Clinical trial NCT03305809
Conditions: Lewy Body Dementia
Keywords: Parkinson Disease Dementia Parkinson Disease Dopamine Cognition Lewy Body Dementia Dementia with Lewy Bodies
Sponsor: Eli Lilly and Company
Start date: 2017-11-09; Completion date: 2020-07-10
Enrollment: 344 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
A randomized placebo-controlled trial to evaluate the safety and efficacy of three doses of study drug LY3154207 treated for 12 weeks in participants with mild-to-moderate dementia associated with LBD (PDD or DLB).

Detailed description:

Arms: arm 1: Participants received placebo administered orally once a day (QD). arm 2: Participants received 10 mg LY3154207 administered orally QD. arm 3: Participants received 30 mg LY3154207 administered orally QD. arm 4: Participants received 75 mg LY3154207 administered orally QD.
Interventions: intervention 1: LY3154207 intervention 2: Placebo
Intervention descriptions: intervention 1: Administered orally. intervention 2: Administered orally.

Protocol documents:
Prot_000.pdf: 
Protocol I7S-MC-HBEH(b)  
 
Effect of LY3154207 on Cognition in Mild-to-Moderate Dementia Due to Lewy Body Dementia  
(LBD) Associated with Idiopathic Parkinson’s Disease (PD) or Dementia with Lewy Bodies (DLB) 
(The PRESENCE Study) 
 
 
NCT03305809 
 
Approval Date: 25-Jan-2019 
 
 


I7S-MC-HBEH(b) Clinical Protocol
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LY3154207
Protocol I7S-MC-HBEH(b)
Effect of LY3154207 on Cognition in Mild-to-Moderate 
Dementia Due to Lewy Body Dementia (LBD) Associated 
with Idiopathic Parkinson’s Disease (PD) or Dementia with 
Lewy Bodies (DLB)
(The PRESENCE Study)
Confidential Information
The information contained in this document is confidential and is intended for the use of 
clinical investigators.  It is the property of Eli Lilly and Company or its subsidiaries and 
should not be copied by or distributed to persons not involved in the clinical investigation of
LY3154207, unless such persons are bound by a confidentiality agreement with Eli Lilly 
and Company or its subsidiaries.
Note to Regulatory Authorities:  This document may contain protected personal data 
and/or commercially confidential information exempt from public disclosure.  Eli Lilly and 
Company requests consultation regarding release/redaction prior to any public release.  In 
the United States, this document is subject to Freedom of Information Act (FOIA) 
Exemption 4 and may not be reproduced or otherwise disseminated without the written 
approval of Eli Lilly and Company or its subsidiaries.
LY3154207
Eli Lilly and Company
Indianapolis, Indiana USA 46285
Protocol Electronically Signed and Approved by Lilly on: 30 August 2017
Amendment (a) Electronically Signed and Approved by Lilly on: 14 February 2018
Amendment (b) Electronically Signed and Approved by Lilly on approval date provided 
below.
Approval Date: 25-Jan-2019 GMT


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Table of Contents
Section
Page
Protocol I7S-MC-HBEH(b) Effect of LY3154207 on Cognition in 
Mild-to-Moderate Dementia Due to Lewy Body Dementia (LBD) 
Associated with Idiopathic Parkinson’s Disease (PD) or Dementia 
with Lewy Bodies (DLB)....................................................................................................1
Table of Contents........................................................................................................................2
1.
Synopsis .............................................................................................................................9
2.
Schedule of Activities .......................................................................................................14
3.
Introduction ......................................................................................................................21
3.1.
Study Rationale............................................................................................................21
3.2.
Background..................................................................................................................21
3.3.
Benefit/Risk Assessment..............................................................................................22
4.
Objectives and Endpoints..................................................................................................24
5.
Study Design.....................................................................................................................27
5.1.
Overall Design .............................................................................................................27
5.1.1.
Screening Period (Visit 1) ....................................................................................28
5.1.1.1 Screening Procedures............................................................................................28
5.1.1.1.1.
BP and Pulse Rate.....................................................................................29
5.1.1.1.2.
CDR-CBB ................................................................................................29
5.1.1.1.3.
Modified Hoehn and Yahr Scale ...............................................................29
5.1.1.1.4.
Clinical Diagnostic Criteria for PD and DLB ............................................29
5.1.1.1.5.
Montreal Cognitive Assessment Scale.......................................................30
5.1.1.1.6.
Geriatric Depression Scale Short Form .....................................................30
5.1.1.1.7.
Columbia-Suicide Severity Rating Scale – Children’s 
Version.....................................................................................................30
5.1.2.
Pretreatment Period (Visit 2)................................................................................31
5.1.2.1 Blood Pressure and Pulse Rate Measures ..............................................................31
5.1.2.2 
Cognitive, Motor, and Functional Assessments...............................................31
5.1.2.3 Actigraphy and iPAD Device................................................................................32
5.1.2.4 Home Blood Pressure Monitoring .........................................................................32
5.1.3.
Double-Blind Period (Visit 3 through Visit 11) ....................................................32
5.1.3.1.
Orthostatic BP/Pulse Rate Measurements .......................................................33
5.1.3.2.
PK Sample......................................................................................................34
5.1.3.3.
Home Blood Pressure Monitoring...................................................................34
5.1.3.4.
Visit 4 to Visit 11 ...........................................................................................35
5.1.4.
Telephone Visit (Visit 111)..................................................................................35


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5.1.5.
Follow-Up Period (Visit 801)...............................................................................35
5.2.
Number of Subjects......................................................................................................35
5.3.
End of Study Definition ...............................................................................................35
5.4.
Scientific Rationale for Study Design...........................................................................36
5.5.
Justification for Dose ...................................................................................................36
6.
Study Population...............................................................................................................38
6.1.
Inclusion Criteria..........................................................................................................38
6.2.
Exclusion Criteria ........................................................................................................40
6.2.1.
Rationale for Exclusion of Certain Study Candidates ...........................................43
6.3.
Lifestyle Restrictions....................................................................................................43
6.4.
Screen Failures.............................................................................................................43
7.
Treatments........................................................................................................................44
7.1.
Treatments Administered .............................................................................................44
7.1.1.
Packaging and Labeling .......................................................................................44
7.2.
Method of Treatment Assignment ................................................................................45
7.3.
Blinding .......................................................................................................................45
7.4.
Dosage Modification....................................................................................................45
7.5.
Preparation/Handling/Storage/Accountability...............................................................46
7.6.
Treatment Compliance .................................................................................................46
7.7.
Concomitant Therapy...................................................................................................46
7.8.
Treatment after the End of the Study............................................................................47
7.8.1.
Treatment after Study Completion........................................................................47
8.
Discontinuation Criteria ....................................................................................................48
8.1.
Discontinuation from Study Treatment.........................................................................48
8.1.1.
Permanent Discontinuation from Study Treatment ...............................................48
8.1.2.
Temporary Discontinuation from Study Treatment...............................................49
8.1.3.
Discontinuation of Inadvertently Enrolled Subjects..............................................49
8.2.
Discontinuation from the Study....................................................................................49
8.3.
Lost to Follow-Up........................................................................................................50
9.
Study Assessments and Procedures ...................................................................................51
9.1.
Efficacy Assessments...................................................................................................51
9.1.1.
Primary Efficacy Assessments .............................................................................51
9.1.2.
Secondary Efficacy Assessments..........................................................................53
9.1.2.1.
Measures of Cognitive Function and Related Outcomes .................................53
9.1.2.1.1.
Alzheimer’s Disease Cooperative Study – Clinician 
Global Impression of Change Scale ..........................................................53
9.1.2.1.2.
Power of Attention Composite Score from the 
CDR-CCB ................................................................................................53


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9.1.2.1.3.
Alzheimer’s Disease Assessment Scale – 13-Item 
Cognitive Subscale ...................................................................................53
9.1.2.1.4.
Delis–Kaplan Executive Function System.................................................54
9.1.2.1.5.
Montreal Cognitive Assessment Scale.......................................................54
9.1.2.1.6.
Penn Parkinson’s Daily Activities Questionnaire-15 .................................56
9.1.2.2.
Measures of Parkinson’s Disease Severity ......................................................56
9.1.2.2.1.
Movement Disorder Society’s United Parkinson’s 
Disease Rating Scale.................................................................................56
9.1.2.3.
Measures of Behavioral Symptoms.................................................................56
9.1.2.3.1.
Neuropsychiatric Inventory.......................................................................56
9.1.2.3.2.
Epworth Sleepiness Scale .........................................................................57
9.1.2.3.3.
Questionnaire for Impulsive-Compulsive Disorders 
in Parkinson’s Disease ..............................................................................58
9.1.3.
Appropriateness of Efficacy Assessments ............................................................58
9.2.
Adverse Events ............................................................................................................58
9.2.1.
Serious Adverse Events........................................................................................59
9.2.1.1.
Suspected Unexpected Serious Adverse Reactions..........................................60
9.2.2.
Complaint Handling.............................................................................................60
9.3.
Treatment of Overdose.................................................................................................60
9.4.
Safety...........................................................................................................................61
9.4.1.
Electrocardiograms ..............................................................................................61
9.4.2.
Vital Signs ...........................................................................................................62
9.4.3.
Laboratory Tests ..................................................................................................63
9.4.4.
Columbia-Suicide Severity Rating Scale – Children’s 
Version ................................................................................................................63
9.4.5.
Physician Withdrawal Checklist...........................................................................63
9.4.6.
Safety Monitoring ................................................................................................64
9.4.6.1.
Hepatic Safety Monitoring..............................................................................64
9.4.7.
Appropriateness of Safety Assessments................................................................64
9.5.
Pharmacokinetics .........................................................................................................64
9.6.
Pharmacodynamics ......................................................................................................65
9.7.
Pharmacogenomics ......................................................................................................65
9.7.1.
Whole Blood Sample for Pharmacogenetic Research ...........................................65
9.8.
Biomarkers...................................................................................................................66
9.8.1.
Digital Biomarkers...............................................................................................66
9.8.1.1.
Lilly Trial Application....................................................................................66
9.8.1.2.
Actigraphy......................................................................................................66
9.9.
Medical Resource Utilization and Health Economics ...................................................67
10.
Statistical Considerations ..................................................................................................68


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10.1. Sample Size Determination ..........................................................................................68
10.2. Populations for Analyses..............................................................................................68
10.3. Statistical Analyses ......................................................................................................69
10.3.1.
General Statistical Considerations ........................................................................69
10.3.1.1.
Handling of Missing Items for Scales .............................................................69
10.3.2.
Treatment Group Comparability...........................................................................69
10.3.2.1.
Time to Study Disposition/Discontinuation.....................................................69
10.3.2.2.
Protocol Deviations ........................................................................................70
10.3.2.3.
Subject Characteristics....................................................................................70
10.3.2.4.
Concomitant Therapy .....................................................................................70
10.3.2.5.
Treatment Compliance....................................................................................70
10.3.3.
Efficacy Analyses ................................................................................................70
10.3.3.1.
Primary Analyses ...........................................................................................70
10.3.3.2.
Secondary Efficacy Analyses..........................................................................71
10.3.3.3.
Tertiary/Exploratory Efficacy Analyses..........................................................71
10.3.4.
Safety Analyses....................................................................................................71
10.3.4.1.
Adverse Events...............................................................................................72
10.3.4.2.
Suicidal Ideation and Behavior .......................................................................72
10.3.4.3.
Vital Signs and Weight...................................................................................73
10.3.4.4.
Laboratory Analyses.......................................................................................74
10.3.4.5.
Electrocardiograms.........................................................................................74
10.3.5.
Pharmacokinetic/Pharmacodynamic Analyses......................................................74
10.3.6.
Other Analyses.....................................................................................................75
10.3.6.1.
Subgroup Analyses.........................................................................................75
10.3.7.
Interim Analyses..................................................................................................75
11.
References ........................................................................................................................76
12.
Appendices .......................................................................................................................83


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List of Tables
Table
Page
Table HBEH.1.
Schedule of Activities for Protocol I7S-MC-HBEH .......................................15
Table HBEH.2.
Objectives and Endpoints...............................................................................24
Table HBEH.3.
Potentially Clinically Significant Vital Sign Criteria......................................34
Table HBEH.4.
Vital Sign Inclusion Criteria [6] for Subjects at Visit 1 and Visit 3 (time 
0)...................................................................................................................34
Table HBEH.5.
Treatment Regimens......................................................................................44


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List of Figures
Figure
Page
Figure HBEH.1. Illustration of study design for Clinical Protocol I7S-MC-HBEH(b). .............27


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List of Appendices
Appendix
Page
Appendix 1.
Abbreviations and Definitions........................................................................84
Appendix 2.
Clinical Laboratory Tests...............................................................................88
Appendix 3.
Study Governance Considerations..................................................................89
Appendix 4.
Hepatic Monitoring Tests for Treatment-Emergent Abnormality....................93
Appendix 5.
MDS Diagnostic Criteria for Parkinson’s Disease – Red Flags and 
Supportive Criteria ........................................................................................94
Appendix 6.
DLB Diagnostic Criteria ................................................................................97
Appendix 7.
Protocol Amendment Summary I7S-MC-HBEH(b) Effect of 
LY3154207 on Cognition in Mild-to-Moderate Dementia Due to Lewy 
Body Dementia (LBD) Associated with Idiopathic Parkinson’s Disease 
(PD) or Dementia with Lewy Bodies (DLB) (The PRESENCE Study) ..........98


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1.
Synopsis
Title of Study:
Effect of LY3154207 on cognition in mild-to-moderate dementia due to Lewy Body Dementia
(LBD) associated with idiopathic Parkinson’s disease (PD) or dementia with Lewy bodies 
(DLB).
Rationale: 
Eli Lilly and Company (Lilly) is developing LY3154207, an orally available, selective positive 
allosteric modulator (PAM, also called “potentiator”) of the dopamine D1 receptor subtype 
(D1PAM). By increasing the affinity of dopamine for the D1 receptor, a D1PAM is 
hypothesized to amplify response to endogenous dopamine, thereby increasing D1 tone at the 
site of dopamine release, and represents a novel mechanism of action.  By potentiating the 
response to the remaining brain dopamine (or administered levodopa) in subjects with 
insufficient physiologic dopamine such as those with LBD (PDD or DLB), a D1PAM should 
improve cognitive performance.  In addition, a D1PAM should have a positive impact on other 
domains affected by LBD (PDD or DLB) including motor deficits, mood, apathy, and daytime 
sleepiness.
LY3154207 has been investigated in healthy subjects and subjects with Parkinson’s disease. 
 
Study I7S-MC-HBEH (HBEH) is a multicenter, randomized, double-blind, parallel-group, 
placebo-controlled, fixed-dosage, Phase 2 study comparing 3 dosages of LY3154207 (10, 30, or 
75 mg administered orally [or 50 mg based on interim analysis] once a day) with placebo over 12 
weeks in subjects with mild-to-moderate dementia associated with LBD (PDD or DLB).  Study 
HBEH will test the hypothesis that LY3154207 administered at 10 mg, 30 mg, and/or 75 mg
daily (or 50 mg based on interim analysis) (QD) oral dosing for 12 weeks will result in a 
significant improvement in cognition in subjects with mild-to-moderate LBD (PDD or DLB)
compared with placebo. Important secondary outcomes will assess the effect of LY3154207 on 
function, parkinsonism, sleep and mood/behavior.
CCI


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Objective(s)/Endpoints:
Objectives
Endpoints
Primary
To test the hypothesis that LY3154207 administered at 
10 mg, 30 mg, and/or 75 mg daily (or 50 mg based on 
interim analysis) (QD) oral dosing for 12 weeks will 
result in a significant improvement in cognition in 
subjects with mild-to-moderate LBD (PDD or DLB)
compared with placebo.
Change in the CoA composite score of the CDR-CCB
from baseline to Week 12.
Secondary
Efficacy:
To evaluate the global efficacy of LY3154207
ADCS-CGIC score from baseline to Week 12
To evaluate the efficacy of LY3154207 on cognitive 
outcomes
Change in the CDR-CCB PoA composite score from 
baseline to Week 12
To evaluate the efficacy of LY3154207 on cognitive 
outcomes
Change in the ADAS-Cog13 score from baseline to 
Week 12
To evaluate the efficacy of LY3154207 on cognitive 
outcomes
Change in the MoCA score from screening to Week 12
To evaluate the efficacy of LY3154207 on 
neuropsychiatric symptoms
Change in the NPI total and individual item scores from 
baseline to Week 12
To evaluate the effect of LY3154207 on daytime 
sleepiness
Change in the ESS score from baseline to Week 12
To evaluate the effect of LY3154207 on PD severity
To evaluate the effect of LY3154207 on PD motor signs
Change in the MDS-UPDRS total score (sum of 
Parts I-III) from baseline to Week 12
Change in the MDS-UPDRS Part III from baseline to 
Week 12
To evaluate the efficacy of LY3154207 on functional 
outcome
Change in the PDAQ-15 total score from baseline to 
Week 12
To evaluate the effect of LY3154207 on verbal fluency
Change in D-KEFS Verbal Fluency test score from 
baseline to Week 12
Safety:
To evaluate the effect of LY3154207 on acute changes 
of vital signs on the first day of dosing
Number of subjects who met the potentially clinically 
significant vital signs criteria at 3 consecutive time 
points at Visit 3 (Day 1 stopping rules).
To evaluate the effect of LY3154207 on SBP on the first 
day of dosing
Change in in-clinic SBP from 0 up to 8 hours post dose 
on the first day of study drug dosing
To evaluate the effect of LY3154207 on pulse rate on 
the first day of dosing
Change in in-clinic pulse rate from 0 up to 8 hours post 
dose on the first day of study drug dosing
To evaluate the effect of LY3154207 on SBP from 
baseline to Week 12
Change in in-clinic mean SBP at baseline to mean SBP 
at Week 12
To evaluate the effect of LY3154207 on pulse rate from 
baseline to Week 12
Change in in-clinic mean pulse rate at baseline to mean 
pulse rate at Week 12


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Objectives
Endpoints
To evaluate the effect of LY3154207 on physical 
withdrawal symptoms 
Change in the PWC-20 total score from Week 12 to in-
clinic follow-up visit
Pharmacokinetics:
To assess the PK of LY3154207 in a population of 
subjects with mild-to-moderate dementia due to PD
Steady-state trough plasma concentrations of 
LY3154207 at Week 12
Abbreviations: ADAS-Cog13 = 13-item Alzheimer’s Disease Assessment Scale – Cognitive subscale;
ADCS-CGIC = Alzheimer’s Disease Cooperative Study – Clinician Global Impression of Change;
CDR-CCB = Cognitive Drug Research – Computerized Cognition Battery; CoA = Continuity of Attention; 
D-KEFS = Delis–Kaplan Executive Function System; DLB = dementia with Lewy bodies; ESS = Epworth 
Sleepiness Scale; LBD = Lewy Body Dementia; MDS-UPDRS = Movement Disorder Society’s Unified 
Parkinson’s Disease Rating Scale; MoCA = Montreal Cognitive Assessment; NPI = Neuropsychiatric Inventory; 
PD = Parkinson’s disease; PDD = Parkinson’s disease dementia; PDAQ-15 = Penn Parkinson’s Daily Activities 
Questionnaire-15; PK = pharmacokinetics; PoA = Power of Attention; PWC-20 = physician withdrawal 
checklist-20; QD = once a day; SBP = systolic blood pressure.
Summary of Study Design:  Study I7S-MC-HBEH (HBEH) is a multicenter, randomized, 
double-blind, parallel-group, placebo-controlled, fixed-dosage, Phase 2 study comparing 
3 dosages of LY3154207 (10, or 30, or 75 mg administered orally [or 50 mg based on interim 
analysis] once a day [QD]) with placebo over 12 weeks in subjects with mild-to-moderate LBD
(PDD or DLB).  The study includes a Screening Period (Visits 1 to 2) of a minimum of 7 days 
and up to 14 days, a Pretreatment Period of a minimum of 11 days and up to 17 days (Visits 2 to 
3), a 12-week Treatment Period (Visits 3 to 11), and a 14-day Safety Follow-Up Period 
(Visits 11 to 801 or early termination [ET]/discontinuation [DC] visit to Visit 801) that includes 
one telephone visit (Visit 111).  Subjects who meet entry criteria will be randomized in a 1:1:1:1 
ratio to LY3154207 (10 or 30 or 75 mg QD) or placebo. 
Treatment Arms and Duration:
Study HBEH involves a comparison of LY3154207 10 mg, 30 mg, and 75 mg (or 50 mg based 
on interim analysis) administered orally QD with placebo over 12 weeks.
Number of subjects:  Approximately 750 subjects will be screened to achieve 340 randomized 
and an estimated total of 85 evaluable subjects per treatment group.
Statistical Analysis:
Efficacy Analysis:
All subjects in the evaluable patient population (EPP) will be considered for the efficacy 
analysis.  The primary analysis on CoA will occur when all subjects complete 12 weeks of 
treatment.  The analysis of CoA will utilize a Bayesian MMRM model.  The Bayesian analysis 
may use uninformative priors for all terms in the model. These will be diffuse Normal 
distributions centered on zero. Priors for variance will follow an inverse gamma distribution. 
Further details of the Bayesian analysis will be provided in the SAP.  The MMRM model will 
account for longitudinal data assessed throughout the study, after 1, 2, 4, 6, 8, 10, and 12 weeks 
of dosing.  The change of CoA from the baseline to Week 12 will be the dependent variable.  


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The model will comprise fixed (baseline value, treatment, visit) and random effects (subject) and 
the interaction terms (treatment by visit, baseline value by visit).  Unstructured variance structure 
will be applied in the model, but if it fails to converge, other suitable structures will be 
investigated. The primary comparison will be the contrast (difference in least squares mean) 
between treatments and placebo for the Week 12 change from baseline.
The secondary efficacy outcomes: the change from baseline at 12-week time point of total 
scores (or composite values) of Alzheimer’s Disease Cooperative Study – Clinician Global 
Impression of Change (ADCS-CGIC), CDR-CCB Power of Attention (PoA), 13-item 
Alzheimer’s Disease Assessment Scale – Cognitive subscale (ADAS-Cog13), Montreal 
Cognitive Assessment (MoCA), Neuropsychiatric Inventory (NPI), Epworth Sleepiness Scale 
(ESS), Movement Disorder Society’s Unified Parkinson’s Disease Rating Scale (MDS-UPDRS), 
Penn Parkinson’s Daily Activities Questionnaire 15 (PDAQ-15), and Delis–Kaplan Executive 
Function System (D-KEFS) will follow the same analysis method as above.
Missing records in some scales (e.g., ADAS-Cog) will be imputed as detailed in the statistical 
analysis plan.  For the scales where the imputation is not done, if any item is missing, any total or 
sum involving that item will be considered missing.  No adjustment for multiple comparisons 
will be made.
Safety Analysis:  Safety analyses are based on the safety population and analysis will include 
listings and/or summaries of the following:  adverse events (AEs), serious adverse events 
(SAEs), treatment-emergent adverse events (TEAEs), laboratory measures, vital signs, 
electrocardiogram readings and number of subjects who met the potentially clinically significant 
vital signs criteria at 3 consecutive time points at Visit 3 (Day 1 stopping rules). 
Mixed-model repeated measures analysis will be used to compare the change in in-clinic blood 
pressure (BP) and pulse rate from pretreatment up to 8 hours post dose measured on the first day 
of study drug dosing (V3).  Two baselines will be considered in the change from baseline 
analyses:  the V3 pretreatment value and the time-matched baselines from Visit 2 (hourly value 0
to 6 hours).  For the second baseline, the V3, 7- and 8-hour time points will use the V2 6-hour 
time point as their baseline value.  A separate change from baseline analysis will be completed 
for each baseline approach.  Mixed-model repeated measures analyses will also be used to 
compare change in in-clinic BP and pulse rate from V2 (daily average 0 to 6 hours) to 
Week 6/Visit 8 and Week 12/Visit 11 (daily average 0 to 6 hours), to evaluate the change in BP 
and pulse rate over 12 weeks of dosing.
Withdrawal: Withdrawal symptom analyses will be conducted on subjects who completed at 
least one pre-withdrawal and one post-withdrawal PWC-20 checklist. Week 12/Visit 11 will be 
considered baseline in the change from baseline analyses; Visit 801 will be considered the post 
baseline assessment. This will be examined using an analysis of covariance (ANCOVA) model 
with treatment arm as an independent factor and baseline value as a covariate in the model. This 
will allow us to assess the withdrawal symptoms between treatments and groups.
Pharmacokinetics (PK):  Pharmacokinetic analyses will be conducted on subjects who receive 
at least 1 dose of the study drug and have 1 measurable concentration.  A model-based approach 


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may be implemented using nonlinear mixed effects modeling (NONMEM) or other appropriate 
software to estimate PK parameters.
Additional endpoints and biomarker data collected during the study will be evaluated in an 
exploratory manner.
Interim Analysis:  Safety interim analyses will be conducted on the number of subjects on each 
treatment who met the potentially clinically significant vital signs criteria (Table HBEH.3) at 3 
consecutive time points at Visit 3 (Day 1 stopping rules).  This will be done after 50, 100, and 
150 subjects have completed Visit 3.  
 
 Those 
already on 75-mg dose and passed the Day 1 stopping rules will remain on 75 mg.  In the event 
of an unacceptable rate of subjects meeting Day 1 stopping rules at other doses, adjustments to 
doses may be made for subsequently randomized subjects at the discretion of the Internal 
Assessment Committee (IAC).  Additional efficacy analyses may be conducted at the time of 
these safety interim analyses. A safety and efficacy interim analysis will be conducted when 170 
randomized subjects have completed Visit 11 (Week 12) assessments and may also be conducted 
at other timepoints prior to study completion.  All potential efficacy analyses may be used for 
internal decision making, but are not planned to stop the study.
CCI


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2. Schedule of Activities


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Table HBEH.1.
Schedule of Activities for Protocol I7S-MC-HBEH
Procedurea
Screening Pretreatment
Double-Blind Treatment
Follow-up
Unscheduled
Visit
ET/DC 
Visitd,t
Study Day
Min 7 
days; 
max
14 days
prior to
V2
Min 11 days; 
max 17 days 
prior to V3
7 
days
14 
days
21 
days
28 
days
42 
days
56 
days
70 
days
84 
days
2 days 
after
V11u
14 
days 
from 
V11 or 
ET/DC
Tolerance Interval for 
Visit (Days)
Baseline 
Visit
Randomization
±1
±1
±1
±1
±3
±3
±3
±3
+1
±3
eCRF Visit No.:
V1b,d
V2b,d
V3b
V4d
V5
V6
V7 V8b,d
V9
V10 V11b,d V111d
V801
V997c
Informed Consent(s) 
Signed (before 
procedures/tests)
X
Register subject in 
IWRS - Subject number 
assigned
X
Complete IWRS
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Demographics
X
Prior/concomitant 
treatment
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Inclusion/exclusion 
criteria
X
X
X
Modified Hoehn and 
Yahr Scale
X
Medical History
X
Physical Examinatione
X
X
X
X
X
Height
X
Weight
X
X
X
X
Orthostatic BP/pulse ratef
X
X
X
X
X
X
X
X
X
X
X
X
X
X
In-clinic BP/Pulse rate 
monitoringg
X
X
X
X
X


I7S-MC-HBEH(b) Clinical Protocol
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LY3154207
Procedurea
Screening Pretreatment
Double-Blind Treatment
Follow-up
Unscheduled
Visit
ET/DC 
Visitd,t
Study Day
Min 7 
days; 
max
14 days
prior to
V2
Min 11 days; 
max 17 days 
prior to V3
7 
days
14 
days
21 
days
28 
days
42 
days
56 
days
70 
days
84 
days
2 days 
after
V11u
14 
days 
from 
V11 or 
ET/DC
Tolerance Interval for 
Visit (Days)
Baseline 
Visit
Randomization
±1
±1
±1
±1
±3
±3
±3
±3
+1
±3
eCRF Visit No.:
V1b,d
V2b,d
V3b
V4d
V5
V6
V7 V8b,d
V9
V10 V11b,d V111d
V801
V997c
Temperature
X
X
X
X
X
12-Lead ECG
X
X
X
X
X
X
Xc
X
Review HBPM
instructionsh
X
X
X
X
X
X
HBPM device returned to 
site
X
X
Hematology
X
X
X
X
X
X
Xc
X
Urinalysis
X
X
X
X
X
X
Xc
X
Clinical Chemistry
X
X
X
X
X
X
Xc
X
Serum FSHi
X
PGx sampling
X
Collection of dose 
administration timing 
(date and time)
X
X
X
X
X
X
X
X
X
X
PK Samplingj
Xj
Xj
Xj
Xj
Xj
Xj
Randomization
X
Study drug dosing at site
X
Xk
Xk
Dispense Investigational 
Product
X
X
X
X
X
X
X
X
Return Investigational 
Product
X
X
X
X
X
X
X
X
X
Adverse Events
X
X
X
X
X
X
X
X
X
X
X
X
X


I7S-MC-HBEH(b) Clinical Protocol
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LY3154207
Procedurea
Screening Pretreatment
Double-Blind Treatment
Follow-up
Unscheduled
Visit
ET/DC 
Visitd,t
Study Day
Min 7 
days; 
max
14 days
prior to
V2
Min 11 days; 
max 17 days 
prior to V3
7 
days
14 
days
21 
days
28 
days
42 
days
56 
days
70 
days
84 
days
2 days 
after
V11u
14 
days 
from 
V11 or 
ET/DC
Tolerance Interval for 
Visit (Days)
Baseline 
Visit
Randomization
±1
±1
±1
±1
±3
±3
±3
±3
+1
±3
eCRF Visit No.:
V1b,d
V2b,d
V3b
V4d
V5
V6
V7 V8b,d
V9
V10 V11b,d V111d
V801
V997c
Review Lilly Trial app (if
available) instructionsl
X
X
X
X
X
X
X
X
X
X
Actigraphy watch
provided to subjects (if 
available)m
X
X
X
Return of Actigraphy 
watch (if available)n
X
X
X
CDR-CCBo,p
X
X
X
X
X
X
X
X
X
X
X
X
X
Alzheimer’s Disease 
Cooperative Study –
Structured Clinical 
Global Impression 
interviewd
X
X
X
X
ADCS-CGICd
X
X
X
ADAS-Cog13p
X
X
X
X
D-KEFSp
X
X
X
X
MoCAp
X
X
X
X
PDAQ-15d
X
X
X
X
MDS-UPDRSd,p
X
X
X
X
X
NPId
X
X
X
X
ESSd
X
X
X
X
X
X
QUIPd
X
X
X
X
GDS-Sd
X
X
X


I7S-MC-HBEH(b) Clinical Protocol
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LY3154207
Procedurea
Screening Pretreatment
Double-Blind Treatment
Follow-up
Unscheduled
Visit
ET/DC 
Visitd,t
Study Day
Min 7 
days; 
max
14 days
prior to
V2
Min 11 days; 
max 17 days 
prior to V3
7 
days
14 
days
21 
days
28 
days
42 
days
56 
days
70 
days
84 
days
2 days 
after
V11u
14 
days 
from 
V11 or 
ET/DC
Tolerance Interval for 
Visit (Days)
Baseline 
Visit
Randomization
±1
±1
±1
±1
±3
±3
±3
±3
+1
±3
eCRF Visit No.:
V1b,d
V2b,d
V3b
V4d
V5
V6
V7 V8b,d
V9
V10 V11b,d V111d
V801
V997c
PWC-20 (Subject)
X
X
X
X
PWC-20d (Caregiver)
X
X
X
X
C-SSRS – Children’s 
Version and Self-Harm 
Supplement Forms
Xq
Xr
Xr
Xr
Xr
Xr
Xr
Xr
Xr
Xr
Xr
Xr
Xr
Xr
Abbreviations:  ADAS-Cog13 = Alzheimer’s Disease Assessment Scale – 13-Item Cognitive Subscale; ADCS-CGIC = Alzheimer’s Disease Cooperative 
Study - Clinician Global Impression of Change; BP = blood pressure; CDR-CCB = Cognitive Drug Research Computerized Cognition Battery;
C-SSRS = Columbia-Suicide Severity Rating Scale; DC = discontinuation; D-KEFS= Delis–Kaplan Executive Function System; ECG = electrocardiogram; 
eCOA = electronic Clinical Outcome Assessment; eCRF = electronic case report form; ED = early discontinuation; ESS = Epworth Sleepiness Scale;
ET = early termination; FSH = follicle-stimulating hormone; GDS-S = Geriatric Depression Scale – Short Form; HBPM = home blood pressure monitoring; 
HCG = human chorionic gonadotropin; HEENT = head, ear, eye, nose, and throat; IWRS = interactive web-response system; MDS-UPDRS = Movement 
Disorder Society’s Unified Parkinson’s Disease Rating Scale; MoCA = Montreal Cognitive Assessment; NPI = Neuropsychiatric Inventory; PDAQ-15= Penn 
Parkinson Daily Activities Questionnaire-15; PGx = pharmacogenomic(s); PK = pharmacokinetic(s); PWC-20 = physician withdrawal checklist-20;
QUIP = Questionnaire for Impulsive-Compulsive Disorders in Parkinson’s Disease; V = visit.
Note:  Be sure that the visit allowance period takes into account the required washout duration needed for medications that are not allowed by the protocol.
a
Every effort should be made for visits to occur on designated study days.  The overall treatment period in the protocol should be maintained (visits should be 
scheduled based on the randomization visit).  Procedures and assessments should be done in the order described in the Operations Manual.
b
Visit 1 may be split over 2 days.  In exceptional circumstances, if the clinical assessments cannot be completed within 1 day at V2, V3, V8, and/or V11, those 
clinical assessments may be completed the next day. The orthostatic blood pressure measurements, in-clinic blood pressure measurements, the CDR-CCB,
and the laboratory procedures including PK must be completed on Day 1 of that visit. The visit interval will start from Day 1.
c
ECGs or samples for clinical laboratory tests (hematology, clinical chemistry, and urinalysis) will only be collected if a retest is needed. All other procedures 
are required for each unscheduled visit.


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LY3154207
d
The caregiver is required to attend Visit 1 at the clinic to sign the informed consent and be informed about the study details.  Caregiver’s attendance will also 
be required at Visit 2, Visit 4, Visit 8, Visit 11, Visit 801, and the ET/DC visit to provide inputs for the PDAQ-15, ADCS-CGIC, GDS-S, MDS-UPDRS, NPI, 
ESS, and QUIP scales. The caregiver is required at Visit 11, Visit 111 and Visit 801 to provide input for the PWC-20.
e
The physical examination should include HEENT, cardiac, lung, abdomen, extremity, skin, and neurological examinations.
f
Orthostatic BP/pulse rate will be measured as part of the vital sign assessments at every visit. At Visit 2, Visit 3, Visit 8, Visit 11, and Visit 801, these
measurements will be collected at time 0 of the in-clinic BP/pulse rate monitoring.  Subjects will have 3 BP/pulse rate measurements taken in the seated 
position approximately 1 minute apart followed by 1 BP/pulse rate measurement taken in the standing position. Subjects should be seated for at least 
5 minutes and stand for at least 3 minutes prior to taking the respective measurements.  If the subject feels unable to stand, vital signs only in the seated 
position will be recorded.
g
In-clinic BP and pulse rate monitoring will be done at Visit 2, Visit 3, Visit 8, Visit 11, and Visit 801.  The BP and pulse rate measurements will occur at 
time 0 and approximately every 60 minutes thereafter at Visit 2, Visit 8, and Visit 11, in-clinic BP and pulse rate will be monitored for up to 6 hours; at 
Visit 3,  for up to 8 hours and at Visit 801 for up to 2 hours..  The initial measurement, time 0 of the in-clinic BP and pulse rate monitoring, will be done as an 
orthostatic BP/pulse rate (refer to footnote f above), and subsequent BP and pulse rate measurements will be done in the seated position only.  Time 0 for 
Visit 3, Visit 8, and Visit 11 will occur just prior to study drug dosing.  At Visit 3, drug dosing should be initiated immediately following confirmation that 
subject meets inclusion criteria [6].  
h
The subject should be given the HBPM device at Visit 2.  Home BP will be measured twice daily in the seated position using the HBPM equipment provided 
by Eli Lilly and Company (Lilly).  Home BP measurements should be conducted for a minimum of 7 days between Visit 2 and Visit 3, for 3 weeks between 
Visit 3 and Visit 6, and for a minimum of 7 days between Visit 10 and Visit 11, and Visit 11 and Visit 801.  Home BP should be measured twice in the 
morning (approximately 1 minute apart) (e.g., 8 AM) immediately following study medication dosing and twice in the evening, approximately 12 hours later 
(approximately 1 minute apart) (e.g., 8 PM).
i
Refer to inclusion criterion [12e] in Section 6.1.
j
PK sampling. At Visit 3, a PK sample is to be collected within 1 to 3 hours after the drug is administered at the site.  At Visit 4, Visit 5, Visit 8, and ET/DC
visit, the PK sample can be collected at any time during the visit.  At Visit 11, the PK sample should be collected prior to the drug being administered at the 
site.  The date and time of the PK sample collection as well as the date and time of the dose administration immediately preceding the PK sampling should be 
entered in the eCRF.
k
Study drug dose to be administered at the clinic on the morning of Visit 8 and Visit 11 following the Time 0 in-clinic BP/pulse rate measurements.
l
An iPad® configured with the Lilly Trial application (Lilly Trial app) will be provided to the subjects at Visit 2 (if available).  Subjects should complete 
assessments from 2 weeks prior to dosing (starting the day following Visit 2), throughout the dosing period, and for 2 weeks after the conclusion of the 
treatment period (until Visit 801).  This assessment should be done up to twice daily. Subjects will self-select for this optional component of the protocol at 
Visit 1.  Subjects can decide to opt out at any time during the study. In case of opt-out or ET, the subject should return the iPad to the site at the visit 
following the subject opt-out or at the ET/DC visit.  For subjects who complete the Lilly trial application assessments throughout the study, the iPad should be 
returned at Visit 801.  Refer to the Operations Manual for details about Opt-in and Opt-out process.
m The actigraphy device (if available) should be worn on the wrist, similar to a watch, beginning at Visit 2, for 3 separate 2-week periods of time:  Visit 2 to
Visit 3, Visit 8 to Visit 9, and Visit 11 to Visit 801.  The site will provide the device to the subjects at Visits 2, 8, and 11.
n
Following 14 days of wearing the device, the subject should bring the device back to the site at the next scheduled visit (Visit 3, Visit 9, or Visit 801).


I7S-MC-HBEH(b) Clinical Protocol
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LY3154207
o
CDR-CCB:  At least 2 training sessions are required at Visit 1. At each visit, the CDR-CCB should be assessed after the study drug has been dosed. At 
Visit 4, Visit 5, Visit 6, Visit 7, Visit 9, and Visit 10, if a subject has not taken the study drug prior to the study visit, the subject must take study drug at the 
site prior to the CDR-CCB.
p
The CDR-CCB, MoCA, ADAS-Cog13, MDS-UPDRS (Part III), and D-KEFS scales should be conducted in the practically defined medication “on” state at 
all visits.  The “on” state is defined as the individual best motor function as determined by the investigator, or at approximately 1 hour after the dose of 
dopaminergic therapy.  Every attempt should be made to conduct these assessments in the “on” state.  In the exceptional circumstance that this is not possible, 
the assessments could be done in the “off” state.  The “on/off” state should be confirmed prior to completion of the respective scales listed above.  This 
information will be collected in the eCOA or the eCRF. If any portion of an assessment is done in the “off” state, then that subject should be rated as in the 
“off” state for the whole assessment.  If the subject is not on dopaminergic therapy the assessment should be documented as “on”.
q
The C-SSRS “Baseline” version will be used at the Screening visit (Visit 1).
r
The C-SSRS “Since Last Visit” scale will be administered at each subsequent visit.
s
If, based on administration of the C-SSRS, it is determined that suicide-related behaviors have occurred, then the Lilly Self-Harm Follow-Up form will be 
used to collect additional information to allow for a more complete assessment of these behaviors.
t
All subjects who discontinue study treatment prior to a scheduled visit should have an ET/DC visit and procedures/assessments performed as soon as possible.
u
If the visit window falls on a weekend/holiday then the visit should be conducted at the next possible day.


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LY3154207
3.
Introduction
3.1.
Study Rationale
LY3154207 is an orally available, selective positive allosteric modulator (PAM, also called 
“potentiator”) of the dopamine D1 receptor subtype (D1PAM). By increasing the affinity of the 
dopamine for the D1 receptor, a D1PAM should amplify the response to endogenous dopamine, 
increasing D1 tone when and where dopamine is released, and represents a novel mechanism of 
action.  This mode of activity is in contrast to a D1 agonist, which should activate all D1 
receptors to which it has access for as long as it is present (Svensson et al. 2017).  In animal 
models of cognition and locomotor activity, D1 agonists often show bell-shaped, dose–response 
relationships, which are probably due to overstimulation at higher doses (Arnsten et al. 2017).  
Some D1 agonists also show rapid development of tolerance due to constant activation of the D1 
receptor (Gulwadi et al. 2001).  In contrast, because a D1PAM would be dependent on 
endogenous tone and thus subject to normal feedback control, it should have a much lower 
propensity for overstimulation.  Furthermore, since endogenous tone is intermittent, there should 
be less potential for development of tolerance.
3.2.
Background
Lewy Body Dementia (LBD), including Parkinson’s disease dementia (PDD) and DLB, is a
progressive neurodegenerative disorder associated with alpha-synuclein deposition, Lewy body 
pathology, and degeneration of nigro-striatal dopaminergic neurons.  According to the 
Parkinson’s Disease Foundation, Parkinson’s disease (PD) affects approximately 1 million 
people in the United States (U.S.) and 7 to 10 million people worldwide (Statistics on 
Parkinson’s). It is estimated that up to 78% of of patients with PD will develop dementia (PDD) 
in their lifetime (Aarsland et al.2005).  DLB is the second most common dementia after 
Alzheimer’s disease (AD) and affects 1.4 million individuals in the U.S., representing an 
estimated 15-20% of all dementia cases worldwide (Lewy Body Dementia Association 
[https://www.lbda.org/go/10-things-you-should-know-about-lbd ).  
LBD is pathologically characterized by intraneuronal inclusions of Lewy bodies throughout 
subcortical and cortical brain regions, a major component of which is misfolded aggregated 
α-synuclein (Beyer et al. 2009).  Lewy body formation and propagation is accompanied by 
progressive neurodegenerative processes, particularly affecting the dopaminergic and cholinergic 
neurons (Harding and Halliday 2001; Klein et al. 2010; Colloby et al. 2012).  These
neuropathological findings are largely indistinguishable between DLB and PDD and have thus 
led the field to consider them the same disease.
The cognitive impairments of PDD and DLB also overlap. Progressive executive dysfunction
and visual-spatial abnormalities are noted in both, but memory remains relatively intact early in 
the course of disease (Lippa et al. 2007). Prodromal and non-motor features are similar for both
conditions and include REM sleep behavior disorder, hyposmia, prominent visual hallucinations, 
fluctuations in arousal, autonomic dysfunction, and depression/anxiety. They share 
neuroimaging characteristics with overlapping patterns of atrophy, glucose utilization, and 
neurotransmitter changes (cortical cholinergic deficits [Colloby et al. 2016] and striatal/cortical 


I7S-MC-HBEH(b) Clinical Protocol
Page 22
LY3154207
dopaminergic deficits [Klein et al. 2010]).  Although once considered as two separate entities,
the constellation of supportive pathological, clinical, imaging, and neurochemical data suggest 
PDD and DLB fall within a spectrum of the same disease (Berg et al. 2014; Gomperts 2016; 
Friedman 2018; Jellinger 2018; Jellinger and Korczyn 2018). 
Because of the dopaminergic fronto-striatal dysfunction and cholinergic deficits associated with 
LBD [Klein et al. 2010], LY3154207, a D1PAM, is a hypothesized mechanism to treat cognitive 
deficits of the disorder. LY3154207 increases the affinity of dopamine for the D1 receptor, thus 
amplifying the response to endogenous dopamine and increasing D1 tone when and where 
dopamine is released.  By potentiating the response to the remaining brain dopamine (or 
administered L-DOPA), a D1PAM should improve cognitive performance through enhancing 
frontal dopaminergic neurotransmission.  In addition to facilitating dopamine neurotransmission, 
LY3154207 may be effective in improving cognitive dysfunction through activation of cortical 
neurons, markers of synaptic plasticity, and D1 mediated enhanced acetylcholine 
neurotransmitter release.  Other potential effects such as reduced daytime sleepiness, enhanced 
motor function, improved mood, and goal-directed behaviors leading to reduced apathy (via 
activation of cortical and striatal D1 receptors) would also be beneficial in LBD.  
3.3.
Benefit/Risk Assessment
 
 
 
 
 Study HBEH is a proof-of-concept study, and no benefit 
for participation should be anticipated.
Subjects participating in Study HBEH may experience 
 
 
 
 
 
 
CCI
CCI
CCI


I7S-MC-HBEH(b) Clinical Protocol
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LY3154207
The development and reproductive risks of LY3154207 administration are unknown and 
therefore women of child-bearing potential (WOCBP) have been excluded from participation in 
Study HBEH.
More information about the known and expected benefits, risks, serious adverse events (SAEs),
and reasonably anticipated adverse events (AEs) of LY3154207 are to be found in the IB.


