Clinical trial NCT03023826
Conditions: Healthy
Sponsor: Eli Lilly and Company
Start date: 2017-01-15; Completion date: 2017-04-04
Enrollment: 26 participants; Allocation: RANDOMIZED; Intervention model: CROSSOVER

Brief summary:
The purposes of this study are to determine:

* If there are any differences in the way LY3202626 is handled by the body when taken in two different forms
* Whether a high fat meal affects the way the body handles LY3202626
* How well tolerated LY3202626 is

There are three (3) study periods for all participants. Participants will be admitted to the clinical research unit (CRU) each period and will be discharged from the CRU following the completion of 2 overnight stays and up to 36 hours after dosing with LY3202626.

The study will last about 50 days, not including screening.

Detailed description:

Arms: arm 1: Single oral dose of LY3202626 (R) capsule under fasting conditions. arm 2: Single oral dose of LY3202626 (T1) tablet under fasting conditions. arm 3: Single oral dose of LY3202626 (T1) following a high fat breakfast.
Interventions: intervention 1: LY3202626 (R-Fasting) intervention 2: LY3202626 (T1-Fasting) intervention 3: LY3202626 (T1-Fed)
Intervention descriptions: intervention 1: Administered orally intervention 2: Administered orally intervention 3: Administered orally

Protocol documents:
Prot_000.pdf: 
I7X-MC-LLCE 
 
Relative Bioavailability and Food Effect Study in Healthy 
Subjects Administered Two Different Formulations of 
LY3202626 
NCT03023826  
Approval Date: 10 Sep 2016 
 


I7X-MC-LLCE Clinical Pharmacology Protocol
Page 1
LY3202626
Protocol I7X-MC-LLCE
Relative Bioavailability and Food Effect Study in Healthy 
Subjects Administered Two Different Formulations of 
LY3202626
Confidential Information
The information contained in this protocol 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 
LY3202626, 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.
LY3202626
Eli Lilly and Company
Indianapolis, Indiana USA 46285
Clinical Pharmacology Protocol Electronically Signed and Approved by Lilly on date 
provided below.
Approval Date: 10-Sep-2016 GMT


I7X-MC-LLCE Clinical Pharmacology Protocol
Page 2
LY3202626
Table of Contents
Relative Bioavailability and Food Effect Study in Healthy 
Subjects Administered Two Different Formulations of 
LY3202626
Section
Page
Protocol I7X-MC-LLCE Relative Bioavailability and Food Effect Study in 
Healthy Subjects Administered Two Different Formulations of 
LY3202626.........................................................................................................................1
Table of Contents........................................................................................................................2
1.
Protocol Synopsis................................................................................................................8
2.
Schedule of Activities .......................................................................................................10
3.
Introduction ......................................................................................................................12
3.1.
Study Rationale............................................................................................................12
3.2.
Background..................................................................................................................12
3.3.
Benefit/Risk Assessment..............................................................................................13
4.
Objectives and Endpoints..................................................................................................15
5.
Study Design.....................................................................................................................16
5.1.
Overall Design .............................................................................................................16
5.2.
Number of Participants.................................................................................................17
5.3.
End of Study Definition ...............................................................................................17
5.4.
Scientific Rationale for Study Design...........................................................................17
5.5.
Justification for Dose ...................................................................................................18
6.
Study Population...............................................................................................................19
6.1.
Inclusion Criteria..........................................................................................................19
6.2.
Exclusion Criteria ........................................................................................................20
6.3.
Lifestyle and/or Dietary Requirements .........................................................................21
6.3.1.
Meals and Dietary Restrictions.............................................................................21
6.3.2.
Xanthine, Alcohol, and Tobacco ..........................................................................22
6.3.3.
Activity................................................................................................................22
6.4.
Screen Failures.............................................................................................................23
7.
Treatment..........................................................................................................................24
7.1.
Treatment Administered...............................................................................................24
7.1.1.
Packaging and Labeling .......................................................................................24
7.2.
Method of Treatment Assignment ................................................................................24
7.2.1.
Selection and Timing of Doses.............................................................................24
7.3.
Blinding .......................................................................................................................24


I7X-MC-LLCE Clinical Pharmacology Protocol
Page 3
LY3202626
7.4.
Dose Modification........................................................................................................24
7.5.
Preparation/Handling/Storage/Accountability...............................................................24
7.6.
Treatment Compliance .................................................................................................25
7.7.
Concomitant Therapy...................................................................................................25
8.
Discontinuation Criteria ....................................................................................................26
8.1.
Discontinuation from Study Treatment.........................................................................26
8.1.1.
Discontinuation of Inadvertently Enrolled Subjects..............................................26
8.2.
Discontinuation from the Study....................................................................................26
8.3.
Subjects Lost to Follow-up...........................................................................................26
9.
Study Assessments and Procedures ...................................................................................27
9.1.
Efficacy Assessments...................................................................................................27
9.2.
Adverse Events ............................................................................................................27
9.2.1.
Serious Adverse Events........................................................................................28
9.2.1.1.
Suspected Unexpected Serious Adverse Reactions..........................................28
9.2.2.
Complaint Handling.............................................................................................28
9.3.
Treatment of Overdose.................................................................................................29
9.4.
Safety...........................................................................................................................29
9.4.1.
Laboratory Tests ..................................................................................................29
9.4.2.
Vital Signs ...........................................................................................................29
9.4.3.
Body Weight........................................................................................................29
9.4.4.
Electrocardiograms ..............................................................................................29
9.4.5.
Safety Monitoring ................................................................................................30
9.5.
Pharmacokinetics .........................................................................................................30
9.5.1.
Bioanalysis...........................................................................................................31
9.6.
Pharmacodynamics ......................................................................................................31
9.7.
Genetics .......................................................................................................................31
9.8.
Biomarkers...................................................................................................................32
9.9.
Health Economics ........................................................................................................32
10.
Statistical Considerations and Data Analysis.....................................................................33
10.1. Sample Size Determination ..........................................................................................33
10.2. Populations for Analyses..............................................................................................33
10.2.1.
Study Participant Disposition ...............................................................................33
10.2.2.
Study Participant Characteristics ..........................................................................33
10.3. Statistical Analyses ......................................................................................................33
10.3.1.
Safety Analyses....................................................................................................34
10.3.1.1.
Clinical Evaluation of Safety..........................................................................34
10.3.1.2.
Statistical Evaluation of Safety.......................................................................34
10.3.2.
Pharmacokinetic Analyses....................................................................................34


I7X-MC-LLCE Clinical Pharmacology Protocol
Page 4
LY3202626
10.3.2.1.
Pharmacokinetic Parameter Estimation...........................................................34
10.3.2.2.
Pharmacokinetic Statistical Inference .............................................................34
10.3.3.
Pharmacodynamic Analysis .................................................................................35
10.3.3.1.
Pharmacodynamic Parameter Estimation ........................................................35
10.3.3.2.
Pharmacodynamic Statistical Inference...........................................................35
10.3.4.
Interim Analyses..................................................................................................35
11.
References ........................................................................................................................36


I7X-MC-LLCE Clinical Pharmacology Protocol
Page 5
LY3202626
List of Tables
Table
Page
Table LLCE.1.
Objectives and Endpoints .......................................................................15
Table LLCE.2.
Dose Administration Sequences..............................................................16
Table LLCE.3.
High-Fat Meal Composition ...................................................................22


I7X-MC-LLCE Clinical Pharmacology Protocol
Page 6
LY3202626
List of Figures
Figure
Page
Figure LLCE.1.
Illustration of Study Design for Protocol I7X-MC-LLCE........................17


I7X-MC-LLCE Clinical Pharmacology Protocol
Page 7
LY3202626
List of Appendices
Appendix
Page
Appendix 1.
Abbreviations and Definitions ................................................................37
Appendix 2.
Clinical Laboratory Tests........................................................................40
Appendix 3.
Study Governance, Regulatory and Ethical Considerations.....................41
Appendix 4.
Blood Sampling Summary......................................................................44


I7X-MC-LLCE Clinical Pharmacology Protocol
Page 8
LY3202626
1. Protocol Synopsis
Title of Study:
Relative Bioavailability and Food Effect Study in Healthy Subjects Administered Two Different Formulations of 
LY3202626
Rationale: 
This study will explore the rate and extent of LY3202626 absorption when administered using a pilot tablet 
formulation, as compared to the drug-in-capsule formulation of LY3202626 that was used in previous studies.  The 
effect of a high fat meal on the rate and extent of LY3202626 absorption will also be explored.  The results of this 
study will be used when selecting doses for future clinical evaluations using a tablet formulation of LY3202626 and 
to understand whether the tablet formulation may be administered without regard to food. The change from baseline 
of amyloid beta (Aß) isoforms (Aβ1-40 and Aβ1-42) will be evaluated at the 12-mg LY3202626 dose level for both 
tablet and capsule formulations.
Objective(s)/Endpoints:
Objectives
Endpoints
Primary

To evaluate the relative bioavailability of a single 
12-mg dose of LY3202626 as a tablet 
formulation (test formulation [T1-12]) compared 
to the capsule formulation (reference formulation 
[R])
The ratio of geometric least square means and 
corresponding 90% confidence interval (CI) between 
T1-12 and R will be calculated for:  maximum 
observed drug concentration (Cmax), area under the 
concentration versus time curve (AUC) from time zero 
to infinity (AUC0-∞), and AUC from time zero to time 
t, where t is the last time point with a measurable 
concentration (AUC0-tlast).
Secondary

To evaluate the effect of a high-fat meal on the 
bioavailability of  LY3202626 when administered 
as a single 12-mg dose of the test tablet 
formulation (T1-12)

To assess the tolerability of LY3202626 when 
administered as a single 12-mg dose to healthy 
subjects
The ratio of geometric least square means and CI 
between LY3202626 T1-12 fed versus fasted will be 
calculated for:  Cmax, AUC0-∞, and AUC0-tlast.
Incidence of treatment-emergent adverse events.
Exploratory

To evaluate plasma Aβ1-40 and Aβ1-42 after a
single 12-mg dose of LY3202626 as a tablet 
formulation (test formulation [T1-12]) and capsule 
formulation (reference formulation [R])
Plasma concentrations of Aβ1-40 and Aβ1-42 will be 
summarized for each treatment based on the nadir 
concentration (Cnadir), and the time to reach Cnadir
(tnadir).  The percent change from baseline in Aβ1-40
and Aβ1-42 will be summarized for each treatment.


