Clinical trial NCT03083561
Conditions: Healthy
Sponsor: Eli Lilly and Company
Start date: 2017-03-15; Completion date: 2017-05-25
Enrollment: 36 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
The main purpose of this study is to evaluate the safety and tolerability of LY3337641 in healthy Japanese and Caucasian participants. The study will also investigate how the body processes LY3337641 and the effect of LY3337641 on the body. The study will last up to 4 weeks for each participant. Screening may occur within 28 days prior to first dose of study drug.

Detailed description:

Arms: arm 1: Multiple doses of 30 mg LY3337641 tablet administered orally every day for two weeks, with a two week follow-up period. arm 2: Multiple doses of placebo administered orally every day for two weeks, with a two week follow-up period. arm 3: Single dose of 5 mg, 80 mg and 160 mg LY3337641 tablet administered orally, with a two week follow-up period. arm 4: Single dose of placebo administered orally, with a two week follow-up period.
Interventions: intervention 1: LY3337641 intervention 2: Placebo
Intervention descriptions: intervention 1: Administered orally. intervention 2: Administered orally.

Protocol documents:
Prot_000.pdf: 
Protocol (a) I8K-JE-JPDB 
 
A Single- and Multiple-Dose Study to Evaluate the Safety, Tolerability, Pharmacokinetics, and 
Pharmacodynamics of LY3337641 in Japanese and Caucasian Healthy Subjects 
 
NCT03083561 
 
Approval Date: 16-Mar-2017 
 
 
 


I8K-JE-JPDB(a)Clinical Pharmacology Protocol
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LY3337641
Protocol I8K-JE-JPDB
A Single-and Multiple-Dose Study to Evaluate the Safety, 
Tolerability, Pharmacokinetics, and Pharmacodynamics of 
LY3337641 in Japanese and Caucasian 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.
Approval Date: 16-Mar-2017 GMT
LY3337641
Eli Lilly Japan K.K.
Kobe Hyogo Japan
Clinical Pharmacology Protocol Electronically Signed and Approved by Lilly:
24December 2016
Amendment (a) Electronically Signed and Approved by Lilly
on approval date provided below.


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Table of Contents
A Single- and Multiple-Dose Study to Evaluate the Safety, 
Tolerability, Pharmacokinetics, and Pharmacodynamics of 
LY3337641 in Japanese and Caucasian Healthy Subjects
Section
Page
Protocol I8K-JE-JPDB A Single- and Multiple-Dose Study to Evaluate the 
Safety, Tolerability, Pharmacokinetics, and Pharmacodynamics of 
LY3337641 in Japanese and Caucasian Healthy Subjects....................................................1
Table of Contents........................................................................................................................2
1.
Protocol Synopsis................................................................................................................8
2.
Schedule of Activities .......................................................................................................10
3.
Introduction ......................................................................................................................15
3.1.
Study Rationale............................................................................................................15
3.2.
Background..................................................................................................................15
3.3.
Benefit/Risk Assessment..............................................................................................16
4.
Objectives and Endpoints..................................................................................................17
5.
Study Design.....................................................................................................................18
5.1.
Overall Design .............................................................................................................18
5.2.
Number of Participants.................................................................................................19
5.3.
End of Study Definition ...............................................................................................19
5.4.
Scientific Rationale for Study Design...........................................................................19
5.5.
Justification for Dose ...................................................................................................20
6.
Study Population...............................................................................................................21
6.1.
Inclusion Criteria..........................................................................................................21
6.2.
Exclusion Criteria ........................................................................................................22
6.3.
Lifestyle and/or Dietary Requirements .........................................................................24
6.3.1.
Meals and Dietary Restrictions.............................................................................24
6.3.2.
Caffeine, Alcohol, and Tobacco ...........................................................................25
6.3.3.
Activity................................................................................................................25
6.4.
Screen Failures.............................................................................................................25
7.
Treatment..........................................................................................................................26
7.1.
Treatment Administered...............................................................................................26
7.1.1.
Packaging and Labeling .......................................................................................27
7.2.
Method of Treatment Assignment ................................................................................27
7.2.1.
Selection and Timing of Doses.............................................................................27
7.3.
Blinding .......................................................................................................................27


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7.4.
Dose Modification........................................................................................................28
7.4.1.
Dose Escalation....................................................................................................28
7.5.
Preparation/Handling/Storage/Accountability...............................................................29
7.6.
Treatment Compliance .................................................................................................29
7.7.
Concomitant Therapy...................................................................................................29
7.8.
Treatment after the End of the Study............................................................................29
8.
Discontinuation Criteria ....................................................................................................30
8.1.
Discontinuation from Study Treatment.........................................................................30
8.1.1.
Discontinuation of Inadvertently Enrolled Subjects..............................................30
8.2.
Discontinuation from the Study....................................................................................31
8.3.
Subjects Lost to Follow-up...........................................................................................31
9.
Study Assessments and Procedures ...................................................................................32
9.1.
Efficacy Assessments...................................................................................................32
9.2.
Adverse Events ............................................................................................................32
9.2.1.
Serious Adverse Events........................................................................................33
9.2.1.1.
Suspected Unexpected Serious Adverse Reactions..........................................33
9.2.2.
Complaint Handling.............................................................................................33
9.3.
Treatment of Overdose.................................................................................................34
9.4.
Safety...........................................................................................................................34
9.4.1.
Laboratory Tests ..................................................................................................34
9.4.2.
Vital Signs ...........................................................................................................34
9.4.3.
Electrocardiograms ..............................................................................................34
9.4.4.
Other Tests...........................................................................................................35
9.4.4.1.
Assessment and Management of Subjects Developing a 
Rash ...............................................................................................................35
9.4.5.
Safety Monitoring ................................................................................................36
9.5.
Pharmacokinetics .........................................................................................................36
9.5.1.
Bioanalysis...........................................................................................................36
9.6.
Pharmacodynamics ......................................................................................................37
9.7.
Genetics .......................................................................................................................37
9.8.
Biomarkers...................................................................................................................37
9.9.
Health Economics ........................................................................................................38
10.
Statistical Considerations and Data Analysis.....................................................................39
10.1. Sample Size Determination ..........................................................................................39
10.2. Populations for Analyses..............................................................................................39
10.2.1.
Study Participant Disposition ...............................................................................39
10.2.2.
Study Participant Characteristics ..........................................................................39
10.3. Statistical Analyses ......................................................................................................39


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10.3.1.
Safety Analyses....................................................................................................39
10.3.1.1.
Clinical Evaluation of Safety..........................................................................39
10.3.1.2.
Statistical Evaluation of Safety.......................................................................40
10.3.2.
Pharmacokinetic Analyses....................................................................................40
10.3.2.1.
Pharmacokinetic Parameter Estimation...........................................................40
10.3.2.2.
Pharmacokinetic Statistical Inference .............................................................40
10.3.3.
Pharmacodynamic Analyses.................................................................................40
10.3.4.
Pharmacokinetic/Pharmacodynamic Analyses......................................................41
10.3.5.
Interim Analyses..................................................................................................41
11.
References ........................................................................................................................42


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List of Tables
Table
Page
Table JPDB.1.
Objectives and Endpoints .......................................................................17
Table JPDB.2.
Treatment Administered .........................................................................26
Table JPDB.3.
Amendment Summary for Protocol I8K-JE-JPDB Amendment(a)..........56


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List of Figures
Figure
Page
Figure JPDB.1.
Illustration of study design for Protocol I8K-JE-JPDB............................19


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List of Appendices
Appendix
Page
Appendix 1.
Abbreviations and Definitions ................................................................43
Appendix 2.
Clinical Laboratory Tests........................................................................47
Appendix 3.
Study Governance, Regulatory and Ethical Considerations.....................48
Appendix 4.
Hepatic Monitoring Tests for Treatment-Emergent Abnormality ............51
Appendix 5.
Blood Sampling Summary......................................................................52
Appendix 6.
Protocol I8K-JE-JPDB Blinding/Unblinding Plan...................................53
Appendix 7.
Protocol Amendment I8K-JE-JPDB(a) Summary
A Single- and Multiple-Dose Study to Evaluate the Safety, 
Tolerability, Pharmacokinetics, and Pharmacodynamics of 
LY3337641 in Japanese and Caucasian Healthy Subjects .......................55


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1. Protocol Synopsis
Title of Study:
A Single- and Multiple-Dose Study to Evaluate the Safety, Tolerability, Pharmacokinetics, and Pharmacodynamics 
of LY3337641 in Japanese and Caucasian Healthy Subjects
Rationale: 
Study I8K-JE-JPDB (JPDB) is the first clinical evaluation of LY3337641 in Japanese subjects and is being 
conducted to assess the safety, tolerability, pharmacokinetics (PK), and pharmacodynamics (PD) of single-dose 
(SD) and multiple-dose (MD) administration of LY3337641 in healthy Japanese and Caucasian subjects.  Findings 
from the study will be used to assess the safety and tolerability of LY3337641 in this study population including 
Japanese subjects, further characterize the PK properties of LY3337641, and explore the PD effects of Bruton’s 
tyrosine kinase inhibition.  Such findings in Japanese subjects are essential for further clinical development in Japan 
for various indications.
Objectives/Endpoints:  
Objectives
Endpoints
Primary
To explore the safety and tolerability of LY3337641 in 
healthy Japanese and Caucasian subjects 
AEs and SAEs
Secondary
To estimate the PK parameters of single and multiple 
doses of LY3337641 following oral administration in 
healthy Japanese and Caucasian subjects
Cmax and AUC
Abbreviations: AEs = adverse events; AUC = area under the plasma concentration-time curve; Cmax = maximum 
drug concentration; PK = pharmacokinetic; SAEs = serious adverse events.
Summary of Study Design:
Study JPDB is a single-site, subject- and investigator-blind, randomized, placebo-controlled, SD and MD study to 
assess the safety, tolerability, PK, and PD of LY3337641 in healthy Japanese and Caucasian subjects.  
Treatment Arms and Duration:  
Screening may occur up to 28 days prior to the first dose (Day 1).  All cohorts will be randomized in a 3:1 ratio of 
LY3337641 to placebo.  Study JPDB will numerically compare LY3337641 (30 mg once daily in MD cohorts and 
5, 80, and 160 mg in SD cohorts) with placebo, when administered orally.  An optional cohort may be included in 
the MD portion. The study drug is supplied as tablets containing 5 or 20 mg of LY3337641 with matching 
placebo tablets.  For the MD cohorts, 6 Japanese subjects and 3 Caucasian subjects will receive LY3337641,
while 2 Japanese subjects and 1 Caucasian subject will receive placebo.  For the SD cohorts, 3 Japanese subjects 
and 3 Caucasian subjects will receive LY3337641, while 1 Japanese subject and 1 Caucasian subject will 
receive placebo.  
In the MD cohorts, LY3337641 or placebo will be dosed on Days 1 through 15, and subjects will be followed for 
approximately 2 weeks.  In the SD cohorts, LY3337641 or placebo will be dosed on Day 1, and subjects will be 
followed for approximately 2 weeks. 


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LY3337641
Number of Subjects:
Up to 60 subjects may be enrolled so that approximately 36 to 48 subjects complete the study.  
Statistical Analysis:
PK analyses will be conducted for all subjects who receive at least 1 dose of LY3337641 and have evaluable PK 
data.  PD analyses will be conducted on the full analysis set, which includes all data from all subjects receiving at 
least 1 dose of LY3337641 or placebo.  Safety analyses will be conducted for all randomized subjects who receive at 
least 1 dose of LY3337641 or placebo and have at least 1 postdose safety assessment, regardless of whether they 
have completed all protocol requirements.  For QT interval, all subjects with at least 1 postdose QT interval 
measurement will be included in the analysis. Summary statistics, data tabulations, and data graphs will be provided 
and may be separated by race (Japanese and Caucasian) as appropriate.
Safety:  All adverse events 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 the investigational product 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 
investigational-product–related serious adverse events will be reported.  Laboratory parameters, vital signs, and 
electrocardiogram parameters will be summarized using standard descriptive statistics.
PK Analysis:  PK parameter estimates for LY3337641 will be calculated using standard noncompartmental methods 
of analysis.  In the SD cohorts, the primary parameters for analysis will be maximum drug concentration (Cmax), 
area under the concentration versus time curve from zero to infinity (AUC0-∞), and area under the concentration 
versus time curve from 0 to 24 hours (AUC0-24) of LY3337641.  In the MD cohorts, the primary parameters to be 
calculated will include Cmax (or Cmax during a dosing interval at steady state [Cmax,ss]) and area under the 
concentration versus time curve during the dosing interval (AUC0-τ) of LY3337641 after the first and last dose of 
investigational product.  Other noncompartmental parameters, such as half-life, apparent clearance, apparent volume 
of distribution, and accumulation ratio (MD period only), may be reported.  
PD Analysis:  Bruton’s tyrosine kinase occupancy will be listed and summarized using standard 
descriptive statistics.  


