Clinical trial NCT03099148
Conditions: Healthy
Sponsor: Eli Lilly and Company
Start date: 2017-04-04; Completion date: 2017-05-31
Enrollment: 29 participants; Allocation: RANDOMIZED; Intervention model: CROSSOVER

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

* If there are any differences in the amount of LY3337641 in the blood/body when it is taken in different formulations. A total of 3 different formulations of LY3337641 are being tested.
* How a high-fat meal affects the amount of LY3337641 in the blood/body.
* How safe and well tolerated LY3337641 is.

The study has four periods. Individuals will participate in all four periods. Each period will include 4 overnight stays (5 days) in the Clinical Research Unit (CRU).

This study is expected to last up to 8 weeks. This includes the initial screening period, the study or dosing period, and the follow up period.

Detailed description:

Arms: arm 1: A single, PO dose of reference formulation (R) given orally with water after an overnight fast in one of four periods. arm 2: A single, PO dose of LY3337641(20mg) test formulation 1 (T1) given orally with water after an overnight fast in one of four periods. arm 3: A single, PO dose of LY3337641 (20mg) test formulation 1 (T1) given orally with water after a high fat meal in one of four periods. arm 4: A single, PO dose of LY3337641 (20 mg) test formulation 2 (T2) given orally with water after an overnight fast in one of four periods.
Interventions: intervention 1: Reference Formulation (R) intervention 2: LY3337641 (T1) intervention 3: LY3337641 (T2)
Intervention descriptions: intervention 1: Administered PO intervention 2: 20 mg PO intervention 3: 20 mg PO

Protocol documents:
Prot_000.pdf: 
 
 
 
 
 
Protocol I8K-MC-JPDF 
 
 
Relative Bioavailability and the Effect of Food on the Bioavailability of LY3337641 in Healthy 
Subjects 
 
 
NCT03099148 
 
Approval Date: 09-Jan-2017 
 


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Protocol I8K-MC-JPDF
Relative Bioavailability and the Effect of Food on the 
Bioavailability of LY3337641 in Healthy Subjects
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 
LY3337641, 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. 
LY3337641
Eli Lilly and Company
Indianapolis, Indiana USA 46285
Clinical Pharmacology Protocol Electronically Signed and Approved by Lilly on date 
provided below.
Approval Date: 09-Jan-2017 GMT


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Table of Contents
Relative Bioavailability and the Effect of Food on the 
Bioavailability of LY3337641 in Healthy Subjects
Section
Page
Protocol I8K-MC-JPDF Relative Bioavailability and the Effect of Food on 
the Bioavailability of LY3337641 in Healthy Subjects........................................................1
Table of Contents........................................................................................................................2
1.
Protocol Synopsis................................................................................................................7
2.
Schedule of Activities .........................................................................................................9
3.
Introduction ......................................................................................................................12
3.1.
Study Rationale............................................................................................................12
3.2.
Background..................................................................................................................12
3.3.
Benefit/Risk Assessment..............................................................................................13
4.
Objectives and Endpoints..................................................................................................14
5.
Study Design.....................................................................................................................15
5.1.
Overall Design .............................................................................................................15
5.2.
Number of Participants.................................................................................................16
5.3.
End of Study Definition ...............................................................................................16
5.4.
Scientific Rationale for Study Design...........................................................................16
5.5.
Justification for Dose ...................................................................................................16
6.
Study Population...............................................................................................................17
6.1.
Inclusion Criteria..........................................................................................................17
6.2.
Exclusion Criteria ........................................................................................................18
6.3.
Lifestyle and/or Dietary Requirements .........................................................................19
6.3.1.
Meals and Dietary Restrictions.............................................................................19
6.3.2.
Caffeine, Alcohol, and Tobacco ...........................................................................20
6.3.3.
Activity................................................................................................................20
6.3.4.
Contraception.......................................................................................................20
6.4.
Screen Failures.............................................................................................................21
7.
Treatment..........................................................................................................................22
7.1.
Treatment Administered...............................................................................................22
7.1.1.
Packaging and Labeling .......................................................................................22
7.2.
Method of Treatment Assignment ................................................................................23
7.2.1.
Selection and Timing of Doses.............................................................................23
7.3.
Blinding .......................................................................................................................23


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7.4.
Dose Modification........................................................................................................23
7.5.
Preparation/Handling/Storage/Accountability...............................................................23
7.6.
Treatment Compliance .................................................................................................23
7.7.
Concomitant Therapy...................................................................................................23
7.8.
Treatment after the End of the Study............................................................................23
8.
Discontinuation Criteria ....................................................................................................24
8.1.
Discontinuation from Study Treatment.........................................................................24
8.1.1.
Discontinuation of Inadvertently Enrolled Subjects..............................................24
8.2.
Discontinuation from the Study....................................................................................24
8.3.
Subjects Lost to Follow-up...........................................................................................24
9.
Study Assessments and Procedures ...................................................................................25
9.1.
Efficacy Assessments...................................................................................................25
9.2.
Adverse Events ............................................................................................................25
9.2.1.
Serious Adverse Events........................................................................................26
9.2.1.1.
Suspected Unexpected Serious Adverse Reactions..........................................26
9.2.2.
Complaint Handling.............................................................................................27
9.3.
Treatment of Overdose.................................................................................................27
9.4.
Safety...........................................................................................................................27
9.4.1.
Laboratory Tests ..................................................................................................27
9.4.2.
Vital Signs ...........................................................................................................27
9.4.3.
Electrocardiograms ..............................................................................................27
9.4.4.
Safety Monitoring ................................................................................................28
9.5.
Pharmacokinetics .........................................................................................................28
9.5.1.
Bioanalysis...........................................................................................................28
9.6.
Pharmacodynamics ......................................................................................................28
9.7.
Genetics .......................................................................................................................29
9.8.
Biomarkers...................................................................................................................29
9.9.
Health Economics ........................................................................................................29
10.
Statistical Considerations and Data Analysis.....................................................................30
10.1. Sample Size Determination ..........................................................................................30
10.2. Populations for Analyses..............................................................................................30
10.2.1.
Study Participant Disposition ...............................................................................30
10.2.2.
Study Participant Characteristics ..........................................................................30
10.3. Statistical Analyses ......................................................................................................30
10.3.1.
Safety Analyses....................................................................................................31
10.3.1.1.
Clinical Evaluation of Safety..........................................................................31
10.3.1.2.
Statistical Evaluation of Safety.......................................................................31
10.3.2.
Pharmacokinetic Analyses....................................................................................31


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10.3.2.1.
Pharmacokinetic Parameter Estimation...........................................................31
10.3.2.2.
Pharmacokinetic Statistical Inference .............................................................31
10.3.3.
Interim Analyses..................................................................................................32
11.
References ........................................................................................................................33


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List of Tables
Table
Page
Table JPDF.1.
Objectives and Endpoints .......................................................................14
Table JPDF.2.
Treatment Sequences in Study I8K-MC-JPDF........................................15


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List of Appendices
Appendix
Page
Appendix 1.
Abbreviations and Definitions ................................................................34
Appendix 2.
Clinical Laboratory Tests........................................................................38
Appendix 3.
Study Governance, Regulatory and Ethical Considerations.....................39
Appendix 4.
Blood Sampling Summary......................................................................42


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1. Protocol Synopsis
Title of Study:
Relative Bioavailability and the Effect of Food on the Bioavailability of LY3337641 in Healthy Subjects
Rationale: 
The effect of formulation may have implications for dosage and administration recommendations.  This study will 
evaluate the relative bioavailability of the LY3337641 test formulation, commercial image tablet (esylate salt) 
[T1fasted] compared to the reference formulation, Phase 1/2 tablet (diHCl salt) [Rfasted].  In addition, this study will 
evaluate the relative bioavailability of the large active pharmaceutical ingredient (API) particle size distribution 
(PSD) commercial image tablet (esylate salt) [T2fasted] compared to the test formulation, commercial image tablet 
(esylate salt) [T1fasted].  This study will also evaluate the effect of a high-fat meal on the relative bioavailability of the 
LY3337641 commercial image tablet (esylate salt) [T1fed].
Objectives/Endpoints:
Objectives
Endpoints 
Primary
To evaluate the relative bioavailability of a single 20-mg 
dose of LY3337641 as the commercial image tablet 
(esylate salt) [T1fasted] compared to the Phase 1/2 tablet 
(diHCl salt) [R fasted].
Ratio of least square means between T1fasted and R fasted
for Cmax and AUC(0-∞).
Secondary

To evaluate the effect of a high-fat meal on the 
bioavailability of a single 20-mg dose of 
LY3337641 when administered as the 
commercial image tablet (esylate salt) [T1fed].

