).
Assessment of female reprotoxicity has not been conducted yet.
Specific toxicological aspects
The liver and the heart were identified as target organs for adverse histopathological changes, 
restricted to the highest tested dose of 750 mg/kg in rats (C02101303).
In the liver, adaptive hypertrophy of the hepatocytes (corresponding to reversibly elevated 
organ weight), mild exacerbation of apoptotic hepatocytes and postnecrotic microgranulomas 
in males were observed. 
Cardiac changes had also been noted in the 2-week oral dose range finding study, including 
multifocal fibrosis/fibroplasia in the septum and the papillary muscle. A nephropathy in the 
kidney was ascribed to the male rat-specific nephropathy due to accumulation of α2u-
globulin and therefore to be of no relevance for humans.
In the dog, the main finding was increased heart rate, ranging from moderate elevation to
tachycardia. Whereas cardiac histopathological changes (slight hemorrhages, inflammatory 
infiltration with focal necrosis) were noted in the escalating dose study with oral doses 
ranging from 10-50 mg/kg administered for 3 or 4 days each, no comparable morphological 
alterations were observed in the pivotal 4-week study up to 40 mg/kg. A slight cellular 
depletion of hematopoietic cells in the bone marrow was only observed in the escalating dose 


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study, was neither confirmed in the 2-week dose range finding study nor the pivotal 4-week 
study and thus may represent an incidental finding.
In summary, the non-clinical safety data of BI 409306 supported a clinical Phase I trial with
oral administration in patients with Alzheimer Disease and schizophrenia. The toxicological 
profile of BI 409306 was characterized by cardiac effects which seem to be consistent with 
those described for phosphodiesterase inhibitors in general. All adverse effects generally 
were restricted to high dose levels and were reversible. Visual side effects occurred shortly 
after dosing because there was widespread distribution of PDE9 in the retina but the side 
effects will mostly be resolved within 1 h. Based on the available non-clinical data, BI 
409306 was associated with an acceptable safety profile for phase I studies with oral 
administration under close monitoring of the toxicities identified, in particular careful 
monitoring of cardiac function and serum liver enzymes.
1.2.3
Clinical Study
Safety data from five phase I studies are available (U12-1034; U13-1182; U12-2165; U13-
1303; c02098989) in healthy young and healthy elderly volunteers. In all five healthy 
volunteer trials, the most frequent drug related adverse events were visual side effects that 
occurred shortly after dosing and mostly resolved within 1 hour. Therefore they are in close 
connection to maximum BI 409306 plasma concentrations as the concentration-time profile 
sharply and steeply peak within the first 1-2 hours and then rapidly decline afterwards.
In vitro data on BI 409306 evaluating potential activity against recombinant human PDE6 
isoforms in the retina revealed no relevant activity, indicating that visual disturbances do not 
seem to be linked to PDE6 or other off-target activity of BI 409306 (cf. Section 1.1). Two 
preclinical studies were then conducted to further explore this phenomenon.  The first study 
confirmed that there was a widespread distribution of PDE9 in the rat and human retina; and 
the second revealed enhanced spike activity of the retinal ganglion cells and that these 
activities were shown to be reversible.  It was concluded that PDE9 protein is expressed in 
retina and PDE9- inhibition leads to changes in retina physiology that likely result in the 
transient visual effects noted in human.
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). Following this observation, pharmacometric analysis of all available human 
data revealed a BI 409306 plasma concentration dependent increase in supine pulse reaching 
a maximum of 7-13 bpm (median) at high exposure end in CYP2C19 poor metabolizers 
treated with BI 409306 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.
None of the safety data presented a safety issue for further clinical trials.


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1.2.4
Pharmacokinetic profile in humans
BI 409306 is rapidly absorbed and distributed with maximum plasma concentrations
occurring within the first hour after oral administration to humans. Drug elimination occurs 
rapidly afterwards in an at least biphasic manner. Less than 2 % of the oral dose is recovered 
unchanged in urine. Plasma protein binding was determined at 27 % in humans.
BI 409306 is extensively metabolized. Compared to CYP2C19 extensive metabolizers (EM), 
poor metabolizers (PM) had about 2.2 - 2.3 and 4.1 - 5.0-fold higher peak and total exposure.
However, the Cmax and AUC0-∞ values observed in the PM group on the 10 mg and 100 mg 
dose level were still fully contained within the exposure-range observed in the EM group up 
to a dose of 350 mg.
In the multiple rising dose trials 1289.2 (U13-1182) and 1289.17 (U13-1303), only minor 
accumulation was seen, regardless of the predicted phenotype of CYP2C19, with mean 
accumulation ratios for Cmax and AUC of 1.02 to 1.41 among the once daily treatment groups 
evaluated. In both multiple dose trials, also elderly male and female volunteers (65 years or 
older) were included, who showed slightly higher exposure compared to the young volunteers 
at the highest tested dose of 100 mg q.d.
While plasma exposure increased slightly more than dose proportional over the dose range of 
0.5 mg to 350 mg tested in the single rising dose trial, no deviation from dose proportionality 
was noted in the multiple dose trial over the dose range from 25 mg to 100 mg given once 
daily.
A drug-drug interaction with fluvoxamine, a strong inhibitor of CYP2C19 and CYP1A2 
induced a 30-fold increase of the total plasma exposure (AUC0-24) and a 6-fold increase in 
Cmax of BI 409306. Mainly non-PMs (10 out of 13 subjects) and only 1 PM were included in 
the study. These results suggest that in non-PM, CYP1A2 is involved in BI 409306 
metabolism, in addition but to a lesser extent to CYP2C19, and that in PMs CYP1A2 is the 
major CYP450 isoform involved in the metabolism of BI 409306 (Study 1289_0035).
BI 409306 enters the CSF as shown in trial 1289.3 (U12-2165) after single dosing from 25 to 
200 mg. The maximum concentration (Cmax) of BI 409306 in plasma was achieved between
0.75 h and 1.25 h after drug administration and between 1.50 h and 2.00 h after drug
administration in CSF. As such, the maximum CSF concentrations were reached 
approximately 0.75 h to 1.25 h after the maximum plasma concentrations and increased with 
increasing dose. The dose-adjusted gMean (90% CI) CSF to plasma ratio of the BI 409306 
Cmax was 28.31% (25.42% to 31.53%). After attainment of Cmax, BI 409306 concentrations 
declined in a monophasic manner in CSF with a similar terminal half-life compared to plasma 
(1.28 h to 2.35 h in plasma and 1.24 h to 1.62 h in CSF).
For further details please see the current version of the BI 409306 Investigator’s Brochure 
(C02101303).


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2.
RATIONALE, OBJECTIVES, AND BENEFIT - RISK 
ASSESSMENT
2.1
RATIONALE FOR PERFORMING THE TRIAL
This trial is designed to evaluate the ocular safety, tolerability and pharmacokinetics of BI 
409306 film coated tablets administered in 25mg q.d. or 100 mg q.d. given orally for 14 days 
in patients with schizophrenia or Alzheimer’s disease, and compared to age-comparable 
healthy volunteers.
There are currently no approved medications indicated for the treatment of cognitive 
impairment in schizophrenia, and currently approved AD treatment is purely symptomatic. 
Registered symptomatic treatment consists of acetylcholinesterase inhibitors (AChE-Is) and 
memantine. AChE-Is in general and donepezil in particular can be currently regarded as gold 
standard for treatment of mild to moderate AD.  As the AD research interest are moving 
toward more effective symptomatic treatment options and new compounds with a disease-
modifying potential, the current focus on a symptomatic treatment that proves to be more 
efficacious than the currently available compounds (AChEIs, memantine) in improving both 
existing cognition deficits and the ability to better perform activities of daily living would 
provide a substantial benefit to patients.
Safety data from five phase I studies are available (U12-1034; U13-1182; U12-2165; U13-
1303; c02098989) in healthy young and healthy elderly volunteers, and one study in patients 
with schizophrenia (Study 1289.18, c02318916). In all six studies, the most frequent drug 
related adverse events were visual side effects (such as sensation of flashing lights, altered
colour perception, photophobia/ increased sensitivity to light or blurred vision) that occurred 
shortly after dosing of BI 409306 and mostly resolved within 1 hour. Therefore they are in 
close connection to maximum BI 409306 plasma concentrations as the concentration-time 
profile sharply and steeply peak within the first 1-2 hours and then rapidly decline afterwards. 
Further preclinical investigations were performed that link PDE9 expression and function in 
rat and human retina to these clinical findings. This study will further characterize the effect 
of BI 409306 on ophthalmologic physiology in patients with AD, patients with CIAS, and 
healthy volunteers.  
Mismatch negativity (MMN), P1, N1 and P3a, and evoked gamma power are auditory ERP 
components that have emerged as translational biomarkers with promising applications for 
use in clinical studies to assess drug sensitivity.
Patients with schizophrenia and Alzheimer’s disease have been shown to have abnormal 
electroencephalographic (EEG) gamma-band responses (GBRs) associated with sensory
(R14-4685; R14-4695; R14-4678; R14-4679; R14-4680), perceptual (R14-4681) attentional 
(R14-4682), and cognitive control (R14-4677) processes. Glutamatergic neurotransmission at 
NMDA receptors provides excitatory regulation of parvalbumin fast-spiking interneurons, 
contributing to the generation of gamma oscillations in pyramidal cell networks (R14-4684).
Gamma oscillatory activity non-invasively measured by EEG in patients with schizophrenia 
is of interest because disrupted GABAergic and glutamatergic cortical activity have been 
implicated in the pathophysiology of the illness.


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MMN, P1, N1 and P3a components are sequentially evoked as an ERP complex in response 
to unattended changes in background stimulation (R14-4688; R14-4689). Since these 
measures require no overt behavioral response and can be elicited even in the absence of 
directed attention (R14-4688; R14-4690), they are presumed to reflect a predominantly 
automatic or pre-conscious process of detecting a “mismatch” between the deviant stimulus 
and a sensory–memory trace (R14-4683).
Previous studies have demonstrated that MMN, P1, N1 and P3a are each significantly 
correlated with distinct domains of cognitive (R14-4687) and psychosocial functioning (R14-
4686).  
Because of the established link between these ERP components, the glutamatergic system, 
and cognitive deficits in AD and schizophrenia, they will be measured in healthy volunteers, 
AD patients and schizophrenia patients to further understand the effect of BI 409306 (R14-
3419, R14-3418, R14-3420).
Single dose of 100 mg BI 409306 in Chinese CYP2C19 poor metabolizers subjects showed a 
rapid and short lasting increase in supine pulse rate of 12.9 ± 4.4 bpm.  Further observations 
on this population revealed a BI 409306 plasma concentration dependent increase in supine 
pulse reaching a maximum of 7-13 bpm (median) at high exposure (median Cmax was 
achieved at 0.417 h) approximately 25 min minutes post dose in Trial 1289.4 and ranged 
from 0.167 to 0.750 h post dose) and disappeared rapidly with declining concentrations
(c02098989). This study will include 24-hour heart rate monitoring to further explore the 
cardiac safety of BI 409306.
The ophthalmologic physiology and neurophysiological biomarkers observations, along with
the additional safety and pharmacokinetic profiles will support further studies to define safety 
and efficacy of BI 409306 in patients with AD and CIAS.
2.2
TRIAL OBJECTIVES
Primary objective:
To investigate the ocular safety of BI 409306 in patients with schizophrenia, Alzheimer’s 
disease, and age-comparable healthy volunteers following oral administration of 25 mg and 
100 mg over 14 days.
Secondary objectives:
To evaluate the systemic safety and pharmacokinetics of BI 409306 in patients with 
schizophrenia, Alzheimer’s disease, and age-comparable healthy volunteers following oral 
administration of 25 mg and 100 mg over 14 days.
It is not planned to test any statistical hypotheses. See Section 5 for details on safety 
endpoints.


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2.3
BENEFIT - RISK ASSESSMENT
The target structure (PDE9) for the compound BI 409306 is widely distributed in various
tissues and organs but predominantly localized throughout the specific brain areas
(hippocampus, cortex, olfactory bulb, striatum, thalamus, hypothalamus, amygdala, midbrain,
cerebellum (R12-4412, R10-5402).
The enzymatic action of cyclic nucleotide PDEs is the primary mechanism for inactivation of
cAMP/cGMP by hydrolyzing. Inhibition of PDE9 increases the intracellular availability of
the second messenger cGMP and consequently could have a positive effect on several aspects
of cognition, including information processing, attention, memory and executive functioning.
Based on its mechanism of action and its preclinical profile, including the in vitro, in vivo
pharmacology data, the data from toxicology studies in two species as well as the data
obtained in the clinical studies (U12-1034, U12-2165, U13-1182), there is no indication that 
BI 409306 should be regarded as a high risk compound.
Overall, BI 409306 shows a favorable nonclinical safety profile. There was no genotoxic
potential of BI 409306. The toxicological profile of BI 409306 is characterized by cardiac
effects which seem to be consistent with those described for phosphodiesterase inhibitors in
general. Previous clinical trials found that BI 409306 was well tolerated in young and elderly 
healthy subjects in single doses of 0.5 to 350 mg and multiple doses up to 100 mg once daily. 
The most frequent drug related adverse events were visual side effects that occurred shortly 
after dosing and mostly resolved within 1 hour. All adverse effects generally were restricted 
to high dose levels and were reversible (U12-1034; U13-1182; U12-2165; U13-1303). 
Cardiac function will be monitored during the study, along with a 24-hour ambulatory heart 
rate monitoring (cf. Flow Chart).
As with all drugs, the potential for hypersensitivity and allergic reactions have to be taken
into consideration when BI 409306 is administered. Other risks are inherent to any early
clinical trial such as unexpected adverse clinical or laboratory event. 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 subjects´ safety. 
No studies have been done with BI 409306 in pregnant women or women who are nursing 
their infants. It is unknown if BI 409306 is safe for pregnant women, unborn babies and 
infants who are nursing. It is unknown either if BI 409306 has an effect on sperm or eggs. 
Hence, female subjects who are nursing or pregnant are not allowed to join the study. Female 
subjects who are of child-bearing potential must accept to use a reliable form of birth control 
throughout the trial and follow-up period.
A potential effect of BI 409306, a centrally acting compound, on suicidality cannot be ruled 
out. Therefore, suicidality monitoring will be performed pre-dose and throughout the study to 
ensure that potential suicidality will be recognized in order to apply appropriate action. 
This is an experimental drug at an early stage of testing and therefore an individual benefit
cannot be guaranteed. The study procedures (e.g. ocular assessments, safety and suicidality 


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monitoring, etc.) may in fact benefit the patients e.g. intensive medical care, a potentially 
better knowledge of the underlying disease which may lead to a better handling of AD and 
CIAS patients. Even if there is no direct benefit for the subjects during participation in this 
trial, it can be assumed that the trial results may contribute to better drug development in 
future. 
This study will explore the ophthalmologic changes with respect to the visual acuity effects
and other neurophysiological changes in order to further investigate the safety, tolerability 
and pharmacokinetics of the doses of BI 409306 (25 mg and 100 mg) that were already 
established to be within the safety margin of therapeutic dose. 


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3.
DESCRIPTION OF DESIGN AND TRIAL POPULATION
3.1
OVERALL TRIAL DESIGN AND PLAN
This is a multi-center, double-blinded, parallel groups study in patients with mild 
Alzheimer’s Dementia (AD) and cognitive impairment associated with schizophrenia (CIAS), 
and healthy volunteers (HV). 
Approximately 60 subjects (20 with AD, 20 with CIAS, and 20 age-comparable HV) who 
met the eligibility criteria will be randomized into either the BI 409306 25mg or 100 mg 
treatment group according to the study design provided (see Figure 3.1: 1).  Refer to Section
3.3.2 for description of age-comparable healthy volunteers (e.g. definition of low age group 
and high age group).
Figure 3.1: 1 Overview of study design
25 mg
n = 10
HV Group
N = 20
100 mg
n = 10
High age group (n = 5)
25 mg
n = 10
CIAS Group
N = 20
100 mg
n = 10
25 mg
n = 10
AD Group
N = 20
100 mg
n = 10
Low age group (n = 5)
High age group (n = 5)
Low age group (n = 5)
Day 1
First dose
Intensive PK
Day 14
Last dose
Intensive PK
Day 21+
EOT
Day -2 
and/or -1
Baseline
Follow-up
BI 409306 25mg QD 
OR
BI 409306 100mg QD


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Subject’s participation starts once they have signed the informed consent form. Eligible 
patient/volunteers enter the trial (Figure 3.1: 1) at Visit 2, are treated for 14 days with either 
the BI 409306 25mg or 100 mg and are then followed up for an additional 1-2 weeks. 
Patient/volunteer participation is concluded when they have completed the End-of-Trial 
(EOT) visit at Day 21+ (unless the patient is lost to follow up, informed consent is withdrawn 
or early discontinued). For more details about the visit schedule please cf. Flow Chart.
Adverse events that begin during treatment with all trial medications (BI 409306 25mg or 
100 mg), or in the 7-day interval thereafter of the residual effect period (REP), will be 
considered “on treatment events”. For more details about the safety assessment in this trial cf. 
Sections 5.2 and 7.3.3.
3.1.1
Administrative structure of the trial
The trial is sponsored by Boehringer Ingelheim. 
Boehringer Ingelheim (BI) will appoint a Trial Clinical Monitor (TCM), who is responsible 
for coordinating the activities required 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 materials as needed for the 
trial, ensuring appropriate training of the clinical monitor local (CML), clinical research 
associates (CRAs) and investigators.
Data management and statistical evaluation will be performed by BI according to BI SOPs.  
For these activities, a Trial Data Manager (TDM) and Trial Statistician (TSTAT) will be 
appointed.
Documents on participating investigators, including their curricula vitae, will be filed in the 
TMF.  
The Investigator Site File (ISF) will be maintained at the sites as required by local regulation 
and BI SOPs. A copy of the ISF documents will be kept as an electronic document in BIRDS
according to BI SOPs.
3.2
DISCUSSION OF TRIAL DESIGN, INCLUDING THE CHOICE OF 
CONTROL GROUP
This randomised, double-blinded, parallel group design was chosen for this study to observe 
the effects of BI 409306 within the patient groups (AD, CIAS) and healthy volunteers for two 
treatments.  Each eligible patient or healthy volunteer will be blindly randomized to either the 
BI 409306 25 mg or 100 mg dose treatment.  The patient or healthy volunteer will be 
dispensed three tablets from the study medication carton assigned.  If randomized to the 25 
mg dose group, they will be taking one BI 409306 25 mg and two BI 409306 50 mg matching 
placebo tablets; or to the 100 mg dose group, one BI 409306 25 mg matching placebo and
two BI 409306 50 mg tablets.
The population/patient group sizes (20 subjects with 10 per dose group) are in general 
considered sufficient for the exploratory nature of this study.