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2. Schedule of Activities


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Study Schedule Protocol I8K-JE-JPDB (Cohorts 1 and 5)
Visit
Screening
Treatment Perioda
Follow-Upa
Study Day
≤28 days
-2
-1
1b
2
4
8
11
15
16
17
19
22
25
29/
EoS
Inpatient stay at CRU
Informed consent 
X
Review eligibility
X
X
Randomization
X
IP administrationc
X
X
X
X
X
X
Complete medical history
X
Review preexisting 
conditions/AEsd
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Review concomitant 
medicationsd
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Complete physical 
examination
X
X
X
Symptom-directed 
physical examinationd
X
X
X
X
X
X
X
X
X
X
X
X
Body weight and heighte
X
X
X
X
Vital signs (pulse rate, 
blood pressure, body 
temperature)f
X
0
0, 1, 2, 4, 12
24i
0
0
0
0, 1, 2, 4, 12
24
48
X
12-Lead ECGg
X
-1, -0.5, 0, 0.5, 
1, 2, 3, 4, 6, 12
24i
0
0
0
0, 0.5, 1, 2, 3, 
4, 6, 12
24
48
X
Chest x-ray (posterior, 
anterior, and lateral)
X
Clinical laboratory 
measures (serum 
chemistry, hematology, 
urinalysis)
X
0
24i
0
48
X
HBcAb, HBsAg, HCV,
and HIV tests
X
Serum pregnancy testh
X
Urine pregnancy testh
X
0
0
X


I8K-JE-JPDB(a) Clinical Pharmacology Protocol
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LY3337641
Visit
Screening
Treatment Perioda
Follow-Upa
Study Day
≤28 days
-2
-1
1b
2
4
8
11
15
16
17
19
22
25
29/
EoS
FSHh
X
Drug and alcohol screen
X
X
QuantiFERON®-TB 
Gold Plus
X
PK sampling: blood
0, 0.25, 0.5, 1, 
2, 3, 4, 6, 8, 10, 
12
24i
0
0
0
0, 0.25, 0.5, 1, 
2, 3, 4, 6, 8, 
10, 12
24, 36
48
X
X
X
X
BTK occupancy 
0, 1, 2, 4, 12
24i
0
0, 1, 2, 4, 12
24
48
X
X
X
X
Skin inspectiond
X
0, 12
24i
0
0
0
0
X
X
X
X
X
X
Non-PGx stored sample
0
0
24
PGx
0
Abbreviations:  AEs = adverse events; BTK = Bruton’s tyrosine kinase; CRU = clinical research unit; ECG = electrocardiogram; EoS = end of study; 
FSH = follicle-stimulating hormone; HBcAb = hepatitis B core antibody; HBsAg = hepatitis B surface antigen; HCV = hepatitis C virus; HIV = human 
immunodeficiency virus; IP= investigational product; PGx = pharmacogenomics; PK = pharmacokinetic; TB = tuberculosis.
Note:  numbers are in hours in relation to dosing; 0 = predose.
a
All planned procedures will be done predose unless the time is indicated.
b
For twice-daily regimen, the time is based on the first dose.  The second dose should be administered after sample collection for the 12-hour time point.
c
Subjects will be dosed every day from Day 1 through Day 15.  For twice-daily regimen, only the morning dose will be administered on Day 15.
d
Assessment should be performed every day during the subject’s stay at the CRU.
e
Height will be measured at screening only.  Body weight will be measured in the morning.
f
Refer to Section 9.4.2 for instructions on vital signs.
g
Refer to Section 9.4.3 for instructions on ECGs.  ECGs should be administered after subject has been resting in the supine position for approximately
5 minutes.  On days without dosing, ECGs should be administered close to the Day 1 dosing time, when possible.  ECGs will be collected in triplicate except 
at the screening visit.
h
All female subjects of childbearing potential will undergo a serum pregnancy test at screening.  For women who are considered postmenopausal, FSH should 
be drawn to confirm postmenopausal status as defined in inclusion criterion [1b] and exemption from further pregnancy tests (urine) during the study.  
i
This 24-hour sample is to be taken predose.


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Study Schedule Protocol I8K-JE-JPDB (Cohorts 2, 3, and 4)
Visit
Screening
Treatment Perioda
Follow-Upa
Study Day
≤28 days
-2
-1
1
2
3
5
8
11
15/EoS
Inpatient stay at CRU
Informed consent 
X
Review eligibility
X
X
Randomization
X
IP administration
X
Complete medical history
X
Review preexisting 
conditions/AEs
X
X
X
X
X
X
X
X
X
X
Review concomitant 
medications
X
X
X
X
X
X
X
X
X
X
Complete physical 
examination
X
X
X
Symptom-directed 
physical examination
X
X
X
X
X
X
X
Body weight and heightb
X
X
X
X
Vital signs (pulse rate, 
blood pressure, body 
temperature)c
X
0
0, 1, 2, 4, 12
24
48
X
12-Lead ECGd
X
-1, -0.5, 0, 0.5, 1, 2, 3, 
4, 6, 12
24
48
X
Chest x-ray (posterior, 
anterior, and lateral)
X
Clinical laboratory 
measures (serum 
chemistry, hematology, 
urinalysis)
X
0
48
X
HBcAb, HBsAg, HCV,
and HIV tests
X
Serum pregnancy teste
X
Urine pregnancy teste
X
X
FSHe
X


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LY3337641
Visit
Screening
Treatment Perioda
Follow-Upa
Study Day
≤28 days
-2
-1
1
2
3
5
8
11
15/EoS
Drug and alcohol screen
X
X
QuantiFERON®-TB 
Gold Plus
X
PK sampling: blood
0, 0.25, 0.5, 1, 2, 3, 4, 
6, 8, 10, 12
24, 36
48
X
X
BTK occupancy 
0, 1, 2, 4, 12
24
48
X
X
Skin inspection
X
0, 12
X
X
X
X
X
X
Non-PGx stored sample
0
X
X
PGx
0
Abbreviations:  AEs = adverse events; BTK = Bruton’s tyrosine kinase; CRU = clinical research unit; ECG = electrocardiogram; EoS = end of study; 
FSH = follicle-stimulating hormone; HBcAb = hepatitis B core antibody; HBsAg = hepatitis B surface antigen; HCV = hepatitis C virus; HIV = human 
immunodeficiency virus; IP= investigational product; PGx = pharmacogenomics; PK = pharmacokinetic; TB = tuberculosis.
Note:  numbers are in hours in relation to dosing; 0 = predose.
a
All planned procedures will be done predose unless the time is indicated.
b
Height will be measured at screening only.  Body weight will be measured in the morning.
c
Refer to Section 9.4.2 for instructions on vital signs.
d
Refer to Section 9.4.3 for instructions on ECGs.  ECGs should be administered after subject has been resting in the supine position for approximately
5 minutes.  On days without dosing, ECGs should be administered close to the Day 1 dosing time, when possible.  ECGs will be collected in triplicate except 
at the screening visit.
e
All female subjects of childbearing potential will undergo a serum pregnancy test at screening.  For women who are considered postmenopausal, FSH should 
be drawn to confirm postmenopausal status as defined in inclusion criterion [1b] and exemption from further pregnancy tests (urine) during the study.  


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LY3337641
3.Introduction
3.1. Study Rationale
Study I8K-JE-JPDB(JPDB) is the first clinical evaluation of LY3337641in Japanese subjects 
and is being conducted to assess the safety, tolerability, pharmacokinetics (PK), and 
pharmacodynamics (PD) of single-dose(SD)and multiple-dose(MD) administrationof 
LY3337641in healthy Japanese and Caucasian subjects.  Findingsfrom the study will be used 
toassess the safety and tolerability of LY3337641 in this study populationincluding Japanese
subjects, further characterize the PK propertiesof LY3337641, and explore the PD effects of 
Bruton’s tyrosine kinase (BTK)inhibition.  Such findings in Japanese subjects areessential for 
further clinical development in Japan for various indications.  
3.2. Background
CCI
LY3337641 is an orally available, irreversible inhibitor of BTK, a member of the TEC family 
ofcytoplasmic tyrosine kinases.  BTK is a key signaling molecule in the B-cell–receptor and 
Fc-receptor pathways and an essential mediator ofB-cell–and myeloid-cell–dependent 
inflammatory arthritis (Di Paolo et al. 2011; Chakravarty et al. 2013).  BTK is primarily 
expressed in hematopoietic cells, including B cells, monocytes, and macrophages (Burger 2014).  
In humans, BTK loss-of-function mutations cause nonlethal X-linked agammaglobulinemia, 
resulting in reduced B-cell and immunoglobulin levels (Aalipour and Advani 2014).  
LY3337641is currently being developed for rheumatoid arthritis (RA), and a Phase 2 study in 
patients with RA(I8K-MC-JPDA[JPDA]) is ongoing.  Potential therapeutic benefits of BTK 
inhibition for RA include reduced pathogenic B-cell autoantibody production and myeloid-cell 
proinflammatory cytokine production and inhibition of mast cell and basophil degranulation 
(Horwoodet al. 2012).  
LY3337641 demonstrates potent, irreversible BTK inhibition in BTK enzyme assays, cell-based 
BTK phosphorylation assays, and BTK occupancy assays.  
The in vivo activity of LY3337641 was investigated in mouse and rat models of collagen-
induced arthritis and mouse models of systemic lupus erythematosus.  LY3337641 was effective 
in the mouse arthritis model, where it halted progression of clinical arthritis and significantly 
diminished structural damage in the joints.  The high level of efficacy for clinical disease activity 
was reproduced in the rat arthritis model.  LY3337641 was also effective in a spontaneous mouse 
model of systemic lupus erythematosus, where it improved skin lesions, reduced proteinuria, and 
improved renal histopathology scores.  Taken together, these results suggest that LY3337641 
may be useful for treatment of autoimmune diseases, including RA.
 
 
 
 
 


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LY3337641
 
 
 
 
 
 
 
 
 
 
 
Results from nonclinical studies with LY3337641 and the Study JPDDsafety profile support the
design of this study.  
3.3. Benefit/Risk Assessment
CCI
No clinically significant safety concerns have been identified at the doses proposed in this study 
for LY3337641.  The dose levels included in this study are within the range of doses studied 
previously,and the tolerability has been confirmed.  
More information about the known and expected benefits, risks, serious adverse events (SAEs) 
and reasonably anticipated adverse events (AEs) of LY3337641are to be found in the 
Investigator’s Brochure.  


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LY3337641
4. Objectives and Endpoints
Table JPDB.1 shows the objectives and endpoints of the study.
Table JPDB.1.
Objectives and Endpoints
Objectives
Endpoints
Primary
To explore the safety and tolerability of LY3337641 in 
healthy Japanese and Caucasian subjects 
AEs and SAEs
Secondary
To estimate the PK parameters of single and multiple 
doses of LY3337641 following oral administration in 
healthy Japanese and Caucasian subjects
Cmax and AUC
Exploratory Objectives
1. To explore the PD following single and multiple 
doses of LY3337641 in healthy Japanese and 
Caucasian subjects  
2. To explore the safety, tolerability, PK, and PD of 
LY3337641 in Japanese subjects in relation to 
Caucasian subjects
3. To explore the effect of LY3337641 on ECG findings
in healthy Japanese and Caucasian subjects 
1. BTK occupancy
2. AEs, SAEs, Cmax, AUC, and BTK occupancy
3. ECG parameters 
Abbreviations: AEs = adverse events; AUC = area under the plasma concentration-time curve; BTK = Bruton’s 
tyrosine kinase; Cmax = maximum drug concentration; ECG = electrocardiogram; PD = pharmacodynamics; 
PK = pharmacokinetic(s); SAEs = serious adverse events.