I7S-MC-HBEH(b) Clinical Protocol
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LY3154207
4.
Objectives and Endpoints
Table HBEH.2 shows the objectives and endpoints of the study.
Table HBEH.2.
Objectives and Endpoints
Objectives
Endpoints
Primary
To test the hypothesis that LY3154207 administered at 
10 mg, 30 mg, and/or 75 mg daily (or 50 mg based on 
interim analysis) (QD) oral dosing for 12 weeks will 
result in a significant improvement in cognition in 
subjects with mild-to-moderate LBD (PDD or DLB)
compared with placebo.
Change in the CoA composite score of the CDR-CCB
from baseline to Week 12
Secondary
Efficacy:
To evaluate the global efficacy of LY3154207
ADCS-CGIC score from baseline to Week 12
To evaluate the efficacy of LY3154207 on cognitive 
outcomes
Change in the CDR-CCB PoA composite score from 
baseline to Week 12
To evaluate the efficacy of LY3154207 on cognitive 
outcomes
Change in the ADAS-Cog13 score from baseline to 
Week 12
To evaluate the efficacy of LY3154207 on cognitive 
outcomes
Change in the MoCA score from screening to Week 12
To evaluate the efficacy of LY3154207 on 
neuropsychiatric symptoms
Change in the NPI total and individual item scores from 
baseline to Week 12
To evaluate the effect of LY3154207 on daytime 
sleepiness
Change in the ESS score from baseline to Week 12
To evaluate the effect of LY3154207 on Parkinson’s 
disease severity
Change in the MDS-UPDRS total score (sum of parts 
I-III) from baseline to Week 12
To evaluate the efficacy of LY3154207 on functional 
outcome
Change in the PDAQ-15 total score from baseline to 
Week 12
To evaluate the effect of LY3154207 on verbal fluency
To evaluate the effect of LY3154207 on motor signs
Change in D-KEFS Verbal Fluency test score from 
baseline to Week 12
Change in MDS- motor exam (Part III) from baseline to 
Week 12


I7S-MC-HBEH(b) Clinical Protocol
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LY3154207
Objectives
Endpoints
Safety:
To evaluate the effect of LY3154207 on home blood 
pressure monitoring (HBPM) of SBP
To evaluate the effect of LY3154207 HBPM of pulse 
rate
To evaluate the effect of LY3154207 on physical 
withdrawal symptoms 
To evaluate the effect of LY3154207 on acute changes 
of vital signs on the first day of dosing
Change in HBPM SBP from baseline to Week 12
Change in HBPM of pulse rate from baseline to 
Week 12
Change in the PWC-20 total score from Week 12 to in-
clinic follow-up visit
Number of subjects who met the potentially clinically 
significant vital signs criteria  at 3 consecutive time 
points at Visit 3 (Day 1 stopping rules)
To evaluate the effect of LY3154207 on BP on the first 
day of dosing
Change in in-clinic BP from 0 up to 8 hours post dose on 
the first day of study drug dosing
To evaluate the effect of LY3154207 on pulse rate on 
the first day of dosing
To evaluate the effect of LY3154207 on BP from 
baseline to Week 12
To evaluate the effect of LY3154207 on pulse rate from 
baseline to Week 12
Change in in-clinic pulse rate from 0 up to 8 hours post 
dose on the first day of study drug dosing
Change in in-clinic mean BP at baseline to mean BP at 
Week 12
Change in in-clinic mean pulse rate at baseline to mean 
pulse rate at Week 12
Pharmacokinetics:
To assess the PK of LY3154207 
Steady-state trough plasma concentrations of 
LY3154207 at Week 12
Tertiary/Exploratory
Efficacy
To evaluate the efficacy of LY3154207 on cognitive 
outcomes
Change in total score of the ADAS-Cog11 from baseline
to Week 12
To evaluate the efficacy of LY3154207 on cognitive 
outcomes
Change in the CDR-CCB Cognitive reaction time
composite score, Reaction Time Variability composite 
score, and Speed Score composite scores from baseline
to Week 12
Change in the CDR-CCB individual task outcomes from 
baseline to Week 12 including simple reaction time, 
digit vigilance, choice reaction time, numeric working 
memory, spatial working memory, verbal memory, and 
visual memory.
To evaluate the effect of LY3154207 on depressed 
mood, apathy, and fatigue
Change in MDS-UPDRS Part IA score from baseline to 
Week 12
To evaluate the effect of LY3154207 on mood
Change in GDS-S score from screening to Week 12


I7S-MC-HBEH(b) Clinical Protocol
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LY3154207
Objectives
Endpoints
To evaluate the effect of LY3154207 on depressive 
symptoms
To evaluate the effect of LY3154207 on impulse control
Change in NPI score (Part D Depression/Dysphoria) 
from baseline to Week 12
Change in QUIP score from baseline to Week 12
Digital biomarkers
To evaluate the feasibility of using the Lilly Trial 
application (Lilly Trial app) to evaluate the effect of 
LY3154207 on motor tasks or cognitive outcomes in a 
subset of subjects
To explore trends, utilizations, and changes in 
quantitative motor and cognitive outcomes as measured 
by the Lilly Trial App scores from predose assessments  
to 12 weeks
To explore the feasibility of using actigraphy to evaluate 
the effect of LY3154207 on various sleep parameters 
and day time activity including but not limited to sleep 
latency, duration of sleep, sleep–wake cycles, sleep 
architecture, and sleep disruption
Change in actigraphy measured sleep parameters as 
measured by an actigraphy watch from predose 
assessments to 12 weeks
Pharmacogenomic
To evaluate genetic interactions with study treatment 
response or safety if appropriate/as warranted
Explore relationships between pharmacogenomic 
variations and relevant clinical outcomes.
Abbreviations: ADAS-Cog11 = 11-item Alzheimer’s Disease Assessment Scale – Cognitive subscale;
ADAS-Cog13 = 13-item Alzheimer’s Disease Assessment Scale – Cognitive subscale; CDR-CCB = Cognitive 
Drug Research Computerized Cognition Battery; ADCS–-CGIC = Alzheimer’s Disease Cooperative Study –
Clinician Global Impression of Change; CoA = Continuity of Attention; D-KEFS = Delis–Kaplan Executive 
Function System ; DLB = dementia with Lewy bodies; ESS = Epworth Sleepiness Scale; LBD = Lewy Body 
Dementia; HBPM = home blood pressure monitoring; MDS-UPDRS = Movement Disorder Society’s Unified 
Parkinson’s Disease Rating Scale; MoCA = Montreal Cognitive Assessment; NPI = Neuropsychiatric Inventory; 
PDD = Parkinson’s disease dementia; PDAQ-15 = Penn Parkinson’s Daily Activities Questionnaire-15;
PK = pharmacokinetics; PoA = Power of Attention; PWC-20 = physician withdrawal checklist-20; QD = once a 
day; QUIP = Questionnaire for ’Impulsive-Compulsive Disorders in Parkinson’s Disease; SBP = systolic blood 
pressure.


I7S-MC-HBEH(b) Clinical Protocol
Page 27
LY3154207
5.
Study Design
5.1.
Overall Design
Study HBEH is a multicenter, randomized, double-blind, parallel-group, placebo-controlled, 
fixed-dosage, Phase 2 study comparing 3 dosages of LY3154207 (10, 30, or 75 mg administered 
orally [or 50 mg based on interim analysis] once a day [QD]) with placebo over 12 weeks in 
subjects with mild-to-moderate dementia associated with LBD (PDD and DLB).  The study 
includes a Screening Period (Visits 1 to 2) of a minimum of 7 days and up to 14 days, a 
Pretreatment Period of a minimum of 11 days and up to 17 days (Visits 2 to 3), a 12-week 
Treatment Period (Visits 3 to 11), and a 14-day Safety Follow-Up Period including a telephone 
visit (Visit 11 + 2 days) and Visit 801 or early termination [ET]/discontinuation [DC]. Subjects 
who meet entry criteria will be randomized in a 1:1:1:1 ratio to LY3154207 (10 or 30 or 75 mg 
QD) or placebo.  The primary objective of this study is to test the hypothesis that LY3154207 
administration for 12 weeks will result in a significant improvement in cognition as measured by 
the change from baseline to Week 12 on the Continuity of Attention (CoA) composite score of 
the Cognitive Drug Research Computerized Cognition Battery (CDR-CCB), in subjects with 
mild-to-moderate dementia associated with LBD (PDD and DLB), compared to placebo.  
(Wesnes et al. 2005; Rowan et al. 2007, McKeith et al 2000).
Figure HBEH.1 illustrates the study design.
Figure HBEH.1.
Illustration of study design for Clinical Protocol I7S-MC-HBEH(b).


I7S-MC-HBEH(b) Clinical Protocol
Page 28
LY3154207
Abbreviations and definitions are provided in Appendix 1; clinical laboratory tests are described 
in Appendix 2; study governance considerations are described in detail in Appendix 3; and
hepatic monitoring tests for treatment-emergent abnormality are provided in Appendix 4.
5.1.1. Screening Period (Visit 1)
At or prior to Visit 1, the study will be explained to the subject (and his or her legal 
representative, if applicable) and caregiver.  Informed consent of the subject and caregiver must 
be obtained prior to any study procedures conducted.  The screening period length is of a 
minimum of 7 days to a maximum of 14 days between Visit 1 and Visit 2.  See the Schedule of 
Activities (Section 2) for the timing of events and the measures to be assessed during the 
screening period.
Current or planned use of concomitant medications, the effects of vacations or absences on 
protocol compliance, and general compliance with the protocol should be discussed at Visit 1.  
Subjects must meet applicable eligibility criteria (Section 6.1 and Section 6.2) to continue to 
Visit 2. Refer to Section 6.4 for more information about rescreening criteria.
Visit 1 is expected to be of a duration of approximately 3 to 5 hours and may be split over 1 to 
2 days.
5.1.1.1 Screening Procedures
Screening, entry and administrative procedures, cognitive and physical assessments, vitals, safety 
assessments, and laboratory assessments (see Schedule of Activities) are to be performed at 
Visit 1. For subjects treated with dopaminergic treatment for parkinsonism symptoms, the
CDR-CCB and MoCA should be conducted in the practically defined medication “on” state.  
The “on” state is defined as the individual’s best motor function as determined by the 
investigator or approximately 1 hour after the dose of dopaminergic therapy.  Every attempt 
should be made to conduct these assessments in the “on” state. In the exceptional circumstance 
that this is not possible, the assessments could be done in the “off” state.  The “on/off” state 
should be confirmed prior to completion of the respective scales listed above.  This information 
will be collected in the electronic Clinical Outcome Assessment (eCOA) or the electronic case 
report form (eCRF).  If any portion of an assessment is done in the “off” state, then that subject 
should be rated as in the “off” state for the whole assessment. Subjects NOT on dopaminergic 
therapy should be recorded as being in the “on” state for the purpose of analysis.
Medical history should include the diagnosis, whether PDD or DLB, and the timing of onset of 
dementia and Parkinson’s symptoms and date of diagnosis if applicable. Additionally, the 
relationship of the onset of dementia relative to motor symptoms will be assessed. Subjects 
without motor symptoms should report their dementia as occurring prior to motor symptoms.
The physical examination should include head, ear, eye, nose, and throat (HEENT), cardiac, 
lung, abdomen, extremity, skin, and neurological examinations.


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5.1.1.1.1. BP and Pulse Rate
Subjects should have a BP or pulse rate at Visit 1 and Visit 3 (time 0), as determined by 
3 sequential BP/pulse rate measurements in the seated position:

Subjects <60 years old:
o
a mean systolic blood pressure (SBP) less than or equal to 
140 mmHg, a mean diastolic BP less than or equal to 90 mmHg,
and a mean pulse rate less than or equal to 90 beats/min in the
seated position.
o
each of the 3 SBP measurement must be less than 180 mmHg.

Subjects ≥60 years old:
o
a mean SBP less than or equal to 150 mmHg, a mean diastolic BP 
less than or equal to 90 mmHg, and a mean pulse rate less than or 
equal to 90 beats/min in the seated position.
o
each of the 3 SBP measurement must be less than 180 mmHg.
5.1.1.1.2. CDR-CBB
At Visit 1, two training sessions of the CDR-CBB will be administered to familiarize subjects 
with the instrument and to minimize practice effects. Subjects must be able to complete both 
training sessions in order to be considered eligible for HBEH.  Scores on the CDR-CCB at V1 
will not be included in the analysis unless the baseline (V2) scores are incomplete or missing and 
then V1 scores may be used for calculation of the baseline. 
5.1.1.1.3. Modified Hoehn and Yahr Scale
The Hoehn and Yahr Scale (Hoehn and Yahr 1967) is used to describe the symptom progression 
of PD. The scale was originally described in 1967 and included Stages 1 through 5.  It has since 
been modified with the addition of Stages 1.5 and 2.5 to account for the intermediate course of 
PD. The modified Hoehn and Yahr scale is as follows:

Stage 0: No signs of disease

Stage 1:  Unilateral disease

Stage 1.5: Unilateral plus axial involvement

Stage 2: Bilateral disease, without impairment of balance

Stage 2.5: Mild bilateral disease, with recovery on pull test

Stage 3: Mild-to-moderate bilateral disease; some postural instability; physically 
independent

Stage 4: Severe disability; still able to walk or stand unassisted

Stage 5: Wheelchair bound or bedridden unless aided
5.1.1.1.4. Clinical Diagnostic Criteria for PD and DLB
Subjects must meet diagnostic criteria for either PD or DLB.
PD Criteria: Subjects should meet MDS criteria for clinically probable PD (Postuma et al.
2015) as detailed in Appendix 5. Subjects must have parkinsonism as defined by the presence of


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bradykinesia with either rest tremor and/or rigidity. Subjects must not have any absolute 
exclusion criteria.  Subjects must not have greater than 2 red flags; if 1 red flag is present then it 
must be offset by 1 supportive criterion and if 2 red flags are present it must be offset by 2 
supportive criteria. The MDS criteria does not have a criterion for the timing of dementia onset 
and therefore subjects may be considered PD whether the timing of dementia occurred prior to, 
concurrently or after parkinsonism. See Appendix 5 for the detailed list of absolute exclusion 
criteria, red flags and supportive criteria.
DLB Criteria: Subjects should meet the Fourth consensus report of the DLB Consortium 
diagnostic criteria for probable DLB (McKeith et al. 2017) as detailed in Appendix 6. In 
addition to dementia, subjects must have 2 or more of the 4 core clinical features of DLB 
(fluctuation in cognition, visual hallucinations, REM sleep behavior disorder and/or 
parkinsonism). Subjects with 1 core feature are eligible if they also have at least 1 indicative 
biomarker as detailed in Appendix 6. Typically, a diagnosis of DLB is made when dementia 
onset occurs before, concurrently, or in absence of parkinsonism. There is no minimal 
requirement for parkinsonism in subjects with DLB, who otherwise meet this criteria. See 
Appendix 6 for the detailed list of core features and indicative biomarkers.
5.1.1.1.5. Montreal Cognitive Assessment Scale
The MoCA will be administered to subjects in Visit 1 to determine if he or she meets entry 
criteria for dementia. Individuals must have a MoCA score of 10 to 23 at screening to be eligible 
for the study.  The MoCA, included here as a screening cognitive assessment, is described in 
detail in Section 9.1.2.1.5.
5.1.1.1.6. Geriatric Depression Scale Short Form
The GDS is a site-administered questionnaire of depression in older adults (Yesavage et al. 
1983).  Users respond in a “Yes/No” format.  Originally developed as a 30-item scale (Long 
Form), it has since been shortened to a 15-item scale (Short Form), which can be completed in 
approximately 5 to 7 minutes (Sheikh and Yesavage 1986).  Of the 15 items, 10 are indicative of 
depression when answered “Yes” and 5 are indicative of depression when answered “No.”
Caregiver’s input may be needed at Visit 1 for the Geriatric Depression Scale – Short form 
(GDS-S).
5.1.1.1.7. Columbia-Suicide Severity Rating Scale – Children’s Version
The C-SSRS is a scale that captures the occurrence, severity, and frequency of suicide-related 
thoughts and behaviors during the corresponding assessment period.  The C-SSRS, included here 
as a screening assessment, is described in detail in Section 9.4.4.  The C-SSRS “Baseline” 
version will be used at screening, and the findings will constitute the baseline assessment.
The C-SSRS will be administered to the patient with the study partner/study informant present or 
available by telephone, after the cognitive and functional assessments. Responses from both the 
study partner/study informant and patient will be considered when administering the scale. If a 
suicide-related thought or behavior is identified at any time during the study, a thorough
evaluation will be performed by a study physician, and appropriate medical care will be
provided.


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The Lilly Self-Harm Supplement should be completed every time the C-SSRS is administered.  
If, based on administration of the C-SSRS, it is determined that suicide-related behaviors have
occurred, then the Lilly Self-Harm Follow-Up form will be used to collect additional information 
to allow for a more complete assessment of these behaviors.
5.1.2. Pretreatment Period (Visit 2)
See the Schedule of Activities (Section 2) for the timing of events and the measures to be 
assessed at Visit 2.  
Visit 2 is expected to be of a duration of approximately 6 hours. All study procedures for the
visit are to be completed within 1 day. In exceptional circumstances, if the clinical assessments 
cannot be completed within 1 day, those clinical assessments may be completed the next day. 
The orthostatic blood pressure measurements, in-clinic blood pressure measurements, the
CDR-CCB, and the laboratory procedures including pharmacokinetics (PK) must be completed 
on Day 1 of that visit. The visit interval will start from Day 1.
Subjects must continue to meet applicable eligibility criteria (Section 6.1 and Section 6.2) to 
continue to Visit 3.  Subjects who do not meet all inclusion criteria or who meet any exclusion 
criteria will be discontinued from the study.
5.1.2.1 Blood Pressure and Pulse Rate Measures
Orthostatic BP/pulse rate measurements will be collected at time 0 of the in-clinic BP/pulse rate 
monitoring.  Subjects will have 3 BP/pulse rate measurements taken in the seated position 
approximately 1 minute apart followed by 1 BP/pulse rate measurement taken in the standing 
position.  Subjects should be seated for at least 5 minutes and stand for at least 3 minutes prior to 
taking the respective measurements.  If the subject feels unable to stand, vital signs only in the 
seated position will be recorded.
In-clinic BP and pulse rate measurements will occur at time 0 and every 60 minutes thereafter up 
to 6 hours. The initial measurement, time 0 of the in-clinic BP and pulse rate monitoring, will be 
done as an orthostatic BP/pulse rate (refer to orthostatic BP/pulse rate above), and subsequent BP
and pulse rate measurements will be done in the seated position only.
5.1.2.2 
Cognitive, Motor, and Functional Assessments
For subjects treated with dopaminergic therapy for parkinsonism symptoms, CDR-CCB, 
Alzheimer’s Disease Assessment Scale – 13-Item Cognitive Subscale [ADAS-Cog13], 
Movement Disorder Society’s Unified Parkinson’s Disease Rating Scale [MDS-UPDRS] 
[Part III]) and Delis–Kaplan Executive Function System (D-KEFS) assessments should be 
conducted in the practically defined medication “on” state.  The “on” state is defined as the 
individual’s best motor function as determined by the investigator or approximately 1 hour after 
the dose of dopaminergic therapy.  Every attempt should be made to conduct these assessments
in the “on” state.  In the exceptional circumstance that this is not possible, the assessments could 
be done in the “off” state.  The “on/off” state should be confirmed prior to completion of the 
respective scales listed above.  This information will be collected in the eCOA or the eCRF. If 
any portion of an assessment is done in the “off” state, then that subject should be rated as in the 


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“off” state for the whole assessment. Subjects NOT on dopaminergic therapy should be recorded 
as being in the “on” state for the purpose of analysis.
Caregiver’s input will be needed at Visit 2 for the Penn Parkinson Daily Activities 
Questionnaire-15 (PDAQ-15), Alzheimer’s Disease Cooperative Study – Clinician Global 
Impression interview, MDS-UPDRS, Neuropsychiatric Inventory (NPI), Epworth Sleepiness 
Scale (ESS), and Questionnaire for Impulsive-Compulsive Disorders in Parkinson’s Disease 
(QUIP) scales.
The C-SSRS “Since Last Visit” scale will be assessed.  If, based on assessment of the C-SSRS, it 
is determined that suicide-related behaviors have occurred, then the Lilly Self-Harm Follow-Up 
form will be used to collect additional information to allow for a more complete assessment of 
these behaviors.
5.1.2.3 Actigraphy and iPAD Device
The actigraphy device, similar to a watch, will be placed on the wrist of the subject at Visit 2 (if 
available and if consented) for the 2-week period of time until Visit 3 (see Section 9.8.1.2 and 
the Operations Manual).
An iPad configured with the Lilly Trial application (Lilly Trial app) will be provided to the 
subjects (if available and if consented) (see Section 9.8.1.1 and the Operations Manual).  
Subjects should complete assessments starting the day following Visit 2, throughout the dosing 
period, and for 2 weeks after the conclusion of the treatment period (until Visit 801).  This 
assessment should be done up to twice daily.
5.1.2.4 Home Blood Pressure Monitoring
The subject should be given the home blood pressure monitoring (HBPM) device at Visit 2 and 
instructed to measure Home BP twice daily in the seated position using the HBPM equipment 
provided by Lilly for a minimum of 7 days between Visit 2 and Visit 3.  Home BP should be 
measured twice in the morning (approximately 1 minute apart) (e.g., 8 AM) immediately 
following study medication dosing and twice in the evening, approximately 12 hours later 
(approximately 1 minute apart) (e.g., 8 PM).
5.1.3. Double-Blind Period (Visit 3 through Visit 11)
See the Schedule of Activities (Section 2) for the timing of events and the measures to be 
assessed during the double-blind period.
Estimated length of study visits:

Visit 3: approximately 8 hours

Visit 4, Visit 5, Visit 6, Visit 7, Visit 9, and Visit 10: approximately 2 hours

Visit 8 and Visit 11: approximately 6 hours
All study procedures for the respective visits should be completed within 1 day. In exceptional 
circumstances, if the clinical assessments cannot be completed within 1 day at V3, V8, and/or 
V11, those clinical assessments may be completed the next day. The orthostatic blood pressure 
measurements, in-clinic blood pressure measurements, the CDR-CCB, and the laboratory 


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procedures including PK must be completed on the first day of that visit. The visit interval will 
start from the first day of visit.
Visit 3 (Day 1 of dosing)  
5.1.3.1.
Orthostatic BP/Pulse Rate Measurements
Prior to dosing, orthostatic BP/pulse rate measurements will be collected at time 0 of the in-clinic 
BP/pulse rate monitoring.  Subjects will have 3 BP/pulse rate measurements taken in the seated 
position approximately 1 minute apart followed by 1 BP/pulse rate measurement taken in the 
standing position.  Subjects should be seated for at least 5 minutes and stand for at least 
3 minutes prior to taking the respective measurements.  If the subject feels unable to stand, vital 
signs only in the seated position will be recorded.
The mean should be calculated from the 3 initial in-clinic BP/pulse rate measurements taken in 
the seated position, and must meet inclusion criteria [6] in order to proceed with dosing
(Table HBEH.4).  At Visit 3, subjects not fulfilling inclusion criteria [6] at their time 0 BP/pulse 
rate measurements can have their BP/pulse rate re-evaluated within 3 days.  If inclusion criteria 
[6] is subsequently met (within 3 days of Visit 3), subject may proceed with dosing.  If inclusion 
criteria [6] is subsequently not met (within 3 days of Visit 3), the subject must be discontinued.  
Subjects who continue to meet entry criteria will be randomized to LY3154207 (10, 30, or 75 mg 
QD) or placebo immediately following confirmation that subject meets inclusion criteria [6].  
Subjects should be dosed immediately after randomization.
The time 0 mean BP and pulse rate will be used for the baseline measurement to assess the 
change threshold for the development of potentially clinically significant BP/pulse rate
(Table HBEH.3).
After time 0, in-clinic BP and pulse rate measurements will be taken every 60 minutes in the 
seated position only for up to 8 hours. Subjects who meet potentially clinically significant 
BP/pulse rate measurement (Table HBEH.3) at 3 consecutive timepoints (Day 1 stopping rules) 
should be discontinued from the study.


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Table HBEH.3.
Potentially Clinically Significant Vital Sign Criteria
Table HBEH.4.
Vital Sign Inclusion Criteria [6] for Subjects at Visit 1 and Visit 3
(time 0)
Subjects <60 Years 
Subjects ≥60 Years
Mean Systolic BPa (mm Hg)
≤140
≤150
Mean Diastolic BP (mm Hg)
≤90
≤90
Mean Pulse Rate (bpm)
≤90
≤90
a
Each of the 3 SBP measurement must be less than 180 mmHg
5.1.3.2.
PK Sample
A PK sample is to be collected within 1 to 3 hours after the drug is administered at the site.  The 
date and time of the PK sample collection as well as the date and time of the dose administration 
immediately preceding the PK sampling will be recorded.
5.1.3.3.
Home Blood Pressure Monitoring
Home BP measurements should be conducted for a minimum of 7 days between Visit 2 and 
Visit 3, for approximately 3 weeks between Visit 3 and Visit 6, and for a minimum of 7 days 
between Visit 10 and Visit 11, and Visit 11 and Visit 801.  Home BP should be measured twice 
in the morning (approximately 1 minute apart) (e.g., 8 AM) immediately following study 
medication dosing and twice in the evening, approximately 12 hours later (approximately 
1 minute apart) (e.g., 8 PM).


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5.1.3.4.
Visit 4 to Visit 11
Visits will occur at weekly intervals (7 days ± 1 day) for Visit 4 through Visit 7, and will occur 
at biweekly intervals (14 days ± 3 days) for Visit 8 through Visit 11.
Study drug is to be administered at the clinic on the morning of Visit 8 and Visit 11 following 
the Time 0 in-clinic BP/pulse rate measurements.
In-clinic BP/pulse rate monitoring at Visit 8 and Visit 11 will be conducted as described in 
Section 5.1.2.
At each visit, the CDR-CCB should be assessed after the study drug has been administered. At 
Visit 4, Visit 5, Visit 6, Visit 7, Visit 9, and Visit 10, if a subject has not taken study drug prior to
the study visit, the subject must take study drug at the site prior to the CDR-CCB assessment.  
MoCA, ADAS-Cog13, MDS-UPDRS [Part III], and D-KEFS will be performed according to the 
Study Schedule.  
Caregiver’s inputs will be needed at Visit 4, Visit 8, Visit 11, or ET/ DC for the PDAQ-15, 
Alzheimer’s Disease Cooperative Study – Clinician Global Impression of Change 
(ADCS-CGIC), MDS-UPDRS, NPI, ESS, GDS-S, and/or QUIP scales.  Caregiver’s input, 
separate from the subject, will be needed at Visit 11, Visit 111 and Visit 801 for the PWC-20
early termination.
5.1.4. Telephone Visit (Visit 111)
A telephone visit will be conducted 2 days following Visit 11.  The PWC-20 will be assessed 
with the subject and caregiver, separately, at this telephone visit.
5.1.5. Follow-Up Period (Visit 801)
A follow-up visit will be performed at Visit 801, which will occur 14 days ± 3 days following 
the subject’s last dose of study medication.
Visit 801 is expected to be of a duration of approximately 2 hours.
Caregiver’s inputs will be needed at Visit 801 for MDS-UPDRS, PWC-20, and ESS.
See the Schedule of Activities (Section 2) for the timing of events and the measures to be 
assessed during the follow-up period.
5.2.
Number of Subjects
Approximately 750 subjects will be screened to achieve 340 randomized and evaluable subjects 
for an estimated total of 85 evaluable subjects per treatment group.
5.3.
End of Study Definition
End of the study is the date of the last scheduled procedure shown in the Schedule of Activities
(Section 2) for the last subject.


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5.4.
Scientific Rationale for Study Design
Study HBEH will include subjects who meet the revised MDS criteria for PD (Postuma et al. 
2015) or those who meet the revised criteria for DLB, and all who have mild-to-moderate 
dementia as defined by a decline in cognitive function, which in the opinion of the investigator 
has resulted in functional impairment and a MoCA score between 10 and 23 (Trzepacz et al. 
2015).  The inclusion of LBD (PDD or DLB) in HBEH meets current thinking about LBD that, 
apart from the timing of cognitive impairment, PDD and DLB are clinically and pathologically 
indistinguishable and would likely respond to similar therapeutic approaches (Aarsland et al. 
2004; Ballard et al. 2006).
Placebo is included as the control, in a blinded manner for investigator and site staff and 
subjects, to allow for an unbiased assessment of the safety data generated, which will allow for a 
more robust comparison between LY3154207 and placebo data. Comparison of 3 dosage levels 
of LY3154207 was chosen to evaluate dosage exposure response for safety and efficacy.  Initial 
visits (Visit 3 to Visit 7) were selected to occur at a weekly interval to provide a detailed 
evaluation of the efficacy and safety of LY3154207 during the initial treatment.  A dosing
duration of 12 weeks was selected, as it is estimated to be the minimum duration in which a 
beneficial effect on cognition may be observed.
5.5.
Justification for Dose
Three fixed dosages of LY3154207 (10, 30, or 75 mg administered orally [or 50 mg QD, see 
Section 10.3.7, Interim Analysis]) were selected based on current preclinical pharmacology and 
toxicology data, and clinical PK, pharmacodynamic and safety data.
The key considerations regarding the dose selection were to:

ensure a broad exposure exploration around the effective concentration 25 (EC25) 
defined as the drug concentration at which 25% of the maximal response has been 
achieved. 
 


explore the possibility of an inverted U-shaped pharmacodynamic effect on cognition

explore whether different dosages of LY3154207 have differential efficacy on domains 
of PD (cognition, motor, wakefulness).
In Study HBEA, CSF samples were collected in healthy subjects, and the peak mean CSF 
concentrations of LY3154207 following a 
 
Given that LY3154207 PK is dose linear, the proposed dosages of 10, 30, and 75 mg 
LY3154207 are expected to encompass 
 
 
 
 
CCI
CCI
CCI
CCI
CCI


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Evidence from D1 agonists and other activating agents working via dopamine pathways suggests 
an inverted U-shaped pharmacodynamics effect on cognition (Cools and D’Esposito 2011).  
Although there is no evidence of an inverted U-shaped response in the Phase 1 data, 
 
 
 
 
in sleep-deprived healthy subjects receiving a single dose of 
LY3154207.
Taken together, these data suggest that a 
 is likely to cover 
a broad exposure range, will allow exploration of the broad range of pharmacodynamic effects, 
may identify an inverted U-shaped dose–response relationship if such effect exists, minimize the 
risk of either under- or overdosing, and explore differential effects on relevant clinical domains 
(cognition, motor, wakefulness).
CCI
CCI
CCI
CCI


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6.
Study Population
Prospective approval of protocol deviations to recruitment and enrollment criteria, also known as 
protocol waivers or exemptions, are not permitted.
6.1.
Inclusion Criteria
Subjects are eligible to be included in the study only if they meet all of the following criteria
(note that inclusion criteria [6] must be met at additional visits):
Type of Subject and Disease Characteristics
[1]
Male and female subjects aged 40 to 85 years (inclusive).
[45] Meet diagnostic criteria for PD (Postuma et al. 2015) or DLB (McKeith et al. 
2017) (See Appendix 5 and 6)
[2]
Inclusion criterion 2 removed with Amendment b
[3]
Have dementia as defined by a decline in cognitive function, which in the 
opinion of the investigator has resulted in functional impairment.
[4]
Have a MoCA score of 10 to 23 
[5]
Are Modified Hoehn and Yahr Stages 0 to 4.
[6]
Have a BP or pulse rate at Visit 1 and Visit 3 (time 0), as determined by 3
sequential BP/pulse rate measurements in the seated position:

Subjects <60 years old:
o
a mean systolic blood pressure (SBP) less than or equal to 
140 mmHg, a mean diastolic BP less than or equal to 90 mmHg,
and a mean pulse rate less than or equal to 90 beats/min in the
seated position.
o
each of the 3 SBP measurement must be less than 180 mmHg.

Subjects ≥60 years old:
o
a mean SBP less than or equal to 150 mmHg, a mean diastolic BP 
less than or equal to 90 mmHg, and a mean pulse rate less than or 
equal to 90 beats/min in the seated position.
o
each of the 3 SBP measurement must be less than 180 mmHg.
[7]
If on anti-parkinsonian agents, subjects must be on stable dosage for at least 
3 weeks prior to Visit 1, and should remain on stable doses during the course 
of the study.
[8]
If on medications affecting cognition (rivastigmine, galantamine, donepezil, 
memantine), subjects must be on stable dosage for at least 3 weeks prior to 
Visit 1 and should remain at a stable dosage during the course of the study.


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[9]
If on antidepressant medications, subjects must be on stable dosage for at least 
3 weeks prior to Visit 1 and should remain at a stable dosage during the 
course of the study.
[10] If on clozapine, quetiapine, and pimavanserin to address drug-induced or 
disease-related psychosis, subjects must be on stable dosage for 3 weeks prior 
to Visit 1 and should remain at a stable dosage during the course of the study.
[11] If on antihypertensive medications, subjects must be on stable dosage for at 
least 3 weeks prior to Visit 1
Subject Characteristics
[12] Contraception.
[12a]
Male subjects, regardless of their fertility status, with nonpregnant WOCBP 
partners must agree to either remain abstinent (if this is their preferred and 
usual lifestyle) or use condoms as well as 1 additional highly effective (less 
than 1% failure rate) method of contraception (such as combination oral 
contraceptives, implanted contraceptives, or intrauterine devices) or effective 
method of contraception (such as diaphragms with spermicide or cervical 
sponges) for the duration of the study and until their plasma concentrations are 
below the level that could result in a relevant potential exposure to a possible 
fetus, predicted to be 90 days following the last dose of study drug (below the 
no-observed-adverse-effect-level [NOAEL]/10) plus 90 days.
[12b] Men and their partners may choose to use a double–barrier method of 
contraception.  (Barrier protection methods without concomitant use of a 
spermicide are not an effective or acceptable method of contraception. Thus, 
each barrier method must include use of a spermicide. It should be noted,
however, that the use of male and female condoms as a double barrier method 
is not considered acceptable due to the high failure rate when these barrier
methods are combined).
[12c]
Men with pregnant partners should use condoms during intercourse for the
duration of the study and until 93 days following the last dose of study drug.
[12d] Men should refrain from sperm donation for the duration of the study and until 
their plasma concentrations are below the level that could result in a relevant
potential exposure to a possible fetus, predicted to be 93 days following the last 
dose of study drug.
[12e]
Female subjects not of childbearing potential may participate and include those 
who are:

infertile due to surgical sterilization (hysterectomy, bilateral
oophorectomy, or tubal ligation), congenital anomaly such as 
Mullerian agenesis; or


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
post-menopausal – defined as:
o
A woman at least 40 years of age with an intact uterus, not on 
hormone therapy, who has had at least 1 year of spontaneous 
amenorrhea with a follicle-stimulating hormone level 
>40 mIU/mL; or
o
A woman 55 or older not on hormone therapy, who has had at
least 6 months of spontaneous amenorrhea; or
o
A woman at least 55 years of age with a diagnosis of 
menopause prior to start of hormone replacement therapy.
[13] In the investigator’s opinion is able to comply with all appointments for clinic
visits, tests, and procedures, including venipuncture, computerized 
assessments and examinations required by the protocol.
[14] Are able to swallow capsules.
[15] Have a level of understanding such that the subject can communicate with the 
site study personnel, understand the study requirements.
[16] All subjects must have a reliable caregiver who is in frequent contact with the
subject (defined as at least 10 hours per week) and will accompany the subject
to Visit 1, Visit 2, Visit 4, Visit 8, Visit 11, Visit 111 (telephone only) and 
Visit 801.
[17] The caregiver must be able to communicate with site personnel and be willing 
to comply with protocol requirements, and in the investigator’s opinion must 
have adequate literacy to complete the protocol-specified questionnaires.
[18] Agree not to post any personal medical data related to the study or 
information related to the study on any website or social media site (e.g., 
Facebook, Twitter, LinkedIn, Google+, etc.).
Informed Consent
[19] Provision of signed and dated informed consent form (ICF) from subject and 
caregiver prior to any study-specific procedures being performed.
6.2.
Exclusion Criteria
Subjects will be excluded from study enrollment if they meet any of the following:
Medical Conditions
[20] Are WOCBP.
[21] Have significant central nervous system or psychiatric disease, other than PD
or DLB, that in the investigator’s opinion may affect cognition or the ability to 
complete the study.
[22] Have a history in the last 6 months of transient ischemic attacks or ischemic 
stroke.


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[23] Have a history of intra-cerebral hemorrhage due to hypertension.
[24] Have a history of hypertensive encephalopathy.
[25] Have atypical or secondary parkinsonism due to drugs (e.g., antipsychotics) or 
disease (such as progressive supranuclear palsy, essential tremor, multiple 
system atrophy [e.g., striatonigral degeneration, olivopontocerebellar 
atrophy], or postencephalitic parkinsonism).
[26] Have a current implantable intracranial stimulator or history of intracranial 
ablation surgery (e.g., subthalamic, globus pallidus-internal segment).
[27] Exclusion criterion 27 removed with Amendment b
[28] Exclusion criterion 28 removed with Amendment b
[29] Exclusion criterion 29 removed with Amendment b
[30] Have a history of substance abuse within the past 1 year (drug categories 
defined by the Diagnostic and Statistical Manual of Mental Disorder, 5th
Edition, and/or substance dependence within the past 1 year, not including 
caffeine and nicotine).
[31] Exclusion criterion 31 removed with Amendment b
[32] Have a serious or unstable medical illness, other than LBD (PDD or DLB),
including cardiovascular, hepatic, respiratory, hematologic, endocrinologic,
neurologic, or renal disease, or clinically significant laboratory or 
electrocardiogram (ECG) abnormality as determined by the investigator.

have a history in the last 6 months of exertional angina, unstable angina, 
myocardial infarction, and acute coronary syndrome

have a history of heart failure of either New York Heart Association 
Class III or IV

have a history of additional risk factors for Torsades de Pointes (e.g., 
chronic hypokalemia, family history of Long QT Syndrome)
[33] Subjects with acute liver disease (e.g., acute viral hepatitis, alcoholic 
hepatitis); subjects with a known chronic liver disease (e.g., hepatitis B, C, 
alcoholic liver disease, cirrhosis); alanine aminotransferase (ALT) or aspartate 
aminotransferase (AST) equal to or higher than 2X upper limit of normal 
(ULN); total bilirubin (TBL) equal to or higher than 1.5X ULN; (except for 
subjects with Gilbert’s syndrome); or alkaline phosphatase (ALP) equal to or 
higher than 2X ULN.


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[34] Subjects have answered “yes” to either Question 4 (Active Suicidal Ideation 
with Some Intent to Act, Without Specific Plan) or Question 5 (Active 
Suicidal Ideation with Specific Plan and Intent) on the “Suicidal Ideation”
portion of the C-SSRS - Children’s version, or answer “yes” to any of the 
suicide-related behaviors (actual attempt, interrupted attempt, aborted attempt, 
preparatory act or behavior) on the “Suicidal Behavior” portion of the 
C-SSRS; and the ideation or behavior occurred within the past month.
Prior/Concomitant Therapy
[35] Have used antipsychotic medications, with the exception of clozapine, 
quetiapine, pimavanserin in the 6 months prior to screening (Visit 1) and at 
any time during the course of the study.
[36] Have used anticholinergics trihexyphenidyl and benztropine in the 4 weeks 
prior to screening (Visit 1) and at any time during the course of the study.
[37] Have motor conditions for which the antiparkinsonian treatment is expected to 
change during the course of the study, as well as unpredictable motor 
fluctuations that in the investigator’s opinion would interfere with conducting 
assessments.
[38] Are taking any medications or food, herbal or dietary supplements that are 
inhibitors (e.g., ketoconazole, grapefruit juice), or strong/moderate inducers of 
cytochrome P450 3A4 (CYP3A4) (e.g., rifampicin) or are unable or unwilling 
to discontinue usage of them 4 weeks prior to Visit 3. If subjects are willing 
and able to discontinue use of CYP3A4 inhibitors or strong/moderate inducers 
at least 4 weeks prior to Visit 3, they may proceed in the study.  Refer to the 
Operations Manual for a list of inhibitors and inducers of CYP3A4.
Prior/Concurrent Clinical Trial Experience
[39] Are currently enrolled in any other clinical study involving an investigational 
product or any other type of medical research judged not to be scientifically or 
medically compatible with this study.
[40] Have participated, within the last 3 months, in a clinical study involving an 
interventional product or device.
[41] Have previously been exposed to LY3154207.
Other Exclusions
[42] Are investigator site personnel directly affiliated with this study and/or their 
immediate families.  Immediate family is defined as a spouse, parent, child, or 
sibling, whether biological or legally adopted.
[43] Are Lilly employees, employees of IQVIA, or employees of a third party 
organization involved in the conduct of the study.
[44] Exclusion criterion 44 removed with Amendment b


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6.2.1. Rationale for Exclusion of Certain Study Candidates
 
 
 
 
 
Subjects with unpredictable motor fluctuations or those expected to require PD medication 
changes during the course of the study will be excluded, as this may affect performance on 
cognitive tasks and influence the interpretation of other clinically relevant outcomes.
CNS diseases and other neuropsychiatric disorders (e.g., active psychosis, substance abuse) that 
can affect performance on cognitive tasks and compliance with the protocol are also excluded.
Medications that negatively affect cognition (e.g., certain anticholinergics, exclusion criterion
#36) and motor function (e.g., certain antipsychotics, exclusion criterion #35) will be excluded, 
given the potential of these medications to confound clinically relevant outcomes.
 