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The healthy volunteer group acts as the control, with double blinding to provide additional 
control. Refer to Section 3.3.2 for description of age-comparable healthy volunteers.
3.3
SELECTION OF TRIAL POPULATION
This study is planned as a -multi-center with approximately 60 male and female subjects will 
be entered into this study: 20 patients with AD, 20 patients with CIAS, and 20 HV (see 
Figure 3.1: 1).
A log of all subjects included in the study (i.e. having given informed consent) will be 
maintained in the ISF at the investigational site irrespective of whether or not they have been 
treated with investigational product. 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.
3.3.1
Main diagnosis for study entry
Patients with established diagnoses of schizophrenia age 18-55 years (per Diagnostic and 
Statistical Manual of Mental Disorders version V (DSM-V)), or Alzheimer’s Disease patients 
55-85 years old currently treatment-naïve or on stable treatment(s) of at least 3 months before 
screening, or healthy volunteers (age-comparable to the two patient groups).
3.3.2
Inclusion criteria
1. Schizophrenia group:
a. Patients with established diagnoses of schizophrenia (per Diagnostic and Statistical 
Manual of Mental Disorders version V (DSM-V, R14-2136)) with the all of the
following clinical features:
i. Clinically stable and are in the residual (non-acute) phase of their illness 
for at least 8 weeks prior to randomisation
ii. Current antipsychotic and concomitant psychotropic medications must 
meet the criteria below: 
ii)-1. Maintained on current atypical (second generation) antipsychotic             
medications (in any approved dosage form) other than Clozapine and on 
current dose for at least 8 weeks prior to randomisation, and/or 
ii)-2. Maintained on current typical (first generation) antipsychotic 
medications and on current dose for at least 6 months, optionally combined 
with anticholinergics if treated with a stable dose for at least 6 months 
prior to randomisation, and/or
ii)-3. Maintained on current concomitant psychotropic medications other 
than anticholinergics, antiepileptics and lithium, and on current dose for at 
least 8 weeks prior to randomisation. Antiepileptics and lithium are 
allowed if initiated at least 6 months prior to randomisation. 
iii. Have no more than a ‘‘moderate’’ severity rating on 
hallucinations and delusions (Positive and Negative Syndrome 
Scale (PANSS)–positive syndrome Hallucinatory Behavior 
item score ≤ 4 and Delusions item score ≤ 4)


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iv. Have no more than a ‘‘moderate’’ severity rating on positive 
formal thought disorder (PANSS–positive syndrome 
Conceptual Disorganization item score ≤ 4)
v. Have a minimal level of extrapyramidal symptoms (Simpson-
Angus Scale total score < 6) and depressive symptoms 
(PANSS–general psychopathology syndrome Depression item 
score ≤ 4)
b. Male or female patients age 18 to 55 years.
OR
Alzheimer’s Disease group:
a. Patients with diagnosis of mild Alzheimer’s Dementia based on DSM-V and in 
accordance with the recommendations from the National Institute on Aging-
Alzheimer’s Association workgroups on diagnostic guidelines for Alzheimer’s 
disease (R13-4115).
b. Mini-Mental State Examination (MMSE, R02-0395) score of 18-26.
c. Male or female patients age 55 to 85 years, who have not been taking acetyl 
cholinesterase inhibitors (donepezil, galantamine, rivastigmine) and/or memantine for 
at least 3 months or on stable dose of acetyl cholinesterase inhibitors (donepezil, 
galantamine, rivastigmine) and/or memantine at least 3 months before randomization.
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.
d. Availability of a pre-existing cranial computer tomography (CCT) or magnetic 
resonance imaging (MRI) scan of the brain (initiation of radiological imaging is not 
required) not older than one year prior to screening; if not available, a CCT must be 
performed at screening. Results of radiological brain imaging must be compatible 
with Diagnosis of Alzheimer Disease and exclusion of relevant signs indicative of 
potential vascular dementia (see also exclusion criteria).
e. If needed, a caregiver may be present during site activities.
OR
Age-comparable male or female healthy volunteers age 18 to 85 years. Healthy 
volunteers 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:
a. After 10 patients with schizophrenia (as described above) are entered into the study, 
the median age of the group will be computed.  Five healthy volunteers at or below 
the median age but greater than 18 years old (low age group) and five healthy 
volunteers above the median but less than 55 (high age group) will be entered into the 
study.  
b. Similarly, after 10 patients with AD are entered , the median age will be computed.  
Five healthy volunteers at or below the median age but greater than 55 years old (low 


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age group) and five healthy volunteers above the median (high age group) will be 
entered into the study.
2. Subjects must exhibit reliability and physiologic capability, per investigator judgment, to 
comply with all protocol procedures.
3. Signed and dated written informed consent by date of Visit 1 in accordance with GCP and 
the local legislation.  If the patient needs a legal representative, then this legal 
representative must give written informed consent as well. 
3.3.3
Exclusion criteria
1. Presence of active ocular conditions with or without visual impairment due to any causes 
(e.g. cataract, chorioretinal macular lesion, amblyopia, active diabetic retinopathy, 
uncontrolled glaucoma, active inflammation or infection, etc.) in one eye or both eyes at 
the screening phase that may interfere with the ocular assessments or analyses and
interpretation of the results from this study, in the clinical judgment of the investigator.
2. Planned ocular treatment (e.g. intravitreal antivascular growth factor, corticosteroids) or 
surgery during the study period.
3. Current or planned use of ocular or systemic corticosteroids.
4. Current or planned use of medications known to be toxic to the retina, lens, optic nerve 
(e.g. choroquine/hydrochoroquine, chlorpromazine, tamoxifen, desferoximine, etc.).
5. Subjects treated with more than two antipsychotic medications (including more than two 
dosage forms).
6. Subjects needing to take long-acting hypnotics or anxiolytic (i.e. Diazapam).
7. Subjects taking medications that are known to be strong or moderate CYP1A2 inhibitors 
(For a list of strong and moderate CYP1A2 inhibitors please consult the ISF Section 11 
“Safety Information”).
8. Dementia in AD patients, secondary to other disorders (based on clinical data and/or 
current laboratory findings and/or on a pre-existing cranial MRI or CCT which is not 
older than 12 months prior to screening visit)*, for example: small vessel disease, 
neurosyphilis, craniocerebral trauma. 
*If it is not already available then a CCT scan must be performed at screening.
9. Neurological disease (other than Dementia of Alzheimer Type such as: Lewy body 
dementia - primary diagnosis, Huntington’s disease, Parkinson’s Disease encephalitis, 
epilepsy, vascular or multi-infarct dementia, stroke, congenital mental deficiency, or 
multiple sclerosis), or mental retardation.


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10. For AD patients, the following drugs are prohibited for 3 months prior to randomization 
and for 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.
e.
Intake of St. Johns wort, Carbamazepine and extracts from Ginko as they are 
relevant CYP2C19 inducers.
The following drugs may be given as needed if the total daily dose was stable 8 weeks 
prior to randomization and is expected to be stable for the duration of the trial:
a.
neuroleptics listed in Section 4.2.2,
b. benzodiazepines and sedatives listed Section 4.2.2.
11. 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 judgment.
12. Any suicidal ideation of type 4 or 5 in the Columbia Suicidal Severity Rating Scale (C-
SSRS) in the past 3 months (i.e. active suicidal thought(s) with intent but without specific 
plan, or active suicidal thought(s) with plan and intent).
13. Any suicidal behavior in the past 2 years (i.e. actual attempt, interrupted attempt, aborted 
attempt, or preparatory acts or behavior).
14. History or diagnosis of symptomatic and unstable/uncontrolled gastrointestinal, hepatic, 
renal, respiratory, cardiovascular, metabolic, immunological, haematological or hormonal 
disorders.
15. For female subjects:
Pre-menopausal women (last menstruation ≤1 year prior to informed consent) who:

are nursing or pregnant or

are of child-bearing potential and are not practicing an acceptable method of birth control, 
or do not plan to continue using this method throughout the trial until 28 days after the 
last treatment administration, and do not agree to submit to periodic pregnancy testing 
during participation in the trial. Acceptable methods of birth control include tubal 
ligation, vasectomized partner, 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).


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For male subjects:
Men who are able to father a child, unwilling to be abstinent or use adequate contraception 
for the duration of study participation and for at least 28 days after treatment has ended.
16. Known history, or new diagnosis per screening labs, of HIV infection.
17. Significant renal disease (primary or secondary) (for example severe renal impairment
(CLCR < 30 mL/min).
18. Bodyweight < 50 kg.
19. Indication of liver disease, defined by serum levels of either ALT (SGPT), AST (SGOT),
or alkaline phosphatase above 3x upper limit of normal (ULN) as determined during
screening.
20. History of neurologic (e.g. stroke, seizure without a clear and resolved etiology, 
concussion accompanying loss of consciousness) or psychiatric condition that the 
investigator deems may interfere with interpretability of data.
21. History of malignancy within the last 5 years, except for basal cell carcinoma.
22. Planned elective surgery requiring general anaesthesia, or hospitalisation during the study 
period.
23. Significant history of drug dependence (with the exception of nicotine dependence) or
abuse (including alcohol, as defined in DSM-V or in the opinion of the investigator) 
within the last two years prior to informed consent, or a positive urine drug screen for 
cocaine, opioid, phencyclidine (PCP), amphetamine or marijuana at screening.
24. Clinically significant uncompensated hearing loss in the judgment of the investigator. Use 
of hearing aids is not allowed.
25. Known hypersensitivity to drug product excipients (gelantin, povidone K25, lactose
monohydrate, microcrystalline cellulose, pregelatinized starch, hydroxypropylcellulose,
croscarmellose sodium, magnesium stearate, hypromellose, propylene glycol, titanium
dioxide, talc and iron oxide yellow).
26. Participation in another trial with an investigational drug or procedure within 30 days 
prior to screening or previous participation in any BI 409306 study.
27. Any evidence of a clinically relevant concomitant disease, or clinical condition that in the 
opinion of the investigator would jeopardize patient’s safety while participating in this 
trial.
28. Subjects not willing or able to comply with the protocol requirements or considered
unreliable by the Investigator concerning the requirements for follow-up during the study 
and/or compliance with study drug administration.


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3.3.4
Removal of subjects from therapy or assessments
3.3.4.1
Removal of individual subjects
An individual patient must be withdrawn from the treatment if:

The patient withdraws consent, without the need to justify the decision.

The patient needs any invasive procedure such as cataract surgery, laser 
photocoagulation or retinal surgery during the study period.

The patient needs any invasive procedure as cardiac catheterism or stent.

The patient becomes pregnant during the trial. Patient will be followed up until birth
or otherwise termination of the pregnancy.

The patient needs to take concomitant drugs that interfere with the investigational
product(s), in the clinical judgment of the investigator.

The patient is no longer able to participate for other medical reasons (e.g. surgery,
AEs, or other diseases).

The patient needs to stop all current antipsychotic or concomitant psychotropic
medications.

The patient’s disease state dramatically worsens, in clinical judgment of investigator.

The patient experiences clinically significant loss of visual acuity and/or any ocular 
symptoms/signs attributable or not to the study medication, by the investigator’s 
judgment (e.g. acute loss of vision ≥5 letters, new macular changes such as intra- or 
sub-retinal fluids or haemorrhage, etc.).

The patient exhibits suicidality, in the clinical judgment of the investigator or
according to criteria below:

Any suicidal behavior (i.e. actual attempt, interrupted attempt, aborted attempt, or 
preparatory acts or behavior)

Any suicidal ideation of type 4 or 5 in the C-SSRS (i.e. active suicidal thought(s)
with intent but without specific plan, or active suicidal thought(s) with plan and
intent).
A patient can be discontinued from treatment after discussion between sponsor and
investigator if eligibility criteria are being violated, or if the patient fails to comply with the
protocol (e.g. non-attendance at study assessments).
Subjects who discontinue participation after signing the informed consent form but prior to
randomization (Visit 2) will be considered screening failures. For screening failure subjects,
the demographic, AE, concomitant medication and randomization eCRFs in RDC must be
completed. The subjects will be identified as screen failures in the randomization eCRF and
no further follow-up is required. SAEs occurring in subjects after having discontinued in the 
study due to screening failures, and who did not receive any study medication, do not need to 
be reported, unless the investigator considers the SAE related to the screening procedures.
Subjects who discontinue or withdraw from the study after randomization (Visit 2) will be
considered as “early discontinuations” and the reason for premature discontinuation must be
recorded in the eCRFs (cf. Section 6.2.3 for early discontinuation procedures). The data will 


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be included in the trial database and will be reported. Subjects who withdraw or discontinue 
from the trial after randomization will not be replaced.
3.3.4.2
Discontinuation of the trial by the sponsor
Boehringer Ingelheim reserves the right to discontinue the trial overall or at a particular trial 
site at any time for the following reasons:
Failure to meet expected enrolment goals overall or at a particular trial site,
Emergence of any efficacy/safety information that could significantly affect continuation of 
the trial,
Violation of GCP, the approved 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
BI 409306, as a film-coated tablet, will be produced by Boehringer Ingelheim Pharma GmbH 
& Co. KG. Each film-coated tablet contains 25 mg or 50 mg BI 409306, or matching placebo 
blistered in 7-count Alu blister strips.
Eligible subjects will be assigned to each treatment group (25 mg or 100 mg) alternatively in 
the order that they randomized (cf. Section 3.1 and Section 3.3.2).
4.1.1
Identity of BI investigational product and comparator product
The following table summarizes the information about the investigational products as used in 
this trial:
Table 4.1.1: 1 
BI 409306, 25 mg and 50 mg
Substance: 
BI 409306
Pharmaceutical form: 
Film-coated tablet
Manufacturer: 
Boehringer Ingelheim Pharma GmbH & Co. KG
Unit Strength: 
25 mg, 50 mg
Daily dose: 
25 mg q.d. or 100 mg q.d.
Route of administration:
Per os (oral)
Posology: 
Once daily
Duration of use:
14 days
Table 4.1.1: 2
Placebo matching BI 409306, 25 mg and 50 mg
Substance: 
BI 409306
Pharmaceutical form: 
Film-coated tablet
Manufacturer: 
Boehringer Ingelheim Pharma GmbH & Co. KG
Unit Strength: 
N/A
Daily dose: 
N/A
Route of administration:
Per os (oral)
Posology: 
Once daily
Duration of use:
14 days


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4.1.2
Method of assigning subjects to treatment groups
Subjects eligible for the trial will be assigned at random in a 1:1 ratio of 25 and 100 mg dose 
per group at Visit 2 (cf. Section 3.1). Details on randomization are provided in Section 7.5. 
Assignment to the treatment groups will be determined at the site by having the next lowest 
sequentially numbered medication kit within each subject population group assigned (AD 
group, CIAS group, HV/AD low age group, HV/AD high age group, HV/CIAS low age 
group, HV/CIAS high age group). The assigned medication number will be entered in the 
eCRF and the corresponding medication kit should be given to the patient/healthy volunteer.
Using this procedure, the Investigator and study staff will be blinded to the assignment to 
which the patient was randomized. Note that the medication numbers assigned to the patient
are different from the patient number.
4.1.3
Selection of doses in the trial
According to the result of previous trials, BI 409306 was well tolerated in young and elderly
healthy subjects in single doses of 0.5 to 350 mg and multiple doses up to 100 mg once daily. 
The doses selected for this trial cover the estimated therapeutic range and include a safety 
margin (cf. Section 1.2).
4.1.4
Drug assignment and administration of doses for each patient
Patient/healthy volunteer will be assigned study medication and the first dose administered on 
site at Visit 3, Day 1. Other doses may be administered at home, according to the home visits 
optional schedule as specified in the Flow Chart.  Each patient/healthy volunteer will be 
administered three tablets, one from each blister dispensed.  Table 4.1.4: 1 outlines the 
treatment and administration of dose for each patient/volunteer.
Table 4.1.4: 1
BI 409306 and matching placebo treatment, oral administration
Treatment Group
Total Drug Administered
Packaging
BI 409306 25 mg
BI 409306 25 mg active
Orange-Label 25 mg Blister
BI 409306 50 mg matching PBO
BI 409306 50 mg matching PBO
Blue-Label 50 mg Blister
BI 409306 100 mg
BI 409306 25 mg matching PBO
Orange-Label 25 mg Blister
BI 409306 50 mg active
BI 409306 50 mg active
Blue-Label 50 mg Blister
The study medication will be administered with about 240 mL of water in the sitting/standing 
position under supervision of the investigating physician or designee.


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Subjects are not allowed to lie down during the 2 hours following drug administration except
for medical examination. They are not allowed to sleep. Water is allowed ad libitum except
for one hour before and after drug administration. During in-patient, standardized meals will 
be served at 1, 5 and 10 hours (± 1 hour) following drug administration post dose on days 1 
and 14. Additionally, snacks will be served at 7 hour and 13 hour (± 1 hour) post dose on all 
days. The time of last meal before drug administration will be recorded on PK blood draw 
Days 1 and 14.
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 unblinding
4.1.5.1
Blinding
Subjects, investigators and everyone involved in analysing or with an interest in this double 
blind study will remain blinded with regard to the randomized treatment assignments until
after database lock.
The randomization code will be kept secret by Clinical Trial Support up to database lock.
They will only release it in accordance with BI standard operating procedures.
The study will only be unblinded after all Adverse Event (AE) related eCRF / electronic data
have been entered into the trial data base and after AE related queries have been resolved.
4.1.5.2
Procedures for emergency unblinding
An emergency code break will be available to the investigator / pharmacist / investigational
product storage manager. This code break may only be opened in emergency situations when 
the identity of the trial drug must be known to the investigator in order to provide appropriate
medical treatment or if required to assure safety of trial participants. If the code break for a
patient is opened, the sponsor must be informed immediately. The reason for opening the
code break must be documented on the envelope or appropriate eCRF page along with the 
date and the initials of the person who broke the code.
4.1.6
Packaging, labelling, and re-supply
Drug supplies will be provided by the Department of Pharmaceutical Development of 
Boehringer Ingelheim Pharma GmbH & Co. KG, Biberach, Germany. The clinical trial 
supply consists of patient specific kits with trial identification that hold the trial medication. 
The blister within the clinical trial supply kits are labelled with:

Trial number

Name of product and strengths

Pharmaceutical dosage form, quantity of dosage units

Route and mode of administration

Term “for clinical trial use”

Sponsor name and address


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
Storage conditions

Use by date

Medication number

Batch number 
Label examples are given in the Investigator Site File (ISF).
All drug supplies will be shipped to sites in the initial shipment with re-supply as needed.
For details of packaging and samples of the label, refer to the ISF.
4.1.7
Storage conditions
Drug supplies will be kept in their original packaging under the labeled storage conditions. 
The trial medication must be stored securely, e.g. in a locked cupboard or at a pharmacy. It 
may only be dispensed to trial subjects according to the protocol by authorized personnel as 
documented in the Trial Staff List in the ISF.
All unused medication must be returned to the sponsor. Receipt, usage and return must be 
documented on the respective forms. Account must be given for any discrepancies.
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. A temperature log 
must be maintained to make certain that the drug supplies are stored at the correct 
temperature.
The investigator / pharmacist / investigational product storage manager will receive the
investigational products 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

availability of the proof of a medical licence for the principal investigator, 

availability of the FDA Form 1572.
The investigator / pharmacist / investigational product storage manager must maintain 
records of the product’s delivery to the trial site, the inventory at the site, the use by each 
patient/healthy volunteer, and the return to the sponsor or alternative disposition of 
unused/expired product(s). 