I7X-MC-LLCE Clinical Pharmacology Protocol
Page 9
LY3202626
Summary of Study Design:
Study I7X-MC-LLCE is a single-center, open-label, single-dose, randomized, 3-period, crossover study in healthy 
subjects.
Subjects will be admitted to the clinical research unit (CRU) on Day -1 of each period.  In each period, subjects will 
be fasted overnight for at least 10 hours, and a single dose of 12 mg LY3202626 will be administered on the 
morning of Day 1.  Blood sampling for assessment of LY3202626 PK and for pharmacodynamic assessments of 
Aβ1-40 and Aβ1-42 will be performed up to 168 hours postdose (Day 8).  Subjects may be discharged from the 
CRU following completion of all 24-hour or 36-hour procedures on Day 2.  Subjects will return to the CRU daily for 
outpatient visits for PK sample collections Days 3 through 8. The washout period between dosing in 2 consecutive 
periods will be at least 10 days.  A follow-up telephone call will be performed approximately 5 to 8 days after 
Period 3, Day 8.
Study completion is defined as completing all 3 study periods. Tolerability will be explored by assessment of 
clinical laboratory tests, vital sign measurements, 12-lead electrocardiograms, and recording of adverse events.
Treatment Arms and Duration:
Subjects will receive single doses of 12 mg LY3202626 on 3 separate occasions as a tablet formulation 
(1 administration under fed conditions and 1 administration under fasted conditions) and as a capsule formulation 
under fasted conditions, with sequence determined by randomization.  Screening will occur up to 28 days prior to 
Day 1 of Period 1 and each period will last approximately 8 days.  A follow-up telephone call will be performed 
approximately 5 to 8 days after Period 3, Day 8.
Number of Subjects:
A maximum of 30 subjects may be enrolled in order that approximately 20 subjects complete the study.
Statistical Analysis:
Pharmacokinetic parameter estimates will be evaluated to delineate effects of LY3202626 formulation and effect of 
food on LY3202626.  Log-transformed Cmax, AUC0-∞, and AUC0-tlast estimates will be evaluated in a linear 
mixed-effects model with fixed effects for formulation or fed/fasted state, period, and a random effect for subject.  
The treatment differences for T1-12 compared to R formulation and for T1-12 under fed conditions versus fasted 
conditions will be back-transformed to present the ratios of geometric least squares means and the corresponding 
90% CI.
The tmax will be analyzed non-parametrically.  Estimates of the median difference and 90% CIs will be calculated.
The ratio of geometric least square means and CI between LY3202626 T1-12 fed versus fasted will be calculated for 
Cmax, AUC0-∞, and AUC0-tlast.
Incidence of treatment-emergent adverse events will be recorded.


I7X-MC-LLCE Clinical Pharmacology Protocol  
Page 10 
LY3202626 
2. Schedule of Activities 
Study Schedule Protocol I7X-MC-LLCE 
 
Screening 
Periods 1, 2, and 3 
ET 
Follow-
upa 
Comments 
Procedure 
≤28 days 
prior to 
Period 1, 
Day 1 
Check-in 
Day -1 
Day 
1 
Day 
2 
Day 
3 
Day 
4 
Day 
5 
Day 
6 
Day 
7 
Day 
8 
 
~5 to 8 
days after 
Period 3 
Discharge 
ET visit should occur as soon as 
possible, up to 8 days, after study 
discontinuation 
Informed Consent 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Subject Admission 
to CRU 
 
X 
 
 
 
 
 
 
 
 
 
 
 
Subject Discharge 
from CRU 
 
 
 
X 
 
 
 
 
 
 
 
 
Subjects may be discharged from the 
CRU following completion of all 
24-hour or 36-hour procedures on 
Day 2.  If discharged after 24-hour 
procedures, subject will return to the 
CRU as an outpatient visit for the 
36-hour PK sample collection. 
Outpatient Visit 
 
 
 
X 
X 
X 
X 
X 
X 
X 
 
 
 
Overnight Fast 
 
X 
 
 
 
 
 
 
 
 
 
 
Overnight fast of at least 10 h to 
begin in the evening prior to day of 
dosing in each study period. 
High-fat Meal 
Administration 
 
 
X 
 
 
 
 
 
 
 
 
 
LY3202626 administered in a fed 
state (Food and Drug Administration 
[FDA] high-fat meal) for food effect 
period only 
LY3202626 
Administration 
 
 
X 
 
 
 
 
 
 
 
 
 
The washout period between dosing 
in 2 consecutive periods will be at 
least 10 days. 
Medical History 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Height 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Weight 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Serology 
X 
 
 
 
 
 
 
 
 
 
 
 
 
AE Assessment 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
Vital Signs (supine 
and standing) 
X 
 
Predose, 
3, 4, 6, 
8 h 
24 h 
X 
X 
 
X 
 
X 
X 
 
Additional vital signs may be 
measured during each study period, 
if warranted. 


I7X-MC-LLCE Clinical Pharmacology Protocol
Page 11
LY3202626
Screening
Periods 1, 2, and 3
ET
Follow-
upa
Comments
Procedure
≤28 days 
prior to 
Period 1,
Day 1
Check-in
Day -1
Day
1
Day
2
Day 
3
Day 
4
Day 
5
Day 
6
Day 
7
Day
8
~5 to 8 
days after 
Period 3 
Discharge
ET visit should occur as soon as 
possible, up to 8 days, after study 
discontinuation
12-lead ECG
X
Predose, 
3, 4, 6, h
24 h
X
X
Triplicate ECGs collected and 
stored. Screening ECG will be 
collected as single ECG and not 
stored.
Clinical Lab Tests
X
X
24 h
X
X
See Appendix 2, Clinical Laboratory 
Tests, for details.  Screening Clinical 
Lab Tests should be repeated and 
reviewed prior to dosing, if not 
performed within 10 days of dosing.
FSH
X
FSH will be performed on 
postmenopausal females only, with 
6-12 months of amenorrhea.
Physical 
Exam/Medical 
Assessment
X
X
X
X
Physical exam performed at 
screening.  After enrollment, 
medical assessment only performed 
to include medical review and 
targeted examination, as appropriate.
PK Sample
Predose, 
0.5, 1, 2, 
3, 4, 5, 6, 
8, 10, 
and 12 h
24 and 
36 h
48 h
72 h
96 h
120 h
144 h
168 h
Sampling times are relative to the 
time of study drug administration 
(0 h).  
PD Sample
Predose, 
0.5, 1, 2, 
3, 4, 5, 6, 
8, 10, 
and 12 h
24 and 
36 h
48 h
72 h
96 h
120 h
144 h
168 h
For Aβ1-40 and Aβ1-42 assessments
Pharmacogenetic 
Sample
Predose
Single sample for pharmacogenetic 
analysis taken prior to/on Day 1 in 
Period 1 only.
Abbreviations:  AE = adverse event; CRU = clinical research unit; ECG = electrocardiogram; ET = early termination; FSH = follicle-stimulating hormone; 
h = hours; PD = pharmacodynamics; PK = pharmacokinetics.
a Follow-up will be conducted as a telephone call and will include recording of adverse events and concomitant medication.


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I7X-MC-LLCE Clinical Pharmacology Protocol
Page 13
LY3202626
associated with the terminal rate constant in noncompartmental analysis
 
The effect of concomitant administration of itraconazole (a strong cytochrome P450 [CYP] 3A 
inhibitor) on the PK of LY3202626 following single doses of 0.4 mg has been evaluated.  In this 
evaluation,
 
 
The LY3202626 capsule formulation has been administered with and without food.  When
administered with food, 
 
 
 
  
 
3.3.
Benefit/Risk Assessment
LY3202626 has been administered to 85 healthy subjects over a range from 0.1 to 45 mg, and at 
steady state from 1 to 26 mg QD.  LY3202626 has been administered to 2 patients with mild 
cognitive impairment due to AD or mild to moderate AD at a 6 mg dose level.
To date, no serious adverse events (SAEs) have been reported in subjects participating in clinical
trials of LY3202626. Overall, 54.5% of all subjects who received LY3202626 or placebo
reported one or more treatment-emergent adverse events (TEAEs). Reported by more than one
study participant were the following TEAEs (Medical Dictionary for Regulatory Activities
[MedDRA] preferred terms):  discoloured faeces (18.2%), post-lumbar puncture syndrome
(15.2%), headache (10.1%), dizziness (7.1%), diarrhoea (6.1%), nausea (4.0%), decreased
appetite (3.0%), arthralgia, chest pain, dysgeusia, fatigue, and somnolence (all 2.0%). No
subjects have discontinued either of the 2 ongoing clinical trials due to adverse events (AEs).
Orthostatic hypotension was reported by 1 study participant who received a single 10-mg 
LY3202626 dose in the single-ascending dose portion of the study, and postural orthostatic 
tachycardia syndrome was reported by 1 study participant who received a 26-mg LY3202626
dose in a multiple-ascending dose cohort. There was no dose response in the orthostatic 
hypotension (since the AEs occurred below the maximum dose 45 mg in the single-ascending 
dose portion of the study).  While the clinical significance of these AEs is unclear, orthostatic 
vital signs will be collected in this study to further assess any potential cardiovascular effect of 
LY3202626.
There were no clinically significant changes in electrocardiograms (ECGs) or safety laboratories. 
 
In order to acquire additional 
clinical QTc data for BACE IV, ECG assessments will be obtained in triplicate near Cmax and at 
24 hours postdose.
.
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The 12-mg dose selected for this study is not expected to demonstrate significant safety or 
tolerability concerns based on the available data.
As this study is enrolling healthy subjects, no clinical benefit is anticipated from study 
participation.
More information about the known and expected benefits, risks, SAEs, and reasonably 
anticipated adverse events (AEs) of LY3202626 are to be found in the IB.


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4. Objectives and Endpoints
Table LLCE.1 shows the objectives and endpoints of the study.
Table LLCE.1.
Objectives and Endpoints
Objectives
Endpoints
Primary
To evaluate the relative bioavailability of a single 12-mg 
dose of LY3202626 as a tablet formulation (test 
formulation [T1-12]) compared to the capsule 
formulation (reference formulation [R])
The ratio of geometric least square means and 
corresponding 90% confidence interval (CI) between 
T1-12 and R will be calculated for:  Cmax, area under the 
concentration versus time curve (AUC) from time zero 
to infinity (AUC0-∞), and AUC from time zero to time 
t, where t is the last time point with a measurable 
concentration (AUC0-tlast).
Secondary

To evaluate the effect of a high-fat meal on the 
bioavailability of  LY3202626 when administered 
as a single 12-mg dose of the test tablet formulation 
(T1-12)

To assess the tolerability of LY3202626 when 
administered as a single 12-mg dose to healthy 
subjects
The ratio of geometric least square means and CI 
between LY3202626 T1-12 fed versus fasted will be 
calculated for:  Cmax, AUC0-∞, and AUC0-tlast.
Incidence of TEAEs.
Exploratory

To evaluate plasma Aβ1-40 and Aβ1-42 after a
single 12-mg dose of LY3202626 as a tablet 
formulation (test formulation [T1-12]) and capsule 
formulation (reference formulation [R])
Plasma concentrations of Aβ1-40 and Aβ1-42 will be 
summarized for each treatment based on the nadir 
concentration (Cnadir), and the time to reach Cnadir
(tnadir).  The percent change from baseline in Aβ1-40
and Aβ1-42 will be summarized for each treatment.