To evaluate the relative bioavailability of a 
single 20-mg dose of LY3337641 when 
administered as the large API PSD commercial 
image tablet (esylate salt) [T2 fasted] compared to 
the commercial image tablet (esylate salt) 
[T1fasted]. 

To assess the tolerability of LY3337641 when 
administered as a single 20-mg dose to healthy 
subjects.
Ratio of least square means between T1fed and T1fasted for 
Cmax and AUC(0-∞).
Ratio of least square means between T2fasted and T1fasted
for Cmax and AUC(0-∞).
Incidence of treatment-emergent adverse events 
(TEAEs).


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Summary of Study Design:
This is an open-label, 4-period, 4-sequence, randomized, crossover study in healthy subjects.
Subjects will be admitted to the clinical research unit (CRU) on Day -1 of Period 1.  In each treatment period, 
subjects will be fasted overnight for at least 10 hours and a single dose of their assigned treatment will be 
administered on the morning of Day 1, following a high-fat meal if applicable.  At a minimum, subjects will reside 
at the CRU until the collection of the 72-hour pharmacokinetic blood sample; all subsequent assessments may be 
conducted on an outpatient visit at the discretion of the investigator.
Blood samples will be collected up to 72 hours (3 days) after each dosing occasion for the measurement of plasma 
concentrations of LY3337641.
Safety assessments performed during the study will include recording of adverse events (AEs), clinical laboratory 
evaluations, vital signs, 12-lead electrocardiograms (ECGs), and physical examinations.
Treatment Arms and Duration:  
Subjects will receive single oral doses of 20 mg LY3337641 on 4 separate occasions, as the Phase 1/2 tablet (diHCl 
salt) in the fasted state (Rfasted), as the commercial image tablet (esylate salt) in the fasted state (T1fasted) and 
following a high-fat meal (T1fed), and as the large API PSD commercial image tablet (esylate salt) in the fasted state
(T2fasted).  There will be a washout period of at least 5 days between dose administrations in consecutive periods. 
Number of Subjects:
Up to 32 subjects may be enrolled in order to ensure that at least 24 subjects complete the study.
Statistical Analysis:
Pharmacokinetic parameter estimates for LY3337641 will be compared between formulations and between the fed 
and fasted states.  Log-transformed Cmax and area under the concentration versus time curve estimates will be 
evaluated in a linear mixed-effects model with fixed effects for treatment, period, and sequence, and random effect 
for subject.  The treatment differences will be back-transformed to present the ratios of geometric means and the 
corresponding 90% confidence interval (CI).
The tmax will be analyzed non-parametrically.  Median of differences and approximate 90% CI for the median of 
differences will be calculated for the fed versus fasted states and for the comparisons between the different 
formulations.


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2. Schedule of Activities


I8K-MC-JPDF Clinical Pharmacology Protocol  
 
 
 
       Page 10 
 
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Study Schedule Protocol I8K-MC-JPDF 
 
Screening 
Periods 1, 2, 3, and 4 
Follow-up/ Early 
discontinuation 
Comments 
Procedure 
Up to 28 days 
prior to 
enrollment 
Day -1 
Days 1 to 3 
Day 4 
≥7 days after last 
dose 
 
 
Informed 
Consent 
X 
 
 
 
 
 
Subject 
Admission to 
CRU 
 
X 
 
 
 
 
Subject 
Discharge 
from CRU 
 
 
 
X 
 
 
Outpatient 
Visit 
 
 
 
 
X 
 
Study Drug 
Administration 
 
 
Day 1, 0 h 
 
 
 
Medical 
History 
X 
 
 
 
 
 
Height 
X 
 
 
 
 
 
Weight 
X 
 
 
 
X 
 
Vital Signs 
(Supine) 
X 
 
Predose, 1, 2, 4, 8, 24, 
48 h 
72 h 
X 
Supine blood pressure and/or pulse rate may be 
measured as clinically indicated.  Additional vital 
signs may be measured during each study period, if 
warranted and agreed by the investigator. 
Clinical Lab 
Tests 
X 
 
Predose, 24 h  
X 
X 
See Appendix 2, Clinical Laboratory Tests, for 
details. 
Pregnancy 
Test  
X 
X 
 
 
X 
Serum pregnancy test will be performed at screening.  
Urine pregnancy test will be performed at other times. 
Physical 
Exam/Medical 
Assessment 
X 
 
Predose 
X 
X 
After screening, medical assessment only performed 
to include medical review and targeted examination, 
as appropriate. 
Single  
12-lead ECG 
X 
 
Predose, 1, 2, 24 h 
72 h 
X 
 


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PK Samples
Predose, 0.25, 0.5, 0.75, 
1, 1.5, 2, 3, 4, 5, 6, 9, 
12, 24, 36, 48 h
72 h
Sampling times are relative to the time of study 
treatment administration (0 min).
These are scheduled sampling times; the actual date 
and time of each PK sample will be recorded.  Minor 
time deviations (e.g. ±5 min for samples prior to 
24 hours) will not be considered a protocol violation.
Genetic 
Sample
Predose (Period 1 only)
Single sample for pharmacogenetic analysis taken on 
Day 1 of Period 1.
Abbreviations:  CRU = clinical research unit; ECG = electrocardiogram; ED = early discontinuation; h = hour(s); PK = pharmacokinetics. 
Note: Predose assessments/sampling will be performed within 4 hours of dosing.


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3. Introduction
3.1.
Study Rationale
The effect of formulation may have implications for dosage and administration 
recommendations.  The aim of this study is to evaluate the relative bioavailability of the 
LY3337641 test formulation, commercial image tablet (esylate salt) [T1fasted] compared to the 
reference formulation, Phase 1/2 tablet (diHCl salt) [Rfasted].  In addition, this study will evaluate 
the relative bioavailability of the large active pharmaceutical ingredient (API) particle size 
distribution (PSD) commercial image tablet (esylate salt) [T2fasted] compared to the test 
formulation, commercial image tablet (esylate salt) [T1fasted].  This study will also evaluate the 
effect of a high-fat meal on the relative bioavailability of the LY3337641 commercial image 
tablet (esylate salt) [T1fed].
A tablet formulation using the diHCl salt has been utilized in Phase 1 and Phase 2a studies. Two 
tablet strengths, 5 and 20 mg, were developed.  Since the the diHCl salt has a tendency to 
disproportionate (physical instability liability), an alternative salt (esylate) has been pursued for 
commercial development.  The esylate salt is more physically stable and has comparable 
solubility to the diHCl.  Neither the diHCl nor the esylate salt is considered highly soluble per 
Biopharmaceutics Classification System (BCS) guidance.  Hence, understanding the impact of 
drug substance particle size on in vivo performance is needed to determine what particle size 
range can be used to supply clinical trials and to justify specifications upon common technical 
document submission.  A 20 mg tablet strength of the esylate salt is the highest tablet strength 
developed so far and is the strength to be used in this relative bioavailability study.  
A pilot food effect evaluation using the Phase 1/2 tablet (diHCl salt) showed that administration 
of LY3337641 after a high-fat meal did not affect the extent of oral absorption (area under the 
concentration versus time curve [AUC]) but decreased the rate of absorption, resulting in a 13% 
lower maximum observed drug concentration (Cmax) and delayed time to the maximum observed 
drug concentration (tmax) by 1.5 hours.  Based on these findings, a high-fat meal is not expected 
to have a significant effect on the bioavailability of LY3337641 when administered as the 
commercial image tablet (esylate salt) formulation.
3.2.
Background
LY3337641 is an orally available, irreversible inhibitor of Bruton’s tyrosine kinase (BTK), a 
member of the TEC family of cytoplasmic tyrosine kinases.  Bruton’s tyrosine kinase is a key 
signaling molecule in the B-cell–receptor and Fc-receptor pathways and an essential mediator of 
B-cell– and myeloid-cell–dependent inflammatory arthritis (Di Paolo et al. 2011; Chakravarty et 
al. 2013).  Bruton’s tyrosine kinase is primarily expressed in hematopoietic cells, including 
B-cells, mast cells, and macrophages.  In humans, BTK loss-of-function mutations cause 
nonlethal X-linked agammaglobulinemia, resulting in reduced B-cell and immunoglobulin (Ig) 
levels (Smith et al. 1994).  
LY3337641 demonstrates potent, irreversible BTK inhibition in BTK enzyme assays, cell-based 
BTK phosphorylation assays, and BTK occupancy assays. 


