A Randomized, Double-Blind, Placebo-Controlled, 2-Part Phase 2 Study to Evaluate the Safety and Efficacy of LY3337641 in Adult Subjects With Rheumatoid Arthritis: The RAjuvenate Study
Phase: PHASE2
Conditions: Rheumatoid Arthritis
Sponsor: Eli Lilly and Company

Protocol I8K-MC-JPDA (d) 
 
 
A Randomized, Double-Blind, Placebo-Controlled, 2-Part Phase 2 Study to Evaluate the Safety 
and Efficacy of LY3337641 in Adult Subjects with Rheumatoid Arthritis: The RAjuvenate Study 
 
NCT02628028 
 
Approval Date: 05-Jul-2017 
 
 
 

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LY3337641
Protocol I8K-MC-JPDA(d)
A Randomized, Double-Blind, Placebo-Controlled, 2-Part 
Phase 2 Study to Evaluate the Safety and Efficacy of 
LY3337641 in Adult Subjects with Rheumatoid Arthritis:  
The RAjuvenate Study
Confidential Information
The information contained in this document is confidential and is intended for the use of 
clinical investigators.  It is the property of Eli Lilly and Company or its subsidiaries and 
should not be copied by or distributed to persons not involved in the clinical investigation of 
LY3337641, unless such persons are bound by a confidentiality agreement with Eli Lilly 
and Company or its subsidiaries.  
Note to Regulatory Authorities:  This document may contain protected personal data 
and/or commercially confidential information exempt from public disclosure.  Eli Lilly and 
Company requests consultation regarding release/redaction prior to any public release.  In 
the United States, this document is subject to Freedom of Information Act (FOIA) 
Exemption 4 and may not be reproduced or otherwise disseminated without the written 
approval of Eli Lilly and Company or its subsidiaries.
LY3337641
Study I8K-MC-JPDA is a 2-part Phase 2, randomized, double-blind, placebo-controlled trial 
in subjects with rheumatoid arthritis.  In Part A, subjects will be dosed with 5, 10, or 30 mg 
of LY3337641 or placebo for 4 weeks.  Following a safety analysis, Part B will enroll 
subjects to be dosed with the planned doses of 5, 10, or 30 mg of LY3337641 or placebo 
for 12 weeks.
Eli Lilly and Company
Indianapolis, Indiana USA 46285
Protocol Electronically Signed and Approved by Lilly: 16 October 2015
Amendment (a) Electronically Signed and Approved by Lilly:  20 June 2016
Amendment (b) Electronically Signed and Approved by Lilly:  07 September 2016
Amendment (c) Electronically Signed and Approved by Lilly:  31 October 2016
Amendment (d) Electronically Signed and Approved by Lilly
on approval date provided below.
Approval Date: 05-Jul-2017 GMT

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Table of Contents
Section
Page
1.
Protocol Synopsis................................................................................................................9
2.
Introduction ......................................................................................................................11
2.1.
Background..................................................................................................................11
2.2.
Study Rationale............................................................................................................12
3.
Objectives and Endpoints..................................................................................................13
4.
Study Design.....................................................................................................................16
4.1.
Overview of Study Design ...........................................................................................16
4.2.
End of Trial Definition.................................................................................................18
4.3.
Scientific Rationale for Study Design...........................................................................18
4.4.
Justification for Dose ...................................................................................................18
4.5.
Benefit/Risk Assessment..............................................................................................19
5.
Study Population...............................................................................................................20
5.1.
Inclusion Criteria..........................................................................................................20
5.2.
Exclusion Criteria ........................................................................................................21
5.3.
Screen Failures.............................................................................................................26
5.4.
Lifestyle and/or Dietary Requirements .........................................................................26
6.
Treatment..........................................................................................................................27
6.1.
Treatments Administered .............................................................................................27
6.2.
Method of Treatment Assignment ................................................................................28
6.2.1.
Selection and Timing of Doses.............................................................................28
6.3.
Blinding .......................................................................................................................28
6.4.
Packaging and Labeling ...............................................................................................29
6.5.
Preparation/Handling/Storage.......................................................................................29
6.6.
Dose Modification........................................................................................................29
6.7.
Treatment Compliance .................................................................................................30
6.8.
Concomitant Therapy...................................................................................................30
6.9.
Treatment after Study Completion................................................................................31
7.
Discontinuation Criteria ....................................................................................................32
7.1.
Discontinuation from Study Treatment.........................................................................32
7.1.1.
Interruption of Study Drug ...................................................................................32
7.1.2.
Permanent Discontinuation from Study Drug .......................................................32
7.1.3.
Discontinuation of Inadvertently Enrolled Subjects..............................................32
7.1.4.
Permanent Discontinuation from the Study ..........................................................32
7.1.5.
Subjects Lost to Follow-Up..................................................................................33

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8.
Study Assessments and Procedures ...................................................................................34
8.1.
Efficacy Assessments...................................................................................................34
8.1.1.
Primary Efficacy Assessments .............................................................................34
8.1.1.1.
Joint Assessments...........................................................................................34
8.1.1.1.1.
Tender Joint Count ...................................................................................35
8.1.1.1.2.
Swollen Joint Count..................................................................................35
8.1.1.2.
Physician’s Global Assessment of Disease Activity 
(VAS).............................................................................................................35
8.1.1.3.
Patient’s Global Assessment of Disease Activity (VAS).................................35
8.1.1.4.
Patient’s Global Assessment of Arthritis Pain (VAS)......................................36
8.1.1.5.
Patient’s Assessment of Physical Function (HAQ-DI) ....................................36
8.1.1.6.
High-Sensitivity C-Reactive Protein ...............................................................36
8.1.2.
Secondary Efficacy Assessments..........................................................................36
8.1.2.1.
Additional ACR Response Levels:  ACR50 and ACR70.................................36
8.1.2.2.
Disease Activity Score:  DAS28-hsCRP .........................................................36
8.1.3.
Appropriateness of Assessments ..........................................................................36
8.2.
Adverse Events ............................................................................................................37
8.2.1.
Serious Adverse Events........................................................................................37
8.2.1.1.
Suspected Unexpected Serious Adverse Reactions..........................................38
8.2.2.
Adverse Events of Special Interest .......................................................................38
8.2.3.
Complaint Handling.............................................................................................39
8.3.
Treatment of Overdose.................................................................................................39
8.4.
Safety Assessments ......................................................................................................39
8.4.1.
Physical Examination...........................................................................................39
8.4.2.
Vital Signs ...........................................................................................................40
8.4.3.
Electrocardiograms ..............................................................................................40
8.4.4.
Chest Radiography and Tuberculosis Testing .......................................................41
8.4.5.
Laboratory Tests ..................................................................................................41
8.4.6.
Assessment and Management of Subjects Developing a Rash ..............................41
8.4.7.
Safety Monitoring ................................................................................................42
8.4.7.1.
Hepatitis B Monitoring...................................................................................42
8.5.
Pharmacokinetics .........................................................................................................43
8.6.
Pharmacodynamics ......................................................................................................44
8.7.
Genetics .......................................................................................................................44
8.8.
Biomarkers...................................................................................................................45
8.9.
Health Outcomes..........................................................................................................45
8.9.1.
SF-36...................................................................................................................45
8.9.2.
FACIT-F..............................................................................................................46

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8.9.3.
Morning Joint Stiffness Duration..........................................................................46
8.9.4.
Patient’s Assessment of Sexual Function (VAS) ..................................................46
9.
Statistical Considerations and Data Analysis.....................................................................47
9.1.
Determination of Sample Size ......................................................................................47
9.2.
General Statistical Considerations ................................................................................47
9.2.1.
Analysis Population .............................................................................................47
9.2.2.
Baseline Definition ..............................................................................................48
9.2.3.
Missing Data Imputation......................................................................................48
9.3.
Treatment Group Comparability...................................................................................48
9.3.1.
Subject Disposition ..............................................................................................48
9.3.2.
Subject Characteristics .........................................................................................48
9.3.3.
Concomitant Therapy...........................................................................................48
9.3.4.
Treatment Compliance .........................................................................................48
9.4.
Primary and Secondary Analyses .................................................................................48
9.4.1.
Primary Analyses.................................................................................................48
9.4.1.1.
Additional Analyses of the Primary Efficacy Measure....................................49
9.4.2.
Secondary Analyses .............................................................................................49
9.5.
Safety Analyses............................................................................................................49
9.5.1.
Adverse Events ....................................................................................................49
9.6.
Pharmacokinetic/Pharmacodynamic Analyses..............................................................50
9.7.
Other Analyses.............................................................................................................50
9.7.1.
Health Outcomes and Biomarkers ........................................................................50
9.7.2.
Subgroup Analyses ..............................................................................................50
9.8.
Interim Analyses ..........................................................................................................51
10.
Study Governance Considerations.....................................................................................52
10.1. Regulatory and Ethical Considerations, Including the Informed 
Consent Process ...........................................................................................................52
10.1.1.
Informed Consent.................................................................................................52
10.1.2.
Ethical Review.....................................................................................................52
10.1.3.
Regulatory Considerations ...................................................................................52
10.1.4.
Investigator Information.......................................................................................53
10.1.5.
Protocol Signatures ..............................................................................................53
10.1.6.
Final Report Signature .........................................................................................53
10.2. Data Quality Assurance................................................................................................53
10.2.1.
Data Capture System............................................................................................54
10.3. Study and Site Closure .................................................................................................54
10.3.1.
Discontinuation of Study Sites .............................................................................54
10.3.2.
Discontinuation of the Study................................................................................54

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11.
References ........................................................................................................................55

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List of Tables
Table
Page
Table JPDA.1.
Objectives and Endpoints for Part A ..............................................................13
Table JPDA.2.
Objectives and Endpoints for Part B ..............................................................14
Table JPDA.3.
Dosing Regimens – Part A.............................................................................27
Table JPDA.4.
Dosing Regimens – Part B.............................................................................27

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List of Figures
Figure
Page
Figure JPDA.1.
Illustration of the study design for Clinical Protocol I8K-MC-JPDA..............17

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List of Appendices
Appendix
Page
Appendix 1.
Abbreviations and Definitions........................................................................57
Appendix 2.
Schedule of Activities....................................................................................61
Appendix 3.
Clinical Laboratory Tests...............................................................................74
Appendix 4.
Hepatic Monitoring Tests for Treatment-Emergent Abnormality....................77
Appendix 5.
Protocol Amendment I8K-MC-JPDA(d) Summary 
A Randomized, Double-Blind, Placebo-Controlled, 2-Part Phase 2 
Study to Evaluate the Safety and Efficacy of LY3337641 in Adult 
Subjects with Rheumatoid Arthritis:  The RAjuvenate Study .........................78

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1.
Protocol Synopsis
Title of Study:
A Randomized, Double-Blind, Placebo-Controlled, 2-Part Phase 2 Study to Evaluate the Safety and Efficacy of 
LY3337641 in Adult Subjects with Rheumatoid Arthritis:  The RAjuvenate Study
Rationale:  
Study I8K-MC-JPDA (JPDA) is a 2-part Phase 2 study designed to determine whether once-daily (qd) oral 
administration of LY3337641, an inhibitor of Bruton’s tyrosine kinase (BTK), is safe and efficacious in subjects
with rheumatoid arthritis (RA).  Part A will enroll subjects with at least mildly active RA to be dosed with 5, 10, or 
30 mg of LY3337641 or placebo for 4 weeks.  Following an interim analysis of safety data from Part A, Part B will 
enroll subjects with moderately to severely active RA to be dosed with the planned doses of 5, 10, or 30 mg of 
LY3337641 or placebo for 12 weeks. Findings from the study are intended to assess the utility of LY3337641 for 
the treatment of RA and related autoimmune diseases, further the understanding of the benefit/risk relationship for 
LY3337641, and inform the design of future studies.  
Objective(s)/Endpoints:
Part A:
Objectives
Endpoints
Primary

to evaluate the safety and tolerability of 
LY3337641 at 5, 10, and 30 mg qd in subjects 
with RA