 
 
In addition, WOCBP have been excluded because nonclinical studies of development and 
reproduction with LY3154207 have not been conducted.
6.3.
Lifestyle Restrictions
Subjects should be instructed not to donate blood or blood products during the study or for 
93 days following the last dose of LY3154207.  Male subjects should be instructed to not donate 
sperm during the study for 93 days following the last dose of LY3154207.
6.4.
Screen Failures
Individuals who do not meet the criteria for participation in this study (screen failure) may be 
rescreened once.  The interval between the initial screening and the rescreen should be at least 
4 weeks.  When the subject is rescreened, the subject must sign a new ICF, be assigned a new 
subject identification number, and undergo all screening procedures.
CCI
CCI


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7. Treatments
7.1.
Treatments Administered
This study involves a comparison of LY3154207 75 mg (or 50 mg, see Section 10.3.7, Interim 
Analyses), 30 mg, and 10 mg administered orally QD with placebo. Table HBEH.5. shows the 
treatment regimens.
Table HBEH.5.
Treatment Regimens
Regimen
Dose
LY Dose Group 1
10 mg LY
(2 5-mg caps and 1 placebo caps)
LY Dose Group 2
30 mg LY
(1 25 -mg caps, 1 x 5 mg caps and 1 placebo caps)
LY Dose Group 3
75 mg LY
(3 25-mg caps)
Or
50 mg LY
(2 x 25-mg caps and 1 placebo caps)
Placebo
3 placebo caps
Abbreviations:  caps = capsule; LY = LY3154207.
The investigator or his/her designee is responsible for the following:

explaining the correct use of the investigational agent(s) to the subject and/or legal 
representative

verifying that instructions are followed properly

maintaining accurate records of investigational product dispensing and collection

at the end of the study returning all unused medication to Lilly, or its designee, unless 
the sponsor and sites have agreed all unused medication is to be destroyed by the site, as 
allowed by local law.
7.1.1. Packaging and Labeling
The drug product is supplied for clinical trial use as capsules for oral administration.
Capsules: Each capsule is composed of LY3154207 with no inactive ingredients other than the
hypromellose capsule shell. Each capsule contains LY3154207 4-Hydroxybenzoic acid
equivalent to 5 mg or 25 mg of the LY3154207 drug substance. The drug product should be 
stored according to instructions on the label.
Clinical trial materials will be labeled according to the country’s regulatory requirements.


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7.2.
Method of Treatment Assignment
Subjects who meet all criteria for enrollment will be randomized to double-blind treatment at 
Visit 3.  Subjects will be randomized in a blinded fashion to the 4 treatment arms (Placebo;
LY3154207 10 mg; LY3154207 30 mg; LY3154207 75 mg [or 50 mg based on interim analysis 
– refer to Section 10.3.7]) at 1:1:1:1 ratio. Randomization will use a minimization procedure in 
order to balance for investigator site and the current use of AChEIs (Yes, No) using an 
interactive web-response system (IWRS).
The IWRS will be used to assign blister packs containing double-blind investigational product to 
each subject. One blister pack will be dispensed for each week of dosing, for example, for 
14-day study intervals, 2 blister packs will be dispensed at each visit.  Site personnel will 
confirm that they have located the correct blister packs by entering a confirmation number found 
on the blister packs into the IWRS.
Selection and Timing of Doses
The doses should be administered at approximately the same time each day in the morning.  At 
Visit 3, Visit 8, and Visit 11, the dose will be administered at the clinic.  The actual date and time 
of the dose administrations on the day of Visit 3, Visit 4, Visit 5, Visit 8, Visit 11, and ET/DC
visit will be recorded in the subject’s eCRF.
7.3.
Blinding
This is a double-blind study.  To preserve the blinding of the study, a minimal number of Lilly 
personnel will see the randomization table and treatment assignments prior to study completion.  
The efficacy and safety interim analyses will be completed by an Independent Internal 
Assessment Committee (IAC) who will be unblinded.  An additional group not directly involved 
in this study will review unblinded digital biomarker data at prespecified interim analyses.
Emergency unblinding for AEs may be performed through the IWRS, which may supplement or 
take the place of emergency codes generated by a computer drug-labeling system.  This option 
may be used ONLY if the subject’s well-being requires knowledge of the subject’s treatment 
assignment.  All calls resulting in an unblinding event are recorded and reported by the IWRS.
If an investigator, site personnel performing assessments, or subject is unblinded, the subject
must be discontinued from the study.  
In case of an emergency, the investigator has the sole responsibility of determining if unblinding 
of a subject’s treatment assignment is warranted for medical management of the event.  The 
subject’s safety must always be the first consideration in making such a determination. Every 
effort should be made to notify Lilly Medical representative prior to unblinding if feasible.  If the 
investigator decides that unblinding is warranted, it is the responsibility of the investigator to 
promptly document the decision and rationale and notify Lilly as soon as possible.
7.4.
Dosage Modification
Investigator-initiated dosage modifications are not allowed in this study.


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7.5.
Preparation/Handling/Storage/Accountability
The investigator or his/her designee is responsible for the following:

confirming appropriate temperature conditions have been maintained during transit for all 
study treatment received and any discrepancies are reported and resolved prior to use of 
the study treatment.

ensuring that only subjects enrolled in the study may receive study treatment and only 
authorized site staff may supply or administer study treatment. All study treatments must 
be stored in a secure, environmentally controlled, and monitored (manual or automated) 
area in accordance with the labeled storage conditions with access limited to the 
investigator and authorized site staff.
The investigator, institution, or the head of the medical institution (where applicable) is 
responsible for study treatment accountability, reconciliation, and record maintenance (such as 
receipt, reconciliation, and final disposition records).
7.6.
Treatment Compliance
Subject compliance with study medication will be assessed at each visit.  Compliance will be 
assessed by counting returned capsules.  Capsules dispensed and returned should be recorded in 
the CRF.
Compliance is defined as having taken ≥80% to <120% of the prescribed amount of medication.
7.7.
Concomitant Therapy
Concomitant medications to treat the underlying PD (known as antiparkinsonian agents) are 
permitted, provided the subject has been on a stable dosage regimen for at least 3 weeks prior to
Visit 1, and should remain on a stable dosage for the duration of the study.  Routine medications 
taken PRN are allowed.  However, if in the investigator’s opinion PD medications need to be 
adjusted to manage motor symptoms during the course of the study, the reason for change in 
medication should be recorded as an AE and the concomitant medication eCRF page updated 
accordingly. In addition, the study sponsor should be notified as soon as feasible and a 
notification generated.
In addition to medications for PD, drugs for common conditions in an older population, such as 
hypertension, hypercholesterolemia, and ischemic heart disease, are acceptable. Specifically, 
antihypertensive medications should be stable for 3 weeks prior to V1. During the course of the 
study, antihypertensive medications may be adjusted for medical need. The concomitant 
medication eCRF page should be updated accordingly and if applicable the reason for change in 
medication should be recorded as an AE.
Drugs and supplements that are known inhibitors or inducers of CYP3A4, as well as
trihexyphenidyl and benztropine, are specifically excluded.
If subjects are taking atorvastatin, they should be instructed to take atorvastatin in the evening 
(approximately 12 hours after study drug dosing).


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Concomitant medications to treat cognition (rivastigmine, galantamine, donepezil, memantine)
and depression are permitted, if subjects have been on a stable dosage regimen for at least 
3 weeks prior to Visit 1 and should remain on a stable dosage for the duration of the study.  
Concomitant medications to treat psychosis (clozapine, quetiapine, and pimavanserin) are 
permitted, provided the subject has been on a stable dosage regimen for at least 3 weeks prior to 
Visit 1 and should remain on a stable dosage for the duration of the study.  However, if in the 
investigators opinion cognitive and antipsychotic medications need to be adjusted during the 
course of the study to address a clinical change, the reason for change in medication should be 
recorded as an AE and the concomitant medication eCRF page updated accordingly.  In addition, 
the Lilly CRP or designee must be contacted as soon as possible to determine whether the subject
should continue in the study.
If the need for concomitant medication arises, inclusion or continuation of the subject may be at 
the discretion of the investigator after consultation with the Lilly CRP or designee.  All 
concomitant medications taken during the study must be recorded on the concomitant medication 
eCRF page.
Subjects and their caregiver should be instructed to consult with the appropriate study personnel 
at the site prior to initiation of any new medications or supplements and prior to changing dose 
or discontinuing from concomitant medications or supplements.
Additional information about concomitant medications is provided in the Operations Manual.
7.8.
Treatment after the End of the Study
7.8.1. Treatment after Study Completion
Study completion will occur following the final analysis of primary and secondary objectives, as 
determined by Lilly. Investigators will continue to follow Schedule of Activities (Section 2) for 
all subjects until notified by Lilly that study completion has occurred.
LY3154207 will not be made available after conclusion of the study to subjects.


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8.
Discontinuation Criteria
8.1.
Discontinuation from Study Treatment
8.1.1. Permanent Discontinuation from Study Treatment
Possible reasons leading to permanent discontinuation of study treatment:

Subject Decision
o
the subject or the subject’s designee, for example, legal guardian, requests to 
discontinue the investigational product.

Day 1 stopping rules - Discontinuation due to change in acute vital signs on Day 1 
(Visit 3) 
If during Day 1 (Visit 3) and following study drug dosing, any of the potentially 
clinically significant vital signs criteria (Table HBEH.3) are met at 3 consecutive time 
points using in-clinic vital sign monitoring, then the subject should be discontinued from 
the study drug. The relative value of the potentially clinically significant vital sign 
criteria is calculated by comparing to the mean of the 3 seated blood pressure and pulse 
rate at Time 0 of Visit 3 (baseline).
o
For vital sign measurements that meet the criteria for potentially clinically 
significant vital signs (Table HBEH.3) after Visit 3, management will be left to 
the discretion of the investigator and may include discontinuation of study drug.  
The investigator should consult with the Lilly CRP or designee.

Discontinuation due to a hepatic event or liver test abnormality
Subjects who are discontinued from the study due to a hepatic event or liver test 
abnormality should have additional hepatic safety data collected via eCRF.
Discontinuation of the investigational product for abnormal liver tests should be 
considered by the investigator when a subject meets 1 of the following conditions after 
consultation with the Lilly-designated medical monitor:
o
ALT or AST >8X ULN
o
ALT or AST >5X ULN for more than 2 weeks
o
ALT or AST >3X ULN and TBL >2X ULN or international normalized 
ratio >1.5
o
ALT or AST >3X ULN with the appearance of fatigue, nausea, vomiting, 
right upper-quadrant pain or tenderness, fever, rash, and/or eosinophilia 
(>5%)
o
ALP >3X ULN
o
ALP >2.5X ULN and TBL >2X ULN
o
ALP >2.5X ULN with the appearance of fatigue, nausea, vomiting, right 
quadrant pain or tenderness, fever, rash, and/or eosinophilia (>5%)


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In addition, subjects will be discontinued from the investigational product in the following 
circumstances:

Mean Fredericia’s corrected QT interval on the ECG (QTcF) >500 milliseconds or an 
absolute change >60 milliseconds when compared with baseline
Subjects discontinuing from the study treatment prematurely for any reason should complete an 
early termination visit and safety follow-up (V801) to complete AE and other follow-up 
procedures per Section 2 (Schedule of Activities), Section 9.2 (Adverse Events) and Section 9.4
(Safety).
8.1.2. Temporary Discontinuation from Study Treatment
Temporary discontinuation from study drug treatment is allowed if a short-term treatment of an 
excluded medication is necessary, secondary to hospitalization, personal circumstances, or to 
evaluate the study drug impact on an uncertain AE. Study drug may be restarted at the 
investigator’s discretion. If temporary discontinuation is due to an AE, it should be reported to 
the Lilly CRP or their representative. Temporary treatment discontinuation and restarting should 
be documented in the eCRF. Restarting treatment after a discontinuation period that is greater 
than 3 consecutive days should be discussed between the investigator and Lilly CRP or their 
representative.
8.1.3. Discontinuation of Inadvertently Enrolled Subjects
If the sponsor or investigator identifies a subject who did not meet enrollment criteria and was 
inadvertently enrolled, then the subject should be discontinued from study treatment. However, 
if the investigator and the sponsor CRP agree that it is medically appropriate to continue in the 
study, the investigator must obtain documented approval from the sponsor CRP to allow the 
inadvertently enrolled subject to continue in the study.
If the subject is discontinued from the study, the subject should complete an early termination 
visit and safety follow-up (V801) to complete safety follow-up as outlined in Section 2
(Schedule of Activities), Section 9.2 (Adverse Events), and Section 9.4 (Safety).
8.2.
Discontinuation from the Study
Subjects will be discontinued in the following circumstances:

enrollment in any other clinical study involving an investigational product or enrollment 
in any other type of medical research judged not to be scientifically or medically 
compatible with this study

participation in the study needs to be stopped for medical, safety, regulatory, or other 
reasons consistent with applicable laws, regulations, and good clinical practice (GCP)

investigator decision
o
the investigator decides that the subject should be discontinued from the study


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o
if the subject, for any reason, requires treatment with another therapeutic agent 
that has been demonstrated to be effective for treatment of the study indication, 
discontinuation from the study occurs prior to introduction of the new agent

subject decision
o
the subject or the subject’s legal representative requests to be withdrawn from the 
study
Subjects discontinuing from the study prematurely for any reason should complete an early 
termination visit and safety follow-up (V801), to complete AE and other safety follow-up per 
Section 2 (Schedule of Activities), Section 9.2 (Adverse Events), and Section 9.4 (Safety).
8.3.
Lost to Follow-Up
A subject will be considered lost to follow-up if he or she repeatedly fails to return for scheduled 
visits and is unable to be contacted by the study site.  Site personnel are expected to make 
diligent attempts to contact subjects who fail to return for a scheduled visit or were otherwise 
unable to be followed up by the site.
Site personnel, or an independent third party, will attempt to collect the vital status of the subject 
within legal and ethical boundaries for all subjects randomized, including those who did not get 
investigational product.  Public sources may be searched for vital status information.  If vital 
status is determined, this will be documented and the subject will not be considered lost to 
follow-up.
Neither Lilly personnel nor Lilly Third Party vendors will be involved in any attempts to collect 
vital status information.


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9.
Study Assessments and Procedures
Study assessments and procedures and their timing (including tolerance limits for timing) are 
summarized in Section 2 (Schedule of Activities).
Appendix 2 lists the clinical laboratory tests that will be performed for this study.
Unless otherwise stated in the subsections below, all samples collected for specified laboratory 
tests will be destroyed within 60 days of receipt of confirmed test results.  Certain samples may 
be retained for a longer period, if necessary, to comply with applicable laws, regulations, or 
laboratory certification standards.
9.1.
Efficacy Assessments
Screening measures used for diagnosis and establishment of study eligibility are described 
elsewhere (Section 2 and Section 5.1.1).
To assess the efficacy of LY3154207, which targets attentional and executive function pathways, 
a set of cognitive tests has been selected as primary and secondary endpoints in Study HBEH.  
Cognitive and functional testing for each subject should be performed in the same order as 
outlined in the Operations Manual to reduce potential variability.  If possible, each assessment 
should be performed on a given subject by the same rater at each visit.  The principal investigator 
has the responsibility of selecting who will administer the instruments at the site, as long as all 
training requirements (see the Operations Manual) have been met by those raters.
The following is a brief description of the assessments that will be used in this study.
9.1.1. Primary Efficacy Assessments
Continuity of Attention Composite Score from the Cognitive Drug Research Computerized 
Cognition Battery:  The CoA component of the CDR-CCB has been selected as the primary 
endpoint for this study because it measures the ability to sustain concentration and has 
demonstrated a significant treatment effect in previous trials in subjects with LBD (PDD or
DLB) within the time frame of the current study (Wesnes et al. 2005; Rowan et al. 2007).  The 
battery is a simple “yes/no” computerized assessment that is feasible across a range of PD motor 
impairment, and as the CoA score is based on accuracy but not speed of response, it is resistant 
to confounding due to motor impairment (Wesnes et al. 2002). The CDR-CCB is not dependent 
on skill of a rater, and hence there is less inter-rater variability; learning effects can be minimized 
with training and it targets domains relevant to subjects with LBD. Treatment effects with
acetylcholinesterase inhibitors in LBD subjects have been demonstrated using the CDR (Wesnes 
et al. 2005; Rowan et al. 2007, McKeith et al 2000).  The CoA is calculated from the CDR-CCB 
by summing the number of correct responses in the digit vigilance and choice reaction time tasks
and then subtracting the number of digit vigilance false alarms.
The CDR-CCB system includes tests of attention (simple and choice reaction time, digit 
vigilance), working memory (spatial and numeric) and episodic memory (word recognition, 
picture recognition) (Wesnes 2008), from which CoA, Power of Attention (PoA), and cognitive 


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reaction time can be determined.  The CDR-CCB is computer controlled, with information 
presented on high resolution monitors and responses recorded via a response module containing 
2 buttons, 1 marked “no” and the other “yes” (Wesnes et al. 2002; Rowan et al. 2007).  The 
CDR-CCB assessment including the tasks listed below will be completed at each visit:
Word presentation: 12 words are presented on the monitor at the rate of 1 every 3 seconds for 
the subject to remember.
Picture presentation: A series of 14 pictures are presented on the monitor at the rate of 1 every 
3 seconds.
Simple reaction time:  The subject is instructed to press the “yes” response button as quickly as 
possible every time the word “yes” is presented on the monitor.  Twenty stimuli are presented 
with a varying interstimulus interval.
Digit vigilance task:  A target digit is randomly selected and then constantly displayed to the 
right of the monitor screen.  A series of digits are then presented in the center of the screen at the 
rate of 80/min and the subject is required to press the “yes” button as quickly as possible every 
time the digit in the series matched the target digit.  There are 15 targets.  The task lasts for 
approximately 2 minutes in total.
Choice reaction time:  Either the word “no” or the word “yes” are presented on the monitor, and 
the subject is instructed to press the corresponding button as quickly as possible.  There are 20 
trials for which each stimulus word is chosen randomly with equal probability and there is a 
varying interstimulus interval.
Spatial working memory:  A picture of a house is presented on the screen with 4 of its 9 
windows lit.  The subject will aim to memorize the position of the lit windows.  For each of the 
18 subsequent presentations of the house, the subject is required to decide whether or not the one 
window lit was also lit in the original presentation.  The subject will record their response by 
pressing the “yes” or “no” response button as appropriate.
Numeric working memory:  A series of 3 digits is presented for the subject to hold in memory.  
This is followed by a series of 18 probe digits for each of which the subject has to decide 
whether or not it was in the original series and press the “yes” or “no” response button as 
appropriate.
Word recognition:  The original words plus 12 distractor words are presented one at a time in a 
randomized order.  For each word, the subject is required to indicate whether or not they 
recognized it as being from the original list of words by pressing the “yes” or “no” button as 
appropriate.
Picture recognition:  The original pictures plus 14 distractor pictures are presented one at a time 
in a randomized order.  For each picture, the subject is required to indicate whether or not they 
recognized it as being from the original series by pressing the “yes” or “no” button as 
appropriate.


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Stanford Sleepiness Scale (Hoddes et al. 1973):  The subject rates his or her alertness at the 
present time using a scale of 1 to 7, with 1 being the most alert and 7 being almost asleep. 
9.1.2. Secondary Efficacy Assessments
The following assessments should be administered in the same order at specified visits (refer to 
the Operations Manual for information about the procedural order).  Measures should be 
administered by the same rater to reduce potential variability.  To minimize missing data, the 
rater should go through each measure orally with the subject or caregiver (as designated in the 
instructions), recording responses appropriately.  The same caregiver should be used as the 
informant at all visits.
9.1.2.1.
Measures of Cognitive Function and Related Outcomes
The following assessments will serve as measures to assess cognitive functioning and related 
outcome:
9.1.2.1.1. Alzheimer’s Disease Cooperative Study – Clinician Global Impression 
of Change Scale
The ADCS-CGIC is a 7-point, categorical scale that provides a single global rating of change 
from baseline (Schneider et al. 1997) and includes a baseline interview to set subject-specific 
probes for the follow-up assessments.  A score of 1 indicates marked improvement; a score of 2, 
moderate improvement; a score of 3, minimal improvement; a score of 4, no change; a score of 
5, minimal worsening; a score of 6, moderate worsening; and a score of 7, marked worsening.  
Minimal changes were predefined as clinically detectable changes that did not affect a subject’s 
clinical status; moderate changes as definite, detectable changes that had a corresponding effect 
on clinical status; and marked changes as those that had a dramatic effect on clinical status.
9.1.2.1.2. Power of Attention Composite Score from the CDR-CCB
The PoA is a composite score derived from the CDR-CCB that measures the intensity of 
concentration (ability to focus attention): the faster the responses, the more processes are being 
brought to bear upon the task.  The PoA composite score will be calculated by summing the 
mean choice reaction time, simple reaction time, and digit vigilance reaction time scores.
9.1.2.1.3. Alzheimer’s Disease Assessment Scale – 13-Item Cognitive Subscale
Cognitive function will be assessed by using a 13-item version of ADAS-Cog.  This version is 
composed of the original 11-item ADAS-Cog, which measures memory, language, and praxis
(Rosen et al. 1984). In addition, it includes Delayed Recall (episodic memory) and Number 
Cancellation (attention) items that have been shown as reliable and sensitive measures for 
assessing a wide range of dementia severity (Mohs et al. 1997).
The ADAS-Cog has been designed to evaluate the cognitive impairment characteristic of 
mild-to-moderate AD dementia. In a placebo-controlled registration study of rivastigmine in 
PDD, the ADAS-Cog11 was used to measure a significant treatment effect over 24 weeks (Emre 
et al. 2004).  ADAS-Cog11 has frequently been used in drug studies in mild-to-moderate AD and 
to date is the only cognition measure used as a primary endpoint in a registration trial for a 
product approved for PDD.  The 2 additional items in the ADAS-Cog13, number cancellation 


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and delayed recall, offer the opportunity for a more comprehensive assessment of cognition in 
LBD than the ADAS-Cog11.
The primary cognitive functions tested include components of memory, language, praxis, and 
attention. Memory is evaluated by the following items: Word Recall (immediate and delayed), 
Orientation, Word Recognition, and Remembering Test Instructions (based on the Word 
Recognition task). Language is evaluated by the following items: Spoken Language Ability, 
Comprehension of Spoken Language, Word-finding Difficulty, Commands, and Naming Objects 
and Fingers. Praxis is evaluated by the items Constructional Praxis and Ideational Praxis. 
Attention is evaluated by the number cancellation task.  The assessment is expected to take 
approximately 35 to 50 minutes.
The ADAS-Cog13 measures severity of impairment. Higher scores reflect greater cognitive 
impairment.  The maximum score is 85.  Most item scores are based on the number of words not 
recalled or the number of errors: Word Recall, Commands, Constructional Praxis, Delayed 
Word Recall, Naming, Ideational Praxis, Orientation, and Word Recognition.  Remembering 
Test Instructions is rated based on the number of reminders during the Word Recognition task. 
Spoken Language Ability, Comprehension of Spoken Language, and Word-finding Difficulty are 
rated on a scale of severity of dysfunction ranging from 0 to 5, where 0 = no impairment, 1 = 
very mild, 2 = mild, 3 = moderate, 4 = moderately severe, and 5 = severe. The score for the 
Number Cancellation item ranges from 0 to 5, based on ranges of numbers of target items 
correctly crossed off by the subject within the time limit; the fewer correct responses, the higher 
the score.
9.1.2.1.4. Delis–Kaplan Executive Function System
The D-KEFS Verbal Fluency test requires subjects to produce as many words per minute as they 
can, starting with a particular letter, with higher scores indicating better performance (Delis et al.
2001).
The D-KEFS verbal fluency has shown a significant response (p<.001) to rivastigmine therapy in 
a 24-week randomized controlled trial in subjects with PDD (Emre et al. 2004).  The D-KEFS 
verbal fluency test is preferred as a measure of executive function in PDD because it is not 
confounded by motor deficits.  This specific measure of executive function, a domain commonly 
affected in LBD, will complement other measures of cognition included in Study HBEH that do 
not adequately assess this domain.
9.1.2.1.5. Montreal Cognitive Assessment Scale
The MoCA (available at www.mocatest.org) was developed as a brief screening instrument for 
mild cognitive impairment and mild AD to address limitations of the Mini-Mental State 
Examination (MMSE) (Nasreddine et al. 2005).  The MoCA has been identified as a suitable 
screening instrument for the detection of cognitive impairment in PD (Hoops et al. 2009) and 
DLB (McKeith et al. 2017).  Since development, it has been increasingly utilized to detect 
cognitive impairment in subjects with PD. The MoCA is divided into 7 subscores (maximum
possible subscore):


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
visuospatial/executive (5 points)

naming (3 points)

memory (5 points for delayed recall)

attention (6 points)

language (3 points)

abstraction (2 points)

orientation to time and place (6 points)
Visuospatial abilities are assessed using a clock-drawing task and a 3-dimensional cube copy.
Multiple aspects of executive function are assessed using an alternation task adapted from the 
Trail Making B task, a phonemic fluency task, and a 2-item verbal abstraction task. The 
short-term memory recall task involves 2 learning trials of 5 nouns and delayed recall after 
approximately 5 minutes. Attention, concentration, and working memory are evaluated using a 
sustained attention task, a serial abstraction task, and digits forward and backward. Language is 
assessed using a 3-item confrontation naming task with low-familiarity animals (lion, camel, and 
rhinoceros), repetition of 2 syntactically complex sentences, and the aforementioned fluency 
task.  Finally, 1 point is added if the subject has <12 years of education.  The MoCA has a 
maximum possible total score of 30 points, with higher scores indicating better cognitive 
performance.  A score of greater than 26 is considered normal (Nasreddine et al. 2005; Hoops et 
al. 2009).
Use of MoCA in the context of PD to screen for subjects with cognitive impairment is consistent 
with the Parkinson Study Group (PSG) Cognitive/Psychiatric Working Group and MDS 
recommendations; although, due to limitations of data for the MoCA on change over time or 
change with treatment, the PSG only reviewed the scale in the context of trials where executive 
functioning was not a primary outcome (Chou et al. 2010; Litvan et al. 2012).  The MoCA has 
consistently demonstrated higher sensitivity than the MMSE for the detection of mild cognitive 
impairment in various subject populations including PD and DLB (Nasreddine et al. 2005; Smith 
et al. 2007, Zadikoff et al. 2008; Olson et al. 2011; Freitas et al. 2012; Biundo et al. 2016; Wang 
et al. 2013).  Using a cut-off score of less than or equal to 26 as a predictor of cognitive 
impairment, results from the MoCA identified from 52% to 83% of subjects with PD who had 
already been identified as having mild cognitive impairment (Smith et al. 2007; Hoops et al. 
2009; Nazem et al. 2009).  A MoCA score of 26 or less has also provided excellent 
discrimination between subjects who had mild cognitive impairment and those who did not 
(receiver operating characteristic curve analyses 78% to 90%; sensitivity 90%; specificity 75% 
(Dalrymple-Alford et al. 2010).  Satisfactory test–retest reliability and inter-rater reliability have 
been demonstrated (interclass correlation coefficients 0.79 and 0.81, respectively) (Gill et al. 
2008).  Additionally, good correlation between the MoCA and a neuropsychological battery 
(assessing the domains of memory and executive function) was observed (coefficient of 0.72)
(Gill et al. 2008).


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9.1.2.1.6. Penn Parkinson’s Daily Activities Questionnaire-15
The PDAQ-15 is a 15-item measure of instrumental activities of daily living (IADL) that is 
impacted by cognitive impairment in subjects with PDD.  The PDAQ-15 is derived from the 
original 50-item scale, which has demonstrated test–retest reliability, construct validity, 
sensitivity, and specificity to PD cognitive impairment (Brennan et al. 2016a, 2016b), and the 
questionnaire is completed by the caregiver. The score range is 0 to 60, with higher scores 
indicating better function. It is derived from a larger 50-item scale that demonstrates excellent 
test–retest reliability and construct validity, and is both sensitive and specific in PD cognitive 
impairment.  The PDAQ-15 demonstrates ability to discriminate between cognitively normal, 
mild cognitive impairment, and dementia in PD, and correlates with global measures of 
cognition (dementia rating scale) and performance-based functional measures. The PDAQ-15 
will provide a disease-specific assessment of the effect of LY3154207 on cognitive IADL in 
order to understand the relationship between change in cognition and change in IADL in PDD
and DLB.
9.1.2.2.
Measures of Parkinson’s Disease Severity
9.1.2.2.1. Movement Disorder Society’s United Parkinson’s Disease Rating Scale
The MDS-UPDRS Part I (non-motor aspects of experiences of daily living) assesses a wide 
spectrum of non-motor symptoms of PD and will be used to assess the impact on non-motor 
features with special interest in apathy, fatigue, and depression.  Part II (motor aspects of 
experience of daily living), Part III (motor examination), and Part IV (motor complications) will 
be used to assess Parkinson’s–related motor function as well as potential impact on motor 
complications (dyskinesias and motor fluctuations).  In general, each item of the scale is scored 
from 0 to 4 using the following clinical descriptors (Goetz et al. 2007):

0 = normal

1 = slight; refers to symptoms/signs with sufficiently low frequency or intensity to cause 
no impact on function

2 = mild; refers to symptoms/signs of frequency or intensity sufficient to cause a modest 
impact on function

3 = moderate; refers to symptoms/signs sufficiently frequent or intense to impact 
considerably, but not prevent, function

4 = severe; refers to symptoms/signs that prevent function.
The total MDS-UPDRS is a sum of Parts I, II, and III and ranges from 0 (no impairment) to 263 
(maximum impairment).
9.1.2.3.
Measures of Behavioral Symptoms 
The following measures will serve as tools to assess the impact of LY3154207 on behavioral 
symptoms associated with LBD as well as the effects on motor functions.
9.1.2.3.1. Neuropsychiatric Inventory
The NPI is a well-validated clinical rating instrument designed specifically to assess a wide 
range of abnormal behaviors encountered in dementia subjects (Cummings et al. 1994; 
Cummings 1997).  The NPI is an informant-based interview that utilizes scripted questions to 


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explore 12 different symptom domains: delusions, hallucinations, agitation/aggression, 
dysphoria, anxiety, euphoria, apathy, disinhibition, irritability/lability, aberrant motor activity, 
night-time behavioral disturbances, and appetite and eating abnormalities.  For each domain, the 
caregiver is asked a screening question to determine whether the abnormal behavior has been 
present within the previous 4 weeks and represents a change in the subject since the onset of 
illness.  If the behavior has been present, then a series of subquestions are asked to obtain more 
detailed information about the specific features of the behavioral disturbance.  For any behavior 
that has been present in the past 4 weeks, the caregiver is asked to rate the frequency of the 
behavior on a 4-point scale (Rarely – less than once per week; Sometimes – about once per 
week; Often – several times per week but less than every day; Very often – once or more per day 
or continuously present), and the severity of the behavior on a 3-point scale (Mild – produces 
little distress in the subject; Moderate – more disturbing to the subject but can be redirected by 
the caregiver; Severe – very disturbing to the subject and difficult to redirect).
A total score for each symptom is calculated by multiplying the frequency rating by the severity 
rating.  The total NPI score is the sum of all symptom scores and has a possible range of 0 to 
144, with higher scores indicating a greater degree of symptomatology.
The NPI also contains a Caregiver Distress Scale (NPI-D) that was designed to quantitate the 
distress experienced by caregivers, as it relates specifically to the individual symptoms assessed 
in the subject by the NPI.  For each symptom deemed to be present in the past 4 weeks, the 
caregiver is asked to rate the distress the symptom has caused him or her on a 6-point scale 
(based on response to the question “How emotionally distressing do you find this behavior?”): 0 
= not at all, 1 = minimally, 2 = mildly, 3 = moderately, 4 = severely, 5 = very severely or 
extremely.  The maximum score for the Caregiver Distress Scale is 60.
9.1.2.3.2. Epworth Sleepiness Scale
The ESS is widely used in the field of sleep medicine as a subjective measure of a subject’s 
sleepiness.  It is an 8-item questionnaire that measures one’s chances of “dozing off” in different 
daytime situations over the past week; scores range from 0 to 24, with scores ≥10 indicating 
excessive daytime sleepiness (Johns 1991).  This scale is easily administered, widely used, and 
deemed “Recommended” by the MDS Sleep Scale Task Force for screening and measuring the 
severity of sleep problems in PD (Högl et al. 2010).  For the purposes of Study HBEH, the ESS 
will be assessed by the caregiver.  The ESS scores correlated significantly with MMSE scores 
and also with cognitive domain scores for attention/working memory, executive function, 
memory, and visuospatial function (Goldman et al. 2013).  Daytime sleepiness in PD is 
associated with cognitive impairment in PD, especially in the setting of dementia, and 
attention/working memory, executive function, memory, and visuospatial deficits (Goldman et 
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9.1.2.3.3. Questionnaire for Impulsive-Compulsive Disorders in Parkinson’s 
Disease
The QUIP is a subject- and/or informant-reported screening questionnaire for impulse control 
disorders (ICDs) and compulsive behaviors in PD.  It assesses behaviors across 3 domains: 
1. ICD including gambling, sexual, buying and eating; 
2. other compulsive behaviors such as punding and hobbyism, and wandering; 
3. compulsive medication use.
Scores for each ICD and related disorder range from 0 to 16, with a higher score indicating 
greater severity (i.e. frequency) of symptoms. The total QUIP rating scale score for all ICDs and 
related disorders combined ranges from 0 to 112. It has demonstrated high discriminant validity 
compared with gold standard diagnostic criteria.  It has good inter-rater and test–retest reliability 
and has demonstrated responsiveness to change in a treatment study of ICD in PD (Weintraub et 
al. 2009; Weintraub et al. 2012).  As medications that enhance dopaminergic tone have been 
associated with the development of ICD in PD, the systematic evaluation of this potential 
complication is critical (Weintraub et al. 2006).
9.1.3. Appropriateness of Efficacy Assessments
Efficacy:  As previously stated, the CoA has demonstrated a significant treatment effect in 
similar populations (Wesnes et al. 2005; Rowan et al. 2007).  The CoA is a parameter calculated 
using the CDR-CCB, which has been widely used in dementia research for more than 25 years.  
Because it is a computerized assessment system, the CDR-CCB has low inter-rater variability.  
Two training sessions in a single day have demonstrated an ability to minimize learning effects 
up to 8 weeks (Wesnes, personal communication).  The CDR-CCB system also has a large 
normative database of over 6000 healthy volunteers from 18 to 87 years of age, thereby making 
it possible to detect both the level of cognitive impairment present in subjects prior to treatment 
and the effect of treatment on cognitive changes (Wesnes 2008).
The secondary efficacy measures described in Section 9.1.2 are also established measures of 
cognitive function and related outcomes, as well as behavioral symptoms associated with PD 
dementia and DLB, and considered appropriate assessments for this population.
9.2.
Adverse Events
Investigators are responsible for monitoring the safety of subjects who have entered this study 
and for alerting Lilly or its designee about any event that seems unusual, even if this event may 
be considered an unanticipated benefit to the subject.
The investigator is responsible for the appropriate medical care of subjects during the study.
Investigators must document their review of each laboratory safety report.
The investigator remains responsible for following, through an appropriate health care option, 
AEs that are serious or otherwise medically important, considered related to the investigational 
product or the study, or that caused the subjects to discontinue the investigational product prior 
to study completion.  The subject should be followed until the event resolves, stabilizes with 


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appropriate diagnostic evaluation, or is reasonably explained.  The frequency of follow-up 
evaluations of the AE is left to the discretion of the investigator.
Lack of drug effect is not an AE in clinical studies, because the purpose of the clinical study is to 
establish treatment effect.
After the ICF is signed, study site personnel will record via eCRF the occurrence and nature of 
each subject’s preexisting conditions, including clinically significant signs and symptoms of the 
disease under treatment in the study.  In addition, site personnel will record any change in the 
condition(s) and any new conditions as AEs. Investigators should record their assessment of the 
potential relatedness of each AE to investigational product and/or protocol procedure via eCRF.
The investigator will interpret and document whether or not an AE has a reasonable possibility 
of being related to study treatment, study device, or a study procedure, taking into account the 
disease, concomitant treatment, or pathologies.
A “reasonable possibility” means that there is a cause-and-effect relationship between the 
investigational product, study device and/or study procedure, and the AE.
The investigator answers yes/no when making this assessment.
Planned surgeries and nonsurgical interventions should not be reported as AEs unless the 
underlying medical condition has worsened during the course of the study.
If a subject’s investigational product is discontinued as a result of an AE, study site personnel 
must report this to Lilly or its designee via eCRF, clarifying if possible the circumstances leading 
to any dosage modifications, or discontinuations of treatment.
9.2.1. Serious Adverse Events
An SAE is any AE from this study that results in 1 of the following outcomes:

death

initial or prolonged inpatient hospitalization

a life-threatening experience (i.e. immediate risk of dying)

persistent or significant disability/incapacity

congenital anomaly/birth defect

important medical events that may not be immediately life-threatening or result in 
death or hospitalization but may jeopardize the patient or may require intervention 
to prevent 1 of the other outcomes listed in the definition above.  Examples of 
such medical events include allergic bronchospasm requiring intensive treatment 
in an emergency room or at home, blood dyscrasias or convulsions that do not 
result in inpatient hospitalization, or the development of drug dependency or drug 
abuse.
All AEs occurring after signing the ICF are recorded in the eCRF and assessed for serious 
criteria.  The submission of SAE reports to the sponsor begins after the subject has signed the 


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ICF and has received investigational product.  However, if an SAE occurs after signing the ICF, 
but prior to receiving investigational product, the SAE report should be submitted to the sponsor 
as per SAE reporting requirements and timelines (see Section 9.2) if it is considered reasonably 
possibly related to study procedure.
Study site personnel must alert Lilly or its designee of any SAE within 24 hours of investigator 
awareness of the event via a sponsor-approved method.  If alerts are issued via telephone, they 
are to be immediately followed with official notification on study-specific SAE forms.  This 
24-hour notification requirement refers to the initial SAE information and all follow-up SAE 
information. Subjects with a serious hepatic AE should have additional data collected using the 
eCRF.
Pregnancy (during maternal or paternal exposure to investigational product) does not meet the 
definition of an AE.  However, to fulfill regulatory requirements any pregnancy should be 
reported following the SAE process to collect data on the outcome for both mother and fetus.
Investigators are not obligated to actively seek AEs or SAEs in subjects once they have 
discontinued and/or completed the study (the patient’s final study disposition CRF has been 
completed).  However, if the investigator learns of any SAE, including a death, at any time after 
a subject has been discharged from the study, and he/she considers the event reasonably possibly 
related to the study treatment or study participation, the investigator must promptly notify Lilly.
9.2.1.1.
Suspected Unexpected Serious Adverse Reactions
Suspected unexpected serious adverse reactions (SUSARs) are serious events that are not listed 
in the IB and that the investigator identifies as related to investigational product or procedure.  
United States 21 CFR 312.32 and European Union Clinical Trial Directive 2001/20/EC and the 
associated detailed guidances or national regulatory requirements in participating countries 
require the reporting of SUSARs.  Lilly has procedures that will be followed for the 
identification, recording, and expedited reporting of SUSARs that are consistent with global 
regulations and the associated detailed guidances.
9.2.2. Complaint Handling
Lilly collects product complaints on investigational products and drug delivery systems used in 
clinical studies in order to ensure the safety of subjects, monitor quality, and to facilitate process 
and product improvements.
Subjects will be instructed to contact the investigator as soon as possible if he or she has a 
complaint or problem with the investigational product so that the situation can be assessed.
9.3.
Treatment of Overdose
For this study, any dose of investigational product greater than twice participant’s assigned daily 
dose within a 24-hour time period will be considered an overdose.
In the event of an overdose, the investigator or treating physician should use supportive therapy 
as necessary and contact the Clinical Research Physician (or designee) immediately.


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Decisions regarding dose interruptions or modifications will be made by the investigator in 
consultation with the CRP based on the clinical evaluation of the participant.
9.4.
Safety
9.4.1. Electrocardiograms
For each subject, 12-lead digital ECGs will be collected as triplicates according to the Schedule 
of Activities (Section 2).  Subjects must be supine for approximately 10 minutes prior to ECG 
collection and remain supine but awake during ECG collection.
Consecutive replicate ECGs will be obtained at approximately 1-minute intervals.  
Electrocardiograms may be obtained at additional times, when deemed clinically necessary.  
Collection of more ECGs (more replicates) than expected at a particular time point is allowed 
when needed to ensure high-quality records.
Electrocardiograms will initially be interpreted by a qualified healthcare provider (the 
investigator or qualified designee) at the site as soon after the time of ECG collection as possible, 
and ideally while the subject is still present to determine whether the subject meets entry criteria
at the relevant visit(s) and for immediate subject management, should any clinically relevant 
findings be identified.
Any clinically significant findings from ECGs that result in a diagnosis and that occur after the 
subject receives the first dose of the investigational treatment should be reported to Lilly or its 
designee as an AE via eCRF.
If a clinically significant quantitative or qualitative change from baseline is identified after 
enrollment, the investigator will assess the subject for symptoms (e.g., palpitations, near 
syncope, syncope) to determine whether the subject can continue in the study.  The investigator 
or qualified designee is responsible for determining if any change in subject management is 
needed and must document his/her review of the ECG printed at the time of evaluation from at 
least 1 of the replicate ECGs from each time point.
All digital ECGs will be electronically transmitted to a designated central ECG laboratory.  A
cardiologist at the central ECG laboratory will then conduct a full over-read on 1 of the replicates 
(including all intervals).  A report based on data from this over-read will be issued to the 
investigative site.  For each set of replicates, the cardiologist will determine the RR and QT 
intervals, QRS duration, and pulse rate on the ECGs that were not fully over-read.  These data 
are not routinely reported back to the investigative site.  However, any clinically significant 
finding that was not present on the fully over-read ECG will be reported to the investigator and 
to Lilly.  All data from the over-reads will be placed in the Lilly database for analytical and study 
report purposes.
When there are differences in ECG interpretation between the investigator (or qualified 
designee) and the cardiologist at the central ECG laboratory, the investigator’s (or qualified 
designee’s) interpretation will be used for study entry and immediate subject management.  


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Interpretations from the cardiologist at the central ECG laboratory will be used for data analysis 
and report writing purposes.
The investigator (or qualified designee) must document his/her review of 1 of the replicate ECGs 
printed at the time of collection, the final over-read ECG report issued by the central ECG 
laboratory, and any alert reports.
9.4.2. Vital Signs
Vital signs including pulse rate, orthostatic BP, temperature, and weight will be measured as
detailed in the Schedule of Activities (Section 2).
Orthostatic Blood Pressure Monitoring: For orthostatic BP monitoring, subjects will have 3 
BP/pulse rate measurements taken in the seated position approximately 1 minute apart followed 
by 1 BP/pulse rate measurement taken in the standing position.  For orthostatic BP monitoring, 
subjects should be seated for at least 5 minutes and stand for at least 3 minutes prior to taking the 
respective measurements.  If the subject feels unable to stand, vital signs only in the seated 
position will be recorded.
Orthostatic BP/pulse rate will be measured as part of the vital sign assessments at every visit. At 
Visit 2, Visit 3, Visit 8, Visit 11, and Visit 801, these measurements will be collected at time 0 of 
the in-clinic BP/pulse rate monitoring. Unscheduled orthostatic vital signs should be assessed, if 
possible, during any AE of dizziness or posture-induced symptoms.  Additional vital signs may 
be measured during each study period if warranted and agreed upon between the sponsor and 
investigator. (Table HBEH.3)
In-clinic Blood Pressure and Pulse Rate Monitoring:  In-clinic BP and pulse rate monitoring 
will be done at Visit 2, Visit 3, Visit 8, Visit 11, and Visit 801.  The BP and pulse rate will be 
measured at time 0 and every 60 minutes thereafter. The initial measurement, at time 0 of the 
in-clinic BP and pulse rate monitoring, will be done as an orthostatic BP/pulse rate (refer to 
Orthostatic Blood Pressure Monitoring above), and subsequent BP and pulse rate measurements 
will be taken in the seated position only. Time 0 at Visit 3, Visit 8 and Visit 11 will occur just 
prior to study drug dosing.  At Visit 3, drug dosing should be initiated immediately following 
confirmation that subject met inclusion criteria [6].  At Visit 2, Visit 8, and Visit 11, in-clinic BP 
and pulse rate will be monitored for up to 6 hours,  At Visit 3, for up to 8 hours and at Visit 801 
for up to 2 hours (Table HBEH.4).
Home Blood Pressure Monitoring:  Home BP measurements will be collected in this study.  
Blood pressure measurements should be taken twice daily in the seated position using the HBPM
equipment provided by Lilly.  The subject should be given the HBPM device at Visit 2. Home 
BP measurements should be conducted for a minimum of 7 days between Visits 2 and 3, for 
3 weeks between Visits 3 and 6, and a minimum of 7 days between Visits 10 and 11, and 
Visits 11 and 801.  Home BP should be taken twice in the morning (approximately 1 minute 
apart) (e.g., 8 AM) immediately following study medication dosing and twice in the evening, 
approximately 12 hours later (approximately 1 minute apart) (e.g., 8 PM).
All HBPM data will be electronically transmitted to a designated HBPM data processing vendor.