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LY3337641
5. Study Design
5.1.
Overall Design
This is a single-site, subject- and investigator-blind, randomized, placebo-controlled, SD and 
MD study to assess the safety, tolerability, PK, and PD of LY3337641 in healthy Japanese and 
Caucasian subjects.  Subjects will be randomized to LY3337641 within each cohort as shown in 
Figure JPDB.1.  All cohorts will be randomized in a 3:1 ratio of LY3337641 to placebo. MD 
Cohort 1 (30 mg QD for 2 weeks) and Cohort 5 (optional) will consist of 12 subjects (8 Japanese 
and 4 Caucasian). SD Cohorts 2, 3, and 4 (5, 80, and 160 mg SD) will consist of 8 subjects 
(4 Japanese and 4 Caucasian).  For each MD cohort, 6 Japanese subjects and 3 Caucasian 
subjects will receive LY3337641, while 2 Japanese subjects and 1 Caucasian subject will 
receive placebo.  For each SD cohort, 3 Japanese subjects and 3 Caucasian subjects will 
receive LY3337641, while 1 Japanese subject and 1 Caucasian subject will receive placebo.
Investigational product (IP) will be administered orally.  Cohorts 1, 2, and 3 may be conducted in 
parallel if the site is able to accommodate more than 1 cohort at a time; however, priority will be 
given to dose Cohort 1, since the timing of this cohort will determine the timing of the interim 
analysis.  Cohort 4 will be started based on the safety assessment up to Day 3 (48 hours 
postdose) of Cohort 2. If the dose level/regimen for Cohort 1 is not tolerated or there is a need to 
dose more subjects to assess safety, a daily dose of 30 mg or less (QD or BID) may be given in 
Cohort 5 based on the findings from Cohort 1.  This will be discussed and agreed upon by the 
investigator and the Lilly clinical pharmacologist.  The randomization rules and procedures will 
be the same as Cohort 1.
Figure JPDB.1 illustrates the study design.


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LY3337641
Abbreviations: BID = twice daily; FU = follow-up; JP = Japanese; LY = LY3337641; 
Pb = placebo; QD = once daily.
*Dose, regimen, and subject number may change for optional cohort.
Figure JPDB.1.
Illustration of study design for Protocol I8K-JE-JPDB.
5.2.
Number of Participants
Up to 60 subjects may be enrolled so that approximately 36 to 48 subjects complete 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 is a single-site, subject- and investigator-blind, randomized, placebo-controlled, SD and 
MD study in healthy Japanese and Caucasian subjects. This study is conducted to support the 
inclusion of Japanese subjects in future studies involving LY3337641.  Healthy Caucasian 
subjects are also included in this study for assessment of both healthy Japanese and Caucasian 
subjects.  The number of subjects in this study is deemed sufficient for the safety, tolerability, 
and PK data that will be assessed in both Japanese and Caucasian subjects.  Intensive assessment 
of electrocardiograms (ECGs) will be done in this study, since thorough ECG data have not been 
obtained so far.  The study will be subject and investigator blind, with the subjects, investigators, 
and site staff unaware of actual treatment (LY3337641 or placebo) but aware of dose level 


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assigned to the cohort.  This design is being used to minimizebias in safety and tolerability 
assessments.
5.5. Justification for Dose
CCI
 
 
 
 
 
 
 
 
  
 
  
 
 
  
 
 
 
 
 
  
 
 
 
 
 
  


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6. Study Population
Eligibility of subjects for study enrollment will be based on the results of screening medical 
history, physical examination, vital signs, clinical laboratory tests, and ECG.  
A chest x-ray will be completed at screening unless one has been obtained within the past 
12 months, and the x-ray and/or report are available for review.
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 Day 1.  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 and females, as determined by medical history and 
physical examination
[1a] male subjects:
agree to use an effective method of contraception (barrier contraceptives, 
such as latex condoms, or complete abstinence from sexual intercourse 
with women) for the duration of the study and 3 months following the last 
dose of IP
[1b] female subjects:
women of childbearing potential may participate and include those who test 
negative for pregnancy prior to initiation of treatment (as indicated by a 
negative serum pregnancy test at the screening visit followed by a negative 
urine pregnancy test within 24 hours prior to exposure) and agree to remain 
abstinent or use either 1 highly effective method of contraception (such as 
combination oral contraceptive, implanted contraceptive, or intrauterine 
device) or a combination of 2 effective methods of contraception (such as 
male or female condom with spermicide, diaphragm with spermicide,
or cervical sponge) during the study and for 4 weeks following the last 
dose of the IP
women not of childbearing potential may participate and include those 
who are:


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A. infertile due to surgical sterilization (hysterectomy, bilateral oophorectomy, or 
tubal ligation) performed at least 6 months prior to dosing or congenital anomaly 
such as müllerian agenesis or
B. postmenopausal, defined as either
i. A woman aged 50 years or older who has an intact uterus, is not on hormone 
therapy, and has had either
a) cessation of menses for at least 1 year or
b) 6 to 12 months of spontaneous amenorrhea with a follicle-stimulating 
hormone >40 mIU/mL or
ii. A woman aged 55 years or older who is not on hormone therapy and has had at 
least 6 months of spontaneous amenorrhea or
iii. A woman aged 55 years or older with a diagnosis of menopause prior to 
starting hormone replacement therapy
[2]
are aged 20 to 64 years, inclusive, at screening
[3]
have a body mass index of 18.0 to 32.0 kg/m2, inclusive, at screening
[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
[37] are 1st generation Japanese or Caucasian.
To qualify as a subject of 1st generation Japanese origin, the subject, the 
subject’s biological parents, and all of the subject’s biological grandparents 
must be of exclusive Japanese descent and born in Japan.
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 or Covance employees


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[10] are currently enrolled in a clinical trial involving an IP or off-label use of a 
drug or device or are concurrently enrolled in 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 IP.  
If the previous IP has a long half-life, 3 months or 5 half-lives (whichever is 
longer, if known) should have passed
[12] have previously completed or withdrawn from this study or any other study 
investigating LY3337641 and have previously received the IP
[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 or
affects or confounds the QTc analysis (the ECG waveform morphology or
rhythm are incompatible with reliable measurement of ECG intervals) or have 
Fridericia-corrected QT interval (QTcF) >450 msec for males and >470 msec 
for females
[15] have an abnormal blood pressure or pulse rate (supine) as determined by 
the investigator
[16] have a significant history of or current cardiovascular, respiratory, hepatic, 
renal, gastrointestinal (cholecystectomy not acceptable), endocrine, 
hematologic, dermatologic, or neurologic disorders capable of significantly 
altering the absorption, metabolism, or elimination of drugs; of constituting a 
risk when taking the IP; or of interfering with the interpretation of data
[17] have known or ongoing psychiatric disorders
[18] regularly use known drugs of abuse and/or show positive findings on urinary 
drug screening
[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 (HBsAg)
[22] are positive for hepatitis B core antibody (HBcAb+)
[23] are women who are lactating
[24] have used or intend to use over-the-counter or prescription medication, 
including herbal medications, within 14 days prior to dosing
[25] have donated blood of more than 500 mL within the month prior to screening


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[26] have an average weekly alcohol intake that exceeds 21 units per week and are 
unwilling to follow instructions in Section 6.3.2 (1 unit = 12 ounces or 
360 mL of beer, 5 ounces or 150 mL of wine, and 1.5 ounces or 45 mL of 
distilled spirits)
[27] are subjects whose tobacco consumption is more than 10 cigarettes per day or 
the equivalent or subjects who are not willing to refrain from smoking for 
48 hours prior to clinical research unit (CRU) admission and during CRU stay
[28] have a history of, in the opinion of the investigator, excessive methylxanthine 
use within the previous 3 months or are unwilling to abide by restrictions as 
specified in Section 6.3.2. Excessive intake is defined as more than 6 units 
of caffeine per day; 1 caffeine unit is contained in the following items:  
1 (177 mL) cup of coffee, 1 (355 mL) cup of tea, 2 (355 mL) cans of cola, 
or 3 ounces (85 g) of chocolate
[29] have had symptomatic herpes zoster within 3 months of screening, as 
determined by clinical history
[30] have active or latent tuberculosis (TB) based on a positive medical history, 
examination, and/or TB test results.  QuantiFERON®-TB Gold Plus test 
(QFT-Plus or equivalent) will be used for TB testing, and subjects must test 
negative to participate
[31] have a screening chest x-ray with evidence of medically significant disease, 
such as malignancy, infection, pulmonary disease, or cardiac failure
[32] have received live vaccine(s) within 1 month of screening or intend to during 
the study
[33] are immunocompromised
[34] in the opinion of the investigator or sponsor, are unsuitable for inclusion in 
the study
[35] have had exposure to significant diagnostic, therapeutic, or 
employment-related radiation within 12 months prior to dosing (eg, serial 
x-ray or computed tomography scans, barium meal, current employment in a 
job requiring radiation exposure monitoring)
[36] have a history of constipation or have had acute constipation within 3 weeks 
prior to admission
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
Before each morning dose in the SD and the MD cohorts, subjects will be fasted overnight for at 
least 10 hours following a light supper on the evening before.  Following dosing, subjects will 


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fast for a period of 4 hours until lunch (for the MD cohorts, fasting after dosing will occur on 
Days 1 and 15 only; on all other dosing days in the MD cohorts, subjects should consume a 
non-standardized breakfast approximately 1 hour after dosing). For BID dosing, if studied, 
subjects will be fasted 1 hour before and after the evening dose.  During fasting, no fluids are 
allowed except for water; however, water is not allowed from 2 hours predose until 1 hour 
postdose (apart from the water taken with the dose).  
6.3.2. Caffeine, Alcohol, and Tobacco
Caffeine—Subjects should not be allowed caffeine consumption for 48 hours prior to all study 
visits and during CRU stays.  At other times during the outpatient period, subjects will be
allowed to maintain their regular caffeine consumption.
Alcohol—Alcohol consumption is not allowed from 48 hours prior to all study visits and during
CRU stays.  At all other times, alcohol consumption should be limited to no more than 2 units 
per day (1 unit = 12 ounces or 360 mL of beer, 5 ounces or 150 mL of wine, and 1.5 ounces or
45 mL of distilled spirits).
Tobacco—Subjects will be asked to refrain from smoking for approximately 48 hours prior to 
CRU admission and during CRU stays.  During the follow-up period, subjects will be asked to 
refrain from smoking for 2 hours prior to study visits.
6.3.3. Activity
No strenuous exercise will be allowed for 48 hours prior to admission and during the study.
6.4.
Screen Failures
Individuals who do not meet the criteria for participation in this study (screen failure) may be 
re-screened.  Individuals may be re-screened once with Lilly clinical pharmacologist’s approval.  
The interval between re-screenings should be at least 2 weeks.  Each time re-screening is 
performed, the individual must sign a new informed consent form (ICF) and will be assigned a 
new identification number.


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7. Treatment
7.1.
Treatment Administered
This study involves a numerical comparison of LY3337641 (30 mg QD in MD cohorts and 5, 80,
and 160 mg in SD cohorts) with placebo, when administered orally.  The study drug is supplied
as tablets containing 5 or 20 mg of LY3337641 with matching placebo tablets (Table JPDB.2).  
LY3337641 and placebo will be administered orally with approximately 200 mL of room 
temperature water in the morning of each dosing day with the subject in a sitting position.  
Subjects will not be allowed to lie supine for 2 hours after dosing, unless clinically indicated 
or as needed for study procedures.
Table JPDB.2.
Treatment Administered
Cohort
Dose
Number of Tablets
Cohort 1
LY 30 mg QD
1 x 20-mg LY tablet
2 x 5-mg LY tablets
Placebo 30 mg QD
1 x 20-mg placebo tablet
2 x 5-mg placebo tablets
Cohort 2
LY 80 mg
4 x 20-mg LY tablets
Placebo 80 mg
4 x 20-mg placebo tablets
Cohort 3
LY 5 mg
1 x 5-mg LY tablet
Placebo 5 mg
1 x 5-mg placebo tablet
Cohort 4
LY 160 mg
8 x 20-mg LY tablets
Placebo 160 mg
8 x 20-mg placebo tablets
Abbreviations:  LY = LY3337641; QD = once daily.
The investigator or designee is responsible for:

explaining the correct use of the IP to the subject, 

verifying that instructions are followed properly,

maintaining accurate records of IP dispensing and collection,

and returning all unused medication to Lilly or its designee at the end of the study.
Note: In some cases, sites may destroy the material if, during the investigative site selection, the 
evaluator has verified and documented that the site has appropriate facilities and written 
procedures to dispose of clinical trial materials.  