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5. Study Design
5.1.
Overall Design
This is a single-center, open-label, single-dose, randomized, 6-sequence, 3-period, crossover 
study in healthy subjects.
Screening will occur up to 28 days prior to the first dose of LY3202626.
Subjects will be admitted to the clinical research unit (CRU) on Day -1 of each period.  In each 
period, subjects will be fasted overnight for at least 10 hours, and a single dose of 12 mg 
LY3202626, as either tablet (T1-12) in a fed state or fasted state or capsule (R) in a fasted state 
according to the randomization schedule, will be administered on the morning of Day 1.  Blood 
sampling for assessment of LY3202626 PK and for pharmacodynamic (PD) assessments of 
Aβ1-40 and Aβ1-42 will be performed up to 168 hours postdose (Day 8).  Subjects may be 
discharged from the CRU following completion of all 24-hour or 36-hour procedures on Day 2.  
If discharged after 24-hour procedures, subject will return to the CRU as an outpatient visit for 
the 36-hour PK sample collection.  Subjects will return to the CRU daily for outpatient visits for 
PK sample collections Days 3 through 8.  The washout period between dosing in 2 consecutive 
periods will be at least 10 days.  A follow-up telephone call will be performed approximately 
5 to 8 days after Period 3, Day 8.
Tolerability will be explored by clinical laboratory tests, vital sign measurements, 12-lead ECGs, 
and recording of AEs.
The 3 dose administrations received by each subject will be:

A = Reference (R):  12-mg LY3202626 capsule; administered in a fasted state

B = Test (T1-12):  12-mg LY3202626 tablet; administered in a fasted state

C = Test (T1-12):  12-mg LY3202626 tablet; administered in a fed state (Food and Drug 
Administration [FDA] high-fat meal)
Subjects will be randomized to 1 of 6 dose administration sequences (Table LLCE.2).
Table LLCE.2.
Dose Administration Sequences
Sequence
Period 1
Period 2
Period 3
ABC
R fasted
T1-12 fasted
T1-12 fed
BCA
T1-12 fasted
T1-12 fed
R fasted
CAB
T1-12 fed
R fasted
T1-12 fasted
CBA
T1-12 fed
T1-12 fasted
R fasted
ACB
R fasted
T1-12 fed
T1-12 fasted
BAC
T1-12 fasted
R fasted
T1-12 fed
Abbreviations:  R = reference (capsule formulation); T1-12 = test (tablet formulation).


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Figure LLCE.1 illustrates the study design.
Figure LLCE.1.
Illustration of Study Design for Protocol I7X-MC-LLCE.
5.2.
Number of Participants
Initially, up to approximately 24 healthy subjects may be enrolled so that approximately 20 
subjects complete the study. Study completion is defined as completing all 3 study periods.  If 
multiple subjects who are randomized withdraw before study end, up to 6 additional subjects 
may be enrolled to ensure completion of 20 subjects. In the event that these 6 additional subjects 
are enrolled, a maximum of 30 subjects may be enrolled in the trial.
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
This study uses a randomized, open-label, crossover design such that each subject acts as their
own control, thus reducing variability.  The open-label design with no placebo control is
considered appropriate because determining the relative bioavailability of the reference capsule 
and test tablet formulation of LY3202626 is the primary objective of the study.
A capsule formulation of LY3202626 has been used in the clinical studies with LY3202626 to 
date.  However, a tablet formulation of LY3202626 is being developed for later phase studies.  
Therefore a relative bioavailability study enables the assessment of the relative PK between the 
Period Day *  -1    1     2    3     4    5     6     7    8    -1   1     2     3    4    5     6    7     8    -1    1    2    3     4     5    6     7    8  
Period 1
Period 3
Period 2
*
Screening (up to 28 days prior to dosing)
Check-in
LY3202626 dosing (with or without high-fat meal)
Pharmacokinetic and pharmacodynamic blood sampling
Follow-up telephone call (5 to 8 days after Period 3 discharge)
Overnight fast
Clinic discharge, after completion of 24-hour or 36-hour study procedures
Outpatient visit
The washout period between dosing in 2 consecutive periods will be at least 10 days.


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reference capsule and test tablet formulations of LY3202626.  LY3202626 has been 
administered as high as 26 mg for 14 days in Phase I studies.  However, the highest dose in the 
current Phase 2 study is 12 mg; therefore the relative bioavailability of a 12 mg dose of the 
capsule and tablet formulation will be assessed in this study.
Reductions of Aβ1-40 from baseline were seen following doses of 1-, 6-, and 26-mg LY3202626 
QD for 14 days in a cohort of healthy subjects.  The change from baseline of Aß isoforms 
(Aβ1-40 and Aβ1-42) after a single 12-mg dose of LY3202626 as a tablet formulation (test 
formulation [T1-12]) and capsule formulation (reference formulation [R]) will be evaluated in 
plasma in this study.
Based on the reported LY3202626 half-life associated with the terminal rate constant (t1/2)
determined using noncompartmental analysis (approximately 
the interval of at least 
10 days between dosing in each period is adequate to ensure that there is no carryover of 
exposure from one dose to the next.
5.5.
Justification for Dose
Nonclinical data as well as safety, PK and PD data to date from the ongoing Phase 1 study in 
healthy subjects and patients with mild cognitive impairment (Study LLCA , see Section 3 above) 
support a single dose study in healthy subjects.  It is anticipated that a single dose of 12 mg 
LY3202626 will be well tolerated by healthy subjects (see Section 3.3).
The 12-mg dose selected is the highest dose currently being evaluated in Phase 2 studies, and is 
projected to be the highest dose to be evaluated in Phase 3 studies. Administration of this dose 
of LY3202626 predicts a 
 in CSF Aß, the primary dose selection biomarker for 
LY3202626. The FDA guidance (FDA Guidance, 2002) recommends the highest strength of a 
drug product intended to be marketed should be tested in food-effect studies. The 12-mg dose 
will enable the objectives of this trial to be addressed and fully characterize the single oral dose 
PK of the compound.
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6. Study Population
Eligibility of subjects for study enrollment will be based on the results of screening medical 
history, physical examination, vital signs, clinical laboratory tests, and ECG.
The nature of any conditions present at the time of the physical examination and any pre-existing 
conditions will be documented.
Screening may occur up to 28 days prior to first dose.  Subjects who are not enrolled within 
28 days of screening may be subjected to an additional medical assessment and/or clinical 
measurements to confirm their eligibility.
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 for inclusion in the study only if they meet all of the following criteria at 
screening and/or enrollment:
[1]
are overtly healthy males or females, as determined by medical history and 
physical examination
[1a] female subjects:
must be of non-childbearing potential confirmed by medical history or menopause
female patients are considered of non-childbearing potential if they have undergone
surgical sterilization (hysterectomy or bilateral oophorectomy or tubal ligation), 
have a congenital anomaly such as mullerian agenesis, or are postmenopausal as 
defined by either:
[i] women 50 years of age or older not on hormone therapy, who have had 
6 to 12 months of spontaneous amenorrhea with a follicle-stimulating 
hormone level greater than 40 mIU/mL; or
[ii] women at least 50 years of age with a diagnosis of menopause prior to 
starting hormone replacement therapy
[2]
are at least 21 years old at the time of screening
[3]
have a body mass index (BMI) of 18.5 to 32.0 kg/m2, inclusive, at screening
[4]
have clinical laboratory test results within normal reference range for the 
investigative site, or results with acceptable deviations that are judged to be 
not clinically significant by the investigator
[5]
have venous access sufficient to allow for blood sampling as per the protocol
[6]
are reliable and willing to make themselves available for the duration of the 
study and are willing to follow study procedures


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[7]
are willing and able to eat the protocol-specified high-fat breakfast
[8]
are able and willing to give signed informed consent
6.2.
Exclusion Criteria
Subjects will be excluded from study enrollment if they meet any of the following criteria at 
screening and/or enrollment:
[9] are investigative site personnel directly affiliated with this study and their 
immediate families.  Immediate family is defined as a spouse, biological or 
legal guardian, child, or sibling
[10] are Lilly or Covance employees
[11] are currently enrolled in a clinical trial involving an investigational product or 
any other type of medical research judged not to be scientifically or medically 
compatible with this study
[12]
have participated, within the last 30 days, in a clinical trial involving an 
investigational product.  If the previous investigational product has a long 
half-life, 3 months or 5 half-lives (whichever is longer) should have passed
[13]
have previously completed or withdrawn from this study or any other study 
investigating LY3202626, and have previously received the investigational 
product 
[14]
have known allergies to LY3202626, related compounds or any components 
of the formulation, or history of significant atopy
[15]
have an abnormality in the 12-lead ECG that, in the opinion of the 
investigator, increases the risks associated with participating in the study
[16]
have an abnormal blood pressure or pulse rate (supine or standing) that, in the 
opinion of the investigator, increases the risks associated with participating in 
the study 
[17]
have a history of or current cardiovascular, respiratory, hepatic, renal, 
gastrointestinal, endocrine, hematological, or neurological disorders capable 
of significantly altering the absorption, metabolism, or elimination of drugs; 
of constituting a risk when taking the investigational product; or of interferin g 
with the interpretation of data
[18]
have a history of seizure(s) (except childhood febrile seizure)
[19]
have a history of head trauma with loss of consciousness within the last 
5 years
[20]
have known or ongoing psychiatric disorders 
[21]
regularly use known drugs of abuse
[22]
show evidence of human immunodeficiency virus (HIV) infection and/or 
positive human HIV antibodies


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[23]
show evidence of hepatitis C and/or positive hepatitis C antibody 
[24]
show evidence of hepatitis B and/or positive hepatitis B surface antigen 
[25]
are women who are lactating, nursing, or have a positive pregnancy test
[26]
intend to use over-the-counter or prescription medication including herbal 
medications within 7 days prior to dosing
[27]
have donated blood of 450 mL or more within the last 3 months or provided 
any blood donation within the last month before screening
[28]
have an average weekly alcohol intake that exceeds 21 units per week for 
males under 65 years of age and 14 units per week for females and for males 
over 65 years of age, or are unwilling to stop alcohol consumption from 
48 hours prior to each admission and while resident in the CRU (1 unit = 
12 oz or 360 mL of beer; 5 oz or 150 mL of wine; 1.5 oz or 45 mL of distilled 
spirits)
[29]
have consumed grapefruits or grapefruit-containing products, Seville oranges 
or Seville orange-containing products, star fruit or star fruit-containing 
products within 7 days prior to dosing or intend to consume during the study
[30]
are currently or have been smokers or users of tobacco or nicotine 
replacement products within the 6 months prior to admission
[31]
are unwilling to refrain from consuming xanthine-containing food and drink 
from 48 hours prior to each admission until discharge from the CRU
[32]
are unwilling to comply with the dietary requirements/restrictions during the
study or unwilling to consume only the meals provided during the inpatient 
visits
[33]
in the opinion of the investigator or sponsor, are unsuitable for inclusion in the 
study
6.3.
Lifestyle and/or Dietary Requirements
Throughout the study, subjects may undergo medical assessments and review of compliance with 
requirements before continuing in the study.  
6.3.1.Meals and Dietary Restrictions
Standardized meals will be provided during each subject’s stay in the CRU.
Subjects will not consume grapefruits or grapefruit-containing products, Seville oranges or 
Seville orange-containing products, star fruit or star fruit-containing products for at least 7 days 
prior to the first dose of LY3202626 until the final PK sample is collected following the last dose 
of LY3202626.