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9.4.3. Laboratory Tests
For each subject, laboratory tests detailed in (Appendix 2) should be conducted according to the 
Schedule of Activities (Section 2).
With the exception of laboratory test results that may unblind the study, Lilly or its designee will 
provide the investigator with the results of laboratory tests analyzed by a central vendor, if a 
central vendor is used for the clinical trial.
Any clinically significant findings from laboratory tests that result in a diagnosis and that occur 
after the subject receives the first dose of investigational product should be reported to Lilly or 
its designee as an AE via eCRF.
9.4.4. Columbia-Suicide Severity Rating Scale – Children’s Version
Consistent with Food and Drug Administration (FDA) regulatory guidance (FDA 2012), any 
occurrence of suicide-related thoughts and behaviors will be assessed as indicated in the Study 
Schedule (Section 2).  The C-SSRS is a scale that captures the occurrence, severity, and 
frequency of suicide-related thoughts and behaviors during the corresponding assessment period.  
The scale includes suggested questions to elicit the type of information needed to determine if a 
suicide-related thought or behavior occurred.
The C-SSRS is available in an adult’s and a children’s version.  There is no version of the 
C-SSRS designed for use in a cognitively impaired population such as subjects with PD 
dementia; therefore, the children’s version will be used.  Terms captured by the use of the 
C-SSRS children’s version can be mapped to Columbia Classification Algorithm for Suicide 
Assessment (Posner et al. 2007), to facilitate future pooling of data.
The first time the scale is assessed in this study, the C-SSRS “Baseline” version will be used, and 
the findings will constitute the baseline assessment.  The C-SSRS “Since Last Visit” scale will 
be used for all subsequent assessments.
The C-SSRS will be assessed after the cognitive and functional assessments.  Responses from 
subject will be considered when assessing the scale. If a suicide-related thought or behavior is 
identified at any time during the study, a thorough evaluation will be performed by a study 
physician, and appropriate medical care will be provided.
If, based on assessment of the C-SSRS, it is determined that suicide-related behaviors have 
occurred, then the Lilly Self-Harm Follow-Up form will be used to collect additional information 
to allow for a more complete assessment of these behaviors.
9.4.5. Physician Withdrawal Checklist
The Penn Physician Withdrawal Checklist (PWC-20) is a 20-item checklist that will be used to 
assess the presence and severity of withdrawal symptoms.  The PWC-20 should be assessed on 
the subject and caregiver, separately. The scale was originally developed to assess the severity 
of withdrawal symptoms in anxiolytic medication discontinuation (Rickels et al. 2008). The 
PWC-20 is a validated, shortened version of the original 35-item checklist, where the 20-items 
were selected based on their statistical ability to differentiate between placebo and active drug 


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plus share correlation with the 35-item checklist (Schweizer et al. 1990; Rickels et al. 1990).  
The 20 items assess the subject’s level of symptoms on a variety of withdrawal symptoms since 
last visit.  Each of the 20 items are scored as 0 (not present), 1 (mild), 2 (moderate), 3 (severe).
9.4.6. Safety Monitoring
Lilly will periodically review evolving aggregate safety data within the study by appropriate 
methods.
In the event that safety monitoring uncovers an issue that needs to be addressed by unblinding at 
the group level, only members of the IAC (an advisory group for this study formed to protect the 
integrity of data; refer to Section 10.3.7) can conduct additional analyses of the safety data.
9.4.6.1.
Hepatic Safety Monitoring
If a subject experiences elevated ALT ≥3X ULN, ALP ≥2X ULN, or elevated TBL ≥2X ULN, 
tests for hepatic parameters (Appendix 4) should be repeated within 3 to 5 days including ALT, 
AST, ALP, TBL, direct bilirubin, gamma-glutamyl transferase, and creatine kinase to confirm 
the abnormality and to determine if it is increasing or decreasing.  If the abnormality persists or 
worsens, clinical and laboratory monitoring should be initiated by the investigator and in 
consultation with the study medical monitor. Monitoring of ALT, AST, TBL, and ALP should 
continue until levels normalize or return to approximate baseline levels.
Hepatic Safety Data Collection
Additional safety data should be collected via the eCRF if 1 or more of the following conditions 
occur:
1. Elevation of serum ALT to ≥5X ULN on 2 or more consecutive blood tests.
2. Elevated serum TBL to ≥2X ULN (except for cases of known Gilbert’s syndrome).
3. Elevation of serum ALP to ≥2X ULN on 2 or more consecutive blood tests.
4. Subject discontinued from treatment due to a hepatic event or abnormality of liver tests.
5. Hepatic event considered to be an SAE.
9.4.7. Appropriateness of Safety Assessments
The clinical safety measurements (AE reporting, physical examinations, vital signs, HBPM, 
ECGs, and clinical safety laboratory tests; Section 9.2 and Section 9.4) are well-established 
methods in drug development research and are standard procedures for clinical trials.
9.5.
Pharmacokinetics
At the visits and times specified in the Schedule of Activities (Section 2), venous blood samples
will be collected to determine the plasma concentrations of LY3154207.  Instructions for the 
collection and handling of blood samples will be provided by the sponsor.  At Visit 3, a PK 
sample is to be collected within 1 to 3 hours after the drug is administered at the site.  At Visit 4, 
Visit 5, Visit 8, and ET/DC, the PK sample can be collected at any time during the visit.  At 
Visit 11, the PK sample should be collected prior to the drug being administered at the site.  The 


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date and time (24-hour clock time) of the PK sample collection as well as the date and time of 
the dose administration immediately preceding the PK sampling will be recorded.
Drug concentration information that may unblind the study will not be reported to investigative 
sites or blinded personnel until the study has been unblinded.
Bioanalytical samples collected to measure investigational product concentration and 
metabolism and/or protein binding will be retained for a maximum of 2 years following last 
subject visit for the study.
The PK analyses will be based on validated bioanalytical assays and will use conventional PK 
analysis methods.
9.6.
Pharmacodynamics
Not applicable.
9.7.
Pharmacogenomics
9.7.1. Whole Blood Sample for Pharmacogenetic Research
A whole blood sample will be collected for pharmacogenetic analysis as specified in the 
Schedule of Activities (Section 2) where local regulations allow.
The collection and storage of samples for genetic studies (including samples for 
pharmacogenetic studies) is to continue our ongoing efforts to understand the correlation 
between the clinical outcome with the drug(s) under study in the clinical trial and the genetic 
makeup of the subject.  DNA extracted from the whole blood samples collected from the subjects 
may be used to generate genetic data on a genome genotyping array. The genotype data may be 
used to perform a targeted genetic analysis of the genes of interest to understand potential safety 
and efficacy concerns should they arise either during this trial, future trials for this drug, or if the 
drug is launched and on the market. For example, genetic variations in well-known 
drug-metabolizing enzymes, such as cytochrome P450 (CYP), including CYP3A4, could be a 
potential set of genes of interest to answer any safety concerns.
Samples will not be used to conduct unspecified disease or population genetic research either 
now or in the future.  Samples may be used to investigate variable response to LY3154207 and to 
investigate genetic variants thought to play a role in LBD.  Assessment of variable response may 
include evaluation of AEs or differences in efficacy.
All samples will be coded with the subject number.  These samples and any data generated can 
be linked back to the subject only by the investigator site personnel.
Samples will be retained at a facility selected by Lilly or its designee for a maximum of 15 years 
after the last subject visit for the study, or for a shorter period if local regulations and/or ethical 
review boards (ERBs) impose shorter time limits.  This retention period enables use of new 
technologies, response to regulatory questions, and investigation of variable response that may 


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not be observed until later in the development of LY3154207 or after LY3154207 becomes 
commercially available.
Molecular technologies are expected to improve during the 15-year storage period and therefore 
cannot be specifically named.  However, existing approaches include whole genome or exome 
sequencing, genome-wide association studies, and candidate gene studies.  Regardless of 
technology utilized, genotyping data generated will be used only for the specific research scope 
described in this section.
9.8.
Biomarkers
9.8.1.
Digital Biomarkers
9.8.1.1.
Lilly Trial Application
The Lilly Trial application (Lilly Trial app), if available, will be used to assess the feasibility of 
collecting clinical research domains such as cognitive and motor functioning under real world 
conditions using an iPad-enabled application (see Operations Manual).  In addition, the ability of 
the Lilly Trial app to measure the effect of LY3154207 on motor and cognitive outcomes in a 
subset of subjects will be explored.  The app uses a series of tasks that activate iPad sensors to 
collect and track data from the subjects.  These measures include a variety of potential tests 
measuring motor functions and cognition (e.g., tapping and memory tests).  An iPad configured 
with the Lilly Trial app will be provided to the subjects at Visit 2 (if available).  Subjects will 
complete assessments from 2 weeks prior to dosing (starting day following Visit 2), throughout 
the dosing period, and for 2 weeks after the conclusion of the treatment period (until Visit 801).  
Subjects will self-select for this optional component of the protocol at Visit 1.  If subject 
consents to participate, sites should capture this information in IWRS at Visit 1 to ensure the 
iPad is provisioned on time for Visit 2. Subjects can decide to opt out at any time during the 
study. The selected domains of the app will be completed up to twice daily.
The Lilly Trial app will be deployed for use during the pretreatment, treatment, and 
post-treatment phases of the study to validate findings from the Phase 1 studies using this app 
and to determine its utility for future studies in this population.
These data are exploratory data and will be used for exploratory purposes.
9.8.1.2.
Actigraphy
As an increase in mean sleep latency in sleep-deprived subjects was identified as a drug-response 
indicator, a wearable device capable of detecting and characterizing changes in various sleep 
parameters including but not limited to sleep latency, duration of sleep, sleep–wake cycles, and 
sleep disruption may be employed, in a subset of subjects, if available.  We will explore the 
feasibility of using actigraphy to evaluate the effect of LY3154207 on various sleep parameters
and day time activity.  If available, the actigraphy device will be worn on the wrist, similar to a 
watch, beginning at Visit 2, for 3 separate 2-week periods of time:  Visit 2 to Visit 3, Visit 8 to 
Visit 9, and Visit 11 to Visit 801.  The site will provide the device to the subjects at Visits 2, 8, 
and 11; and following 14 days of wearing the device, the subject will bring the device to the site 


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at the regularly scheduled visit at the end of the 14-day period (Visit 3, Visit 9, or Visit 801), 
whereupon the site will mail it to the vendor using previously addressed mailing materials (see 
Operations Manual).  These data are exploratory data and will be used for exploratory purposes.
9.9.
Medical Resource Utilization and Health Economics
Medical Resource Utilization and Health Economics parameters will not be evaluated in this 
study.


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10. Statistical Considerations
10.1. Sample Size Determination
Approximately 750 subjects may be screened in order that 340 subjects are randomized in the 
study. 
 
 If the true effect 
size for LY3154207 relative to placebo on the CoA is 0.4 with the sample size of 340 there will 
be over 80% probability of passing this criterion. A 20% discontinuation rate by Week 12 has 
been accounted for in the sample size determination.
Sample size was estimated based on the work of Wesnes et al. (2005) where the difference in 
mean change from baseline for rivastigmine compared to placebo and the pooled standard 
deviation (SD) for CoA were estimated as 5.7 units and 18 units, respectively.  The rivastigmine 
effect corresponding to a reduction in the deficit of subjects compared to age-matched healthy 
volunteers is approximately 45%.  Based on this, the effect size of 0.4 in this study corresponds 
to a mean difference of 7.2 units (approximately 57% reduction in the deficit).
This sample size will allow for assessment of the in-clinic BP and pulse rate on the first day of 
dosing in order to evaluate any changes after the first dose of treatment that were observed in 
Phase 1.  If the SD of the in-clinic SBP is assumed to be 15 mmHg, then the difference from the 
mean to the upper limit of a 95% confidence interval (CI) of the change from baseline of SBP 
relative to placebo is expected to be <4.7 mmHg.  If there is any initial rise in BP or pulse rate, 
the in-clinic 6- and 12-week assessments along with the HBPM measure will be used to assess if 
the rise accommodates.  The difference from the mean to the upper limit of a 95% CI of the 
change in average SBP measured at each of these visits relative to placebo is expected to be 
<3.5 mmHg.  This assumes an SD of 10 mmHg and a 20% discontinuation rate.
10.2. Populations for Analyses
For purposes of analysis, the following populations are defined:
Population
Description
Entered
All subjects who sign informed consent
Evaluable Patient Population 
(EPP)
All randomized subjects who received at least 1 dose of study treatment, who
have the baseline efficacy assessment and have at least 1 post-dose efficacy 
assessment.  Analyses will be according to the treatment the subject actually 
received.
Completers
All randomized subjects who have completed all study procedures, including 
follow-up and/or ET/DC visit.
Safety population
All randomized subjects who take at least 1 dose of study treatment.  In the 
event of a treatment error, subjects will be analyzed according to the treatment 
they actually received.
Per Protocol population
Subjects who complete the study with no major protocol deviations
PK Analysis Population
PK analyses will be conducted on subjects who receive at least 1 dose of the 
study drug and have one measurable concentration
Abbreviations:  DC = discontinuation; ET = early termination; PK = pharmacokinetic.
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10.3. Statistical Analyses
10.3.1. General Statistical Considerations
Statistical analysis for this study will be the responsibility of Lilly or its designee.
Unless otherwise specified, all efficacy analyses will be conducted on the evaluable patient 
population (EPP). This includes all data from all randomized subjects who received at least 1 
dose of study medication and have the baseline efficacy assessment and at least 1 postdose 
efficacy assessment.  Analyses will be according to the treatment the subject actually received.  
Efficacy analyses will be repeated with a per-protocol analysis set including only those subjects
who completed the study with no major protocol deviations to verify robustness of the results.
No adjustments will be made for multiple comparisons.  When change from baseline is assessed, 
subjects will be included in the analysis only if both the baseline and a postbaseline measures are 
available. Unless otherwise defined, a baseline measure is the last non-missing observation 
collected prior to the subject receiving study treatment.
Safety analyses will be conducted on the safety analysis set comprising all subjects who received 
at least 1 dose of study medication. Summary statistics, tabulations, and graphs will be provided, 
as appropriate.
Any change to the data analysis methods described in the protocol will require an amendment 
ONLY if it changes a principal feature of the protocol.  Any other change to the data analysis 
methods described in the protocol, and the justification for making the change, will be described 
in the clinical study report (CSR). Additional exploratory analyses of the data will be conducted, 
as deemed appropriate. However, these analyses may not be included in the CSR.
The statistical analyses specified in the protocol will be detailed in the statistical analysis plan 
(SAP).  However, some of the exploratory analysis suggested by data will not be specified in 
SAP.
10.3.1.1. Handling of Missing Items for Scales
The total and subscale scores will be derived from individual items. If any of the individual 
items are missing or unknown, every effort will be made to obtain the score for the missing item 
or items. However, failing to gather missing information, some scales (e.g., ADAS-Cog) will be 
imputed as appropriate. The scales for which imputation is adopted will be detailed in the SAP.
For the scales where imputation is not done, if any item is missing, any total or sum involving 
that item will be considered missing.
10.3.2. Treatment Group Comparability
10.3.2.1. Time to Study Disposition/Discontinuation
The reasons for discontinuation and the time in days-to-study disposition will be summarized by 
treatment group for all randomized subjects.  A corresponding listing will also be produced.


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The reason for discontinuation will be collected when the subject’s participation in the study 
ends and will be summarized as frequency and percentage by treatment group for all randomized 
subjects.
10.3.2.2. Protocol Deviations
Listings of subjects with significant protocol deviations will be provided based on the safety 
population. Protocol deviations will be summarized using frequencies and percentages.
10.3.2.3. Subject Characteristics
Baseline characteristics will be summarized for the EPP and per-protocol populations by 
treatment group and overall. Summaries will include descriptive statistics for continuous 
measures and frequencies and percentage for categorical measures.  Comparability between 
treatment groups will be evaluated based on the point estimates and the associated variability.
10.3.2.4. Concomitant Therapy
Prior medications are defined as those that stop before randomization (Visit 3). Concomitant
medications are defined as those being taken on or after randomization (Visit 3).  A summary of
concomitant medications will be presented as frequencies and percentages for each treatment
group. If the start or stop dates of therapies are missing or partial to the degree that 
determination cannot be made as to whether the therapy is prior or concomitant, the therapy will 
be deemed concomitant.
Summary tables will also be provided for PD concomitant medications and cognitive enhancing
medications.
Prior and concomitant medications will also be listed.
Medications will be coded using the World Health Organization drug dictionary.
10.3.2.5. Treatment Compliance
Treatment compliance information for each treatment arm will be collected through capsule
counts at each visit, and the number of capsules taken relative to the number expected to be taken 
will be summarized.
10.3.3. Efficacy Analyses
10.3.3.1. Primary Analyses
The primary analysis on CoA will occur when all subjects complete 12 weeks of treatment.  The 
analysis of CoA will utilize a Bayesian MMRM model.  The Bayesian analysis may use 
uninformative priors for all terms in the model. These will be diffuse Normal distributions 
centered on zero. Priors for variance will follow an inverse gamma distribution.  Further details 
of the Bayesian analysis will be provided in the SAP.  The MMRM model will account for 
longitudinal data assessed throughout the study, after 1, 2, 4, 6, 8, 10, and 12 weeks of dosing.  
The change of CoA from the baseline to Week 12 will be the dependent variable.  The model 
will comprise fixed (baseline value, treatment, visit) and random effects (subject) and the 
interaction terms (treatment by visit, baseline value by visit). Unstructured variance structure 
will be applied in the model, but if it fails to converge, other suitable structures will be 


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investigated. The primary comparison will be the contrast (difference in least squares mean) 
between treatments and placebo for the Week 12 change from baseline.
10.3.3.2. Secondary Efficacy Analyses
The secondary efficacy outcomes (ADCS-CGIC, PDAQ-15, ADAS-Cog13, CDR-CCB PoA, 
D-KEFS, MoCA, NPI, ESS, and MDS-UPDRS [total and Part III]) will be assessed at the 
12-week time point.  Each of these secondary endpoints will be analyzed using an MMRM 
model, which will include terms for: baseline value, treatment, visit, and the relevant interaction 
terms.  Further covariates may be included such as age, site, and the severity of PD motor 
function as well as severity of dementia at baseline as appropriate.  The change of the score from 
baseline will be the dependent variable.  If subscores for a particular scale are deemed clinically 
relevant to analysis, it will be completed as an exploratory analysis.
10.3.3.3. Tertiary/Exploratory Efficacy Analyses
The following exploratory efficacy endpoints will be analyzed using MMRM model.

Change in the total score for the ADAS-Cog11 from baseline to Week 12 (as a subset 
of ADAS-Cog13)

Change in the CDR elements (Cognitive reaction time composite score, Reaction 
Time Variability composite score, Speed Score composite scores, Simple Reaction 
Time outcomes, Choice Reaction time task outcomes, Digit Vigilance outcomes, 
Numeric Working Memory outcomes, Spatial Working Memory Outcomes, Verbal 
Memory outcomes, Visual Memory outcomes) from baseline to Week 12

Change in MDS-UPDRS individual subscales – non-motor experiences of daily living 
(Part I), motor experiences of daily living (Part II), and motor complications 
(Part IV) subscales from baseline to Week 12

Change in MDS-UPDRS Part IA score from baseline to Week 12

Change in GDS-S score from screening to Week 12

Change in NPI score (Part D Depression/Dysphoria) from baseline to Week 12

Change in QUIP score from baseline to Week 12
Where appropriate, these results will be investigated in more depth.
Exploratory Digital Biomarker Analysis:  Data from digital biomarkers (Lilly Trial app and 
Actigraphy watch) from baseline to Week 12 will be explored using appropriate visual, 
univariate, and multivariate methods to understand the relationship of the biomarker endpoints to 
other clinical endpoints in terms of treatment effect. The data may also be used to explore the 
validity and reliability of these assays in LBD subjects. If applicable, potential predictive 
biomarkers associated with interpretable clinical benefit may further be examined with biological 
evidence.
10.3.4. Safety Analyses
All subjects who receive at least 1 dose of LY3154207 will be evaluated for safety and toxicity.
Safety parameters (AEs, laboratory analytes, vital signs, ECGs) and number of subjects who 
meet the potentially clinically significant vital signs criteria at 3 consecutive time points at 


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Visit 3 (Day 1 stopping rules) will be summarized using descriptive statistics for continuous 
variables and frequencies along with percentages for categorical variables during the treatment 
period.
Comparisons between 3 doses of LY3154207 and placebo will be made using an MMRM model 
for the in-clinic BP, pulse rate, and HBPM measurements during the treatment period.  No 
adjustments for multiple comparisons will be made.
The PWC-20 endpoint will be analyzed using an ANCOVA model with a covariate for baseline 
score. The primary analyses will be a change from baseline (Visit 11) to the in person follow up 
visit (Visit 801).
10.3.4.1. Adverse Events
Treatment-emergent adverse events will be defined as events that first occurred or worsened on
or after randomization (Visit 3). Should there be insufficient data for AE start date, stop date, 
and time, the AE will be considered treatment emergent.
Treatment-emergent adverse events will be calculated based on AE identifier and coded 
according to established Medical Dictionary for Regulatory Activities (MedDRA) terms and 
summarized by MedDRA System Organ Class (SOC) and Preferred Term.  Adverse event terms 
and severity grades will be assigned by the investigator using Common Terminology Criteria for 
Adverse Events, version 4.0.
An overview of AEs, including the number and percentage of subjects who died, suffered serious 
adverse events (SAEs), discontinued due to AEs, and who suffered TEAEs, will be provided.
Summaries of AEs by decreasing frequency of Preferred Term within SOC will be provided for
the following:

preexisting conditions

TEAEs

TEAEs by maximum severity

TEAEs occurring in greater than 1% of subjects by Preferred Term

SAEs

AEs reported as reason for discontinuation
These summaries will include number and percentages of subjects with TEAEs
A summary of TEAEs by visit will also be provided.
Preexisting conditions, TEAEs, SAEs, and discontinuations due to AEs will be listed.
10.3.4.2. Suicidal Ideation and Behavior
Suicide-related thoughts and behaviors, based on the C-SSRS, will be listed by subject and visit.  
Only subjects who show suicidal ideation/behavior will be displayed (i.e. if a subject’s answers 
are all “no” for the C-SSRS, then that subject will not be displayed). However, if a subject
reported any ideation or behavior at any time point, then all their ideation and behavior will be 
displayed, even if not positive.


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10.3.4.3. Vital Signs and Weight
Vital sign measurements and weight will be analyzed as continuous data (change from baseline
to each visit) and the treatment-emergent abnormalities as categorical data.
If there are multiple records of vital sign or weight measurements at baseline or postbaseline
visits, the last record will be used. The exception is for the orthostatic BP and pulse rate taken as 
part of the vital sign assessments at Visit 1, Visit 4, Visit 5, Visit 6, Visit 7, Visit 9, Visit 10, 
unscheduled visit, and ET/DC visit, and the initial measurement at time 0 of the in-clinic BP and 
pulse rate monitoring.  At these visits, 3 BP/pulse rate measurements will be taken in the seated 
position and the mean of these will be utilized for analysis purposes.  Orthostatic changes will be 
calculated by comparing the mean of the 3 BP and pulse rate measurements taken in the seated 
position to the value of the single BP and pulse rate measurement taken in the standing position.
Summary statistics will be presented for observed values at baseline and for change from 
baseline results at each scheduled postbaseline visit. Systolic and diastolic BP and pulse 
(collected in sitting position), orthostatic SBP, orthostatic diastolic and orthostatic pulse 
(measurement after 5 minutes in the seated position minus that after 3 minutes in the standing 
position), temperature, and weight will be summarized by treatment group for all subjects in the 
safety population.
The incidence of treatment-emergent abnormal high or low vital signs will be presented by 
treatment group and visit. Treatment-emergent vital sign evaluations are defined for evaluations 
collected after the initiation of study medication. Any vital sign meeting the criteria will be 
considered abnormal.  For each vital sign at each postbaseline visit, only subjects who had a 
baseline result and had a non-missing result at that postbaseline visit will be included in the 
denominator when computing the proportion of subjects with treatment-emergent high, low, or 
abnormal values.
Summary statistics of change from baseline in weight will be provided. Body mass index at 
baseline will be summarized by treatment.
A listing of treatment-emergent abnormal vital signs will also be presented.

Day 1 (Visit 3) in-clinic BP and pulse rate change post first dose
Change in in-clinic BP and pulse rate from 0 up to 8 hours postdose measured on the first 
day of study drug dosing will be analyzed using an MMRM analysis with baseline value, 
treatment, time postdose (hours), and the relevant interaction terms.  Two baselines will 
be considered: the Visit 3 pretreatment value (time 0) and the time-matched baselines 
from Visit 2 (hourly value 0 to 6 hours). For the second of these, there is no 
time-matched value for the 7- and 8-hour time points of Visit 3, so the 6-hour time point 
of Visit 2 will be used as their baseline value.  A separate change from baseline analysis 
will be completed for each baseline approach.

Change in in-clinic BP and pulse rate from baseline (Visit 2, predrug) up to Week 12 
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Change in in-clinic BP and pulse rate measured at Visit 2 (daily average 0 to 6 hours) to 
the in-clinic BP and pulse rate measured at Week 6/Visit 8 and Week 12/Visit 11 (daily 
average 0 to 6 hours) will be analyzed by an MMRM model with baseline value, 
treatment, and the relevant interaction terms. Analysis at 6 weeks will help to evaluate 
any significant changes (if any) in BP and pulse rate earlier than 12 weeks (end of study) 
and if they accommodate by 6 weeks.

Daily average change in home BP measurements and pulse rate from baseline to 
Week 12.
10.3.4.4. Laboratory Analyses
Laboratory measurements will be analyzed as continuous data (change from baseline) measured 
as International System Units or as categorical data (proportion of treatment-emergent 
abnormalities).
If there are multiple records of laboratory measurements at baseline or postbaseline visits, the
last record will be used.
Change from baseline to postbaseline visits at which laboratory measurements are taken will be
summarized using descriptive statistics.
For all laboratory analytes, frequencies of subjects with notable changes (i.e. increases or
decreases of a prespecified amount unique to each analyte) from baseline to each postbaseline
visit will also be summarized for all subjects and stratified by low, normal, or high at baseline.
10.3.4.5. Electrocardiograms
The ECG measurements will be analyzed as continuous data (change from baseline) or as 
categorical data (proportion of treatment-emergent abnormalities).
Electrocardiogram is measured in triplicates and the average of triplicates will be used at 
baseline and each double-blind period visit.  If there are multiple records after averaging ECG 
triplicates within a visit, the last record of averages will be used.
All ECG parameters change from baseline to each postbaseline visit at which ECG 
measurements are taken will be summarized.
Incidence of treatment-emergent abnormal ECGs will be also be summarized.
10.3.5. Pharmacokinetic/Pharmacodynamic Analyses
LY3154207 concentrations will be illustrated graphically and summarized descriptively. If 
warranted and based on availability of data, the exposure–response relationship of plasma 
LY3154207 concentrations to efficacy endpoints and/or safety endpoints may be explored.  
Subject and healthy subject data, including but not limited to plasma LY3154207 concentrations, 
from other clinical studies evaluating LY3154207 may be combined with data from this study to 
support additional analyses. A model-based approach may be implemented using nonlinear 
mixed effects modeling (NONMEM) or other appropriate software to estimate PK or 
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10.3.6. Other Analyses
10.3.6.1. Subgroup Analyses
The CDR-CCB CoA and its component scores will be assessed based on the following 
subgroups: concomitant PD therapy, concomitant AChEI therapy, PDD or DLB, and GDS (less 
than or equal to 6). All subgroup analyses will be considered exploratory and additional 
subgroup analyses may be performed as suggested by the data.
10.3.7. Interim Analyses
A limited number of pre-identified individuals may gain access to the limited unblinded data, as 
specified in the unblinding plan.  Information that may unblind the study during the analyses will 
not be reported to study sites or blinded study team until the study has been unblinded.
The efficacy and safety interim analyses will be completed and reviewed by an IAC.
Study sites will receive information about interim results ONLY if they need to know for the 
safety of their subjects.
Safety interims will be conducted on the number of subjects on each treatment who met the 
potentially clinically significant vital signs criteria at 3 consecutive time points at Visit 3 (Day 1 
stopping rules).  This will be done after 50, 100, and 150 subjects have completed Visit 3.   
 
 
Those already on 75-mg dose and passed the 
Day 1 stopping rules will remain on 75 mg.  In the event of an unacceptable rate of subjects 
meeting Day 1 stopping rules at other doses, adjustments to doses may be made for subsequently 
randomized subjects at the discretion of the IAC.  Additional efficacy analyses may be 
conducted at the time of these safety interim analyses or as needed to inform internal decision 
making.
A safety and efficacy interim analysis will be conducted when 170 randomized subjects have had 
the opportunity to complete Visit 11 (Week 12) assessments.  The statistical analysis will include 
all 170 subjects in the interim analysis, which will evaluate both the efficacy and the safety.  In 
addition, the PK data may be reviewed.  An additional interim analysis of efficacy and safety 
may be conducted prior to study completion for internal decision making. While all potential
efficacy analyses may be used for internal decision making, they are not planned to stop the 
study for efficacy or futility because this is an exploratory study and there are other key 
endpoints being assessed, not just the primary endpoint.
Unblinding details are specified in the unblinding plan section of the SAP or a separate 
unblinding plan document.
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12.
Appendices


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Appendix 1.
Abbreviations and Definitions
Term
Definition
AChEI
acetylcholinesterase inhibitor
AD
Alzheimer’s disease
ADAS-Cog13
Alzheimer’s Disease Assessment Scale – 13-item Cognitive Subscale
ADAS-Cog11
Alzheimer’s Disease Assessment Scale – 11-item Cognitive Subscale
ADCS-CGIC
Alzheimer’s Disease Cooperative Study - Clinician Global Impression of Change
AE
adverse event:  Any untoward medical occurrence in a subject or clinical investigation 
subject administered a pharmaceutical product that does not necessarily have a causal 
relationship with this treatment.  An adverse event can therefore be any unfavorable and 
unintended sign (including an abnormal laboratory finding), symptom, or disease 
temporally associated with the use of a medicinal (investigational) product, whether or 
not related to the medicinal (investigational) product.
ALP
alkaline phosphatase
ALT
alanine aminotransferase
AST
aspartate aminotransferase
blinding/masking
A single-blind study is one in which the investigator and/or his staff are aware of the 
treatment but the subject is not, or vice versa, or when the sponsor is aware of the 
treatment but the investigator and/his staff and the subject are not.
A double-blind study is one in which neither the subject nor any of the investigator or 
sponsor staff who are involved in the treatment or clinical evaluation of the subjects are 
aware of the treatment received.
Cmax
maximum observed drug concentration
C-SSRS
Columbia-Suicide Severity Rating Scale
CDR-CCB
Cognitive Drug Research Computerized Cognition Battery
CI
confidence interval
CIOMS
Council for International Organizations of Medical Sciences
CoA
Continuity of Attention
Companion diagnostic
An in vitro diagnostic device (assay or test) that provides information that is essential for 
the safe and effective use of a corresponding therapeutic product


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complaint
A complaint is any written, electronic, or oral communication that alleges deficiencies 
related to the identity, quality, purity, durability, reliability, safety or effectiveness, or 
performance of a drug or drug delivery system.
compliance
Adherence to all study-related requirements, good clinical practice (GCP) requirements, 
and applicable regulatory requirements.
CRP
clinical research physician: Individual responsible for the medical conduct of the study.  
Responsibilities of the CRP may be performed by a physician, clinical research scientist, 
global safety physician or other medical officer.
CSF
cerebrospinal fluid
CSR
clinical study report
CV
cardiovascular
CYP
cytochrome P450
CYP3A4
cytochrome P450 3A4
D1PAM
positive allosteric modulator of the dopamine D1 receptor
D-KEFS
Delis–Kaplan Executive Function System
DLB
dementia with Lewy bodies
EC25
effective concentration 25
ECG
electrocardiogram
eCOA
electronic Clinical Outcome Assessment
Enroll
The act of assigning a subject to a treatment.  Subjects who are enrolled in the study are 
those who have been assigned to a treatment.
Enter
Subjects entered into a study are those who sign the informed consent form directly or 
through their legally acceptable representatives.
EPP
evaluable patient population
ERB
ethical review board
ESS
Epworth Sleepiness Scale
GCP
good clinical practice
GDS-S
Geriatric Depression Scale – Short Form
HEENT
head, ear, eye, nose, and throat
HBPM
home blood pressure monitoring
IB
Investigator’s Brochure


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IAC
Internal Assessment Committee
IADL
instrumental activities of daily living
ICD
impulse control disorder
ICF
informed consent form
ICH
International Council for Harmonisation
Informed consent
A process by which a subject voluntarily confirms his or her willingness to participate in 
a particular study, after having been informed of all aspects of the study that are relevant 
to the subject’s decision to participate.  Informed consent is documented by means of a 
written, signed and dated informed consent form.
interim analysis
An interim analysis is an analysis of clinical study data, separated into treatment groups, 
that is conducted before the final reporting database is created/locked.
investigational product
A pharmaceutical form of an active ingredient or placebo being tested or used as a 
reference in a clinical trial, including products already on the market when used or 
assembled (formulated or packaged) in a way different from the authorized form, or 
marketed products used for an unauthorized indication, or marketed products used to 
gain further information about the authorized form.
IWRS
LBD
interactive web-response system
Lewy Body Dementia
MDS
Movement Disorder Society
MDS-UPDRS
Movement Disorder Society’s United Parkinson’s Disease Rating Scale
MedDRA
Medical Dictionary for Regulatory Activities
MMRM
mixed-model repeated measures
MMSE
Mini-Mental State Examination
MoCA
Montreal Cognitive Assessment
NOAEL
no-observed-adverse-effect level
NONMEM
nonlinear mixed effects modeling
NPI
Neuropsychiatric Inventory
PD
Parkinson’s disease
PDAQ-15
Penn Parkinson’s Daily Activities Questionnaire-15
PDD
Parkinson’s disease dementia
PK
pharmacokinetic(s)


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PoA
Power of Attention
PSG
Parkinson Study Group
QD
once a day
QTcF
Fredericia’s corrected QT interval on the ECG
QUIP
Questionnaire for Impulsive-Compulsive Disorders in Parkinson’s Disease
REM
rapid eye movement
SAE
serious adverse event
SAP
statistical analysis plan
SBP
systolic blood pressure
Screen
The act of determining if an individual meets requirements for participation in a clinical 
study. 
SD
standard deviation
SOC
System Organ Class
SUSAR
suspected unexpected serious adverse reaction
TBL
total bilirubin
TEAE
Treatment-emergent adverse event:  An untoward medical occurrence that emerges 
during a defined treatment period, having been absent pretreatment, or worsens relative 
to the pretreatment state, and does not necessarily have to have a causal relationship with 
this treatment.
ULN
upper limit of normal
WOCBP
women of child-bearing potential


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Appendix 2.
Clinical Laboratory Tests
Clinical Laboratory Tests
Hematologya,b
Clinical Chemistrya,b,c
Hemoglobin
Serum Concentrations of:
Hematocrit
Sodium
Erythrocyte count (RBC)
Potassium
Mean cell volume
Total bilirubin
Mean cell hemoglobin concentration
Direct bilirubin
Leukocytes (WBC)
Alkaline phosphatase
Neutrophils, segmented
Alanine aminotransferase (ALT)
Lymphocytes
Aspartate aminotransferase (AST)
Monocytes
Blood urea nitrogen (BUN)
Eosinophils
Creatinine
Basophils
Uric acid
Platelets
Calcium
Glucose, nonfasting 
Urinalysisa,b
Albumin
Specific gravity
Cholesterol
pH
Creatine kinase (CK)
Protein
Glucose
Ketones
Serum FSH (females only)a,b,c,d
Blood
Urine leukocyte esterase
Abbreviations:  FSH = follicle-stimulating hormone; RBC = red blood cells; WBC = white blood cells.
a
Assayed by the Lilly-designated Central Laboratory.
b
Results will be confirmed by the Lilly-designated Central Laboratory at the time of initial testing.
c
Refer to the Schedule of Activities.
d
Refer to inclusion criteria [12e] in Section 6.1.


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Appendix 3.
Study Governance Considerations
Appendix 3.1. Regulatory and Ethical Considerations, Including the 
Informed Consent Process
Appendix 3.1.1.
Informed Consent
The investigator is responsible for:

ensuring that the subject/subject’s legal representative understands the nature of the 
study, the potential risks and benefits of participating in the study, and that their 
participation is voluntary.

ensuring that informed consent is given by each subject or legal representative.  This 
includes obtaining the appropriate signatures and dates on the informed consent form 
(ICF) prior to the performance of any protocol procedures and prior to the administration 
of investigational product.

answering any questions the subject/subject’s legal representative may have throughout 
the study and sharing in a timely manner any new information that may be relevant to 
the subjects/subject’s legal representative’s willingness to continue his or her 
participation in the study.

ensuring that a copy of the ICF is provided to the subject or the subject’s legal 
representative and is kept on file.

ensuring that the medical record includes a statement that written informed consent was 
obtained before the subject was enrolled in the study and the date the written consent 
was obtained. The authorized person obtaining the informed consent must also sign the 
ICF.
Caregivers will also sign a separate informed consent. If it is not known that the caregiver will 
change, the new caregiver would need to sign the ICF when he/she takes over the care for the 
subject and study participation. The change in caregiver would also need to be documented on 
the eCRF.
As used in this protocol, the term “informed consent” includes all consent and assent given by
subject or their legal representatives and by caregivers.
Appendix 3.1.2.
Recruitment
Lilly or its designee is responsible for the central recruitment strategy for subjects.  Individual 
investigators may have additional local requirements or processes.
Appendix 3.1.3.
Ethical Review
The investigator or an appropriate local representative must give assurance that the ethical 
review board (ERB) was properly constituted and convened as required by International Council 
for Harmonisation (ICH) guidelines and other applicable laws and regulations.


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Documentation of ERB approval of the protocol and the ICF must be provided to Lilly before the 
study may begin at the investigative site(s).  Lilly or its representatives must approve the ICF, 
including any changes made by the ERBs, before it is used at the investigative site(s).  All ICFs 
must be compliant with the ICH guideline on Good Clinical Practice (GCP).
The study site’s ERB(s) should be provided with the following:

the protocol and related amendments and addenda, current Investigator 
Brochure (IB) and updates during the course of the study

informed consent form

other relevant documents (e.g., curricula vitae, advertisements)
Appendix 3.1.4.
Regulatory Considerations
This study will be conducted in accordance with the protocol and with:

the consensus ethics principles derived from international ethics guidelines, 
including the Declaration of Helsinki and Council for International Organizations
of Medical Sciences (CIOMS) International Ethical Guidelines

the applicable ICH GCP Guidelines

the applicable laws and regulations
Some of the obligations of the sponsor will be assigned to a third party.
Appendix 3.1.5.
Investigator Information
Physicians with a specialty in neurology, geriatric medicine, and/or psychiatry will participate as 
investigators in this clinical trial.
Appendix 3.1.6.
Protocol Signatures
The sponsor’s responsible medical officer will approve the protocol, confirming that, to the best 
of his or her knowledge, the protocol accurately describes the planned design and conduct of the 
study.
After reading the protocol, each principal investigator will sign the protocol signature page and 
send a copy of the signed page to a Lilly representative.
Appendix 3.1.7.
Final Report Signature
The clinical study report (CSR) coordinating investigator will sign the final CSR for this study, 
indicating agreement that, to the best of his or her knowledge, the report accurately describes the 
conduct and results of the study.
The investigator with the most qualified subjects will serve as the CSR coordinating investigator.  
If this investigator is unable to fulfill this function, another investigator will be chosen by Lilly to 
serve as the CSR coordinating investigator.


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The sponsor’s responsible medical officer and statistician will approve the final CSR for this 
study, confirming that, to the best of his or her knowledge, the report accurately describes the 
conduct and results of the study.
Appendix 3.2.
Data Quality Assurance
To ensure accurate, complete, and reliable data, Lilly or its representatives will do the following:

provide instructional material to the study sites, as appropriate

sponsor investigator study site trainings to instruct the investigators and study 
coordinators.  This training will give instruction on the protocol, the completion 
of the eCRFs, and study procedures.

make periodic visits to the study site

be available for consultation and stay in contact with the study site personnel by 
mail, telephone, and/or fax

review and evaluate eCRF data and use standard computer edits to detect errors in 
data collection

conduct a quality review of the database
In addition, Lilly or its representatives will periodically check a sample of the subject data 
recorded against source documents at the study site.  The study may be audited by Lilly or its 
representatives, and/or regulatory agencies at any time.  Investigators will be given notice prior 
to an audit.
The investigator will keep records of all original source data.  This might include laboratory 
tests, medical records, and clinical notes.  If requested, the investigator will provide the sponsor, 
applicable regulatory agencies, and applicable ERBs with direct access to original source 
documents.
Appendix 3.2.1.
Data Capture System
An electronic data capture system will be used in this study.  The site maintains a separate source 
for the data entered by the site into the sponsor-provided electronic data capture system.
Electronic Clinical Outcome Assessment (eCOA) measures (e.g., a rating scale) are entered into 
an eCOA instrument (at the time that the information is obtained).  In these instances, where 
there is no prior written or electronic source data at the site, the eCOA instrument record will 
serve as the source.
If eCOA records are stored at a third-party site, investigator sites will have continuous access to 
the source documents during the study and will receive an archival copy at the end of the study 
for retention.
Any data for which the eCOA instrument record will serve to collect source data will be 
identified and documented by each site in that site’s study file.


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Case report form data will be encoded and stored in a clinical trial database.  Data managed by a 
central vendor, such as laboratory test data or electrocardiogram data, will be stored 
electronically in the central vendor’s database system.  Data will subsequently be transferred 
from the central vendor to the Lilly data warehouse.
Any data for which paper documentation provided by the subject will serve as the source 
document will be identified and documented by each site in that site’s study file.
Data from complaint forms submitted to Lilly will be encoded and stored in the global product 
complaint management system.
Appendix 3.3.
Study and Site Closure
Appendix 3.3.1.
Discontinuation of Study Sites
Study site participation may be discontinued if Lilly or its designee, the investigator, or the ERB 
of the study site judges it necessary for medical, safety, regulatory, or other reasons consistent 
with applicable laws, regulations, and GCP.
Appendix 3.3.2.
Discontinuation of the Study
The study will be discontinued if Lilly or its designee judges it necessary for medical, safety, 
regulatory, or other reasons consistent with applicable laws, regulations, and GCP.
Appendix 3.4.
Publication Policy
The publication policy for Study HBEH is described in the Clinical Trial Agreement.