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7.1.1. Packaging and Labeling
IP will be supplied by the sponsor in accordance with current good manufacturing practices.  The 
material will be labeled with a unique identifier for drug accountability. Clinical trial materials 
will be labeled according to the country’s regulatory requirements and will be labeled with the 
identity of the material contained in the package.  
The study drug will be supplied as tablets containing 5 or 20 mg of LY3337641 with matching
placebo tablets. The LY3337641 5-mg tablets and corresponding 5-mg matched placebo are
identical in appearance, and the LY3337641 20-mg tablets and corresponding 20-mg matched
placebo are identical in appearance. However, the 5 - and 20-mg tablets are not identical 
in appearance.
Packaging will be as follows:
5 mg LY3337641 blister card—9 tablets
Placebo to match 5 mg LY3337641 blister card—9 tablets
20 mg LY3337641 blister card—9 tablets
Placebo to match 20 mg LY3337641 blister card—9 tablets
7.2.
Method of Treatment Assignment
Randomization tables for allocation of LY3337641 or placebo will be prepared by the statistician 
for the study and provided to the site pharmacists involved in dose preparation.  The allocation 
and dispensing of the IP will be fully documented and verified by a second person.  Detailed 
records of the amounts of the IP received, dispensed, and remaining at the end of the study will 
be maintained by the site pharmacist.
7.2.1. Selection and Timing of Doses
SDs will be administered in the morning.  For the QD cohort(s), doses will be administered at 
approximately the same time in the morning on each day for each subject.  If the BID regimen is 
tested in Cohort 5, the dose will be administered in the morning and the evening.  The evening 
dose should be taken 12 hours apart from the morning dose.  On Day 15, only the morning dose 
will be administered.
Meal conditions are discussed in Section 6.3.1.  The actual time of all dose administrations will 
be recorded in the subject’s electronic case report form (eCRF).
7.3.
Blinding
Blinding will be maintained throughout the conduct of the trial until all data are cleaned to an 
acceptable level of quality and locked.  The details are included in the Blinding/Unblinding 
Plan (Appendix 6).
The site pharmacist will be responsible for dispensing the IP to the subjects in a blinded manner.  
The investigator and subjects should remain blinded to study treatment within each cohort
throughout the conduct of the study.


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If a subject’s study treatment assignment is unblinded, the subject must be discontinued from the 
study, unless the investigator obtains specific approval from a Lilly clinical pharmacologist or 
clinical research physician or for the study participant to continue in the study.  
In case of an emergency, the investigator has the sole responsibility for determining if unblinding 
of a subject’s treatment assignment is warranted for medical management of the event.  Subject’s
safety must always be the first consideration in making such a determination.  If the investigator 
decides that unblinding is warranted, the investigator should make every effort to contact the 
Lilly clinical pharmacologist or clinical research physician prior to unblinding a study subject’s 
treatment assignment, unless this could delay emergency treatment of the subject.  If a study 
subject’s treatment assignment is unblinded, Lilly must be notified immediately.
7.4.
Dose Modification
7.4.1. Dose Escalation
All doses in this study have been previously tested and shown to be well tolerated in Study JPDD.  
However, Japanese subjects have not received LY3337641 previously. The dose escalation 
decision will be made based on the safety data from both Japanese and Caucasian subjects up
to Day 3 (48 hours postdose) of 80-mg SD administration (Cohort 2) to proceed to the 160 mg 
SD cohort (Cohort 4).  
Safety data for the 80-mg SD will be the primary criteria for dose escalation to the 160-mg SD.  
In addition, if available at the time of dose escalation decision, PK (Cmax, AUC, and clearance) 
results may be used as supporting data for dose escalation, but such data are not required.  No 
dose escalation can occur without prior discussion and agreement between the investigator and 
the Lilly clinical pharmacologist or clinical research physician.  
Safety data, in particular AEs, SAEs, and adverse laboratory abnormalities, will be 
independently assessed by the investigator and will be considered related to the IP, unless 
there is clear evidence that the event is not related.  
After review of these data, an agreement on the appropriate dose escalation will be made by the 
investigator and sponsor for the 160-mg SD cohort.  The magnitude of the dose escalation may 
be reduced following data review, but the highest SD will not exceed 160 mg.
If any of the following scenarios occur, dosing at the current level and further dose escalation 
will be stopped until the safety data can be reviewed:
1) 1 or more subjects experience an SAE
2) 2 or more subjects experience a clinically significant event that is related to 
LY3337641 administration
3) greater than 3 subjects at 1 dose level experience moderate treatment-related AEs
that impair normal activities
After the safety review is completed, if Cohort 2 dosing has not been completed, dosing may 
resume if agreed upon by the investigator and sponsor.  Once all data from Cohort 2 has been 


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obtained, an agreement on the appropriate dose escalation will be made by the investigator and 
sponsor for the 160-mg SD cohort or a lower dose.
7.5.
Preparation/Handling/Storage/Accountability
Only participants enrolled in the study may receive IP 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, institution, or the head of the medical institution (where applicable) is 
responsible for study treatment accountability, reconciliation, and record maintenance (such as
receipt, reconciliation, and final disposition records).
7.6.
Treatment Compliance
The IP will be administered at the CRU, and documentation of treatment administration will 
occur at the CRU.
7.7.
Concomitant Therapy
If the need for concomitant medication arises, inclusion or continuation of the subject may be at 
the discretion of the investigator after consultation with a Lilly clinical pharmacologist 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 for this study.


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8. Discontinuation Criteria
8.1.
Discontinuation from Study Treatment
Discontinuation of the IP for abnormal liver tests should be considered by the investigator when 
a subject meets one of the following conditions after consultation with the Lilly-designated 
medical monitor:

Alanine aminotransferase (ALT) or aspartate aminotransferase (AST) >5X upper limit 
of normal (ULN)

ALT or AST >3X ULN along with one of the following criteria
o
sustained for more than 2 weeks or
o
total bilirubin level (TBL) >2X ULN or
o
prothrombin time >1.5X ULN or
o
the appearance of fatigue, nausea, vomiting, right upper-quadrant pain or 
tenderness, fever, rash, and/or eosinophilia (>5%)

Alkaline phosphatase (ALP) >3X ULN

ALP>2.5X ULN and TBL >2X ULN

ALP>2.5 ULN with the appearance of fatigue, nausea, vomiting, right quadrant pain or 
tenderness, fever, rash, and/or eosinophilia (>5%)
In addition, subjects will be discontinued from the IP in the following circumstances:

The investigator decides that the subject should be discontinued from the IP  

The subject requests to be discontinued from the IP

Subject experiences an SAE or clinically significant event that is related to 
LY3337641 administration, or

Subject experiences moderate treatment-related AEs that impair normal activities
When this situation arises, the investigator should inform a Lilly clinical pharmacologist or 
clinical research physician.
When subjects discontinue the IP early, procedures to be performed will be discussed between 
the investigator and the Lilly clinical pharmacologist or clinical research physician.
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 clinical pharmacologist or 
clinical research physician 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 clinical pharmacologist or clinical research physician to 
allow the inadvertently enrolled subject to continue in the study with or without continued 
treatment with IP.


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8.2.
Discontinuation from the Study
Subjects will be discontinued in the following circumstances:

Enrollment in any other clinical trial involving an IP or enrollment in any other type of 
medical research judged not to be scientifically or medically compatible with this study

Participation in the study needs to be stopped for medical, safety, regulatory, or other 
reasons consistent with applicable laws, regulations, and good clinical practice

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
Subjects who discontinue the study early will have end-of-study procedures performed as shown 
in the Schedule of Activities (Section 2).
8.3.
Subjects Lost to Follow-up
A subject will be considered lost to follow-up if he or she repeatedly fails to return for scheduled 
visits and is unable to be contacted by the study site.  Site personnel are expected to make 
diligent attempts to contact subjects who fail to return for a scheduled visit or were otherwise 
unable to be followed up by the site.


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9. Study Assessments and Procedures
Section 2 lists the Schedule of Activities, detailing the study procedures and their timing 
(including tolerance limits for timing).
Appendix 2 lists the laboratory tests that will be performed for this study.
Appendix 5 provides a summary of the maximum number and volume of invasive samples, for 
all sampling, during the study.
Unless otherwise stated in subsections below, all samples collected for specified laboratory tests 
will be destroyed within 60 days of receipt of confirmed test results.  Certain samples may be 
retained for a longer period, if necessary, to comply with applicable laws, regulations, or 
laboratory certification standards.
Investigators must document their review of each laboratory safety report.
9.1.
Efficacy Assessments
This section is not applicable for this study.
9.2.
Adverse Events
Investigators are responsible for monitoring the safety of subjects who have entered this study 
and for alerting Lilly or its designee to any event that seems unusual, even if this event may be 
considered an unanticipated benefit to the subject.
The investigator is responsible for the appropriate medical care of subjects during the study.
The investigator remains responsible for following, through an appropriate health care option, 
AEs that are serious or otherwise medically important, considered related to the IP or the study, 
or that caused the subject to discontinue the IP before completing the study.  The subject should 
be followed until the event resolves, stabilizes with appropriate diagnostic evaluation, or is 
reasonably explained.  The frequency of follow-up evaluations of the AE is left to the discretion 
of the investigator.
After the 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 IP, 
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 IP 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.
Pregnancy (maternal or paternal exposure to IP) does not meet the definition of an AE.  
However, to fulfill regulatory requirements any pregnancy should be reported following the 
SAE process to collect data on the outcome for both mother and fetus.
9.2.1.1.
Suspected Unexpected Serious Adverse Reactions 
Suspected unexpected serious adverse reactions (SUSARs) are serious events that are not listed 
in the Investigator’s Brochure and that the investigator identifies as related to the 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.
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 or drug delivery system so that the situation can be assessed.


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9.3.
Treatment of Overdose
For the purposes of this study, an overdose of LY3337641 is considered any dose higher than the 
dose assigned through randomization.
Refer to the Investigator’s Brochure.
9.4.
Safety
9.4.1. Laboratory Tests
For each subject, laboratory tests detailed in Appendix 2 should be conducted according to the 
Schedule of Activities (Section 2) and as clinically indicated.  
9.4.2. Vital Signs
For each subject, vital sign measurements including body (oral) temperature, supine and standing 
blood pressure, and pulse rate should be conducted according to the Schedule of Activities 
(Section 2) and as clinically indicated.  
Subjects will rest in the supine position for at least 5 minutes and have supine blood pressure and 
pulse rate measured.  Subjects will then stand for 3 minutes and have standing blood pressure 
and pulse rate measured.
If the subject feels unable to stand, only supine vital signs will be recorded.  
Unscheduled orthostatic vital signs should be assessed, if possible, during any AE of dizziness or 
posture-induced symptoms.  Additional vital signs may be measured during each study period if 
warranted and agreed upon between the sponsor and investigator.
9.4.3. Electrocardiograms
For each subject, ECGs should be collected according to the Schedule of Activities (Section 2) as 
clinically indicated and the study-specific recommendations included in the Manual of 
Operations for the study.  
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 12-lead digital ECG will be collected in triplicate according to the Schedule 
of Activities (Section 2).  ECGs must be recorded before collecting any blood for safety or PK 
tests.  Subjects must be supine for approximately 5 to 10 minutes before ECG collection and 
remain supine but awake during ECG collection.  Consecutive triplicate ECGs will be obtained 
at approximately 1-minute intervals.  ECGs may be administered at additional times, when
deemed clinically necessary.  
ECGs will be interpreted by a qualified physician (the investigator or qualified designee) at the 
site as soon after the time of ECG collection as possible, and ideally while the subject is still 