The safety endpoints evaluated will include but 
are not limited to the following:
o
TEAEs, AESIs, SAEs
o
clinical laboratory tests, vital signs, 
physical examinations
Abbreviations:  AESIs = adverse events of special interest; qd = once daily; RA = rheumatoid arthritis; 
SAEs = serious adverse events; TEAEs = treatment-emergent adverse events.
Part B:
Objectives
Endpoints
Primary

to evaluate the efficacy, safety, and tolerability 
of LY3337641 at 5, 10, and 30 mg qd versus 
placebo at Week 12 for the treatment of 
subjects with moderately to severely active RA

proportion of subjects who achieve ACR20 

The safety endpoints evaluated will include but 
are not limited to the following:
o
TEAEs, AESIs, SAEs
o
clinical laboratory tests, vital signs, 
physical examinations
Secondary

to evaluate the efficacy of LY3337641 at 5, 10,
and 30 mg qd versus placebo at Week 12 on 
RA clinical endpoints

proportions of subjects achieving ACR50 and 
ACR70 

change from baseline in the DAS28-hsCRP

proportion of subjects achieving LDA based on 
DAS28-hsCRP

proportion of subjects achieving clinical 
remission based on DAS28-hsCRP 

to characterize the PK of LY3337641 in 
subjects with RA

population PK model estimate of clearance

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Abbreviations:  ACR = American College of Rheumatology; ACR20 = at least 20% improvement in the ACR 
criteria; ACR50 = at least 50% improvement in the ACR criteria; ACR70 = at least 70% improvement in the 
ACR criteria; AESIs = adverse events of special interest; DAS28 = Disease Activity Score modified to include 
the 28 diarthrodial joint count; hsCRP = high-sensitivity C-reactive protein; LDA = low disease activity; 
PK = pharmacokinetics; qd = once daily; RA = rheumatoid arthritis; SAEs = serious adverse events; 
TEAEs = treatment-emergent adverse events.
Summary of Study Design:  
Study JPDA is a multicenter, randomized, double-blind, placebo-controlled trial with 2 parts.  Part A has 3 study 
periods in subjects with at least mildly active RA with a dosing period of 4 weeks.  Part B has 3 study periods in 
subjects with moderately to severely active RA with a dosing period of 12 weeks.
Treatment Arms and Duration:  
In Part A, the study will include 4 arms: 3 experimental arms in which LY3337641 will be dosed orally at 5, 10, or 
30 mg qd and 1 placebo comparator arm.  In Part B, the study will include 4 arms:  3 experimental arms in which 
LY3337641 will be dosed orally at the planned doses of 5, 10, or 30 mg qd and 1 placebo comparator arm. Blinding 
will be maintained throughout.  The study periods include a screening period (Weeks −4 to 0), a dosing period 
(Weeks 0 to 4 in Part A and Weeks 0 to 12 in Part B), and a follow-up period (Weeks 4 to 6 in Part A and Weeks 12 
to 14 in Part B).  
Number of Subjects:  
In Part A, approximately 32 subjects with RA will be enrolled and randomly assigned in a 1:1:1:1 ratio to 1 of the 
4 arms. In Part B, approximately 244 subjects with RA will be enrolled and randomly assigned in a 1:1:1:1 ratio to
1 of the 4 arms.  In Part B, the percentage of subjects who are naive to biologic disease-modifying antirheumatic 
drugs (DMARDs) will be limited to approximately 25% of the study population; the remaining subjects in Part B
will have had previous exposure to biologic DMARDs.  There will be no limits on the percentage of subjects naive 
to biologic DMARDs in Part A.  Subjects participating in Part A will not be eligible to participate in Part B.
Statistical Analysis:
Efficacy and health outcomes analyses will be conducted on the modified intent-to-treat population, defined as all 
randomized subjects receiving at least 1 dose of study drug. Subjects will be grouped according to the randomized 
treatment. The analysis population (for applicable treatment outcome measures) will be all subjects with both a 
baseline and at least 1 postbaseline data measurement. Safety analyses will be conducted on the safety population, 
defined as all randomized subjects receiving at least 1 dose of the study drug. Subjects will be grouped according to 
the randomized treatment.  Data from Part A will be summarized separately from data from Part B. No statistical 
hypothesis testing is planned for Part A. All tests of treatment effects for Part B will be conducted at the 2-sided 
level of .05 unless otherwise stated. No adjustments for multiplicity will be performed.
The primary endpoint in Part B will be analyzed by a logistic regression model with ACR20 at Week 12 as the 
dependent variable and treatment, biologic disease-modifying antirheumatic drug (DMARD) experience (yes/no), 
region (Japan vs non-Japan), and baseline DAS28-hsCRP as independent variables.  A comparison of each 
LY3337641 dose to placebo will be presented.  Subjects who discontinue from the study earlier than Week 12 and 
subjects who complete 12 weeks of dosing but do not have sufficient data to derive the ACR20 response will be 
considered as failing to meet the ACR20.

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2. Introduction
2.1.
Background
Rheumatoid arthritis (RA) is a systemic inflammatory autoimmune disease and is the most 
common type of autoimmune arthritis.  The clinical features of RA include chronic joint 
inflammation and swelling that typically involve the small joints of the hands and feet.  
Rheumatoid arthritis can result in destruction of cartilage and juxta-articular bone with resultant 
joint space narrowing and deformities.  Chronic joint destruction can lead to functional 
impairment with increasing disability (Klareskog et al. 2009).  The disease is associated with not 
only progressive joint destruction and disability but also compromised quality of life as well as 
cardiovascular and other comorbidities (Scott et al. 2010).
Current treatment strategies for RA include synthetic and biologic disease-modifying 
antirheumatic drugs (DMARDs), which are often supported by nonsteroidal anti-inflammatory
medications and/or corticosteroids (Stoll and Yasothan 2009).  However, despite the multiple 
available agents with diverse mechanisms of action, RA is not well controlled in up to 30% of 
patients (Koenders and van den Berg 2015).  Therefore, the need for additional treatment 
approaches remains.
LY3337641 (chemical name, 2-propenamide, N-[3-[[2-[[4-(4-methyl-1-
piperazinyl)phenyl]amino]furo[3,2-d]pyrimidin-4-yl]oxy]phenyl]) is an orally available,
irreversible inhibitor of Bruton’s tyrosine kinase (BTK), a member of the TEC family of 
cytoplasmic tyrosine kinases.  BTK is a key signaling molecule in the B-cell–receptor and 
Fc-receptor pathways and an essential mediator of B-cell– and myeloid-cell–dependent 
inflammatory arthritis (Di Paolo et al. 2011; Chakravarty et al. 2013). 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 (Ig) levels (Aalipour and Advani 2014).  
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 (Horwood et 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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A single Phase 1 study (Study 12-HM71224-101, subsequently referred to as 
Study I8K-MC-JPDD [JPDD]) was conducted in healthy adult males to determine the safety, 
tolerability, pharmacokinetics (PK), and food effect of single and multiple doses of orally 
administered LY3337641. In the single-dose portion of the study, the drug was well tolerated.  
In the multiple-dosing portion of the study during which subjects were dosed for 14 days, the 
drug was generally well tolerated at dosages up to 40 mg once daily (qd) (inclusive).  At dosages 
totaling 80 mg per day and higher, significant treatment-emergent adverse events (TEAEs) (ie, 
TEAEs leading to discontinuation or deemed significant by the investigator) were reported. The 
majority of these events involved skin-related manifestations, the most common being rash. 
Some cases were associated with systemic signs and symptoms, such as fever, arthritis, and 
laboratory abnormalities.  The highest dosage in Study I8K-MC-JPDA (JPDA) is 30 mg qd, 
which is below the doses at which skin rashes or significant TEAEs were reported in 
Study JPDD.  On the basis of projected BTK occupancy using the Phase 1 data, the 5- to 30-mg 
qd dosages are predicted to result in mean BTK occupancy of approximately 70% to 90% 
(Section 4.4).  LY3337641 was rapidly absorbed after oral administration, and plasma 
elimination was rapid; the geometric mean half-life was 4.6 to 6.6 hours. Administering 
LY3337641 with food did not affect the extent of oral absorption but resulted in a slight delay in 
absorption and a slightly lower maximal observed plasma concentration (Cmax) in humans.
The results from nonclinical studies with LY3337641 and the Phase 1 safety profile support 
further clinical development of the drug substance for treatment of autoimmune diseases, 
including RA.  
2.2.
Study Rationale
Study JPDA is a 2-part Phase 2 study designed to determine whether oral qd dosing of 
LY3337641 is safe and efficacious in subjects with RA.  Findings from the study will be used to 
assess the safety, efficacy, and tolerability of LY3337641 in this study population, further 
characterize the PK properties, and explore the pharmacodynamic (PD) effects of BTK 
inhibition.  Such findings will afford a greater understanding of the benefit/risk relationship for 
LY3337641 and inform the design of future studies.

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3. Objectives and Endpoints
Table JPDA.1 shows the objectives and endpoints for Part A of the study.  Table JPDA.2 shows 
the objectives and endpoints for Part B of the study.
Table JPDA.1.
Objectives and Endpoints for Part A
Objectives
Endpoints
Primary

to evaluate the safety and tolerability of 
LY3337641 at 5, 10, and 30 mg qd in subjects 
with RA

The safety endpoints evaluated will include but 
are not limited to the following:
o
TEAEs, AESIs, SAEs
o
clinical laboratory tests, vital signs, 
physical examinations
Exploratory

to explore the effects of treatment with 
LY3337641 at 5, 10, and 30 mg qd on RA 
clinical endpoints over the course of the study

proportions of subjects achieving ACR20

hybrid ACR

change from baseline in DAS28-hsCRP

change from baseline in the individual 
components of the ACR core set

to explore the effect of treatment with 
LY3337641 at 5, 10, and 30 mg qd on morning 
joint stiffness duration

change from baseline in morning joint stiffness 
duration 

to characterize the dose-response and 
exposure-response relationships of LY3337641 
for efficacy measures and PD effects

model parameters (eg, slope) for the dose-
response and exposure-response relationships 
for efficacy measures and PD effects

to identify the plasma metabolites of 
LY3337641

qualitative identification of the circulating 
metabolites of LY3337641 after oral 
administration
Abbreviations:  ACR = American College of Rheumatology; ACR20 = at least 20% improvement in the ACR 
criteria; AESIs = adverse events of special interest; DAS28 = Disease Activity Score modified to include the 
28 diarthrodial joint count; hsCRP = high-sensitivity C-reactive protein; PD = pharmacodynamic; qd = once 
daily; RA = rheumatoid arthritis; SAEs = serious adverse events; TEAEs = treatment-emergent adverse events.