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Preclinical data suggests that LY3337641 may be useful for treatment of a variety of 
autoimmune diseases.
In healthy adult subjects, LY3337641 was rapidly absorbed after oral administration in the fasted 
state, with geometric mean tmax ranging from 1 to 3 hours after a single dose and 1 to 2 hours 
after multiple doses, and elimination of LY3337641 from systemic circulation was rapid; the 
geometric mean half-life associated with the terminal rate (t1/2) was 4.6 to 6.6 hours. 
The metabolism of LY3337641 has not been fully elucidated.  However, two metabolites, 
N-demethylation (M1) and N-oxidation (M2), have been detected in human plasma and urine.  
M1 and M2 plasma concentrations are low relative to parent concentrations in humans.  Mean 
renal excretion of unchanged LY3337641 was <0.5% of the administered dose in humans.  In 
excretion studies in rats and monkeys in which radiolabelled [14C] LY3337641 was orally 
administered, the urine recovery of total radioactivity (metabolites and/or parent compound) was 
3% of the administered dose, so renal elimination is expected to be a minor clearance route in 
humans.
3.3.
Benefit/Risk Assessment
A single Phase 1 study (Study I8K-MC-JPDD [JPDD]) was conducted in healthy adult males to 
determine the safety, tolerability, pharmacokinetics (PK), and food effect of single and multiple 
doses of orally administered LY3337641.  In the single dose portion of the study, the drug was 
well tolerated following single doses ranging from 10 to 200 mg.  In the 20 mg dosing arm, 4 of 
the 6 subjects administered LY3337641 reported 6 treatment-emergent AEs (TEAEs), only one 
of which (nausea, mild intensity) was attributed to study drug.  In the multiple-dosing portion of 
the study (14 days duration, once daily and twice-daily dosing), the drug was generally well 
tolerated at dosages up to 40 mg once daily.  At dosages totaling 80 mg per day and higher, 
significant TEAEs (ie, TEAEs leading to discontinuation or deemed clinically significant by the 
investigator) were reported. The majority of these events involved skin-related manifestations, 
the most common being rash, with an onset occurring on or after 10 days of 
LY3337641administration.  Some cases were associated with systemic signs and symptoms, 
such as fever, arthritis, and laboratory abnormalities.  Skin related TEAEs were all accompanied 
with a rise in C-reactive protein and in one subject with a mild increase in tryptase as well.  In 
Study JPDD, over a dose range of 10 to 200 mg single oral doses, Cmax and AUC of LY3337641 
were proportional to dose.  
On the basis of projected BTK occupancy using the Phase 1 data, 20 mg is expected to be in the 
clinically efficacious dose range. The Phase 1 safety profile supports further clinical 
development of LY3337641 for treatment of autoimmune diseases; LY3337641 is currently 
progressing into Phase 2 at dose levels of 5, 10, and 30 mg once daily.
More information about the known and expected benefits, risks, serious adverse events (SAEs) 
and reasonably anticipated adverse events (AEs) of LY3337641 are to be found in the 
Investigator’s Brochure (IB).  


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4. Objectives and Endpoints
Table JPDF.1 shows the objectives and endpoints of the study.
Table JPDF.1.
Objectives and Endpoints
Objectives
Endpoints
Primary
To evaluate the relative bioavailability of a single 20-mg 
dose of LY3337641 as the commercial image tablet 
(esylate salt) [T1fasted] compared to the Phase 1/2 tablet 
(diHCl salt) [R fasted].
Ratio of least square means between T1fasted and Rfasted
for Cmax and AUC(0-∞).
Secondary

To evaluate the effect of a high-fat meal on the 
bioavailability of a single 20-mg dose of 
LY3337641 when administered as the 
commercial image tablet (esylate salt) [T1fed].

To evaluate the relative bioavailability of a 
single 20-mg dose of LY3337641 when 
administered as the large API PSD commercial 
image tablet (esylate salt) [T2 fasted] compared to 
the commercial image tablet (esylate salt) 
[T1fasted]. 

To assess the tolerability of LY3337641 when 
administered as a single 20-mg dose to healthy 
subjects.
Ratio of least square means between T1fed and T1fasted for 
Cmax and AUC(0-∞).
Ratio of least square means between T2fasted and T1fasted
for Cmax and AUC(0-∞).
Incidence of treatment-emergent adverse events 
(TEAEs).


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5. Study Design
5.1.
Overall Design
This is an open-label, 4-period, 4-sequence, randomized, crossover study in healthy subjects.  Up 
to 32 subjects may be enrolled in order to ensure that at least 24 subjects complete the study (ie, 
complete all 4 treatment periods).  
Subjects will receive single oral doses of 20 mg LY3337641 on 4 separate occasions.  Each 
subject will receive the following:

Reference formulation (Rfasted):  20 mg LY3337641 Phase 1/2 tablet (diHCl salt) 
administered in the fasted state;

Test formulation 1 (T1fasted):  20 mg LY3337641 commercial image tablet (esylate salt) 
administered in the fasted state;

Test formulation 1 (T1fed):  20 mg LY3337641 commercial image tablet (esylate salt) 
administered in the fed state;

Test formulation 2 (T2fasted):  20 mg LY3337641 large API PSD commercial image tablet 
(esylate salt) administered in the fasted state.
Subjects will be randomly allocated to one of the treatment sequences below (Table JPDF.2).
Table JPDF.2.
Treatment Sequences in Study I8K-MC-JPDF
Sequence
Period 1
Period 2
Period 3
Period 4
1
Reference 
formulation (Rfasted)
Test formulation 2 
(T2fasted)
Test formulation 1 
(T1fasted)
Test formulation 1 
(T1fed)
2
Test formulation 1 
(T1fasted)
Reference 
formulation (Rfasted)
Test formulation 1 
(T1fed)
Test formulation 2 
(T2fasted)
3
Test formulation 1 
(T1fed)
Test formulation 1 
(T1fasted)
Test formulation 2 
(T2fasted)
Reference 
formulation (Rfasted)
4
Test formulation 2 
(T2fasted)
Test formulation 1 
(T1fed)
Reference 
formulation (Rfasted)
Test formulation 1 
(T1fasted)
In each period, subjects will be admitted to the clinical research unit (CRU) on Day -1.  In each 
treatment period, subjects will be fasted overnight and a single dose of 20 mg LY3337641 will 
be administered in the morning of Day 1.  Subjects will receive a high-fat meal prior to dosing 
with LY3337641 if applicable (see Section 6.3.1).  Subjects will reside at the CRU until the 
collection of the 72-hour pharmacokinetic blood sample.
There will be a washout period of at least 5 days between dose administrations in consecutive 
periods.