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Appendix 4.
Hepatic Monitoring Tests for
Treatment-Emergent Abnormality
Selected tests may be obtained in the event of a treatment-emergent hepatic abnormality and may 
be required during follow-up with subjects in consultation with the Lilly, or its designee, clinical 
research physician.
Hepatic Monitoring Tests
Hepatic Hematologya
Haptoglobina
Hemoglobin
Hematocrit
Hepatic Coagulationa
RBC
Prothrombin Time
WBC
Prothrombin Time, INR
Neutrophils, segmented
Lymphocytes
Hepatic Serologiesa,b
Monocytes
Hepatitis A antibody, total
Eosinophils
Hepatitis A antibody, IgM
Basophils
Hepatitis B surface antigen
Platelets
Hepatitis B surface antibody
Hepatitis B Core antibody
Hepatic Chemistrya
Hepatitis C antibody
Total bilirubin
Hepatitis E antibody, IgG
Direct bilirubin
Hepatitis E antibody, IgM
Alkaline phosphatase
ALT
Anti-nuclear antibodya
AST
GGT
Alkaline Phosphatase Isoenzymesa
CPK
Anti-smooth muscle antibody (or anti-actin 
antibody)a
Abbreviations:  ALT = alanine aminotransferase; AST = aspirate aminotransferase; CPK = creatinine 
phosphokinase; GGT = gamma-glutamyl transferase; Ig = immunoglobulin; INR = international normalized 
ratio; RBC = red blood cells; WBC = white blood cells.
a
Assayed by Lilly-designated laboratory.
b
Reflex/confirmation dependent on regulatory requirements and/or testing availability.


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Appendix 5.
MDS Diagnostic Criteria for Parkinson’s 
Disease – Red Flags and Supportive 
Criteria
Postuma et al. 2015
ABSOLUTE EXCLUSION CRITERIA
1. unequivocal cerebellar abnormalities on exam;
2. downward vertical supranuclear gaze palsy or selective slowing of downward vertical
saccades;
3. diagnosis of behavioral variant of frontotemporal dementia or primary progressive 
aphasia within the first 5 years of disease;
4. parkinsonian features restricted to the lower limb for greater than 3 years;
5. treatment with a dopamine receptor blocker or dopamine depleting agent that temporally 
suggests drug-induced parkinsonism;
6. absence of observable response to high-dose levodopa therapy;
7. unequivocal cortical sensory loss, clear limb ideomotor apraxia, or progressive aphasia;
8. normal functional imaging of the presynaptic dopaminergic system (PET or SPECT);
9. documentation of an alternative condition to account for parkinsonism or expert opinion 
that an alternative diagnosis is more likely than PD.
RED FLAGS
1. Rapid progression of gait impairment requiring regular use of wheelchair within 5 years
of onset.
2. A complete absence of progression of motor symptoms or signs over 5 or more years 
unless stability is related to treatment.
Note: This criterion is targeted at patients who may have been misdiagnosed with
parkinsonism. This must be defined based on observation (i.e. historical information 
cannot suffice). The absence of progression must be continuous over a minimum of 
5 years.
3. Early bulbar dysfunction, defined as one of severe dysphonia, dysarthria (speech 
unintelligible most of the time), or severe dysphagia (requiring soft food, NG tube, or 
gastrostomy feeding) within the first 5 y of disease.
Note: Severity definitions are from the Movement Disorder Society’s – sponsored 
revision of the United Parkinson’s Disease Rating Scale (MDS-UPDRS) (i.e. 4 for 
dysarthria, ≥3 for dysphagia).
4. Inspiratory respiratory dysfunction defined as either diurnal or nocturnal inspiratory 
stridor or frequent inspiratory sighs.
5. Severe autonomic failure in the first 5 y of disease.
This can include:


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a.
Orthostatic hypotension: orthostatic decrease of blood pressure within 3 min of 
standing by at least 30 mmHg systolic or 15 mmHg diastolic, in the absence of 
dehydration, medication, or other diseases that could plausibly explain autonomic 
dysfunction.
b. Severe urinary incontinence or urinary retention in the first 5 y of disease (excluding 
longstanding low-volume stress incontinence in women), which is not simply 
functional incontinence (i.e., inability to get to the bathroom in a reasonable time). 
In men, urinary retention must not be caused by prostate disease, and this must be 
associated with erectile dysfunction.
Note: Autonomic dysfunction is a common feature of PD; however, this criterion is
intended to identify the severe autonomic dysfunction associated particularly with 
multiple system atrophy. If the patient has more than 5 years’ disease duration at 
assessment, these features must have occurred within the first 5 years (documented 
either by chart review for orthostatic hypotension or by a clear onset time on history 
for urinary incontinence).
6. Recurrent (>1/y) falls because of impaired balance within 3 years of onset.
Note: For this criterion, falls are considered to be attributable to impaired balance, 
implying that falls attributable to loss of consciousness (syncope, seizure), or to 
situations during which persons with normal balance would also fall (athletic activities, 
violence, slipping on ice, and so forth) are not included. Clinical judgment is required to 
determine whether impaired balance played a key role in the fall.
7. The presence of disproportionate anterocollis (dystonic in nature) or contractures of hand 
or feet within the first 10 y.
8. Absence of any of the common non-motor features of disease despite 5 y disease 
duration.  These include:

Sleep dysfunction: sleep-maintenance insomnia, excessive daytime somnolence, 
symptoms of rapid eye movement sleep behavior disorder

Autonomic dysfunction: constipation, daytime urinary urgency (i.e., not simply 
nocturia), symptomatic orthostasis

Hyposmia

Psychiatric dysfunction: depression, anxiety, or hallucinations
Note: This criterion is designed primarily to detect nonparkinsonian conditions 
mimicking PD (e.g., subjects without evidence of dopaminergic deficit, dystonic 
tremor, essential tremor)
9. Otherwise unexplained pyramidal tract signs, defined as pyramidal weakness or clear 
pathologic hyperreflexia (excluding mild reflex asymmetry in the more affected limb, and 
isolated extensor plantar response).
Note: Mild reflex asymmetry is excluded because it can commonly be seen in PD. 
Isolated extensor plantar response is excluded because of the difficulty in differentiating 
this from a “striatal toe” (an occasional finding in PD), and the possibility that unrelated 
pathology (e.g., mild cervical myelopathy) can produce this finding.


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10. Bilateral symmetric parkinsonism throughout the disease course. The patient or caregiver 
reports bilateral symptom onset with no side predominance, and no side predominance is 
observed on objective examination.
SUPPORTIVE CRITERIA
1. Clear and dramatic beneficial response to dopaminergic therapy. To meet this criterion, 
during initial treatment, patients should have returned to normal or near-normal level of 
function. In the absence of clear documentation of initial response (e.g., initial treatment 
with lower-efficacy agents or very low dose), a dramatic response also can be classified 
as:
a.
Marked improvement with dose increases or marked worsening with dose 
decreases. Mild changes with dose changes do not qualify. This can be 
documented either objectively (defined as >30% in UPDRS III with change in 
treatment), or subjectively with a clear history of marked changes provided by a 
reliable patient or caregiver.
b. Unequivocal and marked on/off fluctuations, which must have at some point 
included predictable end-of-dose wearing off.
Note: To meet this criterion, it is not sufficient to document some beneficial response to 
dopaminergic therapy; the response must be unequivocal and of large amplitude. If 
treatment response is of modest amplitude, the patient does not meet this criterion.  The 
requirement of predictable end-of-dose wearing off is to ensure that these are true 
dopaminergic fluctuations (as opposed to day-to-day variability, for example). The 
documentation of predictable end-of-dose wearing off can be from retrospective history 
(i.e., patients do not have to currently be experiencing predictable fluctuations).
2. Presence of levodopa-induced dyskinesia
3. Rest tremor of a limb, documented on clinical examination (in the past, or on current 
examination).
Note: This is included primarily for two reasons: (1) rest tremor is less common in 
alternate conditions, and (2) rest tremor may occasionally be less responsive to therapy; 
if so, criterion 1 may be harder to meet in tremor-predominant PD.
4. Positive results from at least one ancillary diagnostic test having a specificity greater than 
80% for differential diagnosis of PD from other parkinsonian conditions. Currently 
available tests that meet this criterion include:

Olfactory loss (in the anosmic or clearly hyposmic range, adjusted for age and sex)

Metaiodobenzylguanidine scintigraphy clearly documenting cardiac sympathetic 
denervation
Note: To meet these criteria, the marker must have been demonstrated to provide more 
than 80% specificity in most studies (with a minimum of three studies from different 
centers).


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Appendix 6.
DLB Diagnostic Criteria
Core Clinical Features
Indicative Biomarkers
Fluctuating cognition with pronounced 
variations in attention, and alertness
Reduced dopamine transporter (DaT) uptake in 
basal ganglia via SPECT or PET
Recurrent visual hallucinations
Abnormal 123iodine-MIBG myocardial 
scintigraphy
REM Sleep behavior disorder (RBD)
Polysomnographic confirmation of REM sleep 
without atonia (RBD)
Spontaneous Parkinsonism (at least one of 
bradykinesia, rest tremor, or rigidity)
Probable DLB requires dementia (Dementia should predate, occur concurrently or within 1 year 
of Parkinsonism) plus 2 or more Core Clinical Features OR 1 Core Feature and 1 or more 
Indicative Biomarkers (McKeith et al, 2017).


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Appendix 7.
Protocol Amendment Summary
I7S-MC-HBEH(b) Effect of LY3154207 on Cognition in 
Mild-to-Moderate Dementia Due to Lewy Body Dementia
(LBD) Associated with Idiopathic Parkinson’s Disease 
(PD) or Dementia with Lewy Bodies (DLB) (The 
PRESENCE Study)
Overview
Protocol I7S-MC-HBEH(b) Effect of LY3154207 on Cognition in mild-to-moderate Dementia 
Due to Lewy Body Dementia (LBD) Associated with Idiopathic Parkinson’s Disease (PD) or 
Dementia with Lewy Bodies (DLB) has been amended.  The new protocol is indicated by
amendment (b) and will be used to conduct the study in place of any preceding version of the 
protocol.
The overall changes and rationale for the specific changes made to this protocol are as follows:

Expanded the patient population to include those individuals with DLB with insufficient 
motor symptoms to meet MDS criteria for PD. Previously only subjects with dementia 
who met MDS criteria for PD were included, this allowed for patients with DLB to enroll 
as long as they met the MDS criteria for PD. This is reflected in changes to the title, 
background and inclusion criteria to allow all patients with dementia associated with 
LBD (PD or DLB) to be enrolled.

A secondary safety objective and endpoint are added to evaluate the effect of LY3154207 
on physical withdrawal symptoms by adding PWC-20 checklist. Understanding the 
symptoms associated with study drug withdrawal will help inform drug discontinuation 
strategies.

The addition of a telephone visit 111 (2 days after v11) to Schedule of activities will 
allow for the assessment of early withdrawal symptoms via PWC-20 (approximately 
5 half-lives after last drug dose) when withdrawal symptoms may be maximum with 
minimal additional participant burden.

Eliminate GDS score of ≤6 at screening, to address a common reason for screen failure.
This may also allow us to better assess the impact of LY3154207 on mood and the 
relationship between mood and cognition.

Changes to the duration of stability requirement for certain concomitant medications to 
ensure consistency across medication classes and improve protocol compliance.

The visit 1 duration was updated to 3 to 5 hours split over 1 to 2 days to reflect feedback 
from sites on the actual time to conduct the visit.

Inclusion and exclusion criteria updated to improve compliance and reduce areas of 
confusion.

Editorial changes throughout document to improve clarity.


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Amendment Summary for Protocol I7S-MC-HBEH Amendment (b)
Section # and Name
Description of Change
Brief Rationale
Section 1. Synopsis and Section 4. 
(Objective(s)/Endpoints)
A secondary safety objective and 
endpoint are added.
Objective:  To evaluate the effect of 
LY3154207 on physical withdrawal 
symptoms
Endpoint:  Change in the PWC-20 
total score from Week 12 to in-clinic 
follow-up visit
PWC-20 added to evaluate the 
effect of LY3154207 on physical 
withdrawal symptoms
Section 1. Synopsis (Summary of 
Study Design)
A telephone visit 111 (2 days after 
V11) is added to the schedule of 
activities to assess withdrawal 
symptoms using the PWC-20.
The addition of a telephone visit 
will allow for the assessment of 
early withdrawal symptoms 
(approximately 5 half-lives after last 
drug dose), when withdrawal 
symptoms may be maximum with 
minimal additional participant 
burden. 
Section 1. Synopsis (Number of 
subjects)
Approximate number of subjects to be 
screened changed from 400 to 750
Compared with a predicted screen 
failure rate of 15%, the observed 
rate is approximately 55%. The 
numbers have been adjusted 
accordingly.
Section 1. Synopsis (Withdrawal)
Assessment of withdrawal symptoms 
using the PWC-20 was added at 
visit 11 
Understanding the symptoms 
associated with study drug 
withdrawal will help inform drug 
discontinuation strategies.
Section 1. Synopsis (Interim 
Analysis)
Added language to allow for 
additional efficacy interim analyses,
as deemed necessary for internal 
decision making only.
Modified text to allow flexibility in 
the timing and number of additional 
efficacy interims.
Section 2 Schedule of Activities 
Modified to account for additional 
assesments and visits 
Added to provide instruction
Section 5.1.1. Screening Period 
(Visit 1)
Visit 1 is expected to be of a duration 
of approximately 2 3 to 4 5 hours and 
may be split over 1 to 2 days.
The visit duration was updated to 
reflect feedback from sites on the 
actual time for conducting the visit.
Section 5.1.1.1. Screening 
Procedures
Screening procedures are updated.
Added CDR-CBB training and 
Clinical diagnostic criteria for PDD 
and DLB
As the primary outcome, it is 
critical to ensure that all subjects 
can complete the CDR, in addition, 
the training reduces practice effects.
6.1. Inclusion Criteria
[2] Meet diagnostic criteria for PD 
(Postuma et al. 2015) or DLB 
(McKeith et al. 2017) (See 
Appendix 5 and 6 for details)
Revised to define expanded patient 
population.


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Section # and Name
Description of Change
Brief Rationale
6.2.1. Rationale for Exclusion of 
Certain Study Candidates
CNS diseases and other 
neuropsychiatric disorders (e.g., 
active psychosis, substance abuse) 
that can affect performance on 
cognitive tasks and compliance with 
the protocol are also excluded.
Clarification and modification based 
on changes to inclusion criteria (e.g. 
GDS >6 removed).
9.4.5. Physician Withdrawal 
Checklist
The Penn Physician Withdrawal 
Checklist (PWC-20) is a 20-item 
checklist originally developed to 
assess the severity of withdrawal 
symptoms in anxiolytic medication 
discontinuation (Rickels et al. 2008).
The PWC-20 is a validated, shortened 
version of the original 35-item 
checklist, where the 20 items were 
selected based on their statistical 
ability to differentiate between 
placebo and active drug, plus share 
correlation with the 35-item checklist 
(Schweizer et al. 1990; Rickels et al. 
1990).  The 20 items assess the 
subject’s level of symptoms on a 
variety of withdrawal symptoms since 
last visit.  Each of the 20 items are 
scored as 0 (not present), 1 (mild), 
2 (moderate), 3 (severe)
Description of PWC-20, added per 
previous rationale.


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Revised Protocol Sections
Note:
Deletions have been identified by strikethroughs.
Additions have been identified by the use of underscore.
1. Synopsis
Title of Study:
Effect of LY3154207 on cognition in mild-to-moderate dementia due to Lewy Body Parkinson’s
Disease Dementias (PDDLBD) associated with idiopathic Parkinson’s disease (PD) or dementia 
with Lewy bodies (DLB).
Rationale: 
Eli Lilly and Company (Lilly) is developing LY3154207, an orally available, selective positive 
allosteric modulator (PAM, also called “potentiator”) of the dopamine D1 receptor subtype 
(D1PAM). By increasing the affinity of dopamine for the D1 receptor, a D1PAM is 
hypothesized to amplify response to endogenous dopamine, thereby increasing D1 tone at the 
site of dopamine release, and represents a novel mechanism of action.  By potentiating the 
response to the remaining brain dopamine (or administered levodopa) in subjects with
insufficient physiologic dopamine such as those with LBD (PDD or DLB)PDD and DLB, a 
D1PAM should improve cognitive performance.  In addition, a D1PAM should have a positive 
impact on other domains affected by LBD (PDD or DLB)PDD and DLB including motor 
deficits, mood, apathy, and daytime sleepiness.
 
Study I7S-MC-HBEH (HBEH) is a multicenter, randomized, double-blind, parallel-group, 
placebo-controlled, fixed-dosage, Phase 2a study comparing 3 dosages of LY3154207 (10, 30, or 
75 mg administered orally [or 50 mg based on interim analysis] once a day [QD]) with placebo 
over 12 weeks in subjects with mild-to-moderate dementia associated with LBD (PDD or 
DLB)PDD. Study HBEH will test the hypothesis that LY3154207 administered at 10 mg, 
30 mg, and/or 75 mg daily (or 50 mg based on interim analysis) (QD) oral dosing for 12 weeks 
will result in a significant improvement in cognition in subjects with mild-to-moderate LBD
(PDD or DLB)PDD compared with placebo. Important secondary outcomes will assess the 
effect of LY3154207 on function, parkinsonism, sleep and mood/behavior.
 
 
CCI
CCI


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Objective(s)/Endpoints:
Objectives
Endpoints
Primary
To test the hypothesis that LY3154207 administered at 
10 mg, 30 mg, and/or 75 mg daily (or 50 mg based on 
interim analysis) (QD) oral dosing for 12 weeks will 
result in a significant improvement in cognition in 
subjects with mild-to-moderate LBD (PDD or DLB)
PDD compared with placebo.
Change in the CoA composite score of the CDR-CCB
from baseline to Week 12.
Secondary
Safety:
To evaluate the effect of LY3154207 on acute changes 
of vital signs on the first day of dosing
Number of subjects who met the potentially clinically 
significant vital signs criteria at 3 consecutive time 
points at Visit 3 (Day 1 stopping rules).
To evaluate the effect of LY3154207 on SBP on the first 
day of dosing
Change in in-clinic SBP from 0 up to 8 hours post dose 
on the first day of study drug dosing
To evaluate the effect of LY3154207 on pulse rate on 
the first day of dosing
Change in in-clinic pulse rate from 0 up to 8 hours post 
dose on the first day of study drug dosing
To evaluate the effect of LY3154207 on SBP from 
baseline to Week 12
To evaluate the effect of LY3154207 on pulse rate from 
baseline to Week 12
To evaluate the effect of LY3154207 on physical 
withdrawal symptoms
To evaluate the effect of LY3154207 on motor signs and
behavioral function
To evaluate the effect of LY3154207 on SBP on the first 
day of dosing
To evaluate the effect of LY3154207 on SBP from 
baseline to Week 12
Change in in-clinic mean SBP at baseline to mean SBP 
at Week 12
Change in in-clinic mean pulse rate at baseline to mean 
pulse rate at Week 12
Change in the PWC-20 total score from Week 12 to in-
clinic follow-up visit
Change in total MDS UPDRS (sum of Part I III) and
individual subscales non motor experiences of daily
living (Part I), motor experiences of daily living
(Part II), motor exam (Part III), and motor complications
(Part IV) subscales from baseline to Week 12
Change in in-clinic SBP from 0 up to 8 hours post dose 
on the first day of study drug dosing
Change in in-clinic mean SBP at baseline to mean SBP
at Week 12


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Abbreviations:  ADAS-Cog11 = 11-item Alzheimer’s Disease Assessment Scale – Cognitive subscale;
ADAS-Cog13 = 13-item Alzheimer’s Disease Assessment Scale – Cognitive subscale; CDR-CCB = Cognitive 
Drug Research Computerized Cognition Battery; ADCS–-CGIC = Alzheimer’s Disease Cooperative Study –
Clinician Global Impression of Change; CoA = Continuity of Attention; D-KEFS = Delis–Kaplan Executive 
Function System ; DLB = dementia with Lewy bodies; ESS = Epworth Sleepiness Scale; LBD = Lewy Body 
Dementia; HBPM = home blood pressure monitoring; MDS-UPDRS = Movement Disorder Society’s Unified 
Parkinson’s Disease Rating Scale; MoCA = Montreal Cognitive Assessment; NPI = Neuropsychiatric Inventory; 
PDD = Parkinson’s disease dementia; PDAQ-15 = Penn Parkinson’s Daily Activities Questionnaire-15;
PK = pharmacokinetics; PoA = Power of Attention; PWC-20 = physician withdrawal checklist-20; QD = once a 
day; QUIP = Questionnaire for ’Impulsive-Compulsive Disorders in Parkinson’s Disease; SBP = systolic blood 
pressure.
Summary of Study Design:  Study I7S-MC-HBEH (HBEH) is a multicenter, randomized, 
double-blind, parallel-group, placebo-controlled, fixed-dosage, Phase 2a 2 study comparing 3 
dosages of LY3154207 (10, or 30, or 75 mg administered orally [or 50 mg based on interim 
analysis] once a day [QD]) with placebo over 12 weeks in subjects with mild-to-moderate LBD
(PDD or DLB)PDD.  The study includes a Screening Period (Visits 1 to 2) of a minimum of 
7 days and up to 14 days, a Pretreatment Period of a minimum of 11 days and up to 17 days
(Visits 2 to 3), a 12-week Treatment Period (Visits 3 to 11), and a 14-day Safety Follow-Up 
Period (Visits 11 to 801 or early termination [ET]/discontinuation [DC] visit to Visit 801) that 
includes one telephone visit (Visit 111).  Subjects who meet entry criteria will be randomized in 
a 1:1:1:1 ratio to LY3154207 (10 or 30 or 75 mg QD) or placebo.  The primary objective of the 
study is to test the hypothesis that LY3154207 administration for 12 weeks will result in a 
significant improvement in cognition as measured by the change from baseline to Week 12 in the 
Continuity of Attention (CoA) composite score of the Cognitive Drug Research Computerized 
Cognition Battery (CDR CCB), in subjects with mild to moderate PDD, compared to placebo.
The CoA has demonstrated a significant treatment effect in previous trials in subjects with PDD 
(Wesnes et al. 2005; Rowan et al. 2007).
Number of subjects:  Approximately 400 750 subjects will be screened to achieve 340 
randomized and an estimated total of 85 evaluable subjects per treatment group.
Withdrawal: Withdrawal symptom analyses will be conducted on subjects who completed at 
least one pre-withdrawal and one post-withdrawal PWC-20 checklist.  Week 12/Visit 11 will be 
considered baseline in the change from baseline analyses; Visit 801 will be considered the post 
baseline assessment. This will be examined using an analysis of covariance (ANCOVA) model 
with treatment arm as an independent factor and baseline value as a covariate in the model. This 
will allow us to assess the withdrawal symptoms between treatments and groups.
Interim Analysis:  Safety interim analyses will be conducted on the number of subjects on each 
treatment who met the potentially clinically significant vital signs criteria (Table HBEH.3) at 
3 consecutive time points at Visit 3 (Day 1 stopping rules).  This will be done after 50, 100, and 
150 subjects have completed Visit 3.  
 
 Those 
CCI


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already on 75-mg dose and passed the Day 1 stopping rules will remain on 75 mg.  In the event 
of an unacceptable rate of subjects meeting Day 1 stopping rules at other doses, adjustments to 
doses may be made for subsequently randomized subjects at the discretion of the Internal 
Assessment Committee (IAC).  Additional efficacy analyses may be conducted at the time of 
these safety interim analyses. A safety and efficacy interim analysis will be conducted when 
170 randomized subjects have completed Visit 11 (Week 12) assessments and may also be 
conducted at other timepoints prior to study completion.  All potential efficacy analyses may be 
used for internal decision making, but are not planned to stop the study.


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Procedurea
Screening Pretreatment
Double-Blind Treatment
Follow-up
Unscheduled
Visit
ET/DC 
Visitd,t
Study Day
Min 7 days; 
max 
14 days 
prior to V2
Min 11 days; 
max 17 days 
prior to V3
7 
days
14 
days
21 
days
28 
days
42 
days
56 
days
70 
days
84 
days
2 days 
after V11u
14 days 
from 
V11 or 
ET/DC
Tolerance Interval for 
Visit (Days)
Baseline Visit Randomi
zation
±1
±1
±1
±1
±3
±3
±3
±3
+1
±3
eCRF Visit No.:
V1b,d
V2b,d
V3b
V4d
V5
V6
V7
V8b,d
V9
V10 V11b,d
V111d
V801
V997c
Informed Consent(s) 
Signed (before 
procedures/tests)
X
Register subject in 
IWRS - Subject 
number assigned
X
Complete IWRS
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Demographics
X
Prior/concomitant 
treatment
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Inclusion/exclusion 
criteria
X
X
X
Modified Hoehn and 
Yahr Scale
X
Medical History
X
Physical Examinatione
X
X
X
X
X
Height
X
Weight
X
X
X
X
Orthostatic BP/pulse 
ratef
X
X
Xd
X
X
X
X
X
X
X
X
X
X
X
In-clinic BP/Pulse rate 
monitoringg
X
X
X
X
X
Table HBEH.1.
Schedule of Activities for Protocol I7S-MC-HBEH


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Procedurea
Screening Pretreatment
Double-Blind Treatment
Follow-up
Unscheduled
Visit
ET/DC 
Visitd,t
Study Day
Min 7 days; 
max 
14 days 
prior to V2
Min 11 days; 
max 17 days 
prior to V3
7 
days
14 
days
21 
days
28 
days
42 
days
56 
days
70 
days
84 
days
2 days 
after V11u
14 days 
from 
V11 or 
ET/DC
Tolerance Interval for 
Visit (Days)
Baseline Visit Randomi
zation
±1
±1
±1
±1
±3
±3
±3
±3
+1
±3
eCRF Visit No.:
V1b,d
V2b,d
V3b
V4d
V5
V6
V7
V8b,d
V9
V10 V11b,d
V111d
V801
V997c
Temperature
X
X
X
X
X
12-Lead ECG
X
X
X
X
X
X
Xc
X
Review HBPM
instructionsh
X
X
X
X
X
X
HBPM device returned 
to site
X
X
Hematology
X
X
X
X
X
X
Xc
X
Urinalysis
X
X
X
X
X
X
Xc
X
Clinical Chemistry
X
X
X
X
X
X
Xc
X
Serum FSHi
X
PGx sampling
X
Collection of dose 
administration timing 
(date and time)
X
X
X
X
X
X
X
X
X
X
PK Samplingj
Xj
Xj
Xj
Xj
Xj
Xj
Randomization
X
Study drug dosing at 
site
X
Xk
Xk
Dispense 
Investigational Product
X
X
X
X
X
X
X
X
Return Investigational 
Product
X
X
X
X
X
X
X
X
X
Adverse Events
X
X
X
X
X
X
X
X
X
X
X
X
X
Review Lilly Trial app (if 
available) instructionsl
X
X
X
X
X
X
X
X
X
X


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Procedurea
Screening Pretreatment
Double-Blind Treatment
Follow-up
Unscheduled
Visit
ET/DC 
Visitd,t
Study Day
Min 7 days; 
max 
14 days 
prior to V2
Min 11 days; 
max 17 days 
prior to V3
7 
days
14 
days
21 
days
28 
days
42 
days
56 
days
70 
days
84 
days
2 days 
after V11u
14 days 
from 
V11 or 
ET/DC
Tolerance Interval for 
Visit (Days)
Baseline Visit Randomi
zation
±1
±1
±1
±1
±3
±3
±3
±3
+1
±3
eCRF Visit No.:
V1b,d
V2b,d
V3b
V4d
V5
V6
V7
V8b,d
V9
V10 V11b,d
V111d
V801
V997c
Actigraphy watch
provided to subjects (if 
available)m
X
X
X
Return of Actigraphy 
watch (if available)n
X
X
X
CDR-CCBo,p
X
X
X
X
X
X
X
X
X
X
X
X
X
Alzheimer’s Disease 
Cooperative Study –
Structured Clinical Global 
Impression interviewd
X
X
X
X
ADCS-CGICd
X
X
X
ADAS-Cog13p
X
X
X
X
D-KEFSp
X
X
X
X
MoCAp
X
X
X
X
PDAQ-15d
X
X
X
X
MDS-UPDRSd,p
X
X
X
X
X
NPId
X
X
X
X
ESSd
X
X
X
X
X
X
QUIPd
X
X
X
X
GDS-Sd
X
X
X
PWC-20 (Subject)
X
X
X
X
PWC-20d (Caregiver)
X
X
X
X
C-SSRS – Children’s 
Version and Self-Harm 
Supplement Forms
Xq
Xr
Xr
Xr
Xr
Xr
Xr
Xr
Xr
Xr
Xr
Xr
Xr
Xr


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Abbreviations:  ADAS-Cog13 = Alzheimer’s Disease Assessment Scale – 13-Item Cognitive Subscale; ADCS-CGIC = Alzheimer’s Disease Cooperative 
Study - Clinician Global Impression of Change; BP = blood pressure; CDR-CCB = Cognitive Drug Research Computerized Cognition Battery;
C-SSRS = Columbia-Suicide Severity Rating Scale; DC = discontinuation; D-KEFS= Delis–Kaplan Executive Function System; ECG = electrocardiogram; 
eCOA = electronic Clinical Outcome Assessment; eCRF = electronic case report form; ED = early discontinuation; ESS = Epworth Sleepiness Scale;
ET = early termination; FSH = follicle-stimulating hormone; GDS-S = Geriatric Depression Scale – Short Form; HBPM = home blood pressure monitoring; 
HCG = human chorionic gonadotropin; HEENT = head, ear, eye, nose, and throat; IWRS = interactive web-response system; MDS-UPDRS = Movement 
Disorder Society’s Unified Parkinson’s Disease Rating Scale; MoCA = Montreal Cognitive Assessment; NPI = Neuropsychiatric Inventory; PDAQ-15= Penn 
Parkinson Daily Activities Questionnaire-15; PGx = pharmacogenomic(s); PK = pharmacokinetic(s); PWC-20 = physician withdrawal checklist-20;
QUIP = Questionnaire for Impulsive-Compulsive Disorders in Parkinson’s Disease; V = visit.
Note:  Be sure that the visit allowance period takes into account the required washout duration needed for medications that are not allowed by the protocol.
a
Every effort should be made for visits to occur on designated study days.  The overall treatment period in the protocol should be maintained (visits should be 
scheduled based on the randomization visit).  Procedures and assessments should be done in the order described in the Operations Manual.
b
Visit 1 may be split over 2 days. In exceptional circumstances, if the clinical assessments cannot be completed within 1 day at V1, V2, V3, V8, and/or V11, 
those clinical assessments may be completed the next day.  The Orthostatic Blood pressure measurements, in-Clinic Blood pressure measurements, the CDR-
CCB, and the laboratory procedures including PK have to be completed on Day 1 of that visit. The visit interval will start from Day 1.
c
ECGs or samples for clinical laboratory tests (hematology, clinical chemistry, and urinalysis) will only be collected if a retest is needed.  All other procedures 
are required for each unscheduled visit.
d
The caregiver is required to attend Visit 1 at the clinic to sign the informed consent and be informed about the study details.  Caregiver’s attendance will also 
be required at Visit 2, Visit 4, Visit 8, Visit 11, Visit 801, and the ET/DC visit to provide inputs for the PDAQ-15, ADCS-CGIC, GDS-S, MDS-UPDRS, NPI, 
ESS, and QUIP scales. The caregiver is required at Visit 11,and Visit 111 and Visit 801 to provide input for the PWC-20.
e
Medical history should include timing of onset of cognitive symptoms relative toand of motor symptoms (less or equal to 1 year).
fe The physical examination should include HEENT, cardiac, lung, abdomen, extremity, skin, and neurological examinations.
gf Orthostatic BP/pulse rate will be measured as part of the vital sign assessments at every visit. At Visit 2, Visit 3, Visit 8, Visit 11, and Visit 801, these
measurements will be collected at time 0 of the in-clinic BP/pulse rate monitoring.  Subjects will have 3 BP/pulse rate measurements taken in the seated 
position approximately 1 minute apart followed by 1 BP/pulse rate measurement taken in the standing position. Subjects should be seated for at least 
5 minutes and stand for at least 3 minutes prior to taking the respective measurements.  If the subject feels unable to stand, vital signs only in the seated 
position will be recorded.
h
The subject’s orthostatic BP and pulse rate measurements must meet inclusion criteria [6] for the subject to proceed with dosing at Visit 3.  Subjects not 
fulfilling inclusion criteria [6] can have their BP/pulse rate re evaluated within 3 days of Visit 3.  If inclusion criteria [6] is subsequently met (within 3 days of 
Visit 3), the subject may proceed with dosing.  If inclusion criteria [6] is subsequently not met (within 3 days of Visit 3), the subject must be discontinued 
from the study.


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ig In-clinic BP and pulse rate monitoring will be done at Visit 2, Visit 3, Visit 8, Visit 11, and Visit 801.  The BP and pulse rate measurements will occur at 
time 0 and every 60 minutes thereafter at Visit 2, Visit 8, and Visit 11, in-clinic BP and pulse rate will be monitored for up to 6 hours; at Visit 3,  for up to 
8 hours and at Visit 801 for up to 2 hours..    The initial measurement, time 0 of the in-clinic BP and pulse rate monitoring, will be done as an orthostatic 
BP/pulse rate (refer to footnote c above), and subsequent BP and pulse rate measurements will be done in the seated position only.  Time 0 for Visit 3, Visit 8,
and Visit 11 will occur just prior to study drug dosing.  At Visit 3, drug dosing should be initiated immediately following confirmation that subject meets 
inclusion criteria [6].  At Visit 2, Visit 8, and Visit 11, in clinic BP and pulse rate will be monitored for up to 6 hours; at Visit 3,  for up to 8 hours and at 
Visit 801 for up to 2 hours.
jh The subject should be given the HBPM device at Visit 2.  Home BP will be measured twice daily in the seated position using the HBPM equipment provided 
by Eli Lilly and Company (Lilly).  Home BP measurements will should be conducted for a minimum of 7 days between Visit 2 and Visit 3, for 3 weeks 
between Visit 3 and Visit 6, and for a minimum of 7 days between Visit 10 and Visit 11, and Visit 11 and Visit 801.  Home BP will should be measured twice 
in the morning (approximately 1 minute apart) (e.g., 8 AM) immediately following study medication dosing and twice in the evening, approximately 12 hours 
later (approximately 1 minute apart) (e.g., 8 PM).
k
The subject should return the HBPM device at Visit 801 or at ET/DC visit, if subject is discontinued early.
l
Laboratory tests to be performed by the central vendor.
mi Refer to inclusion criteria [12e] in Section 6.1.
nj PK sampling. At Visit 3, a PK sample is to be collected within 1 to 3 hours after the drug is administered at the site.  At Visit 4, Visit 5, Visit 8, and ET/DC
visit, the PK sample can be collected at any time during the visit.  At Visit 11, the PK sample should be collected prior to the drug being administered at the 
site.  The date and time of the PK sample collection as well as the date and time of the dose administration immediately preceding the PK sampling should be
entered in the eCRF.
o
First dose to be administered at the clinic on the morning of Visit 3 following the Time 0 in clinic BP/pulse rate measurements.  The subject’s initial in clinic 
BP/pulse rate measurements taken in the seated position must meet inclusion criteria [6] for the subject to proceed with dosing.  Subjects not fulfilling 
inclusion criteria [6] can have their BP/pulse rate re evaluated within 3 days of Visit 3.  If inclusion criteria [6] is subsequently met (within 3 days of Visit 3), 
the subject may proceed with dosing.  If inclusion criteria [6] is subsequently not met (within 3 days of Visit 3), the subject must be discontinued from the 
study.
pk Study drug dose to be administered at the clinic on the morning of Visit 8 and Visit 11 following the Time 0 in-clinic BP/pulse rate measurements.
ql An iPad® configured with the Lilly Trial application (Lilly Trial app) will be provided to the subjects at Visit 2 (if available).  Subjects will should complete 
assessments from 2 weeks prior to dosing (starting the day following Visit 2), throughout the dosing period, and for 2 weeks after the conclusion of the 
treatment period (until Visit 801).  This assessment will should be done up to twice daily. Subjects will self-select for this optional component of the protocol 
at Visit 1.  Subjects can decide to opt out at any time during the study. In case of opt-out or ET, the subject should return the iPad to the site at the visit 
following the subject opt-out or at the ET/DC visit.  For subjects who complete the Lilly trial application assessments throughout the study, the iPad should be 
returned at Visit 801.  Refer to the Operations Manual for details about Opt-in and Opt-out process.
rm The actigraphy device (if available) will should be worn on the wrist, similar to a watch, beginning at Visit 2, for 3 separate 2-week periods of time:  Visit 2 to
Visit 3, Visit 8 to Visit 9, and Visit 11 to Visit 801.  The site will provide the device to the subjects at Visits 2, 8, and 11.
sn Following 14 days of wearing the device, the subject will should bring the device back to the site at the next scheduled visit (Visit 3, Visit 9, or Visit 801).


I7S-MC-HBEH(b) Clinical Protocol
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to CDR-CCB:  At least 2 training sessions are required at Visit 1. At each visit, the CDR-CCB should be assessed after the study drug has been dosed. At 
Visit 4, Visit 5, Visit 6, Visit 7, Visit 9, and Visit 10, if a subject has ’not taken the study drug prior to the study visit, the subject must take study drug at the 
site prior to the CDR-CCB is assessed.
up The CDR-CCB, MoCA, ADAS-Cog13, MDS-UPDRS (Part III), and D-KEFS scales should be conducted in the practically defined medication “on” state at 
all visits.  The “on” state is defined as the individual best motor function as determined by the investigator or approximately 1 hour after the dose of 
dopaminergic therapy.  Every attempt should be made to conduct these assessments in the “on” state.  In the exceptional circumstance that this is not possible, 
the assessments could be done in the “off” state.  The “on/off” state should be confirmed prior to completion of the respective scales listed above.  This 
information will be collected in the eCOA or the eCRF. If any portion of an assessment is done in the “off” state, then that subject should be rated as in the 
“off” state for the whole assessment. If the subject is not on dopaminergic therapy the assessment should be documented as “on”.
vq The C-SSRS “Baseline” version will be used at the Screening visit (Visit 1).
wr The C-SSRS “Since Last Visit” scale will be administered at each subsequent visit.
xs If, based on administration of the C-SSRS, it is determined that suicide-related behaviors have occurred, then the Lilly Self-Harm Follow-Up form will be 
used to collect additional information to allow for a more complete assessment of these behaviors.
yt All subjects who discontinue study treatment prior to a scheduled visit should have an ET/DC visit and procedures/assessments performed as soon as possible.
zu  If the visit window falls on a weekend/holiday then the visit should be conducted at the next possible day.


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3.2. Background
Lewy Body Dementia (LBD), including Parkinson’s disease dementia (PDD) and DLB, is a
progressive neurodegenerative disorder associated with alpha-synuclein deposition, Lewy body 
pathology, and degeneration of nigro-striatal dopaminergic neurons.  According to the 
Parkinson’s Disease Foundation, Parkinson’s disease (PD) affects approximately 1 million 
people in the United States (U.S.) and 7 to 10 million people worldwide (Statistics on 
Parkinson’s). It is estimated that up to 78% of of patients with PD will develop dementia (PDD) 
in their lifetime (Aarsland et al.2005).  DLB is the second most common dementia after 
Alzheimer’s disease (AD) and affects 1.4 million individuals in the U.S., representing an 
estimated 15-20% of all dementia cases worldwide (Lewy Body Dementia Association 
[https://www.lbda.org/go/10-things-you-should-know-about-lbd ).  
LBD is pathologically characterized by intraneuronal inclusions of Lewy bodies throughout 
subcortical and cortical brain regions, a major component of which is misfolded aggregated 
α-synuclein (Beyer et al. 2009).  Lewy body formation and propagation is accompanied by 
progressive neurodegenerative processes, particularly affecting the dopaminergic and cholinergic 
neurons (Harding and Halliday 2001; Klein et al. 2010; Colloby et al. 2012).  These 
neuropathological findings are largely indistinguishable between DLB and PDD and have thus 
led the field to consider them the same disease. 
The cognitive impairments of PDD and DLB also overlap. Progressive executive dysfunction 
and visual-spatial abnormalities are noted in both, but memory remains relatively intact early in 
the course of disease (Lippa et al. 2007).  Prodromal and non-motor features are similar for both 
conditions and include REM sleep behavior disorder, hyposmia, prominent visual hallucinations, 
fluctuations in arousal, autonomic dysfunction, and depression/anxiety.  They share 
neuroimaging characteristics with overlapping patterns of atrophy, glucose utilization, and 
neurotransmitter changes (cortical cholinergic deficits [Colloby et al. 2016] and striatal/cortical 
dopaminergic deficits [Klein et al. 2010]).  Although once considered as two separate entities,
the constellation of supportive pathological, clinical, imaging, and neurochemical data suggest 
PDD and DLB fall within a spectrum of the same disease (Berg et al. 2014; Gomperts 2016; 
Friedman 2018; Jellinger 2018; Jellinger and Korczyn 2018). 
Because of the dopaminergic fronto-striatal dysfunction and cholinergic deficits associated with 
LBD [Klein et al. 2010], LY3154207, a D1PAM, is a hypothesized mechanism to treat the 
cognitive deficits of the disorder. LY3154207 increases the affinity of dopamine for the D1 
receptor, thus amplifying the response to endogenous dopamine and increasing D1 tone when 
and where dopamine is released.  By potentiating the response to the remaining brain dopamine
(or administered L-DOPA), a D1PAM should improve cognitive performance through enhancing 
frontal dopaminergic neurotransmission.  In addition to facilitating dopamine neurotransmission, 
LY3154207 may be effective in improving cognitive dysfunction through activation of cortical 
neurons, markers of synaptic plasticity, and D1 mediated enhanced acetylcholine 
neurotransmitter release.  Other potential effects such as reduced daytime sleepiness, enhanced 
motor function, improved mood, and goal-directed behaviors leading to reduced apathy (via 
activation of cortical and striatal D1 receptors) would also be beneficial in LBD.  