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Table JPDA.2.
Objectives and Endpoints for Part B
Objectives
Endpoints
Primary

to evaluate the efficacy, safety, and tolerability 
of LY3337641 at 5, 10, and 30 mg qd versus 
placebo at Week 12 for the treatment of 
subjects with moderately to severely active RA

proportion of subjects who achieve ACR20 

The safety endpoints evaluated will include but 
are not limited to the following:
o
TEAEs, AESIs, SAEs
o
clinical laboratory tests, vital signs, 
physical examinations
Secondary

to evaluate the efficacy of LY3337641 at 
5, 10, and 30 mg qd versus placebo at Week 12 
on RA clinical endpoints

proportions of subjects achieving ACR50 and 
ACR70 

change from baseline in the DAS28-hsCRP

proportion of subjects achieving LDA based on 
DAS28-hsCRP 

proportion of subjects achieving clinical 
remission based on DAS28-hsCRP

to characterize the PK of LY3337641 in 
subjects with RA

population PK model estimate of clearance
Tertiary/Exploratory

to evaluate the efficacy of treatment with 
LY3337641 at 5, 10, and 30 mg qd versus 
placebo on RA clinical endpoints over the 
course of the study

proportions of subjects achieving ACR20, 
ACR50, ACR70, and ACR90 

ACR-N, hybrid ACR

change from baseline in DAS28-hsCRP

proportion of subjects achieving clinical 
remission based on DAS28-hsCRP

proportion of subjects achieving LDA based on 
DAS28-hsCRP 

change from baseline in the individual 
components of the ACR core set 

to assess the effect of treatment with 
LY3337641 at 5, 10, and 30 mg qd versus 
placebo on other patient-reported outcomes 
over the course of the study

change from baseline in morning joint stiffness 
duration 

change from baseline in patient’s assessment of 
sexual function (VAS)

change from baseline in SF-36 Physical 
Component Score and Mental Component 
Score

change from baseline in FACIT-F score

to evaluate the effect of treatment with 
LY3337641 at 5, 10, and 30 mg qd versus 
placebo on PD measures and biomarkers over 
the course of the study

percentage of BTK occupancy 

change from baseline in phosphorylated BTK 

change from baseline in T-cell and B-cell 
subsets

to characterize the dose-response and 
exposure-response relationships of LY3337641 
for efficacy measures and PD effects

model parameters (eg, slope) for the 
dose-response and exposure-response 
relationships for efficacy measures and PD 
effects

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LY3337641
Objectives
Endpoints

to evaluate the effect of treatment with 
LY3337641 on autoantibody formation at 
Week 12 in subjects whose test results are 
positive for these antibodies at baseline and to 
characterize the relationship between baseline 
status and clinical response

change from baseline in rheumatoid factor

change from baseline in ACPA

association (if any) between baseline status for 
these antibodies (positive or negative) and 
clinical response
Abbreviations:  ACPA = anti-citrullinated peptide antibodies; ACR = American College of Rheumatology; 
ACR20 = at least 20% improvement in the ACR criteria; ACR50 = at least 50% improvement in the ACR 
criteria; ACR70 = at least 70% improvement in the ACR criteria; ACR90 = at least 90% improvement in the 
ACR criteria; ACR-N = continuous measure of percentage of improvement from baseline in the ACR criteria; 
AESI = adverse event of special interest; BTK = Bruton’s tyrosine kinase; DAS28 = Disease Activity Score 
modified to include the 28 diarthrodial joint count; FACIT-F = Functional Assessment of Chronic Illness 
Therapy–Fatigue; hsCRP = high-sensitivity C-reactive protein; LDA = low disease activity; 
PD = pharmacodynamic; PK = pharmacokinetics; qd = once daily; RA = rheumatoid arthritis; SAE = serious 
adverse event; SF-36 = Medical Outcomes Study 36-Item Short Form Health Survey; 
TEAE = treatment-emergent adverse event; VAS = visual analog scale.

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4.
Study Design
4.1.
Overview of Study Design
Study JPDA is a multicenter, randomized, double-blind, placebo-controlled, 2-part Phase 2 trial 
in adult subjects with RA.  Part A will enroll subjects with at least mildly active RA.  Part B will 
enroll subjects with moderately to severely active RA who have had an inadequate response, loss 
of response, or intolerance to at least 1 synthetic or biologic DMARD treatment for RA.  In 
Part B only, the percentage of subjects who are naive to biologic DMARDs will be limited to 
approximately 25% of the study population.
In Part A, after a screening period of up to 28 days, subjects will be randomly assigned in a 
1:1:1:1 ratio to receive oral dosages of LY3337641 at 5, 10, or 30 mg qd or placebo for 4 weeks.  
At Week 6, there will be a safety follow-up visit for Part A.  An internal Assessment Committee 
will conduct an unblinded interim analysis of safety data at least 2 weeks after all subjects have 
had their last dose, and will provide a recommendation to the study team whether or not to 
proceed to Part B.  If a decision to proceed with the study is made, Part B will start enrolling new 
subjects who did not participate in Part A (see details in Section 8.4.7).  In Part B, after a 
screening period of up to 28 days, subjects will be randomly assigned in a 1:1:1:1 ratio to receive 
the planned oral dosages of LY3337641 of 5, 10, or 30 mg qd or placebo for 12 weeks.  The 
primary efficacy endpoint of the study will be assessed at the Week 12 visit in Part B.  At 
Week 14, there will be a safety follow-up visit for Part B (see Figure JPDA.1).

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4.2.
End of Trial Definition
The end of the trial is the date of the last visit or last scheduled procedure shown in the Schedule 
of Activities for the last subject.
4.3.
Scientific Rationale for Study Design
Study JPDA is the first clinical trial evaluating the safety and efficacy of LY3337641 in subjects 
with RA.  The trial is conducted in 2 parts.  Part A will enroll subjects with at least mildly active 
RA to be dosed for 4 weeks. Findings from Part A will provide additional understanding of the 
safety and tolerability of LY3337641 in subjects with RA prior to testing a longer-term dosing 
period in Part B.  Three active dose levels of LY3337641 will allow an evaluation of safety and 
tolerability across a broad dose range.  An unblinded interim analysis of safety data will take 
place at least 2 weeks after all subjects have had their last dose.  All interim analyses for the 
study (both Parts A and B) will be reviewed by an Assessment Committee comprised of 
members who are external to the JPDA study team to minimize operational and statistical bias.  
If the decision is made to proceed with Part B after reviewing the Assessment Committee 
recommendation, Part B will initiate with enrollment.  As the primary objective of Part B is to 
test the efficacy of LY3337641, in addition to safety and tolerability, a moderately to severely 
active RA patient population was deemed most appropriate to understand the effect of 
LY3337641 on clinical disease activity.  As this is the initial study evaluating the efficacy of 
LY3337641 in RA, subjects in Part B must have demonstrated an inadequate response, loss of 
response, or intolerance to a synthetic or biologic DMARD therapy to participate in the study.  
Three active doses of LY3337641 are planned for Part B to assess efficacy across a broad dose 
range. The American College of Rheumatology (ACR) 20% response rate (ACR20) is the 
proportion of patients who achieve at least a 20% improvement in a core set of measures that 
include patient-reported assessments, physician assessments, and an acute-phase reactant.  It is 
widely used in RA clinical trials, continues to be an accepted measure to demonstrate reduction 
in RA disease activity (FDA 2013), and is an appropriate primary outcome measure for an early 
phase proof-of-concept study.  A double-blind placebo-controlled design limits bias for both 
patient and investigator assessments. 
In addition to the ongoing safety monitoring of subjects by the study team, the Assessment 
Committee will review unblinded safety data at planned intervals during the study, as well as 
unplanned requests based on emerging data, to ensure subject safety.
4.4.
Justification for Dose 
The LY3337641 dosage range of 5 to 30 mg qd administered orally is based on nonclinical 
toxicology data, clinical safety data from the Phase 1 study, as well as the effective BTK 
occupancies projected on the basis of both the Phase 1 clinical data and the nonclinical results.  
The maximum dose of 30 mg qd provides >1-fold exposure multiple (margin of safety) based on 
area under the curve (AUC) in 2 species (rat and monkey) at the NOAEL in the 13-week 
nonclinical toxicology studies (see Section 5.2.1 of the Investigator’s Brochure [IB]).  This dose 
is also below the highest dosage tested in the Phase 1 study (40 mg qd) at which there were no 

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skin rashes or significant TEAEs (that is, TEAEs leading to discontinuation or deemed 
significant by the investigator).  
In a rat collagen-induced arthritis model, BTK occupancy of approximately 80% was sufficient 
to achieve efficacy.  On the basis of Phase 1 BTK occupancy data in humans, 30 mg qd is 
expected to achieve BTK occupancy of approximately 90%.  The 5- and 10-mg qd dosages are 
projected to achieve BTK occupancy of approximately 70% and 80%, respectively. Thus, this 
study will test dosages that were well tolerated in the Phase 1 study and are projected to achieve 
BTK occupancies that are expected to be efficacious.
4.5.
Benefit/Risk Assessment
There are currently no human data regarding the efficacy of LY3337641 in RA.  Nonclinical data
and safety data in Phase 1 support further development of LY3337641 in RA at the proposed
doses. 
The safety profile for LY3337641 has been informed by the results from nonclinical toxicology 
and safety pharmacology studies and the Phase 1 clinical study (JPDD).  The primary toxicity 
observed in animal studies was gastrointestinal tract injury.  Pancreatic and immune system 
effects were also observed (see Section 5.2.1 of the IB).  In humans, the drug was generally well 
tolerated at dosages up to 40 mg per day.  At total daily dosages of 80 mg and higher in the 
multiple dose portion of the study, significant TEAEs were reported in some subjects.  The 
majority involved skin manifestations, the most common being skin rash. Associated signs and 
symptoms ranged from pruritus to systemic features such as fever and elevated levels of acute 
phase reactants. The highest dosage in Study JPDA is 30 mg qd, which is below the doses at 
which skin rashes or significant TEAEs were reported in Study JPDD. However, adverse events 
(AEs) of skin rash will be monitored over the course of the study by the medical monitor using 
blinded data.  In addition, skin rash will be monitored by an Assessment Committee using 
unblinded data.  The Assessment Committee members will be independent from the Lilly study 
team (Section 8.4.7).
More information about the known and expected benefits, risks, serious adverse events (SAEs), 
and reasonably anticipated AEs of LY3337641 can be found in the IB.

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5. Study Population
Part A will include subjects with at least mildly active RA.  Part B will include subjects with 
moderately to severely active RA who have had an inadequate response, loss of response, or 
intolerance to at least 1 DMARD therapy (synthetic and/or biologic).  In Part B only, the 
percentage of subjects who are naive to biologic DMARDs will be limited to approximately 25% 
of the study population; the remaining subjects in Part B will have had previous exposure to 
biologic DMARDs.  Subjects participating in Part A will not be eligible to participate in Part B.
Subjects must give written informed consent (approved by Lilly or its designee and the ethical 
review board [ERB] governing the site) before being allowed to participate in the study and 
before any screening assessments are performed.  
Study investigator(s) will review the subject’s records and/or history and screening test 
results/measurements to determine if the subject meets all inclusion and no exclusion criteria to 
qualify for participation in the study.  All screening activities must be completed and reviewed 
before the subject is randomly assigned to study drug.
Prospective approval of protocol deviations to recruitment and enrollment criteria, also known as 
protocol waivers or exemptions, are not permitted.  
5.1.
Inclusion Criteria
Subjects are eligible to be included in the study only if they meet all of the following criteria:
[1]
are male or female between the ages of 18 and 65 years (inclusive) at the time 
of initial screening and are able and willing to provide written informed 
consent as a legal adult according to local regulations
[2]
female subjects of childbearing potential:  test negative for pregnancy at 
screening and agree not to breastfeed from the start of screening until 2 weeks 
after the last dose of study drug
[3]
female subjects:  agree to use a reliable method of birth control (eg, 
intrauterine contraceptive devices, hormonal contraceptives, or complete 
abstinence from sexual intercourse with men) from the start of screening until 
28 days after the last dose of study drug or be classified as female subjects of 
nonchildbearing potential, defined as meeting at least 1 of the following 
criteria:  

are postmenopausal with spontaneous amenorrhea for at least 12 months and have 
a follicle-stimulating hormone level >40 mIU/mL (>40 IU/L) at screening

have undergone bilateral tubal ligation, bilateral oophorectomy, and/or 
hysterectomy at least 6 weeks prior to screening

have another medical cause of female infertility that has been discussed with and 
accepted in writing by the sponsor

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[4]
male subjects:  agree to use a reliable method of birth control from the start of 
screening until 2 weeks after the last dose of study drug (eg, barrier 
contraceptives, such as latex condoms, or complete abstinence from sexual 
intercourse with women) or have undergone vasectomy at least 6 weeks prior 
to screening with documentation of sperm-free ejaculate
[5]
have a diagnosis of RA based on the 2010 ACR/European League against 
Rheumatism criteria (Aletaha et al. 2010) for at least 6 months prior to 
screening.
[6]
have at least 1 of the following:

positive test results for rheumatoid factor or anti-citrullinated peptide antibodies 
(ACPA) at screening 
OR

previous radiographs documenting bony erosions in hands or feet consistent with 
RA
[7]
have active RA, defined as meeting all of the following criteria at screening:
Part A:  ≥3 swollen joints (based on 66-joint counts) 
Part B:  

≥6 swollen joints (based on 66-joint counts) 