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Administration of LY3202626 in the fasted state
Administration of each LY3202626 dose will be preceded by at least a 10-hour fast.  No fluid 
will be allowed from 1 hour prior to dosing until 1 hour after dosing except for the approximate 
240 mL water required for dose administration.  No food will be allowed until approximately 
4 hours postdose.
Administration of LY3202626 in the fed state
Following an overnight fast of at least 10 hours, subjects will start the high-fat, high-calorie meal 
30 minutes prior to administration of LY3202626; the meal should contain approximately 800 to 
1000 calories in total, of which approximately 500 to 600 calories should be derived from fat and 
approximately 150 and 250 calories should be derived from protein and carbohydrate, 
respectively.  An example meal is detailed in Table LLCE.3.  It is intended that the meal will be 
ingested in its entirety over an approximate 25-minute period, such that it is completed at least 
5 minutes before dosing.  No water will be allowed from 1 hour prior to dosing until 1 hour after 
dosing except for the approximate 240 mL water required for dose administration.  No further 
food will be permitted until at least 5 hours postdose.
Table LLCE.3.
High-Fat Meal Composition
2 eggs fried in butter
2 strips of bacon
2 slices of toast with butter
4 ounces of hash brown potatoes
8 ounces of whole milk
For the dosing period in the fed state, the date and start time of high fat meal consumption on 
Day 1 will be recorded.
6.3.2.Xanthine, Alcohol, and Tobacco
Subjects will be advised to refrain from consuming xanthine-containing food or drinks from 
48 hours prior to admission and while resident in the CRU.
Subjects will not consume alcohol for 48 hours prior to admission and while resident in the 
CRU.
Smoking will not be permitted throughout the study.
6.3.3.Activity
Subjects should avoid strenuous physical activity for 72 hours before the first dose of
LY3202626 until completion of the study.


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6.4.
Screen Failures
Individuals who do not meet the criteria for participation in this study (screen failure) may not be 
re-screened.


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7. Treatment
7.1.
Treatment Administered
One 12-mg capsule or one 12-mg tablet of LY3202626 will be administered orally with 
approximately 240 mL of room temperature water in the morning of each dosing day in a sitting 
position.  Subjects will not be allowed to lie supine for 2 hours after dosing, unless clinically 
indicated or for study procedures.
The investigator or designee is responsible for:

explaining the correct use of the investigational products to the subject and site personnel, 

verifying that instructions are followed properly,

maintaining accurate records of investigational product dispensing and collection,

and returning all unused medication to Lilly or its designee at the end of the study.
Note: In some cases, sites may destroy the material if, during the investigative site selection, the 
evaluator has verified and documented that the site has appropriate facilities and written 
procedures to dispose of clinical trial materials. 
7.1.1.Packaging and Labeling
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.
7.2.
Method of Treatment Assignment
Subjects will be randomized to 1 of 6 dose administration sequences using a computer-generated 
allocation schedule (see Table LLCE.2).
7.2.1.Selection and Timing of Doses
The doses will be administered at approximately the same time on each dosing day.  The actual 
date, time, LY3202626 amount, formulation (capsule-reference or tablet-test) as well as 
administration condition (fasted or fed) of all dose administrations will be recorded in the 
subject’s electronic case report form (eCRF).
7.3.
Blinding
This is an open-label study.
7.4.
Dose Modification
Dose reductions or adjustments will not be allowed during this study.
7.5.
Preparation/Handling/Storage/Accountability
Only participants enrolled in the study may receive investigational product (IP) and only 
authorized site staff may supply or administer study treatment.  All study treatments should be 


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stored in an 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
The investigational product will be administered at the clinical site, and documentation of dose
administration will occur at the site.
7.7.
Concomitant Therapy
Additional drugs are to be avoided during the study unless required to treat an AE.  If the need 
for concomitant medication arises, inclusion or continuation of the subject may be at the 
discretion of the investigator after consultation with a Lilly clinical pharmacologist (CP) or 
clinical research physician (CRP), or designee.  The use of topical medicine, provided there is no 
evidence of chronic dosing with risk of systemic exposure, is acceptable.  Hormone replacement 
therapy and/or occasional acetaminophen administration will be allowed at the discretion of the 
investigator.  Any additional medication used during the course of the study must be 
documented.


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8. Discontinuation Criteria
8.1.
Discontinuation from Study Treatment
Subjects who discontinue the study early will have procedures performed as shown in the 
Schedule of Activities (Section 2).
8.1.1.Discontinuation of Inadvertently Enrolled Subjects
If the Sponsor or investigator identifies a subject who did not meet enrollment criteria and was 
inadvertently enrolled, the subject will be discontinued from the study and early discontinuation 
assessments will be performed as described in the Schedule of Activities (Section 2).
8.2.
Discontinuation from the Study
Subjects will be discontinued in the following circumstances:

enrollment in any other clinical trial involving an IP 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

subject decision
o
the subject requests to be withdrawn from the study
Subjects who discontinue the study early will have end-of-study procedures performed as shown 
in the Schedule of Activities (Section 2).
8.3.
Subjects 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.


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9. Study Assessments and Procedures
Section 2 lists the Schedule of Activities, detailing the study procedures and their timing.
Appendix 2 lists the laboratory tests that will be performed for this study.
Appendix 4 provides a summary of the maximum number and volume of invasive samples, for
all sampling, during the study.
Unless otherwise stated in 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.
Investigators must document their review of each laboratory safety report.
9.1.
Efficacy Assessments
This section is not applicable for this study.
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 to 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.
The investigator remains responsible for following, through an appropriate health care option, 
AEs that are serious or otherwise medically important, considered related to the IP or the study, 
or that caused the subject to discontinue the IP before completing the study.  The subject should 
be followed until the event resolves, stabilizes with appropriate diagnostic evaluation, or is 
reasonably explained.  The frequency of follow-up evaluations of the AE is left to the discretion 
of the investigator.
After the informed consent form (ICF) is signed, study site personnel will record, via eCRF, the 
occurrence and nature of each subject’s preexisting conditions.  Additionally, site personnel will 
record any change in the condition(s) and the occurrence and nature of any AEs.  
The investigator will interpret and document whether or not an AE has a reasonable possibility 
of being related to study treatment or a study procedure, taking into account concomitant 
treatment or pathologies.  
Planned surgeries should not be reported as AEs unless the underlying medical condition has 
worsened during the course of the study.
If a subject’s IP is discontinued as a result of an AE, study site personnel must report this to Lilly 
or its designee via eCRF.


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9.2.1.Serious Adverse Events
An SAE is any AE from this study that results in one of the following:

death

initial or prolonged inpatient hospitalization

a life-threatening experience (that is, immediate risk of dying)

persistent or significant disability/incapacity

congenital anomaly/birth defect

events considered significant by the investigator based upon appropriate medical 
judgment
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.
Investigators are not obligated to actively seek AEs or SAEs in subjects once they have 
discontinued from and/or completed the study (the subject 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. 
Pregnancy (maternal or paternal exposure to IP) 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.
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 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 trials in order to ensure the safety of study participants, monitor quality, and to facilitate 
process and product improvements.
Subjects should be instructed to contact the investigator as soon as possible if he or she has a 
complaint or problem with the IP so that the situation can be assessed.


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9.3.
Treatment of Overdose
For the purposes of this study, an overdose of LY3202626 is considered any dose higher than the 
dose assigned.  There is no specific antidote for LY3202626.  In the event of overdose, the
subject should receive appropriate supportive care and any AEs should be documented.
9.4.
Safety
9.4.1.Laboratory Tests
For each subject, laboratory tests detailed in Appendix 2 should be conducted according to the 
Schedule of Activities (Section 2) and following the manual of operations.
9.4.2.Vital Signs
For each subject, vital sign measurements should be conducted according to the Schedule of 
Activities (Section 2).  Additional unscheduled vital sign measurements may be conducted if 
clinically indicated.
Blood pressure and pulse rate will be measured with automated equipment.  Use of the same arm 
for blood pressure determination throughout the study is recommended, whenever possible.  The 
cuff should be the correct size for the subject’s arm.  The arm with the cuff should be supported 
at approximately the heart level whether supine or standing.
Blood pressure and pulse rate will be measured supine and standing.  Supine blood pressure and 
pulse rate should be taken after at least 5 minutes of supine rest.  The subject should then sit for 
3 minutes before standing.  Standing blood pressure and pulse rate should be taken 3 minutes 
after standing.  If the subject feels unable to stand, only supine vital signs will be recorded.  
Symptoms occurring during a subject’s change in position or that prevent standing should be 
recorded as AEs.
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.
9.4.3.Body Weight
Body weight will be recorded as specified in the Schedule of Activities (Section 2).
9.4.4.Electrocardiograms
For each subject, ECGs should be collected according to the Schedule of Activities (Section 2).
Any clinically significant findings from ECGs that result in a diagnosis and that occur after the 
subject receives the first dose of the IP, should be reported to Lilly, or its designee, as an AE via 
eCRF.
For each subject during each dosing period, a 12-lead digital ECG will be collected in triplicate
and stored.  Screening ECG will be collected as a single ECG and not stored. 
Electrocardiograms must be recorded before collecting any blood for safety or pharmacokinetic 


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tests.  Subjects must be supine for approximately 5 to 10 minutes before 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.  
Electrocardiograms will be interpreted by a qualified physician (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.
If a clinically significant quantitative or qualitative change from baseline is identified after 
enrollment, the investigator will assess the subject for symptoms (for example, 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.
Digital ECGs will be electronically transmitted to a central ECG laboratory designated by Lilly.  
The central ECG laboratory will perform a basic quality control check (for example, 
demographics and study details) then store the ECGs in a database.  At a future time, the stored 
ECG data may be overread at the central ECG laboratory for further evaluation of machine-read 
measurements or to meet regulatory requirements.
The machine-read ECG intervals and heart rate may be used for data analysis and report writing 
purposes unless a cardiologist overread of the ECGs is conducted prior to completion of the final 
study report (in which case the overread data would be used).
9.4.5.Safety Monitoring
The Lilly CP or CRP will monitor safety data throughout the course of the study.
Lilly will review SAEs within time frames mandated by company procedures.  The Lilly CP or 
CRP will consult with the functionally independent Global Patient Safety therapeutic area 
physician or clinical research scientist when appropriate, and periodically review:

trends in safety data

laboratory analytes

AEs
9.5.
Pharmacokinetics
At the visits and times specified in the Schedule of Activities (Section 2), venous blood samples 
of approximately 3 mL each will be collected to determine the plasma concentrations of 
LY3202626.  A maximum of 2 samples may be collected at additional time points during the 
study if warranted and agreed upon between both the investigator and sponsor.  Instructions for 


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LY3202626
the collection and handling of blood samples will be provided by the sponsor.  The actual date 
and time (24-hour clock time) of each sampling will be recorded.
9.5.1.Bioanalysis
Samples will be analyzed at a laboratory approved by the sponsor and stored at a facility 
designated by the sponsor.
Concentrations of LY3202626 will be assayed using a validated liquid chromatography with 
tandem mass spectrometric detection method.
Bioanalytical samples collected to measure investigational product concentrations will be 
retained for a maximum of 2 years following last subject visit for the study.  During this time, 
samples remaining after the bioanalyses may be used for exploratory analyses such as 
metabolism and/or protein binding work.
9.6.
Pharmacodynamics
At the visits and times specified in the Schedule of Activities (Section 2) venous blood samples 
of approximately 2 mL will be collected for measurement of plasma Aβ concentrations. 
Plasma concentrations of Aβ1-40 and Aβ1-42 will be determined using validated immunoassay 
methods. The samples will be identified by the subject number (coded) and stored for up to a 
maximum of 1 year after the last subject visit for the study at a facility selected by the sponsor.
9.7.
Genetics
A blood sample will be collected for pharmacogenetic analysis as specified in the Schedule of 
Activities (Section 2), where local regulations allow.  
Samples will not be used to conduct unspecified disease or population genetic research either 
now or in the future.  Samples will be used to investigate variable response to LY3202626 and to 
investigate genetic variants thought to play a role in neurodegenerative disease.  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 investigative site personnel.  
Samples will be retained for a maximum of 15 years after the last subject visit, or for a shorter 
period if local regulations and/or Ethical Review Boards (ERBs/IRBs) impose shorter time 
limits, for the study at a facility selected by Lilly or its designee.  This retention period enables 
use of new technologies, response to regulatory questions, and investigation of variable response 
that may not be observed until later in the development of LY3202626 or after LY3202626 is 
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, multiplex assays, and candidate gene studies.  