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present, to determine whether the subject meets entry criteria at the relevant visit(s) and for 
immediate subject management, should any clinically relevant findings be identified.  
If a clinically significant quantitative or qualitative change from baseline is identified after 
enrollment, the investigator will assess the subject for symptoms (for example, palpitations, near 
syncope, syncope) to determine whether the subject can continue in the study.  The investigator 
or qualified designee is responsible for determining if any change in subject management is 
needed and must document his or her review of the ECG printed at the time of evaluation from at 
least 1 of the triplicate ECGs from each time point.
Digital ECGs will be electronically transmitted to a central ECG laboratory designated by Lilly.  
The central ECG laboratory will perform a basic quality control check (for example, 
demographics and study details) then store the ECGs in a database.  At a future time, the stored 
ECG data may be overread at the central ECG laboratory for further evaluation of machine-read 
measurements or to meet regulatory requirements.
The machine-read ECG intervals and heart rate may be used for data analysis and report writing 
purposes unless a cardiologist overread of the ECGs is conducted prior to completion of the final 
study report (in which case the overread data would be used).
9.4.4. Other Tests 
9.4.4.1.
Assessment and Management of Subjects Developing a Rash
Subjects who develop a rash should be evaluated as soon as possible.  Investigators will be 
prompted to categorize and diagnose the rash (per clinical judgment), assess relatedness to IP, 
and grade its severity.  This information will be recorded on the source document and entered 
into the eCRF.  Additional information related to the rash evaluation will also be recorded on the 
source document and will include a history of infections and allergies and recent exposure to 
prescription or over-the-counter medications, skin products, detergents, or other potential skin 
irritants.  A review of systems will be completed to assess for systemic symptoms and concurrent 
illnesses. A symptom-directed physical examination should be performed, including an 
evaluation of the rash distribution and type, vital signs and temperature, and other organ systems, 
as clinically indicated. In addition, photographs and laboratory measurements should be 
obtained as clinically indicated, according to investigator judgment. The subject should be 
evaluated to determine whether there are any signs or symptoms suggesting a severe, potentially 
life-threatening condition.
If a subject develops a rash that is assessed as not related to IP, is transient, or is not clinically 
significant in the opinion of the investigator, the IP may be continued without interruption. In 
some cases, the investigator may instead choose to interrupt the IP and restart it at a later date.  
The dates for stopping and restarting the IP should be captured.  Immediate and permanent 
discontinuation of IP should be considered for all subjects with clinically significant rash. For 
rashes deemed clinically significant, punch biopsy of the rash may also be performed.  In 
addition, a venous blood sample may be collected for PK analysis at the time of evaluation with 
documentation of the date and time of administration of the most recent dose of IP.


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Subjects should be followed up until resolution of the rash, to the extent possible.  The site 
should manage any rash that occurs during the study according to the judgment of the 
investigator.  Interventions may include supportive care, pharmacotherapy, laboratory evaluation, 
additional skin biopsies, and consultation with a dermatologist, as clinically indicated. Data 
from these additional interventions should be provided to the sponsor as part of the AE reporting 
after being deidentified and summarized by the investigative site.
9.4.5. Safety Monitoring
The Lilly clinical pharmacologist 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 will consult with the functionally independent Global Patient Safety therapeutic 
area physician or clinical research scientist when appropriate and periodically review:

trends in safety data

laboratory analytes

AEs, including monitoring of rash
If a study subject experiences elevated ALT ≥3X ULN, ALP ≥2X ULN, or elevated total 
bilirubin ≥2X ULN, clinical and laboratory monitoring should be initiated by the investigator.  
Details for hepatic monitoring depend upon the severity and persistence of observed 
laboratory test abnormalities.  To ensure subject safety and compliance with regulatory 
guidance, the investigator is to consult with the Lilly-designated clinical research physician
regarding collection of specific recommended clinical information and follow-up laboratory 
tests (Appendix 4).
9.5.
Pharmacokinetics
At the visits and times specified in the Schedule of Activities (Section 2), venous blood samples 
of approximately 2 mL each will be collected to determine the plasma concentrations of 
LY3337641.  A maximum of 3 samples may be collected at additional time points during the 
study 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.
Drug concentration information that may unblind the study will not be reported to investigative 
sites or blinded personnel until the study has been unblinded.
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-tandem 
mass spectrometry method.  Analyses of samples collected from placebo-treated subjects are 
not planned.


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Bioanalytical samples collected to measure IP concentrations will be retained for a maximum of 
1 year following last subject visit for the study.  During this time, samples remaining after the 
bioanalyses may be used for exploratory analyses such as additional metabolism and/or protein 
binding work.
9.6.
Pharmacodynamics
At the visits and times specified in the Schedule of Activities (Section 2), venous blood of 
approximately 16 mL at each time point will be collected to determine free BTK and total BTK 
amount. Peripheral blood nuclear cells will be isolated. Lysates of the peripheral blood nuclear 
cells will be used to determine the concentrations of compound free BTK and total BTK using an 
enzyme-linked immunosorbent assay–based methodology. 
The sample(s) will be stored for up to a maximum of 1 year after the last subject visit for the 
study at a facility selected by the sponsor.  
9.7.
Genetics
A blood sample will be collected for pharmacogenetic analysis as specified in the Schedule of 
Activities (Section 2), where local regulations allow.  
Samples will not be used to conduct unspecified disease or population genetic research either 
now or in the future.  Samples will be used to investigate variable exposure and response to 
LY3337641 and to investigate genetic variants thought to play a role in the perceived mechanism 
of action of LY3337641.  Assessment of variable response may include evaluation of AEs or 
differences in efficacy.  
All samples will be coded with the subject number.  These samples and any data generated can 
be linked back to the subject only by the investigative site personnel.  
Samples will be retained for a maximum of 15 years after the last subject visit, or for a shorter 
period if local regulations and/or ERBs (ethical review boards) 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 the technology utilized, data generated will be used only for the specific research 
scope described in this section.  
9.8.
Biomarkers
Biomarker research is performed to address questions of relevance to drug disposition, target 
engagement, PD, mechanism of action, variability of patient response (including safety), and 
clinical outcome.  Sample collection is incorporated into clinical studies to enable examination of 


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these questions through measurement of biomolecules including DNA, RNA, proteins, lipids, 
and other cellular elements.  
Serum, plasma, and/or whole blood RNA samples for nonpharmacogenetic biomarker research 
may be collected at the times specified in the Schedule of Activities (Section 2) where local 
regulations allow.
Samples will be used for research on the drug target, disease process, variable response to 
LY3337641, pathways associated with diseases related to the immune system, mechanism of 
action of LY3337641, and/or research method, or for validating diagnostic tools or assay(s) 
related to diseases related to the immune system.
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 ERBs impose shorter time limits, at a facility selected by Lilly.  
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.  
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 60 subjects may be enrolled so that approximately 36 to 48 subjects complete the study.
The sample size is customary for Phase 1 studies evaluating safety, PK, and/or PD parameters 
and is not based on the power of statistical hypothesis tests.  
Subjects who are randomized but discontinue the study may be replaced in the same cohort and 
race (Japanese or Caucasian) at the discretion of the sponsor.  
10.2. Populations for Analyses
10.2.1. Study Participant Disposition
All subjects who discontinue from the study will be identified, and the extent of their 
participation in the study will be reported.  If known, a reason for their discontinuation will 
be given.  
10.2.2. Study Participant Characteristics
Subjects’ age, sex, weight, body mass index, height, race/subcategory, or other demographic 
characteristics will be recorded and summarized by treatment group as well as overall.
10.3. Statistical Analyses
Statistical analysis of this study will be the responsibility of Eli Lilly and Company or 
its designee.
PK analyses will be conducted for all subjects who receive at least 1 dose of LY3337641 and 
have evaluable PK data. PD analyses will be conducted on the full analysis set, which includes 
all data from all subjects receiving at least 1 dose of LY3337641 or placebo.  Safety analyses 
will be conducted for all randomized subjects who receive at least 1 dose of LY3337641 or 
placebo and have at least 1 postdose safety assessment, regardless of whether they have 
completed all protocol requirements.  For QT interval, all subjects with at least 1 postdose
QT interval measurement will be included in the analysis.
Summary statistics, data tabulations, and data graphs will be provided and may be separated by 
race (Japanese and Caucasian) as appropriate.
Additional exploratory analyses of the data will be conducted as deemed appropriate.  Study 
results may be pooled with the results of other studies for population PK/PD analysis purposes.  
10.3.1. Safety Analyses
10.3.1.1. Clinical Evaluation of Safety
All IP and protocol procedure AEs will be listed, and if the frequency of events allows, safety 
data will be summarized using descriptive methodology.


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The incidence of symptoms for each treatment will be presented by severity and by association 
with the 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 IP-related SAEs will be reported.
10.3.1.2. Statistical Evaluation of Safety
Safety parameters that will be assessed include laboratory parameters, vital signs, and ECG 
parameters.  The parameters will be listed and summarized using standard descriptive statistics.  
Prior to any statistical analysis of QT interval, QT values will be corrected for heart rate based on 
QTcF.  The relationship between concentrations of LY3337641 and changes from baseline QTcF
(ΔQTcF) will be explored to assess the effect of LY3337641 concentration on the ΔQTcF.  A
detailed analysis for QT interval will be provided in the Statistical Analysis Plan. Additional 
analysis will be performed if warranted upon review of the data.
10.3.2. Pharmacokinetic Analyses
10.3.2.1. Pharmacokinetic Parameter Estimation
PK parameter estimates for LY3337641 will be calculated by standard noncompartmental 
methods of analysis.
In the SD cohorts, the primary parameters for analysis will be Cmax, area under the concentration 
versus time curve from zero to infinity (AUC0-∞), and area under the concentration versus time 
curve from 0 to 24 hours (AUC0-24) of LY3337641.  In the MD cohorts, the primary parameters 
to be calculated will include Cmax (or Cmax during a dosing interval at steady state [Cmax,ss]) and 
area under the concentration versus time curve during the dosing interval (AUC0-τ) of 
LY3337641 after the first and last dose of IP.  Other noncompartmental parameters, such as 
half-life, apparent clearance, apparent volume of distribution, and accumulation ratio (MD period 
only), may be reported.  
Additional analysis may be conducted if appropriate.
10.3.2.2. Pharmacokinetic Statistical Inference
The dose proportionality of selected LY3337641 PK parameters, including log transformed Cmax
and relevant AUC values will be examined for all subjects and for each population across the 
entire dose range using a power model approach (Smith et al. 2000) to estimate the slope of the 
power model, which represents the ratio of dose-normalized geometric means.  Exploratory 
power model analysis based on the model including race and race-by-dose interaction terms will 
also be performed to examine the effect of the race on dose proportionality.
10.3.3. Pharmacodynamic Analyses
BTK occupancy will be listed and summarized using standard descriptive statistics.  Additional 
analysis will be performed if warranted upon review of the data.


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10.3.4. Pharmacokinetic/Pharmacodynamic Analyses
Exploratory graphical PK/PD analyses may be conducted to evaluate the relationship between 
LY3337641 concentrations (or exposure) and PD measures.  Additional model-based analyses 
may be conducted if deemed appropriate.
10.3.5. Interim Analyses
The Lilly study team is unblinded.  Data may be analyzed while the trial is ongoing, but no 
changes to the study design are planned.  An assessment committee will not be formed.
Up to 3 interim analyses are planned to occur during the study according to the following 
timeframe: when at least safety and PK data of (1) Day 2 predose (24 hours after first dose) 
become available from at least 11 subjects in Cohort 1, including at least 4 Caucasian subjects; 
(2) Day 17 (48 hours after last dose) become available from Cohort 1; and (3) Day 29 become 
available from Cohort 1.  All safety and PK data available from other cohorts by this time will be 
included in the interim analysis.  The purpose of the interim analysis is to support the inclusion 
of Japanese subjects in future studies.  The investigator and the Lilly clinical pharmacologist will 
review the safety and tolerability data, and the PK/PD scientist will review the PK data.  The 
investigator will remain blinded, and the Lilly study team will be unblinded during this 
interim review.
Information that may unblind the study during the analyses will not be reported to study site or 
blinded personnel until the study has been unblinded.
Additional interim analysis may be conducted at any time throughout the study as required to 
ensure subject safety or to help guide dosing.
If an unplanned interim analysis is deemed necessary, the Lilly clinical pharmacologist, clinical 
research physician/investigator, or designee will consult with the appropriate medical director or 
designee to determine if it is necessary to amend the protocol.