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If the investigator decides not to administer the first dose to a subject or not to enroll a subject on 
a particular day, the subject may be rescheduled to participate in the study; and any procedures 
performed up to that point may be repeated.   
Blood samples will be collected up to 72 hours after each dosing occasion for the measurement 
of plasma concentrations of LY3337641.
Safety assessments will be performed during the study included recording of AEs, clinical 
laboratory evaluations, vital signs, 12-lead electrocardiograms (ECGs), and physical 
examinations.
5.2.
Number of Participants
Up to 32 subjects may be enrolled in order to ensure that at least 24 subjects complete all 
4 periods of the study.
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 will be an open-label study.  Blinding is not necessary because the primary endpoint is PK, 
and thus not vulnerable to subject or investigator bias.
A crossover design is chosen to enable each subject to act as their own control in the assessment 
of formulation and food effects.  Treatment order randomization will prevent any selection bias 
that might otherwise result from treatment order, and will mitigate period effects.
Conducting the study in healthy subjects mitigates the potential confounding effects of the 
disease state and concomitant medications in patients.  
5.5.
Justification for Dose
The dose level of 20 mg is in the expected therapeutic dose range and is high enough to fully 
characterize the single-dose PK of the compound.  This is also the highest unit dose strength.  In 
addition, as single doses up to 200 mg LY3337641 have been well tolerated, the 20-mg dose is 
considered appropriate for this study.


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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 electrocardiogram (ECG). 
The nature of any conditions present at the time of the physical examination and any preexisting 
conditions will be documented.
Screening may occur up to 28 days prior to enrollment.  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] male subjects:
agree to use an effective method of contraception and not donate sperm for 
the duration of the study and for 90 days following the last dose of study 
drug (see Section 6.3.4)
[1b] female subjects:
(i)
women not of child-bearing potential may participate, and include those who 
are:
a) infertile due to surgical sterilization (hysterectomy, bilateral oophorectomy, 
or tubal ligation), congenital anomaly such as mullerian agenesis; or
b) postmenopausal – postmenopausal is defined as women with an intact uterus 
who have not taken hormones or oral contraceptives within 1 year, who 
have had either cessation of menses for at least 1 year, or 6 to 12 months of 
spontaneous amenorrhea with follicle-stimulating hormone (FSH) consistent 
with menopause (FSH >40 IU/L). 
(ii)
women of child-bearing potential may participate, and include those 
who test negative for pregnancy prior to initiation of treatment based 
on a urine pregnancy test and agree to use one highly effective 
method of contraception or a combination of 2 effective methods of 
contraception during the study and for 28 days following the last 
dose of study drug (see Section 6.3.4).
[2]
aged 21 to 65 years (inclusive) at the time of screening 


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[3]
have a body mass index of 18.5 to 32.0 kg/m2, inclusive  
[4]
have clinical laboratory test results within normal reference range for the 
population or 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
[7]
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:
[8] 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
[9] are Lilly employees
[10] 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  
[11]
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
[12]
have previously completed or withdrawn from this study or any other study 
investigating LY3337641, and have previously received the investigational 
product 
[13]
have known allergies to LY3337641, related compounds or any components 
of the formulation, or history of significant atopy
[14]
have an abnormality in the 12-lead ECG that, in the opinion of the 
investigator, increases the risks associated with participating in the study
[15]
have an abnormal blood pressure as determined by the investigator
[16]
have significant history of or current cardiovascular, dermatological (such as 
eczema, psoriasis, and acne), respiratory, hepatic, renal, gastrointestinal 
(cholecystectomy is not acceptable), 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 interfering with the interpretation of data
[17]
have known or ongoing psychiatric disorders
[18]
regularly use known drugs of abuse


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[19]
show evidence of human immunodeficiency virus (HIV) infection and/or 
positive human HIV antibodies
[20]
show evidence of hepatitis C and/or positive hepatitis C antibody 
[21]
show evidence of hepatitis B and/or positive hepatitis B surface antigen 
[22]
are women who are lactating
[23]
have used or intend to use over-the-counter or prescription medication, 
including herbal medications, within 14 days prior to planned dosing 
[24]
have donated blood or had blood loss of more than 450 mL within 3 months 
of screening
[25]
have an average weekly alcohol intake that exceeds 21 units per week (males) 
and 14 units per week (females), or are unwilling to stop alcohol consumption 
for 48 hours prior to admission in each study period, 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)
[26]
have had symptomatic herpes zoster infection within 3 months of screening
[27]
medical history, examination finding(s) and/or chest radiograph suggestive of 
active or latent tuberculosis
[28] have received live vaccine(s) within 1 month of screening, or intend to during 
the study
[29]
are immunocompromised
[30]
are currently smoking more than 10 cigarettes per day (or equivalent in 
tobacco or nicotine products) or are unwilling to abide by smoking 
restrictions as specified in Section 6.3.2
[31]
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 (except when test 
meals are administered prior to dosing).
Administration of LY3337641 in the fasted state
Following an overnight fast of at least 10 hours, subjects will be administered 20 mg LY3337641 
with approximately 240 mL water.  Water can be allowed as desired except from 1 hour before 
until 1 hour after drug administration.  No food will be allowed for at least 4 hours postdose, 


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after which time a standardized meal will be provided.  Meals will be provided as appropriate at 
all other times.
Administration of LY3337641 in the fed state
Following an overnight fast of at least 10 hours, subjects will start a Food and Drug 
Administration (FDA)-defined high-fat meal 30 minutes prior to administration of LY3337641.  
It is intended that the meals will be ingested in their entirety over an approximate 25-minute 
period, such that they are completed at least 5 minutes before dosing.  A 20-mg dose of 
LY3337641 will be given with approximately 240 mL of water.  Water can be given as desired, 
except for 1 hour before and 1 hour after drug administration.  No further food will be permitted 
until at least 4 hours postdose, after which time a standardized meal will be provided.  Meals will 
be provided as appropriate at all other times.
High-fat meal
The high-fat meal (fat comprises approximately 50% of total calorific content) should consist of 
approximately 800 to 1000 calories in total.  No additional food or substitute is allowed.  An 
example of a typical test meal is 2 eggs fried in butter, 2 strips of bacon, 2 slices of toast with 
butter, 4 ounces of hash brown potatoes, and 8 ounces of whole milk.  The test meal derives 
approximately 150, 250, and 500 to 600 calories from protein, carbohydrate, and fat, respectively.
6.3.2. Caffeine, Alcohol, and Tobacco
Caffeine – Subjects will refrain from consuming xanthine- or caffeine-containing food and 
drinks from 48 hours prior to admission in each study period, and while resident in the CRU.  
Examples of these food and drinks include coffee, tea, cola drinks and chocolate.
Alcohol – Subjects will not consume alcohol for 48 hours prior to admission in each study period, 
and while resident in the CRU.
Smoking – Subjects should not smoke or use any nicotine products from 2 hours prior to each 
admission until after collection of the 72-hour PK sample.
6.3.3. Activity
No strenuous activity will be allowed for 48 hours prior to admission and during the study.
6.3.4. Contraception
Male subjects
Male subjects or their partners will be required to use an effective method of contraception 
during the study and for 90 days after the last dose of study drug. Acceptable methods of 
contraception may include:

Condom (male condom or female condom) in conjunction with spermicidal gel, foam, 
cream, film, or suppository.


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
Diaphragm or cervical vault cap used in conjunction with spermicidal gel, foam, cream, 
film, or suppository.

Male sterilization, with the appropriate post-vasectomy documentation of the absence of 
sperm in the ejaculate.

True abstinence (this must be due to subject’s lifestyle choice; ie, the subject should not 
become abstinent just for the purpose of study participation). Withdrawal or calendar 
methods are not considered acceptable.