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LY3202626
Regardless of technology utilized, data generated will be used only for the specific research 
scope described in this section. 
9.8.
Biomarkers
This section is not applicable for this study.
9.9.
Health Economics
This section is not applicable for this study.


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LY3202626
10.
Statistical Considerations and Data Analysis
10.1. Sample Size Determination
Up to approximately 24 healthy subjects may be enrolled to ensure that at least 20 subjects 
complete the study. This sample size is based on a calculation of precision of the estimated ratio 
of area under the concentration versus time curve (AUCs).
 
 
 
 
 
At the discretion of the investigator and sponsor, if multiple subjects who are randomized 
withdraw before study end, an additional 6 subjects (up to a total enrollment of 30 subjects) may 
be enrolled to ensure completion of 20 subjects. The replacement subject will be assigned the 
same dose administration sequence as the withdrawn subject’s dose administration sequence 
(receiving each dose administration allocated).
10.2. Populations for Analyses
10.2.1.
Study Participant Disposition
A detailed description of subject disposition will be provided at the end of the study. 
10.2.2.
Study Participant Characteristics
The subject’s age, sex, weight, height, BMI, race, and other demographic characteristics will be 
recorded and summarized using descriptive statistics.
10.3. Statistical Analyses
Statistical analysis of this study will be the responsibility of Eli Lilly and Company or its 
designee.
Pharmacokinetic analyses will be conducted on the full analysis set.  This set includes all data 
from all subjects receiving at least 1 dose of LY3202626, according to the dose administration
the subjects actually received.  Safety analyses will be conducted for all enrolled subjects, 
whether or not they completed all protocol requirements.
Additional exploratory analyses of the data will be conducted as deemed appropriate.  Study 
results may be pooled with the results of other studies for population PK analysis purposes to 
avoid issues with post-hoc analyses and incomplete disclosures of analyses.
No adjustments for multiple comparisons will be made.
CCI


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10.3.1.
Safety Analyses
10.3.1.1. Clinical Evaluation of Safety
All investigational product and protocol procedure AEs will be listed, and if the frequency of 
events allows, safety data will be summarized using descriptive methodology.
The incidence of symptoms for each dose administration will be presented by severity and by 
association with LY3202626 as perceived by the investigator.  Symptoms reported to occur prior 
to study entry will be distinguished from those reported as new or increased in severity during 
the study.  Each symptom will be classified by the most suitable term from the medical 
regulatory dictionary.
The number of investigational product-related SAEs will be reported.
10.3.1.2. Statistical Evaluation of Safety
Safety parameters that will be assessed include safety lab parameters and vital signs.  The 
parameters and changes from baseline (check-in), where appropriate, will be listed and 
summarized using standard descriptive statistics.  Additional analysis will be performed if 
warranted upon review of the data.
10.3.2.
Pharmacokinetic Analyses
10.3.2.1. Pharmacokinetic Parameter Estimation
Pharmacokinetic parameter estimates for LY3202626 will be calculated by standard 
noncompartmental methods of analysis.
The primary parameters for analysis will be Cmax, AUC from time zero to infinity (AUC0-∞), 
AUC from time zero to time t, where t is the last time point with a measurable concentration 
(AUC0-tlast), and time of maximum observed drug concentration (tmax) of LY3202626.  Other 
noncompartmental parameters, such as t 1/2, apparent total body clearance of drug calculated after 
extra-vascular administration (CL/F), and apparent volume of distribution during the terminal 
phase after extra-vascular administration (Vz/F) will be reported if evaluable based on available 
data.
10.3.2.2. Pharmacokinetic Statistical Inference
Pharmacokinetic parameter estimates will be evaluated to delineate relative bioavailability and
food effects.
The following comparisons will be interests of statistical analysis of PK parameters:

relative bioavailability:  LY3202626 T1-12 fasted (test) versus LY3202626 R fasted 
(reference)

food effect:  LY3202626 T1-12 fed (test) versus LY3202626 T1-12 fasted (reference).
Log-transformed Cmax and AUC estimates will be evaluated in a linear mixed-effects model
with fixed effects for dose administration and period and a random effect for subject. The ratio
of geometric least squares means and corresponding 90% CI will be presented for LY3202626


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LY3202626
T1-12 versus LY3202626 R for analysis of relative bioavailability, and LY3202626 T1-12 
administered with a high-fat meal versus LY3202626 T1-12 administered fasted for the analysis 
of the food effect.  One model will be used for the assessment of relative bioavailability and the 
effect of food.
The tmax will be analyzed non-parametrically.  Median of differences and approximate 90% CI 
for the median of differences will be calculated. P-values will also be calculated using a 
Wilcoxon signed rank test.
Additional analyses may be performed if deemed necessary.
10.3.3.
Pharmacodynamic Analysis
10.3.3.1. Pharmacodynamic Parameter Estimation
Plasma concentrations of Aβ1-40 and Aβ1-42 will be summarized for each treatment based on the 
nadir concentration (Cnadir), the time to reach Cnadir (tnadir), and the 24-hour average values 
expressed as percentage change from baseline.
10.3.3.2. Pharmacodynamic Statistical Inference
No formal statistical testing will be conducted.
10.3.4.
Interim Analyses
No interim analyses are planned for this study.  If an unplanned interim analysis is deemed 
necessary, the Lilly CP, CRP/investigator, or designee will consult with the appropriate medical 
director or designee to determine if it is necessary to amend the protocol.


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LY3202626
11.
References
Shankar GM, Li S, Mehta TH, Garcia-Munoz A, Shepardson NE, Smith I, Brett FM, Farrell MA,
Rowan MJ, Lemere CA, Regan CM, Walsh DM, Sabatini BL, Selkoe DJ. Amyloid-beta
protein dimers isolated directly from Alzheimer’s brains impair synaptic plasticity and
memory. Nat Med. 2008;14(8):837-842.
FDA. US Department of Health and Human Services, Food and Drug Administration, Center for
Drug Evaluation and Research. Guidance for Industry:  Food-Effect Bioavailability and Fed
Bioequivalence Studies. 2002.


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Appendix 1.
Abbreviations and Definitions
Term
Definition
Aß
amyloid beta
AD
Alzheimer’s disease
AE
adverse event:  Any untoward medical occurrence in a patient or clinical investigation 
subject administered a pharmaceutical product that does not necessarily have a causal 
relationship with this treatment.  An AE 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.
APP
amyloid precursor protein
AUC
area under the concentration versus time curve
AUC0-tlast
area under the concentration versus time curve from time zero to time t, where t is the last 
time point with a measurable concentration
AUC0-∞
area under the concentration versus time curve from time zero to infinity
BACE1
ß-site amyloid precursor protein-cleaving enzyme
BMI
body mass index
CI
confidence interval
CL/F
apparent total body clearance of drug calculated after extra-vascular administration
Cmax
maximum observed drug concentration
Cnadir
nadir concentration
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 the trial-related requirements, good clinical practice (GCP) requirements, 
and the applicable regulatory requirements.
confirmation
A process used to confirm that laboratory test results meet the quality requirements defined 
by the laboratory generating the data and that Lilly is confident that results are accurate.  
Confirmation will either occur immediately after initial testing or will require that samples 
be held to be retested at some defined time point, depending on the steps required to obtain 
confirmed results.
CP
clinical pharmacologist


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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.
CRU
clinical research unit
CSF
cerebral spinal fluid
CV
coefficient of variation
CYP
cytochrome P450
ECG
electrocardiogram
eCRF
electronic case report form
end of trial (study)
End of trial is the date of the last visit or last scheduled procedure shown in the Study
Schedule for the last subject.
enroll
The act of assigning a subject to a treatment.  Subjects who are enrolled in the trial are those 
who have been assigned to a treatment.
enter
Subjects entered into a trial are those who sign the informed consent form directly or 
through their legally acceptable representatives.
ERB/IRB
ethical review board
ET
early termination
FDA
Food and Drug Administration
FSH
follicle-stimulating hormone
GCP
good clinical practice
HIV
human immunodeficiency virus
IB
Investigator’s Brochure
ICF
informed consent form
ICH
International Conference on Harmonization
informed consent
A process by which a subject voluntarily confirms his or her willingness to participate in a 
particular trial, after having been informed of all aspects of the trial 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.  
Investigational 
product (IP)
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.


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investigator
A person responsible for the conduct of the clinical trial at a trial site.  If a trial is conducted 
by a team of individuals at a trial site, the investigator is the responsible leader of the team 
and may be called the principal investigator.
MEDRA
Medical Dictionary for Regulatory Activities
open-label
A study in which there are no restrictions on knowledge of treatment allocation, therefore 
the investigator and the study participant are aware of the drug therapy received during the 
study.
PD
pharmacodynamics(s)
PK
pharmacokinetic(s)
QD
once daily
R
reference formulation (12 mg capsule)
SAE
serious adverse event
screen
The act of determining if an individual meets minimum requirements to become part of a 
pool of potential candidates for participation in a clinical trial.  
subject
An individual who is or becomes a participant in clinical research, either as a recipient of
the investigational product(s) or as a control.  A subject may be either a healthy human or a
patient.
SUSARs
suspected unexpected serious adverse reactions
t1/2
half-life associated with the terminal rate constant (λ) in noncompartmental analysis
T1-12
test formulation (12 mg tablet)
TEAE
treatment-emergent adverse event:  Any 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 
tmax
time of maximum observed drug concentration
tnadir
time to reach nadir concentration
Vz/F
apparent volume of distribution during the terminal phase after extra-vascular 
administration


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Appendix 2.
Clinical Laboratory Tests
Laboratory Tests
Hematologya
Clinical Chemistrya
Hematocrit
Sodium
Hemoglobin
Potassium
Erythrocyte count (RBC)
Bicarbonate
Mean cell volume 
Chloride
Mean cell hemoglobin 
Glucose, random
Mean cell hemoglobin concentration 
Blood urea
Leukocytes (WBC)
Total protein
Absolute counts of:
Creatinine
Neutrophils
Liver tests:
Lymphocytes
Albumin
Monocytes
Total bilirubin
Eosinophils
Alkaline phosphatase (ALP)
Basophils
Aspartate aminotransferase (AST)
Platelets
Alanine aminotransferase (ALT)
Gamma-glutamyl transferase (GGT)
Urinalysisa
Specific gravity
pH
Protein
Hepatitis B surface antigend
Glucose
Hepatitis C antibodyd
Ketone
HIVd
Bilirubin
FSHb
Urobilinogen
Blood
Nitrite
Leukocyte
Microscopyc
Abbreviations:  FSH = follicle-stimulating hormone; HIV = human immunodeficiency virus; RBC = red blood cells; 
WBC = white blood cells.
Note:  Results of these assays will be validated by the local laboratory at the time of testing.
Additional tests may be performed or auto-calculated by the laboratory as part of its standard panel that cannot be 
removed. Some of the above parameters are calculated from measured values. Omission of calculated values will 
not be considered as a protocol violation.
a
Results will be validated by the local lab at the time of testing.
b
Performed at screening only, in post-menopausal women with 6-12 months of amenorrhea.
c If clinically indicated, per investigator’s discretion.
d Performed at screening only. This test will be performed unless results of the same test have been obtained from 
the subject within the last 6 months.