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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 subjects. The 
investigator / pharmacist / investigational product storage manager will maintain records that 
document adequately that the subjects 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 product storage manager must verify 
that all unused or partially used/expired drug supplies have been returned by the clinical trial 
patient and that no remaining supplies are in the investigator’s possession.
4.2
CONCOMITANT THERAPY, RESTRICTIONS, AND RESCUE 
TREATMENT
4.2.1
Rescue medication, emergency procedures, and additional treatment
There are no special emergency procedures to be followed. No rescue medication, emergency 
procedure or additional treatment is foreseen for this study.
Throughout the duration of the trial subjects should continue to take their current
antipsychotic and concomitant psychotropic medications, the dose of which should remain
unchanged unless necessary for the welfare of the patient. These medications will not be
provided as part of the clinical trial supplies, unless required by local laws and regulations.
Any change in dose of antipsychotic and concomitant psychotropic medications should be
recorded in the source documentation and on the appropriate pages of the eCRF.
Any additional treatment that is considered necessary for the patient’s/healthy volunteer’s
welfare may be given at the discretion of the Investigator.
4.2.2
Restrictions
4.2.2.1
Restrictions regarding concomitant treatment
Any medication that may interfere with the action of BI 409306 or whose action may be
altered by concomitant administration of BI 409306 during the treatment period and the 14-
day follow-up period, in the clinical judgment of the investigator, is not permitted.
Chronic use (≥ 14 days) of topical or systemic corticosteroids is restricted during the study 
period.
Use of medications that are known to be strong or moderate CYP1A2 inhibitors is not 
permitted. (For a list of strong and moderate CYP1A2 inhibitors please consult the ISF 
Section 11 “Safety Information”).
No entering or modification of smoking-cessation programs may occur during the conduct of 
the trial.
Patient will not begin or increase frequency/duration of psychotherapy during the study 
period, receive electroconvulsive therapy, nor begin any type of non-Western therapies.


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For CIAS patients, use of hypnotics and anxiolytics is not prohibited; however, these 
medications should be administered to patients according the instruction below: 

Long-acting hypnotics and anxiolytics (i.e. Diazepam) are not permitted during the 
study period. 

Short-acting or intermediate-acting hypnotics and anxiolytics (e.g. lorazepam and 
zaleplon) are permitted if treated with a stable dose for at least 8 weeks. 

Short-acting hypnotics and anxiolytics are allowed if taken PRN. 

Short-acting or intermediate hypnotics and anxiolytics should not be taken within 8 
hours of study procedures.
Also for CIAS patients:

Use of Clozapine (atypical antipsychotic medication) is not permitted during the study 
period.

Anticholinergics are allowed to be used if subjects are on first generation 
antipsychotics and have been treated at a stable dose for at least 6 months prior to 
randomisation. 

Antiepileptics and lithium are allowed if initiated at least 6 months prior to 
randomisation.
For AD patients, intake of the following medications with the mentioned exceptions is 
prohibited during the entire duration of the trial including follow-up:

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, anti-epileptics, 
benzodiazepines, other hypnotics or sedatives (including sedative antihistamines), 
muscle relaxants, or central analgesics, e.g., opioids.
Note: Zolpidem (10 mg/day), chloral hydrate (1 g/day), triazolam, quetiapine,
temazepam and oxazepam if needed for sleep are allowed as needed. Olanzapine or 
risperidone are allowed as needed for occasional intake in case of psychotic
symptoms.

Agents having central dopamine antagonist activity, i.e. reserpine, methyldopa,
antiemetic’s etc. However, the serotonin and combined serotonin/norepihnephrine Re-
Uptake Inhibitors (SSRIs/SNRIs) like fluoxetin, es-citalopram, citalopram, sertalin, 
venlafaxin, duloxetin are allowed, but paroxetine is excluded. Other antidepressant 
drugs without anticholinergic effects may be given as needed if the total daily dose 
was stable 8 weeks prior to randomization and is expected to be maintained for the 
duration of the trial.

Intake of other phospodiesterase inhibitors (for example theophylline, roflumilast, 
sildenafil, tadalafil, vardenafil, avanafil).


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
Intake of St. Johns wort, Carbamazepine, extracts from Gingko, artemisinin, 
enzalutamide, efavirenz, lopinavir, ritonavir, tipranavir, rifampicin as they are 
relevant CYP2C19 inducers.

Initiation of non-prescription drugs or vitamins including medical nutrition 
formulations.  However if such medications were initiated before Visit 1, then they 
can be continued concomitantly during the study.
4.2.2.2
Restrictions on diet and life style
Because psychoactive drugs may impair thinking, judgment, and/or motor skills, subjects will 
be cautioned about operating machinery, including automobiles, until they are reasonably 
certain that the study medication does not adversely affect their ability to engage in such 
activities.
Subjects should not abuse of alcohol or drugs during study as defined in the 5th edition of the 
Diagnostic and Statistical Manual of Mental Disorders (DSM-V), or in the opinion of the 
investigator, or as indicated by a positive urine drug screen for cocaine, opioid, PCP, 
amphetamine, heroin, or marijuana during the trial.
There are no other restrictions on diet, exercise, or smoking except that the patient’s usual 
habits, including nicotine and caffeine intake, should not be drastically changed. Also refer to 
Section 4.1.4 for further intake guidelines.
4.3
TREATMENT COMPLIANCE
Subjects who are non-compliant, e.g., they do not appear for treatment or violate the 
restrictions, may be withdrawn from the trial at the discretion of the investigator and the 
eCRF will be completed accordingly (for further procedures cf. Section 6.2.3). If a patient 
withdraws during the treatment period, after first administration of the study drug, a complete 
post examination, done at EOT, will be performed.
Compliance will be assured by administration of all study medication under supervision of 
the investigating physician or a designee. 


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5.
VARIABLES AND THEIR ASSESSMENT
5.1
EFFICACY - CLINICAL PHARMACODYNAMICS
5.1.1
Endpoints of efficacy
Efficacy measurements will not be performed.
5.1.2
Assessment of efficacy
Not applicable
5.2
SAFETY
5.2.1
Endpoints of safety
Primary endpoint:

The number (%) of subjects with AEs, coded to the MedDRA-SOC ‘Eye disorders’, 
as determined by the investigator at End of Trial
Secondary endpoint:

The number (%) of subjects with drug-related AEs as determined by the investigator 
at End of Trial
 
 
 
 
 
Further safety and tolerability will be assessed in a descriptive way based on:

Adverse events (ocular and systemic)



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
Occurrence of Protocol-specified AESI (adverse events of special interest)
5.2.2
Assessment of adverse events
Safety assessments will consist of monitoring and recording all adverse events (AEs) and
serious adverse events (SAEs) and includes clinically significant ophthalmological findings, 
EEGs, periodic physical examinations, measurement of vital signs, assessment of cardiac 
function with periodic ECGs and 24-hour heart rate monitoring, monitoring of laboratory 
tests (i.e. haematology, chemistry, coagulation, urine analysis), pregnancy test etc., as 
outlined in the Flow Chart.  Ocular and systemic safety will be captured and analysed 
separately.
5.2.2.1
Definitions of adverse events
Adverse event
An adverse event (AE) is defined as any untoward medical occurrence in a patient or clinical 
investigation subject administered a pharmaceutical product and which does not necessarily 
have to have a causal relationship with this treatment.
An AE can therefore be any unfavourable and unintended sign (including an abnormal 
laboratory finding), symptom, or disease temporally associated with the use of a medicinal 
product, whether or not considered related to the medicinal product.
Serious adverse event
A serious adverse event (SAE) is defined as any AE which:

results in death,

is life-threatening,

requires inpatient hospitalisation or prolongation of existing hospitalisation,

results in persistent or significant disability or incapacity,

is a congenital anomaly/birth defect,
or

is to be deemed serious for any other reason if it is an important medical event when 
based upon appropriate medical judgment which may jeopardize the patient and may 
require medical or surgical intervention to prevent one of the other outcomes listed in 
the above definitions.
Life-threatening in this context refers to an event in which the patient was at risk of death at 
the time of the event; it does not refer to an event that hypothetically might have caused death 
if more severe.
Every occurrence of cancer or exacerbation of an existing cancer must be reported as a 
serious event regardless of the duration between discontinuation of the drug and the 
occurrence of the cancer.
AEs considered “Always Serious”
In accordance with the European Medicines Agency initiative on Important Medical Events, 
Boehringer Ingelheim has set up a list of AEs, which by their nature, can always be 


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considered to be “serious” even though they may not have met the criteria of an SAE as given 
above.
The latest list of “Always Serious AEs” can be found in the RDC system.
Adverse events of special interest (AESIs)
The term AESI relates to any specific AE that has been identified at the project level as being 
of particular concern for prospective safety monitoring and safety assessment within this trial, 
e.g. the potential for AEs based on knowledge from other compounds in the same class. AESI 
need to be reported to the Sponsor’s Pharmacovigilance Department within the same 
timeframe that applies to SAE, see Section 5.2.2.2.
The following are considered as AESIs:

Hepatic injury
A hepatic injury is defined by the following alterations of hepatic laboratory 
parameters: 
-
An elevation of AST and/or ALT >3 fold ULN combined with an elevation of 
total bilirubin >2 fold ULN measured in the same blood draw sample, and/or
-
Marked peak aminotransferase (ALT, and/or AST) elevations ≥10 fold ULN
These lab findings constitute a hepatic injury alert and the subjects showing these lab 
abnormalities need to be followed up according to the drug-induced liver injury
(DILI) checklist provided in the ISF. In case of clinical symptoms of hepatic injury 
(icterus, unexplained encephalopathy, unexplained coagulopathy, right upper quadrant 
abdominal pain, etc.) without lab results (ALT, AST, total bilirubin) available, the 
investigator should make sure these parameters are analysed, if necessary in an 
unscheduled blood test. Should the results meet the criteria of hepatic injury alert, the 
procedures described in the DILI checklist should be followed.

Clinically significant loss of vision  (assessed by BCVA) based on investigator’s 
judgment

Clinically significant change of color vision (assessed by F-M 100) based on 
investigator’s judgment

Marcus Gunn pupil sign

Acute corneal edema

Increase of IOP ≥ 30 mmHg

Retinal vascular occlusion and/or retinal hemorrhage or edema

Blurred papillary margin (papillary-edema)
Intensity of AEs
The intensity of the AE should be judged based on the following:
Mild:
Awareness of sign(s) or symptom(s) that is/are easily tolerated
Moderate:
Enough discomfort to cause interference with usual activity
Severe:
Incapacitating or causing inability to work or to perform usual activities


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Causal relationship of AEs
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.
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.
5.2.2.2
Adverse event collection and reporting
AE Collection
The following must be collected and documented on the appropriate eCRF  by the 
Investigator from signing the informed consent onwards through the Residual Effect period 
REP), until individual patient’s End of Trial, all AEs (serious and non-serious), and AESIs.
The REP is defined as 7 days after the last trial medication application. All AEs which 
occurred through the treatment phase and throughout the REP will be considered as on 
treatment (cf. Section 7.3.3). Events which occurred after the REP will be considered as post 
treatment events.
After the individual patient’s End of Trial the investigator does not need to actively monitor 
the patient for AEs but should only report relevant SAEs and relevant AESIs of which the 
investigator may become aware of through the SAE reporting process, not on eCRF.
AE reporting to sponsor and timelines
The Investigator must report SAEs, AESIs, and non-serious AEs which are relevant for the 
reported SAE or AESI, on the BI SAE form via fax immediately (within 24 hours ) to the 
Sponsor’s (SAE form and specific contact details will be provided in the ISF). The same 
timeline applies if follow-up information becomes available. In specific occasions the 
Investigator could inform the Sponsor upfront via telephone. This does not replace the 
requirement to complete and fax the BI SAE form.


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Information required
For each AE, the Investigator should provide the information requested on the appropriate 
(e)CRF pages and the BI SAE form, e.g. onset, end date, intensity, treatment required, 
outcome, seriousness, and action taken with the investigational drug(s). The Investigator 
should determine the causal relationship to the trial medication and any possible interactions 
between the investigational drug(s) and a Non-Investigational Medicinal Product (NIMP).
The following should also be recorded as an (S)AE in the (e)CRF and SAE form (if 
applicable):
Worsening of the underlying disease or of other pre-existing conditions
Changes in vital signs, ECG, physical examination and laboratory test results, if they 
are judged clinically relevant by the Investigator.
If such abnormalities already pre-exist prior trial inclusion they will be considered as 
baseline conditions.
All (S)AEs, including those persisting after trial completion must be followed up until they 
have resolved, have been sufficiently characterized, or no further information can be 
obtained.
Pregnancy
In the rare case that a female subject participating in this clinical trial becomes pregnant after 
having taken trial medication, the Investigator must report immediately (within 24 hours) the 
drug exposure during pregnancy (DEDP) to the Sponsor’s (form and specific contact details 
will be provided in the ISF). The Pregnancy Monitoring Form for Clinical Trials (Part A) 
should be used. 
The outcome of the pregnancy associated with the drug exposure during pregnancy must be 
followed up and reported to the Sponsor’s unique entry point on the Pregnancy Monitoring 
Form for Clinical Trials (Part B). 
As pregnancy itself is not to be reported as an AE, in the absence of an accompanying SAE, 
only the Pregnancy Monitoring Form for Clinical Trials and not the SAE form is to be 
completed. If there is an SAE associated with the pregnancy then the SAE has to be reported 
on the SAE form in addition. 
The ISF will contain the Pregnancy Monitoring Form for Clinical Trials (Part A and 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. Fasting is not required. 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.
Laboratory results of the subjects will be available to the respective investigator and to the BI 
Clinical Monitor (central laboratory website), and selected abnormal laboratory alerts will be 
sent automatically to the sites and to the sponsor within 24 hours.


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Clinically relevant laboratory values should be commented on lab report print-outs if there is 
no validated and certified e-medical record for the comments of laboratory data. A clinically 
relevant value may be either in- or outside the reference range. Clinically relevant abnormal 
laboratory test results must be confirmed using an unscheduled visit lab kit and should be
repeated until normalisation or stabilisation or until an alternative explanation has been
found.
Table 5.2.3: 1 Routine Laboratory test
Haematology

Hematocrit (Hct)

Hemoglobin (Hb)

Red Blood Cell Count/ Erythrocytes (RBC)

Reticulocyte Count

White Blood Cells / Leukocytes (WBC)

Platelet Count/ Thrombocytes

Differential. Automatic (manual  if
differential automatic is abnormal)            
-
Neutrophils
-
Eosinophils
-
Basophils
-
Monocytes
-
Lymphocytes
Coagulation

Partial Thromboplastin Time (=aPTT)

Prothrombin time (Quick and INR)
Chemistry

AST(SGOT)

ALT(SGPT)

Alkaline Phosphatase (AP)

Albumin

Creatine Kinase (CK)

CK-MB, only if CK is elevated

Gamma-Glutamyl Transferase (GGT/γ-GT)

Lactic Dehydrogenase (LDH)

Calcium Sodium

Potassium Chloride 

Bicarbonate 

Glucose

Creatinine

BUN

Bilirubin Total

Bilirubin Direct

Bilirubin Indirect

Protein Total

Uric Acid

Cholesterol Total

Triglycerides
Pregnancy test (females only)
Human urine chorionic gonadotropin
Urinalysis1 (Stix)

Urine Nitrite

Urine Protein

Urine Glucose

Urine Ketone

Urobilinogen

Urine Bilirubin

Urine RBC/ Erythrocytes

Urine WBC/ Leukocytes

Urine pH

Urine creatinine
Urine-Sediment (microscopic examination), (only if
urine analysis abnormal)

Urine Sediment Bacteria

Urine Cast in Sediment

Urine Squamous Epith Cells

Urine Sediment RBC/ Erythrocytes

Urine Sediment WBC/ Leucocytes
1At screening, baseline andend of trial.


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The following tests will be performed only at screening examination; the results will not be 
part of the Clinical Trial Report. Exclusionary testing may be repeated during the screening 
period if necessary. Subjects must have a negative drug screening prior to inclusion in the 
study.
Table 5.2.3: 2 Exclusionary Laboratory test (screening visit only)
Drug Screening (Urine)

Cannabis

Barbiturates

Opiates

Cocaine

Amphetamines

Methadone 

Phencyclidine
5.2.4
Electrocardiogram
The 12-lead ECGs will be performed as scheduled in the Flow Chart. ECG will be recorded 
after the subjects have rested for at least 5 minutes in a supine position.  The investigator or a 
designate will evaluate whether the ECG is normal or abnormal and whether it is clinically 
significant, if abnormal. The electronic version of the ECG is regarded as source data. Dated 
and signed printouts will be stored in the patient’s medical file if there is no validated and 
certified e-medical record for ECG data.
ECGs may be repeated for quality reasons and the repeat used for analysis. Additional ECGs 
may be collected by the investigator for safety reasons. The recordings will be checked for 
pathological results (to be reported as baseline conditions or AEs) by the investigator. Any 
ECG abnormalities will be carefully monitored and if necessary the patient will be removed 
from the trial and medically treated. Baseline will be the measurements taken prior to the first 
administration. Notable findings are defined as occurrence of any QTc interval from any 
individual >450 ms, >480 ms or >500 ms or the occurrence of any individual increase from 
baseline by >30 ms or >60 ms.
5.2.5
Physical examination
The physical examination will be carried out within -28 to -3 days before the study 
(Screening), on Day -2 or -1 (Baseline), Day 7 and End of Trial examination (7-14 days after 
the last drug administration for each patient). At the screening visit, a complete medical 
examination will include documentation of patient information, informed consent, 
demographics including height and weight, smoking and alcohol history, relevant medical 
history and concomitant medication, review of inclusion/exclusion criteria, review of vital 
signs (BP, PR), 12-lead ECG and laboratory, and a physical examination. At the End of Trial 
examination, it will include review of vital signs, 12-lead ECG and laboratory, and a physical 
examination. Adverse events and concomitant therapies will be assessed throughout the 
study.
Physical examination will include weight and an examination of general appearance, skin, 
lungs, heart, abdomen, lymph nodes, extremities and basic nervous system evaluation. 