Female partner with placement of an effective hormonal intrauterine device.

Female partner with established use of oral, injected, or implanted hormonal methods of 
contraception.
Sexual intercourse with pregnant partners should also be avoided during the course of the study 
unless condoms are used from the time of the first dose until 28 days after dosing.
Male subjects must agree not to donate sperm for the duration of the study and for 90 days 
following the last dose of study drug
Female subjects of child-bearing potential
Female subjects of child-bearing potential must agree to use one highly effective method of 
contraception or a combination of 2 effective methods of contraception during the study and for 
28 days following the last dose of study drug.
Highly effective methods of contraception are contraceptive measures with a failure rate of <1% 
per year, and include:

Intrauterine device (IUD; eg, Mirena). Steel or copper IUDs are not acceptable.

Established use of oral, implanted, transdermal, or hormonal method of contraception 
associated with inhibition of ovulation.

Male sterilization, with verbal confirmation of surgical success 

Bilateral tubal ligation.
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
This study involves comparisons of different formulations of LY3337641. LY3337641 will be 
administered at a dose of 20 mg in each treatment period. 
The treatment arms are as follows:

Reference formulation (Rfasted):  20 mg LY3337641 Phase 1/2 tablet (diHCl salt) 
administered in the fasted state;

Test formulation 1 (T1fasted):  20 mg LY3337641 commercial image tablet (esylate salt) 
administered in the fasted state;

Test formulation 1 (T1fed):  20 mg LY3337641 commercial image tablet (esylate salt) 
administered in the fed state;

Test formulation 2 (T2fasted):  20 mg LY3337641 large API PSD commercial image tablet 
(esylate salt) administered in the fasted state.
The investigator or designee is responsible for:

explaining the correct use of the investigational products to the site personnel;

verifying that instructions are followed properly;

maintaining accurate records of investigational product dispensing and collection;

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
Tablets containing 20 mg LY3337641 will be provided to the site.  
Multiple subjects may be dosed from a single package.
Clinical trial materials will be labeled according to the country’s regulatory requirements.  
Packages will be labeled to distinguish each tablet in the dosing schedule:

Phase 1/2 diHCl salt (reference formulation)

Commercial image tablet (esylate salt) (test formulation 1)

Large API PSD commercial image tablet (esylate salt) (test formulation 2)
There is no requirement to store retention samples.


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7.2.
Method of Treatment Assignment
Subjects will be randomized to 1 of 4 treatment sequences using a computer-generated allocation 
schedule.
7.2.1. Selection and Timing of Doses
The doses will be administered at approximately the same time on each dosing day.  The actual 
time of all dose administrations will be recorded in the subject’s case report form (CRF).
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 and only authorized 
site staff may supply or administer study treatment.  All study treatments should be 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 or designee 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 
treatment administration will occur at the site.
7.7.
Concomitant Therapy
The use of topical medication, provided there is no evidence of chronic dosing with the risk of 
systemic exposure, and occasional acetaminophen/ibuprofen is acceptable at the discretion of the 
investigator.  Additional drugs are prohibited 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 with consultation with a Lilly clinical pharmacologist or clinical 
research physician.  Any additional medication used during the course of the study must be 
documented.
7.8.
Treatment after the End of the Study
This section is not applicable to this study.


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8. Discontinuation Criteria
8.1.
Discontinuation from Study Treatment
Subjects who discontinue the investigational product 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, a discussion must occur between the Lilly CP/CRP and the investigator to 
determine if the subject may continue in the study.  If both agree it is medically appropriate to 
continue, the investigator must obtain documented approval from the Lilly CP/CRP to allow the 
inadvertently enrolled subject to continue in the study with or without continued treatment with 
investigational product.
8.2.
Discontinuation from the Study
Subjects will be discontinued in the following circumstances:

enrollment in any other clinical trial involving an investigational product or enrollment in 
any other type of medical research judged not to be scientifically or medically compatible 
with this study;

participation in the study needs to be stopped for medical, safety, regulatory, or other 
reasons consistent with applicable laws, regulations, and good clinical practice (GCP);

Investigator Decision:
o
the investigator decides that the subject should be discontinued from the study;
o
if the subject, for any reason, requires treatment with another therapeutic agent 
that has been demonstrated to be effective for treatment of the study indication, 
discontinuation from the study occurs prior to introduction of the new agent;

Subject Decision:
o
the subject, or designee, for example, parents or legal guardian requests to be 
withdrawn from the study.
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 investigational 
product or the study, or that caused the subject to discontinue the investigational product 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, including clinically significant 
signs and symptoms of the disease under treatment in the study.  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 the disease, 
concomitant treatment or pathologies.  
A “reasonable possibility” means that there is a cause and effect relationship between the 
investigational product, study device and/or study procedure and the AE.
Planned surgeries should not be reported as AEs unless the underlying medical condition has 
worsened during the course of the study.


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If a subject’s investigational product is discontinued as a result of an AE, study site personnel 
must report this to Lilly or its designee via eCRF.
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.
Although all AEs are recorded in the eCRF after signing informed consent, SAE reporting begins 
after the subject has signed informed consent and has received investigational product.  
However, if an SAE occurs after signing informed consent, but prior to receiving Investigational 
product (IP), AND is considered reasonably possibly related to a study procedure then it MUST 
be reported.
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 adverse event.  
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 IP 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.


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9.2.2. Complaint Handling
Lilly collects product complaints on IPs 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.
9.3.
Treatment of Overdose
For the purposes of this study, an overdose of LY3337641 is considered any dose higher than the 
planned study dose.  There is no specific antidote for LY3337641.  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). 
9.4.2. Vital Signs
For each subject, vital signs measurements should be conducted according to the Schedule of 
Activities (Section 2).  
Blood pressure and pulse rate should be measured after at least 5 minutes supine.
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 by the investigator.
9.4.3. 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, a single 12-lead digital ECG will be collected according to the Schedule of 
Activities.  Electrocardiograms must be recorded before collecting any blood for safety or 
pharmacokinetic tests.  Subjects must be supine for approximately 5 to 10 minutes before ECG 
collection and remain supine but awake during ECG collection.  Electrocardiograms may be 
obtained at additional times, when deemed clinically necessary.  All ECGs recorded should be 
stored at the investigational site.
Electrocardiograms will be interpreted by a qualified physician (the investigator or qualified 
designee) at the site as soon as possible after the time of ECG collection, and ideally while the 
subject is still present, to determine whether the subject meets entry criteria at the relevant 


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visit(s) and for immediate subject management, should any clinically relevant findings be 
identified.  
If a clinically significant finding is identified (including, but not limited to, clinically significant 
changes in QT/QTc interval from baseline) after enrollment, the investigator will determine if 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 collection.  Any new clinically relevant finding should be 
reported as an adverse event.
9.4.4. Safety Monitoring
The Lilly CP/CRP/clinical research scientist will monitor safety data throughout the course of
the study.
Lilly will review SAEs within time frames mandated by company procedures.  The Lilly clinical 
pharmacologist or research physician will consult with the functionally independent Global 
Patient Safety medical 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 venous blood samples of 
approximately 2 mL each will be collected to determine the plasma concentrations of 
LY3337641.  A maximum of 2 samples per treatment period may be collected at additional time 
points if warranted and agreed upon between both the investigator and sponsor.  Instructions for 
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 LY3337641 will be assayed using a validated liquid chromatography with 
tandem MS detection methods.  
Bioanalytical samples collected to measure LY3337641 concentrations will be retained for a 
maximum of 1 year following last subject visit for the study.  
9.6.
Pharmacodynamics
This section is not applicable for this study.