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LY3202626
Appendix 3.
Study Governance, Regulatory and Ethical 
Considerations
Informed Consent
The investigator is responsible for:

ensuring that the subject understands the potential risks and benefits of participating in 
the study.

ensuring that informed consent is given by each subject or legal representative.  This 
includes obtaining the appropriate signatures and dates on the ICF prior to the 
performance of any protocol procedures and prior to the administration of investigational 
product.

answering any questions the subject may have throughout the study and sharing in a 
timely manner any new information that may be relevant to the subject ’s willingness to 
continue his or her participation in the trial.
Ethical Review
The investigator must give assurance that the ERB was properly constituted and convened as 
required by ICH guidelines and other applicable laws and regulations.
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 
before it is used at the investigative site(s).  All ICFs must be compliant with the ICH guideline 
on GCP.
The study site’s ERB(s) should be provided with the following:

the current IB

ICF

relevant curricula vitae
Regulatory Considerations
This study will be conducted in accordance with:
1) 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 
2) applicable ICH GCP Guidelines 
3) applicable laws and regulations
Some of the obligations of the sponsor will be assigned to a third party organization.


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LY3202626
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.
Final Report Signature
The investigator or designee will sign the clinical study report for this study, indicating 
agreement with the analyses, results, and conclusions of the report.
The sponsor’s responsible medical officer and statistician will sign/approve the final clinical 
study report for this study, confirming that, to the best of his or her knowledge, the report 
accurately describes the conduct and results of the study.
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.

provide training to instruct the investigators and study coordinators.  This training will 
give instruction on the protocol, the completion of the CRFs, 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 CRF data and/or 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 and/or 
regulatory agencies at any time.  Investigators will be given notice before an audit occurs.
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 the original source 
documents.
Data Collection Tools/Source Data
An electronic data capture system will be used in this study.  The site must define and retain all 
source records and must maintain a record of any data where source data are directly entered into 
the data capture system.


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Study and Site Closure
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.
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.


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Appendix 4.
Blood Sampling Summary
This table summarizes the approximate number of venipunctures and blood volumes for all 
blood sampling (screening, safety laboratories, and bioanalytical assays) during the study.  Fewer 
venipunctures and blood draws may actually occur, but this will not require a protocol 
amendment.
Protocol I7X-MC-LLCE Sampling Summary
Purpose
Maximum Blood Volume 
per Sample (mL)
Maximum Number 
of Blood Samples
Maximum Total 
Volume (mL)
Screening testsa
15
1
15
Clinical laboratory testsa
9
9
81
Pharmacokineticsb
3
59
177
Pharmacodynamics
2
57
114
Pharmacogenetics
10
1
10
Total
397
Total for clinical purposes [rounded up to nearest 10 mL]
400
a
Additional samples may be drawn if needed for safety purposes.
b
Includes an additional 2 samples which may be collected at additional time points during the study if warranted 
and agreed upon between both the investigator and sponsor.


Leo Document ID = 114c4e79-b2cf-4dc1-83b6-75b5265dbfc9
Approver: 
Approval Date & Time: 08-Sep-2016 20:33:51 GMT
Signature meaning: Approved
Approver: 
Approval Date & Time: 10-Sep-2016 07:18:09 GMT
Signature meaning: Approved
PPD
PPD


Leo Document ID = 8dc6cd7c-6e78-4134-9dc8-cc4750e454e4
Approver: Oliver Schmidt (AM\C243405)
Approval Date & Time: 08-May-2018 18:17:39 GMT
Signature meaning: Approved

SAP_001.pdf: 
I7X-MC-LLCE 
 
Relative Bioavailability and Food Effect Study in Healthy 
Subjects Administered Two Different Formulations of 
LY3202626 
NCT03023826 
Approval Date: 17 Jan 2017 
 


Final, 03 Jan 2016
             Page 1 of 16
STATISTICAL ANALYSIS PLAN
Relative Bioavailability and Food Effect Study in Healthy Subjects Administered Two 
Different Formulations of LY3202626
Statistical Analysis Plan Status:  Final
Statistical Analysis Plan Date:  03-January-2016
Study Drug: LY3202626
Sponsor Reference:  I7X-MC-LLCE
Covance CRU Study: 1000071-8348777
Clinical Phase I
Approval Date: 17-Jan-2017 GMT


Final, 03 Jan 2016
             Page 2 of 16
Statistical Analysis Plan 
CONFIDENTIAL
Covance Clinical Study No. 8348777
Sponsor Reference I7X-MC-LLCE
1. TABLE OF CONTENTS
1.
TABLE OF CONTENTS ............................................................................................... 2
2.
ABBREVIATIONS........................................................................................................ 3
3.
INTRODUCTION ......................................................................................................... 5
4.
STUDY OBJECTIVES.................................................................................................. 5
4.1
Primary Objective.................................................................................................... 5
4.2
Secondary Objectives .............................................................................................. 5
4.3
Exploratory Objective.............................................................................................. 6
5.
STUDY DESIGN........................................................................................................... 6
6.
TREATMENTS ............................................................................................................. 7
7.
SAMPLE SIZE JUSTIFICATION ................................................................................. 7
8.
DEFINITION OF ANALYSIS POPULATIONS............................................................ 8
9.
STATISTICAL METHODOLOGY ............................................................................... 8
9.1
General.................................................................................................................... 8
9.2
Demographics and Subject Disposition.................................................................... 9
9.3
Pharmacokinetic Assessment................................................................................... 9
9.3.1
Pharmacokinetic Analysis............................................................................... 9
9.3.2
Pharmacokinetic Parameter Estimation......................................................... 13
9.4
Pharmacodynamic Assessment .............................................................................. 13
9.4.1
Pharmacodynamic Parameter Estimation ...................................................... 14
9.4.2
Pharmacodynamic Statistical Inference......................................................... 14
9.5
Safety and Tolerability Assessments ...................................................................... 14
9.5.1
Adverse events ............................................................................................. 14
9.5.2
Concomitant medication............................................................................... 14
9.5.3
Clinical laboratory parameters ...................................................................... 15
9.5.4
Vital signs .................................................................................................... 15
9.5.5
Electrocardiogram (ECG)............................................................................. 15
9.5.6
Other assessments......................................................................................... 15
9.5.7
Safety and Tolerability Statistical Methodology ............................................ 15
10. INTERIM ANALYSES ............................................................................................... 15
11. CHANGES FROM THE PROTOCOL SPECIFIED STATISTICAL ANALYSES ...... 15
12. REFERENCES ............................................................................................................ 15
13. DATA PRESENTATION ............................................................................................ 16
13.1 Derived Parameters ............................................................................................... 16
13.2 Missing Data ......................................................................................................... 16
13.3 Insufficient Data for Presentation .......................................................................... 16


Final, 03 Jan 2016
             Page 3 of 16
Statistical Analysis Plan 
CONFIDENTIAL
Covance Clinical Study No. 8348777
Sponsor Reference I7X-MC-LLCE
2. ABBREVIATIONS
Abbreviations pertain to the Statistical Analysis Plan (SAP) only (not the tables, figures and 
listings [TFLs]).
AE
Adverse event
AUC
Area under the concentration versus time curve
AUC(0-tlast)
Area under the concentration versus time curve from time zero to 
time t, where t is the last time point with a measurable concentration
AUC(0-∞)
Area under the concentration versus time curve from zero to infinity
%AUC(tlast-∞)
Percentage of AUC(0-∞) extrapolated
BQL
Below the quantifiable lower limit of the assay
Cmax
Maximum observed drug concentration
CI
Confidence interval
Clast
Last quantifiable drug concentration
CL/F
Apparent total body clearance of drug calculated after extra-vascular
administration
Cnadir
Nadir concentration
CRF
Case Report Form
CSR
Clinical Study Report
CRU
Clinical Research Unit
CV
Coefficient of variation
EC
Early Clinical 
ECG
Electrocardiogram
e.g.
For example (Latin: exempli gratia)
FDA
Food and Drug Administration
ICH
International Council on Harmonisation
LLOQ
Lower limit of quantification
MedDRA
Medical Dictionary for Regulatory Activities
PD
Pharmacodynamic
PK
Pharmacokinetic
QTcB
QT interval corrected using Bazett’s formula
QTcF
QT interval corrected using Fridericia’s formula


Final, 03 Jan 2016
             Page 4 of 16
Statistical Analysis Plan 
CONFIDENTIAL
Covance Clinical Study No. 8348777
Sponsor Reference I7X-MC-LLCE
SAP
Statistical Analysis Plan
SD
Standard deviation 
SOP
Standard Operating Procedure
TFLs
Tables, Figures, and Listings
t1/2
Half-life associated with the terminal rate constant (λz) in non-
compartmental analysis
tnadir
Time to reach nadir concentration
tmax
Time of maximum observed drug concentration
Vss/F
Apparent volume of distribution at steady state after extra vascular 
administration
Vz/F
Apparent volume of distribution during the terminal phase after 
extra-vascular administration
WHO
World Health Organization


Final, 03 Jan 2016
             Page 5 of 16
Statistical Analysis Plan 
CONFIDENTIAL
Covance Clinical Study No. 8348777
Sponsor Reference I7X-MC-LLCE
3. INTRODUCTION
This SAP has been developed after review of the Clinical Study Protocol ( final version dated 
10 September 2016).
This SAP describes the planned analys is of the safety, tolerability, pharmacokinetic (PK) and 
pharmacodynamic (PD) data from this study. A detailed description of the planned TFLs to be 
presented in the clinical study report (CSR) is provided in the accompanying TFL shell 
document.
The intent of this document is to provide guidance for the statistical , PD, and PK analyses of 
data. In general, the analyses are based on information from the protocol, unless they ha ve been 
modified by agreement between Eli Lilly and Company and Covance Early Clinical (EC)
Biometrics.
A limited amount of information concerning this study (e.g., objectives, study 
design) is given to help the reader’s interpretation. This SAP must be signed off prior to first 
subject administration for this study.
When the SAP and TFL shells are agreed upon and 
finalized, they will serve as the template for this study’s CSR.
This SAP supersedes
the statistical considerations identified in the protocol ; where 
considerations are substantially different, they will be so identified.
If additional analyses are 
required to supplement the planned analyses described in this SAP, they may be performed and 
will be identified in the CSR. Any substantial deviations from this SAP will be agreed upon 
between Eli Lilly and Company and Covance EC Biometrics and identified in the CSR.
Any 
minor deviations from the TFLs may not be documented in the CSR.
This SAP is written with consideration of the recommendations out lined in the International 
Council on Harmonisation (ICH) E9 Guideline entitled Guidance for Industry: 
Statistical 
Principles for Clinical Trials1 and the ICH E3 Guideline entitled Guidance for Industry: 
Structure and Content of Clinical Study Reports2.
4. STUDY OBJECTIVES
4.1
Primary Objective

To evaluate the relative bioavailability of a single 12 mg dose of LY3202626 as a tablet 
formulation (test formulation [T1 -12]) compared to the capsule formulation (reference 
formulation [R]).
4.2
Secondary Objectives

To evaluate the effect of a high-fat meal on the bioavailability of LY3202626 when 
administered as a single 12 mg dose of the test tablet formulation (T1-12).