I7S-MC-HBEH(b) Clinical Protocol
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4. Objectives and Endpoints
Objectives
Endpoints
Primary
To test the hypothesis that LY3154207 administered at 
10 mg, 30 mg, and/or 75 mg daily (or 50 mg based on 
interim analysis) (QD) oral dosing for 12 weeks will 
result in a significant improvement in cognition in 
subjects with mild-to-moderate LBD (PDD or 
DLB)PDD compared with placebo.
Pharmacokinetics
To assess the PK of LY3154207 in a population of 
subjects with mild to moderate dementia due to 
Parkinson’s disease
Change in the CoA composite score of the CDR-CCB
from baseline to Week 12
Steady-state trough plasma concentrations of 
LY3154207 at Week 12
Secondary
Safety:
To evaluate the effect of LY3154207 on physical 
withdrawal symptoms 
Change in the PWC-20 total score from Week 12 to in-
clinic follow-up visit
Abbreviations: DLB = dementia with Lewy bodies; LBD = Lewy Body Dementia; PWC-20 = physician withdrawal 
checklist-20
5.1 Overall Design
Study HBEH is a multicenter, randomized, double-blind, parallel-group, placebo-controlled, 
fixed-dosage, Phase 2a study comparing 3 dosages of LY3154207 (10, 30, or 75 mg 
administered orally [or 50 mg based on interim analysis] once a day [QD]) with placebo over
12 weeks in subjects with mild-to-moderate dementia associated with LBD (PDD and 
DLB)PDD.  The study includes a Screening Period (Visits 1 to 2) of a minimum of 7 days and 
up to 14 days, a Pretreatment Period of a minimum of 11 days and up to 17 days (Visits 2 to 3), a 
12-week Treatment Period (Visits 3 to 11), and a 14-day Safety Follow-Up Period including a 
telephone visit (Visit 11 + 2 days) and Visit 801 or early termination [ET]/discontinuation [DC]
(Visits 11 to 801). Subjects who meet entry criteria will be randomized in a 1:1:1:1 ratio to 
LY3154207 (10 or 30 or 75 mg QD) or placebo.  The primary objective of this study is to test the 
hypothesis that LY3154207 administration for 12 weeks will result in a significant improvement 
in cognition as measured by the change from baseline to Week 12 on the Continuity of Attention 
(CoA) composite score of the Cognitive Drug Research Computerized Cognition Battery 
(CDR-CCB), in subjects with mild-to-moderate dementia associated with LBD (PDD and 
DLB)PDD, compared to placebo.  Treatment effects with acetylcholinesterase inhibitors in LBD
(PDD and DLB) subjects have been demonstrated using the CDR (Wesnes et al. 2005; Rowan et 
al. 2007, McKeith et al 2000).The Continuity of Attention (CoA) has demonstrated a significant 
treatment effect in previous trials in subjects with PDD and is resistant to learning and placebo 
effects.


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5.1.1.1. Screening Procedures
Screening, entry and administrative procedures, cognitive and physical assessments, vitals, safety 
assessments, and laboratory assessments (see Schedule of Activities) are to be performed at 
Visit 1. For subjects treated with dopaminergic treatment for parkinsonism symptoms, the 
CDR-CCB and MoCA should be conducted in the practically defined medication “on” state.  
The “on” state is defined as the individual’s best motor function as determined by the 
investigator or approximately 1 hour after the dose of dopaminergic therapy.  Every attempt 
should be made to conduct these assessments in the “on” state.  In the exceptional circumstance 
that this is not possible, the assessments could be done in the “off” state.  The “on/off” state 
should be confirmed prior to completion of the respective scales listed above.  This information 
will be collected in the electronic Clinical Outcome Assessment (eCOA) or the electronic case 
report form (eCRF).  If any portion of an assessment is done in the “off” state, then that subject 
should be rated as in the “off” state for the whole assessment. Subjects NOT on dopaminergic 
therapy should be recorded as being in the “on” state for the purpose of analysis.
Medical history should include the diagnosis, whether PDD or DLB, and the timing of onset of 
dementia and Parkinson’s symptoms and date of diagnosis if applicable. Additionally, the 
relationship of the onset of dementia relative ofto motor symptoms will be assessed. Subjects 
without motor symptoms should report their dementia as occurring prior to motor symptoms.
The physical examination should include head, ear, eye, nose, and throat (HEENT), cardiac, 
lung, abdomen, extremity, skin, and neurological examinations.
5.1.1.1.1. BP and Pulse Rate
Subjects should have a BP or pulse rate at Visit 1 and Visit 3 (time 0), as determined by 
3 sequential BP/pulse rate measurements in the seated position:

Subjects <60 years old:
o
a mean systolic blood pressure (SBP) less than or equal to 
140 mmHg, a mean diastolic BP less than or equal to 90 mmHg, 
and a mean pulse rate less than or equal to 90 beats/min in the 
seated position.
o
each of the 3 SBP measurement must be less than 180 mmHg.

Subjects ≥60 years old:
o
a mean SBP less than or equal to 150 mmHg, a mean diastolic BP 
less than or equal to 90 mmHg, and a mean pulse rate less than or 
equal to 90 beats/min in the seated position.
o
each of the 3 SBP measurement must be less than 180 mmHg.
5.1.1.1.2. CDR-CBB
At Visit 1, two training sessions of the CDR-CBB will be administered to familiarize subjects 
with the instrument and to minimize practice effects. Subjects must be able to complete both 


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training sessions in order to be considered eligible for HBEH.  Scores on the CDR-CCB at V1 
will not be included in the analysis unless the baseline (V2) scores are incomplete or missing and 
then V1 scores may be used for calculation of the baseline. 
5.1.1.1.3.
Modified Hoehn and Yahr Scale
Enrolled individuals must be Hoehn and Yahr Stage 1 to Stage 4 at screening.  The Hoehn and 
Yahr Scale (Hoehn and Yahr 1967) is used to describe the symptom progression of PD.  The 
scale was originally described in 1967 and included Stages 1 through 5.  It has since been 
modified with the addition of Stages 1.5 and 2.5 to account for the intermediate course of PD.  
The modified Hoehn and Yahr scale is as follows:

Stage 0:  No signs of disease

Stage 1:  Unilateral disease

Stage 1.5:  Unilateral plus axial involvement

Stage 2:  Bilateral disease, without impairment of balance

Stage 2.5:  Mild bilateral disease, with recovery on pull test

Stage 3:  Mild-to-moderate bilateral disease; some postural instability; physically 
independent

Stage 4:  Severe disability; still able to walk or stand unassisted

Stage 5:  Wheelchair bound or bedridden unless aided
5.1.1.1.4.
Clinical Diagnostic Criteria for PD and DLB
Subjects must meet diagnostic criteria for either PD or DLB. 
PD Criteria: Subjects should meet MDS criteria for clinically probable PD (Postuma et al. 
2015) as detailed in Appendix 5. Subjects must have parkinsonism as defined by the presence of 
bradykinesia with either rest tremor and/or rigidity.  Subjects must not have any absolute 
exclusion criteria.  Subjects must not have greater than 2 red flags; if 1 red flag is present then it
must be offset by 1 supportive criterion and if 2 red flags are present it must be offset by 2 
supportive criteria.  The MDS criteria does not have a criterion for the timing of dementia onset 
and therefore subjects may be considered PD whether the timing of dementia occurred prior to, 
concurrently or after parkinsonism. See Appendix 5 for the detailed list of absolute exclusion 
criteria, red flags and supportive criteria.
DLB Criteria:  Subjects should meet the Fourth consensus report of the DLB Consortium 
diagnostic criteria for probable DLB (McKeith et al. 2017) as detailed in Appendix 6.  In 
addition to dementia, subjects must have 2 or more of the 4 core clinical features of DLB 
(fluctuation in cognition, visual hallucinations, REM sleep behavior disorder and/or 
parkinsonism).  Subjects with 1 core feature are eligible if they also have at least 1 indicative 
biomarker as detailed in Appendix 6.  Typically, a diagnosis of DLB is made when dementia 
onset occurs before, concurrently, or in absence of parkinsonism.  There is no minimal 
requirement for parkinsonism in subjects with DLB, who otherwise meet this criteria.  See 
Appendix 6 for the detailed list of core features and indicative biomarkers.


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Section 5.1.1.1.5
Montreal Cognitive Assessment Scale
The MoCA will be administered to subjects in Visit 1 to determine if he or she meets entry 
criteria for dementia. Enrolled iIndividuals must have a MoCA score of 10 to 23 at screening to 
be eligible for the study.  The MoCA, included here as a screening cognitive assessment, is 
described in detail in Section 9.1.2.1.5.
Section 5.1.1.1.6.
Geriatric Depression Scale Short Form
Enrolled individuals must have a Geriatric Depression Scale Short Form (GDS S) score of ≤6 
at screening.  The GDS is a site-administered questionnaire of depression in older adults 
(Yesavage et al. 1983).  Users respond in a “Yes/No” format.  Originally developed as a 30-item 
scale (Long Form), it has since been shortened to a 15-item scale (Short Form), which can be 
completed in approximately 5 to 7 minutes (Sheikh and Yesavage 1986).  Of the 15 items, 10 are 
indicative of depression when answered “Yes” and 5 are indicative of depression when answered 
“No.” Caregiver’s input may be needed at Visit 1 for the Geriatric Depression Scale – Short form 
(GDS-S).
Section 5.1.1.1.7.
Columbia-Suicide Severity Rating Scale – Children’s Version
The C-SSRS is a scale that captures the occurrence, severity, and frequency of suicide-related 
thoughts and behaviors during the corresponding assessment period.  The C-SSRS, included here 
as a screening assessment, is described in detail in Section 9.4.4.   The C-SSRS “Baseline” 
version will be used at screening, and the findings will constitute the baseline assessment.
The C-SSRS will be administered to the patient with the study partner/study informant present or 
available by telephone, after the cognitive and functional assessments. Responses from both the 
study partner/study informant and patient will be considered when administering the scale. If a 
suicide-related thought or behavior is identified at any time during the study, a thorough 
evaluation will be performed by a study physician, and appropriate medical care will be 
provided. 
The Lilly Self-Harm Supplement should be completed every time the C-SSRS is administered.  
If, based on administration of the C-SSRS, it is determined that suicide-related behaviors have 
occurred, then the Lilly Self-Harm Follow-Up form will be used to collect additional information 
to allow for a more complete assessment of these behaviors.The C SSRS will be administered to 
the subject after the cognitive and functional assessments.  Responses from subject will be 
considered when administering the scale.  If it is determined that the subject has suicidal ideation 
or behavior at this baseline assessment, then the subject will not be randomized and will be 
discontinued from the study.


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Figure HBEH.1.
Illustration of study design for Clinical Protocol I7S-MC-HBEH(b).
5.1.2.1 Blood Pressure and Pulse Rate Measures
Orthostatic BP/pulse rate measurements will be collected at time 0 of the in-clinic BP/pulse rate 
monitoring.  Subjects will have 3 BP/pulse rate measurements taken in the seated position 
approximately 1 minute apart followed by 1 BP/pulse rate measurement taken in the standing 
position.  Subjects should be seated for at least 5 minutes and stand for at least 3 minutes prior to 
taking the respective measurements.  If the subject feels unable to stand, vital signs only in the 
seated position will be recorded.
In-clinic BP and pulse rate measurements will occur at time 0 and every 60 minutes thereafter up 
to 8 hours. The initial measurement, time 0 of the in-clinic BP and pulse rate monitoring, will be 
done as an orthostatic BP/pulse rate (refer to orthostatic BP/pulse rate above), and subsequent BP
and pulse rate measurements will be done in the seated position only.
5.1.2.2. Cognitive, Motor, and Functional Assessments
For subjects treated with dopaminergic therapy for parkinsonism symptoms,The following 
assessments (CDR-CCB, Alzheimer’s Disease Assessment Scale – 13-Item Cognitive Subscale
[ADAS-Cog13], Movement Disorder Society’s Unified Parkinson’s Disease Rating Scale 
[MDS-UPDRS] [Part III]) and Delis–Kaplan Executive Function System (D-KEFS) 
assessments) should be conducted in the practically defined medication “on” state.  The “on” 


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state is defined as the individual’s best motor function as determined by the investigator or 
approximately 1 hour after the dose of dopaminergic therapy.  Every attempt should be made to 
conduct these assessments in the “on” state.  In the exceptional circumstance that this is not 
possible, the assessments could be done in the “off” state.  The “on/off” state should be 
confirmed prior to completion of the respective scales listed above.  This information will be 
collected in the eCOA or the eCRF.  If any portion of an assessment is done in the “off” state, 
then that subject should be rated as in the “off” state for the whole assessment. Subjects NOT on 
dopaminergic therapy should be recorded as being in the “on” state for the purpose of analysis.
5.1.2.3 Actigraphy and iPAD Device
The actigraphy device, similar to a watch, will be placed on the wrist of the subject at Visit 2 (if 
available and if consented), similar to a watch for the 2-week periods of time until Visit 3 (see 
Section 9.8.1.2 and the Operations Manual).
An iPad configured with the Lilly Trial application (Lilly Trial app) will be provided to the 
subjects (if available and if consented) (see Section 9.8.1.1 and the Operations Manual).  
Subjects should complete assessments starting the day following Visit 2, throughout the dosing 
period, and for 2 weeks after the conclusion of the treatment period (until Visit 801).  This 
assessment should be done up to twice daily.
5.1.2.4 Home Blood Pressure Monitoring
The subject should be given the home blood pressure monitoring (HBPM) device at Visit 2 and 
instructed to measure Home BP twice daily in the seated position using the HBPM equipment 
provided by Lilly for a minimum of 7 days between Visit 2 and Visit 3.  Home BP will should be 
measured twice in the morning (approximately 1 minute apart) (e.g., 8 AM) immediately 
following study medication dosing and twice in the evening, approximately 12 hours later 
(approximately 1 minute apart) (e.g., 8 PM).
An iPad configured with the Lilly Trial application (Lilly Trial app) will be provided to the 
subjects (if available) (see Section 9.8.1.1 and the Operations Manual).  Subjects will complete 
assessments starting the day following Visit 2, throughout the dosing period, and for 2 weeks 
after the conclusion of the treatment period (until Visit 801).  This assessment will be done up to 
twice daily.
5.1.3. Double-Blind Period (Visit 3 through Visit 11)
All study procedures for the respective visits are should to be completed within 1 day.  In 
exceptional circumstances, if the clinical assessments cannot be completed within 1 day at V3, 
V8, and/or V11, those clinical assessments may be completed on the next day.  The orthostatic 
blood pressure measurements, in-clinic blood pressure measurements, the CDR-CCB, and the 
laboratory procedures including PK have tomust be completed on Day 1the first day of that visit.  
The visit interval will start from Day 1the first day of visit.


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Visit 3 (Day 1 of dosing) -
5.1.3.1 Orthostatic BP/Pulse Rate Measurements
Prior to dosing, Oorthostatic BP/pulse rate measurements will be collected at time 0 of the 
in-clinic BP/pulse rate monitoring.  Subjects will have 3 BP/pulse rate measurements taken in the 
seated position approximately 1 minute apart followed by 1 BP/pulse rate measurement taken in 
the standing position.  Subjects should be seated for at least 5 minutes and stand for at least 
3 minutes prior to taking the respective measurements.  If the subject feels unable to stand, vital
signs only in the seated position will be recorded.
The mean should be calculated from of the 3 initial in-clinic BP/pulse rate measurements taken 
in the seated position, and must meet inclusion criteria [6] in order to proceed with dosing
(Table HBEH.4).  At Visit 3, Ssubjects not fulfilling inclusion criteria [6] at their time 0 
BP/pulse rate measurements can have their BP/pulse rate re-evaluated within 3 days.  If inclusion 
criteria [6] is subsequently met (within 3 days of Visit 3), subject may proceed with dosing.  If 
inclusion criteria [6] is subsequently not met (within 3 days of Visit 3), the subject must be 
discontinued.  Subjects who continue to meet entry criteria will be randomized to LY3154207 
(10, 30, or 75 mg QD) or placebo immediately following confirmation that subject meets
inclusion criteria [6].  Subjects should be dosed immediately after randomization.
The time 0 mean BP and pulse rate will be used for the baseline measurement to assess the 
change threshold for the development of potentially clinically significant BP/pulse rate. 
After time 0, in-clinic BP and pulse rate measurements will be taken every 60 minutes in the 
seated position only for up to 8 hours.  Subjects who meet potentially clinically significant 
BP/pulse rate measurement (Table HBEH.3) at 3 consecutive timepoints (Day 1 stopping rules) 
should be discontinued from the study. 
Table HBEH.3.
Potentially Clinically Significant Vital Sign Criteria


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Table HBEH.4.
Vital Sign Inclusion Criteria [6] for Subjects at Visit 1 and Visit 3 
(time 0)
Subjects <60 Years 
Subjects ≥60 Years
Mean Systolic BPa (mm Hg)
≤140
≤150
Mean Diastolic BP (mm Hg)
≤90
≤90
Mean Pulse Rate (bpm)
≤90
≤90
a
Each of the 3 SBP measurement must be less than 180 mmHg
5.1.3.2. PK Sample
A PK sample is to be collected within 1 to 3 hours after the drug is administered at the site.  The 
date and time of the PK sample collection as well as the date and time of the dose administration 
immediately preceding the PK sampling will be entered in the eCRFrecorded.
5.1.3.3. Home Blood Pressure Monitoring
The subject should be instructed to take Home BP measurements twice daily in the seated 
position using the HBPM equipment provided by Lilly for a minimum of 7 days between Visit 3
and Visit 4.  Home BP shouldwill be taken twice in the morning (approximately 1 minute apart) 
(e.g., 8 AM) immediately following study medication dosing and twice in the evening, 
approximately 12 hours later (approximately 1 minute apart) (e.g., 8 PM).
Appointments should be made for all remaining visits and should be scheduled as close as 
possible to the target date, relative to Visit 3.
5.1.3.4. Visit 4 to Visit 11
During the double blind period, vVisits will occur at weekly intervals (7 days ± 1 day) for Visit 4
through Visit 7, and will occur at biweekly intervals (14 days ± 3 days) for Visit 8 through 
Visit 11.
Study drug is to be administered at the clinic on the morning of Visit 8 and Visit 11 following 
the Time 0 in-clinic BP/pulse rate measurements.
In-clinic BP/pulse rate monitoring at Visit 8 and Visit 11 will be conducted as described in 
Section 5.1.2.
At each visit, the CDR-CCB should be assessed after the study drug has been administered. At 
Visit 4, Visit 5, Visit 6, Visit 7, Visit 9, and Visit 10, if a subject has not taken study drug prior to
the study visit, the subject must take study drug at the site prior to the CDR-CCB assessment.  
MoCA, ADAS-Cog13, MDS-UPDRS [Part III], and D-KEFS will be performed according to the 
Study Schedule.  


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Caregiver’s inputs will be needed at Visit 4, Visit 8, Visit 11, or ET/ DC for the PDAQ-15, 
Alzheimer’s Disease Cooperative Study – Clinician Global Impression of Change 
(ADCS-CGIC), MDS-UPDRS, NPI, ESS, GDS-S, and/or QUIP scales.  Caregiver’s input, 
separate from the subject, will be needed at Visit 10 (in person or via telephone) and Visit 11, 
Visit 111 and Visit 801 for the PWC-20 early termination.
5.1.4. Telephone Visit (Visit 111)
A telephone visit will be conducted 2 days following Visit 11.  The PWC-20 will be assessed 
with the subject and caregiver, separately, at this telephone visit.
5.1.5. Follow-Up Period (Visit 801)
A follow-up visit will be performed at Visit 801, which will occur 14 days ± 3 days following 
the subject’s last dose of study medication.
Visit 801 is expected to be of a duration of approximately 2 hours.
Caregiver’s inputs will be needed at Visit 801 for MDS-UPDRS, PWC-20, and ESS.
See the Schedule of Activities (Section 2) for the timing of events and the measures to be 
assessed during the follow-up period.
The CDR CCB assessment should be conducted in the practically defined medication “on” state.  
The “on” state is defined as the individual’s best motor function as determined by the 
investigator or approximately 1 hour after the dose of dopaminergic therapy.  Every attempt 
should be made to conduct this assessment in the “on” state.  In the exceptional circumstance 
that this is not possible, the assessment could be done in the “off” state.  The “on/off” state 
should be confirmed prior to assessment completion of the respective scale listed above.  This 
information will be collected in the eCOA or the eCRF.  If any portion of the assessment is done 
in the “off” state, then that subject should be rated as in the “off” state for the whole assessment.
5.2. Number of Subjects
Approximately 400 750 subjects will be screened to achieve 340 randomized and evaluable 
subjects for an estimated total of 85 evaluable subjects per treatment group.
5.3. End of Study Definition
End of the study is the date of the last visit or last scheduled procedure shown in the Schedule of 
Activities (Section 2) for the last subject.
5.4. Scientific Rationale for Study Design
Study HBEH will include subjects who meet the revised MDS criteria for PD (Postuma et al. 
2015) or those who meet the revised criteria for DLB, and all who have mild-to-moderate 
dementia as defined by a decline in cognitive function, which in the opinion of the investigator 
has resulted in functional impairment and a MoCA score between 10 and 23 (Trzepacz et al. 
2015).  Per the revised MDS criteria, PDD can be diagnosed in the presence of dementia, 
regardless of the timing of dementia onset relative to PD diagnosis.  Subjects diagnosed with 


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dementia with Lewy bodies (DLBs) should be considered as also having PD if they meet the 
MDS PD criteria.  Therefore, subjects may have dementia prior to, at the time of, or subsequent 
to the diagnosis of PD.  Unlike registration trials of symptomatic therapies in PDD (Emre et al. 
2004), the current study will include some subjects who would otherwise have met the traditional 
criteria (dementia prior to or within 1 year of motor onset) for DLB based on the timing of their 
dementia (Mckeith et al. 2005).  This criterion was that the dementia occurs prior to or within 
1 year of Parkinson’s symptoms.  The 1 year rule is arbitrary and based on the historical belief 
that PD was not associated with dementia; however, there is increasing controversy about the 
validity of this traditional approach to splitting the diagnoses (Berg et al. 2014).  In support of 
the proposed approach, both disorders share a variety of clinical, genetic, and pathological 
features (Lippa et al. 2007; Postuma et al. 2009; Johansen et al. 2010).  Both DLB and PDD are 
associated with similar impairments in cognition with predominant visuoperceptual 
abnormalities, improvement in memory with cues, and so on.  Both are associated with 
prominent psychosis, neuroleptic sensitivity, and alterations in arousal.  Prodromal features (e.g., 
rapid eye movement [REM] sleep behavior disorder, olfactory loss) are the same in both 
conditions.  Non motor symptoms with depression, anxiety, autonomic dysfunction and sleep 
disturbances occur with similar relative frequency in both.  The same genetic mutations 
(alpha synuclein duplications, glucocerebrosidase mutations) are associated with the 
development of either condition.  Finally, they have a shared pathology with alpha synuclein and 
Lewy body formation in the brain stem and cortex.  Therefore,The inclusion of LBD (PDD or
DLB)both PDD and DLB the Studyin HBEH meets current thinking about LBD PDD and DLB
that, apart from the timing of cognitive impairment, PDD and DLB are clinically and 
pathologically indistinguishable and would likely respond to similar therapeutic approaches 
(Aarsland et al. 2004; Ballard et al. 2006).
6.1. Inclusion Criteria
Study HBEH will include men and women aged 40 to 85 years with mild to moderate PDD.  
Subjects are eligible to be included in the study only if they meet all of the following criteria
(note that inclusion criteria [6] to [10] must be met or at an additional visits):
Type of Subject and Disease Characteristics
[1]
Male and female subjects aged 40 to 85 years (inclusive).
[45] Meet diagnostic criteria for PD (Postuma et al. 2015) or DLB (McKeith et al. 
2017) (See Appendix 5 and 6 for details)
[2]
Have idiopathic PD per MDS criteria (Postuma et al. 2015) with at least 
2 years of PD symptoms.
[5]
Are Modified Hoehn and Yahr Stages 1 0 to 4.
[6]
Have a BP or pulse rate at Visit 1 and Visit 3 (time 0), as determined by 3
sequential BP/pulse rate measurements in the seated position:


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[7]
If on anti-parkinsonian agents, subjects must be on stable dosage for at least 4
3 weeks prior to Visit 1 2, and it is anticipated that no changes will be 
neededshould remain on stable doses during the course of the study.
[8]
If on medications affecting cognition (rivastigmine, galantamine, donepezil, 
memantine), subjects must be on stable dosage for at least 8 3 weeks prior to 
Visit 2 1 and expected toshould remain at a stable dosage during the course of 
the study.
[9]
If on antidepressant medications, subjects must be on stable dosage for at least 
8 3 weeks prior to Visit 2 1 and expected toshould remain at a stable dosage 
during the course of the study.
[10] If on clozapine, quetiapine, and pimavanserin to address drug-induced or 
disease-related psychosis, subjects must be on stable dosage for 3 4 weeks 
prior to Visit 12 and expected to remain at a stable dosage during the course 
of the study.
[11] If on antihypertensive medications, subjects must be on stable dosage for at 
least 3 months3 weeks prior to Visit 1.
[12c] Men with pregnant partners should use condoms during intercourse for the
duration of the study and until the end of estimated relevant potential exposure 
in WOCBP (below the NOAEL/10) plus 903 days following the last dose of 
study drug).
[12d] Men should refrain from sperm donation for the duration of the study and
until their plasma concentrations are below the level that could result in a
relevant potential exposure to a possible fetus, predicted to be 930 days
following the last dose of study drug (below the NOAEL/10) plus 90 days.
[13] In the investigator’s opinion is able to comply with all appointments for clinic
visits, tests, and procedures, including venipuncture, computerized 
assessments and examinations required by the protocol.
[16] All subjects must have a reliable caregiver who is in frequent contact with the
subject (defined as at least 10 hours per week) and will accompany the subject
to Visit 1, Visit 2, Visit 4, Visit 8, Visit 11, Visit 111 (telephone only) and 
Visit 801.
6.2. Exclusion Criteria
[21] Have significant central nervous system or psychiatric disease, other than PD
or DLB, that in the investigator’s opinion may affect cognition or the ability to 
complete the study.may affect cognition or the ability to complete the study, 
including but not limited to other dementias (e.g., Alzheimer’s disease [AD]).
[27] Have a current or any previous diagnosis of bipolar disorder, schizophrenia, or 
other primary psychotic disorder. Exclusion criterion [27] has been deleted.


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[28] Have poorly controlled psychosis (hallucinations or delusions) that in the 
opinion of the investigator would interfere with the subject’s ability to be 
compliant with the study protocol. Exclusion criterion [28] has been deleted.
[29] Have any other psychiatric disorder that, in the judgment of the investigator, 
would interfere with compliance with the study protocol. Exclusion criterion 
[29] has been deleted.
[31] Have a GDS S score of >6 at Visit 1. Exclusion criterion [31] has been 
deleted.
[32] Have a serious or unstable medical illness, other than idiopathic LBD (PDD or
DLB)PDD, including cardiovascular, hepatic, respiratory, hematologic, 
endocrinologic, neurologic, or renal disease, or clinically significant 
laboratory or electrocardiogram (ECG) abnormality as determined by the 
investigator.
[36] Have used anticholienergics trihexyphenidyl and benztropine in the 4 weeks 
prior to screening (Visit 1) and at any time during the course of the study.
[38] Are currently takingHave taken any medications or food, herbal or dietary 
supplements that are inhibitors (e.g., ketoconazole, grapefruit juice), or 
strong/moderate inducers of cytochrome P450 3A4 (CYP3A4) (e.g., 
rifampicin) or are unable or unwilling to discontinue usage of them 4 weeks 
prior to Visit 3. If subjects are willing and able to discontinue use of CYP3A4 
inhibitors or strong/moderate inducers at least 4 weeks prior to Visit 3, they 
may proceed in the study.  Refer to the Operations Manual for a full list of 
inhibitors and inducers of CYP3A4.
[43] Are Lilly employees, employees of Quintiles IMSIQVIA, or employees of a 
third party organization involved in the conduct of the study.
[44] Are unwilling or unable (e.g., visually impaired or physically unable) to 
comply with the use of a data collection device (e.g., HBPM, eCOA, 
CDR CCB) to directly record data from the subject. Exclusion criterion [44] 
has been deleted.
6.2.1. Rationale for Exclusion of Certain Study Candidates
CNS diseases and Depression affects approximately 50% of subjects with PD and can affect 
cognitive performance that may confound the analysis of cognitive outcomes.  Therefore, 
subjects with active depression will be excluded.  Oother neuropsychiatric disorders (e.g., active 
psychosis, substance abuse) that can affect performance on cognitive tasks and compliance with 
the protocol are also excluded.
Medications that negatively affect cognition (e.g., certain anticholinergics, exclusion criteria 
#36) and motor function (e.g., certain antipsychotics, exclusion criteria #35) will be excluded, 
given the potential of these medications to confound clinically relevant outcomes.


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6.3. Lifestyle Restrictions
Subjects should be instructed not to donate blood or blood products during the study or for 
930 days following the last dose (below the NOAEL/10) plus 90 days of LY3154207.  Male 
subjects should be instructed to not donate sperm during the study for 930 days following the last 
dose of LY3154207.
6.4. Screen Failures
Individuals who do not meet the criteria for participation in this study (screen failure) may be 
rescreened once.  The interval between the initial screening and the rescreen should be at least 
4 weeks.  When the subject is rescreened, the subject must sign a new ICF, and be assigned a 
new subject identification number, and undergo all screening procedures.
7.2 Method of Treatment Assignment
Selection and Timing of Doses
The doses will should be administered at approximately the same time each day in the morning.  
At Visit 3, Visit 8, and Visit 11, the dose will be administered at the clinic.  The actual date and 
time of the dose administrations on the day of Visit 3, Visit 4, Visit 5, Visit 8, Visit 11, and 
ET/DC visit will be recorded in the subject’s eCRF.
7.3. Blinding
If an investigator, site personnel performing assessments, or subject is unblinded, the subject
must be discontinued from the study.  In cases where there are ethical reasons to have the subject 
remain in the study, the investigator must obtain specific approval from a Lilly clinical research 
physician (CRP) for the subject to continue in the study.
In case of an emergency, the investigator has the sole responsibility of determining if unblinding 
of a subject’s treatment assignment is warranted for medical management of the event.  The 
subject’s safety must always be the first consideration in making such a determination. Every 
effort should be made to notify Lilly Medical representative prior to unblinding if feasible. If the 
investigator decides that unblinding is warranted, it is the responsibility of the investigator to 
promptly document the decision and rationale and notify Lilly as soon as possible.
7.6. Treatment Compliance
Subject compliance with study medication will be assessed at each visit.  Compliance will be 
assessed by counting returned capsules.  Deviation(s) from the prescribedCapsules dispendsed 
and returned dosage regimen should be recorded in the CRF.
7.7. Concomitant Therapy
Concomitant medications to treat the underlying PD (known as antiparkinsonian agents) are 
permitted, provided the subject has been on a stable dosage regimen for at least 4 3 weeks prior 
to Visit 1 2, and is expected toshould remain on a stable dosage for the duration of the study.  


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Routine medications taken PRN are allowed.  However, if in the investigator’s opinion PD 
medications need to be adjusted to manage motor symptoms during the course of the study, the 
reason for change in medication should be recorded as an AE and the concomitant medication 
eCRF page updated accordingly. In addition, the study sponsor should be notified as soon as 
feasible and a notification generated.
In addition to medications for PD, drugs for common conditions in an older population, such as 
hypertension, hypercholesterolemia, and ischemic heart disease, are acceptable at stable dosages. 
Specifically, antihypertensive medications should be stable for 3 months prior to screening (V1)3
weeks prior to V1. During the course of the study, antihypertensive medications may be 
adjusted for medical need.  The concomitant medication eCRF page should be updated 
accordingly and if applicable the reason for change in medication should be recorded as an AE.
Concomitant medications to treat cognition (rivastigmine, galantamine, donepezil, memantine)
and depression are permitted, if subjects have been on a stable dosage regimen for at least 
8 3 weeks prior to Visit 2 1 and is expected toshould remain on a stable dosage for the duration 
of the study.  Concomitant medications to treat psychosis (clozapine, quetiapine, and 
pimavanserin) are permitted, provided the subject has been on a stable dosage regimen for at 
least 4 3 weeks prior to Visit 2 1 and is expected toshould remain on a stable dosage for the 
duration of the study.  However, if in the investigators opinion cognitive and antipsychotic 
medications need to be adjusted during the course of the study to address a clinical change, the 
reason for change in medication should be recorded as an AE and the concomitant medication 
eCRF page updated accordingly.  In addition, the Lilly CRP or designee must be contacted as 
soon as possible to determine whether the subject should continue in the study.
Subjects and their caregiver will should be instructed to consult the investigator or otherwith the 
appropriate study personnel at the site prior to initiation of any new medications or supplements 
and prior to changing dose or discontinuing fromof any current concomitant medications or 
supplements.
Table HBEH.4.
Prohibited Concomitant Medications and Supplements
Drug Class
Allowed 
as 
Needed
Chronic 
Use 
Allowed
Conditions for Use
All inhibitors of CYP3A4
N
N
Topical may be permitted
Strong/moderate inducers of CYP3A4
N
N
Topical may be permitted
Antipsychotics (except clozapine, quetiapine, and
pimavanserin)
N
N
Trihexyphenidyl and benztropine
N
N
Illicit use of any drugs of abuse
N
N
Abbreviations: CYP3A4 = cytochrome P450 3A4; N = No.
Additional information about concomitant medications is provided in the Operations ManualA 
complete list of prohibited concomitant medications and supplements is included in the 
Operations Manual.


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8.1.1. Permanent Discontinuation from Study Treatment
Possible reasons leading to permanent discontinuation of study treatment:

Subject Decision
o
the subject or the subject’s designee, for example, parents or legal guardian,
requests to discontinue the investigational product.

Day 1 stopping rules - Discontinuation due to change in acute vital signs on – Day 1 
(Visit 3) (Day 1 stopping rules)
(Day 1 of dosing)
If during Day 1 (Visit 3) and following of study drug dosing, any of the potentially 
clinically significant vital signs criteria (Table HBEH.3) are met at 3 consecutive time 
points using in-clinic vital sign monitoring, then the subject should be discontinued from 
the study drug.  The relative value of the potentially clinically significant vital sign 
criteria is calculated by comparing to the mean of the 3 seated blood pressure and pulse 
rate at Time 0 of Visit 3 (baseline).
Table HBEH.5.
Potentially Clinically Significant Vital Sign Criteria
For vital sign measurements that meet the criteria for potentially clinically significant 
vital signs (Table HBEH.3) after Visit 3, management will be left to the discretion of the 
investigator and may include discontinuation of study drug.  Prior to study drug 
discontinuation after Visit 3, theThe investigator should consult with the Lilly CRP or 
designee.

Discontinuation due to a hepatic event or liver test abnormality
Subjects who are discontinued from the study due to a hepatic event or liver test abnormality 
should have additional hepatic safety data collected via CRF/electronic data entryeCRF.
Subjects discontinuing from the study treatment prematurely for any reason should complete an 
early termination visit and safety follow-up (V801) to complete AE and other follow-up 


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procedures per Section 2 (Schedule of Activities), Section 9.2 (Adverse Events) and Section 9.4
(Safety).
8.1.2. Temporary Discontinuation from Study Treatment
Temporary discontinuation from study drug treatment is allowed if a short-term treatment of an 
excluded medication is necessary, secondary to hospitalization, personal circumstances, or to 
evaluate the study drug impact on an uncertain AE. Study drug may be restarted at the 
investigator’s discretion. If temporary discontinuation is due to an AE, it should be reported to 
the Lilly CRP or their representative. Temporary treatment discontinuation and restarting should 
be documented in the eCRF. Restarting treatment after a discontinuation period that is greater 
than 3 consecutive days should be discussed between the investigator and Lilly CRP or their 
representative.
8.1.3. Discontinuation of Inadvertently Enrolled Subjects
If the sponsor or investigator identifies a subject who did not meet enrollment criteria and was 
inadvertently enrolled, then the subject should be discontinued from study treatment unless there 
are extenuating circumstances that make it medically necessary for the subject to continue on 
study treatment. However, if the investigator and the sponsor CRP agree that it is medically 
appropriate to continue in the study, the investigator must obtain documented approval from the 
sponsor CRP to allow the inadvertently enrolled subject to continue in the study with or without 
treatment with the investigational product.
If the subject is discontinued from the study, the subject should complete an early termination 
visit and safety follow-up (V801) to complete safety follow-up as outlined in Section 2
(Schedule of Activities), Section 9.2 (Adverse Events), and Section 9.4 (Safety).
8.2 Discontinuation from the Study
Subjects discontinuing from the study prematurely for any reason should complete an early 
termination visit and safety follow-up (V801), to complete must complete AE and other safety 
follow-up per Section 2 (Schedule of Activities), Section 9.2 (Adverse Events), and Section 9.4
(Safety).
9.1.1. Primary Efficacy Assessments
The CoA component of the CDR-CCB has been selected as the primary endpoint for this study 
because it measures the ability to sustain concentration and has demonstrated a significant 
treatment effect in previous trials in subjects with LBD (PDD or DLB) within the time frame of 
the current study (Wesnes et al. 2005; Rowan et al. 2007).  The battery is a simple “yes/no” 
computerized assessment that is feasible across a range of PD motor impairment, and as the CoA 
score is based on accuracy but not speed of response, it is resistant to confounding due to motor 
impairment (Wesnes et al. 2002).  The CDR-CCB is not dependent on skill of a rater, and hence 
there is less inter-rater variability; learning effects can be minimized with training and it targets 


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domains relevant to subjects with LBD (PDD and DLB). The CDR CCB, described below, has 
been widely used in dementia research for more than 25 years.  The CoA component of the 
CDR CCB, which includes attention, concentration, and vigilance assessments, will be used as 
the primary efficacy measure in this study.  Treatment effects with acetylcholinesterase 
inhibitors in LBD (PDD and DLB) subjects have been demonstrated using the CDR (Wesnes et 
al. 2005; Rowan et al. 2007, McKeith et al 2000)The CoA composite score reflects the ability to 
sustain concentration and has demonstrated a significant treatment effect in previous trials in 
PDDsimilar populations subjects (Wesnes et al. 2005; Rowan et al. 2007).  The CoA is 
calculated from the CDR-CCB by summing the number of correct responses in the digit 
vigilance and choice reaction time tasks and then subtracting the number of digit vigilance false 
alarms.
The CDR CCB should be assessed in the practically defined medication “on” state at all visits.  
The “on” state is defined as the individual best motor function as determined by the investigator 
or approximately 1 hour after the dose of dopaminergic therapy.  Every attempt should be made 
to conduct this assessment in the “on” state.  In the exceptional circumstance that this is not 
possible, the assessment could be done in the “off” state.  The “on/off” state should be confirmed 
prior to assessment completion of the respective scales listed above.  This information will be 
collected in the eCOA or the eCRF.  If any portion of the assessment is done in the “off” state, 
then that subject should be rated as in the “off” state for the whole assessment.
9.1.2.1.3. Alzheimer’s Disease Assessment Scale – 13-Item Cognitive Subscale
The ADAS Cog13 should be conducted in the practically defined medication “on” state at all 
visits.  The “on” state is defined as the individual’s best motor function as determined by the 
investigator or approximately 1 hour after the dose of dopaminergic therapy.  Every attempt 
should be made to conduct this assessment in the “on” state.  In the exceptional circumstance 
that this is not possible, the assessment could be done in the “off” state.  The “on/off” state 
should be confirmed prior to assessment completion of the respective scales listed above.  This 
information will be collected in the eCOA or the eCRF.  If any portion of the assessment is done 
in the “off” state, then that subject should be rated as in the “off” state for the whole assessment.
9.1.2.1.4. Delis-Kaplan Executive Function System
The D-KEFS verbal fluency has shown a significant response (p<.001) to rivastigmine therapy in 
a 24-week randomized controlled trial in subjects with PDD (Emre et al. 2004).  The D-KEFS 
verbal fluency test is preferred as a measure of executive function in PDD because it is not 
confounded by motor deficits.  This specific measure of executive function, a domain commonly 
affected in LBD (PDD and DLB)PDD, will complement other measures of cognition included in 
Study HBEH that do not adequately assess this domain.
The D KEFS should be conducted in the practically defined medication “on” state at all visits.  
The “on” state is defined as the individual best motor function as determined by the investigator 
or approximately 1 hour after the dose of dopaminergic therapy.  Every attempt should be made 
to conduct this assessment in the “on” state.  In the exceptional circumstance that this is not 
possible, the assessment could be done in the “off” state.  The “on/off” state should be confirmed 


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prior to assessment completion of the respective scales listed above.  This information will be 
collected in the eCOA or the eCRF.  If any portion of the assessment is done in the “off” state, 
then that subject should be rated as in the “off” state for the whole assessment.
9.1.2.1.5. Montreal Cognitive Assessment Scale
The MoCA (available at www.mocatest.org) was developed as a brief screening instrument for 
mild cognitive impairment and mild AD to address limitations of the Mini-Mental State 
Examination (MMSE) (Nasreddine et al. 2005).  The MoCA has been identified as a suitable 
screening instrument for the detection of cognitive impairment in PD (Hoops et al. 2009) and 
DLB (McKeith et al. 2017).  Since development, it has been increasingly utilized to detect 
cognitive impairment in subjects with PD. The MoCA is divided into 7 subscores (maximum
possible subscore):
Use of MoCA in the context of PD to screen for subjects with cognitive impairment is consistent 
with the Parkinson Study Group (PSG) Cognitive/Psychiatric Working Group and MDS 
recommendations; although, due to limitations of data for the MoCA on change over time or 
change with treatment, the PSG only reviewed the scale in the context of trials where executive 
functioning was not a primary outcome (Chou et al. 2010; Litvan et al. 2012).  The MoCA has 
consistently demonstrated higher sensitivity than the MMSE for the detection of mild cognitive 
impairment in various subject populations including PD and DLB (Nasreddine et al. 2005; 
Smith et al. 2007, Zadikoff et al. 2008; Olson et al. 2011; Freitas et al. 2012; Biundo et al. 2016; 
Wang et al. 2013).  Using a cut-off score of less than or equal to 26 as a predictor of cognitive 
impairment, results from the MoCA identified from 52% to 83% of subjects with PD who had 
already been identified as having mild cognitive impairment (Smith et al. 2007; Hoops et al. 
2009; Nazem et al. 2009).  A MoCA score of 26 or less has also provided excellent 
discrimination between subjects who had mild cognitive impairment and those who did not 
(receiver operating characteristic curve analyses 78% to 90%; sensitivity 90%; specificity 75% 
(Dalrymple-Alford et al. 2010).  Satisfactory test–retest reliability and inter-rater reliability have 
been demonstrated (interclass correlation coefficients 0.79 and 0.81, respectively) (Gill et al. 
2008).  Additionally, good correlation between the MoCA and a neuropsychological battery 
(assessing the domains of memory and executive function) was observed (coefficient of 0.72)
(Gill et al. 2008).
The MoCA should be conducted in the practically defined medication “on” state at all visits.  
The “on” state is defined as the individual best motor function as determined by the investigator 
or approximately 1 hour after the dose of dopaminergic therapy.  Every attempt should be made 
to conduct this assessment in the “on” state.  In the exceptional circumstance that this is not 
possible, the assessment could be done in the “off” state.  The “on/off” state should be confirmed 
prior to completion of the respective scales listed above.  This information will be collected in 
the eCOA or the eCRF.  If any portion of the assessment is done in the “off” state, then that 
subject should be rated as in the “off” state for the whole assessment.