≥6 tender joints (based on 68-joint counts)

high-sensitivity C-reactive protein (hsCRP) levels greater than the upper limit of 
normal (ULN) OR positive test results for ACPA
[8]
Part B only:  have had inadequate response, loss of response, or intolerance 
to at least 1 synthetic or biologic DMARD treatment for RA, regardless of 
treatment duration
[9]
have venous access sufficient to allow blood sampling per protocol
[10] are reliable, willing, and able to follow study procedures (in the opinion of the 
investigator) and will be available for the duration of the study
5.2.
Exclusion Criteria
Subjects will be excluded from study enrollment if they meet any of the following criteria:
[11] have previously completed or withdrawn from any part of this study (does not 
apply to subjects who are allowed to rescreen prior to randomization)
[12] have received any of the following synthetic immunosuppressive therapies 
under the defined conditions:

methotrexate (MTX), hydroxychloroquine, sulfasalazine, or leflunomide at an 
UNSTABLE PRESCRIBED DOSE (defined as a change in prescription) within 
28 days prior to baseline or planned dose change (including initiation or 

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discontinuation) during the study.  The following therapies are permitted during 
the study:
o
parenteral MTX up to 20 mg/week OR oral MTX up to 25 mg/week
(subjects on MTX should receive supplementation with folic acid 
according to local standard of care)
o
hydroxychloroquine up to 400 mg/day
o
oral sulfasalazine up to 3000 mg/day
o
leflunomide up to 20 mg/day

concomitant treatment with MTX plus leflunomide within 28 days prior to 
baseline or planned concomitant treatment with both during the study

gold salts, kinase inhibitors (such as tofacitinib), cyclophosphamide, 
mycophenolic acid, azathioprine, cyclosporine, sirolimus, or tacrolimus within 
28 days prior to screening or planned treatment during the study

Part B only:  any prior treatment with a product directly targeting BTK 
(marketed or investigational) 
[13] have received any of the following biologic immunosuppressive therapies 
under the defined conditions or plan any such treatments during the study 
(other biologic agents may be allowed after discussion with the sponsor and 
upon agreement in writing):

etanercept, adalimumab, or anakinra within 14 days prior to baseline

infliximab, certolizumab pegol, golimumab, abatacept, or tocilizumab within 
4 weeks prior to baseline

belimumab, natalizumab, or vedolizumab within 6 months prior to baseline

Part A only:  B-cell–depleting agents (such as rituximab) or other cell-depleting 
biologics (eg, anti-CD3 antibody) within 12 months prior to screening

Part B only: B-cell–depleting agents (such as rituximab) or other cell-depleting 
biologics (eg, anti-CD3 antibody) at any time prior to screening
[14] have received any of the following other types of therapies under the defined 
conditions:

parenteral corticosteroids within 28 days prior to baseline or planned treatment 
during the study.  (A single intra-articular corticosteroid injection is permitted 
within 28 days prior to baseline if no more than 40 mg triamcinolone [or 
equivalent] is administered and no further injections are planned during the study.  
The treated joint should be excluded from any joint-specific evaluations during 
the study.)

prescription for oral prednisone (or equivalent) >10 mg/day or UNSTABLE 
PRESCRIBED DOSE within 28 days prior to baseline

a chronic narcotic drug at an UNSTABLE PRESCRIBED DOSE within 28 days 
prior to baseline or planned increase/new prescription during the study

gemfibrozil (a strong cytochrome P450 2C8 inhibitor) or alfentanil, 
dihydroergotamine, dofetilide, ergotamine, fentanyl, pimozide, or quinidine 

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(sensitive narrow therapeutic index cytochrome P450 3A substrates) within 
28 days prior to baseline or planned treatment during the study
[15] have any clinically significant hematological or chemistry abnormalities at 
screening, including

hemoglobin level <8.5 g/dL (<85 g/L)

total platelet count <100 × 109/L (<100 × 103/µL or <100 Gi/L)

total white blood cell count <3.0 × 109/L (<3.0 × 103/µL or <3.0 Gi/L)

aspartate aminotransferase (AST) level >2.5 × ULN 

alanine aminotransferase (ALT) level >2.5 × ULN

creatinine level ≥1.5 mg/dL (≥129 μmol/L)

amylase >1.5 x ULN

lipase >1.5 x ULN
A single repeat analysis is allowed according to investigator judgment prior to 
making a final determination of eligibility.  The repeat laboratory test does not 
require a reconsent because the result does not constitute a screening failure
until the clinically significant, out-of-range value is confirmed.
[16] have known hypogammaglobulinemia or a screening serum IgG level 
<565 mg/dL (<5.65 g/L)
A single repeat analysis is allowed according to investigator judgment prior to 
making a final determination of eligibility.  The repeat laboratory test does not 
require a reconsent because the result does not constitute a screening failure
until the clinically significant out-of-range value is confirmed.
[17] have evidence of or test positive for hepatitis C virus (HCV) at screening 
(defined as a positive test result for hepatitis C antibody [anti-HCVAb] plus a
positive confirmatory test result for HCV [eg, HCV RNA])
Subjects whose results are anti-HCVAb positive and HCV RNA negative can 
be enrolled in the study, according to investigator judgment.
[18] have evidence of or test positive for hepatitis B virus (HBV) at screening,
defined as (1) testing positive for hepatitis B surface antigen OR (2) testing 
positive for anti–hepatitis B core antibody (HBcAb) AND positive for HBV 
DNA
Subjects whose results are HBcAb positive and HBV DNA negative may be 
enrolled in the study, according to investigator judgment.  Subjects whose 
results are HBcAb positive and HBV DNA negative at screening will be 
monitored for HBV during the study as detailed in Section 8.4.7.1.
[19] have evidence of or test positive for human immunodeficiency virus at 
screening
[20] have symptomatic herpes zoster within 6 months prior to screening that 
constitutes a clinically significant risk to the subject (according to investigator 
judgment)

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[21] have active tuberculosis (TB) determined on the basis of a positive medical 
history, physical examination, or chest radiography (per local standard of 
care) or have exclusionary TB test results, which include either of the 
following:

a positive tuberculin skin test (TST) result (defined as a skin induration >5 mm at 
48 to 72 hours after the test date, regardless of Bacillus Calmette-Guérin
vaccination history) or 

a positive (or persistently indeterminate/invalid/borderline) interferon release 
test (eg, QuantiFERON®-TB Gold or T-Spot®.TB)  
The choice to perform either a TST or an interferon release test will be made 
by the investigator according to local licensing and standard of care. If the 
QuantiFERON-TB Gold is indeterminate or the T-Spot.TB is invalid or 
borderline, one retest is allowed according to investigator judgment.  If the 
repeat test is also indeterminate, the subject will be excluded.  The interferon 
release test can be used only in countries where it is licensed, and the use of 
this test is dependent on previous treatment(s).  
Subjects with known latent TB should not undergo a TST or interferon 
release test and must have documentation of receiving at least 4 weeks of 
appropriate, ongoing latent TB therapy, according to local standard of care, 
prior to screening.  Such patients must continue/complete appropriate latent 
TB therapy during the course of the study in order to remain eligible.
[22] are at high risk of infection or have recent evidence of clinically significant 
infection, based on findings that include the following:

fever of 100.5ºF (38ºC) or above at screening or baseline that is not due to the 
underlying autoimmune disease (eg, RA)

history of serious opportunistic or chronic/recurring infection(s) within 6 months 
prior to screening (such as infections requiring IV antibiotics, hospitalization, or 
prolonged treatment) or deemed by the investigator to be immune compromised, 
such that participation in the study would pose an unacceptable risk to the subject

have a predisposed high risk of infection or risk of serious complications from 
infection, such as a history of infected joint or heart valve prosthesis (with 
prosthesis still in situ), an indwelling urinary catheter, etc.
[23] have had lymphoma, leukemia, or any malignancy within the previous 5 years 
except for basal cell or squamous epithelial carcinomas of the skin that have 
been resected with no evidence of recurrence or metastatic disease
[24] have a concomitant autoimmune or connective tissue disease at screening that 
is deemed active enough to interfere with the subject’s safety or with 
evaluation of RA disease activity, in the opinion of the investigator

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[25] have a bleeding disorder, anti-phospholipid antibody syndrome or other 
hypercoagulable disorder, are on chronic anticoagulation therapy such as 
warfarin or heparin, or are on an antiplatelet agent such as clopidogrel or 
ticlopidine (a stable regimen of aspirin is permitted)
[26] have a history of acute or chronic pancreatitis of any etiology, or severely 
uncontrolled hypertriglyceridemia, in the opinion of the investigator
[27] have had any surgical procedure (except for minor surgery requiring only 
local or no anesthesia and without any complications or sequelae) within 
12 weeks prior to screening or have any planned surgical procedure scheduled 
to occur during the study
[28] have a history of clinically significant multiple or severe drug allergies or a 
history of severe posttreatment hypersensitivity reactions (including, but not 
limited to, erythema multiforme major, linear IgA dermatosis, toxic epidermal 
necrolysis, or exfoliative dermatitis)
[29] have clinically significant or uncontrolled cardiovascular disease (eg,
hypertension, angina, or congestive heart failure); endocrine disorder (eg, 
diabetes, thyroid dysfunction); or respiratory, hepatic, renal, gastrointestinal, 
hematologic, or neuropsychiatric disorder, including recent history of suicide 
attempt
[30] have any other clinically significant condition, abnormality, or finding that 
may compromise the subject’s safety or confound data analysis, according to
investigator judgment
[31] have received a live (attenuated) vaccine within 28 days prior to baseline or 
plan to receive one during the study
[32] are currently enrolled in any other clinical trial involving an investigational 
product (IP) or any other type of medical research judged not to be 
scientifically or medically compatible with this study or have received any of 
the following IPs under the defined conditions:

any nonbiologic IP within 5 half-lives prior to baseline

any leukocyte-depleting agent (eg, anti-CD22 or anti-CD3) at any time

any non–cell depleting biologic IP within 90 days or 5 drug half-lives (whichever 
is longer) prior to screening 
[33] have donated more than 500 mL of blood within 28 days of screening or plan 
to donate blood during the study
[34] have a history of significant alcohol or drug abuse or are currently a heavy 
smoker, in the opinion of the investigator
[35] are investigator site personnel directly affiliated with this study and/or their 
immediate families (defined as a spouse, parent, child, or sibling, whether 
biological or legally adopted)

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[36] are Lilly employees or are employees of third-party organizations involved in 
the study
5.3.
Screen Failures
Individuals who do not meet the criteria for participation in this study (screen failure) may be 
rescreened ONE time in selected situations upon written approval from the sponsor (eg, if they 
failed to meet minimum disease activity criteria defined in Inclusion Criterion [7] at initial 
screening, required more time for appropriate drug washout periods, tested positive for latent TB 
and subsequently completed at least 4 weeks of appropriate prophylactic treatment, or had a 
fever (Exclusion Criterion [22]) that resolved, did not require IV antibiotics or hospitalization, 
and did not pose a risk to the subject for participation in the study, according to investigator 
judgment).  Subjects who failed screening in Part A may be rescreened for either Part A or 
Part B; however, only ONE rescreen is permitted regardless of which part the subject is 
rescreening for.
Subjects who fail screening because of administrative reasons (eg, fall out of the screening 
window because of scheduling reasons) may be rescreened ONE time (in addition to the above) 
upon written approval from the sponsor.  
If rescreening is performed, the individual must sign a new informed consent form (ICF) for each 
rescreening and will be assigned a new identification number.  Subjects in rescreening who have 
previously completed screening chest radiography and/or TB tests according to the protocol do 
not need to repeat these procedures if they were performed within 90 days before their 
rescreening date of consent but may do so at the discretion of the investigator.
5.4.
Lifestyle and/or Dietary Requirements
Strenuous exercise should be avoided for at least 24 hours before study visits.
Subjects should continue their usual dietary intake during the study.