To assess the tolerability of LY3202626 when administered as a single 12 mg dose to 
healthy subjects.


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Statistical Analysis Plan 
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Covance Clinical Study No. 8348777
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4.3
Exploratory Objective

To evaluate plasma Aβ1-40 and Aβ1-42 after a single 12 mg dose of LY3202626 as a 
tablet formulation (test formulation [T1 -12]) and capsule formulation (reference 
formulation [R]).
5. STUDY DESIGN
This is a single-center, open-label, single-dose, randomized, 6-sequence, 3-period, crossover
study in healthy subjects.
Screening will occur up to 28 days prior to the first dose of LY3202626.
Subjects will be admitted to the clinical research unit (CRU) on Day -1 of each period. In each
period, subjects will be fasted overnight for at least 10 hours, and a single dose of 12 mg
LY3202626, as either tablet (T1-12) in a fed state or fasted state or capsule (R) in a fasted state
according to the randomization schedule, will be administered on the mo rning of Day 1. Blood
sampling for assessment of LY3202626 PK and for PD assessments of Aβ1-40 and Aβ1-42 will 
be performed up to 168 hours postdose (Day 8). Subjects may be discharged from the CRU 
following completion of all 24-hour or 36-hour procedures on Day 2. If discharged after 24-hour 
procedures, subject will return to the CRU as an outpatient visit for the 36-hour PK sample 
collection. Subjects will return to the CRU daily for outpatient visits for PK sample collections 
Days 3 through 8. The washout period between dosing in 2 consecutive periods will be at least 
10 days. A follow-up telephone call will be performed approximately 5 to 8 days after Period 3, 
Day 8.
Tolerability will be explored by clinical laboratory tests, vital sign measuremen ts, 12-lead 
electrocardiograms (ECGs), and recording of adverse events (AEs).
The 3 dose administrations received by each subject will be:

A = Reference (R): 12 mg LY3202626 capsule; administered in a fasted state

B = Test (T1-12): 12 mg LY3202626 tablet; administered in a fasted state

C = Test (T1-12): 12 mg LY3202626 tablet; administered in a fed state (Food and Drug
Administration [FDA] high-fat meal)
Subjects will be randomized to 1 of 6 dose administration sequences (Table 1).
Table 1. Dose Administration Sequences
Sequence
Period 1
Period 2
Period 3
ABC
R fasted
T1-12 fasted
T1-12 fed
BCA
T1-12 fasted
T1-12 fed
R fasted
CAB
T1-12 fed
R fasted
T1-12 fasted
CBA
T1-12 fed
T1-12 fasted
R fasted
ACB
R fasted
T1-12 fed
T1-12 fasted
BAC
T1-12 fasted
R fasted
T1-12 fed
Abbreviations: R = reference (capsule formulation); T1-12 = test (tablet formulation)
CCI


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Statistical Analysis Plan 
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Covance Clinical Study No. 8348777
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Figure 1 illustrates the study design.
Figure 1. Illustration of Study Design for Protocol I7X-MC-LLCE
6. TREATMENTS
The following is a list of the study treatment abbreviations that will be used in the TFLs.
Study Treatment Name
Abbreviation
Treatment order in 
TFL
12 mg LY3202626 capsule (fasted)
R fasted
1
12 mg LY3202626 tablet (fasted)
T1-12 fasted
2
12 mg LY3202626 tablet (fed)
T1-12 fed
3
7. SAMPLE SIZE JUSTIFICATION
Up to approximately 24 healthy subjects may be enrolled to ensure that at least 20 subjects 
complete the study. This sample size is based on a calculation of precision of the estimated ratio 
of area under the concentration versus time curve (AUCs).
 
CCI


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Covance Clinical Study No. 8348777
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At the discretion of the investigator and sponsor, if multiple subjects who are randomized 
withdraw before study end, an additional 6 subjects (up to a total enrollment of 30 subjects) may 
be enrolled to ensure completion of 20 subjects. The replacement subject will be assigned the 
same dose administration sequence as the withdrawn subject’s dose administration sequence 
(receiving each dose administration allocated).
8. DEFINITION OF ANALYSIS POPULATIONS
The “Safety” population will consist of all enrolled subjects, whether or not they completed all 
protocol requirements.
The PK analyses will be conducted on the full analysis set.  This set includes all data from all 
subjects who received at least one dose of LY3202626.
The “Pharmacodynamic” population will consist of all subjects who received at least one dose of 
study drug and have evaluable PD data.
All protocol deviations that occur during the study wil l be considered for their severity/impact 
and will be taken into consideration when subjects are assigned to analysis populations.
9. STATISTICAL METHODOLOGY
9.1
General
Data listings will be provided for all data that is databased. Summary statistics and statistical 
analysis will only be presented for data where detailed in this SAP. 
For continuous data, 
summary statistics will include the arithmetic mean, arithmetic standard deviation (SD), median, 
min, max and N; for log-normal data (e.g. the PK parameters: AUCs and maximum observed 
drug concentration [Cmax]) the geometric mean and geometric coefficient of variation (CV%) 
will also be presented. For categorical data, frequency count and percentages will be presented. 
Data listings will be provided for all subjects up to the point of withdrawal, with any subjects 
excluded from the relevant population highlighted. Summary statistics and statistical analyses 
will generally only be performed for subjects included in the r elevant analysis population.
For 
the calculation of summary statistics and statistical analysis, unrounded data will be used. 
Mean change from baseline is the mean of all individual subjects’ change from baseline values. 
Each individual change from baseline will be calculated by subtracting the individual subject’s 
baseline value from the value at the timepoint. The individual subject’s change from baseline 
values will be used to calculate the mean change from baseline using a SAS procedure such as 
Proc Univariate.
Data analysis will be performed using SAS® Version 9.3 or greater.
CCI


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Statistical Analysis Plan 
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Covance Clinical Study No. 8348777
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9.2
Demographics and Subject Disposition
Subject disposition will be listed. The demographic variables age, sex, race, ethnicity, country of 
enrolment, site ID, body weight, height and body mass index will be summarized and listed.
9.3
Pharmacokinetic Assessment
9.3.1 Pharmacokinetic Analysis
PK parameter estimates will be determined using non-compartmental procedures in validated 
software program (Phoenix WinNonlin Version 6.4.1 or later).
Plasma concentrations of LY3202626 will be used to determine the following PK parameters, 
when possible:  
Parameter
Units
Definition
AUC(0-tlast)
ng.h/mL
area under the concentration versus time curve from time zero to 
time t, where t is the last time point with a measurable 
concentration
AUC(0-∞)
ng.h/mL
area under the concentration versus time curve from zero to 
infinity
%AUC(tlast-)
%
percentage of AUC(0-∞) extrapolated
Cmax
ng/mL
maximum observed drug concentration
tmax
h
time of maximum observed drug concentration
t1/2
h
half-life associated with the terminal rate constant (λz) in non-
compartmental analysis
CL/F
L/h
apparent total body clearance of drug calculated after 
extra-vascular administration
Vz/F
L
apparent volume of distribution during the terminal phase after 
extra-vascular administration
Vss/F
L
apparent volume of distribution at steady state after extra-vascular 
administration
An alternative AUC measure, such as AUC to a common time point, may be calculated if 
AUC(0-∞) cannot be reliably calculated.
Additional PK parameters may be calculated, as appropriate.  The software and version used for 
the final analyses will be specified in the CSR. Any exceptions or special handling of data will 
be clearly documented within the final study report.
Formatting of tables, figures and abbreviations will follow the Eli Lilly Global PK/PD/TS Tool: 
NON-COMPARTMENTAL PHARMACOKINETIC STYLE GUIDE. The version of the tool
effective at the time of PK analysis will be followed.


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Statistical Analysis Plan 
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Covance Clinical Study No. 8348777
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General PK Parameter Rules

Actual sampling times will be used in the final analyses of individual PK parameters, 
except for non-bolus pre-dose sampling times which will be set to zero. For non-bolus, 
multiple dose profiles, the pre-dose time will be set to zero unless a time deviation falls 
outside of the protocol blood collection time window which is considered to impact PK 
parameter derivation.

Cmax and tmax will be reported from observed values.  If Cmax occurs at more than one time 
point, tmax will be assigned to the first occurrence of Cmax. 

AUC parameters will be calculated using a combination of the linear and logarithmic 
trapezoidal methods (linear-log trapezoidal rule).  The linear trapezoidal method will be 
applied up to tmax and then the logarithmic trapezoidal method will be used after tmax. The 
minimum requirement for the calculation of AUC will be the inclusion of at least three 
consecutive plasma concentrations above the lower limit of quantification ( LLOQ), with 
at least one of these concentrations following C max. 
AUC(0-) values where the 
percentage of the total area extrapolated is more than 20% will be flagged. 
Any 
AUC(0-) value excluded from summary statistics will be noted in the footnote of the 
summary table.

Half-life (t½) will be calculated, when appropriate, based on the apparent terminal log -
linear portion of the concentration-time curve. The start of the terminal elimination phase 
for each subject will be defined by visual inspection and generally will be the first point 
at which there is no systematic deviation from the log -linear decline in plasma 
concentrations.  Half-life will only be calculated when a reliable estimate for this
parameter can be obtained comprising of at least 3 data points.  If t ½ is estimated over a 
time window of less than 2 half-lives, the values will be flagged in the data listings. Any 
t½ value excluded from summary statistics will be documented in the foo tnote of the 
summary table. 

A uniform weighting scheme will be used in the regression analysis of the terminal log -
linear portion of the concentration-time curve.

The parameters based on observed last quantifiable drug concentration (Clast) will be 
reported.
Individual PK Parameter Rules

Only quantifiable concentrations will be used to calculate PK parameters with the 
exception of special handling of certain concentrations reported below the lower limit of 
quantitation (BQL).  Plasma concentrations reported as BQL will be set to a value of zero 
when all of the following conditions are met: 

The compound is non-endogenous.


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Covance Clinical Study No. 8348777
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
The samples are from the initial dose period for a subject or from a subsequent 
dose period following a suitable wash-out period.

The time points occur before the first quantifiable concentration.

All other BQL concentrations that do not meet the above criteria will be set to missing. 

Also, where two or more consecutive concentrations are BQL towards the end of a 
profile, the profile will be deemed to have terminated and therefore any further 
quantifiable concentrations will be set to missing for the calculation of the PK parameters 
unless it is considered to be a true characteristic of the profile of the drug.
Individual Concentration vs. Time Profiles

Individual concentrations will be plotted utilizing actual sampling times.