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Information about the physical examination must be present in the source documentation at 
the study site. Physical examination and ECG data are not collected on eCRF, however, any 
significant findings made after the start of study drug which meet the definition of an AE 
must be recorded as the Adverse Event in eCRF.
5.2.6
Vital signs
Vital signs (orthostatic measurements of systolic/diastolic blood pressure and pulse rate as 
outlined below) will be recorded at the time points and study visits as described in the Flow 
Chart, including the End of Trial visit. 
Orthostatic measurements:
1) Have the patient lie down for at least 5 minutes
2) Measure blood pressure and pulse rate in supine position
3) Have the patient stand and measure blood pressure and pulse rate immediately after 
the patient stand up
4) Repeat blood pressure and pulse rate measurements after standing 3 minutes
Only on Day 1, the following additional vital sign assessments need to be performed which 
include (cf. Flow Chart):

Pulse rate is to be measured in a supine position after at least 5 minutes of rest pre-dose 
and at the time points of post-dose PK sampling until 110 mins post-dose (20 ±5 min, 30
±5 min, 45 ±10 min and 90 ±20 min). 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 at pre-dose (baseline) and at 70~110 minutes post dose.
All above mentioned procedures are 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 measurements 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. The investigator may repeat the post-dose pulse
rate assessment at any other visit under the conditions described for Day 1 if deemed
clinically necessary for any reason.
Clinically relevant abnormal findings noticed after baseline assessment will be reported as
(S)AEs.
5.2.7
24-hour holter monitoring
Holter monitoring will be performed over a 24 hour period at Screening and repeated again 
on Day 3.  Holter data will be recorded using equipment provided and also analysed by a 
central ECG vendor.  Holter monitoring procedure is to be initiated after all other laboratory 
related tests are completed.


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5.4
APPROPRIATENESS OF MEASUREMENTS
All measurements performed during this trial are standard measurements and will be 
performed in order to monitor safety aspects and to determine pharmacokinetic of BI 409306 
in an appropriate way.
 
The scheduled measurements are appropriate to see drug induced changes in vital signs,
standard laboratory values and ECG. These primary and secondary endpoints are standard
and accepted for evaluation of safety and tolerability of an oral drug, and they are widely
used in this kind of study.


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5.5
DRUG CONCENTRATION MEASUREMENTS AND 
PHARMACOKINETICS
Date and exact clock time of study medication administration as well as of pharmacokinetic 
sampling times will be documented in the eCRFs. These actual sampling times will be used 
for determination of pharmacokinetic parameters.
5.5.1
Pharmacokinetic endpoints
Pharmacokinetic parameters of BI 409306 will be determined as secondary endpoints:

Cmax,ss - maximum measured concentration of the analyte in plasma at steady-state

tmax,ss - time from dosing to maximum measured concentration of the analyte in
plasma at steady-state.
 
 
 
At Day 14, BI 409306 pharmacokinetics will be presumed to be at steady state for these 
endpoints.
5.5.2
Methods of sample collection
Plasma sampling for pharmacokinetic analysis
For quantification of BI 409306 and metabolites (CD 13896 and CD 14084) plasma 
concentrations, approximately 6 mL of blood will be taken from a forearm vein in a K2-
EDTA (dipotassium ethylendiaminetetraacetic acid)-anticoagulant blood drawing tube at the 
time points listed in the Flow Chart.
The EDTA-anticoagulated blood samples will be centrifuged as soon as possible after
collection. Centrifugation will last for about 10 minutes (at about 2000 x g to 4000 x g) at 4-
8°C. Three plasma aliquots will be prepared and stored in polypropylene tubes. The first two


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aliquots should contain at least 1 mL plasma whereas the third aliquot should contain the 
remaining plasma. Until shipment on dry ice to the analytical laboratory, plasma samples will 
be stored frozen in an upright position at about –20°C or below until transfer on dry ice to the 
analytical laboratory. The third aliquot will be shipped after the bioanalyst has acknowledged 
safe arrival of the first and second aliquots. At the analytical laboratory the plasma samples 
will be stored at about –20°C or below until analysis.
The sample tube labels should list at least the following information: study number, subject 
number, visit, planned time and aliquot. Further information such as matrix and analyte may 
also be given.
After completion of the study the plasma samples may be used for further methodological 
investigations, e.g. for stability testing. However, only data related to the analyte and/or its 
metabolite(s) will be generated by these additional investigations. The study samples will be
discarded after completion of the additional investigations but not later than 3 years after the 
final study report has been signed.
5.5.3
Analytical determinations
The concentrations of BI 409306 and its two major metabolites in plasma will be determined 
by a validated liquid chromatography tandem mass spectrometry (LC-MS/MS) assay. 
Analysis of BI 409306 and its two major metabolites in PK plasma study samples will be 
performed using validated LC-MS/MS assays.
Analysis of BI 409306 and the two major metabolites (CD 13896 and CD 14084) will be 
performed at:
Boehringer Ingelheim Pharma GmbH & Co. KG
Drug Metabolism and Pharmacokinetics Germany
G144
Birkendorfer Straße 65
88397 Biberach/ Riß, Germany
5.6
BIOMARKER
Not applicable.
5.7
PHARMACODYNAMICS
Not applicable.
5.8
PHARMACOKINETIC - PHARMACODYNAMIC RELATIONSHIP
Not applicable.


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6.
INVESTIGATIONAL PLAN
6.1
VISIT SCHEDULE
All subjects are to adhere to visit schedule as specified in the Flow Chart. With the exception 
of the Screening visit and End of Trial visit where there is an allowable time window for visit 
scheduling, all other visits starting at Day -2 or -1 (Baseline) to Day 14 must occur on the 
scheduled day.
The following study visits: Visits 4-6 (Day 2-4), Visit 8 (Day 6), Visits 10-14  (Day 9-12),
may be conducted as home visits in lieu of study center visits.
In-patient stay is optional. If feasible for in-patient stay, the following procedures would 
apply: eligible study participants will be admitted to the study center in-patient facility for 
overnight stays.  All CIAS patients will remain in-patient for the duration of the treatment 
period, starting on Day -2 and will be allowed to leave after the last study procedure and after 
their fitness has been confirmed by the investigator on Day 14. AD patients and healthy 
volunteers will check into clinic on Day -2 and remain in-patient till Day 1, return for daily 
visits till Day 12, and check into clinic again on Day 13 to Day 14.  If there is a need that 
required AD subjects to remain in-patient, then the CIAS schedule plan may be ultilized, per 
investigator discretion.
Exact times of measurements outside the permitted time windows will be documented. Time
windows are permitted as follows:

General medical/physical examination: at screening (-3 to -28 days prior to the first 
study day), on Day -2 or -1 (Baseline), Day 7 and at the End of Trial (within 14 days 
following the last trial procedure).

 
 
 
 

For planned individual plasma concentration sampling refer to the Flow Chart. While 
these nominal times should be adhered to as closely as possible, the actual sampling 
times will be recorded and used for determination of pharmacokinetic parameter. In 
the event that a sample time point is not adhered to or missed, subsequent samples 
should be taken based on the time of drug administration.

The designation “before” on study Day 1 refers to the time period of within 2 hours 
before drug administration (see Flow Chart), (i.e. study measurements and 
assessments scheduled to occur “before” have to be performed and completed within 
2 hours prior to drug administration).

In-patient meal and snacks times may be ± 1 hour of planned times, if applicable.
Relevant time violations will be identified and their handling discussed no later than at the 
Blinded Report Planning Meeting (BRPM).


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If a study visit is missed, subjects should continue to the next planned visit and study 
procedures per Flow Chart.
 
6.2
DETAILS OF TRIAL PROCEDURES AT SELECTED VISITS
6.2.1
Screening and baseline period
No trial procedures should be performed until the patient has provided written informed 
consent in accordance with GCP and local legislation.  Once the patient/healthy volunteer has 
signed consent, a patient number will be assigned and enrolment will be recorded on the 
eCRF and Subject Enrolment Log in the ISF.
For the medical examination, vital signs, 12-lead ECG, 
 
and laboratory examinations during the screening visit, cf. 
Section 5.2. The screening investigations will be performed within -3 to -28 days preceding 
the first study drug administration.
 
6.2.2
Treatment periods
If the patient/healthy volunteer has completed screening and has been determined potentially 
eligible by the investigator, the following baseline investigations will be performed on Day -
2 and/or -1:

Physical examination including vital signs


Review Adverse Events (AEs) and Concomitant Therapies (CTs)

Clinical laboratory/urinalysis

Review Inclusion/Exclusion criteria 

 
Subjects, who meet all the inclusion criteria, and none of the exclusion criteria, will be 
eligible for the study. Eligible subjects will be randomized (cf. Section 4.1.2).
Each randomized participant will receive study medication daily from Day 1 through 14 
according to the Flow Chart. Study drug will be taken orally in the morning of each treatment 
day under direct supervision of the investigator or designee.


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The measurements performed during the treatment period are specified under Section 5.2 of 
this protocol and Flow Chart.
For details on time points for collection of plasma samples for PK analysis, cf. Flow Chart
and Sections 5.5.1 and 5.5.2.  
 
 
In general, if several measurements including venipuncture are scheduled for the same point 
of time, venipuncture should be the last of the measurements 
 due to 
its inconvenience to the patient and possible influence on physiologic parameters.
 
 
 
6.2.3
End of trial and follow-up period
The End of Trial visit will be performed 7 to 14 days after last drug administration. EOT
evaluation will include a physical exam, vital signs, 12-lead ECG, standard laboratory tests,
and review of AEs and CTs.
All clinically significant abnormal values (including laboratory parameters) will be followed 
up using the appropriate tests until a return to a medically acceptable level is achieved.
All (S)AEs, including those persisting after trial completion must be followed up until they 
have resolved, have been sufficiently characterized, or no further information can be 
obtained.
In case of premature discontinuation from the 14 day treatment, (e.g. removal of patient from 
treatment due to AE or abnormal laboratory test result), the EOT visit should be performed 
within 7 days of last intake of study drug.


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7.
STATISTICAL METHODS AND DETERMINATION OF
SAMPLE SIZE
7.1
STATISTICAL DESIGN - MODEL
This is a Phase Ic, randomised, parallel-group, double-blind study.
The primary objective is to investigate the ocular safety of BI 409306 in patients with 
schizophrenia, Alzheimer’s disease, and age-comparable healthy volunteers following oral 
administration of 25 mg and 100 mg over 14 days.
The primary endpoint is number (%) of subjects with AEs, coded to the MedDRA-SOC ‘Eye 
disorders’, as determined by the investigator at End of Trial.
The secondary objectives are the evaluation of systemic safety and exploration of the 
pharmacokinetics of BI 409306. 
Secondary endpoints include the number (%) of subjects with drug-related AEs as determined 
by the investigator at End of Trial. Secondary endpoints also include the following 
pharmacokinetic parameters of BI 409306:

Cmax,ss - maximum measured concentration of the analyte in plasma at steady-state 
(Day 14).

tmax,ss - time from dosing to maximum measured concentration of the analyte in
plasma at steady-state (Day 14).
The derivation of the PK parameters is given in Appendix Section 10.1.
No statistical testing will be performed on the primary and secondary endpoints.
 
 
 
 
 
 
 
 
 


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General tolerability will be evaluated on the basis of the following investigations: physical 
examination, vital signs (BP, PR), 12-lead ECG (electrocardiogram), clinical laboratory tests 
(haematology, clinical chemistry and urinalysis) and adverse events.
7.2
NULL AND ALTERNATIVE HYPOTHESES
It is not planned to test any statistical hypotheses. Descriptive statistics will be presented.
7.3
PLANNED ANALYSES 
7.3.1
Primary analyses
All subjects who received at least one dose of study drug will be included in the assessment 
of ocular adverse events. Safety analyses will be performed in accordance with BI standards, 
essentially, tabulations of frequencies/proportions will be displayed.
Ocular adverse events will be those events coded to the SOC ‘Eye disorders’.
Adverse events will be coded using the Medical Dictionary for Drug Regulatory Affairs 
(MedDRA). The analysis of adverse events will be based on the concept of treatment 
emergent adverse events. All adverse events occurring before drug intake will be assigned to 
“screening”.  All adverse events occurring between drug intake until 7 days (inclusive) after 
last treatment administration will be assigned to “treatment”.  Adverse events occurring after 
this period and prior to End of Trial will be assigned to “post-treatment”.   Adverse events 
occurring after End of Trial will be considered “post-study”.  Independent of this rule, the 
relationship of an adverse event to the study drugs treatments will be assessed by the 
investigator. Adverse event information as reported in the CRFs will be aggregated in a two-
step process. First, multiple recordings (AE occurrences) of the same adverse event will be 
combined into one AE episode (collapsing). The second step will combine all of the AE 
episodes of an adverse event into one AE record as needed for by-subject summaries 
(condensing). The evaluation of adverse events will comprise various frequency tabulations.


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7.3.2
Secondary analyses
Secondary endpoints include the number (%) of subjects with drug-related adverse events 
(AEs) as determined by the investigator. Details regarding AE analyses are provided in 
Section 7.3.1.
Pharmacokinetic analyses are described in Section 7.3.5.
7.3.3
Safety analyses
All treated subjects will be included in the safety analysis. However, if a treated subject has 
no post-randomization data, this subject will not be included in the safety analyses. In 
general, safety analyses will be descriptive in nature and will be based on BI standards. No 
hypothesis testing is planned.
Statistical analysis and reporting of adverse events will concentrate on treatment-emergent 
adverse events. To this end, all adverse events occurring between start of treatment and end 
of the residual effect period will be considered ‘treatment-emergent’.  The residual effect 
period is defined as 7 days (inclusive) after last treatment administration. 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).
 
 
 
 
 
 
 
  
 
 


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Laboratory and other safety
Laboratory data will be analysed both quantitatively as well as qualitatively. The latter will 
be done via comparison of laboratory data to their reference ranges. Values outside the 
reference range as well as values defined as clinically relevant will be highlighted in the 
listings. Treatment groups will be compared descriptively with regard to distribution 
parameters as well as with regard to frequency and percentage of subjects with abnormal 
values or clinically relevant abnormal values.
Vital signs (BP, PR) will be measured in supine and standing positions. Descriptive statistics 
will be provided for both positions separately. Orthostatic testing is done by comparing the 
individual results of both measurements (supine and standing). 
Physical examinations, or other safety-relevant data observed at screening, baseline, during 
the course of the trial and at the  End of Trial evaluation will be assessed with regard to 
possible changes compared to findings before start of treatment
 
 
 
 
7.3.4
Interim analyses
No interim analysis is planned, but in the event that AD recruitment goals are not met as 
planned, the CIAS and age-comparable healthy volunteers may be unblinded for analysis 
after the last CIAS and the corresponding 10 age-comparable healthy volunteers have 
completed the study. 
7.3.5
Pharmacokinetic analyses
For pharmacokinetic analysis and displays, concentrations will be used in the same format as
reported in the bioanalytical report. Only concentrations within the validated concentration
range and actual sampling times will be used for the calculation of pharmacokinetic
parameters. For derivation of pharmacokinetic parameters see Appendix Section 10.1.2.
Non-compartmental pharmacokinetic analyses of the plasma concentration-time data will be
performed using a validated software program and for this purpose the actual sampling time
for pre-dose samples will be set to zero. Plasma concentrations will be plotted graphically 
versus time for all subjects as listed in the drug plasma concentration-time tables. For the 
presentation of the mean profiles, the arithmetic and geometric mean and the planned blood 
sampling times will be used. If the actual sampling time deviates significantly from the 
planned time, the corresponding plasma concentration will be excluded from the calculation 
of descriptive statistics.


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7.3.6
Pharmacogenomic analyses
 
7.4
HANDLING OF MISSING DATA
With respect to safety evaluations, it is not planned to impute missing values other than AE 
start dates and times. 
For handling of missing data in PK evaluation, refer to Appendix Section 10.1.2.
7.5
RANDOMISATION
Subjects will be randomized in blocks to double-blind treatment. Equal numbers of subjects 
will be randomized to each treatment group.  BI will arrange for the randomization and the 
packaging and labelling of study medication.    The randomization list will be generated using 
a validated system, which involves a pseudo-random number generator so that the resulting 
treatment will be both reproducible and non-predictable. The block size will be documented 
in the Clinical Trial Report.
A blinded randomization list will be provided to the site.  It will list sequential medication 
numbers. Study medication kits will be labelled using these medication numbers.  The site 
will be instructed to use designated blocks of medication numbers for Alzheimer’s patients, 
for schizophrenia patients, for healthy volunteers in the lower age category and for healthy 
volunteers in the higher age category.  The site will be instructed to assign one medication 
numbers to each subject sequentially at the time of randomization.  Medication number will 
be captured on the eCRF.
7.6
DETERMINATION OF SAMPLE SIZE
It is planned to include a total of 60 subjects in this study: 20 healthy volunteers; 20 patients 
with Alzheimer’s disease and 20 patients diagnosed with schizophrenia. The planned sample 
size is not based on a power calculation nor on statistical consideration. The size of 10
subjects per population and per dose group is in general considered as sufficient for the 
exploratory evaluation of multiple dose ophthalmologic assessment, safety and 
pharmacokinetics. 


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8.
INFORMED CONSENT, DATA PROTECTION, TRIAL
RECORDS
The trial will be carried out in compliance with the protocol, the ethical principles laid down 
in the Declaration of Helsinki, in accordance with the ICH Harmonized Tripartite Guideline 
for Good Clinical Practice (GCP) 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 will inform the Sponsor immediately of any urgent safety measures taken to 
protect the trial subjects against any immediate hazard, and also of any serious breaches of 
the protocol or of ICH GCP.
The rights of the Investigator and of the Sponsor with regard to publication of the results of 
this trial are described in the Investigator contract. As a rule, no trial results should be 
published prior to finalization of the Clinical Trial Report.
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 (or the patient’s legally accepted representative) according to ICH / GCP and to the 
regulatory and legal requirements of the participating country. Each signature must be 
personally dated by each signatory and the informed consent and any additional patient-
information form retained by the Investigator as part of the trial records. A signed copy of the 
informed consent and any additional patient information must be given to each patient or the 
patient’s legally accepted representative.
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.
8.2
DATA QUALITY ASSURANCE
This trial will be conducted in accordance with the International Conference on 
Harmonization (ICH) Good Clinical Practice (GCP) guidelines, local regulations and the 
company standard operating procedures (SOPs).