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9.7.
Genetics
A blood sample will be collected for pharmacogenetic analysis as specified in the Schedule of 
Activities, 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 LY3337641 and to 
investigate genetic variants thought to play a role in rheumatoid arthritis.  Assessment of variable 
response may include evaluation of AEs or differences in exposure.  
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 the ethical review board (ERB)/institutional review board 
(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 
LY3337641 or after LY3337641 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.  
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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10.
Statistical Considerations and Data Analysis
10.1. Sample Size Determination
Up to 32 subjects may be enrolled in order to ensure that 24 subjects complete all 4 study periods.  
The sample size chosen will provide a precision of 8% for the estimate of the geometric mean 
ratio in AUC between the test formulations versus the reference formulation, and between the 
test formulations administered in the fed versus the fasted state.  It means that there is a 90% 
probability that the half-width of the resulting 90% confidence interval (CI) of the geometric 
mean ratio in AUC is no larger than 8%.  No direct estimate of intra-subject variability is 
available. 
The sample size chosen will provide a precision of 13% for the estimate of the geometric mean 
ratio in Cmax between the test formulations versus the reference formulation, and between the test 
formulations administered in the fed versus the fasted state.   It means that there is a 90% 
probability that the half-width of the resulting 90% CI of the geometric mean ratio in AUC is no 
larger than 13%.  No direct estimate of intra-subject variability is available. 
Based on Study JPDD, the coefficient of variation (CV%) for AUC and Cmax were approximately 
30% and 50%, respectively, for a 20-mg dose of LY3337641 administered. Assuming that half 
of the total CV% is contributed by intra-subject variability, an approximation of the intra-subject 
variability of 15% for AUC and 25% for Cmax.
Subjects who are randomized but not complete all 4 treatment periods may be replaced to ensure 
that enough subjects complete the study.  The replacement subject will assume the withdrawn 
subject’s treatment sequence (receiving each treatment 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 subjects’ age, sex, weight, height, 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 randomized subjects receiving at least one dose of the IP according to the treatment the 
subjects actually received.  Safety analyses will be conducted on the safety population, defined 
as all randomized subjects receiving at least one dose of the IP, whether or not they completed all 
protocol requirements.


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Additional exploratory analyses of the data will be conducted as deemed appropriate.    
10.3.1. Safety Analyses
10.3.1.1. Clinical Evaluation of Safety
All drug-related and procedural 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 treatment will be presented by severity and by association 
with IP as perceived by the investigator.  Symptoms reported to occur prior to enrollment 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 drug-related SAEs will be reported.
10.3.1.2. Statistical Evaluation of Safety
Safety parameters that will be assessed include clinical laboratory parameters, vital signs, and 
ECGs.  The parameters will be listed and summarized using standard descriptive statistics, as 
appropriate.  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 LY3337641 will be calculated by standard 
noncompartmental methods of analysis and reported by treatment period.
The primary parameters for analysis will be Cmax and AUC from time zero to infinity 
(AUC[0-∞]), and AUC from time zero to time t, where t is the last time point with a measurable 
concentration (AUC[0-tlast]).  The tmax will be observed from the data.  Other noncompartmental 
parameters, such as half-life associated with the terminal rate constant in noncompartmental 
analysis (t1/2), 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) may be reported.
10.3.2.2. Pharmacokinetic Statistical Inference
Pharmacokinetic parameter estimates for LY3337641 will be compared between formulations 
and between the fed and fasted states.  Log-transformed Cmax and the AUC estimates will be 
analyzed using a linear mixed-effects model with PK estimate as response variable, treatment, 
period, and sequence as fixed effects; and a random effect for subject.  The treatment differences 
will be back-transformed to present the ratios of geometric means and the corresponding 90% 
CI.
The tmax will be analyzed non-parametrically.  Median of differences and approximate 90% CI 
for the median of differences will be calculated for the fed versus fasted states and for the 
comparisons between the different formulations.


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10.3.3. Interim Analyses 
An interim analysis is scheduled to occur after approximately 24 subjects complete the first 
3 periods to support an internal formulation decision for clinical planning activities associated 
with LY3337641. The primary purpose of this interim analysis is to compare the AUC(0-∞) and 
Cmax of T1fasted and Rfasted, however all available PK data will be evaluated during the interim. 
After Period 3, crossover data from approximately 12 subjects for these 2 treatments should be 
available.  A sample size of 12 subjects will provide a precision of 13% and 20% for the estimate 
of the geometric mean ratio in AUC and Cmax, respectively, between the two formulations. 
Assumptions are the same as detailed in Section 10.1.  An additional interim analysis after 
Period 4 and before the final database lock may be conducted if needed.


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11.
References
Chakravarty SD, Poulikakos PI, Ivashkiv LB, Salmon JE, Kalliolias GD. Kinase inhibitors: A 
new tool for the treatment of rheumatoid arthritis. Clin Immunol. 2013;148(1):66-78.
Di Paolo JA, Huang T, Balazs M, Barbosa J, Barck KH, Bravo BJ, Carano RA, Darrow J, Davies 
DR, DeForge, LE, Diehl L, Ferrando R, Gallion SL, Giannetti AM, Gribling P, Hurez V, 
Hymowitz SG, Jones R, Kropf JE, Lee WP, Maciejewski PM, Mitchell SA, Rong H, Staker BL, 
Whitney JA, Yeh S, Young WB, Yu C, Zhang J, Reif K, Currie KS. Specific Btk inhibition 
suppresses B cell- and myeloid cell-mediated arthritis. Nat Chem Biol. 2011;7(1):41-50.
Smith CI, Baskin B, Humire-Greiff P, Zhou JN, Olsson PG, Maniar HS, Kjéllen P, Lambris JD, 
Christensson B, Hammarström L, Bentley D, Vetrie D, Islam KB, Vořechovský I, Sideras P. 
Expression of Bruton’s agammaglobulinemia tyrosine kinase gene, BTK, is selectively 
downregulated in T lymphocytes and plasma cells. J Immunol. 1994;152(2):557−565.


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Appendix 1.
Abbreviations and Definitions


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Term
Definition
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.
API
active pharmaceutical ingredient 
AUC
area under the concentration versus time curve 
AUC(0-∞)
AUC from time zero to infinity
AUC(0-tlast)
AUC from time zero to time t, where t is the last time point with a measurable concentration
BTK
Bruton’s tyrosine kinase 
CI
confidence interval
CL/F
apparent total body clearance of drug calculated after extra vascular administration
Cmax
maximum observed drug 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
CRF
case report form
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 
ECG
electrocardiogram
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.


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enter
Subjects entered into a trial are those who sign the informed consent form directly or 
through their legally acceptable representatives.
ERB
ethical review board
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
IND
Investigational New Drug:  An application to the FDA to allow testing of a new drug in 
humans.
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.
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.
Non-
investigational 
product (non-IP)
A product that is not being tested or used as a reference in the clinical trial, but is provided 
to subjects and used in accordance with the protocol, such as:  concomitant or rescue/escape 
medication for preventative, diagnostic, or therapeutic reasons, medication to ensure 
adequate medical care, and/or products used to induce a physiological response.
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.
PK
pharmacokinetic(s)
PSD
particle size distribution
SAE
serious adverse event


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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.  
SUSARs
suspected unexpected serious adverse reactions 
t1/2
half-life associated with the terminal rate constant in noncompartmental analysis 
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 to the maximum observed drug 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)
Chloride
Mean cell volume 
Calcium
Mean cell hemoglobin 
Phosphorus
Mean cell hemoglobin concentration 
Fasting glucose 
Leukocytes (WBC)
Urea
Absolute counts of:
Uric acid
Neutrophils
Total protein
Lymphocytes
Albumin
Monocytes
Total bilirubin
Eosinophils
Alkaline phosphatase (ALP)
Basophils
Aspartate aminotransferase (AST)
Platelets
Alanine aminotransferase (ALT)
Creatinine
Urinalysisa
Gamma-glutamyl transferase (GGT)
Specific gravity
Lactate dehydrogenase (LDH)
pH
Protein
Glucose
Ketones
Hepatitis B surface antigenb,c
Bilirubin
Hepatitis C antibodyb,c
Urobilinogen
HIVb,c
Blood
Pregnancy test
Nitrite
FSHb
Leukocytes
Microscopic examination of sediment (test only if 
dipstick result is abnormal and per investigator’s 
discretion)
Abbreviations:  FSH = follicle-stimulating hormone; HIV = human immunodeficiency virus; RBC = red blood cells; 
WBC = white blood cells.
a
Results will be reported and validated by the local lab at the time of testing.
b
Performed at screening only if clinically indicated and per investigator’s discretion.
c
Tests may be waived if they have been performed within 6 months before screening with reports available for 
review.  