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11.
References
Aalipour A, Advani RH. Bruton's tyrosine kinase inhibitors and their clinical potential in the 
treatment of B-cell malignancies: focus on ibrutinib. Ther Adv Hematol. 2014;5(4):121-133.
Burger JA. Bruton’s tyrosine kinase (BTK) inhibitors in clinical trials. Curr Hematol Malig Rep. 
2014;9(1):44-49.
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 JH, 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.
Horwood NJ, Urbaniak AM, Danks L. Tec family kinases in inflammation and disease. Int Rev 
Immunol. 2012;31(2):87-103.
Smith BP, Vandenhende FR, DeSante KA, Farid NA, Welch PA, Callaghan JT, Forgue ST. 
Confidence interval criteria for assessment of dose proportionality. Pharm Res. 
2000;17(10):1278-1283.


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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.
ALP
alkaline phosphatase
ALT
alanine aminotransferase
AST
aspartate aminotransferase
AUC
area under the plasma concentration-time curve
AUC0-∞
area under the concentration versus time curve from zero to infinity
AUC0-24
area under the concentration versus time curve from 0 to 24 hours
AUC0-
area under the concentration versus time curve during the dosing interval
BID
twice daily
blinding
A procedure in which one or more parties to the trial are kept unaware of the treatment 
assignment(s).  Unless otherwise specified, blinding will remain in effect until final 
database lock.
BTK
Bruton’s tyrosine kinase
Cmax
maximum drug concentration
Cmax,ss
maximum drug concentration during a dosing interval at steady state
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 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.
clinical research 
physician
Individual responsible for the medical conduct of the study.  Responsibilities of the clinical 
research physician may be performed by a physician, clinical research scientist, global 
safety physician, or other medical officer.
CRU
clinical research unit


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ECG
electrocardiogram
eCRF
electronic case report form
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.
entered
Subjects entered into a trial are those who sign the informed consent form directly or 
through their legally acceptable representatives.
ERB
ethical review board
GCP
Good Clinical Practice
HBcAb
hepatitis B core antibody
HBsAg
hepatitis B surface antigen
HIV
human immunodeficiency virus
ICF
informed consent form
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.  
interim analysis
An interim analysis is an analysis of clinical trial data, separated into treatment groups, that 
is conducted before the final reporting database is created/locked.
investigational 
product 
A pharmaceutical form of an active ingredient or placebo being tested or used as a reference 
in a clinical trial, including products already on the market when used or assembled 
(formulated or packaged) in a way different from the authorized form, or marketed products 
used for an unauthorized indication, or marketed products used to gain further information 
about the authorized form.
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.
IP
investigational product
legal 
representative
An individual or judicial or other body authorized under applicable law to consent, on 
behalf of a prospective subject, to the subject’s participation in the clinical trial.
MD
multiple dose
PD
pharmacodynamics(s)
PK
pharmacokinetic(s)
QD
once daily
QTcF
Fridericia-corrected QT interval


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RA
rheumatoid arthritis
SAE
serious adverse event
screen
The act of determining if an individual meets minimum requirements to become part of a 
pool of potential candidates for participation in a clinical trial.  
SD
single dose
SUSARs
suspected unexpected serious adverse reactions 
TB
tuberculosis
TBL
total bilirubin level
TEAE
treatment-emergent adverse event 
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
ULN
upper limit of normal


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Appendix 2.
Clinical Laboratory Tests
Laboratory Testsa
Hematology
Clinical Chemistry
Hematocrit
Sodium
Hemoglobin
Potassium
Erythrocyte count (RBCs)
Bicarbonate
Mean cell volume 
Chloride 
Mean cell hemoglobin 
Calcium
Mean cell hemoglobin concentration 
Phosphorus
Leukocytes (WBCs)
Magnesium
Absolute counts of:
Glucose fasting
Neutrophils
Blood urea nitrogen (BUN)
Lymphocytes
Uric acid
Monocytes
Total cholesterol
Eosinophils
Total protein
Basophils
Albumin
Platelets
Total bilirubin
Alkaline phosphatase (ALP)
Urinalysis
Aspartate aminotransferase (AST)
Specific gravity
Alanine aminotransferase (ALT)
pH
Creatinine
Protein
Gamma-glutamyl transferase (GGT)
Glucose
CRP
Ketones
Amylase
Bilirubin
Lipase
Urobilinogen
Ethanol testingb,c
Blood
Urine drug screenb,c
Nitrite
Hepatitis B surface antigenb
Hepatitis B core antibodyb
Hepatitis C antibodyb
HIVb
Pregnancy testd
FSHb,d
QuantiFERON®-TB Gold testb
Abbreviations:  CRP = C-reactive protein; FSH = follicle-stimulating hormone; HIV = human immunodeficiency 
virus; RBCs = red blood cells; TB = tuberculosis; WBCs = white blood cells.
a
To be performed at local laboratory.
b
Performed at screening only.  
c
May be repeated prior to admission to the clinical research unit.  
d
To be performed for female subjects of childbearing potential.  Serum pregnancy test at screening; urine 
pregnancy test at all other visits.


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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 informed consent 
form (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 ethical review 
board (ERB) was properly constituted and convened as required by International Council for 
Harmonisation (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 good clinical practice (GCP).
The study site’s ERB(s) should be provided with the following:

the current Investigator’s Brochure 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 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 electronic case report forms, 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 electronic case report form 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.


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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.
Study and Site Closure
Discontinuation of Study Sites
Study site participation may be discontinued if Lilly, 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 judges it necessary for medical, safety, regulatory, or 
other reasons consistent with applicable laws, regulations, and GCP.


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


I8K-JE-JPDB(a) Clinical Pharmacology Protocol
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LY3337641
Appendix 5.
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-JE-JPDB Sampling Summary for Cohorts 1 and 5
Purpose
Maximum Blood Volume 
per Sample (mL)
Maximum Number 
of Blood Samples
Maximum Total 
Volume (mL)
Screening testsa
45
1
45
Clinical laboratory testsa
12
5
60
Pharmacokinetics 
2
33
66
Pharmacodynamics (BTK 
occupancy)
16
18
288
Pharmacogenetics
10
1
10
Non-PGx stored sample
9.5
3
28.5
Total
497.5
Total for clinical purposes [rounded up to nearest 10 mL]
500
Abbreviations:  BTK = Bruton’s tyrosine kinase; PGx = pharmacogenomics.
a
Additional samples may be drawn if needed for safety purposes.
Protocol I8K-JE-JPDB Sampling Summary for Cohorts 2, 3, and 4
Purpose
Maximum Blood Volume 
per Sample (mL)
Maximum Number 
of Blood Samples
Maximum Total 
Volume (mL)
Screening testsa
45
1
45
Clinical laboratory testsa
12
3
36
Pharmacokinetics 
2
16
32
Pharmacodynamics (BTK 
occupancy)
16
9
144
Pharmacogenetics
10
1
10
Non-PGx stored sample
9.5
3
28.5
Total
295.5
Total for clinical purposes [rounded up to nearest 10 mL]
300
Abbreviations:  BTK = Bruton’s tyrosine kinase; PGx = pharmacogenomics.
a
Additional samples may be drawn if needed for safety purposes.


I8K-JE-JPDB(a) Clinical Pharmacology Protocol
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LY3337641
Appendix 6.
Protocol I8K-JE-JPDB Blinding/Unblinding 
Plan
Levels of unblinding are indicated in the table below.  This table provides general guidance as to 
who will be allowed access to randomization codes at various steps of the trial.  The information 
in the protocol will always take precedence over this table.  For interim analysis, appropriate 
interim analysis team members, including statistician, programmer, and data manager will be 
identified and agreed upon between Lilly and the third-party organization.  
Randomization data are kept strictly confidential and are accessible only by authorized personnel 
until unblinding of the trial as described below.  All measures possible must be taken to maintain 
the blind, which means that access to randomization codes must be restricted to authorized 
personnel as described in the protocol and summarized in the table below.


I8K-JE-JPDB(a) Clinical Pharmacology Protocol
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LY3337641
Protocol I8K-JE-JPDB Blinding and Unblinding Plan
Study Timelines
Study Team Member
Screening
Randomization
Treatment 
Phase
Follow-Up
Database 
Lock
General
Drug Supply
NA
U
U
U
U
Randomization Statisticians
NA
U
U
U
U
ECG Reader
NA
B
B
B
B
Bioanalysis Lab/Sample Analysis
NA
U
U
U
U
Clinical Site
Pharmacist
NA
U
U
U
U
Dosing Nurse
NA
U
U
U
U
Subject
NA
B
B
B
B
Investigator
NA
B
B
B
B
Study Monitor 
NA
U
U
U
U
Covance/CDARO
Project Integration
NA
U
U
U
U
Data Management
NA
U
U
U
U
Programming
NA
U
U
U
U
Statistician
NA
U
U
U
U
Medical Writing 
NA
U
U
U
U
Pharmacokinetic Scientist/Associate
NA
U
U
U
U
Lilly
Biopharm Coordinator
NA
U
U
U
U
CPA
NA
U
U
U
U
DSA
NA
U
U
U
U
SDTM Core Team
NA
U
U
U
U
Statistician
NA
U
U
U
U
Medical Writing
NA
U
U
U
U
CP
NA
U
U
U
U
Pharmacokinetic Scientist/Associate
NA
U
U
U
U
Medical Writing 
NA
U
U
U
U
Abbreviations:  B = blinded; CP = clinical pharmacologist; CPA = clinical pharmacology associate; DSA = data 
sciences associate; ECG = electrocardiogram; SDTM = study data tabulation model; U = unblinded.


I8K-JE-JPDB(a) Clinical Pharmacology Protocol
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LY3337641
Appendix 7.
Protocol Amendment I8K-JE-JPDB(a) 
Summary
A Single- and Multiple-Dose Study to Evaluate the Safety, 
Tolerability, Pharmacokinetics, and Pharmacodynamics 
of LY3337641 in Japanese and Caucasian Healthy 
Subjects
Overview
Protocol I8K-JE-JPDB, A Single- and Multiple-Dose Study to Evaluate the Safety, Tolerability, 
Pharmacokinetics, and Pharmacodynamics of LY3337641 in Japanese and Caucasian Healthy 
Subjects, has been amended.  The new protocol is indicated by Amendment (a) and will be used 
to conduct the study in place of any preceding version of the protocol.
The overall changes and rationale for the changes made to this protocol are as follows:

Addition of “Review preexisting conditions/AEs” and “Review concomitant 
medications” to the Days 17, 22, 25, and 29/EoS for Cohorts 1 and 5 and to the Days 3, 8, 
11, and 15/EoS for the Cohorts 2, 3, and 4 in the table of Schedule of Activities as these 
assessments are required for all visits.

Clarified that on Day 15 in Cohort 5, only the morning dose will be administered for 
twice-daily regimen in the footnote of the Schedule of Activities.

Addition of the exemption criteria for a chest x-ray at screening.

Addition of subject’s race criteria and the definition of 1st generation Japanese.


I8K-JE-JPDB(a) Clinical Pharmacology Protocol
Page 56
LY3337641
The overall changes and rationale for the changes made to this protocol are described in the 
following table:
Table JPDB.3.
Amendment Summary for Protocol I8K-JE-JPDB Amendment(a)
Section # and Name
Description of Change
Brief Rationale
2. Schedule of Activities
Addition of “Review preexisting 
conditions/AEs” and “Review concomitant 
medications” to the Days 17, 22, 25, and 
29/EoS for Cohorts 1 and 5 and to the 
Days 3, 8, 11, and 15/EoS for the Cohorts 
2, 3, and 4 in the table of Schedule of 
Activities.
Both “Review preexisting 
conditions/AEs” and “Review 
concomitant medications” are required 
for all visits throughout the study, but 
were inadvertently missing for the visits.
2. Schedule of Activities
Clarified that on Day 15 in Cohort 5, only 
the morning dose will be administered for 
twice-daily regimen in the footnote of the 
Schedule of Activities.
The correct text is written in the section 
7.2.1. Selection and Timing of Doses. 
However, to resolve the inconsistency 
between the 2 sections, the footnote was 
corrected.
6. Study Population
Addition of the exemption criteria for a 
chest x-ray at screening.
This sentence was added to avoid 
unnecessary x-rays.
6.1. Inclusion Criteria
Addition of subject’s race criteria and the 
definition of 1st generation Japanese.
This criterion was inadvertently missing 
and has been added to ensure quality of 
study data by recruiting the intended 
race groups to the study.