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6. Treatment
6.1.
Treatments Administered
This study involves a comparison of each LY3337641 dosing regimen (5, 10, and 30 mg 
administered orally qd) with placebo.  The study drug is supplied as tablets containing 5 and 
20 mg of LY3337641 with matching placebo tablets. A single dose in Part A will include 
4 tablets in various combinations depending on the assigned regimen.  Table JPDA.3 shows the 
combinations of tablets used for the 4 dosing regimens.  A single dose in Part B will include 
4 tablets in various combinations depending on the assigned regimen.  Table JPDA.4 shows the 
combinations of tablets used for the 4 dosing regimens.  More information on the tablets and 
blinded regimens can be found in Section 6.4.
Table JPDA.3.
Dosing Regimens – Part A
Regimena
20-mg Tablets
5-mg Tablets
LY 30 mg
1 20-mg LY tablet
1 20-mg matching placebo tablet
2 5-mg LY tablets
LY 10 mg
2 20-mg matching placebo tablets
2 5-mg LY tablets
LY 5 mg
2 20-mg matching placebo tablets
1 5-mg LY tablet plus
1 5-mg matching placebo tablet
Placebo Comparator
2 20-mg matching placebo tablets
2 5-mg matching placebo tablets
Abbreviation:  LY = LY3337641.
a
Each dose consists of 4 tablets taken orally once daily (qd).  The 5- and 20-mg placebo tablets match the 
respective 5- and 20-mg LY tablets.
Table JPDA.4.
Dosing Regimens – Part B
Regimena
20-mg Tablets
5-mg Tablets
LY 30 mg
1 20-mg LY tablet
2 5-mg LY tablets
1 5-mg matching placebo tablet
LY 10 mg
1 20-mg matching placebo tablet
2 5-mg LY tablets
1 5-mg matching placebo tablet
LY 5 mg
1 20-mg matching placebo tablet
1 5-mg LY tablet
2 5-mg matching placebo tablet
Placebo Comparator
1 20-mg matching placebo tablet
3 5-mg matching placebo tablets
Abbreviation:  LY = LY3337641.
a
Each dose consists of 4 tablets taken orally once daily (qd).  The 5- and 20-mg placebo tablets match the 
respective 5- and 20-mg LY tablets.  Four (4) tablets are required to provide for intermediate doses in the event 
of dose modification as defined in Section 6.6.
The investigator or his/her designee is responsible for the following:

explaining the correct use of the study drug to the subject

verifying that instructions are followed properly

maintaining accurate records of study drug dispensing and collection

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
returning all unused medication to Lilly, or its designee, at the end of the study,
unless the sponsor and sites have agreed that all unused medication is to be 
destroyed by the site, as allowed by local law
6.2.
Method of Treatment Assignment
For Part A, subjects who meet all criteria for enrollment will be randomly assigned in a 
1:1:1:1 ratio to 1 of the 4 study arms at Visit 2 in a double-blind fashion.  For Part B, subjects 
who meet all criteria for enrollment will be randomly assigned in a 1:1:1:1 ratio to 1 of the 
4 study arms at Visit 102 in a double-blind fashion.  Assignment to treatment groups will be 
determined by a computer-generated random sequence using an interactive web-response system
(IWRS).  The IWRS will be used to assign packages containing double-blind study drug to each 
subject.  Site personnel will confirm that they have located the correct packages by entering a 
confirmation number found on the package label into the IWRS.
To achieve between-group comparability in Part B, randomization will be stratified by biologic 
DMARD experience (yes/no), region (Japan vs non-Japan), and disease severity (Disease 
Activity Score modified to include the 28 diarthrodial joint count [DAS28]-hsCRP 5.1 vs 5.1).  
The screening value for hsCRP will be used to calculate DAS28-hsCRP (Section 8.1.2.2) for 
randomization.
6.2.1. Selection and Timing of Doses
Subjects will be randomly assigned to the dosing regimens as described in Section 6.2, and the 
assigned study drug will be administered as described in Section 6.1.  Subjects will be instructed 
to take doses at approximately the same time each day.  Study drug may be taken with or without 
food.  The time of dose administration before a scheduled PK sampling should be recorded by 
the site at the clinic visit.
6.3.
Blinding
This is a double-blind study; investigators, subjects, and study site personnel will be blinded to 
assigned dosing regimens throughout the study.  
To preserve the blinding of the study, a minimum number of Lilly personnel will see the 
randomization table and treatment assignments before the study is complete (Section 8.4.7).
Emergency unblinding for AEs may be performed through the IWRS.  This option may be used 
ONLY if the subject’s well-being requires knowledge of the subject’s treatment assignment.  All 
transactions resulting in an unblinding event are recorded and reported by the IWRS.
If an investigator, the site personnel performing assessments, or a subject is unblinded, the 
subject must be discontinued from the study.  In cases where there are ethical reasons to have the 
subject remain in the study, the investigator must obtain written approval from Lilly or its 
designee for the subject 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.  Subject safety must always be the first 

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consideration in making such a determination.  If the investigator decides that unblinding is 
warranted, the investigator should make every effort to contact the Lilly medical monitor prior to 
unblinding a subject’s treatment assignment.  If a subject’s treatment assignment is unblinded, 
Lilly or its designee must be notified immediately.
6.4.
Packaging and Labeling
The study drug 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.
The study drug will be supplied as tablets containing 5 and 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.  To maintain blinding in Part A, individual doses will include 4 tablets:  2 from the 
5-mg LY3337641/5-mg matched placebo set and 2 from the 20-mg LY3337641/20-mg matched 
placebo set, corresponding to the specific dose (see Table JPDA.3 for a listing of the various 
combinations for each of the 3 doses and placebo).  For Part B, individual doses will include 
4 tablets:  3 from either the 5-mg LY3337641/5-mg matched placebo set and 1 of the 20-mg 
LY3337641/20-mg matched placebo (see Table JPDA.4 for a listing of the various combinations 
for each of the 3 doses and placebo).  Thus, there should be no distinguishable differences 
between doses.  Subjects will be given a sufficient number of tablets to supply the required doses 
and maintain blinding for the duration of the visit interval (Schedule of Activities, Appendix 2).  
6.5.
Preparation/Handling/Storage
The study drug should be stored within the temperature range specified on the product label.  
The study drug should not be removed from the original packaging until the time that each dose 
is taken.  All clinical trial materials will be stored, inventoried, and reconciled according to 
applicable regulations.
6.6.
Dose Modification
Dose adjustments for individual subjects are not planned for this study.  
However, during the course of the study, the dose for a study arm may be lowered for safety 
reasons.  The Assessment Committee may review unblinded safety data throughout the study 
(Section 8.4.7) to assess the incidence and nature of significant AEs (including adverse events of 
special interest [AESIs, Section 8.2.2]).  
On the basis of emerging safety information, the Assessment Committee will determine whether 
any LY3337641 dose level(s) should be reduced in order to maintain continued subject safety.  
Reduction of LY3337641 dose level(s) in this study will not require a protocol amendment, but 
all sites will be notified in writing. For example, if subjects in a 30-mg arm report any AEs that 
prompt the Assessment Committee to endorse a dose reduction for all subjects in that arm, the 
committee may select a lower dose reassignment, based on the nature and clinical course of the 

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reported AE.  In this example, if a 10-mg dose reassignment is selected, all active subjects in the 
30-mg arm will exchange their study drug supply for new study drug in a blinded fashion and 
continue dosing at the reduced dose; any new subjects randomly assigned to the 30-mg dose arm 
will receive only the reduced dose during their study participation.  Subjects in the 5-mg, 10-mg,
or placebo arm will continue at their current doses but will also participate in the study drug
exchange in order to maintain the study blind for all subjects; this exchange will be carried out 
for all subjects using the IWRS.  
If the Assessment Committee determines that it is appropriate to reduce the dose below 5 mg qd, 
the dose and/or frequency of administration for ALL subjects on LY3337641 (whether randomly 
assigned to a 30-, 10-, or 5-mg arm) will be reduced. As above, all active subjects in the study 
(including those receiving placebo tablets) will participate in the study drug exchange in order to 
maintain the study blind.  
If the Assessment Committee decides to reduce any study arm dose of LY3337641, a return to 
the original dose will not be permitted in any part of the study.  However, doses may be adjusted 
to levels that are intermediate to the dose levels planned, as long as they are lower than doses 
that have been discontinued for safety reasons.  
Replacement of subjects: If the study drug dose is reduced and results in an insufficient number 
of subjects (per dose) completing either Part A or B to allow assessment of the primary endpoint, 
the sponsor might choose to replace study subjects by increasing enrollment.  If this occurs, all 
sites will be notified in writing.
6.7.
Treatment Compliance
Subject compliance with study medication will be assessed at each visit.  Compliance will be 
assessed by counting returned tablets of study drug.  Deviation(s) from the prescribed dosage 
regimen should be recorded in the electronic case report form (eCRF).
A subject will be considered significantly noncompliant if he or she misses more than 20% of the 
prescribed doses during the study.  Similarly, a subject will be considered significantly 
noncompliant if he or she is judged by the investigator to have intentionally or repeatedly taken 
more than the prescribed amount of medication.  Subjects found to be noncompliant with the 
study drug should be assessed to determine the reason for noncompliance and educated and/or 
managed as deemed appropriate by the investigator to improve compliance, or they should be 
discontinued from the study.
6.8.
Concomitant Therapy
Allowed and excluded medications and procedures will be provided in the Listing of Excluded 
and Restricted Medications tool.  
Subjects on concurrent, protocol-permitted RA treatments should remain on stable doses during 
the course of the study.  
Subjects taking other concomitant medications should be on stable doses at baseline and should 
remain at stable doses throughout the study to the extent possible, unless changes are needed for 

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treatment of an AE.  The introduction of any other new prescription or over-the-counter drugs is 
to be avoided during the study unless required to treat an AE.  Any medication used during the 
course of the study must be documented.
6.9.
Treatment after Study Completion
Study drug is experimental and will be provided to study subjects only according to the protocol; 
it will not be made available to subjects after they have completed or discontinued from the study 
unless the subject qualifies to continue study drug in another protocol.

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7. Discontinuation Criteria
7.1.
Discontinuation from Study Treatment
7.1.1. Interruption of Study Drug
According to investigator judgment, study drug doses may be temporarily interrupted in subjects 
who develop skin rash, an AESI.  See Section 8.4.6 for details on the assessment and 
management of subjects developing a rash.
7.1.2. Permanent Discontinuation from Study Drug
Discontinuation of the study drug for abnormal liver test results should be considered by the 
investigator (in consultation with the Lilly designated medical monitor) when a subject meets 
any of the following conditions:

ALT or AST >8×ULN

ALT or AST >5×ULN for more than 2 weeks

ALT or AST >3×ULN and either total bilirubin level >2×ULN or 
international normalized ratio >1.5

ALT or AST >3×ULN with the appearance of fatigue, nausea, vomiting, right 
upper-quadrant pain or tenderness, fever, rash, and/or eosinophilia (>5%)
In addition, immediate and permanent discontinuation of study drug should be considered for all
subjects after the development of a rash (an AESI) deemed clinically significant by the 
investigator.  See Section 8.4.6 for details on the assessment and management of subjects 
developing a rash.  
The reason for and date of discontinuation from study drug will be collected for all randomized 
subjects.  Subjects who discontinue study drug should also be discontinued from the study 
according to Section 7.1.4.  All subjects who discontinue study drug early will have 
end-of-therapy procedures performed as shown for the early discontinuation visit (EDV) in the 
Schedule of Activities (Appendix 2).  
7.1.3. Discontinuation of Inadvertently Enrolled Subjects
If the sponsor or investigator identifies a subject who did not meet enrollment criteria and was 
inadvertently enrolled, a discussion must occur between the sponsor’s medical monitor 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 sponsor to 
allow the inadvertently enrolled subject to continue in the study with or without treatment with 
study drug.
7.1.4. Permanent Discontinuation from the Study
Possible reasons that may lead to permanent discontinuation include

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
enrollment in any other clinical trial involving an IP or enrollment in any 
other type of medical research judged not to be scientifically or medically 
compatible with this study

participation in the study needs to be stopped for medical, safety, regulatory, 
or other reasons consistent with applicable laws, regulations, and good clinical 
practice (GCP)

investigator decision
o
the investigator decides that the subject should be discontinued from 
the study drug or study
o
the subject, for any reason, requires treatment with another therapeutic 
agent that has been demonstrated to be effective for treatment of RA 
but is contraindicated in this study (in such cases, discontinuation from 
the study occurs prior to introduction of the new agent)

subject decision
o
the subject requests to be withdrawn from the study
The reason for and date of discontinuation from study will be collected for all randomized 
subjects.  All subjects who have received study drug and discontinue the study early will have 
end-of-study procedures performed as shown for the EDV in the Schedule of Activities 
(Appendix 2).  Subjects who are randomized but discontinue the study prior to receiving a single 
dose of study drug will not have an EDV or a safety follow-up visit.  
7.1.5. 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 cannot 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 are otherwise unavailable 
for follow-up by the site.