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A central laboratory will be used to collect, analyze and report the results of all blood 
samples and cultures. Centralized Holter Monitoring will be utilized for this trial. Data will 
be collected using a Remote Data Capture (RDC) system.
Training will be provided to all investigators, coordinators and field monitors to ensure
consistency and accuracy of the data. The data will be source verified by the field monitors.
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 TMF.
A quality assurance audit/inspection of this trial may be conducted by the Sponsor, Sponsor’s 
designees, or by IRB / IEC or by regulatory authorities. The quality assurance auditor will 
have access to all medical records, the Investigator’s trial-related files and correspondence, 
and the informed consent documentation of this clinical trial.
8.3
RECORDS
Electronic Case Report Forms (eCRFs) for individual subjects will be provided by the 
sponsor 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 reported on the eCRF must be consistent with the source data or the discrepancies must 
be explained. The Investigator may need to request previous medical records or transfer 
records, depending on the trial; current medical records must also be available.
For the eCRF, the following data need to be derived from source documents:

Patient identification (gender, date of birth)

Patient participation in the trial (substance, trial number, patient number, date patient was 
informed)

Dates of Patient’s visits, including dispensing of trial medication

Medical history (including trial indication and concomitant diseases, if applicable)

medication history

Adverse events and outcome events (onset date (mandatory), and end date (if available))

Serious adverse events (onset date (mandatory), and end date (if available))

Concomitant therapy (start date, changes)

Originals or copies of laboratory results (in validated electronic format, if available)

Completion of Patient’s Participation in the trial”
Prior to allocation of a patient to a treatment into a clinical trial, there must be documented 
evidence in the source data (e.g. medical records) that the trial participant meets all inclusion 
criteria and does not meet any exclusion criteria. The absence of records (either medical 
records or testing conducted specific for a protocol) to support inclusion/exclusion criteria 
does not make the patient eligible for the clinical trial


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For eCRFs all data must be derived from source documents.
8.3.2
Direct access to source data and documents
The investigator / institution will permit trial-related monitoring, audits, IRB / IEC review 
and regulatory inspection, providing direct access to all related source data / documents. 
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 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 fulfill the regulatory requirements for expedited safety reporting, the sponsor evaluates 
whether a particular adverse event is "listed", i.e. is a known side effect of the drug or not.
Therefore a unique reference document for the evaluation of listedness needs to be provided. 
For the BI 409306 this is the current version of the Investigator’s Brochure (C02101303).
The current version of the IB 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. 
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.
8.6
END OF TRIAL
The end of the trial is defined as the last clinical study visit for the last participating subject
(e.g. End of Trial visit, 7-14 days after last drug administration).  Cf. Section 6.2.3 for further 
information and details regarding follow-up of AEs or ongoing abnormal findings.


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9.
REFERENCES
9.1
PUBLISHED REFERENCES
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AL. The functional significance of symptomatology and cognitive function
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the occurrence of dementia: findings from a population-based cohort with a 
large sample of nonagenarians. Arch Neurol 1999;56:587-592.
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dementia occurrence in the world. Alzheimer Dis Assoc Disord 
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Bliss TVP, Collingridge GL. A synaptic model of memory: long-term
potentiation in the hippocampus. Nature 1993;361:31-39.
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responsive soluble guanylyl cyclase activity in the superior temporal cortex of 
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Tamminga CA. The neurobiology of cognition in schizophrenia. Roundtable 
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Illness', Dallas, 13 Jan 2006. J Clin Psychiatry 2006;67(Suppl 9):9-13.
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MN, Scheltens P, Carrillo MC, Thies B, Weintraub S, Phelps CH. The 
diagnosis of dementia due to Alzheimer's disease: recommendations from the 
National Institute on Aging-Alzheimer's Association workgroups on diagnostic 
guidelines for Alzheimer's disease. Alzheimers Dement 7, 263 - 269 (2011).
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(PANSS) for schizophrenia. Schizophr Bull 13 (2), 261 - 276 (1987).


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manual of mental disorders: DMS-5. 5th ed. Arlington: American Psychiatric 
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biomarkers of synaptic dysfunction across the stages of Alzheimer's disease. J 
Alzheimers Dis 26 (3), 215 - 228 (2011).
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Luck SJ, Mathalon DH, O'Donnell BF, Hamalainen MS, Spencer KM, Javitt 
DC, Uhlhaas PJ. A roadmap for the development and validation of event-
related potential biomarkers in schizophrenia research. Biol Psychiatry 70, 28 -
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Bokde ALW, Lopez-Bayo P, Meindl T, Pecher S, Born C, Faltraco F, Teipel 
SJ, Moeller HJ, Hampel H. Functional connectivity of the fusiform gyrus 
during a face-matching task in subjects with mild cognitive impairment. Brain 
129, 1113 - 1124 (2006).
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Uhlhaas PJ, Linden DE, Singer W, Haenschel C, Lindner M, Maurer K, 
Rodriguez E. Dysfunctional long-range coordination of neural activity during 
Gestalt perception in schizophrenia. J Neurosci 26 (31), 8168 - 8175 (2006).
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Stam CJ, Jones BF, Nolte G, Breakspear M, Scheltens P. Small-world 
networks and functional connectivity in Alzheimer's disease. Cereb Cortex 17 
(1), 92 - 99 (2007).
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Mathalon DH, Ford JM, Pfefferbaum A. Trait and state aspects of P300 
amplitude reduction in schizophrenia: a retrospective longitudinal study. Biol 
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R14-3532
Phillips WA, Silverstein SM. Convergence of biological and psychological 
perspectives on cognitive coordination in schizophrenia. Behav Brain Sci 26 
(1), 65 - 137 (2003).
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Light GA, Makeig S. EEG biomarkers of psychosis, present and future. 
http://sccn.ucsd.edu/~scott/pdf/Light_Makeig_Commentary14.pdf (access 
date: 20 November 2014) ; Biological Psychiatry, in press Biol Psychiatry 
2014.
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Lee J, et al. Verbal working memory in schizophrenia from the Consortium on 
the Genetics of Schizophrenia (COGS) study: the moderating role of smoking 
status and antipsychotic medications. Schizophrenia Research, article in press, 
Corrected Proof, Published Online: September 20, 2014, doi: 
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substrates and functional correlates of auditory deviance processing deficits in 
schizophrenia. Neuroimage 2014. 6:424-437.


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Tarasenko MA, Swerdlow NR, Makeig S, Braff DL, Light GA. The auditory 
brain-stem response to complex sounds: a potential biomarker for guiding 
treatment of psychosis. Front Psychiatry 2014. 5:142.
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predictive biomarker: clinical and socio-demographic modulators in COGS-2. 
Schizophrenia Research, article in press, Corrected Proof, Published Online: 
October 09, 2014, doi: 10.1016/j.schres.2014.09.024 Schizophr Res 2014.
R14-4682
Light GA, et al. Validation of mismatch negativity and P3a for use in multi-
site studies of schizophrenia: characterization of demographic, clinical, 
cognitive, and functional correlates in COGS-2. Schizophrenia Research, 
article in press, Published Online: October 23, 2014, doi: 
10.1016/j.schres.2014.09.042 Schizophr Res 2014.
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Naatanen R, Teder W, Alho K, Lavikainen J. Auditory attention and selective 
input modulation: a topographical ERP study. Neuroreport 1992. 3(6):493-
496.
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Kirihara K, Rissling AJ, Swerdlow NR, Braff DL, Light GA. Hierarchical 
organization of gamma and theta oscillatory dynamics in schizophrenia. Biol 
Psychiatry 2012. 71:873-880.
R14-4685
Light GA, Braff DL. Mismatch negativity deficits are associated with poor 
functioning in schizophrenia patients. Arch Gen Psychiatry 2005. 62:127-136.
R14-4686
Light GA, Braff DL. Stability of mismatch negativity deficits and their 
relationship to functional impairments in chronic schizophrenia. Am J 
Psychiatry 2005. 162(9):1741-1743.
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Light GA, Swerdlow NR, Braff DL. Preattentive sensory processing as 
indexed by the MMN and P3a brain responses is associated with cognitive and 
psychosocial functioning in healthy adults. J Cogn Neurosci 2007. 
19(10):1624-1632.
R14-4688
Rissling AJ, Braff DL, Swerdlow NR, Hellemann G, Rassovsky Y, Sprock J, 
Pela M, Light GA. Disentangling early sensory information processing deficits 
in schizophrenia. Clin Neurophysiol 2012. 123:1942-1949.
R14-4689 
Takahashi H, Rissling AJ, Pascual-Marqui R, Kirihara K, Pela M, Sprock J, 
Braff DL, Light GA. Neural substrates of normal and impaired preattentive 
sensory discrimination in large cohorts of nonpsychiatric subjects and 
schizophrenia patients as indexed by MMN and P3a change detection 
responses. Neuroimage 2013. 66:594-603.
R14-4690 
Rissling AJ, Park SH, Young JW, Rissling MB, Sugar CA, Sprock J, Mathias 
DJ, Pela M, Sharp RF, Braff DL, Light GA. Demand and modality of directed 


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attention modulate 'pre-attentive' sensory processes in schizophrenia patients 
and nonpsychiatric controls. Schizophr Res 2013. 146:326-335.
R14-4695 
Light G, et al. Comparison of the heritability of schizophrenia and 
endophenotypes in the COGS-1 family study. Schizophr Bull 2014. 
40(6):1404-1411.
9.2
UNPUBLISHED REFERENCES
U10-2281
. To evaluate, in LeadProfilingScreen, the activity of test
compound 25004777 (PT# 1103060). BI 409306-Rosenbrock-1007-C. 27-
Mar-2008.
U10-2282
Individual Tests Data Report. On Compounds TH-
6820, 25005037 To TH-6821, 25005038. BI 409306-Rosenbrock-1007-D. 
12-Jun-2009.
U10-2283
To evaluate, in Radioligand Binding assays, the activity
of test compound 25005038 (PT# 1118368). BI 409306-Rosenbrock-1007-
E. 18-May-2010.
U10-2284
Effect of test compounds (25004777 and Denopezil) in
the t-maze alternation task in the mouse. BI 409306-Rosenbrock-1007-F.
17-Oct-2008.
U10-2286
 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. BI 409306-Rosenbrock-1007-H. 17-Jul-2007.
U10-2287
 In vivo microdialysis investigation of BI Pharma's PDE inhibitor 
effects on extracellular cGMP levels in the rat prefrontal cortex - final report. 
BI 409306-Rosenbrock-1007-I. 22-May-2009.
U10-2288
 In vivo microdialysis investigation of BI Pharma's PDE inhibitor 
effects on extracellular cGMP levels in the rat prefrontal cortex - final report 
II. BI 409306-Rosenbrock-1007-K. 12-Nov-2009.
U10-2472
 In vivo microdialysis investigation of BI Pharma's PDE inhibitor 
effects on extracellular cGMP levels in the rat prefrontal cortex - final report 
II. BI 409306-Rosenbrock-1007-K. 12-Nov-2009.
U10-2597 
BI 409306 : Escalating dose oral (gavage) 
toxicity study in beagle dog 09B128. 13-Dec-2010.


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U10-2646
 Investigations on the in vitro 
metabolism of [14C]BI 409306 and assessment of the human cytochrome 
P450 enzymes that are involved. B4022,A277/10LU. 30-Aug-2011.
U10-2959 
 Metabolism of [14C]BI 409306 after intravenous and oral 
administration in rats. a576-10bc. 06-Sep-2011.
U10-4089
 
 BI 409306: 2-week oral (gavage) dose range finding 
study in beagle dogs. 09B194. 31-Mar-2011.
U11-1173
 
 BI 409306: 4-week oral (gavage) 
toxicity study in beagle dogs. 10B084. 10-Jan-2012.
U11-2807
 Investigations on the in vitro metabolism of [14C]BI 
409306 in liver microsomes of CYP 2C19 PMs. A300/11LU,B4443. 22-Mar-
2012.
U12-1034
 A randomised, double-blind, 
placebo-controlled (within dose groups) Phase I study to assess the safety, 
tolerability and pharmacokinetics of single rising doses 0.5 mg to 500 mg of 
BI 409306 administered orally in healthy male volunteers 1289.1 19-Jan-2012.
U12-2165
 Randomised, doubleblind, 
placebo-controlled, parallel-group proof of mechanism study to assess the
pharmacokinetics and to evaluate the pharmacodynamic effect of different 
single oral doses of BI 409306 in healthy male volunteers. 1289.3. 17-Sep-
2012.
U13-1182
 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/femalevolunteers (randomised, double-blind, placebo-
controlled within dose groups Phase I study). 1289.2. 20 Feb 2013.
U13-1303
 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
 Safety, tolerability and pharmacokinetics 
of single oral doses of BI 409306 (tablet) in healthy Chinese and Japanese 
male volunteers and multiple oral doses of BI 409306 (tablet) in healthy 
Japanese male volunteers (randomised, double-blind, placebocontrolled within 
dose groups). 1289.4. 13 Mar 2014.


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c02318916
 Safety, tolerability, pharmacokinetics 
and pharmacodynamics of BI 409306 film-coated tablets given orally q.d. for 
14 days in patients with schizophrenia (randomized, parallel-group, double-
blind, placebo-controlled study). 1289.18. 28 June 2014.
C02101303
Investigator’s Brochure: BI 409306 in Alzheimer’s Disease and Cognitive
Impairment associated with Schizophrenia.


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10.
APPENDICES
10.1
PHARMACOKINETIC METHODS
10.1.1
Evaluation of Pharmacokinetic Parameter
Individual Cmax(ss), tmax(ss), Ct,N and Cpre,N values will be directly determined from the plasma 
concentration time profiles of each subject. If the same Cmax(ss) concentration occurs at 
different time points, tmax(ss) is assigned to the first occurrence of Cmax,ss.
AUC: The area under the curve will be calculated using the linear up/log down algorithm. If 
an analyte concentration is equal to or higher than the preceding concentration, the linear 
trapezoidal method will be used. If the analyte concentration is smaller than the preceding 
concentration, the logarithmic method will be used.
Linear trapezoidal rule (t2 > t1 and Ct2 Ct1):
The area of the trapezoid between the two data points (t1, Ct1) and (t2, Ct2) will be computed 
by:



t2
t1
1
2
t2
-
t1
C
C
t
t
0.5
AUC





Logarithmic trapezoid rule (t2 > t1 and Ct2 < Ct1):
The area of the trapezoid between the two data points (t1, Ct1) and (t2, Ct2) will be computed 
by:





t1
t2
t1
t2
1
2
t2
t1
/C
C
ln
C
C
t
t
AUC





RA,Cmax: Accumulation ratios are derived as follows for the respective doses (e.g. after 14th
dose RA,Cmax,14):
max
max,
max
,
C
C
R
ss
C
A

Metabolic ratio: With respect to Cmax,ss
parent
ss
metabolite
ss
Met
ss
C
C
RC
,
max,
,
max,
,
max,

gMean, gCV: The geometric mean (gMean) and coefficient of variation, gCV (given in %), 
will be calculated by the formulae:

)
ln(x
exp
)
ln(x
exp
gMean
i
n
1
i
i
n
1










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
1
))
Var(ln(x
exp
100
gCV(%)
i



where


2
n
1
i
i
i
i
)
ln(x
)
ln(x
1
n
1
))
Var(ln(x





10.1.2
Handling of missing data
10.1.2.1 Plasma concentration - time profiles
Concentration data identified with NOS (no sample available), NOR (no valid result), NOA 
(not analyzed), BLQ (below the limit of quantification), and NOP (no peak detectable) will 
be ignored and not replaced by zero at any time point (applies also to the lag phase including 
the pre-dose value). Descriptive statistics of concentrations at specific time points will be 
calculated only when at least 2/3 of the individuals have concentrations within the validated 
concentration range. The overall sample size to decide whether the “2/3 rule” is fulfilled will 
be based on the total number of samples intended to be drawn for that time point (i.e. BLQ, 
NOR, NOS, NOA, NOP are included).
10.1.2.2 Pharmacokinetic parameters
In the noncompartmental analysis, concentration data identified with NOS, NOR, and NOA 
will not be considered. BLQ and NOP values in the lag phase will be set to zero. The lag 
phase is defined as the period between time zero and the first time point with a concentration 
above the quantification limit. All other BLQ and/or NOP values of the profile will be 
ignored.
If the predose concentration before the first dose is less than or equal to 5% of Cmax value in 
that subject, the subject’s data without any adjustments can be included in all 
pharmacokinetic measurements and calculations (i.e. the predose value will not be changed to 
zero). If the predose value is greater than 5% of Cmax, the subject should be dropped from all 
statistical evaluations. The individual pharmacokinetic parameters can be calculated and 
listed separately. 
Every effort will be made to include all concentration data in an analysis. If not possible, a 
case to case decision is required whether the value should only be excluded from half-life 
estimation or the complete analysis. 

If a concentration is only excluded from half-life determination, it will be used for all 
other calculations (e.g. descriptive statistics) and for graphical presentation.

If a concentration value is excluded from all calculations, it will not be presented 
graphically or used for the calculation of descriptive statistics and parameter 
determination. However the excluded concentration itself will be listed in the clinical trial 
report associated with an appropriate flag.


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Descriptive statistics of parameters are calculated only when at least 2/3 of the individual 
parameter estimates of a certain parameter are available. If the actual sampling time will not 
be recorded or will be missing for a certain time point, the planned time will generally be 
used for this time point instead. Pharmacokinetic parameters which cannot be determined will 
be identified by "not calculated" (NC).