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9.1.2.1.6. Penn Parkinson’s Daily Activities Questionnaire-15
The PDAQ-15 is a 15-item measure of instrumental activities of daily living (IADL) that is 
impacted by cognitive impairment in subjects with PDD.  The PDAQ-15 is derived from the 
original 50-item scale, which has demonstrated test–retest reliability, construct validity, 
sensitivity, and specificity to PD cognitive impairment (Brennan et al. 2016a, 2016b), and the 
questionnaire is completed by the caregiver. The score range is 0 to 60, with higher scores 
indicating better function. It is derived from a larger 50-item scale that demonstrates excellent 
test–retest reliability and construct validity, and is both sensitive and specific in PD cognitive 
impairment.  The PDAQ-15 demonstrates ability to discriminate between cognitively normal, 
mild cognitive impairment, and dementia in PD, and correlates with global measures of 
cognition (dementia rating scale) and performance-based functional measures. The PDAQ-15 
will provide a disease-specific assessment of the effect of LY3154207 on cognitive IADL in 
order to understand the relationship between change in cognition and change in IADL in PDD
and DLB.
9.1.2.2.1. Movement Disorder Society’s United Parkinson’s Disease Rating Scale
The MDS UPDRS (Part III) should be conducted in the practically defined medication “on” state 
at all visits.  The “on” state is defined as the individual best motor function as determined by the 
investigator or approximately 1 hour after the dose of dopaminergic therapy.  Every attempt 
should be made to conduct this assessment in the “on” state.  In the exceptional circumstance 
that this is not possible, the assessment could be done in the “off” state.  The “on/off” state 
should be confirmed prior to completion of the respective scales listed above.  This information 
will be collected in the eCOA or the eCRF.  If any portion of the assessment is done in the “off” 
state, then that subject should be rated as in the “off” state for the whole assessment.
9.1.2.3. Measures of Behavioral Symptoms Associated with Parkinson’s Disease 
Dementia
The following measures will serve as tools to assess the impact of LY3154207 on behavioral 
symptoms associated with LBD (PDD and DLB)PDD as well as the effects on motor functions.
9.1.2.3.1. Neuropsychiatric Inventory
The NPI assessment results will be recorded on worksheets or direct data entry.
9.1.3. Appropriateness of Efficacy Assessments
As previously stated, the CoA has demonstrated a significant treatment effect in previous trials in 
PDD subjectssimilar populations (Wesnes et al. 2005; Rowan et al. 2007).  The CoA is a 
parameter calculated using the CDR-CCB, which has been widely used in dementia research for 
more than 25 years.  Because it is a computerized assessment system, the CDR-CCB has low 
inter-rater variability.  Two training sessions in a single day have demonstrated an ability to 
minimize learning effects up to 8 weeks (Wesnes, personal communication).  The CDR-CCB 
system also has a large normative database of over 6000 healthy volunteers from 18 to 87 years 


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of age, thereby making it possible to detect both the level of cognitive impairment present in 
subjects prior to treatment and the effect of treatment on cognitive changes (Wesnes 2008).
The secondary efficacy measures described in Section 9.1.2 are also established measures of 
cognitive function and related outcomes, as well as behavioral symptoms associated with PD 
dementia and DLB, and considered appropriate assessments for the mild to moderate PD 
dementia populationthis population.
9.2.1. Serious Adverse Events
Investigators are not obligated to actively seek AEs or SAEs in subjects once they have 
discontinued and/or completed the study (the patient’s final study dispositionsubject summary
CRF has been completed).  However, if the investigator learns of any SAE, including a death, at 
any time after a subject has been discharged from the study, and he/she considers the event 
reasonably possibly related to the study treatment or study participation, the investigator must 
promptly notify Lilly.
9.3. Treatment of Overdose
For this study, any dose of investigational product greater than twice participant’s assigned daily 
dose within a 24-hour time period will be considered an overdose.
In the event of an overdose, the investigator or treating physician should use supportive therapy 
as necessary and contact the Clinical Research Physician (or designee) immediately.
Decisions regarding dose interruptions or modifications will be made by the investigator in 
consultation with the CRP based on the clinical evaluation of the participant.
Refer to the LY3154207 IB.
9.4.1. Electrocardiograms
Electrocardiograms will initially be interpreted by a qualified physician healthcare provider (the 
investigator or qualified designee) at the site as soon after the time of ECG collection as possible, 
and ideally while the subject is still present to determine whether the subject meets entry criteria
at the relevant visit(s) and for immediate subject management, should any clinically relevant 
findings be identified.
9.4.5. Physician Withdrawal Checklist
The Penn Physician Withdrawal Checklist (PWC-20) is a 20-item checklist that will be used to 
assess the presence and severity of withdrawal symptoms.  The PWC-20 should be assessed on 
the subject and caregiver, separately.  The scale was originally developed to assess the severity 
of withdrawal symptoms in anxiolytic medication discontinuation (Rickels et al. 2008).  The 
PWC-20 is a validated, shortened version of the original 35-item checklist, where the 20-items 
were selected based on their statistical ability to differentiate between placebo and active drug 
plus share correlation with the 35-item checklist (Schweizer et al. 1990; Rickels et al. 1990).  
The 20 items assess the subject’s level of symptoms on a variety of withdrawal symptoms since 
last visit.  Each of the 20 items are scored as 0 (not present), 1 (mild), 2 (moderate), 3 (severe).


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9.5. Pharmacokinetics
At the visits and times specified in the Schedule of Activities (Section 2), venous blood samples
will be collected to determine the plasma concentrations of LY3154207.  Instructions for the 
collection and handling of blood samples will be provided by the sponsor.  At Visit 3, a PK 
sample is to be collected within 1 to 3 hours after the drug is administered at the site.  At Visit 4, 
Visit 5, Visit 8, and ET/DC, the PK sample can be collected at any time during the visit.  At 
Visit 11, the PK sample should be collected prior to the drug being administered at the site.  The 
date and time (24-hour clock time) of the PK sample collection as well as the date and time of 
the dose administration immediately preceding the PK sampling will be entered in the 
eCRFrecorded.
9.7.1. Whole Blood Sample for Pharmacogenetic Research
The collection and storage of samples for genetic studies (including samples for 
pharmacogenetic studies) is to continue our ongoing efforts to understand the correlation 
between the clinical outcome with the drug(s) under study in the clinical trial and the genetic 
makeup of the subject.  DNA extracted from the whole blood samples collected from the subjects 
may be used to generate genetic data on a genome genotyping array. The genotype data may be 
used to perform a targeted genetic analysis of the genes of interest to understand potential safety 
and efficacy concerns should they arise either during this trial, future trials for this drug, or if the 
drug is launched and on the market. For example, genetic variations in well-known 
drug-metabolizing enzymes, such as cytochrome P450 (CYP), including CYP3A4, CYP1A2, and 
so on, could be a potential set of genes of interest to answer any safety concerns.
Samples will not be used to conduct unspecified disease or population genetic research either 
now or in the future.  Samples may be used to investigate variable response to LY3154207 and to 
investigate genetic variants thought to play a role in PDLBD.  Assessment of variable response 
may include evaluation of AEs or differences in efficacy.
10.1. Sample Size Determination
Approximately 400 750 subjects may be screened in order that 340 subjects are randomized in
the study. 
 
If the true 
effect size for LY3154207 relative to placebo on the CoA is 0.4 with the sample size of 340 there 
will be over 80% probability of passing this criterion. A 20% discontinuation rate by Week 12 
has been accounted for in the sample size determination.
10.2. Populations for Analyses
Population
Description
Entered Enrolled
All subjects who sign informed consent
CCI


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10.3.2.4. Concomitant Therapy
Prior medications are defined as those that stop before randomization (Visit 32). Concomitant
medications are defined as those being taken on or after randomization (Visit 32).  A summary of
concomitant medications will be presented as frequencies and percentages for each treatment
group. If the start or stop dates of therapies are missing or partial to the degree that 
determination cannot be made as to whether the therapy is prior or concomitant, the therapy will 
be deemed concomitant.
10.3.3.2 Secondary Efficacy Analyses
The secondary efficacy outcomes (ADCS-CGIC, PDAQ-15, ADAS-Cog13, CDR-CCB PoA, 
D-KEFS, MoCA, NPI, ESS, and MDS-UPDRS) will be assessed at the 12-week time point as 
the primary analysis.  Each of these secondary endpoints will be analyzed using an MMRM 
model, which will include terms for: baseline value, treatment, visit, and the relevant interaction 
terms.  Further covariates may be included such as age, site, and the severity of PD motor 
function as well as severity of dementia at baseline as appropriate.  The change of the score from 
baseline will be the dependent variable.  If subscores for a particular scale are deemed clinically 
relevant to analysis, it will be completed as an exploratory analysis.
10.3.3.3. Tertiary/Exploratory Efficacy Analyses
The following exploratory efficacy endpoints will be analyzed using MMRM model.

Change in total MDS-UPDRS (sum of Parts I to III) and individual subscales –
non-motor experiences of daily living (Part I), motor experiences of daily living 
(Part II), motor exam (Part III), and motor complications (Part IV) subscales from 
baseline to Week 12

Change in GDS-S score from screening to Week 12

Change in QUIP score from baseline to Week 12
Exploratory Digital Biomarker Analysis:  Data from digital biomarkers (Lilly Trial app and 
Actigraphy watch) from baseline to Week 12 will be explored using appropriate visual, 
univariate, and multivariate methods to understand the relationship of the biomarker endpoints to 
other clinical endpoints in terms of treatment effect.  The data may also be used to explore the 
validity and reliability of these assays in PDD LBD subjects.  If applicable, potential predictive 
biomarkers associated with interpretable clinical benefit may further be examined with biological 
evidence.
10.3.4.3. Vital Signs and Weight

Day 1 (Visit 3) in-clinic BP and pulse rate change post first dose


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Change in in-clinic BP and pulse rate from 0 up to 8 hours postdose measured on the first 
day of study drug dosing will be analyzed using an MMRM analysis with baseline value, 
treatment, time postdose (hours), and the relevant interaction terms.  Two baselines will 
be considered:  the Visit 3 pretreatment value (time 0) and the time-matched baselines 
from Visit 2 (hourly value 0 to 6 hours).  For the second of these, there is no 
time-matched value for the 7- and 8-hour time points of Visit 3, so the 6-hour time point 
of Visit 2 will be used as their baseline value.  A separate change from baseline analysis 
will be completed for each baseline approach.

Change in in-clinic BP and pulse rate from baseline (Visit 2, predrug) up to Week 12 
(V11)
Change in in-clinic BP and pulse rate measured at Visit 2 (daily average 0 to 6 hours) to 
the in-clinic BP and pulse rate measured at Week 6/Visit 8 and Week 12/Visit 11 (daily 
average 0 to 6 hours) will be analyzed by an MMRM model with baseline value, 
treatment, and the relevant interaction terms.  Analysis at 6 weeks will help to evaluate 
any significant changes (if any) in BP and pulse rate earlier than 12 weeks (end of study) 
and if they accommodate by 6 weeks.

Daily average change in home BP measurements and pulse rate from baseline to 
Week 12.
10.3.4. Safety Analyses
The PWC-20 endpoint will be analyzed using an ANCOVA model with a covariate for baseline 
score. The primary analyses will be a change from baseline (Visit 11) to the in person follow up 
visit (Visit 801).
10.3.6.1. Subgroup Analyses
The CDR-CCB CoA and its component scores will be assessed based on the following 
subgroups: concomitant PD therapy, concomitant AChEI therapy, Land timing of dementia 
onset (less or equal to 1 year versus greater than 1 year relative to onset of motor symptoms LBD
(PDD or DLB), and GDS (less than or equal to 6)). All subgroup analyses will be considered 
exploratory and additional subgroup analyses may be performed as suggested by the data.
10.3.7 Interim Analyses
A limited number of pre-identified individuals may gain access to the limited unblinded data, as 
specified in the unblinding plan.  Information that may unblind the study during the analyses will 
not be reported to study sites or blinded study team until the study has been unblinded.
The efficacy and safety interim analyses will be completed and reviewed by an IAC.


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Only the IAC is authorized to evaluate unblinded interim efficacy and safety analyses.  Study 
sites will receive information about interim results ONLY if they need to know for the safety of 
their subjects.
Safety interims will be conducted on the number of subjects on each treatment who met the 
potentially clinically significant vital signs criteria at 3 consecutive time points at Visit 3 (Day 1 
stopping rules).  This will be done after 50, 100, and 150 subjects have completed Visit 3.   
 
  Those already on 75-mg dose and passed the 
Day 1 stopping rules will remain on 75 mg.  In the event of an unacceptable rate of subjects 
meeting Day 1 stopping rules at other doses, adjustments to doses may be made for subsequently 
randomized subjects at the discretion of the IAC.  Additional efficacy analyses may be 
conducted at the time of these safety interim analyses or as needed to inform internal decision 
making.
A safety and efficacy interim analysis will be conducted when 170 randomized subjects have had 
the opportunity to complete Visit 11 (Week 12) assessments.  The statistical analysis will include 
all 170 subjects in the interim analysis, which will evaluate both the efficacy and the safety.  In 
addition, the PK data may be reviewed.  An additional interim analysis of efficacy and safety 
may be conducted prior to study completion for internal decision making. While Aall potential
efficacy analyses may be used for internal decision making, but they are not planned to stop the 
study for efficacy or futility because this is an exploratory study and there are other key 
endpoints being assessed, not just the primary endpoint.
CCI


Leo Document ID = cfa0b6c1-d553-4c3f-9316-73c00b4eef9a
Approver: 
Approval Date & Time: 25-Jan-2019 16:25:11 GMT
Signature meaning: Approved
Approver: 
Approval Date & Time: 25-Jan-2019 21:17:45 GMT
Signature meaning: Approved
PPD
PPD

SAP_001.pdf: 
Statistical Analysis Plan Version 3 I7S-MC-HBEH 
 
Effect of LY3154207 on Cognition in Mild-to-Moderate Dementia Due to Lewy Body Dementia 
(LBD) Associated with Idiopathic Parkinson’s Disease (PD) or Dementia with Lewy Bodies (DLB)  
 
 
NCT03305809 
 
Approval Date: 08-Feb-2021 
 
 
 


I7 S -M C -H B E H St ati sti c al A n al y si s Pl a n V er si o n 3
P a g e 1
L Y 3 1 5 4 2 0 7
1.
St ati sti c al A n al y si s Pl a n:
I 7 S-M C -H B E H : Eff e ct of L Y 3 1 5 4 2 0 7 o n C o g niti o n
i n Mil d-t o-M o d er at e D e m e nti a D u e t o L e w y B o d y 
D e m e nti a ( L B D) A s s o ci at e d wit h I di o p at h i c P ar ki n s o n’ s 
D i s e a s e ( P D) or D e m e nti a wit h L e w y B o di e s ( D L B)
C o nfi d e nti al I nf or m ati o n
T h e i nf or m ati o n c o nt ai n e d i n t hi s d o c u m e nt i s c o nfi d e nti al a n d t h e i nf or m ati o n c o nt ai n e d 
wit hi n it m a y n ot b e r e pr o d u c e d or ot h er wi s e di s s e mi n at e d wit h o ut t h e a p pr o v al of Eli Lill y 
a n d C o m p a n y or it s s u b si di ari e s.
N ot e t o R e g ul at or y A ut h oriti e s : T hi s d o c u m e nt m a y c o nt ai n pr ot e ct e d p er s o n al d at a 
a n d/ or c o m m er ci all y c o nfi d e nti al i nf or m ati o n e x e m pt fr o m p u bli c di s cl o s ur e. Eli Lill y a n d 
C o m p a n y r e q u e st s c o n s ult ati o n r e g ar di n g r el e a s e/r e d a cti o n pri or t o a n y p u bli c r el e a s e. I n 
t h e U nit e d St at e s, t hi s d o c u m e nt i s s u bj e ct t o Fr e e d o m of I nf or m ati o n A ct ( F OI A) 
E x e m pti o n 4 a n d m a y n ot b e r e pr o d u c e d or ot h er wi s e di s s e mi n at e d wit h o ut t h e writt e n 
a p pr o v al of Eli Lill y a n d C o m p a n y or it s s u b si di ari e s.
L Y 3 1 5 4 2 0 7 L e w y B o d y D e m e nti a
St u d y I 7 S-M C -H B E H i s a m ulti c e nt er, r a n d o mi z e d, d o u bl e -bli n d, p ar all el -gr o u p, 
pl a c e b o -c o ntr oll e d, fi x e d -d o s a g e, P h a s e 2 a st u d y c o m p ari n g 3 d o s a g e s of L Y 3 1 5 4 2 0 7 
( 1 0, 3 0, or 7 5 m g a d mi ni st er e d or all y o n c e a d a y ) wit h pl a c e b o o v er 1 2 w e e k s i n s u bj e ct s 
wit h mil d -t o-m o d er at e P ar ki n s o n’ s di s e a s e d e m e nti a .
Eli Lill y a n d C o m p a n y
I n di a n a p oli s, I n di a n a U S A 4 6 2 8 5
Pr ot o c ol I 7 S-M C -H B E H
P h a s e 2
St ati sti c al A n al y si s Pl a n V er si o n 1 el e ctr o ni c all y si g n e d a n d a p pr o v e d b y Lill y:
2 8 N o v e m b er 2 0 1 7
St ati sti c al A n al y si s Pl a n V er si o n 2 el e ctr o ni c all y si g n e d a n d a p pr o v e d b y Lill y: 
1 7 J ul y 2 0 2 0
St ati sti c al A n al y si s Pl a n V er si o n 3 el e ctr o ni c all y si g n e d a n d a p pr o v e d b y Lill y o n d at e 
pr o vi d e d b el o w.
A p pr o v al D at e: 0 8- F e b- 2 0 2 1 G M T


I7S-MC-HBEH Statistical Analysis Plan Version 3
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2.
Table of Contents
Section
Page
1.
Statistical Analysis Plan: I7S-MC-HBEH: Effect of LY3154207 on 
Cognition in Mild-to-Moderate Dementia Due to Lewy Body 
Dementia (LBD) Associated with Idiopathic Parkinson’s Disease 
(PD) or Dementia with Lewy Bodies (DLB) .......................................................................1
2.
Table of Contents................................................................................................................2
3.
Revision History .................................................................................................................7
4.
Study Objectives.................................................................................................................8
5.
Study Design.....................................................................................................................12
5.1.
Summary of Study Design............................................................................................12
5.2.
Determination of Sample Size ......................................................................................13
5.3.
Method of Assignment to Treatment ............................................................................13
6.
A Priori Statistical Methods ..............................................................................................14
6.1.
Populations for Analyses..............................................................................................14
6.2.
General Considerations ................................................................................................14
6.3.
Adjustments for Covariates ..........................................................................................15
6.4.
Handling of Dropouts or Missing Data.........................................................................15
6.5.
Handling Missing Items for Scales ...............................................................................16
6.6.
Multicenter Studies ......................................................................................................17
6.7.
Multiple Comparisons/Multiplicity...............................................................................17
6.8.
Subject Disposition ......................................................................................................17
6.9.
Subject Characteristics .................................................................................................17
6.10. Concomitant Therapy...................................................................................................18
6.11. Treatment Compliance .................................................................................................18
6.12. Efficacy Analyses ........................................................................................................18
6.12.1.
Primary Outcome and Methodology.....................................................................18
6.12.2.
Additional Analyses of the Primary Outcome.......................................................20
6.12.3.
Secondary Efficacy Analyses ...............................................................................20
6.12.4.
Tertiary/Exploratory Efficacy Analyses................................................................21
6.12.5.
Sensitivity Analyses.............................................................................................22
6.12.6.
Dose Response Modeling.....................................................................................22
6.12.7.
COVID-19 ...........................................................................................................23
6.13. Pharmacokinetic/Pharmacodynamic Analyses..............................................................24
6.14. Safety Analyses............................................................................................................24
6.14.1.
Extent of Exposure...............................................................................................24
6.14.2.
Adverse Events and Serious Adverse Events........................................................24


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6.14.3.
Deaths, Other Serious Adverse Events, and Other Notable 
Adverse Events ....................................................................................................25
6.14.4.
Clinical Laboratory Evaluation.............................................................................25
6.14.5.
Vital Signs and Other Physical Findings...............................................................26
6.14.6.
Electrocardiograms ..............................................................................................26
6.14.7.
Additional Safety Sections ...................................................................................27
6.14.7.1.
Secondary Safety Analyses: In-Clinic Blood 
Pressure/Pulse Rate ........................................................................................27
6.14.7.2.
Tertiary/Exploratory Safety Analyses .............................................................28
6.14.7.3.
Home Blood Pressure Monitoring Analyses....................................................28
6.14.7.4.
Addendum Safety Analyses............................................................................28
6.15. Subgroup Analyses.......................................................................................................29
6.16. Protocol Deviations......................................................................................................29
6.17. Interim Analyses and Data Monitoring.........................................................................30
6.18. Planned Exploratory Analyses of Digital Biomarkers...................................................30
6.19. Development Safety Update Report..............................................................................31
6.20. Clinical Trial Registry Analyses...................................................................................31
7.
References ........................................................................................................................32
8.
Appendices .......................................................................................................................33


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Table of Contents
Table
Page
Table HBEH.4.1.Objectives and Endpoints ................................................................................8
Table HBEH.6.1.LED Conversion Factors................................................................................21


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Table of Contents
Figure
Page
Figure HBEH.5.1.
Illustration of study design for Clinical Protocol I7S-MC-HBEH..............12


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Table of Contents
Appendix
Page
Appendix 1.
Potentially Clinically Significant Vital Signs .................................................34


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3.
Revision History
SAP Version 1 was approved prior to unblinding.
SAP Version 2 was approved prior to unblinding and includes updates from Amendment (b) and 
information on coronavirus disease 2019 (COVID-19) impact.
SAP Version 3 was approved after unblinding. The overall changes and rationale for the changes 
incorporated in Version 3 are as follows:

Edits were made to comply with ALCOA+++ principles.

Administrative changes (not affecting content), such as correcting typographical and 
formatting errors, were made.


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4.
Study Objectives
Table HBEH.4.1 shows the objectives and endpoints of the study.
Table HBEH.4.1.
Objectives and Endpoints
Objectives
Endpoints
Primary
To test the hypothesis that LY3154207 administered at 
10 mg, 30 mg, and/or 75 mg daily (or 50 mg based on 
interim analysis) (QD) oral dosing for 12 weeks will 
result in a significant improvement in cognition in 
subjects with mild-to-moderate LBD compared with 
placebo.
Change in the CoA composite score of the CDR-CCB
from baseline to Week 12
Secondary
Efficacy:
To evaluate the global efficacy of LY3154207
ADCS-CGIC score from baseline to Week 12
To evaluate the efficacy of LY3154207 on cognitive 
outcomes
Change in the CDR-CCB PoA composite score from 
baseline to Week 12
To evaluate the efficacy of LY3154207 on cognitive 
outcomes
Change in the ADAS-Cog13 score from baseline to 
Week 12
To evaluate the efficacy of LY3154207 on cognitive 
outcomes
Change in the MoCA score from screening to 
Week 12
To evaluate the efficacy of LY3154207 on 
neuropsychiatric symptoms
Change in the NPI total and individual items scores 
from baseline to Week 12
To evaluate the effect of LY3154207 on daytime 
sleepiness
Change in the ESS score from baseline to Week 12
To evaluate the effect of LY3154207 on Parkinson’s 
disease severity
Change in the MDS-UPDRS total score (sum of parts 
I-III) from baseline to Week 12
To evaluate the efficacy of LY3154207 on functional 
outcome
Change in the PDAQ-15 total score from baseline to 
Week 12
To evaluate the effect of LY3154207 on verbal fluency
Change in D-KEFS Verbal Fluency test score from 
baseline to Week 12
To evaluate the effect of LY3154207 on motor 
symptoms and signs 
Change in MDS-UPDRS Parts II (motor experiences 
of daily living) and III (motor exam) from baseline to 
Week 12


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Objectives and Endpoints
Objectives
Endpoints
Secondary
Safety:
To evaluate the effect of LY3154207 on acute changes 
of vital signs on the first day of dosing
Number of subjects who met the potentially clinically 
significant vital signs criteria at 3 consecutive time 
points at Visit 3 (Day 1 stopping rules)
To evaluate the effect of LY3154207 on SBP and DBP 
on the first day of dosing
Change in in-clinic BP from 0 up to 8 hours post dose 
on the first day of study drug dosing
To evaluate the effect of LY3154207 on pulse rate on 
the first day of dosing
Change in in-clinic pulse rate from 0 up to 8 hours 
post dose on the first day of study drug dosing
To evaluate the effect of LY3154207 on SBP and DBP 
from baseline to Week 12
Change in in-clinic mean BP at baseline to mean SBP 
at Week 12
To evaluate the effect of LY3154207 on pulse rate from 
baseline to Week 12
Change in in-clinic mean pulse rate at baseline to 
mean pulse rate at Week 12
To evaluate the effect of LY3154207 using HBPM 
Change in HBPM for SBP, DBP, and pulse rate from 
baseline to Week 12
To evaluate the effect of LY3154207 on physical 
withdrawal symptoms
Change in the PWC-20 total score from Week 12 to 
in-clinic follow-up visit 
Pharmacokinetics:
To assess the PK of LY3154207 in a population of 
subjects with mild-to-moderate dementia due to Lewy 
Body Dementia
Steady-state trough plasma concentrations of 
LY3154207 at Week 12


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Objectives and Endpoints
Objectives
Endpoints
Tertiary/Exploratory
Efficacy:
To evaluate the efficacy of LY3154207 on cognitive 
outcomes
Change in total score of the ADAS-Cog11 from 
baseline to Week 12
To evaluate the efficacy of LY3154207 on cognitive 
outcomes
Change in the CDR-CCB Cognitive reaction time
composite score, Reaction Time Variability composite 
score, and Attention Ratio and Speed Score composite 
scores from baseline to Week 12
Change in the CDR-CCB individual task outcomes 
from baseline to Week 12 including simple reaction 
time, digit vigilance, choice reaction time, numeric 
working memory, spatial working memory, verbal 
memory, and visual memory.
To evaluate the effect of LY3154207 on non-motor 
symptoms 
Change in MDS-UPDRS 

Part I Non-motor experiences (Total Score)
To evaluate the effect of LY3154207 on sleep
Change in MDS-UPDRS items 1.7 sleep problems and 
1.8 daytime sleepiness
To evaluate the effect on motor complications
Change in MDS-UPDRS Part IV (motor 
complications) from baseline to Week 12
To evaluate the effect of LY3154207 on depressive 
symptoms
Change in NPI score (Part D Depression/Dysphoria) 
from baseline to Week 12
Change in MDS-UPDRS item 1.3 Depressed Mood 
from baseline to Week 12
Change in GDS total score from baseline to Week 12
To evaluate the effect of LY3154207 on apathy
Change in NPI score (Part G Apathy and Difference) 
from baseline to Week 12
Change in item 1.5 Apathy in MDS-UPDRS from 
baseline to Week 12
To evaluate the effect of LY3154207 on fatigue
Change in MDS-UPDRS item 1.13 fatigue from 
baseline to Week 12


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Objectives and Endpoints
Objectives
Endpoints
Tertiary/Exploratory
Safety:
To evaluate the effect of LY3154207 on hallucinations 
and psychosis including dose response
Change in item 1.2 score of the MDS-UPDRS Part IA 
from baseline to Week 12
Change in score for the delusion (Part A) and 
hallucinations (Part B) domains of the NPI from 
baseline to Week 12
To evaluate the effect of LY3154207 on impulse 
control symptoms
Change in QUIP total score from baseline to Week 12
To evaluate the effect of LY3154207 on dyskinesias 
Change in MDS-UPDRS Items 4.1 and 4.2 from 
baseline to Week 12
Digital Biomarkers:
To evaluate the feasibility of using the Lilly Trial 
application (Lilly Trial app) to evaluate the effect of 
LY3154207 on motor tasks or cognitive outcomes in a 
subset of subjects
To explore trends, utilizations, and changes in 
quantitative motor and cognitive outcomes as 
measured by the Lilly Trial App scores from predose 
assessments to 12 weeks
To explore the feasibility of using actigraphy to 
evaluate the effect of LY3154207 on various sleep 
parameters and daytime activity including but not 
limited to sleep latency, duration of sleep, sleep–wake 
cycles, sleep architecture, and sleep disruption
Change in actigraphy measured sleep parameters as 
measured by an actigraphy watch from predose 
assessments to 12 weeks
Pharmacogenomic:
To evaluate genetic interactions with study treatment 
response or safety if appropriate/as warranted
Explore relationships between pharmacogenomics 
variations and relevant clinical outcomes.
Abbreviations: ADAS-Cog11 = 11-item Alzheimer’s Disease Assessment Scale – Cognitive subscale; 
ADAS-Cog13 = 13-item Alzheimer’s Disease Assessment Scale – Cognitive subscale; 
ADCS-CGIC = Alzheimer’s Disease Cooperative Study – Clinician Global Impression of Change;
CDR-CCB = Cognitive Drug Research Computerized Cognition Battery; CoA = Continuity of Attention; 
DBP = diastolic blood pressure; D-KEFS = Delis-Kaplan Executive Function System; DLB = dementia with 
Lewy bodies; ESS = Epworth Sleepiness Scale; GDS = Geriatric Depression Scale; HBPM = home blood 
pressure monitoring; LBD = Lewy Body Dementia; MDS-UPDRS = Movement Disorder Society’s Unified 
Parkinson’s Disease Rating Scale; MoCA = Montreal Cognitive Assessment; NPI = Neuropsychiatric Inventory; 
PDD = Parkinson’s disease dementia; PDAQ-15 = Penn Parkinson’s Daily Activities Questionnaire-15; 
PK = pharmacokinetics; PoA = Power of Attention; PWC-20 = physician withdrawal checklist-20; QD = once 
a day; QUIP = Questionnaire for Impulsive-Compulsive Disorders in Parkinson’s Disease; SBP = systolic 
blood pressure.


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5.
Study Design
5.1.
Summary of Study Design
Study I7S-MC-HBEH (HBEH) is a multicenter, randomized, double-blind, parallel-group, 
placebo-controlled, fixed-dosage, Phase 2a study comparing 3 dosages of LY3154207 (10, 30, or 
75 mg administered orally once a day [QD]) with placebo over 12 weeks in subjects with mild-
to-moderate dementia associated with Lewy body dementia (LBD) (Parkinson’s disease 
dementia [PDD] and dementia with Lewy bodies [DLB]). The study includes a Screening Period 
(Visits 1 to 2) of a minimum of 7 days and up to 14 days, a 14-day Pretreatment Period (Visits 2 
to 3), a 12-week Treatment Period (Visits 3 to 11), and a 14-day Safety Follow-Up Period 
(Visits 11 to 801) (Figure HBEH.5.1). Subjects who meet entry criteria will be randomized in a 
1:1:1:1 ratio to LY3154207 (10 or 30 or 75 mg QD) or placebo. The primary objective of this 
study is to test the hypothesis that LY3154207 administration for 12 weeks will result in a 
significant improvement in cognition as measured by the change from baseline to Week 12 in the 
Continuity of Attention (CoA) composite score of the Cognitive Drug Research Computerized 
Cognition Battery (CDR-CCB), in subjects with mild-to-moderate LBD, compared to placebo. 
The CoA has demonstrated a significant treatment effect in previous trials in subjects with PDD 
and is resistant to learning and placebo effects (Wesnes et al. 2005; Rowan et al. 2007).
Figure HBEH.5.1.
Illustration of study design for Clinical Protocol I7S-MC-HBEH.


I7 S -M C -H B E H St ati sti c al A n al y si s Pl a n V er si o n 3
P a g e 1 3
L Y 3 1 5 4 2 0 7
5. 2.
D et er mi n ati o n of S a m pl e Si z e
A p pr o xi matel y  7 5 0 s u bjects will be scree ne d t o ac hie ve 3 4 0 ra n d o mize d s u bjects. T he 
ra n d omizat i on will be 1: 1: 1: 1 t o L Y 3 1 5 4 2 0 7 ( 1 0, 3 0 , or 7 5 m g Q D ) or place b o treat me nt ar ms. 
 
 If t he tr ue effect size f or L Y 3 1 5 4 2 0 7 relati ve t o place b o o n t he C o A is 0. 4 wit h t he 
sa m ple size of 3 4 0, t here will be greater t ha n 8 0 % pr o ba bilit y o f passi n g t his criteri o n. A 2 0 % 
di sc o nti n uati on rate b y  Wee k 1 2 has bee n acc o u nte d f or i n t he sa m ple size deter mi nati o n.
S a m ple size est i mati on was base d o n a n article b y Wes nes
et al. ( 2 0 0 5) w her e t he differe nce i n 
mea n c ha n ge fr o m baseli ne f or ri vast i gmi ne c o m p are d t o place b o a n d t he p o ole d sta n dar d 
de viat i on ( S D ) f or C o A were esti mate d as 5. 7 u nits a n d 1 8 u nits, res pecti vel y. T he ri vasti gmi ne 
effect c orres p o n de d t o a re d ucti o n i n t he deficit of s u bjects c o m pare d t o a ge -mat c he d healt h y 
v o l unt eers of a p pr o xi matel y 4 5 %. Base d o n t his res ult, t he effect size of 0. 4 i n t his st u d y 
c orres p o n ds t o a mea n differe nce o f 7. 2 u nits (a p pr o xi matel y 5 7 % re d ucti o n i n t he deficit).
T his sa m ple size will all o w assess me nt of t he i n- cli nic bl o o d press ure ( B P ) a n d p ulse rate ( P R )
val ues o n t he first da y  of d osi n g i n or der t o e val uate a n y c ha n ges after t he first d ose of treat me nt 
t hat was see n i n P hase 1. If t he S D of  t he i n-cli nic s yst olic bl o o d press ure (S B P ) val ue is 
ass u me d t o be 1 5 m m H g, t he n t he differe nce fr o m t he mea n t o t he u p per li mit of a 9 5 % 
c o nfi de nce i nter val ( CI) of t he c ha n ge fr o m baseli ne i n S B P rel at i ve t o place b o is e x pecte d t o be 
< 4. 7 m m H g. If t here i s a n y ini tial rise i n B P or P R , t he i n-cli nic 6- a n d 1 2-wee k assess me nts 
alo n g wi t h t he h o me bl o o d press ure m o nit ori n g ( H B P M ) a n d a m b ulat or y blo o d press ure 
m o nit ori n g ( A B P M ) meas ures will be use d t o assess w het her t he r ise acc o m m o dates. T he 
differe nce fr o m t he mea n t o t he u p per li mit of a 9 5 % CI i n t he c ha n ge i n a vera ge S B P meas ure d 
at eac h of t hese visit s relat i ve t o place b o is e x pecte d t o be < 3. 5 m m H g. T his ass u mes a n S D of  
1 0 m m H g a n d a 2 0 % di sc o nti n uati on rate.
Si m ulati o ns were c o n d ucte d i n F A C Ts Versi o n 5. 1. 1 usi n g a Ba yesia n n or m al d y na mic li near 
m o d el  (N D L M ).
5. 3.
M et h o d of A s si g n m e nt t o Tr e at m e nt
S u bjects w h o meet all criteria f or e nr oll me nt will be ra n d o mize d t o d o u ble -bli n d treat me nt at
Vi sit 3. S u bjects will be ra n d omize d i n a bli n de d fas hi o n t o t he 4 treat me nt ar ms ( L Y 3 1 5 4 2 0 7 
1 0, 3 0 , or 7 5 m g Q D or pl ace b o ) i n a 1: 1: 1: 1 rati o. Ra n d o mizati o n will use a mi ni mizati on 
pr oce d ure i n or der t o bala nce f or i n vesti gat or site a n d t he c urre nt use of acet ylc h o li nesterase 
i nhi bi t ors ( A C h EIs) ( Yes, N o) usi n g a n i nteracti ve we b-res p o nse s yste m (I W R S).
T he I W R S will be use d t o assi g n blister pac ks c o ntai ni n g d o u ble -bli n d i n vest i gati onal pr o d uct t o 
eac h s u bject. O ne blister pac k will be dis pe nse d f or eac h wee k of d osi n g (f or e xa mple, f or 
1 4- d a y  st u d y int er vals, 2 blister pac ks will be dis pe nse d at eac h visit ). Site pers o n nel will 
c o nfir m t hat t he y ha ve locate d t he c orrect blister pac ks b y e nteri n g a c o nfir mat i on n u m ber f o u n d 
o n t he blister pac ks i nt o t he I W R S.
C CI


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6.
A Priori Statistical Methods
6.1.
Populations for Analyses
For purposes of analyses, the following populations are defined:
Population
Description
Enrolled 
All subjects who sign informed consent.
Evaluable Patient population (EPP)
All randomized subjects who received at least 1 dose of study 
medication, who have the baseline efficacy assessment, and have at least 
1 post-dose efficacy assessment. Analyses will be according to the 
treatment the subject actually received.
Completers
All randomized subjects who have completed all study procedures 
including follow-up and/or early termination/discontinuation visit.
Safety population
All randomized subjects who take at least 1 dose of double-blind study 
treatment. In the event of a treatment error, subjects will be analyzed 
according to the treatment they actually received.
Per Protocol population
Subjects who complete the study with no major protocol deviations.
PK Analysis population
PK analyses will be conducted on subjects who receive at least 1 dose of 
the study drug and have 1 measurable concentration.
Abbreviations: PK = pharmacokinetic.
6.2.
General Considerations
Statistical analysis for this study will be the responsibility of Eli Lilly Company (Lilly) or its
designee. The statistical analyses performed as part of the interim analyses will be conducted by 
the designated statistical analysis center, which forms part of the internal assessment committee
(IAC) (see Unblinding and Communication Plan for more details).
Analyses will be conducted in SAS Version 9.4 or greater, and Spotfire graphical package will 
be used to review safety data on an ongoing basis during the trial (for example, for trial level 
safety reviews). Packages to be used for the analysis of digital biomarker data will be specified 
in the Digital Biomarker Analysis Plan.
As HBEH is a Phase 2 study, the appropriate estimand is a de jure estimand, where efficacy of 
LY3154207 is assessed under the paradigm of all subjects taking study drug as intended. 
Intercurrent events for HBEH are defined to be when subjects discontinue the study prior to 
completing the 12 weeks of treatment. While subjects are allowed to be on steady doses of 
symptomatic treatments, the protocol does not allow for subjects to initiate any therapeutic agent 
that has been demonstrated to be effective for treatment of cognition in LBD during the trial. The 
primary analyses use a Bayesian mixed-model repeated measures (MMRM) analyses of the 
CDR-COA to evaluate cognition in subjects with mild-to-moderate LBD compared with placebo. 
This analysis assumes that the intercurrent events lead to data that is missing at random (MAR). 
Unless otherwise specified, all efficacy analyses will be conducted on the Evaluable Patient 
population (EPP). Analyses will be conducted according to the treatment the subject actually 
received.


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When change from baseline is assessed, subjects will be included in the analysis only if both the 
baseline and a postbaseline measure are available. Unless otherwise defined, a baseline measure 
is the last non-missing observation collected prior to the subject receiving study treatment. 
Safety analyses will be conducted on the safety analysis set comprising all subjects who received 
at least 1 dose of study medication. Summary statistics, tabulations, and graphs will be provided 
as appropriate. 
Longitudinal analyses from baseline to Week 12 will use the change from baseline score as the 
response variable. An unstructured covariance matrix will be considered for MMRM; however,
if this fails to converge, other structures will be considered based on the trial design. Unless 
stated otherwise, for all MMRM analyses, the difference in least squares (LS) means between 
LY3154207 and placebo, corresponding 95% credible or CIs, and p-values will be presented.
Any change to the data analysis methods described in the protocol will require an amendment 
ONLY if it changes a principal feature of the protocol. Any other change to the data analysis 
methods described in the protocol, and the justification for making the change, will be described 
in the clinical study report (CSR).
Only key analyses and results relating to primary and secondary objectives will be presented in 
the CSR. Exploratory and sensitivity analyses are not expected to be included in the CSR, unless 
they are relevant to the trial conclusions. Further exploratory analyses, in addition to those
specified in this SAP may be conducted, if deemed appropriate.
6.3.
Adjustments for Covariates
Unless stated otherwise, the following covariates will be included in efficacy analyses: baseline, 
baseline by visit interaction, age, and concomitant use of AChEIs at baseline.
6.4.
Handling of Dropouts or Missing Data
There will be no imputation for missing data unless specified otherwise.
General rule for the imputation of dates
If the adverse event (AE) onset date is missing or partial, the date will be compared as far as 
possible with the date of first dose of study medication when determining whether or not the AE 
is present at baseline. In this case, the AE will be assumed to be treatment emergent, unless there 
is clear evidence (through comparison of partial dates) to suggest that the AE started prior to the 
first dose of study medication.
Efficacy analysis
The chosen method of analysis for the longitudinal data, MMRM, can handle missing data, as it 
uses all available data across subjects to estimate parameters. Under the assumption of data being 
MAR or the non-random missing data is ignorable, the estimates based on restricted maximum 
likelihood (REML) are unbiased. In the Bayesian analysis, under the assumption of MAR and 
distinct parameters determining the probability model and missingness mechanism, Bayesian 
inferences can be obtained for model parameters using a likelihood based only on the observed 
data (Gelman et al. 2004).


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Repeated measures analyses will only use data from visits at which the data were scheduled to be 
collected (Andersen and Millen 2013). When subjects discontinue from the study early, there 
may be efficacy or safety data measurements at visits at which the variables were not scheduled 
to be collected. These data will be used in all other analyses.
Subjects with missing baseline data or with no postbaseline visit data will not be included. The 
only exception to this is for the primary analysis (see Section 6.5).
6.5.
Handling Missing Items for Scales
Total and subscale scores for questionnaire-based safety and efficacy outcome measures will be 
derived from individual items. If any of the individual items are missing or unknown, every 
effort will be made to obtain the score for the missing item or items. If this is not possible, any 
total or sum involving that item will be considered missing. However, imputations will be 
adopted for the Alzheimer’s Disease Assessment Scale – Cognitive subscale (ADAS-Cog) if 
complete data cannot be gathered and potentially for the baseline measurements of the 
primary outcome, CoA. For additional considerations due to the COVID-19 pandemic, see 
Section 6.12.7.
ADAS-Cog13
For the 13-item Alzheimer’s Disease Assessment Scale – Cognitive subscale (ADAS-Cog13),
if 4 or fewer of a total of 13 items (approximately 30%) are missing, the total score 
(maximum = 85) will be imputed as follows: The total from the remaining items will be 
multiplied by a factor that includes the maximum score for the missing items. For example, if 
the first item, “Word-Recall Task,” which ranges from a score of 0 through 10 (maximum = 10),
is missing, and the second item “Commands,” which ranges from a score of 0 through 5 
(maximum = 5), is missing then the multiplication factor = 85/(85 - [10 + 5]) = 85/70 = 1.21. 
Thus, the total score for this example will be the sum of the remaining 11 items multiplied by 
1.21. The imputed number will be rounded up to the nearest integer. If more than 4 items are 
missing, the total score for ADAS-Cog13 at that visit will be considered missing. The same 
imputation technique will be applied to the 11-item Alzheimer’s Disease Assessment Scale –
Cognitive subscale (ADAS-Cog11) subscore.
CoA
Missing baseline data for CoA will be imputed using a regression approach. A simple linear 
regression model of CoA at baseline in terms of CoA scores at screening will be produced. 
Scores from the 2 screening assessments will be included as separate explanatory variables (first 
screening score and second screening score). This model will be based on data from subjects 
who have both screening and baseline CoA scores. 
If missing, a subject’s Visit 2 baseline score will be imputed with a predicted value from the 
model based on the subject’s own CoA screening data. If a subject is missing both baseline and 
screening visit CoA data, the subject will be excluded from the analyses of CoA.