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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 IP.

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 or appropriate local representative 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 and updates during the course of the study;

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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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 I8K-MC-JPDF Sampling Summary
Purpose
Maximum Blood Volume 
per Sample (mL)
Maximum Number 
of Blood Samples
Maximum Total 
Volume (mL)
Screening testsa
17
1
17
Clinical laboratory testsa
11
13
143
Pharmacokineticsb
2
76
152
Pharmacogenetics
10
1
10
Total
322
Total for clinical purposes [rounded up to nearest 10 mL] 
330
a
Additional samples may be drawn if needed for safety purposes.
b
Includes up to 2 additional samples per treatment period.


Leo Document ID = 703e9077-f89a-47f5-82ab-b423ca236f45
Approver: 
Approval Date & Time: 09-Jan-2017 13:48:54 GMT
Signature meaning: Approved
Approver: 
Approval Date & Time: 09-Jan-2017 13:53:47 GMT
Signature meaning: Approved
PPD
PPD

SAP_001.pdf: 
Statistical Analysis Plan: I8K-MC-JPDF (Final)
Relative Bioavailability and the Effect of Food on the Bioavailability of LY3337641 in Healthy 
Subjects 
NCT03099148 
Approval Date: 08-Mar-2017 


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STATISTICAL ANALYSIS PLAN
Relative Bioavailability and the Effect of Food on the Bioavailability of LY3337641 in 
Healthy Subjects
Statistical Analysis Plan Status:  Final
Statistical Analysis Plan Date:  24 February 2017
Study Drug:  LY3337641
Sponsor Reference:  I8K-MC-JPDF
Clinical Phase I
Approval Date: 08-Mar-2017 GMT
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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
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..........................................................................8
9.3
Pharmacokinetic Assessment.........................................................................................9
9.3.1
Pharmacokinetic Analysis.....................................................................................9
9.3.2
Pharmacokinetic Statistical Methodology ...........................................................12
9.4
Safety and Tolerability Assessments ............................................................................13
9.4.1
Adverse events ...................................................................................................13
9.4.2
Concomitant medication.....................................................................................13
9.4.3
Clinical laboratory parameters ............................................................................14
9.4.4
Vital signs ..........................................................................................................14
9.4.5
Electrocardiogram (ECG)...................................................................................14
9.4.6
Other assessments...............................................................................................14
9.4.7
Safety and Tolerability Statistical Methodology ..................................................14
10. INTERIM ANALYSES .....................................................................................................14
11. CHANGES FROM THE PROTOCOL SPECIFIED STATISTICAL ANALYSES ............14
12. REFERENCES ..................................................................................................................15
13. DATA PRESENTATION ..................................................................................................15
13.1 Derived Parameters .....................................................................................................15
13.2 Missing Data ...............................................................................................................15
13.3 Insufficient Data for Presentation ................................................................................15
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2. ABBREVIATIONS
Abbreviations pertain to the Statistical Analysis Plan (SAP) only (not the tables, figures and 
listings [TFLs]).
AE
Adverse event
API
Active pharmaceutical ingredient
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 lower limit of quantitation
Clast
Last quantifiable drug concentration
Cmax
Maximum observed drug concentration
CI
Confidence interval
CL/F
Apparent total body clearance of drug calculated after extra-vascular
administration
CRF
Case Report Form
CRU
Clinical Research Unit
CSR
Clinical Study Report
CV
Coefficient of variation
EC
Early Clinical 
ECG
Electrocardiogram
e.g.
For example (Latin: exempli gratia)
ICH
International Conference on Harmonisation
LLOQ
Lower limit of quantification
MedDRA
Medical Dictionary for Regulatory Activities
PK
Pharmacokinetic
PSD
Particle size distribution
SAP
Statistical Analysis Plan
SD
Standard deviation 
TFLs
Tables, Figures, and Listings
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t1/2
Half-life associated with the terminal rate constant (λz) in 
non-compartmental analysis
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
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3. INTRODUCTION
This SAP has been developed after review of the Clinical Study Protocol (final version dated 
09 January 2017).
This SAP describes the planned analysis of the safety, tolerability and pharmacokinetic (PK) 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 and PK analyses of data. In 
general, the analyses are based on information from the protocol, unless they have been modified 
by agreement between Eli Lilly and Company and 
. 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 
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 outlined in the International 
Conference 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 20 mg dose of LY3337641 as the 
commercial image tablet (esylate salt) [T1fasted] compared to the Phase 1/2 tablet 
(diHCl salt) [Rfasted].
4.2
Secondary Objectives

To evaluate the effect of a high-fat meal on the bioavailability of a single 20 mg dose of 
LY3337641 when administered as the commercial image tablet (esylate salt) [T1fed].

To evaluate the relative bioavailability of a single 20 mg dose of LY3337641 when 
administered as the large active pharmaceutical ingredient (API) particle size distribution
(PSD) commercial image tablet (esylate salt) [T2fasted] compared to the commercial image 
tablet (esylate salt) [T1fasted].
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
To assess the tolerability of LY3337641 when administered as a single 20 mg dose to 
healthy subjects.
5. STUDY DESIGN
This is an open-label, 4-period, 4-sequence, randomized, crossover study in healthy subjects. Up 
to 32 subjects may be enrolled in order to ensure that at least 24 subjects complete the study (ie, 
complete all 4 treatment periods).
Subjects will receive single oral doses of 20 mg LY3337641 on 4 separate occasions. Each 
subject will receive the following:

Reference formulation (Rfasted): 20 mg LY3337641 Phase 1/2 tablet (diHCl salt) 
administered in the fasted state;

Test formulation 1 (T1fasted): 20 mg LY3337641 commercial image tablet (esylate salt) 
administered in the fasted state;

Test formulation 1 (T1fed): 20 mg LY3337641 commercial image tablet (esylate salt) 
administered in the fed state;