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11.
DESCRIPTION OF GLOBAL AMENDMENTS
Number of global amendment
1
Date of CTP revision
26-June-2015
EudraCT number
NA
BI Trial number
1289.27
BI Investigational Product
BI 409306
Title of protocol
Randomised, parallel-group, double-blind study 
of systemic and ocular safety and 
pharmacokinetics of BI 409306 in patients with 
schizophrenia, Alzheimer’s disease, and age-
comparable healthy volunteers
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
Protocol Synopsis
Description of change
Revise criteria for Alzheimer’s disease:
Diagnosis: Patients with schizophrenia in stable 
clinical status and on stable antipsychotic 
treatment OR patients with diagnosis of mild 
Alzheimer’s disease currently treatment-naïve 
or on stable treatment(s) donepezil OR age-
comparable healthy volunteers.
Main criteria for inclusion: Patients with 
diagnosis of mild Alzheimer’s Dementia 
according to the recommendations from the 
National Institute on Aging-Alzheimer’s 
Association workgroups on diagnostic guidelines 


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Number of global amendment
1
for Alzheimer’s disease, who are currently 
treatment-naïve or on stable treatment of acetyl 
cholinesterase inhibitors and/or memantine
donepezil for at least 3 months before screening
randomization. A MMSE (Mini-Mental-State-
Examination) score between 18-26, and age 55 -
85 years with availability of pre-existing brain 
CCT or MRI compatible with diagnosis of 
Alzheimer’s disease.
Rationale for change
Widen the restriction criteria for Alzheimer’s 
subjects.
Section to be changed
Protocol Synopsis, Flow Chart and through out 
protocol
Description of change
Change of terminology from End of Study to End 
of Trial for the last study visit:
End of Study Trial
Rationale for change
To align with RDC system set-up and reporting
Section to be changed
Flow Chart footnotes and Section 6.1
Description of change
Add texts:
If there is a need that required AD subjects to 
remain in-patient, then the CIAS schedule plan 
may be ultilized, per investigator discretion.
Rationale for change
To allow for AD subjects to remain in-patient if 
required.
Section to be changed
Flow Chart footnotes, Figure 3.1.1, Sections 
5.2.5, 6.1, 6.2.2
Description of change
Add or remove text to allow Visit 2 procedures to 
be completed either on Day -2 or Day -1:
Footnote 5: In addition, urine (dipstick) 
pregnancy tests will be performed at Visit 2 (Day 
-1).
Figure 3.1.1, Sections 5.2.5, 6.1: Day -2 or -1 
(Baseline)
Section 6.2.2: If the patient/healthy volunteer has 
completed screening and has been determined 
potentially eligible by the investigator, the 
patient/healthy volunteer will be admitted to the 


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Number of global amendment
1
in-patient facility on Day -2 and the following 
baseline investigations will be performed on Day 
-2 and/or -1.
Rationale for change
To allow some baseline procedures to be 
completed either on Day -2 and/or Day -1 of Visit 
2.
Section to be changed
Flow Chart footnotes, Sections 5.2.7, 6.2.1
Description of change
Change text:
Footnote: The 24-hour heart rate monitor will be 
set up after completion of all laboratory other 
study procedures and removed at about the same 
time the following day.
Section 5.2.7: Holter monitoring procedure is to 
be initiated after all other laboratory study
related tests are completed.
Section 6.2.1: The holter monitor will be set up 
after completion of all other laboratory study
procedures.  
Rationale for change
Allow for other procedures to be completed while 
subject is on holter monitor to better replicate 
normal daily activities
Section to be changed
Section 3.3.2
Description of change
Revise criteria for Alzheimer’s disease:
Alzheimer’s Disease group:
a. Patients with diagnosis of mild Alzheimer’s 
Dementia according to based on DSM-V and in
accordance with the recommendations from the 
National Institute on Aging-Alzheimer’s 
Association workgroups on diagnostic guidelines 
for Alzheimer’s disease (R13-4115).
c. Male or female patients age 55 to 85 years, who 
are have not been taking acetyl cholinesterase
inhibitors (donepezil, galantamine, 
rivastigmine) and/or memantine for at least 3 
months or on stable dose of donepezil acetyl 
cholinesterase inhibitors (donepezil, 
galantamine, rivastigmine) and/or memantine
at least 3 months before screening


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Number of global amendment
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randomization.
Rationale for change
Widen the restriction criteria for Alzheimer’s 
subjects.
Section to be changed
Section 3.3.3
Description of change
Remove exclusion text:
10. Subjects already having received anti-
dementia drugs other than donepezil (such as 
acetyl cholinesterase inhibitors (galantamine, 
rivastigmine, tacrine, phenserine) or memantine) 
or having participated in studies on innovative 
causal interventions on AD (patients who stopped 
treatment of these drugs due to lack of efficacy or 
tolerability will not be enrolled).
Rationale for change
Widen the restriction criteria for Alzheimer’s 
Disease subjects.
Section to be changed
Section 3.3.3
Description of change
Add text:
25. Clinically significant uncompensated hearing 
loss in the judgment of the investigator. Use of 
hearing aids is not allowed.
Rationale for change
Use of hearing aids is contra-indicated for 
administering of auditory stimuli for EEG 
procedures.
Section to be changed
Section 4.2.2.1
Description of change
Revise text:
Only Short-acting hypnotics and anxiolytics are 
permitted the allowed if taken PRN medications. 
Rationale for change
To clarify use as PRN during study
Section to be changed
Section 5.2.2.2
Description of change
Moving statement regarding reporting of AEs 
after End of Trial to paragraph after REP, away 
from eCRF reference.
Rationale for change
To clarify that after End of Trial, (S)AE should be 
reported via SAE reporting process, not eCRF.
Section to be changed
Section 5.2.5
Description of change
Revise text:


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Number of global amendment
1
Physical examination will include weight and an 
examination of general appearance, skin, lungs, 
heart, abdomen, lymph nodes, extremities and 
basic nervous system evaluation. Information 
about the physical examination must be present in 
the source documentation at the study site. 
Physical examination and ECG data are not 
collected on eCRF, however, any significant 
findings made after the start of study drug which 
meet the definition of an AE must be recorded as 
the Adverse Event in eCRF.
Rationale for change
To clarify collection of weight during physical 
exams and data from physical exams and ECG 
will not be collected on eCRF.
Section to be changed
Section 5.2.8
Description of change
Revise text:
All assessments should be completed evaluated
by an ophthalmologist or certified opticians
ophthalmic technicians, with the exception of F-
M 100 which may be completed by trained 
technician at the principal investigator’s site.  
Rationale for change
To clarify that all ocular assessments should be 
evaluated by ophthalmologist or certified 
ophthalmic technicians.
Section to be changed
Section 5.2.8
Description of change
Revise text:
Best Corrected Visual Acuity (BCVA) 
The refractive error using Refraction Chart R will 
be determined at the baseline visit and used
collected throughout the remainder of the study 
period when BCVA is performed. Both eyes will 
be evaluated separately and the results captured in 
the eCRF, as well as the occurrence of any 
deviations from ETDRS chart reading.
Rationale for change
To clarify collection of refractive error when 
BCVA are performed.
Section to be changed
Section 5.2.8
Description of change
Add text:
Spectral domain optical coherence tomography 


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Number of global amendment
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(SD-OCT)
High definition optical coherence tomography 
(spectral domain OCT) (Cirrus HD-OCT, Model 
#4000) will be performed to evaluate the retinal 
and sub-retinal structures of both eyes. The 
central retinal thickness, along with other 
anatomical findings such as presence or not of 
intra-retinal fluid, sub-retinal fluid, and choroid
and retinal pigmented epithelial layer changes
will be documented and recorded in the eCRF. 
Rationale for change
To clarify collection of choroid durin OCT 
assessments.
Section to be changed
Section 5.2.8
Description of change
Revise text:
Pupil Diameter Measurement
Both left and right pupil measurements will be 
taken separately using a pupil gauge under 
standardized lighting conditions, by the same 
ophthalmologist or certified optician technician
at Day -1 (Baseline), Day 2, Day 4, Day 5 (peak 
exposure), Day 7, Day 14 and at End of Trial.  
Measurements for each eye will be recorded in 
the eCRF.
Rationale for change
To clarify procedure performed by appropriate 
technician.
Section to be changed
Section 5.3.3.1
Description of change
Add text:
Blood samples collected in PAXgene Blood DNA 
tubes have to be stored and shipped at a 
temperature of approximately -20°C or below. 
Once frozen, thawing of the samples should be 
avoided.
Rationale for change
For allowance of storage flexibility.
Section to be changed
Section 5.2.3
Description of change
Add text:
Coagulation

Partial Thromboplastin Time (=aPTT)

Prothrombin time (Quick and INR)
Rationale for change
Added missing lab assessments.


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Number of global amendment
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Section to be changed
Section 7.3.4
Description of change
Revise and add text:
No interim analysis will be conducted is planned, 
but in the event that AD recruitment goals are 
not met as planned, the CIAS and age-
comparable healthy volunteers may be 
unblinded for safety analysis after the last 
CIAS and the corresponding 10 age-
comparable have completed the study.
Rationale for change
To allow for the analysis of the CIAS and healthy 
volunteer groups in the event that the AD group is 
not fully recruited.


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Number of global amendment
2
Date of CTP revision
29-Feb-2016
EudraCT number
NA
BI Trial number
1289.27
BI Investigational Product
BI 409306
Title of protocol
Randomised, parallel-group, double-blind study 
of systemic and ocular safety and 
pharmacokinetics of BI 409306 in patients with 
schizophrenia, Alzheimer’s disease, and age-
comparable healthy volunteers
To be implemented only after 
approval of the 
IRB/IEC/Competent 
Authorities
To be implemented 
immediately in order to 
eliminate hazard –
IRB / IEC / Competent 
Authority to be notified of 
change with request for 
approval
Can be implemented without 
IRB/IEC/ Competent 
Authority approval as changes 
involve logistical or 
administrative aspects only
Section to be changed
Title Page
Description of change
Revised text:
Principal Coordinating Investigator
Rationale for change
Adding role of Coordinating Investigator as study 
design changed from single to multi-sites study.
Section to be changed
Protocol Synopsis
Description of change
Revised text to include Coordinating Investigator 
contact information:
Coordinating Investigator 
Changed Trial Site to multi-center
Revised text in Methodology:
Single Multi-center


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Number of global amendment
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Rationale for change
Changing study from single to multi-center study 
design.
Section to be changed
Flow Chart
Description of change
Removed laboratory assessments ‘X’ at Visits 5 
and 12. 
Rationale for change
To reduce procedural burden for patients, and 
there is no safety need to have <7 days interval 
for laboratory assessments.
Section to be changed
Flow Chart
Description of change
Added C-SSRS assessements ‘X’ for Visits 3 and 
16.
Rationale for change
To accommodate assessment completed at every 
clinic visit per FDA guidance, if there is no 
overnight/in-patient stay. 
Section to be changed
Flow Chart
Description of change
Removed all visual assessments ‘X11’ planned for 
Visits 4, 6 and 9.  Footnote for 11 for these 
assessments were also deleted and shifted 
previous footnotes 12 to 11, 13 to 12 and 14 to 
13.
Rationale for change
To reduce procedural burden for patients as
previous test schedule was considered to be more 
frequent than necessary.
Section to be changed
Flow Chart, Footnotes
Description of change
Revised text as noted:
#2, added statement: 
In-patient stay is optional. If feasible for in-
patient stay.
#11 footnote was deleted, and thus shift original 
numbers 11-14 to only 11-13.
#12 (now #11), edited text: 
Visual procedures to be completed at estimated 
peak exposure time point (20-45 90 minutes after 
dosing). Visual procedures at peak exposure time 
point can be completed within the time window 
on any treatment days between Day 5 and Day 10
(except Day 7).  Dosing on these days may be 


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done at the ophthalmologist office at the 
discretion of the investigator.
#13 (now #12), edited text:
The Event Related Potentials (ERP) component of 
the EEG will be performed at peak exposure time 
point (20-45 90  minutes after dosing) on Day 13 
following resting EEG.
Rationale for change
To allow for in-patient stay as optional, and 
extend the peak exposure timeframe.
Section to be changed
Section 3.1 Overall Trial Design and Plan
Description of change
Edited text:
This is a single multi-center, double-blinded, 
parallel groups study
Rationale for change
Changed study plan to add more sites to study
Section to be changed
Section 3.3 Selection of Trial Population
Description of change
Edited text:
This is a single site multi-center, double-blinded, 
parallel groups study
Rationale for change
Changed study plan to add more sites to study
Section to be changed
Section 3.3.1 Main diagnosis for study entry
Description of change
Revised text:
Patients with established diagnoses of 
schizophrenia age 18-55 years (per Diagnostic 
and Statistical Manual of Mental Disorders 
version V (DSM-V)), or Alzheimer’s Disease 
patients 55-85 years old currently on stable
treatment-naïve or on stable treatment(s)
donepezil of at least 3 months before screening, 
or healthy volunteers (age-comparable to the two 
patient groups).
Rationale for change
From Amendment 1 that was inadvertently left 
unchanged.
Section to be changed
Section 5.2.8 Ophthalmological examination
Description of change
Removed text:
Best Corrected Visual Acuity (BCVA)


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BCVA will be determined and recorded at Day -1 
(Baseline), Day 2, Day 4, Day 5 (peak exposure), 
Day 7, Day 14 and at End of Trial.
Pupil Diameter Measurement
Both left and right pupil measurements will be 
taken separately using a pupil gauge under 
standardized lighting conditions, by the same 
ophthalmologist or technician at Day -1 
(Baseline), Day 2, Day 4, Day 5 (peak exposure), 
Day 7, Day 14 and at End of Trial.  
Measurements for each eye will be recorded in 
the eCRF.
Anterior and posterior biomicroscopy 
The anterior and posterior chamber slit lamp 
examination will be performed in both eyes, at 
Day -1 (Baseline), Day 2, Day 4, Day 5 (peak 
exposure), Day 7, Day 14 and at End of Trial.  
Intra-Ocular Pressure Measurement (IOP)
Intra-ocular pressure of both eyes will be 
measured separately using the Goldmann 
applanation tonometry (Haag Streit AT900). IOP 
of both eyes will be measured separately at Day -
1 (Baseline), Day 5 (peak exposure), Day 7, Day 
14 and at End of Trial. The results will be entered 
in the eCRF.
Rationale for change
To correspond to the procedures removed from 
Flow Chart.
Section to be changed
5.3.1.2 Assessment of suicidality
Description of change
Removed text:
The C-SSRS will be administered by the medical 
qualified clinician or expert clinician and will be 
assessed at the screening visit with the aim to 
exclude patients with active moderate or severe 
symptomatology prior to the Screen Visit, or 
recent (or current) suicidal or suicide attempt 
according to the C-SSRS (baseline/screening 
version). Subsequently, the C-SSRS “since last 
visit” assessment will be performed at each clinic
visit after Visit 3 and as shown in the Flow Chart.


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Rationale for change
To note assessments to be completed at every 
clinic visit.
Section to be changed
Section 5.3.2.1 Electroencephalography (EEG)
Description of change
Revised text:
Event Related Potentials:
These ERPs will be measured in healthy 
volunteers, AD patients and schizophrenia 
patients at baseline and Day 13 at peak exposure
time point (20-45 90 minutes after dosing).
Method:
MMN/P1/N1/P3a Paradigm: 
Auditory stimuli will be presented to participants 
at 85 dB sound pressure level or adjusted 
hearing threshold via Etymotic ER3-A insert 
earphones.
Rationale for change
To expand the peak exposure timeframe, and 
allow for patients with low hearing threshold to 
still be able to pick up auditory stimuli.
Section to be changed
Section 6.1 Visit Schedule
Description of change
Revised text:
In-patient stay is optional. If feasible for in-
patient stay, eligible study participants will be 
admitted to the study center in-patient facility for 
overnight stays.  
Rationale for change
To allow for in-patient stay as optional, providing 
flexibility for patients and sites.
Section to be changed
Section 6.1 Visit Schedule
Description of change
Revised text:
7. Peak exposure time point is approximately 20-
45 90 minutes after dosing. Visual tests 
should be performed within this time range.
Visual procedures at this time point can be 
completed within the time window on any 
treatment days between Day 5 and Day 10
(except Day 7).  Dosing on these days may be 
done at the ophthalmologist office at the 
discretion of the investigator.


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
In-patient meal and snacks times may be ± 1 
hour of planned times, if applicable.
Rationale for change
To align with previous revisions, and to allow 
flexibility if patients opt to stay in-patient.
Section to be changed
Section 6.2.2 Treatment periods
Description of change
Revised text:
If the patient/healthy volunteer has completed 
screening and has been determined potentially 
eligible by the investigator, the patient/healthy 
volunteer will be admitted to the in-patient 
facility on Day -2 and the following baseline 
investigations will be performed on Day -2 and/or 
-1.
Rationale for change
To align with previous revisions that in-patient 
stay is optional.
Section to be changed
Section 6.2.2 Treatment periods
Description of change
Revised text:
Each randomized patient participant will receive 
study medication daily from Day 1 through 14 
according to the Flow Chart. Study drug will be 
taken orally in the morning of each treatment day 
under direct supervision of the investigator or 
designee.
Rationale for change
To align the language for patients and healthy 
volunteers.
Section to be changed
Section 7.1 Statistical Design - Model
Description of change
Revised text:
All collected timepoints for all endpoints will be 
assessed.  However, for the first 5 endpoints listed 
above emphasis will be on change from baseline 
at the estimated peak exposure timepoint, 20-45
90 minutes after dosing between Days 5 and 10.
Rationale for change
To align with previous revisions to expand peak 
exposure timeframe.


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Section to be changed
Section 7.3.4 Interim analyses
Description of change
Revised text:
No interim analysis is planned, but in the event 
that AD recruitment goals are not met as planned, 
the CIAS and age-comparable healthy volunteers 
may be unblinded for safety analysis after the last 
CIAS and the corresponding 10 age-comparable
healthy volunteers have completed the study. 
Rationale for change
To allow flexibility to analyze other parameters, 
other than safety.


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Number of global amendment
3
Date of CTP revision
22-Feb-2017
EudraCT number
NA
BI Trial number
1289.27
BI Investigational Product
BI 409306
Title of protocol
Randomised, parallel-group, double-blind study 
of systemic and ocular safety and 
pharmacokinetics of BI 409306 in patients with 
schizophrenia, Alzheimer’s disease, and age-
comparable healthy volunteers
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
Protocol Synopsis: Main criteria for inclusion, 
Section 3.3.2 Inclusion Criteria
Description of change
Revised and added texts: 
Patients with diagnosis of mild Alzheimer’s 
Dementia …, and age at least 55 - 85 years with 
availability of pre-existing brain CCT or MRI 
compatible with diagnosis of Alzheimer’s disease.
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.
OR
Age-comparable healthy volunteers age 18 to 85 
years. Healthy volunteers older than 85 years 
may be included based on an acceptable 


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Number of global amendment
3
general health status, (e.g. concomitant 
diseases, physical capability to follow the 
required study procedures [visits etc.]) per 
investigators judgement.
b. Similarly, after 10 patients with AD are 
entered , the median age will be computed.  
Five healthy volunteers at or below the 
median age but greater than 55 years old (low 
age group) and five healthy volunteers above 
the median but less than 85 (high age group) 
will be entered into the study.
Rationale for change
For consistency with other studies in the same 
project (studies 1289.5 and 1289.7) and to 
provide flexibility for subjects who may be 
interested in participating in the study.
Section to be changed
Flow Chart, Section 6.1 Visit Schedule
Description of change
Asterisks added in Flow Charts to Visits 4, 5, 6, 8, 
10, 11, 12, 13, and 14, with corresponding 
footnote:
**Home visits may be conducted for these 
visits in lieu of study center visits. 
Added texts to visit schedule:
The following study visits: Visits 4-6 (Day 2-4), 
Visit 8 (Day 6), Visits 10-14  (Day 9-12), may be 
conducted as home visits in lieu of study center 
visits.
Rationale for change
To potentially reduce subject burden and provide 
increased flexibility and convenience if subjects 
opt to participate in home visits in lieu of study 
center visits.
Section to be changed
Flow Chart – Footnote #2, Section 6.1 Visit 
Schedule
Description of change
Added text: 
In-patient stay is optional. If feasible for in-
patient stay, the following procedures would 
apply: eligible study participants will be admitted 
to the study center in-patient facility for overnight 
stays.  
Rationale for change
Clarified that procedures in the in-patient stay
section only applies to those subjects who stay in-
patient at the clinic during the study.