I8K-JE-JPDB(a) Clinical Pharmacology Protocol
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LY3337641
Revised Protocol Sections
Note:
All deletions have been identified by strikethroughs.
All additions have been identified by the use of underscore.
2. Schedule of Activities
Study Schedule Protocol I8K-JE-JPDB (Cohorts 1 and 5)
Visit
Follow-Upa
Study Day
16
17
19
22
25
29/
EoS
Review preexisting 
conditions/AEsd
X
X
X
X
X
X
Review concomitant 
medicationsd
X
X
X
X
X
X
c
Subjects will be dosed every day from Day 1 through Day 15.  For twice-daily regimen, only the morning dose 
will be administered on Day 15dose will be administered in the morning only.
Study Schedule Protocol I8K-JE-JPDB (Cohorts 2, 3, and 4)
Visit
Follow-Upa
Study Day
2
3
5
8
11
15/EoS
Review preexisting 
conditions/AEs
X
X
X
X
X
X
Review concomitant 
medications
X
X
X
X
X
X
6. Study Population
Eligibility of subjects for study enrollment will be based on the results of screening medical 
history, physical examination, vital signs, clinical laboratory tests, and ECG.  
A chest x-ray will be completed at screening unless one has been obtained within the past 
12 months, and the x-ray and/or report are available for review.
6.1.
Inclusion Criteria
[37] are 1st generation Japanese or Caucasian.
To qualify as a subject of 1st generation Japanese origin, the subject, the 
subject’s biological parents, and all of the subject’s biological grandparents 
must be of exclusive Japanese descent and born in Japan.


PPD
Leo Document ID = 722f39a5-0f6a-47dd-9bd4-1c4fe6829144
Approver: 
Approval Date & Time: 16-Mar-2017 08:35:40 GMT
Signature meaning: Approved
Approver: 
Approval Date & Time: 16-Mar-2017 19:18:38 GMT
Signature meaning: Approved
PPD

SAP_001.pdf: 
Statistical Analysis Plan I8K-JE-JPDB 
 
A Single- and Multiple-Dose Study to Evaluate the Safety, Tolerability, Pharmacokinetics, and 
Pharmacodynamics of LY3337641 in Japanese and Caucasian Healthy Subjects 
 
NCT03083561 
Approval Date: 24-Mar-2017 
 
 
 


Final, 22 Mar 2017
             Page 1 of 13
STATISTICAL ANALYSIS PLAN
A Single- and Multiple-Dose Study to Evaluate the Safety, Tolerability, Pharmacokinetics, 
and Pharmacodynamics of LY3337641 in Japanese and Caucasian Healthy Subjects
Statistical Analysis Plan Status:  Final
Statistical Analysis Plan Date:  22 March 2017
Study Drug: LY3337641
Sponsor Reference:  I8K-JE-JPDB
Covance CRU Study: 1000071-8356528
Clinical Phase I
Approval Date: 24-Mar-2017 GMT


Final, 22 Mar 2017
             Page 2 of 13
Statistical Analysis Plan 
CONFIDENTIAL
Covance Clinical Study No. 100071-8356528
Sponsor Reference I8K-JE-JPDB
1. TABLE OF CONTENTS
1.
TABLE OF CONTENTS .....................................................................................................2
2.
ABBREVIATIONS..............................................................................................................3
3.
INTRODUCTION ...............................................................................................................4
4.
STUDY OBJECTIVES........................................................................................................4
4.1
Primary Objective..........................................................................................................4
4.2
Secondary Objective......................................................................................................4
4.3
Exploratory Objectives ..................................................................................................4
5.
STUDY DESIGN.................................................................................................................5
6.
TREATMENTS ...................................................................................................................6
7.
SAMPLE SIZE JUSTIFICATION .......................................................................................7
8.
DEFINITION OF ANALYSIS POPULATIONS..................................................................7
9.
STATISTICAL METHODOLOGY .....................................................................................7
9.1
General..........................................................................................................................7
9.2
Demographics and Subject Disposition..........................................................................8
9.3
Pharmacokinetic Assessment.........................................................................................8
9.3.1
Pharmacokinetic Analysis.....................................................................................8
9.3.2
Pharmacokinetic Statistical Methodology .............................................................8
9.4
Pharmacodynamic Assessment ......................................................................................9
9.4.1
Pharmacodynamic Analysis..................................................................................9
9.4.2
Pharmacodynamic Statistical Methodology ..........................................................9
9.5
Pharmacokinetic/Pharmacodynamic Assessment ...........................................................9
9.6
Safety and Tolerability Assessments ..............................................................................9
9.6.1
Adverse events .....................................................................................................9
9.6.2
Concomitant medication.....................................................................................10
9.6.3
Clinical laboratory parameters ............................................................................10
9.6.4
Vital signs ..........................................................................................................10
9.6.5
Electrocardiogram (ECG)...................................................................................10
9.6.6
Other assessments...............................................................................................11
9.6.7
Safety and Tolerability Statistical Methodology ..................................................11
10. INTERIM ANALYSES .....................................................................................................11
11. CHANGES FROM THE PROTOCOL SPECIFIED STATISTICAL ANALYSES ............12
12. REFERENCES ..................................................................................................................12
13. DATA PRESENTATION ..................................................................................................12
13.1 Derived Parameters .....................................................................................................12
13.2 Missing Data ...............................................................................................................12
13.3 Insufficient Data for Presentation ................................................................................13


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Statistical Analysis Plan 
CONFIDENTIAL
Covance Clinical Study No. 100071-8356528
Sponsor Reference I8K-JE-JPDB
2. ABBREVIATIONS
Abbreviations pertain to the Statistical Analysis Plan (SAP) only (not the tables, figures and 
listings [TFLs]).
AE
Adverse event
AUC
Area under the concentration versus time curve
BID
Twice daily
BTK
Bruton’s tyrosine kinase 
Cmax
Maximum observed drug concentration
CRF
Case Report Form
CRU
Clinical Research Unit
CSR
Clinical Study Report
CV
Coefficient of variation
e.g.
For example (Latin: exempli gratia)
EC
Early Clinical 
ECG
Electrocardiogram
ICH
International Conference on Harmonisation
IP
Investigational product
MD
Multiple dose
MedDRA
Medical Dictionary for Regulatory Activities
PD
Pharmacodynamic
PK
Pharmacokinetic
QD
Once daily
QTcB 
Bazett-corrected QT interval  
QTcF 
Fridericia-corrected QT interval
SAP
Statistical Analysis Plan
SD
Single dose
TFLs
Tables, Figures, and Listings
tmax
Time of maximum observed drug concentration
WHO
World Health Organization


Final, 22 Mar 2017
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Statistical Analysis Plan 
CONFIDENTIAL
Covance Clinical Study No. 100071-8356528
Sponsor Reference I8K-JE-JPDB
3. INTRODUCTION
This SAP has been developed after review of the Clinical Study Protocol (final version dated 
24 December 2016).
This SAP describes the planned analysis of the safety, tolerability, pharmacokinetic (PK) and 
pharmacodynamic (PD) data from this study. A detailed description of the planned TFLs to be 
presented in the clinical study report (CSR) is provided in the accompanying TFL shell 
document.
The intent of this document is to provide guidance for the statistical 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 Covance Early Clinical (EC) Biometrics. A 
limited amount of information concerning this study (e.g., objectives, study design) is given to 
help the reader’s interpretation. This SAP must be signed off prior to first subject administration
for this study. When the SAP and TFL shells are agreed upon and finalized, they will serve as 
the template for this study’s CSR.
This SAP supersedes the statistical considerations identified in the protocol; where 
considerations are substantially different, they will be so identified. If additional analyses are 
required to supplement the planned analyses described in this SAP, they may be performed and 
will be identified in the CSR. Any substantial deviations from this SAP will be agreed upon 
between Eli Lilly and Company and Covance EC Biometrics and identified in the CSR. Any 
minor deviations from the TFLs may not be documented in the CSR.
This SAP is written with consideration of the recommendations 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 explore the safety and tolerability of LY3337641 in healthy Japanese and Caucasian 
subjects.
4.2
Secondary Objective

To estimate the PK parameters of single and multiple doses of LY3337641 following oral 
administration in healthy Japanese and Caucasian subjects.
4.3
Exploratory Objectives

To explore the PD following single and multiple doses of LY3337641 in healthy 
Japanese and Caucasian subjects.


Final, 22 Mar 2017
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Statistical Analysis Plan 
CONFIDENTIAL
Covance Clinical Study No. 100071-8356528
Sponsor Reference I8K-JE-JPDB

To explore the safety, tolerability, PK, and PD of LY3337641 in Japanese subjects in 
relation to Caucasian subjects.

To explore the effect of LY3337641 on ECG findings in healthy Japanese and Caucasian 
subjects.
5. STUDY DESIGN
This is a single-site, subject- and investigator-blind, randomized, placebo-controlled, single dose 
(SD) and multiple dose (MD) study to assess the safety, tolerability, PK, and PD of LY3337641 
in healthy Japanese and Caucasian subjects. Subjects will be randomized to LY3337641 within 
each cohort as shown in Figure JPDB.1. All cohorts will be randomized in a 3:1 ratio of 
LY3337641 to placebo. MD Cohort 1 (30 mg once daily [QD] for 2 weeks) and Cohort 5 
(optional) will consist of 12 subjects (8 Japanese and 4 Caucasian). SD Cohorts 2, 3, and 4 (5, 
80, and 160 mg SD) will consist of 8 subjects (4 Japanese and 4 Caucasian). For each MD 
cohort, 6 Japanese subjects and 3 Caucasian subjects will receive LY3337641, while 2 Japanese 
subjects and 1 Caucasian subject will receive placebo. For each SD cohort, 3 Japanese subjects 
and 3 Caucasian subjects will receive LY3337641, while 1 Japanese subject and 1 Caucasian 
subject will receive placebo.  Investigational product (IP) will be administered orally. Cohorts 1, 
2, and 3 may be conducted in parallel if the site is able to accommodate more than 1 cohort at a 
time; however, priority will be given to dose Cohort 1, since the timing of this cohort will 
determine the timing of the interim analysis. Cohort 4 will be started based on the safety 
assessment up to Day 3 (48 hours postdose) of Cohort 2. If the dose level/regimen for Cohort 1 
is not tolerated or there is a need to dose more subjects to assess safety, a daily dose of 30 mg or 
less (QD or twice daily [BID]) may be given in Cohort 5 based on the findings from Cohort 1. 
This will be discussed and agreed upon by the investigator and the Lilly clinical pharmacologist. 
The randomization rules and procedures will be the same as Cohort 1.  


Final, 22 Mar 2017
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Statistical Analysis Plan 
CONFIDENTIAL
Covance Clinical Study No. 100071-8356528
Sponsor Reference I8K-JE-JPDB
Abbreviations: BID =  twice daily; FU = follow-up; JP = Japanese; LY = LY3337641; 
Pb = placebo; QD = once daily.
*Dose, regimen, and subject number may change for optional cohort.
Figure JPDB.1. Study Design
6. TREATMENTS
The following is a list of the study treatment abbreviations that will be used in the Safety TFLs.
Study Treatment Name
Treatment order in TFL
Pooled Placebo SD
1
LY3337641 5 mg SD
2
LY3337641 80 mg SD
3
LY3337641 160 mg SD
4
Pooled Placebo QD
5
LY3337641 30 mg QD (Day 1)*
6
LY3337641 30 mg QD (Day 15)*
7
LY3337641 TBD mg BID or QD
TBD
* Split by Day for vital signs and ECG data only.
The following is a list of the study treatment abbreviations that will be used in the PK TFLs.