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6.6.
Multicenter Studies
Approximately 75 sites, predominantly in the United States (with some sites in Canada), will be 
participating in the trial. In the IWRS process, minimization will be adopted to maintain balance 
in treatment allocation at each site. Site is not an intended covariate for any statistical modeling,
as the majority of sites are expected to only recruit a small number of subjects. Adjusting for 
such a large number of small sites would result in a high possibility of detecting a false site 
effect, due to multiplicity, and could also result in unreliable estimates of the treatment effect. 
6.7.
Multiple Comparisons/Multiplicity
No adjustments will be made for multiple comparisons.
6.8.
Subject Disposition
All subjects who discontinue from the study will be identified, and the extent of their 
participation in the study will be reported. The reason for discontinuation and the time in days to 
study disposition will be summarized as frequencies and percentages.
A listing of the subject disposition will also be produced.
6.9.
Subject Characteristics
Baseline characteristics will be summarized for the EPP and the per-protocol population by 
treatment group and overall. Summaries will include descriptive statistics for continuous 
measures and frequencies and percentages for categorical measures.
Subject characteristics that will be summarized include:
•
age (continuous and categorized into <65, 65-84 and 85+)
•
gender
•
race (and ethnicity)
•
height
•
weight
•
body mass index (weight (kg) / [height (m)]^2)
•
country
•
tobacco use at baseline
•
alcohol use at baseline
•
AChEI use at baseline
•
memantine use at baseline
•
dopaminergic therapy in levodopa equivalency dose (LED)
•
time since Parkinson’s disease (PD) or dementia diagnosis (whichever occurred first)
•
diagnosis (PDD vs LBD)


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•
baseline severity of impairment as measured by CoA, Penn Parkinson’s Daily Activities 
Questionnaire-15 (PDAQ-15), ADAS-Cog13, Power of Attention (PoA), Delis-Kaplan 
Executive Function System (D-KEFS), Montreal Cognitive Assessment (MoCA), 
Neuropsychiatric Inventory (NPI), Epworth Sleepiness Scale (ESS), and Movement 
Disorder Society’s Unified Parkinson’s Disease Rating Scale (MDS-UPDRS), and
•
cardiovascular risk factors (diabetes, hypertension, hyperlipidemia, coronary artery 
disease, cardiovascular disease, and peripheral arterial disease).
6.10. Concomitant Therapy
Prior medications are defined as those that stop before randomization (Visit 3). Concomitant 
medications are defined as those being taken on or after randomization (Visit 3).
A summary of concomitant medications will be presented, with frequencies and percentages for 
each treatment group. If the start or stop dates of therapies are missing or partially missing, to the 
extent that it cannot be determined whether the therapy is prior or concomitant, the therapy will 
be deemed concomitant.
Summary tables will also be provided for PD medications, antidepressants, and cognitive 
enhancing medications; specifically, a separate summary for prior and concomitant use of 
AChEIs will be produced.
Investigators are permitted to adjust a subject’s PD, cognitive, and antipsychotic medications in 
order to manage motor or other symptoms during the study; the frequency and reason for change 
in medication will be captured in a listing.
Medications will be coded using the World Health Organization (WHO) drug dictionary.
6.11. Treatment Compliance
Compliance is defined as having taken ≥80 % to <120 % of the prescribed amount of 
medication. Treatment compliance information for each treatment arm will be collected through 
counts of dispensed and returned capsules. The number of capsules taken relative to the number 
expected to be taken will be summarized.
6.12. Efficacy Analyses
6.12.1. Primary Outcome and Methodology
The primary objective is to evaluate whether LY3154207, administered at 10 mg, 30 mg, and/or 
75 mg QD oral dosing for 12 weeks, will show an improvement in cognition compared to 
placebo in subjects with mild-to-moderate LBD. This objective will be assessed in the EPP using 
a Bayesian MMRM analysis of the change in the CDR-CCB CoA data from baseline to 
Week 12. Continuity of Attention (CoA) is defined as the sum of correct responses from the 
Choice Reaction Time and Digit Vigilance Task with the number of Digit Vigilance Errors 
subtracted.
The primary analysis on CoA will occur when all subjects have had the opportunity to complete 
12 weeks of treatment.


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The analysis of CoA will utilize a Bayesian MMRM model. The Bayesian analysis will use 
uninformative priors for all terms in the model. For the model coefficients, these will be diffuse 
Normal distributions centered on zero. Prior for covariance matrix will follow an inverse-
Wishart distribution (the multivariate generalization of an inverse gamma distribution for a 
variance component). The MMRM model will account for longitudinal data assessed throughout 
the study after 1, 2, 4, 6, 8, 10, and 12 weeks of dosing. The change in CoA from baseline to 
Week 12 will be the dependent variable. The model will comprise fixed (baseline value, 
treatment, visit, age, and use of AChEIs) with the interaction terms (treatment by visit, baseline 
value by visit) with repeated measures of visit within subject. Visit will be considered a 
categorical variable with values equal to the visit numbers at which the CoA was assessed. 
Covariates may be centered prior to analysis to aid model convergence.
The primary comparison will be the contrast between treatments and placebo for the Week 12 
change from baseline against a null hypothesis of no difference. This will be presented as both a 
difference in estimated means of the 12-week change and the effect sizes over the 12 weeks. The
average effect size from the last 4 visit time points (Weeks 6, 8, 10, and 12) will be the primary 
comparison between treatments and placebo. These will be averaged after the model has been fit.
Example codes, for the purposes of aiding programming of the primary analysis, using Bayesian 
MMRM and equivalent frequentist MMRM, are given below.
Bayesian MMRM Model:
Proc MCMC data=coa_final nbi=2000 ntu=50 nmc=10000 seed=2019143 thin=10 diag=all
plots(smooth)=all dic outpost=coa_test_final_10000
array CoA [9] x1 - x9;
array mu [9] mu1 - mu9;
array covar [9, 9];
array s [9, 9];
array sigma [9];
array beta_v [8]   beta_v1 - beta_v8;     %* visit specific effect;
array beta_t [3]    beta_t1 - beta_t3  ;
%* treatment specific effect;
array beta_vt[8,3]  beta_vt1 - beta_vt24;
%* visit treatment interaction;
array beta_bv[8]   beta_bv1 - beta_bv8;
%* baseline visit interaction;
begincnst;
call identity(s);
endcnst;
parms beta0 beta1 beta2 beta3 0;  
parms beta_v1 beta_v2 beta_v3 beta_v4 beta_v5 beta_v6 beta_v7 beta_v8  0 ;
parms beta_t1  beta_t2  beta_t3 0;
parms beta_vt1 beta_vt2 beta_vt3 beta_vt4 beta_vt5 beta_vt6 beta_vt7 beta_vt8  beta_vt9 
beta vt10 beta vt11 beta vt12 beta vt13 beta vt14 beta vt15 beta_vt16 beta_vt17 beta_vt18 
beta_vt19 beta_vt20 beta_vt21 beta_vt22 beta_vt23  beta_vt24  0;
parms beta_bv1 beta_bv2 beta_bv3 beta_bv4 beta_bv5 beta_bv6 beta_bv7 beta_bv8  0;
parms covar ;
%macro tprior1;
%do i = 1 %to 8;
prior beta_v&i ~ N (0, prec=0.00001);
prior beta_bv&i ~ N (0, prec=0.00001);
%end;
%do i = 1 %to 3;
prior beta_t&i ~ N (0, prec=0.00001);
%end;


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%do i = 1 %to 24;
prior beta_vt&i ~ N (0, prec=0.00001);
%end;
%mend;
%tprior1;
prior beta0 ~ N (0, prec=0.00001);  %* overall intercept;
prior beta1 ~ N (0, prec=0.00001);  %* baseline coefficient;
prior beta2 ~ N (0, prec=0.00001);  %* age coefficient;
prior beta3 ~ N (0, prec=0.00001);  %* AChEI coefficient;
prior covar ~ iwish(9, S);
    
do i=1 to 9;
if trt > 1 then do;
if i>1 then mu[i]=beta0+beta1*base+beta2*age+beta3*AChEI+beta_t[trt-1]+beta_v[i-
1]+beta_vt[(i-1),(trt-1)] +beta_bv[i-1]*base ;
else mu[i]=beta0+ beta1*base + beta2*age + beta3*AChEI+ beta_t[trt-1];
end;
else if trt eq 1 then do;
if i>1 then mu[i]=beta0+ beta1*base + beta2*age + beta3*AChEI + beta_v[i-1] + 
beta_bv[i-1]*base;
else  mu[i]=beta0 + beta1*base + beta2*age + beta3*AChEI;
end;
end;
do i=1 to 9;
  Sigma[i] = sqrt(covar[i,i]);
    
end;
model coa ~ mvn(mu, covar);
run;
Corresponding Frequentist MMRM Model:
proc mixed data=efficacy_data order=data;
class treatmentt subject visit AChEI;
model CFB_CoA = base treatment visit visit*base treatment*visit age AChEI/ 
ddfm=kr outp=pred solution residual;
repeated visit/subject=subject type=un  ;
lsmeans treament*visit  /pdiff cl alpha=0.05;
ods output lsmeans=lsmean diffs=diff; 
run;
6.12.2. Additional Analyses of the Primary Outcome
The primary efficacy analysis will be repeated with a per-protocol analysis set including only 
those subjects who completed the study with no major protocol deviations to verify robustness of 
the results.
6.12.3. Secondary Efficacy Analyses
The secondary efficacy outcomes (PDAQ-15, ADAS-Cog13, CDR-CCB PoA, D-KEFS, MoCA, 
NPI, ESS, and MDS-UPDRS) will be assessed at the 12-week time point as the primary analysis. 
Each of these secondary endpoints will be analyzed using a frequentist MMRM model, which 
will include terms for: baseline value, treatment, visit, age, concomitant use of AChEIs, and the 
relevant interaction terms (treatment by visit, baseline by visit). The change in score from 
baseline will be the dependent variable. If subscores for a particular scale are deemed clinically 
relevant to analysis, it will be completed as an exploratory analysis.


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For the Alzheimer’s Disease Cooperative Study – Clinician Global Impression of Change
(ADCS-CGIC), a logistic regression analysis will be performed with treatment, visit, age, 
concomitant medication of AChEIs, and relevant interaction terms. Two different endpoints will 
be assessed: “moderately or better,” defined as subjects who had moderate/marked improvement 
and “minimally or better” defined as subjects who had minimal/moderate/marked improvement 
on the ADCS-CGIC scale. 
Levodopa equivalency dose (LED) will be calculated using the conversion factors (Tomlinson et 
al. 2010) of the actual daily dose (mg) of the relevant PD drugs (Table HBEH.6.1). After the 
LED is calculated for each concomitant medication that a subject is taking, the total LED will be 
used as a covariate for the analyses of the MDS-UPDRS scales. The impact of LED may be 
explored for various efficacy and safety measures.
Table HBEH.6.1.
LED Conversion Factors
Medication
Multiplication Factor
Immediate release L-dopa dose
1
Controlled release L-dopa dose
0.75
*Entacapone
LD × 0.33
*Tolcapone
LD × 0.5
Duodopa
1.11
Pramipexole (as salt)
100
Ropinirole
20
Rotigotine
30
Selegiline – oral
10
Selegiline – sublingual
80
Rasagiline
100
Amantadine
1
Apomorphine
10
Abbreviation: LED = levodopa equivalency dose.
Note: *LD represents immediate release L-dopa dose for particular patient.
6.12.4. Tertiary/Exploratory Efficacy Analyses
The following exploratory efficacy endpoints will be analyzed using an MMRM model:

change in the total score for the ADAS-Cog11 from baseline to Week 12 (a subset of 
ADAS-Cog13)

change in the CDR-CCB Cognitive reaction time composite score, Reaction Time 
Variability composite score, and Attention Ratio and Speed Score composite scores from 
baseline to Week 12

change in the CDR-CCB individual task outcomes from baseline to Week 12 including 
simple reaction time, digit vigilance, choice reaction time, numeric working memory, 
spatial working memory, verbal memory, and visual memory

change in total MDS-UPDRS (sum of Part I-III) and individual subscales non-motor 
experiences of daily living (Part I), motor experiences of daily living (Part II), motor 
exam (Part III), and motor complications (Part IV) subscales from baseline to Week 12


I7 S -M C -H B E H St ati sti c al A n al y si s Pl a n V er si o n 3
P a g e 2 2
L Y 3 1 5 4 2 0 7

cha n ge i n ite ms 4. 3 t hr o u g h 4. 6 (ti me off, i m pact of o ff, c om p le xity of  off, off d yst o nia) 
of  t he M D S-U P D R S fr o m baseli ne t o Wee k 1 2

cha n ge i n N PI sc ore ( Part D De pressi o n/ D ys p h oria) fr o m baseli ne t o Wee k 1 2 , a n d

cha n ge i n G eri atric De pressi o n Scale ( G D S ) t otal sc ore fr o m baseli ne t o W ee k 1 2.
W here
a p pr o priat e, f urt her e x pl orat or y a nal yses will be c om p lete d.
6. 1 2. 5. S e n siti vit y A n al y s e s
A fre q ue ntist M M R M a nal ysis of t he pri mar y  a nal ysis will be c o n d ucte d.
A n alter nati ve M M R M a nal ysis of c ha n ge i n C o A fr o m baseli ne t o Wee k 1 2, usi n g t he a vera ge 
c ha n ge fr o m baseli ne o ver Wee k 6 t o Wee k 1 2 as t he res p o nse varia ble, ma y als o be c o nsi dere d. 
If t here is a treat me nt differe nce pri or t o Wee k 1 2, w hic h re mai ns t hr o u g h t o W ee k 1 2, t his 
a p pr oac h ma y be more se nsi tive t ha n j ust l o o ki n g at W ee k 1 2.
If baseli ne val ues are i m p ute d fr o m scree ni n g val ues i n t he pri mar y  a nal ysis of C o A, a se nsit i vity 
a nal ysis will be c o n d ucte d t o c o m pare t his a p pr oac h wit h e xcl u di n g s u bjects wit h missi n g 
baseli ne sc ores.
Differe nces i n baseli ne c haracterist ics of t he treat me nt gr o u ps ma y be i n vesti gate d usi n g t he 
C hi -s q uare d test a n d 2 sa m ple t-tests f or cate g orical a n d c o nti n u o us variables, res pect i vel y, 
if a p pr o priate.
6. 1 2. 6. D o s e R e s p o n s e M o d eli n g
D ose res p o nse m o deli n g ma y be utilize d t o u n dersta n d t he d ose res p o nse relat i ons hi p of select 
efficac y a nd safet y  meas ures i nclu di n g C o A, A D A S -C o g, M D S -U P D R S, S B P, diast olic bl o o d 
press ure ( D B P ), a n d P R.
A tre n d test ma y  be c o mplete d t o assess e vi de nce of a d ose res p o nse b y fitt i n g a c o ntrast 
state me nt i n t he M M R M m o del. I n its si m plest f or m, t he a nal ysis assi g ns e q uall y s pace d 
c oefficie nts i n t he c o ntrast, t hat s u m t o zer o acr oss t he le vels o f t he treat me nt fact or (f or 
e xa m ple, -3, -1, 1, 3). T his a nal ysis ass u mes t hat t he c ha n ge i n be nefit fr o m 7 5 m g c o m pare d t o 
3 0 m g is e q ui vale nt t o t he c ha n ge fr om 3 0 m g t o 1 0 m g a n d 1 0 m g t o place b o. Alter nat i ve 
c oefficie nts ma y be use d if t his ass u m pt i on is i na p pr o priate.
A Ba yesia n m o del a vera gi n g a p pr oac h ma y be use d t o esti mate t he d ose res p o nse relat i ons hi p. 
T his Ba yesia n m o del a vera gi n g a p pr oac h is t he Ba yesia n a nal o g of t he M ul tiple C o m paris o n 
Pr oce d ure – M o deli n g ( M C P - Mo d ) met h o d ol o g y  ( Bretz et al. 2 0 05), a n d t he Q ualificat i on of t he 
M C P - M o d pr oce d ure ( F D A 2 0 1 5) is s u p p orti ve i n t he use of M C P- Mo d or Ba y esia n mo d el  
a vera gi n g t o assist i n d ose select i on decisi o ns.
Ba yesia n m o del a vera gi n g is a ge neral mi xt ure distri b uti o n, w here eac h mi xt ure c o m p o ne nt is a 
differe nt para metric m o del. Pri or wei g hts are place d o n eac h m o del a n d t he p osteri or m o del 
w ei g hts are u p date d base d o n h o w well eac h m o del fits t he data. Let  ( ) re prese nt t he mea n of 
t he d ose res p o nse c ur ve at d ose  ,  = {   , …,  } be t he o bser v e d data, a n d  ∈
{1, …,  } be 


I7 S -M C -H B E H St ati sti c al A n al y si s Pl a n V er si o n 3
P a g e 2 3
L Y 3 1 5 4 2 0 7
a n i n de x o n t he para m etric mo d el s. T he n t he p osterior of  t he d ose res p o nse c ur ve,  ( ), of t he 
Ba yesia n m o del a vera gi n g m o del is
 (  ( ) ∣ ) =
 (  ( ) ∣, )
   ( ∣ )
 ( ∣ ) =
 (  ∣ ) ( )
∑
 (  ∣∗)(  ∗)
∗
w here  (  ( ) ∣,  ) is the p osteri or m ea n d ose res p o nse c ur ve fr o m m o del  ,  ( ∣ ) is t he 
p osteri or wei g ht of  mo d el   ,  (  ∣ ) is t he mar gi nal li keli h oo d of t he data u n der m o del  , 
a n d  ( ) is t he pri or wei g ht assi g ne d t o m o del  . I n cases w here  (  ∣ ) is diffic ult t o 
c o mp ute, G o ul d ( 2 0 1 9 ) pr o p oses usi n g t he o bser ve d data’s fit t o t he p osteri or pre dict i ve 
di stri b uti on as a s urr o gate i n calc ulat i n g t he p osteri or wei g hts; t his is t he a p pr oac h use d i n 
t his a nal ysis.
P ote nti al c a n did at e m o dels t hat will be use d are q ua dratic, l o g -q ua dratic, li near, l o g -li near, a n d 
E M A X m o dels.
6. 1 2. 7. C O VI D -1 9
D ue t o t he C O VI D -1 9 pa n de mic q uara nt i ne a n d tra vel restricti o ns, alter nati ve met h o ds of 
c ollect i n g ke y efficac y a n d safety data were i m ple me nte d t o all o w s u bjects t o safel y  re mai n i n 
t he trial.
Be gi n n i n g i n Marc h 2 0 2 0, e nr olle d s u bjects u na ble t o atte n d i n-pers o n cli nic visits d ue t o 
C O VI D -1 9 restrict i ons were a ble t o c o nti n ue i n t he st u d y  b y re placi n g i n-pers o n visits wit h 
t ele p h o ne visits. All s u bjects ha d t o ha ve access t o i n vesti gati onal pr o d uct a n d an H B P M de vice 
t o partici pate i n t he st u d y r e motel y. D uri n g t he tele p h o ne visits, i n vest i gat ors c ollecte d vital 
sig ns usi n g t he H B P M, A Es, c o nc o mita nt me dicat i o ns, a n d t he rele va nt i nf or mat i on fr om t he
C ol u m bia -S uici de Se verit y Rat i n g Scale (C- S S R S ). A d dit i onal efficac y o utc o mes were als o 
c ollecte d, at a p pr o priate visit s, b y p h o ne a n d i nclu de d t he A D C S -C GI C, D -K E F S, P D A Q -1 5, 
M D S -U P D R S P arts I/II/I V, N PI, Q uesti o n naire f or I m p ulsi ve -C o m p ulsi ve Dis or ders i n 
Par ki ns o n’s Disease (Q UI P ), Geriatric De pressi o n Scale – S h ort F or m (G D S - S), E S S, a n d 
p h ysicia n wit h dra wal c hec klist -2 0 ( P W C - 2 0). I n A pril 2 0 2 0, t he st u d y im ple me nte d a n o pti o n t o 
all o w we b-base d vi de oc o nfere nce visits t o assess a d dit i onal meas ures t hat re q uire d vis ual 
i ns pecti o n: t he A D A S-C o g 1 3 , M D S-U P D R S P art  III, a n d M o C A. T he pri mar y o ut c o me, 
C D R -C C B C o A, was n ot c ollecte d re m otel y  a n d is missi n g f or all virt ual visits. Visits c o n d ucte d 
via tel e p h o ne a n d/ or vi de o were d oc u me nte d wit hi n t he st u d y data base. Gi ve n t he varia bility i n 
m o dali t y of c ollecti o n a m o n g s u bjects, visits, a n d scales , se nsiti vity a nal yses will be c o n d ucte d 
o n t he rel e va nt scales e xcl u di n g data c ollecte d via virt ual visit s.
Missi n g ness d ue t o C O VI D -1 9 d oes n ot de pe n d o n t he o utc o me meas ure me nts a n d t heref ore will 
still be c onsi dere d M A R. T he M M R M a nal yses a p pr oac h ca n ha n dle missi n g val ues.
Si nce t here is n o a ntici pate d i nterr u pti o n or disc o nti n uat i on of treat me nt, t he defi nit i on of a n 
i nterc urre nt e ve nt re mai ns u nc ha n ge d.


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Additionally, a COVID-19 impacted population will include any subject after 01 March 2020 
who had at least 1 virtual visit. This will allow for a variety of exploratory analyses regarding the 
impact of COVID-19 and mitigation strategies.
6.13. Pharmacokinetic/Pharmacodynamic Analyses 
LY3154207 plasma concentrations will be illustrated graphically and summarized descriptively. 
Subject data, including but not limited to plasma LY3154207 concentrations, from other clinical 
studies evaluating LY3154207 may be combined with data from this study to support additional 
analyses.
If warranted and based on availability of data, the exposure-response relationship of plasma 
LY3154207 concentrations to efficacy endpoints and/or safety endpoints may be explored.
6.14. Safety Analyses
All subjects who receive at least 1 dose of double-blind study treatment will be evaluated for 
safety and toxicity.
Safety parameters (AEs, laboratory tests, vital signs, electrocardiograms [ECGs], and 
discontinuation rates) for meeting Day 1 (Visit 3) stopping rules will be summarized for the 
treatment period using descriptive statistics for continuous variables and frequencies and 
percentages for categorical variables.
Comparisons between the 3 LY3154207 doses and placebo will be made using a frequentist 
MMRM model for the in-clinic BP, PR, and HBPM measurements during the treatment period.
6.14.1. Extent of Exposure
Days of exposure will be calculated for all subjects as the (Date of last dose – date of first 
dose + 1). Summary statistics will be presented for the total number of days of exposure 
by treatment.
Cumulative exposure will be calculated for each subject and will be summarized with descriptive 
statistics by treatment arm.
A listing of drug accountability by subject will be created and the reason for any drug 
interruptions given.
6.14.2. Adverse Events and Serious Adverse Events
Treatment-emergent AEs will be defined as events that first occurred or worsened on or after 
randomization (Visit 3). Should there be insufficient data to determine whether an AE is 
treatment emergent, the AE will be considered treatment emergent.
Treatment-emergent AEs will be calculated based on adverse event identifier (AEID) and coded 
according to established Medical Dictionary for Regulatory Activities (MedDRA) terms and 
summarized by MedDRA System Organ Class (SOC) and Preferred Term. Adverse event terms 
and severity grades will be assigned by the investigator using Common Terminology Criteria for 
Adverse Events (CTCAE) version 4.0.


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An overview of AEs, including the number and percentage of subjects who died, suffered serious 
AEs (SAEs), discontinued due to AEs, and who suffered treatment-emergent AEs (TEAEs), will 
be provided.
Summaries of AEs by decreasing frequency of Preferred Term within SOC will be provided for 
the following:

preexisting conditions (medical history)

TEAEs

TEAEs by maximum severity

TEAEs occurring in greater than 1% of subjects by Preferred Term

SAEs, and 

AEs reported as reason for discontinuation.
These summaries will include number and percentages of subjects with TEAEs.
A summary of TEAEs by visit will also be provided.
SAEs and discontinuations due to AEs will be listed.
An SAE is any AE from this study that results in 1 of the following outcomes:

death

initial or prolonged inpatient hospitalization

a life-threatening experience (i.e. immediate risk of dying)

persistent or significant disability/incapacity

congenital anomaly/birth defect

important medical events that may not be immediately life-threatening or result in death 
or hospitalization but may jeopardize the subject or may require intervention to prevent 
1 of the other outcomes listed in the definition above. Examples of such medical events 
include allergic bronchospasm requiring intensive treatment in an emergency room or at 
home, blood dyscrasias or convulsions that do not result in inpatient hospitalization, or 
the development of drug dependency or drug abuse.
6.14.3. Deaths, Other Serious Adverse Events, and Other Notable 
Adverse Events
Any deaths will be listed and summarized.
Separate summaries by treatment group will be produced for any major cardiovascular TEAEs
(including congestive heart failure, hypertension, myocardial infarction, stroke, and tachycardia) 
and major nervous system disorders TEAEs (including dyskinesias, impulse control disorders, 
delirium, confusion, and psychosis).
6.14.4. Clinical Laboratory Evaluation
Laboratory measures (clinical chemistry, hematology, and urinalysis) will be analyzed as 
continuous data (change from baseline) measured as International System of Units (SI) or as 


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categorical data (proportion of treatment-emergent abnormalities). If there are multiple records 
of laboratory measurements at baseline or postbaseline visits, the last record will be used.
Change from baseline to postbaseline visits at which laboratory measurements are taken will be 
summarized using descriptive statistics. A listing of abnormal laboratory data will be produced.
For all laboratory tests, frequencies of subjects with notable changes (that is, increases or 
decreases of a prespecified amount unique to each analyte) from baseline to each postbaseline 
visit will also be summarized for all subjects and stratified by low, normal, or high at baseline.
6.14.5. Vital Signs and Other Physical Findings
Vital Signs
Vital sign measurements and weight will be analyzed as continuous data (change from baseline)
and the treatment-emergent abnormalities as categorical data.
If there are multiple records of vital sign or weight measurements at baseline or a postbaseline 
visit, the last record will be used. The only exception is for orthostatic BP and PR taken at 
Visit 1, Visit 4, Visit 5, Visit 6, Visit 7, Visit 9, Visit 10, unscheduled visit, and early 
termination/discontinuation visit and the initial measurement at time 0 of the in-clinic BP and PR
monitoring. At these visits, 3 seated BP/PR measurements will be taken and the mean of these 
will be utilized for analysis purposes. Orthostatic changes will be calculated by comparing the 
mean of the 3 seated BP and PR values to the single standing BP and PR values.
The incidence of treatment-emergent abnormal high or low vital signs will be presented by 
treatment group and visit. Treatment-emergent vital sign evaluations are defined for evaluations 
collected after the initiation of study medication. Any vital sign meeting the criteria will be 
considered abnormal. For each vital sign at each postbaseline visit, only subjects who had a 
baseline result and had a non-missing result at that postbaseline visit will be included in the 
denominator when computing the proportion of subjects with treatment-emergent high, low, or 
abnormal values. Criteria for abnormal postbaseline vital signs are presented in Appendix 1.
The following will be summarized by treatment group and visit for all subjects in the Safety 
population: SBP, DBP, and PR (collected in sitting position); orthostatic SBP, orthostatic DBP,
and orthostatic PR (measurement after 5 minutes in the seated position minus that after 3 minutes 
in the standing position); temperature; and weight. Body mass index at baseline will be 
summarized by treatment. Summary statistics will be presented for observed values at baseline 
and for change from baseline results at each scheduled postbaseline visit.
A listing of treatment-emergent abnormal vital signs by subject and visit will also be presented.
6.14.6. Electrocardiograms
The ECG measurements will be analyzed as continuous data (change from baseline) or as 
categorical data (proportion of treatment-emergent abnormalities).


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Electrocardiogram is measured in triplicate during the double-blind period, and the average of 
triplicates will be used at baseline and each double-blind period visit. If there are multiple 
records after averaging ECG triplicates within a visit, the last record of averages will be used.
All ECG parameter changes from baseline to each postbaseline visit at which ECG 
measurements are taken will be summarized. All analyses of QTc will be carried out using the 
Fridericia’s correction (QTcF) method.
Incidence of treatment-emergent abnormal ECGs will be also be summarized. For example, the 
frequency of subjects with abnormal treatment-emergent increases from baseline in QTcF 
intervals will be summarized into the following categories: >30 msec and >60 msec. 
Treatment-emergent elevated QTc intervals will be summarized into the following categories: 
>450 msec, >480 msec, and >500 msec. Baseline is the average of the last set of triplicates 
measured prior to taking study drug. Each category will show the number of subjects who have 
at least 1 treatment-emergent value meeting that criteria, and therefore those meeting the top 
criteria of >60 and >500 with be counted in lower categories as well.
6.14.7. Additional Safety Sections
6.14.7.1. Secondary Safety Analyses: In-Clinic Blood Pressure/Pulse Rate

Day 1 (Visit 3) In-clinic BP and PR change post first dose
Change in in-clinic BP and PR from 0 up to 8 hours post dose measured on the first day of study 
drug dosing will be analyzed using an MMRM analysis with baseline value, treatment, time post 
dose (hours) as fixed effects, and treatment by time and baseline by time as interaction terms
with repeated measures of time (hour) within subject. Two baselines will be considered: the 
Visit 3 pretreatment value (Time 0) and the time-matched baseline values from Visit 2 (hourly 
value 0-6 hours). For the second of these, there is no time-matched value for the Visit 3 7- and 
8-hour time points, so these will use the Visit 2 6-hour time point as their baseline value. A 
separate change from baseline analysis will be completed for each baseline approach.

Change in in-clinic BP and PR from baseline (Visit 2, predose) up to Week 12 (Visit 11)
To assess the impact of LY3154207 on BP and PR over time, change from baseline in in-clinic 
BP and PR to Week 12 will be analyzed using MMRM with response variable being the daily 
average of 0 to 6 hours, with fixed effects for baseline value, treatment, visit, and treatment by 
visit and baseline by visit as interaction terms with repeated measures of visit within subject. 
Change from baseline in BP and PR will be assessed at both 6 and 12 weeks. Analysis at 6 weeks 
will help to evaluate any significant changes (if any) in BP and PR earlier than 12 weeks (end of 
study) and if they accommodate by 6 weeks.


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6.14.7.2. Tertiary/Exploratory Safety Analyses
The following exploratory safety endpoints will also be analyzed using an MMRM model 
adjusting for baseline reading:

daily average change in HBPM measurements and PR from baseline to Week 12

change in MDS-UPDRS items 4.1 and 4.2, time with dyskinesias, and impact of dyskinesias

change in item 1.2 (hallucinations/psychosis) score of the MDS-UPDRS Part IA from 
baseline to Week 12

change in score for the delusion (Part A) and hallucinations (Part B) domains of the NPI from 
baseline to Week 12

change in QUIP score from baseline to Week 12, and

change in PWC-20 total score will be analyzed using an analysis of covariance (ANCOVA) 
model with a covariate for baseline score. The primary analysis will be a change from 
baseline (Visit 11) to the in-person follow-up visit (Visit 801).
6.14.7.3. Home Blood Pressure Monitoring Analyses
Change from baseline in (i) average daily, (ii) morning, and (iii) evening home BP and PR to 
Week 3 will be analyzed using an MMRM with fixed effects for baseline value, treatment, day, 
and treatment by day and baseline by day interaction terms with repeated measures of day within 
subject. The baseline value for each analysis will be defined as the average of all relevant 
samples taken prior to first dose of LY3154207. A similar analysis will be completed for the 
7 days before and after last dose. The MMRM analysis of the HBPM will provide daily estimates 
of change from baseline for the first 3 weeks of treatment. If there is a rise in BP and PR, the 
duration taken to accommodate can be assessed using the daily estimates of change from 
baseline. Visualizations will be used to characterize the temporal course of BP and PR changes, 
including accommodation. Additional exploratory analyses may be considered as necessary to 
further characterize the cardiovascular effects of LY3154207.
6.14.7.4. Addendum Safety Analyses
ABPM Addendum Objective
The objectives of the ABPM assessments are to explore any diurnal effects of LY3154207 on 
SBP and PR in subjects with PDD and whether these diurnal effects change over the study 
period—in particular, to evaluate the effect of LY3154207 on nocturnal dip in SBP.
ABPM Analysis
Only subjects participating in the ABPM addendum will be included in this analysis. The ABPM 
results will be summarized and represented graphically.
The ABPM will be used to assess the effect of LY3154207 on the dip in nocturnal SBP. A 
nocturnal dip is defined as a greater than 10% reduction in average SBP during the night 
compared to the average during the day. In order to reduce variability in the subject’s sleep and 
awake period, the nighttime is defined as 0100 hours to 0600 hours. Similarly, the daytime, for 
purposes of analysis, is defined as 0900 hours to 2100 hours, when most subjects would be 


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expected to be awake, and the morning surge is defined as the mean of 4 readings over a period 
of 2 hours after subjects wake up from the lowest nocturnal SBP (mean of 3 readings centered 
around the lowest nighttime SBP). For each ABPM assessment period following dose 
administration (assessments will be between Visits 3 and 4, between Visits 7 and 8, and between 
Visits 10 and 11), the proportion of subjects who have a nocturnal dip will be summarized by
treatment group, and a logistic regression will be performed to evaluate any treatment effect. The 
regression model will include the % reduction in SBP at baseline (measured between Visits 2
and 3) as a covariate. Odds ratios and associated 95% CIs will be presented.
Individual subject time courses will be reviewed graphically to investigate whether there is any 
morning surge effect.
In addition, the 24-hour average and the daytime and nighttime average SBP and PR changes 
from baseline at each ABPM assessment period will be analyzed using an MMRM analysis. 
Only the first 24 hours of data collected for each ABPM assessment period will be included. This 
will assess for any treatment effects and if there are any, whether they accommodate over the 
trial. The analyses will include fixed effects for baseline value, visit, treatment, treatment by time 
and baseline by time interaction with repeated measures of visit within subject. The time variable 
relates to the ABPM assessment period and will be assigned value of 1, 2, 3, or 4. An 
unstructured covariance matrix will be considered initially; however, if this fails to converge, 
other suitable structures will be considered. Baseline values will be defined as the 24-hour mean 
of the recordings taken following Visit 2; the mean of the recordings taken between 0900 hours 
to 2100 hours following Visit 2; and the mean of the recordings taken between 0100 hours to 
0600 hours following Visit 2.
6.15. Subgroup Analyses
Change in CoA, ADAS-Cog13, and CGIC from baseline to Week 12 may be assessed based on 
the following subgroups: concomitant PD therapy; use of concomitant AChEI therapy; use of 
memantine therapy; mild/moderate cognition (moderate: 10-16 total MoCA score; mild: 17-23
total MoCA score); and timing of dementia onset (less than or equal to 1 year versus greater than 
1 year relative to onset of motor symptoms). These analyses will involve running the analysis 
outlined in Section 6.12.1 on subsets of the EPP according to each level of each variable listed 
above separately.
All subgroup analyses will be considered exploratory, and additional subgroup analyses may be 
performed as suggested by the data.
6.16. Protocol Deviations
Important protocol deviations that have the potential to compromise data integrity and subject 
safety will be listed and summarized by treatment group for the Safety population.
A list of the categories, subcategories, and study-specific terms of important protocol deviations 
can be found in the Trial Issue Management Plan v1.0 (available in the electronic trial master file 
[eTMF]).


I7 S -M C -H B E H St ati sti c al A n al y si s Pl a n V er si o n 3
P a g e 3 0
L Y 3 1 5 4 2 0 7
Di sc o nti n uatio n d ue t o m eet i n g Da y 1 car dio v asc ular safety criteria d oes n ot q ualif y as a 
pr ot oc ol  de viati on.
6. 1 7. I nt eri m A n al y s e s a n d D at a M o nit ori n g
A li mite d n u m ber of pre-i de ntifie d i n di vi d uals ma y gai n access t o t he li mite d u n bli n de d data, as 
s pecifie d i n t he u n bli n di n g pla n. I nf or mat i on t hat ma y u n bli n d t he st u d y  d uri n g t he a nal yses will 
n ot be re p orte d t o st u d y  sit es or t he bli n de d st u d y  t e a m u ntil t he st u d y has bee n u n bli n de d.
T he efficac y a n d safet y i nteri m a nal yses will be c o m plete d a n d re vie we d b y a n I A C. O nl y t he 
I A C is a ut h orize d t o e val uate u n bli n de d i nteri m efficac y a n d safety a nal yses. St u d y sites will 
recei ve i nf or mati on a b o ut i nteri m res ults O N L Y if t he y  nee d t his i nf or mati on t o e ns ure t he safet y 
of  t h eir s u bjects.
S af et y i nteri m a nal yses will  be c o n d ucte d o n t he n u m ber of s u bjects o n eac h treat me nt w h o met 
t he p ote ntiall y cli nicall y si g nifica nt vit al si g ns crit eria at 3 c o nsec uti ve t i me p oi nts at Visit 3 
( D a y 1 st o p pi n g r ules). T his will be d o ne after 5 0, 1 0 0, a n d 1 5 0 s u bjects ha ve c o m plete d Visit 3. 
 
 
 T h ose alrea d y o n 7 5 -m g d ose w h o passe d t he 
D a y 1 st o p pi n g r ules will re mai n o n 7 5 m g. T he s pecific a nal ysis will be defi ne d i n t he I nteri m 
Stati stical A nal ysis Pla n. I n t he e ve nt of a n u nacce pta ble rate of s u bjects meet i n g Da y 1 st o p pi n g 
r ules at ot her d oses, a dj ust me n ts t o d oses ma y be ma de f or s u bse q ue ntl y ra n d omize d s u bjects at 
t he discret i on of t he I A C. A safet y a n d efficac y i nteri m a nal ysis will be c o n d ucte d w he n 
a p pr o xi matel y 1 7 0 ra n d o mize d s u bjects ha ve ha d t he o p p ort u nity t o c o mplete Vi sit 1 1 
( Wee k 1 2) assess me n ts. T he statistical a nal ysis will i ncl u de all 1 7 0 s u bjects i n t he i nteri m 
a nal ysis, w hic h will e val uate b ot h efficac y a n d safet y . I n a d ditio n, t he p har mac o ki net ic data m a y 
be re vie we d. T he efficac y a nal ysis ma y be use d f or i nter nal decisi o n ma ki n g, b ut is n ot pl a n ne d 
t o st o p t he st u d y for efficac y or f utilit y beca use t his is a n e x pl orat or y  st u d y a n d t here are ot her 
k e y  e n d p oi nts bei n g assesse d, n ot j ust t he pri mar y e n d p oi nt.
F or m ore details, see t he U n bli n di n g a n d C o m m u nicat i on Pl a n.
6. 1 8. Pl a n n e d E x pl or at or y A n al y s e s of Di git al Bi o m ar k er s
Di gi t al bio m ar kers ( P R E S E N C E a p p a n d Acti gra p h y watc h) data fr o m baseli ne t o Wee k 1 2 will 
be e x pl ore d usi n g a p pr o priate vis ual, u ni variate , a n d m ult i variate met h o ds t o u n dersta n d t he 
r elat i ons hi p of t he bi o mar ker e n d p o i nts t o ot her cli nical e n d p oi nts i n ter ms of treat me nt effect. 
T he data ma y als o be use d t o e x pl ore t he vali dit y a n d relia bilit y of  t hese assa ys i n s u bjects wi t h 
P D D . If a p plicable, p ote nti al pre dicti ve bi o mar kers ass ociat i n g wit h i nter preta ble cli nical be nefit 
ma y be f urt her e xa mi ne d wit h bi o l ogical  e vide nce. F urt her details are o utli ne d i n t he Di gital 
Bi o m ar ker E x plor at or y  Statistical A nal ysis Pla n.
C CI


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6.19. Development Safety Update Report
Annual listings of deaths from any cause and discontinuations due to AEs during the current 
development safety update report (DSUR) period will be created for the DSUR each year until 
trial completion. The format of the tables will be based on the most current guidance document.
An age flag will be created to meet requirements of DSUR summary table: <65, 65-84, and 85+.
6.20. Clinical Trial Registry Analyses
Additional analyses will be performed for the purpose of fulfilling the Clinical Trial Registry 
(CTR) requirements.
Analyses provided for the CTR requirements include the following:

Summary of AEs, provided as a dataset that will be converted to an XML file. Both Serious 
Adverse Events and ‘Other’ Adverse Events are summarized: by treatment group, by 
MedDRA Preferred Term.
-
An adverse event is considered ‘Serious’ whether or not it is a treatment-emergent 
adverse event (TEAE).
-
An adverse event is considered in the ‘Other’ category if it is both a TEAE and is not 
serious. For each Serious AE and ‘Other’ AE, for each term and treatment group, the 
following are provided:
o
the number of participants at risk of an event
o
the number of participants who experienced each event term, and
o
the number of events experienced.
-
Consistent with www.ClinicalTrials.gov requirements, ‘Other’ AEs that occur in 
fewer than 5% of subjects in every treatment group may not be included if a 5% 
threshold is chosen (5% is the minimum threshold).
-
Adverse event reporting is consistent with other document disclosures for example, 
the CSR, manuscripts, and so forth.


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7.
References
Andersen SW, Millen BA. On the practical application of mixed effects models for repeated 
measures to clinical trial data Pharm Stat. 2013;12(1):7-16. https://doi.org/10.1002/pst.1548
Bretz F, Pinheiro JC, Branson M. Combining multiple comparisons and modeling techniques 
in dose-response studies. Biometrics. 2005;61(3)738-748.
https://doi.org/0.1111/j.1541-0420.2005.00344.x
[FDA] United States Food and Drug Administration Office of Clinical Pharmacology Division of 
Pharmacometrics. Janssen Pharmaceuticals and Novartis Pharmaceuticals request for 
qualification of MCP-Mod as an efficient statistical methodology for model-based design 
and analysis of Phase II dose finding studies under model uncertainty. 2015. Accessed 
February 03, 2020. https://www.fda.gov/media/99313/download
Gelman A, Carlin JB, Stern HS, Rubin DB. Bayesian Data Analysis. 2nd ed. CRC Press; 2004.
Gould AL. BMA-Mod: A Bayesian model averaging strategy for determining dose-response 
relationships in the presence of model uncertainty. Biom J. 2019;61(5):1141-1159. 
https://doi.org/10.1002/bimj.201700211
Rowan E, McKeith IG, Saxby BK, et al. Effects of donepezil on central processing speed and 
attentional measures in Parkinson’s disease with dementia and dementia with Lewy bodies. 
Dement Geriatr Cogn Disord. 2007;23(3):161-167. https://doi.org/10.1159/000098335
Tomlinson CL, Stowe R, Patel S, et al. Systematic review of levodopa dose equivalency 
reporting in Parkinson’s disease. Mov Disord. 2010;25(15):2649-2653. https://doi.org/
10.1002/mds.23429
Wesnes KA, McKeith I, Edgar C, et al. Benefits of rivastigmine on attention in dementia 
associated with Parkinson disease. Neurology. 2005;65(10):1654-1656.
https://doi.org/10.1212/01.wnl.0000184517.69816.e9


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8.
Appendices


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Appendix 1.
Potentially Clinically Significant Vital 
Signs
Parameter
Unit
Observed 
Value
Change Relative to 
Baseline
Change from 
Supine to 
Standing
SBP (supine or sitting)
mm Hg
≥180
≤90
Increase of ≥20 
Decrease of ≥20
–
–
DBP (supine or sitting)
mm Hg
≥105
≤50
Increase of ≥15 
Decrease of ≥15
–
–
Pulse (supine or sitting)
bpm
≥120
≤50
Increase of ≥15 
Decrease of ≥15
–
–
Orthostatic hypotension (systolic)
Decrease in SBP when going from 5 minutes supine to 3 minutes 
standing of ≥20 mm Hg or the inability to stand quickly for the 
measurements due to symptoms of orthostasis
Orthostatic hypotension (diastolic)
Decrease in DBP when going from 5 minutes supine to 3 minutes 
standing of ≥10 mm Hg or the inability to stand quickly for the 
measurements due to symptoms of orthostasis
Orthostatic pulse (tachycardia)
Increase in heart rate when going from 5 minutes supine to 3 minutes 
standing of ≥30 bpm
Abbreviations: DBP = diastolic blood pressure; SBP = systolic blood pressure.