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Number of global amendment
3
Section to be changed
Section 1.2.4 Pharmacokinetic profile in humans
Description of change
Added text:
A drug-drug interaction with fluvoxamine, a 
strong inhibitor of CYP2C19 and CYP1A2 
induced a 30-fold increase of the total plasma 
exposure (AUC0-24) and a 6-fold increase in 
Cmax of BI 409306. Mainly non-PMs (10 out 
of 13 subjects) and only 1 PM were included in 
the study. These results suggest that in non-
PM, CYP1A2 is involved in BI 409306 
metabolism, in addition but to a lesser extent 
to CYP2C19, and that in PMs CYP1A2 is the 
major CYP450 isoform involved in the 
metabolism of BI 409306 (Study 1289_0035).
Rationale for change
Include results from clinical DDI study 
1289_0035.
Section to be changed
Section 3.3 Selection of trial population
Description of change
Added text:
A log of all subjects included in the study (i.e. 
having given informed consent) will be 
maintained in the ISF at the investigational site 
irrespective of whether or not they have been 
treated with investigational product. 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.
Rationale for change
For consistency with other studies in the project 
(Studies 1289.5 and 1289.7) and to provide 
subjects a second chance to participate.
Section to be changed
Section 3.3.3 Exclusion Criterion #3
Description of change
Per Administrative change letter, v1 dated 31-
Oct-2016, the bold text below were added to 
Exclusion #3.
3. Current or planned use of ocular or systemic 
corticosteroids, which in the clinical judgment 
of the investigator and ophthalmologist will 
interfere with the ocular assessments in the 
study.
Further consideration reverted this criterion back 
to the original text:


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3. Current or planned use of ocular or 
systemic corticosteroids. which in the 
clinical judgment of the investigator 
and ophthalmologist will interfere with 
the ocular assessments in the study
The current wording in this amendment 
supercedes all previous Administrative change 
letters.
Rationale for change
No change to text from previous amendment.
This is noted here to provide the sequence of 
changes per Administrative change and to 
document the final wording for this amendment.
Section to be changed
Section 3.3.3 Exclusion Criterion #7, Section 
4.2.2.1 Restrictions
Description of change
Revised text:
7. Subjects taking medications that are known to 
be strong or moderate CYP3A4 CYP1A2
inhibitors (For a list of strong and moderate 
CYP3A4 CYP1A2 inhibitors please consult 
the ISF Section 11 “Safety Information”).
Use of medications that are known to be strong or 
moderate CYP3A4 CYP1A2 inhibitors is not 
permitted. (For a list of strong and moderate 
CYP3A4 CYP1A2 inhibitors please consult the 
ISF Section 11 “Safety Information”).


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Rationale for change
Clinical data (Study 1289_0023) did not show 
evidence for clinically significant changes in 
exposure to BI 409306 after CYP3A4 inhibition.  
Recent data (Study 1289_0035) showed that 
CYP1A2 inhibitors do have an effect on BI 
409306.
Section to be changed
Section 3.3.3 Exclusion Criterion #10
Description of change
Deleted text:
10. Subjects having participated in studies on 
innovative causal interventions on AD 
(patients who stopped treatment of these drugs 
due to lack of efficacy or tolerability will not 
be enrolled).
All exclusion criteria following are re-numbered.
Rationale for change
This criterion is not relevant to this safety, non-
efficacy study.
Section to be changed
Section 3.3.3 Exclusion Criterion #15
Description of change
Added text:
For female subjects:

Pre-menopausal women (last menstruation ≤1 
year prior to informed consent) who:

are nursing or pregnant or
are of child-bearing potential and are not 
practicing an acceptable method of birth control, 
or do not plan to continue using this method 
throughout the trial until 28 days after the last 
treatment administration, and do not agree to 
submit to periodic pregnancy testing during 
participation in the trial. Acceptable methods of 
birth control include tubal ligation, vasectomized 
partner, 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.
Rationale for change
Recent data (Study 1289_0035) showed that 
CYP1A2 inhibitors do have an effect on BI 
409306.


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3
Section to be changed
Section 4.1.4 Drug Assignment, Section 6.2.2 
Treatment periods
Description of change
Added text:
Patient/healthy volunteer will be assigned study 
medication and the first dose administered on 
site at Visit 3, Day 1. Other doses may be 
administered at home, according to the home 
visits optional schedule as specified in the Flow 
Chart.  Each patient/healthy volunteer will be 
administered three tablets, one from each blister 
dispensed.  Table 4.1.4: 1 outlines the treatment 
and administration of dose for each 
patient/volunteer.
Rationale for change
To allow for dosing during home visits.
Section to be changed
Section 4.1.6 Packaging, labelling, and re-supply
Description of change
Revised text:
All drug supplies will be shipped to sites in the 
initial shipment, no with re-supply as needed is 
planned.
Rationale for change
To allow for re-supply of expired study drugs.
Section to be changed
Section 4.2.1 Rescue medication
Description of change
Deleted text:
Use of donepezil is allowed in this study, as a 
drug-drug interaction (DDI) is not expected with 
this drug, commonly used in AD patient 
population. Specifically, BI 409306 is 
predominantly metabolized by CYP2C19 with 
minor contribution from CYP3A4, which are not 
inhibited by donepezil. Also, BI 409306 is not a 
substrate of the DDI-relevant renal and hepatic 
drug transporters. As such, donepezil is not 
expected to increase exposure to BI 409306.
While potential of donepezil to induce CYP2C19 
or CYP3A4 is not known, but any potential time 
dependent decrease in BI 409306 exposure will 
be evident based on Day 1 and Day 14 
pharmacokinetics.
Donepezil is metabolized by CYP3A4 and 
CYP2D6. BI 409306 is not expected to inhibit 
CYP3A4, CYP2D6 or any renal or hepatic 
transporters relevant for drug-drug interaction. 


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Number of global amendment
3
Also, BI 409306 is not an inducer of CYP450 
enzymes. As such, BI 409306 is not expected to 
either increase or decrease donepezil exposure.
Rationale for change
No longer relevant per Study 1289_0023.
Section to be changed
 
 
 
 
 
 
Section to be changed
Section 5.3.2.1 Electroencephalography (EEG)
Description of change
Revised texts: 
Event Related Potentials:
ERPs are a noninvasive method of measuring the 
distinct electrocortical processing stages enabling 
cognition and have become a popular tool in 
neuroscience, and increasingly in clinical and 
pharmacological investigations. In particular, the 
MMN and P3a, P1, N1 and MMN components 
have been widely applied in the scientific study of 
cognitive dysfunction, because they reflect 
attentional and memory processes and their 
amplitude is they are reduced in both disorders 
and may be used as biomarkers of Alzheimer´s 
disease and Schizophrenia (R14-3416; R14-
3417).  These ERPs will be measured in healthy 
volunteers, AD patients and schizophrenia 
patients at baseline and Day 13 at peak exposure
time point (20-90 minutes after dosing). In 
addition to MMN and P3a, further ERP 
parameters of interest might also be assessed 
and evaluated.


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Function                         ERP Component
Sensory registration
P1, N1 amplitude
Sensory Discrimination 
and Echoic Memory        
MMN amplitude
Orienting of Attention     P3a amplitude
Multi-regional brain 
communication
Evoked gamma 
power
Method:
EEG data will be continuously recorded and 
referenced offline. Vertical and horizontal electro-
oculograms, recorded from electrodes above and 
below the left eye and at the outer canthi of both 
eyes, respectively, will be used to correct EEG for 
eye movement and blink artifacts. An electrode 
will be placed at the tip of the nose for additional 
offline re-referencing positions. All EEG setup 
and data acquisition will take approximately 60 
minutes with breaks. Subjects will be assessed on 
EEG biomarkers in the same sequential order: 
resting state EEG (5 minutes), MMN/P1/N1/P3a
ERPs via Passive Auditory Oddball paradigm 
(20 minutes), GBR Auditory Steady State 
Response paradigm (5 minutes), and then 
resting state EEG (5 minutes). The study team 
has extensive experience in the testing of 
thousands of subjects using the above paradigms 
and are thus well-positioned to monitor the 
comfort and tolerability of the subjects. 
MMN/P1/N1/P3a Passive Auditory Oddball
Paradigm for Assessing ERPs: 
Auditory stimuli will be presented to participants 
at 85 dB sound pressure level. or adjusted hearing 
threshold via Etymotic ER3-A insert earphones 
(Etymotic Research, Inc., Elk Grove Village, 
Illinois). The MMN/P3a paradigm will be 
comprised of a A pseudorandom sequence of 
tones will be presented to participants where , 
of which 82% 85% are standards (50 msec, 1000 
Hz) and 15% differ in their duration or 
duration plus pitch (125 msec, 1000 Hz or 1500 
Hz). 18 are deviants (6% per deviant type): for 
duration MMN, deviants are 100 milliseconds, 
1000 Hz; for frequency MMN, deviants are 50 


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milliseconds, 1500 Hz; for double-deviant MMN, 
deviants are 100 milliseconds, 1500 Hz. All tones 
have 5 millisecond rise/fall times and are 
presented with a 500-millisecond stimulus onset 
synchrony. Participants will be instructed to 
ignore auditory stimuli while they view a silent 
cartoon movie.  Independent component 
analyses will be used to correct for ocular and 
other artifacts in the continuous EEG 
recordings.  After artifact correction, ERP 
averaging of standards and each deviant type 
will be generated. Conventional ERP averaging 
of standards and each deviant type will be 
generated. ERP data will then be low-pass filtered 
at 20 Hz and baseline corrected prior to 
generating deviant-standard difference waves. 
MMN amplitude will be defined as the peak area
between 140 and 200 milliseconds in each deviant 
type difference wave; P1 will be defined as the 
peak area between 50-150 msec; N1 will be 
defined as the negative peak area between 100-
200 msec; P3a will be defined as the peak area 
between 250-350 msec in each deviant type 
difference wave. Scalp topography plots activity 
will be inspected to ensure that each subject is 
showing the expected pattern of activity (i.e., 
negativity at frontocentral regions and polarity 
inversion at the mastoids for MMN, positivity at 
frontocentral regions for P3a).
Auditory Steady State Response Gamma Band 
Entrainment Paradigm:
Gamma evoked EEG power and phase locking 
will be assessed in response to 40-Hz stimulation 
at Fz, as this is the electrode with maximal 
responses and relationships to cognition as per 
established methods which demonstrated 
impairments in large cohorts of CIAS patients 
(R14-4685). The stimuli will be 1-millisecond 
duration, 93 85 dB clicks presented in 500 msec 
trains. Blocks contain 200 trains of clicks with 
500-millisecond intertrain intervals. For evoked 
power analyses, the averaged epochs across the 
click trains will be transformed into power 
spectra by means of fast Fourier transform 


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(FFT). For evoked power analyses, averages will 
be computed on 120 artifact-free epochs in each 
block and digitally filtered using a zero-phase 
shift, 10-60 Hz bandpass filter (24 dB/octave).  
The averaged epochs across the click trains (0-
512 msec) will then be transformed into power 
spectra by means of fast Fourier transform (FFT) 
using a bin width of 1.95 Hz for the assessment of 
evoked power analyses.
Gamma phase locking will be calculated 
following wavelet transformation of the 
segmented data.  Mean values across the 40 Hz 
frequency layer will be obtained for the each of 
the six 100-ms windows from -100 to 500 ms 
relative to stimulus onset. 
Rationale for change
Texts revised to describe actual EEG assessment 
performed.
Section to be changed
Section 6.1 Visit Schedule
Description of change
Added text:
The following study visits: Visits 4-6 (Day 2-4), 
Visit 8 (Day 6), Visits 10-14  (Day 9-12) may be 
conducted as home visits in lieu of study center 
visits.
If a clinic study visit is missed, subjects should 
continue to the next planned visit and study 
procedures per Flow Chart.
Rationale for change
To allow for home visits.

SAP_001.pdf: 
TITLE PAGE
Trial Statistical Analysis Plan
c03413910-02
BI Trial No.:
1289.27
Title:
Randomised, parallel-group, double-blind study of systemic and 
ocular safety and pharmacokinetics of BI 409306 in patients with 
schizophrenia, Alzheimer’s disease, and age-comparable healthy 
volunteers
Including Protocol Amendment 3
1289.27-revised-protocol-03 [c02218444-07]
Investigational
Product:
BI 409306
Responsible trial 
statistician:
TEL: 
FAX:
Date of statistical 
analysis plan:
08 August 2017    REVISED
Version:
Revised
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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.
CHANGES IN THE PLANNED ANALYSIS OF THE STUDY ......9
5.
ENDPOINTS ........................................................................................10
5.1
PRIMARY ENDPOINT ....................................................................................10
5.2
SECONDARY ENDPOINTS............................................................................10
5.2.1
(Other) Secondary endpoints .......................................................................10
.............................................................................10
.............................................................................11
......................................................................................11
......................................................................................11
6.
GENERAL ANALYSIS DEFINITIONS...........................................12
6.1
TREATMENTS..................................................................................................12
6.2
IMPORTANT PROTOCOL VIOLATIONS ..................................................14
6.3
SUBJECTS SETS ANALYSED........................................................................16
.....................................................................................................16
6.5
POOLING OF CENTRES ................................................................................16
6.6
HANDLING OF MISSING DATA AND OUTLIERS ...................................16
6.7
BASELINE, TIME WINDOWS AND CALCULATED VISITS ..................17
7.
PLANNED ANALYSIS.......................................................................18
7.1
DEMOGRAPHIC AND OTHER BASELINE CHARACTERISTICS........18
7.2
CONCOMITANT DISEASES AND MEDICATION ....................................18
7.3
TREATMENT COMPLIANCE .......................................................................18
7.4
PRIMARY ENDPOINT ....................................................................................18
7.5
SECONDARY AND FURTHER ENDPOINTS..............................................19
7.5.1
Key secondary endpoints..............................................................................19
7.5.2
(Other) Secondary endpoints .......................................................................19
.................................................................................19
7.7
EXTENT OF EXPOSURE................................................................................20
7.8
SAFETY ANALYSIS.........................................................................................20
7.8.1
Adverse events ...............................................................................................20
7.8.2
Laboratory data.............................................................................................21
7.8.3
Vital signs.......................................................................................................22
7.8.4
ECG ................................................................................................................22
7.8.5
Others .............................................................................................................22
8.
REFERENCES.....................................................................................23
......................24
..........................24
..........................27


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...............................................27
...............................................28
...............................................33
10.
HISTORY TABLE...............................................................................35


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LIST OF TABLES
Table 6.1: 1
Treatment regimens / study intervals ...............................................................13
Table 6.1: 2
Adverse events analysing treatment: ‘Active + 7 days’...................................14
Table 6.2: 1
Important protocol violations...........................................................................15
Table 6.3: 1
Subject sets analysed........................................................................................16
.....................................................24
.....................................................28
.....................................................29
......................................................35


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2.
LIST OF ABBREVIATIONS
Term
Definition / description
AD
Alzheimer’s Disease / Alzheimer’s Dementia
AE
Adverse Event
AESI
Adverse Events of Special Interest
ATC
Anatomical Therapeutic Chemical
AUC
Area under the Curve
BDS
Biostatistics & Data Sciences
BI
Boehringer Ingelheim
BP
Blood Pressure
BPM
Beats Per Minute
BRPM
Blinded report planning meeting
CARE
Clinical data Analysis and Reporting Environment
CDR
Clinical Data Repository
CIAS
Cognitive Impairment Associated with Schizophrenia
Cmax,ss
Maximum concentration of the analyte in plasma at steady state
conc.
concentration
CPPL
Clinical Pharmacology Program Leadership
CRF
Case Report Form
CTP
Clinical Trial Protocol
CTR
Clinical Trial Report
CYP
Cytochrome P450
eCFR
electronic Case Report Form
ECG
Electrocardiogram
EMEA
European Agency for the Evaluation of Medicinal Products
EoT
End-of-Text
EOT
End of Trial
EX
Exclusion criteria from CTP
geom.
geometric
HR
Heart Rate
HV
Healthy Volunteer(s)
ICF
Informed Consent Form
ICH
International Conference on Harmonisation
IDC
International Development Committee
IMC
International Medical Committee
IN
Inclusion criteria from CTP
IPV
Important Protocol Violation
iPROG
independent Programmer


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Term
Definition / description
iSTAT
independent Statistician
MedDRA
Medical Dictionary for Regulatory Activities
N
Number of subjects
O*C
Oracle Clinical
PAC
Premature Atrial Complexes
PCPK
Project Clinical PharmacoKineticist
PDM
Project Data Manager
PK
Pharmacokinetics
PKA
Pharmacokinetics Analyst
PKProg
PK Programmer
PKS
Pharmacokinetic Set
PMW
Project Medical Writer
PPROG
Project Programmer
PR
Pulse Rate 
PSTAT
Project Statistician
PVC
Premature Ventricular Contraction
QD
quaque die (once a day)
QRS
Combination of Q, R and S waves
RAGe
Report Appendix Generator
R on T
refers to the R wave of the premature beat being so premature that it 
coincides with the T wave of the previous beat
RR
ECG interval from the peak of the R wave to the peak of the subsequent 
R wave
SAS
Statistical Analysis System (SAS® System, SAS Institute Inc., Cary, 
North Carolina)
SD
Standard Deviation
SDTM
Study Data Tabulation Model
SOC
System Organ Class
STATANA
Statistical analysis
SVT
Supraventricular
TA
Therapeutic Area
TAC
Therapeutic Area Committee
TAH
Therapeutic Area Head
TALT
Therapeutic Area Leadership Team
TCM
Trial Clinical Monitor
TCPK
Trial Clinical PharmacoKineticist
TCPKa
Trial Clinical PharmacoKinetics Analyst
TDM
Trial Data Manager
tmax,ss
time from dosing to maximum measured concentration of the analyte in
plasma at steady-state
TME
Team Member  
TMM
Team Member Medicine


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Term
Definition / description
TMW
Trial Medical Writer
TProg
Trial Programmer
TS
Treated Set
TSAP
Trial Statistical Analysis Plan
TSTAT
Trial Statistician
V
Visit
VT
Ventricular
WHO
World Health Organization


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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 or higher will be used for all analyses.