Final, 22 Mar 2017
             Page 7 of 13
Statistical Analysis Plan 
CONFIDENTIAL
Covance Clinical Study No. 100071-8356528
Sponsor Reference I8K-JE-JPDB
Study Treatment Name
Treatment order in TFL
LY3337641 5 mg SD
1
LY3337641 30 mg QD (Day 1)
2
LY3337641 80 mg SD
3
LY3337641 160 mg SD
4
LY3337641 30 mg QD (Day 15)
5
LY3337641 TBD mg BID or QD
TBD
7. SAMPLE SIZE JUSTIFICATION
Up to 60 subjects may be enrolled so that approximately 36 to 48 subjects complete the study.  
The sample size is customary for Phase 1 studies evaluating safety, PK, and/or PD parameters
and is not based on the power of statistical hypothesis tests.  Subjects who are randomized but 
discontinue the study may be replaced in the same cohort and race (Japanese or Caucasian) at the 
discretion of the sponsor.
8. DEFINITION OF ANALYSIS POPULATIONS
The “Safety” population will consist of all subjects who received at least one dose of 
LY3337641 or placebo, and have at least one postdose safety assessment.
The “Pharmacokinetic” population will consist of all subjects who received at least one dose of 
LY3337641 and have evaluable PK data. 
The “Pharmacodynamic” population will consist of all subjects who received at least one dose of 
LY3337641 or placebo and have evaluable PD data
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, median, min, 
max and N; for log-normal data (e.g. the PK parameters: area under the concentration versus 
time curve [AUC] and maximum observed drug concentration [Cmax]) the geometric mean and 
geometric coefficient of variation (CV%) will also be presented. For categorical data, frequency 
count and percentages will be presented. Data listings will be provided for all subjects up to the 
point of withdrawal, with any subjects excluded from the relevant population highlighted.
Summary statistics and statistical analyses will generally only be performed for subjects included 
in the relevant analysis population. For the calculation of summary statistics and statistical 
analysis, unrounded data will be used. 


 
Final, 22 Mar 2017 
 
             Page 8 of 13 
Statistical Analysis Plan  
 
CONFIDENTIAL 
Covance Clinical Study No. 100071-8356528  
Sponsor Reference I8K-JE-JPDB 
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 will be also summarized by population (overall, Japanese and Caucasian) where 
appropriate. 
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/subcategory, 
ethnicity, country of enrolment, site ID, body weight, height and body mass index will be 
summarized by population and listed.  All other demographic data, including associated person 
demographics, will be listed only. 
9.3 
Pharmacokinetic Assessment 
9.3.1 Pharmacokinetic Analysis 
PK parameter estimates for LY3337641 will be calculated by standard noncompartmental 
methods of analysis.  The PK analysis of this study will be the responsibility of Eli Lilly and 
Company.  
 
9.3.2 Pharmacokinetic Statistical Methodology 
Dose proportionality among the 5 mg, 30 mg (Day 1), 80 mg and 160 mg dose levels will be 
assessed using a power model. 
The PK parameters Cmax, AUC0-∞ , and AUC0-24 will be assessed separately using a power model 
as follows: 
logሺܲܭ௜ሻൌߙ൅ߚ௜∙logሺ݀݋ݏ݁௜ሻ൅ߝ௜ 
where ݅ represents the ݅th subject, PK represents a pharmacokinetic parameter (AUC or Cmax), 
and ߝ௜ is a residual error term.  The dose proportionality will be reported as the estimated ratio of 
dose-normalized means 
ܴ෠ௗ௡௠ൌ൬݄
݈൰
ఉ෡భିଵ
 
and its 90% CI, where ݄ and ݈ denote the highest and lowest doses included in the model, 
respectively.  The estimates of ߚ along with its 90% CI, predicted geometric mean, and ratio of 
dose normalized geometric mean will be reported for each parameter. 
 


Final, 22 Mar 2017
             Page 9 of 13
Statistical Analysis Plan 
CONFIDENTIAL
Covance Clinical Study No. 100071-8356528
Sponsor Reference I8K-JE-JPDB
The following SAS code will be used:
proc mixed data=pk;
    by parameter;
    model lpk = ldose / alpha=0.1 residual ddfm=kr;
    estimate 'xx mg' intercept 1 ldose yy / cl; 
    estimate 'zz mg - xx mg' ldose pp / alpha=0.1 cl; 
    ods output solutionf=est;
    ods output estimates=estims;
run;
The above analysis will be repeated for Japanese and Caucasian subjects seperatey to examine 
the effect of the population on dose proportionality.  
The PK summary tables and figures will be the responsibility of Eli Lilly and Company. 
9.4
Pharmacodynamic Assessment
9.4.1 Pharmacodynamic Analysis
Free Bruton’s tyrosine kinase (BTK), total BTK, and BTK occupancy will be listed and 
summarized by population, treatment, and timepoint using standard descriptive statistics.  BTK 
occupancy will be calculated as follows:
BTK occupancy = Total BTK −Free BTK
Total BTK
Change from baseline (Day 1 predose) in BTK occupancy will also be summarized and listed.  
Furthermore, mean and individual profiles of BTK occupancy will be presented over time.
Additional analysis will be performed if warranted upon review of the data.
9.4.2 Pharmacodynamic Statistical Methodology
Not applicable.
9.5
Pharmacokinetic/Pharmacodynamic Assessment
Exploratory graphical PK/PD analyses may be conducted to evaluate the relationship between
LY3337641 concentrations (or exposure) and PD measures. Additional model-based analyses
may be conducted if deemed appropriate.  Any PK/PD analyses will be the responsibility of Eli 
Lilly and Company.  
9.6
Safety and Tolerability Assessments
9.6.1 Adverse events
Where changes in severity are recorded in the Case Report Form (CRF), each separate severity 
of the adverse event (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 


Final, 22 Mar 2017
             Page 10 of 13
Statistical Analysis Plan 
CONFIDENTIAL
Covance Clinical Study No. 100071-8356528
Sponsor Reference I8K-JE-JPDB
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.  AEs by day of onset will be presented for Cohorts 1 and 5.
All AEs will be listed.  Treatment-emergent AEs will be summarized by population, 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 population, 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.
9.6.2 Concomitant medication
Concomitant medication will be coded using the World Health Organization (WHO) drug 
dictionary (Version September 2016).  Concomitant medication will be listed.
9.6.3 Clinical laboratory parameters
All clinical chemistry and hematology data will be summarized by population, treatment and 
timepoint, 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.
9.6.4 Vital signs
Vital signs data will be summarized by population and treatment together with changes from 
baseline, where baseline is defined as Day 1 predose. Figures of mean vital signs and mean 
changes from baseline profiles will be presented by population and treatment. Furthermore, 
values for individual subjects will be listed.
9.6.5 Electrocardiogram (ECG)
The ECG data will be obtained directly from the 12-lead ECG traces.  These data include the PR, 
QT,  QRS duration and heart rate. In addition, QTcF (the QT interval corrected using 
Fridericia’s formula) will be calculated as follows:


3 60HR
QT
QTcF 
The ECGs will be collected in triplicate; the mean of triplicates will be used in the analysis. The 
ECG data will be summarized by population and treatment together with changes from baseline, 
where baseline is defined as the mean of the Day 1 predose measurements.  Figures of mean 
ECG data and mean changes from baseline will be presented by population and treatment.  As 


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Statistical Analysis Plan 
CONFIDENTIAL
Covance Clinical Study No. 100071-8356528
Sponsor Reference I8K-JE-JPDB
suggested by ICH E14 Guidline, the frequency of subjects with a maximum increase from 
baseline in QTcF interval will be summarized for each population and treatment according to the 
following categories: >30 ms and >60 ms.  In addition, the frequency of subjects with QTcF 
postdose values, according to the following categories: >450 ms, >480 ms and >500 ms, will be 
summarized by population and treatment. 
9.6.6 Other assessments
All other safety assessments not detailed in this section will be listed but not summarized or 
statistically analyzed.
9.6.7 Safety and Tolerability Statistical Methodology
The relationship between concentrations of LY3337641 and changes from baseline QTcF 
(ΔQTcF) will be explored to assess the effect of LY3337641 concentration on the ΔQTcF.  A 
scatter plot of the change from baseline in QTcF versus the concentrations with the fitted lines 
will also be plotted.  A linear mixed-effects model will be fitted with the ΔQTcF as the response, 
the time-matched concentration as a covariate, population (Japanese/Caucasian) as a fixed effect, 
the population-by-concentration interaction term, and subject as a random effect.  If there is no 
evidence of a difference between Japanese and Caucasian subjects, population will be removed 
from the model.  The intercept and slope from the model along with their 90% CI will be 
reported.  In addition, prediction intervals using C max estimated at the highest given dose in the 
study will be reported together with its 90% prediction intervals.
Example SAS code:
proc mixed data=ecg alpha=0.1;
    class subject race;
    model change = conc race race*conc / cl solution ddfm=kr;
    random subject;
run;
10.
INTERIM ANALYSES
The Lilly study team is unblinded. Data may be analyzed while the trial is ongoing, but no
changes to the study design are planned. An assessment committee will not be formed.
Up to 3 interim analyses are planned to occur during the study according to the following
timeframe: when at least safety and PK data of (1) Day 2 predose (24 hours after first dose)
become available from at least 11 subjects in Cohort 1, including at least 4 Caucasian subjects;
(2) Day 17 (48 hours after last dose) become available from Cohort 1; and (3) Day 29 become
available from Cohort 1. All safety and PK data available from other cohorts by this time will be
included in the interim analysis. The purpose of the interim analysis is to support the inclusion
of Japanese subjects in future studies. The investigator and the Lilly clinical pharmacologist will
review the safety and tolerability data, and the PK/PD scientist will review the PK data. The
investigator will remain blinded, and the Lilly study team will be unblinded during this interim 
review.


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Statistical Analysis Plan 
CONFIDENTIAL
Covance Clinical Study No. 100071-8356528
Sponsor Reference I8K-JE-JPDB
Information that may unblind the study during the analyses will not be reported to study site or
blinded personnel until the study has been unblinded.
Additional interim analysis may be conducted at any time throughout the study as required to
ensure subject safety or to help guide dosing.
If an unplanned interim analysis is deemed necessary, the Lilly clinical pharmacologist, clinical
research physician/investigator, or designee will consult with the appropriate medical director or 
designee to determine if it is necessary to amend the protocol.
11.
CHANGES FROM THE PROTOCOL SPECIFIED STATISTICAL ANALYSES
There were no changes from the protocol specified statistical analyses.
12.
REFERENCES
1. International Conference on Harmonization of Technical Requirements for Registration of 
Pharmaceuticals for Human Use, ICH Harmonized Tripartite Guideline, Statistical Principles 
for Clinical Trials (E9), 5 February 1998.
2. International Conference on Harmonization of Technical Requirements for Registration of 
Pharmaceuticals for Human Use, ICH Harmonized Tripartite Guideline, Structure and 
Content of Clinical Study Reports (E3), 30 November 1995.
3. International Conference on Harmonization of Technical Requirements for Registration of 
Pharmaceuticals for Human Use, ICH Harmonized Tripartite Guideline, The Clinical 
Evaluation of QT/QTc Interval Prolongation and Proarrhythmic Potential for 
Non-Antiarrhythmic Drugs (E14), 12 May 2005.
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. time of maximum observed drug concentration (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.


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Statistical Analysis Plan 
CONFIDENTIAL
Covance Clinical Study No. 100071-8356528
Sponsor Reference I8K-JE-JPDB
13.3
Insufficient Data for Presentation
Some of the TFLs may not have sufficient numbers of subjects or data for presentation. If this 
occurs, the blank TFL shell will be presented with a message printed in the centre of the table, 
such as, “No serious adverse events occurred for this study.”


Leo Document ID = 44d88d91-e75b-415b-bf2c-637f2e27aa4a
Approver: 
Approval Date & Time: 23-Mar-2017 15:32:13 GMT
Signature meaning: Approved
Approver: 
Approval Date & Time: 23-Mar-2017 23:43:40 GMT
Signature meaning: Approved
Approver: 
Approval Date & Time: 24-Mar-2017 13:18:47 GMT
Signature meaning: Approved
PPD
PPD
PPD