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8. Study Assessments and Procedures
Study procedures and their timing (including tolerance limits for timing) are summarized in the 
Schedule of Activities (Appendix 2).
A list of the laboratory tests that will be performed for this study is provided in Appendix 3.
Unless otherwise stated in the subsections below, all samples collected for specified laboratory 
tests will be destroyed within 60 days of receipt of confirmed test results.  Certain samples may 
be retained for a longer period, if necessary, to comply with applicable laws, regulations, or 
laboratory certification standards.
8.1.
Efficacy Assessments
8.1.1. Primary Efficacy Assessments 
The primary efficacy assessment is the proportion of subjects in Part B who achieve an ACR20 
response.
To achieve the ACR20 response, a subject must have at least 20% improvement from baseline in 
the following ACR core set components:

tender joint count (TJC; 68-joint count)

swollen joint count (SJC; 66-joint count)

at least 3 of the following 5 assessments:
(1) Physician’s Global Assessment of Disease Activity (visual analog scale [VAS])
(2) Patient’s Global Assessment of Disease Activity (VAS)
(3) Patient’s Global Assessment of Arthritis Pain (VAS)
(4) Patient’s assessment of physical function as measured by the Health Assessment 
Questionnaire–Disability Index (HAQ-DI)
(5) acute phase reactant as measured by hsCRP
While the primary efficacy assessment is calculated based on data from Part B, the ACR core set 
components will still be collected as exploratory endpoints in Part A.
8.1.1.1.
Joint Assessments
For the joint count evaluations, a joint assessor, who should be a rheumatologist or skilled 
arthritis assessor, will be responsible for completing the joint counts.  To ensure consistent joint 
evaluation throughout the trial, evaluations of an individual subject should be performed by the 
same joint assessor for all study visits. The joint assessor should not have access to or discuss 
with the subject the patient-reported assessments, Physician’s Global Assessment of Disease 
Activity, and safety assessments.  
Missing, replaced, ankylosed, or arthrodesed joints will be identified at the screening visit and 
will be excluded from evaluation during the trial.  The locations (or a listing) of previous surgical 
procedures should be documented in the subject’s source documents/eCRF pages for the joint 
and in the AE eCRF for any surgical procedures that may occur during the study.  

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8.1.1.1.1. Tender Joint Count 
The number of tender and painful joints will be determined by examination of 68 joints (34 joints 
on each side of the subject’s body).  The 68 joints to be assessed and classified as tender or not 
tender are 2 temporomandibular joints, 2 sternoclavicular joints, 2 acromioclavicular joints, 
2 shoulder joints, 2 elbow joints, 2 wrist joints, 10 metacarpophalangeal joints, 2 interphalangeal 
joints of the thumb, 8 proximal interphalangeal joints of the hands, 8 distal interphalangeal joints 
of the hands, 2 hip joints, 2 knee joints, 2 ankle joints, 2 tarsus, 10 metatarsophalangeal joints of 
the feet, 2 great toes (first proximal interphalangeal joint of the feet), and 8 proximal 
interphalangeal joints of the feet.  
Joints will be assessed for tenderness by pressure and joint manipulation on physical 
examination.  The subject will be asked for pain sensations on these manipulations and watched 
for spontaneous pain reactions.  Any positive response on pressure, movement, or both will then 
be translated into a single tender-versus-nontender dichotomy.  
8.1.1.1.2. Swollen Joint Count
The number of swollen joints will be determined by examination of 66 joints (33 joints on each 
side of the subject’s body).  The 66 joints to be assessed and classified as swollen or not swollen 
are 2 temporomandibular joints, 2 sternoclavicular joints, 2 acromioclavicular joints, 2 shoulder 
joints, 2 elbow joints, 2 wrist joints, 10 metacarpophalangeal joints, 2 interphalangeal joints of 
the thumb, 8 proximal interphalangeal joints of the hands, 8 distal interphalangeal joints of the 
hands, 2 knee joints, 2 ankle joints, 2 tarsus, 10 metatarsophalangeal joints of the feet, 2 great 
toes (first proximal interphalangeal joint of the feet), and 8 proximal interphalangeal joints of the 
feet.  
Joints will be classified as either swollen or not swollen.  Swelling is defined as palpable 
fluctuating synovitis of the joint.  Swelling secondary to osteoarthrosis will be assessed as not 
swollen, unless there is unmistakable fluctuation.  
8.1.1.2.
Physician’s Global Assessment of Disease Activity (VAS)
The investigator will be asked to give an overall assessment of the severity of the subject’s 
current RA disease activity using a 100-mm horizontal VAS, where the left end represents no 
disease activity and the right end represents extremely active disease.  
Results will be expressed in millimeters measured between the left end of the scale and the 
crossing point of the vertical line; this procedure is applicable for all VAS measures used in the 
trial.
8.1.1.3.
Patient’s Global Assessment of Disease Activity (VAS)
Subjects will be asked to give an overall assessment of the severity of their current RA disease 
activity using a 100-mm horizontal VAS where the left end represents no disease activity (“very 
well”) and the right end represents extremely active disease (“very poor”). This assessment
should be completed before the study visit examinations.

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8.1.1.4.
Patient’s Global Assessment of Arthritis Pain (VAS)
Subjects will be asked to assess their current level of arthritis pain by using a 100-mm horizontal 
VAS where the left end represents no pain and the right end represents the worst possible pain.  
This assessment should be completed before the study visit examinations.  
8.1.1.5.
Patient’s Assessment of Physical Function (HAQ-DI)
The HAQ-DI is a patient-reported questionnaire that is commonly used in RA to measure 
disease-associated disability (assessment of physical function).  It consists of 24 questions 
referring to 8 domains:  dressing/grooming, arising, eating, walking, hygiene, reach, grip, and 
other daily activities (Fries et al. 1980, 1982; Ramey et al. 1996).  The disability section of the 
questionnaire scores the patient’s self-perception of the degree of difficulty (0 = without any 
difficulty, 1 = with some difficulty, 2 = with much difficulty, and 3 = unable to do) covering the 
8 domains mentioned above.  The reported use of special aids or devices and/or the need for 
assistance of another person to perform these activities is also assessed.  The scores for each of 
the functional domains will be averaged to calculate the functional disability index. This 
assessment should be completed before the study visit examinations.
8.1.1.6.
High-Sensitivity C-Reactive Protein
The ACR core set measure of acute phase reactant will be hsCRP (measured at the central 
laboratory from blood samples obtained at specified study visits [Schedule of Activities, 
Appendix 2]).
8.1.2. Secondary Efficacy Assessments 
8.1.2.1.
Additional ACR Response Levels:  ACR50 and ACR70
The ACR50 and ACR70 responses are calculated as improvements of at least 50% and 70%, 
respectively, in the ACR core set using an algorithm similar to that used for ACR20.  
8.1.2.2.
Disease Activity Score:  DAS28-hsCRP
The DAS28-hsCRP is a measure of disease activity in 28 joints that consists of a composite 
numerical score of the following variables:  TJC, SJC, hsCRP (mg/L), and the Patient’s Global 
Assessment of Disease Activity (Vander Cruyssen et al. 2005).
For DAS28-hsCRP, the 28 joints to be examined and assessed as tender or not tender (TJC) and 
swollen or not swollen (SJC) are 14 joints on each side of the subject’s body:  the 2 shoulders, 
2 elbows, 2 wrists, 10 metacarpophalangeal joints, 2 interphalangeal joints of the thumb, 
8 proximal interphalangeal joints, and 2 knees (Smolen et al. 1995).
Clinical remission is defined as DAS28-hsCRP <2.6, and low disease activity (LDA) as 
DAS28-hsCRP ≤3.2.
8.1.3. Appropriateness of Assessments
All of the clinical and safety assessments made in this study are standard, widely used, and 
generally recognized as reliable, accurate, and relevant.

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8.2.
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.
Investigators must document their review of each laboratory safety report.
The investigator remains responsible for following, through an appropriate health care option, 
AEs that are serious or otherwise medically important, considered related to the study drug or the 
study, or that caused the subject to discontinue the study drug 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.
Lack of drug effect is not an AE in this study because the purpose of the clinical study is to 
establish treatment effect.
After the ICF is signed, study site personnel will record via the eCRF the occurrence and nature 
of each subject’s pre-existing conditions, including clinically significant signs and symptoms of 
the disease under treatment in the study.  In addition, site personnel will record via the eCRF any 
change in the condition(s) and any new conditions as AEs. Investigators should record their 
assessment of the potential relatedness of each AE to protocol procedure or study drug, via the 
eCRF.
The investigator decides whether he or she interprets the observed AEs as reasonably possibly 
related to RA, study drug, study procedure, or other concomitant treatment or pathology. To 
assess the relationship of the AEs, the following is defined:
reasonably possibly related:  reasonable and temporal possibility that there is a cause and 
effect relationship between the study drug and/or study procedure and the AE
The investigator answers yes/no when making this assessment.
Adverse events will be graded for severity as mild, moderate, or severe, except for rashes 
(AESIs), which will be graded according to the Common Terminology Criteria for Adverse 
Events.  
Planned nonsurgical interventions should not be reported as AEs unless the underlying medical 
condition has worsened during the course of the study.
If a subject’s study drug is discontinued as a result of an AE, study site personnel must report 
this to Lilly or its designee via the eCRF, clarifying if possible the circumstances leading to any 
dose interruptions or discontinuations of treatment.  
8.2.1. Serious Adverse Events
An SAE is any AE from this study that results in one of the following outcomes:

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
death

initial or prolonged inpatient hospitalization

a life-threatening experience (ie, immediate risk of dying)

persistent or significant disability/incapacity

congenital anomaly/birth defect

considered significant by the investigator for any other reason:  important medical 
events that may not result in death, be life-threatening, or require hospitalization 
may be considered serious, based upon appropriate medical judgment.
Although all AEs occurring after a subject signs the ICF are recorded in the eCRF, SAE 
reporting begins after the subject has both signed the ICF and received study drug.  However, if 
an SAE occurs after a subject signs the ICF but prior to receiving study drug, it needs to be 
reported ONLY if it is considered reasonably possibly related to study procedure.
Study site personnel must alert Lilly or its designee of any SAE within 24 hours of investigator 
awareness of the event via a sponsor-approved method.  If alerts are issued via telephone, they 
are to be immediately followed with official notification on study-specific SAE forms.  This 
24-hour notification requirement refers to the initial SAE information and all follow-up SAE 
information.  
Pregnancy (during maternal or paternal exposure to study drug) does not meet the definition of 
an AE.  However, to fulfill regulatory requirements, any pregnancy should be reported following 
the SAE process to collect data on the outcome for both mother and fetus.
Investigators are not obligated to actively seek AEs or SAEs in subjects once they have 
discontinued and/or completed the study (the subject’s summary eCRF has been completed).  
However, if the investigator learns of any SAE, including a death, at any time after a subject has 
been discharged from the study, and he/she considers the event reasonably possibly related to the 
study drug or study participation, the investigator must promptly notify Lilly.
8.2.1.1.
Suspected Unexpected Serious Adverse Reactions
Suspected unexpected serious adverse reactions (SUSARs) are serious events that are not listed 
in the IB and that the investigator identifies as related to study drug 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.
8.2.2. Adverse Events of Special Interest
Skin rash is considered an AESI.  If a subject develops a rash during the study, the subject should 
notify the site immediately in order to conduct an unscheduled visit. The visit should be 