Test formulation 2 (T2fasted): 20 mg LY3337641 large API PSD commercial image tablet 
(esylate salt) administered in the fasted state.
Subjects will be randomly allocated to one of the treatment sequences below:
Sequence
Period 1
Period 2
Period 3
Period 4
1
Reference 
formulation 
(Rfasted)
Test formulation 2 
(T2fasted)
Test formulation 1 
(T1fasted)
Test formulation 1 
(T1fed)
2
Test formulation 1 
(T1fasted)
Reference 
formulation 
(Rfasted)
Test formulation 1 
(T1fed)
Test formulation 2 
(T2fasted)
3
Test formulation 1 
(T1fed)
Test formulation 1 
(T1fasted)
Test formulation 2 
(T2fasted)
Reference 
formulation 
(Rfasted)
4
Test formulation 2 
(T2fasted)
Test formulation 1 
(T1fed)
Reference 
formulation 
(Rfasted)
Test formulation 1 
(T1fasted)
In each period, subjects will be admitted to the clinical research unit (CRU) on Day -1. In each 
treatment period, subjects will be fasted overnight and a single dose of 20 mg LY3337641 will 
be administered in the morning of Day 1. Subjects will receive a high-fat meal prior to dosing 
with LY3337641 if applicable. Subjects will reside at the CRU until the collection of the 
72-hour PK blood sample.
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There will be a washout period of at least 5 days between dose administrations in consecutive 
periods.
If the investigator decides not to administer the first dose to a subject or not to enroll a subject on 
a particular day, the subject may be rescheduled to participate in the study; and any procedures 
performed up to that point may be repeated.
Blood samples will be collected up to 72 hours after each dosing occasion for the measurement 
of plasma concentrations of LY3337641.
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 TFLs
20 mg LY3337641 Phase 1/2 tablet (diHCl salt)
(Reference fasted)
Rfasted
1
20 mg LY3337641 commercial image tablet 
(esylate salt) (Test 1 fasted)
T1fasted
2
20 mg LY3337641 commercial image tablet 
(esylate salt) (Test 1 fed)
T1fed
3
20 mg LY3337641 large API PSD commercial 
image tablet (esylate salt) (Test 2 fasted)
T2fasted
4
7. SAMPLE SIZE JUSTIFICATION
Up to 32 subjects may be enrolled in order to ensure that 24 subjects complete all 4 study 
periods.
The sample size chosen will provide a precision of 8% for the estimate of the geometric mean 
ratio in area under the concentration versus time curve (AUC) between the test formulations 
versus the reference formulation, and between the test formulations administered in the fed 
versus the fasted state.  It means that there is a 90% probability that the half-width of the 
resulting 90% confidence interval (CI) of the geometric mean ratio in AUC is no larger than 8%.  
No direct estimate of intra-subject variability is available.
The sample size chosen will provide a precision of 13% for the estimate of the geometric mean 
ratio in maximum observed drug concentration (Cmax) between the test formulations versus the 
reference formulation, and between the test formulations administered in the fed versus the 
fasted state.  It means that there is a 90% probability that the half-width of the resulting 90% CI 
of the geometric mean ratio in Cmax is no larger than 13%.  No direct estimate of intra-subject 
variability is available.
Based on Study JPDD, the coefficient of variation (CV%) for AUC and Cmax were approximately 
30% and 50%, respectively, for a 20 mg dose of LY3337641 administered.  Assuming that half 
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of the total CV% is contributed by intra-subject variability, an approximation of the intra-subject 
variability of 15% for AUC and 25% for Cmax.
Subjects who are randomized but not complete all 4 treatment periods may be replaced to ensure 
that enough subjects complete the study.  The replacement subject will assume the withdrawn 
subject’s treatment sequence (receiving each treatment allocated).
8. DEFINITION OF ANALYSIS POPULATIONS
The “Safety” population will consist of all subjects who received at least one dose of study drug, 
whether or not they completed all protocol requirements.
The “Pharmacokinetic” population will consist of all subjects who received at least one dose of 
study drug and have evaluable PK data.  PK data may be excluded from the summary statistics
and statical analysis where a subject has an adverse event (AE) of vomiting that occurs at or 
before 2 times median time of maximum observed drug concentration (tmax).
All protocol deviations that occur during the study will 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 Cmax) the geometric 
mean and geometric 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 
relevant 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.
9.2
Demographics and Subject Disposition
Subject disposition will be listed. The demographic variables age, sex, race, ethnicity, body 
weight, height and body mass index will be summarized and listed.
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9.3
Pharmacokinetic Assessment
9.3.1 Pharmacokinetic Analysis
Noncompartmental methods applied with a validated software program (Phoenix WinNonlin 
Version 6.4 or later) to the plasma concentrations of LY3337641, 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
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.
General PK Parameter Rules

Actual sampling times will be used in the final analyses of individual PK parameters, 
except for non-bolus predose sampling times which will be set to zero. For non-bolus, 
multiple dose profiles, the predose 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. 
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
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 Cmax. 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 t½ 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 footnote 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).  Concentrations reported as BQL will be set to a value of zero when 
all of the following conditions are met:
o
The compound is non-endogenous.
o
The samples are from the initial dose period for a subject or from a subsequent 
dose period following a suitable wash-out period.
o
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.
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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 using arithmetic average 
concentrations.

The predose 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.
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 analysis if any of the following
criteria are met:

For PK profiles during single dosing of non-endogenous compounds, the concentration in 
a predose sample is quantifiable.
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
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 lo g 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.
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.Insert from PKAP (note PKAP should detail 
WinNonlin version)
9.3.2 Pharmacokinetic Statistical Methodology
The PK parameter estimates for LY3337641 will be compared between formulations and 
between the fed and fasted states.  Log-transformed AUC(0-∞), AUC(0-tlast) and Cmax estimates 
will be analyzed using a linear mixed-effects model with fixed effects for treatment, period, and 
sequence and a random effect for subject.  The treatment differences will be back-transformed to 
present the ratios of geometric least squares means and the corresponding 90% CI.
One model will be used for all of the following comparisons:

Relative bioavailability:  test formulation 1 (T1fasted) versus reference formulation 
(Rfasted);
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
Food effect:  test formulation 1 administered in the fed state  (T1fed) versus test 
formulation 1 administered in the fasted state (T1 fasted);

Relative bioavailability:  test formulation 2 (T2fasted) versus Test formulation 1 (T1fasted).
Example SAS code:
proc mixed data=DATA covtest alpha=0.1;
    class treatment period sequence subject;
    model log_pk = treatment period sequence / ddfm=kr;
    random subject;
    lsmeans treatment / pdiff cl alpha=0.1;
    ods output lsmeans=lsmeans;
    ods output diffs=diffs;
    ods output covparms=cov;
run;
The tmax will be analyzed non-parametrically.  Median of differences and approximate 90% CI 
for the median of differences will be calculated for the fed versus fasted states and for the 
comparisons between the different formulations.  P-values will also be calculated using the 
Wilcoxon signed rank test.
9.4
Safety and Tolerability Assessments
9.4.1 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 dosing. 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.
9.4.2 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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9.4.3 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.
9.4.4 Vital signs
Supine vital signs data will be summarized by parameter and treatment together with changes 
from baseline, where baseline is defined as Day 1 predose (of each period). Figures of mean 
vital signs and mean changes from baseline will be presented by parameter and treatment. 
Furthermore, values for individual subjects will be listed.
9.4.5 Electrocardiogram (ECG)
ECGs will be performed for safety monitoring purposes only and will not be presented. 
9.4.6 Other assessments
All other safety assessments not detailed in this section will be listed but not summarized or 
statistically analyzed.
9.4.7 Safety and Tolerability Statistical Methodology
No inferential statistical analyses are planned.
10.
INTERIM ANALYSES
An interim analysis is scheduled to occur after approximately 24 subjects complete the first 3 
periods to support an internal formulation decision for clinical planning activities associated with 
LY3337641.  The primary purpose of this interim analysis is to compare the AUC(0-∞) and Cmax
of T1fasted and Rfasted, however all available PK data will be evaluated during the interim.  After 
Period 3, crossover data from approximately 12 subjects for these 2 treatments should be 
available.
A sample size of 12 subjects will provide a precision of 13% and 20% for the estimate of the 
geometric mean ratio in AUC and C max, respectively, between the two formulations.  
Assumptions are the same as detailed in Section 7.
An additional interim analysis after Period 4 and before the final database lock may be 
conducted if needed.
11.
CHANGES FROM THE PROTOCOL SPECIFIED STATISTICAL ANALYSES
There were no changes from the protocol specified statistical analyses.
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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.
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. tmax, 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.”
CCI


Leo Document ID = a3f220ac-34d5-408c-ade8-ef2e7d3d4783
Approver: 
Approval Date & Time: 06-Mar-2017 12:24:13 GMT
Signature meaning: Approved
Approver: 
Approval Date & Time: 06-Mar-2017 16:06:11 GMT
Signature meaning: Approved
Approver: 
Approval Date & Time: 08-Mar-2017 13:12:06 GMT
Signature meaning: Approved
Approver: 
Approval Date & Time: 08-Mar-2017 15:07:01 GMT
Signature meaning: Approved
PPD
PPD
PPD
PPD