The terminal point selections will be indicated on a semi-logarithmic plot.
Average Concentration vs. Time Profiles

The average concentration profiles will be graphed using scheduled (nominal) sampling 
times. 

The average concentration profiles will be graphed us ing arithmetic average 
concentrations.

The pre-dose average
concentration for single-dose data from non-endogenous 
compounds will be set to zero.  Otherwise, only quantifiable concentrations will be used 
to calculate average concentrations.

Concentrations at a sampling time exceeding the sampling time window specified in the 
protocol, or ± 10%, will be excluded from the average concentration profiles.

Concentrations excluded from the mean calculation will be documented in the final study 
report.

A concentration average will be plotted for a given sampling time only if 2/3 of the 
individual data at the time point have quantifiable measurements that are within the 
sampling time window specified in the protocol or ± 10%. An average concentration 
estimated with less than 2/3 but more than 3 data points may be displayed on the mean 
concentration plot if determined to be appropriate and will be documented within the 
final study report.


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Statistical Analysis Plan 
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Covance Clinical Study No. 8348777
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Treatment of Outliers during Pharmacokinetic Analysis
Application of this procedure to all PK analyses is not a requirement. Rather, this procedure 
provides justification for exclusion of data when scientifically appropriate. 
This procedure 
describes the methodology for identifying an individual value as an outlier for potential 
exclusion, but does not require that the value be excluded from analysis.  The following 
methodology will not be used to exclude complete profiles from analysis.
Data within an Individual Profile
A value within an individual profile may be excluded from an alysis if any of the following 
criteria are met:

For PK profiles during multiple dosing, the concentration of the pre-dose sample exceeds 
all measured concentrations for that individual in the subsequent post-dose samples.

For PK profiles during single dosing of non-endogenous compounds, the concentration in 
a pre-dose sample is quantifiable.

For any questionable datum that does not satisfy the above criteria, the profile will be 
evaluated and results reported with and without the suspected datum. 
Data between Individual Profiles
1.
If n<6, then the dataset is too small to conduct a reliable range test.  Data will be 
analyzed with and without the atypical value, and both sets of results will be reported.  
2.
If n6, then an objective outlier test will be used to compare the atypical value to other 
values included in that calculation:
a.
Transform all values in the calculation to the logarithmic domain.
b. Find the most extreme value from the arithmetic mean of the log transformed 
values and exclude that value from the dataset.
c.
Calculate the lower and upper bounds of the range defined by the arithmetic 
mean ±3*SD of the remaining log-transformed values.
d. If the extreme value is within the range of arithmetic mean ±3*SD, then it is not 
an outlier and will be retained in the dataset.
e.
If the extreme value is outside the range of arithmetic mean ±3*SD, then it is an 
outlier and will be excluded from analysis.
If the remaining dataset contains another atypical datum suspected to be an outlier and n ≥ 6 
following the exclusion, then repeat step 2 above. This evaluation may be repeated as many 
times as necessary, excluding only one suspected outlier in each iteration, until all data 
remaining in the dataset fall within the range of arithmetic mean ±3* SD of the log-transformed 
values.


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Statistical Analysis Plan 
CONFIDENTIAL
Covance Clinical Study No. 8348777
Sponsor Reference I7X-MC-LLCE
Reporting of Excluded Values
Individual values excluded as outliers will be documented in the final report.  Approval of the 
final report will connote approval of the exclusion.
9.3.2 Pharmacokinetic Parameter Estimation
The primary parameters for analysis, Cmax, AUC(0-∞), AUC(0-tlast), and tmax of LY3202626,will 
be evaluated to delineate relative bioavailability and food effects.
The following comparisons will be interests of statistical analysis of PK parameters:

relative bioavailability: LY3202626 T1-12 fasted (test) versus LY3202626 R fasted 
(reference)

food effect: LY3202626 T1-12 fed (test) versus LY3202626 T1-12 fasted (reference).
Log-transformed Cmax and AUC estimates will be evaluated in a linear mixed -effects model with 
fixed effects for dose administration and period and a random effect for subject. The ratio of 
geometric least squares means and corresponding 90% CI will be presented for LY3202626
T1-12 versus LY3202626 R for analysis of relative bioavailability, and LY3202626 T1 -12
administered with a high-fat meal versus LY3202626 T1-12 administered fasted for the analysis
of the food effect. One model will be used for the assessment of relative bioavailability and the
effect of food.
The tmax will be analyzed non-parametrically for the same comparisons stated above. Median of 
differences and approximate 90% CI for the median of differences will be calculated. P-values 
will also be calculated using a Wilcoxon signed rank test.
Additional analyses may be performed if deemed necessary.
Example SAS code:
proc mixed data=test covtest alpha=0.1;
   class treatment period subject;
   model log_pk = treatment period / ddfm=kr alpha=0.1;
   random subject;
   lsmeans treatment / pdiff cl alpha=0.1;
   ods output lsmeans=lsmeans;
   ods output diffs=diffs;
ods output covparms=cov;
run;
9.4
Pharmacodynamic Assessment
Plasma concentrations of Aβ 1-40 and Aβ1-42 will be summarized by timepoint and treatment 
together with changes from baseline, where baseline is defined as Day 1 predose of the 
respective period, and listed.  Additionally, percent changes from baseline will also be 
summarised and listed.  Figures of mean profiles, mean changes from baseline, and mean percent 
changes from baseline will be presented by treatment. 


 
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Statistical Analysis Plan  
 
CONFIDENTIAL
Covance Clinical Study No. 8348777 
 
Sponsor Reference I7X-MC-LLCE
9.4.1 Pharmacodynamic Parameter Estimation 
Plasma concentrations of Aβ1-40 and Aβ1-42 will be used to derive baseline predose concentration 
(Cpredose, defined as the Day 1 predose concentration of each respective treatment period), the 
nadir concentration (Cnadir), time to reach Cnadir (tnadir), and the 0-24-hour average percent change 
from baseline values.  Cnadir is defined as the lowest observed Aβ1-40 or Aβ1-42 concentration 
following study drug administration.  The percent change from baseline (predose) at Cnadir  will 
be reported, as will the 0-24-hour average change from baseline, which will be derived as  
%Time Average Change From Baseline ൌ
ܣܷܥ଴ିଶସ
24
െܥ௣௥௘ௗ௢௦௘
ܥ௣௥௘ௗ௢௦௘
∙100. 
The PD parameters will be summarized by treatment and listed.  
 
9.4.2 Pharmacodynamic Statistical Inference 
No formal statistical testing will be conducted. 
9.5 
Safety and Tolerability Assessments 
9.5.1 Adverse events 
Where changes in severity are recorded in the Case Report Form (CRF), each separate severity 
of the AE will be reported in the listings, only the most severe will be used in the summary 
tables.  A pre-existing condition is defined as an AE that starts before the subject has provided 
written informed consent and is ongoing at consent.  A non-treatment emergent AE is defined as 
an AE which starts after informed consent but prior to the first dose.  A treatment-emergent AE 
is defined as an AE which occurs postdose or which is present prior to dosing and becomes more 
severe postdose.   
All AEs will be listed.  Treatment-emergent AEs will be summarized by treatment, severity and 
relationship to the study drug.  The frequency (the number of AEs, the number of subjects 
experiencing an AE and the percentage of subjects experiencing an AE) of treatment-emergent 
AEs will be summarized by treatment,  Medical Dictionary for Regulatory Activities (MedDRA) 
version 19.1 system organ class and preferred term.  The summary and frequency AE tables will 
be presented for all causalities and those considered related to the study drug.  Any serious AEs 
will be tabulated. 
9.5.2 Concomitant medication 
Concomitant medication will be coded using the World Health Organization (WHO) drug 
dictionary (Version September 2016).  Concomitant medication will be listed. 


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Statistical Analysis Plan 
CONFIDENTIAL
Covance Clinical Study No. 8348777
Sponsor Reference I7X-MC-LLCE
9.5.3 Clinical laboratory parameters
All clinical chemistry and hematology data will be summarized by parameter and treatment, and 
listed. Urinalysis data will be listed. Additionally clinical chemistry, hematology and urinalysis 
data outside the reference ranges will be listed.
Values for any clinical chemistry, hematology and urinalysis values outside the reference ranges 
will be flagged on the individual subject data listings.
9.5.4 Vital signs
Vital signs data will be summarized by treatment together with changes from baseline, where 
baseline is defined as Day 1 predose of the respective period. Figures of mean vital signs and 
mean changes from baseline profiles by treatment will be presented by treatment. Furthermore, 
values for individual subjects will be listed.
9.5.5 Electrocardiogram (ECG)
ECGs will be performed for safety monitoring purposes only and will not be presented. 
9.5.6 Other assessments
All other safety assessments not detailed in this section will be listed but not summarized or 
statistically analyzed.
9.5.7 Safety and Tolerability Statistical Methodology
No inferential statistical analyses are planned.
10.
INTERIM ANALYSES
No interim statistical analyses are planned.
11.
CHANGES FROM THE PROTOCOL SPECIFIED STATISTICAL ANALYSES
There were no changes from the protocol specified statistical analyses.
12.
REFERENCES
1. International Conference on Harmonization of Technical Requirements for Registration of 
Pharmaceuticals for Human Use, ICH Harmonized Tripartite Guideline, Statistical Principles 
for Clinical Trials (E9), 5 February 1998.
2. International Conference on Harmonization of Technical Requirements for Registration of 
Pharmaceuticals for Human Use, ICH Harmonized Tripartite Guideline, Structure and 
Content of Clinical Study Reports (E3), 30 November 1995.


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Covance Clinical Study No. 8348777
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13.
DATA PRESENTATION
13.1
Derived Parameters
Individual derived parameters (e.g. PK parameters) and appropriate summary statistics will be 
reported to three significant figures. Observed concentration data, e.g. Cmax, should be reported 
as received. Observed time data, e.g. t max, should be reported as received. N and percentage 
values should be reported as whole numbers.
Median values should be treated as an observed 
parameter and reported to the same number of decimal places as minimum and maximum values.
13.2
Missing Data
Missing data will not be displayed in listings.
13.3
Insufficient Data for Presentation
Some of the TFLs may not have sufficient numbers of subjects or data for presentation. If this 
occurs, the blank TFL shell will be presented with a message printed in the centre of the table, 
such as, “No serious adverse events occurred for this study.”


Leo Document ID = f429a255-2bfc-417f-8035-f858ca81e79b
Approver: 
Approval Date & Time: 13-Jan-2017 11:02:11 GMT
Signature meaning: Approved
Approver: 
Approval Date & Time: 17-Jan-2017 09:59:38 GMT
Signature meaning: Approved
Approver: 
Approval Date & Time: 17-Jan-2017 12:29:12 GMT
Signature meaning: Approved
Approver: 
Approval Date & Time: 17-Jan-2017 14:33:00 GMT
Signature meaning: Approved
PPD
PPD
PPD
PPD


Leo Document ID = 6e21bfae-10a3-47a4-831a-98da631e2fd3
Approver: Oliver Schmidt (AM\C243405)
Approval Date & Time: 08-May-2018 18:17:39 GMT
Signature meaning: Approved