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scheduled as soon as possible to enable evaluation of the rash while it is still present. See 
Section 8.4.6 for instructions on rash assessment and management.
8.2.3. Complaint Handling
Lilly collects product complaints on IPs and drug delivery systems used in clinical studies in 
order to ensure the safety of study participants, monitor quality, and facilitate process and
product improvements.
Subjects will be instructed to contact the investigator as soon as possible if they have a complaint 
or problem with the study drug so that the situation can be assessed.
8.3.
Treatment of Overdose
In case of suspected overdose, subjects should be closely monitored for electrocardiogram 
(ECG) changes; clinical laboratory abnormalities (hematology and serum chemistry); and 
adverse skin reactions and any associated localized, generalized, and/or systemic symptoms, 
which may include skin irritation, rash, skin exfoliation, pruritus, urticaria, fever, edema, or joint 
pain/swelling.  Investigators should remain vigilant for unknown effects related to LY3337641 
overdose.
There is no known antidote for overdose of LY3337641. 
8.4.
Safety Assessments
8.4.1. Physical Examination
Complete physical examinations and symptom-directed physical examinations will be conducted 
as specified in the Schedule of Activities (Appendix 2) and as clinically indicated.  A complete 
physical examination should include evaluation of the following regions/systems:

general appearance

skin

head, ears, eyes, nose, throat

lymph nodes

cardiovascular

respiratory

abdominal

genitourinary (only as clinically indicated)

extremities (tender/swollen joint counts to be documented separately)

neurologic

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On visit days where a complete physical examination is not required, as detailed in the Schedule 
of Activities (Appendix 2), the investigator may conduct a symptom-directed physical 
examination as clinically indicated.
8.4.2. Vital Signs
Blood pressure and heart rate will be measured as specified in the Schedule of Activities 
(Appendix 2) and as clinically indicated.  These should be measured after at least 5 minutes of 
sitting.  
Unscheduled orthostatic vital signs should be assessed, if possible, during any AE of dizziness or 
posture-induced symptoms.  If the subject feels unable to stand, sitting or supine vital signs 
should be recorded.
Additional vital signs may be measured during each study visit if warranted, as determined by 
the investigator.
Body temperature will be measured as specified in the Schedule of Activities (Appendix 2) and 
as clinically indicated.
Any clinically significant findings that occur after the subject receives the first dose of study 
drug should be reported to Lilly or its designee as an AE via the eCRF.  
8.4.3. Electrocardiograms
For each subject, ECGs should be collected according to the Schedule of Activities (Appendix 
2). 
Subjects should lie supine for approximately 5 to 10 minutes before ECG collection and remain 
supine but awake during ECG collection.  If possible, ECGs should be recorded prior to drawing 
blood and measuring blood pressure and pulse.  
Electrocardiograms may be obtained at additional times when deemed clinically necessary.  
Collection of more ECGs than expected at a particular time point is allowed when needed to 
ensure high quality records.
Electrocardiograms will be locally interpreted by a qualified physician (the investigator or 
qualified designee) at the site as soon after the time of ECG collection as possible, and ideally 
while the subject is still present, to determine whether the subject meets entry criteria and for 
immediate subject management, should any clinically relevant findings be identified.  The 
investigator (or qualified designee) must document the review of the ECG.  All recorded ECGs 
should be stored at the site and made available to the sponsor as requested.
Any clinically significant findings from ECGs that result in a diagnosis and that occur after the 
subject receives the first dose of the study drug should be reported to Lilly or its designee as an 
AE via the eCRF.

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8.4.4. Chest Radiography and Tuberculosis Testing
Posteroanterior and lateral chest radiography will be performed at screening for all subjects 
unless these have been obtained within 90 days prior to initial screening and the radiographs or 
report is available for investigator review.  Variations on the chest radiography view 
requirements will only be permitted if the country/local guidelines of care for standard TB 
screening differ from these protocol specifications.
All subjects will undergo a TB test at screening (TST or interferon release test).  Refer to 
Exclusion Criterion [21] for details regarding TB testing.
See Section 5.3 for subjects who are rescreening for this study and have undergone radiography 
and/or TB testing as part of their initial screening.
8.4.5. Laboratory Tests
For each subject, the laboratory tests detailed in Appendix 3 should be conducted according to 
the Schedule of Activities (Appendix 2).  
Any clinically significant findings that occur after the subject receives the first dose of study
drug should be reported to Lilly or its designee as an AE via the eCRF.
8.4.6. Assessment and Management of Subjects Developing a Rash
Subjects who develop a skin rash should be evaluated as soon as possible.  Investigators will be 
prompted to categorize and diagnose the rash (per clinical judgment), assess relatedness to study 
drug, and grade severity according to Common Terminology Criteria for Adverse Events.  This 
information will be entered into a form incorporated into the eCRF.  Additional information 
related to the rash evaluation will also be entered into this form 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 targeted 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 study drug, is transient, or is not 
clinically significant in the opinion of the investigator, the study drug may be continued without 
interruption.  In some cases, the investigator may instead choose to interrupt the study drug and 
restart it at a later date.  The dates for stopping and restarting the study drug should be captured.  
Immediate and permanent discontinuation of study drug should be considered for all subjects 
with clinically significant rash.  For rashes deemed clinically significant, punch biopsy(ies) of 
the rash should also be performed.  In addition, a venous blood sample should 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 study drug.  

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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.
8.4.7. Safety Monitoring
Lilly will periodically review evolving aggregate safety data within the study by appropriate 
methods.
Lilly will review SAEs within time frames mandated by company procedures.  The Lilly medical 
monitor or designee will, as is appropriate, consult with the functionally independent Global 
Patient Safety medical physician or clinical scientist and periodically review the following in a 
blinded fashion:

trends in safety data

laboratory analytes 

AEs (including AESIs)
If a study subject experiences elevated ALT ≥3×ULN or elevated total bilirubin level ≥2×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 comply with regulatory guidance, the investigator is to consult with 
the Lilly medical monitor regarding collection of specific recommended clinical information and 
follow-up laboratory tests (Appendix 4).
In addition to the safety reviews performed by the blinded Study JPDA team mentioned above, 
the Assessment Committee will review the safety data in an unblinded fashion during the study 
and will determine whether dose reductions to any study arm should be made, and whether 
enrollment of Part B may proceed after review of Part A data.  The Assessment Committee 
reviewing the safety data will include, at a minimum, a Lilly medical physician, a statistician, 
and a representative from Global Patient Safety; it will not include any Lilly study team 
members.
8.4.7.1.
Hepatitis B Monitoring
Subjects whose results are HBcAb positive at screening, regardless of hepatitis B surface 
antibody (HBsAb) status, will have an HBV DNA test performed by the central laboratory.  
Subjects whose results are found to be HBV DNA positive (detectable) at screening will be 
excluded from the trial.  Subjects whose results are HBV DNA negative (undetectable) may be 
enrolled into the study, according to investigator judgment, with HBV DNA monitoring 
approximately every 4 weeks during treatment as detailed in the Schedule of Activities 
(Appendix 2).  Subjects participating in Part B who are positive for HBcAb will continue to have 
HBV DNA monitoring every 3 months (for 6 months) after the last dose of study drug.  Once 

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subjects test positive for HBV DNA, they should be managed as clinically indicated and 
discontinued from the study (HBV monitoring is no longer required within the study at that 
point).
Subjects whose results are HBcAb negative and HBsAb positive will not require testing for HBV 
DNA because they are likely to have been vaccinated for HBV and have a very low risk of 
reactivation.  These subjects will be followed up by routine liver tests as part of the monitoring 
process.  
If the result of the HBV DNA testing is positive at any time after screening, the subject must 
discontinue the study drug and should receive appropriate follow-up medical care, including 
consideration for antiviral therapy. A specialist physician in the care of patients with hepatitis 
(for example, infectious disease physician or hepatologist) should be consulted.  The timing of 
discontinuation from the study drug and any other immunosuppressant therapy should be based 
on the recommendations of the consulting specialist physician in conjunction with the 
investigator and medical guidelines/standard of care.
8.5.
Pharmacokinetics
At the visits and times specified in the Schedule of Activities (Appendix 2), venous blood 
samples of approximately 4 mL each will be collected to determine the plasma concentrations of 
LY3337641.  At the baseline visit (Visit 2 in Part A and Visit 102 in Part B), the first dose of 
study drug will be administered, and subjects will remain at the site and have the PK sample 
drawn between 30 minutes and 2 hours postdose.  At subsequent visits, the PK sample will be 
drawn at any time during the visit; it is not required that the dose be administered during the 
visit.
A maximum of 2 PK samples may be drawn at additional time points during the study if 
warranted and agreed upon between both the investigator and sponsor.  For example, if an SAE 
or a clinically significant rash is observed by the investigator and a PK sample is not scheduled 
for that visit, a sample may be drawn at that time.  
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.  It is essential 
that the actual times of dosing and sampling are recorded accurately.
Drug concentration information that may unblind the study will not be reported to investigative
sites or personnel who are blinded to study data.
Plasma samples will be analyzed for LY3337641 at a laboratory approved by the sponsor using 
validated liquid chromatography-tandem mass spectrometry methodology.  Analysis of samples 
collected from placebo-treated subjects is not planned.
Plasma PK samples may be analyzed for exploratory metabolite identification, as deemed 
appropriate by the sponsor.  The results of such exploratory metabolism work may only be 
included in the clinical study report (CSR) if deemed appropriate by the sponsor or may be 
reported in a separate exploratory metabolism report.

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Bioanalytical samples collected to measure LY3337641 concentration will be retained for a 
maximum of 1 year following the last subject visit for the study.  
8.6.
Pharmacodynamics
At the visits and times specified in the Schedule of Activities (Appendix 2), venous blood 
samples will be collected for the analysis of PD endpoints.  Pharmacodynamic endpoints that are 
planned to be measured include total Ig, IgG, IgM, and IgA (Part B only).  Additionally, BTK 
occupancy and phosphorylated BTK will be assessed and samples will be drawn only at sites that 
meet assay requirements.  
Bioanalytical samples collected to measure PD endpoints will be identified by the subject 
number (coded) and retained for a maximum of 1 year following last subject visit for the study at 
a facility selected by the sponsor.  
8.7.
Genetics
A blood sample will be collected for pharmacogenetic analysis as specified in the Schedule of 
Activities (Appendix 2) where local regulations and ERBs allow.  
Samples will not be used to conduct unspecified disease or population genetic research either 
now or in the future.  Samples will be used to investigate variable response to LY3337641 and to 
investigate genetic variants thought to play a role in RA.  Assessment of variable response may 
include evaluation of AEs or differences in efficacy.  These studies may include but are not 
limited to genetic variants thought to play a role in RA and genes that play a role in leukocyte 
(B-cell receptor, Fc receptor, or T-cell receptor) signaling pathways to evaluate their association 
with observed response to LY3337641.
All pharmacogenetic samples will be coded with the subject number.  These samples and any 
data generated can be linked back to the subject only by the investigator site personnel.  Samples 
will be destroyed according to a process consistent with local regulations.
Samples will be retained for a maximum of 15 years after the last subject visit for the study, or 
for a shorter period if local regulations and/or ERBs impose shorter time limits, at a facility 
selected by the sponsor.  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 drug development or when the drug 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, candidate gene studies, and epigenetic analyses.  
Regardless of the technology utilized, genotyping data generated will be used only for the 
specific research scope described here.  

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8.8.
Biomarkers
Serum, plasma, and whole blood samples for nongenetic biomarker research will be collected at 
the times specified in the Schedule of Activities (Appendix 2) where local regulations and ERBs 
allow.
Samples will be used for research on the drug target, disease process, pathways associated with 
RA, mechanism of action of LY3337641, and/or research method or in validating diagnostic 
tools or assay(s) related to RA.  Proteomic, gene-expression, genomic, epigenetic, or 
metabolomic analyses may be performed on these samples.
All biomarker samples will be coded with the subject number.  These samples and any data 
generated can be linked back to the subject only by the investigator site personnel.  Samples will 
be destroyed according to a process consistent with local regulations.
Samples will be retained for a maximum 15 years after the last subject visit for the study, or for a 
shorter period if local regulations and ERBs impose shorter time limits, at a facility selected by 
the sponsor.  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 drug 
development or when the drug is commercially available.
8.9.
Health Outcomes
Health outcomes measures should be administered according to the Schedule of Activities
(Appendix 2) in countries where the questionnaires have been translated into the native language 
of the region and linguistically validated.
The health outcomes measures to be assessed in this study are described in the following 
subsections (refer to Section 8.1.1 for health outcomes measures included in the ACR20 efficacy 
assessment).  