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4.
CHANGES IN THE PLANNED ANALYSIS OF THE STUDY
There are no changes to the planned analysis described in the CTP.


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5.
ENDPOINTS
This trial is designed to evaluate the ocular and systemic safety and pharmacokinetics during 
a 14-day treatment period in patients with schizophrenia, Alzheimer’s disease, and age-
comparable healthy volunteers treated with oral film-coated tablet of BI 409306 25 or 
100 mg.  
.
5.1
PRIMARY ENDPOINT
The primary endpoint is:

The number (%) of subjects with AEs, coded to the MedDRA-SOC ‘Eye disorders’, 
as determined by the investigator at End of Trial
5.2
SECONDARY ENDPOINTS
5.2.1
(Other) Secondary endpoints
Secondary endpoints include:

The number (%) of subjects with drug-related AEs as determined by the investigator 
at End of Trial
The following two pharmacokinetic parameters of BI 409306 are also secondary endpoints:

Cmax,ss - maximum measured concentration of the analyte in plasma at steady-state

tmax,ss - time from dosing to maximum measured concentration of the analyte in
plasma at steady-state.


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6.
GENERAL ANALYSIS DEFINITIONS
6.1
TREATMENTS
For basic study information on treatments to be administered, assignment of subjects to dose 
group, and selection of doses, see CTP, Section 4.
The two dose levels for this trial are described as following:
Long label
Short label
BI 409306 25 mg QD
BI 25mg QD
BI 409306 100 mg QD
BI 100mg QD
The populations for this trial are described as:  Alzheimer’s Dementia (AD), cognitive 
impairment associated with schizophrenia (CIAS), and healthy volunteers (HV).  Populations
will be determined using ‘Group under which subject is entering trial’ captured on the 
demographics page at visit 1. For some displays, HV will be split into two groups:  healthy 
volunteers comparable in age to AD subjects (HV_AD) and healthy volunteers comparable in 
age to CIAS subjects (HV_CIAS).  HV_CIAS are all HV subjects from site 
.  HV_AD
are all HV subjects from sites 
 and 
.
Short label
unblinded
Interval
blinded
Sort order
CRF field
AD
AD
01
Group under which subject is entering trial
CIAS
CIAS
03
HV
HV
05
HV_AD
HV_AD
02
HV_CIAS
HV_CIAS
04
Total
Total
06
The following column headers will be used in the CTR displays.  
The 7-column display shows population by dose and Total.
AD
CIAS
HV
Total
BI 25mg QD
BI 100mg QD
BI 25mg QD
BI 100mg QD
BI 25mg QD
BI 100mg QD
The 4-column display shows populations and Total
AD
CIAS
HV
Total
Tables displaying HV split into two groups will have the following layouts:
AD
HV_AD
Total
and
CIAS
HV_CIAS
Total


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The 3-column display shows dose and Total
BI 25mg QD
BI 100mg QD
Total
The following treatment phase definitions will be applied to the analyses of data except 
adverse events:
The screening phase will be defined as the time from informed consent to the date of Visit 2 
(sites
 and 
) or Visit 2 minus 1 day (site
).
The baseline phase will be defined as the date of Visit 2 (sites 
 and 
) or Visit 2 
minus 1 day (site
) to (one minute before) the first administration of trial medication.
The on-treatment phase will be defined as the time from first administration of trial 
medication to last visit with trial medication intake. 
The post-treatment phase will be defined as starting on the day after the last visit with drug 
intake to end of trial visit.
The post-study phase will be defined as starting from 0:00 a.m. on the day after the end of 
trial visit onwards.
Table 6.1: 1
Treatment regimens / study intervals 
Short label
unblinded
Interval
blinded
Sort order+
Start date (CRF)
Start time 
(CRF/derived)
Screening
Screening
01
V1, Date of informed consent
00:00
Baseline
For site 
*
For sites
&
#
Baseline
Baseline
02
02
V2, Date of visit – 1 day
V2, Date of visit
00:00
00:00
25 mg QD or
100 mg QD
Treat
03
V3, Date of study drug intake
V3, Time of study 
drug intake
Post-treatment
Post-treat
04
From EOT page, Date of last 
administration of trial drug 
+ 1 day
V16, Time of study 
drug intake
Post-study
Post-study
05
EOT visit, Date of visit + 
1 day
00:00
+ The sort order refers to the unblinded regimens.
* Site 
 (subjects 
) is using the date of randomization to populate the visit 2 date 
(Using the CTP flowchart notation, this is Day -1). The date that the subject checked into the site is Day -2. 
This will be the start of the Baseline period and will be derived by subtracting one day from the visit 2 date.
# Sites 
 & 
 (subjects 
) are not admitting any patients for in-patient stays. At 
these sites, the date of randomization is the visit 2 date and is the start of the Baseline period.


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Table 6.1: 2
Adverse events analysing treatment: ‘Active + 7 days’
Label
Sort order
Start date (CRF)
Stop date
Screening
01
V1, Date of informed consent
V2, Date of visit 2 – 1 day* or
V2, Date of visit 2#
Baseline
V2, Date of visit 2 – 1 day* or
V2, Date of visit 2#
V3, Date of study drug intake
Treatment
02
V3, Date of study drug intake
From EOT page, Date of last 
administration of trial drug + 
1 day + 7 days
Post-treatment
03
From EOT page, Date of last 
administration of trial drug + 
1 day + 7 days
EOT visit, Date of visit + 1 day
Post-study
04
EOT visit, Date of visit + 1 day
Date of data base lock
*Site 
#Sites 
 & 
The treatment phase definitions for adverse events analyses are described above in 
Table 6.1: 2. All adverse events occurring from informed consent until the day before visit 2 
(site 
) or the day of visit 2 (sites 
 & 
) will be assigned to “screening”.  All 
adverse events occurring the day before visit 2 (site 
) or the day of visit 2 (sites 
 
& 
) until first dose of study drug will be assigned to “baseline”.  All adverse events 
occurring between first dose of study drug until 7 days (inclusive) after last treatment 
administration will be assigned to “treatment”.  Adverse events occurring after this period 
and prior to end-of-trial will be assigned to “post-treatment”.   Adverse events occurring after 
end-of-trial will be considered “post-study”.  
6.2
IMPORTANT PROTOCOL VIOLATIONS
The following table defines the different categories of important protocol violations (IPVs). 
The final column describes which IPVs will be used to exclude subjects from the different 
subject analysis sets.


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Table 6.2: 1
Important protocol violations
Category/
Code
Description
Example/Comment
Potentially 
excluded 
from
A
Entrance criteria not met
A1
Inclusion criteria not met
A1.1
Diagnoses of schizophrenia not 
established 
IPV if any of the clinical features defining 
the population (IN1) are not met.  
None
A1.2
Diagnosis of AD not established
IPV if any of the clinical features defining 
the population (IN1) are not met
None
A2
Exclusion criteria met
A2.1
Presence of active ocular conditions
Any of EX1-EX4 are met.
None
A2.2
Suicidal ideation or behavior
Any of EX13-EX14
None
A2.3
Other clinically relevant baseline 
conditions
Any of EX12, 15, 17-22, 24-26, 28 
None
B
Informed consent
B1
Informed consent not available/not 
done
Informed consent date missing; no 
signature on ICF
All
B2
Informed consent too late
Informed consent date <actual consent 
date> was after Visit 1 date <Visit 1 date>
None
C
Trial medication and 
randomisation
C1
Incorrect trial medication kit 
assigned
Medication (kit) number assigned is not 
from the correct group (AD, CIAS etc.). 
OR Medication number was not assigned 
in sequential order (as subjects were
randomized).
None 
C2
Incorrect trial medication 
administered
C2.1
Incorrect trial medication 
administered on any of days 2-13.
Trial medication administered on any of 
days 2-13 was not from the medication kit 
assigned to subject.
None
C2.2
Incorrect trial medication 
administered on PK day 1 or 14.
Subject was administered medication from  
kit assigned to another subject on days 1 or 
14 (PK visit)
PKS
C3
Medication code broken 
inappropriately
Medication code broken inappropriately -
reason for medication code break 
<reason>
None
D
Concomitant medication
D1
Prohibited medication use 3 days 
prior to Day 1 and/or Day 14.
Use of St. Johns wort, Carbamazepine, 
extracts from Gingko, artemisinin, 
enzalutamide, efavirenz, lopinavir, 
ritonavir, tipranavir, & rifampicin.
None
F
Incorrect timing
F1
Peak exposure visual procedures 
performed outside time range.
Visual procedures were not completed 
during estimated peak exposure time range 
(between Day 5 and Day 10 (except Day 
7), 20-90 minutes after dosing).
None
Z
Other
Z3
Other protocol violations affecting 
safety only
None
PKS: PK set
Note: Missing visits, evaluations, and tests will be considered missing data, not protocol deviations. All final 
decisions as to whether any deviation is relevant will be taken at the BRPM.


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6.3
SUBJECTS SETS ANALYSED

Randomised set:
This subject set includes all randomised subjects, whether treated or not.

Treated set (TS):
This subject set includes all subjects who were documented to have been administered 
at least one dose of investigational treatment. 

Pharmacokinetic set (PKS):
This subject set includes all subjects in the treated set who provide at least one
evaluable observation for at least one PK endpoint without important protocol 
violations relevant to the evaluation of PK.
Table 6.3: 1
Subject sets analysed
Subject set
Class of endpoint
Treated set
Pharmacokinetics set
Primary endpoint 
X
(other) Secondary and further 
endpoints 
X
X
Safety endpoints 
X
Demographic/baseline 
endpoints
X
Pharmacokinetics analysis
X
In addition, the population group is defined as Alzheimer’s Dementia group, schizophrenia 
group and healthy volunteer group.  The ophthalmological assessment will be done by 
population group.  
6.5
POOLING OF CENTRES
This section is not applicable.
6.6
HANDLING OF MISSING DATA AND OUTLIERS
With respect to safety evaluations, it is not planned to impute missing values other than AE 
start dates and times. Missing or incomplete AE dates are imputed according to BI standards 
(see “Handling of missing and incomplete AE dates”). (1)
For handling of missing data in PK evaluation, refer to CTP Appendix Section 10.1.2 and 
029-DCP-102. (2)


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6.7
BASELINE, TIME WINDOWS AND CALCULATED VISITS
Unless otherwise specified, the baseline is the last available measurement before the first trial 
medication intake. For laboratory data that were repeatedly measured, baseline is defined to 
be the last available measurement before the first trial medication intake.  


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7.
PLANNED ANALYSIS
No statistical hypothesis testing is planned. Variables will be evaluated by descriptive 
statistical methods in this trial.
For End-Of-Text (EoT) tables, the set of summary statistics is: N / Mean / SD / Min / Median 
/ Max. 
For displays 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 subjects in the respective subject
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
DEMOGRAPHIC AND OTHER BASELINE CHARACTERISTICS
Only descriptive statistics are planned for this section of the report, based on the TS. The 
following variables will be displayed: gender, age, race, ethnicity, height, weight, body mass 
index, smoking and alcohol status.
7.2
CONCOMITANT DISEASES AND MEDICATION
Only descriptive statistics are planned for this section of the report.  The concomitant disease 
will be summarized by MedDRA primary system organ class and preferred term. The 
concomitant medications taken at baseline and those while on treatment will be coded using 
the WHO Drug coding dictionary. Concomitant medications will be summarized by WHO 
Drug ATC coding.
7.3
TREATMENT COMPLIANCE
On each treatment day, study drug is administered to the subject at the study centre or at the 
ophthalmology site.  Date and time of study drug intake is documented on day 1-14 of the 
treatment interval.
7.4
PRIMARY ENDPOINT
Ocular adverse events will be those events coded to the SOC ‘Eye disorders’ determined by 
the investigator at end of trial. The assessment of ocular adverse events will be done on 
treated set. Ocular adverse events analyses will be performed in accordance with BI 
standards, essentially, tabulations of frequencies will be displayed. Refer to Section 7.8.1 for 
a description of the analysis of adverse events.  


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7.5
SECONDARY AND FURTHER ENDPOINTS
7.5.1
Key secondary endpoints
This section is not applicable as no key secondary endpoint has been specified in the 
protocol.
7.5.2
(Other) Secondary endpoints
Summary of drug-related AEs as determined by the investigator at end of trial will be 
performed in accordance with BI standards, essentially, tabulations of frequencies will be 
displayed. Refer to Section 7.8.1 for a description of the analysis of adverse events.  
The analysis of standard PK parameters, Cmax,ss and tmax,ss, will be performed as described in 
CTP Section 7.3.5 and also according to 029-DCG-103 (3).  Descriptive analyses are 
planned.


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7.7
EXTENT OF EXPOSURE
Extent of exposure will be summarized by treatment group using descriptive statistics for 
days of exposure as well as number (percent) of patients whose total exposure falls in the 
following categories: 
1 day, 2 days, 3 days, 4 days, etc. until 14 days, and >=15 days
Exposure to treatment will be calculated as study drug stop date minus study drug start date 
plus 1. Total exposure will summarize exposure to both doses.
7.8
SAFETY ANALYSIS
All safety analyses will be performed on the treated set.
7.8.1
Adverse events
The analyses of adverse events (AEs) will be descriptive in nature. All analyses of AEs will 
be based on the number of subjects with AEs and NOT on the number of AEs. AEs will be 
coded using the Medical Dictionary for Drug Regulatory Affairs (MedDRA).
For analysis, multiple AE occurrence data on the CRF will be collapsed into an AE provided 
that all of the following applies:
•
All AE attributes are identical (LLT, intensity, action taken, therapy required, seriousness, 
reason for seriousness, relationship, outcome, AE of special interest).
•
The occurrences were time-overlapping or time-adjacent (time-adjacency of 
2 occurrences is given if the second occurrence started ≤24 hours from the end of the first 
occurrence).


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For further details on summarization of AE data, please refer to the guideline 'Handling and 
summarization of adverse event data for clinical trial reports and integrated summaries' (4)
[001-MCG-156].
The relationship of an AE to the study drugs treatments will be assessed by the investigator.
The analysis of AEs will be based on the concept of treatment-emergent AEs. That means 
that all AEs occurring between first study drug intake till 7 days (inclusive) after last study 
drug intake will be considered “treatment-emergent” and be assigned to the randomised 
treatment.. AEs occurring before first study drug intake will be assigned to ‘screening’ or 
‘baseline’; AEs occurring after last study drug intake + 7 days till end-of-trial visit will be 
assigned to ‘post-treatment’ (for listings only). AEs occurring after the end-of-trial visit will 
be assigned to ‘post-study’ (for listings only). For details on the treatment definition, see 
Section 6.1.
According to ICH E3 (5), 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.
Overall summaries of adverse events will be presented to summarise any AEs, severe AEs, 
drug-related AEs, AEs leading to treatment discontinuation, serious AEs, drug-related serious 
AEs, and AEs leading to death. 
The frequency of subjects with adverse events will be summarised by treatment, primary 
system organ class and preferred term. Separate tables will be provided for subjects with 
other significant adverse events according to ICH E3 (5), for subjects with adverse events of 
special interest (AESI) and for subjects with serious adverse events.  The AESI are described 
in Section 5.2.2.1 of the CTP. There is a field on the eCRF for the site to designate that an AE 
is an AESI.  This variable will be used to identify the AESI.
The system organ classes will be sorted alphabetically, preferred terms will be sorted by 
frequency (within system organ class).
 
7.8.2
Laboratory data
The analyses of laboratory data will be descriptive in nature and will be based on BI 
standards (6).


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7.8.3
Vital signs
Descriptive statistics of vital signs (BP and PR) observed values and change from baseline 
will be provided for both supine and standing positions separately. Orthostatic BP and PR 
will also be summarized descriptively.  Orthostatic changes in BP are flagged for falls in 
systolic blood pressure of at least 20 mm Hg or diastolic blood pressure of at least 10 mm Hg. 
Orthostatic changes are calculated as standing − supine.
Baseline values for vital signs will be the observations taken at Visit 2
7.8.4
ECG
Clinically significant findings for ECG will be recorded as baseline conditions or AEs and 
will be analyzed accordingly.
7.8.5
Others
24-hour Holter Monitoring 
The 24-hour Holter monitoring will be analyzed using descriptive statistics.
 
 
 
 
 
 


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8.
REFERENCES
1
001-MCG-156_RD-01: "Handling of missing and incomplete AE dates", current 
version; IDEA for CON.
2
029-DCP-102: "Noncompartmental Pharmacokinetic Analyses of Clinical 
Studies", current version; IDEA for CON.
3
029-DCG-103: "Noncompartmental Pharmacokinetic Analyses using 
WinNonlin®", current version; IDEA for CON.
4
001-MCG-156: "Handling and summarisation of adverse event data for clinical 
trial reports and integrated summaries", current version; IDEA for CON.
5
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.
6
001-MCG-157: "Display and Analysis of Laboratory Data", current version, IDEA 
for CON.


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10.
HISTORY TABLE
Table 10: 1
History table
This is a revised TSAP including the following modifications to the final TSAP
Version
Date
(DD-Mmm-YY)
Author
Sections 
changed
Brief description of change
Final
21-Apr-16
None
This is the final TSAP without any 
modification
Revised
08-Aug-17
Title 
page
Section 
6.1
Section 
6.1
Section 
6.2
Section 
7.8.1
Multiple 
sections
To indicate that the TSAP covers CTP 
Amendments 1-3.
In selected AE tables, HV will be split 
out to display results for HV_AD and 
HV_CIAS groups.
The definition of the start of the 
baseline period was revised to reflect 
study conduct differences at the new 
sites (Subjects at site 
 were in-
patients; subjects at sites 
 & 
 were not.)
CTP Amendment #3 allowed subjects 
> age 85 to participate in the trial.  
Exclusion of PK data for subjects 
outside the original age cut-offs was no 
longer deemed necessary. The IPV
‘Age criteria not met’ was removed.
Section now correctly describes 
analysis & presentation of AE data
based on Version 8 of the guideline.
 
 
CTP Amendment #1 changed 
terminology from ‘End of Study’ to 
‘End of Trial’ for the last study visit.