Medical Outcomes Study 36-Item Short Form Health Survey (SF-36) (only in Part B) 

Functional Assessment of Chronic Illness Therapy–Fatigue (FACIT-F) (only in Part B)

morning joint stiffness duration

patient’s assessment of sexual function (VAS) (only in Part B).
Any measures that are subject self-assessments should be completed before the study visit 
examinations.  
8.9.1. SF-36 
The SF-36v2 Acute measure (SF-36) is a subjective, generic, health-related quality of life 
instrument that is patient-reported and consists of 36 questions covering 8 health domains:  
physical functioning, bodily pain, role limitations due to physical problems, role limitations due 
to emotional problems, general health perceptions, mental health, social function, and vitality.  
Each domain is scored by summing the individual items and transforming the scores into a 0 to 
100 scale with higher scores indicating better health status or functioning.  In addition, 
2 summary scores, the PCS (physical component score) and the MCS (mental component score), 

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will be evaluated based on the 8 SF-36v2 Acute domains (Brazier et al. 1992; Ware and 
Sherbourne 1992).
8.9.2. FACIT-F
The FACIT-F scale (Cella and Webster 1997) is a brief, 13-item, symptom-specific 
questionnaire that specifically assesses the self-reported severity of fatigue and its impact upon 
daily activities and functioning.  The FACIT-F uses 0 (“not at all”) to 4 (“very much”) numeric 
rating scales to assess fatigue and its impact in the past 7 days.  Scores range from 0 to 52 with 
higher scores indicating less fatigue.
8.9.3. Morning Joint Stiffness Duration
Subjects will be asked by site personnel to assess their duration of morning joint stiffness on the 
day prior to the visit. Responses will be recorded in minutes.
8.9.4. Patient’s Assessment of Sexual Function (VAS)
Subjects will be asked to assess the extent of the effect that RA has had on their sexual activity 
over the past week by using a 100-mm horizontal VAS where the left end represents “no effect 
on my sexual activity” and the right end represents “completely stopped my sexual activity.”

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9.
Statistical Considerations and Data Analysis
9.1.
Determination of Sample Size
Approximately 32 at least mildly active RA subjects will be enrolled and randomly assigned in a 
1:1:1:1 ratio to 1 of the 3 doses of LY3337641 (5, 10, or 30 mg) or placebo in Part A.  This 
sample size is customary for evaluating safety and PK and/or PD parameters, and is not powered 
on the basis of statistical hypothesis testing.
Approximately 244 moderately to severely active RA subjects will be enrolled and randomly 
assigned in a 1:1:1:1 ratio to 1 of the 3 doses of LY3337641 (5, 10, or 30 mg) or placebo in 
Part B.  All subjects who discontinue the treatment early (before Week 12) will be considered as 
failing the primary endpoint in Part B.  The sample size of 61 subjects per arm will provide at 
least 80% power at the 2-sided .05 significance level to detect a difference of 25% in the primary 
endpoint (ACR20 response rate at Week 12) between each LY3337641 dose and placebo, 
assuming a 30% placebo response rate.
If the Assessment Committee determines that a dose adjustment is needed (Section 6.6), the total 
study sample size may be adjusted.  
9.2.
General Statistical Considerations
Statistical analysis of this study will be the responsibility of Eli Lilly and Company or its 
designee.
In general, continuous variables will be summarized including number of observations; mean; 
standard deviation; and minimum, median, and maximum values.  Categorical variables will be 
presented as counts and percentages.  Data from Part A will be summarized separately from data 
from Part B.  No statistical hypothesis testing is planned for Part A.  All tests of treatment effects 
in Part B will be conducted at the 2-sided level of .05, unless otherwise stated.  No adjustments 
for multiplicity will be performed.
Complete details of the planned analyses will be documented in the statistical analysis plan 
(SAP). Any change to the data analysis methods described in the protocol will require an 
amendment ONLY if it changes a principal feature of the protocol.  Any other change to the data 
analysis methods described in the protocol and the justification for making the change will be 
described in the CSR.  Additional exploratory analyses of the data will be conducted as deemed 
appropriate.  
9.2.1. Analysis Population
Unless otherwise specified, efficacy and health outcomes analyses will be conducted on the 
modified intent-to-treat population, defined as all randomized subjects receiving at least 1 dose 
of study drug.  The analysis population (for applicable treatment outcome measures) will be all 
subjects with both a baseline and at least 1 postbaseline data measurement. Subjects will be 
grouped according to the randomized treatment. In addition, the primary analysis of Part B will 
be repeated using the per-protocol set, defined as all subjects randomly assigned to the study 
drug and using the study drug for 12 weeks.

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Safety analyses will be conducted on the safety population, defined as all randomized subjects 
receiving at least 1 dose of the study drug.  Subjects will be grouped according to the randomized 
treatment.
9.2.2.
Baseline Definition
The baseline will be defined as the last available value before the first administration of study 
drug for both efficacy and safety analyses, including unscheduled measurements for both parts 
separately.  In most cases, this will be the measure recorded on Study Day 1 (Visit 2 in Part A, 
Visit 102 in Part B).  Change from baseline values will be calculated as the postbaseline value 
minus the baseline value for each scheduled postbaseline time point.  If the baseline value is 
missing (ie, no screening values, no Day 1 value, and no unscheduled measurements), the change 
from baseline will be missing as well.  
9.2.3. Missing Data Imputation
The methods for imputation of missing data will be outlined in the SAP.
9.3.
Treatment Group Comparability
9.3.1. Subject Disposition
A detailed description of subject disposition will be provided.  Details will be outlined in the 
SAP.
9.3.2. Subject Characteristics
The subject’s sex, weight, height, and other demographic characteristics will be recorded.  
Details will be outlined in the SAP.
9.3.3. Concomitant Therapy
Details will be outlined in the SAP.
9.3.4. Treatment Compliance
Treatment compliance will be evaluated by visit and overall during the study. Details will be 
provided in the SAP.  
9.4.
Primary and Secondary Analyses
9.4.1. Primary Analyses
The primary objective in Part A is safety (Section 9.5).  
The primary endpoint in Part B will be analyzed by a logistic regression model with ACR20 at 
Week 12 as the dependent variable and treatment, biologic DMARD experience (yes/no), region 
(Japan vs non-Japan), and baseline DAS28-hsCRP as independent variables.  The comparison of 
each LY3337641 dose to placebo will be presented.  Subjects who discontinue from the study 
earlier than Week 12 and subjects who complete 12 weeks of dosing but do not have sufficient 

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data to derive the ACR20 response (Section 8.1.1) will be considered as failing to meet the 
ACR20.  
9.4.1.1.
Additional Analyses of the Primary Efficacy Measure
The number and percentage of subjects achieving the ACR20 response over time in both parts 
will be summarized separately by treatment group. All subjects who discontinue study drug at 
any time for any reason will be defined as nonresponders from time of discontinuation forward 
for ACR analyses.  
The ACR20 will also be analyzed using the per-protocol set (Section 9.2.1) as a sensitivity 
analysis in Part B.  Details will be outlined in the SAP.
Each component of the ACR20 (ie, TJC, SJC, Physician’s Global Assessment of Disease 
Activity, Patient’s Global Assessment of Disease Activity, pain score, HAQ-DI, and hsCRP) in 
both parts will be summarized separately over time by treatment.  The change from baseline to 
postbaseline in Part B will be analyzed by a maximum-likelihood–based mixed model repeated
measures (MMRM) analysis of covariance.  The change from baseline for each component of the 
ACR20 to each postbaseline time point in Part B is the dependent variable in the model.  
Baseline, treatment, weeks of treatment (categorical), the interaction of treatment and weeks, 
biologic DMARD experience (yes/no), region (Japan vs non-Japan), and baseline DAS28-hsCRP 
are fixed effects; subjects and error are random effects.
9.4.2. Secondary Analyses 
ACR50 and ACR70 will be summarized for both parts separately.  Data from Part B will be
analyzed using methods similar to those for the primary analysis.
DAS28-hsCRP will be summarized separately for each part by treatment and each postbaseline 
visit.  Change from baseline in DAS28-hsCRP to each postbaseline time point in Part B will be 
analyzed by the MMRM approach.  Subjects with DAS28-hsCRP <2.6 will be considered as 
having achieved clinical remission; the criterion for achieving LDA will be DAS28-hsCRP ≤3.2.  
The number and percentage of subjects who achieve clinical remission or LDA will be 
summarized separately and analyzed using methods similar to those for the primary analysis.
9.5.
Safety Analyses
All safety summaries and analyses will be based on the safety population as defined in 
Section 9.2.1.  Safety will be assessed by evaluating all reported AEs, AESIs, changes in vital 
signs, and changes in laboratory analytes.
Exposure to each study regimen will be calculated for each subject and summarized for both 
parts separately by treatment group.  Safety analyses will be conducted for both parts separately 
by treatment group.
9.5.1. Adverse Events
Adverse events will be classified by system organ class and preferred term as defined by the 
Medical Dictionary for Regulatory Drug Activities.  A TEAE is defined as an event that first 

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occurs or worsens in severity after baseline and on or prior to the date of the last visit within the 
dosing period.  All pre-existing conditions recorded at Visit 1 (Part A) or Visit 101 (Part B) and 
any AEs recorded before the first dose of study drug (during the interval between Visits 1 and
2 for Part A or Visits 101 and 102 for Part B and recorded with the time of onset before the first 
dose of study drug) will be used as baseline. The dosing period will be included as the 
postbaseline period for analysis.  For the Follow-Up Period, a follow-up–emergent adverse event 
is defined as an event that first occurs or worsens in severity after the last dose of study drug.  
For events that are sex specific, the denominator and computation of the percentage will only 
include subjects of the given sex.
Adverse events will be summarized as TEAEs.  The frequency and percentage of TEAEs will be 
presented for each treatment group.  All AEs, including pre-existing conditions, will be listed by 
subject, visit, preferred term, treatment group, severity, and relationship to the treatment.
9.6.
Pharmacokinetic/Pharmacodynamic Analyses
Pharmacokinetic and exploratory PK/PD analyses will be performed using a nonlinear 
mixed-effect modeling approach as implemented in NONMEM® on a computer that meets or 
exceeds the minimum system requirements for this program.  It is possible that other validated 
equivalent PK software programs may be used if appropriate.  The version of any software used 
for the analysis will be documented. Data from Parts A and B may be combined for population 
PK and PK/PD analyses.  
Population PK analyses will be performed to characterize the PK of LY3337641 after qd dosing
in subjects with RA.  These analyses will include model-based and graphical evaluations of the 
data.  Estimates of PK model parameters and covariate effects and corresponding 95% CIs will 
be reported.  The PK data may be combined with data from other studies in order to obtain 
improved PK parameter estimates.
Exploratory graphical PK/PD analyses will be conducted to evaluate the relationship between 
LY3337641 concentrations (or exposure) and selected measures of clinical response (efficacy 
measures, PD measures, or biomarkers).  These analyses may include analyses of relationships at 
specific time points as well as the development of longitudinal exposure-response models.  
Additional model-based analyses may be conducted if deemed appropriate.
9.7.
Other Analyses
9.7.1. Health Outcomes and Biomarkers
Health outcomes and biomarkers will be collected throughout the study.  These will be 
summarized.  Details will be outlined in the SAP.
9.7.2. Subgroup Analyses
Subgroup analyses will be conducted for ACR20, ACR50, ACR70, and DAS28-hsCRP using the 
modified intent-to-treat population using Part B data.  Subgroups that may be evaluated include 

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past or ongoing RA treatment at baseline and baseline DAS28-hsCRP.  Details will be provided 
in the SAP.
9.8.
Interim Analyses
The Assessment Committee is authorized to evaluate unblinded interim efficacy and safety 
analyses.  Study sites will receive information about interim results ONLY if they need to know 
for the safety of their subjects.
Unblinding details are specified in the unblinding plan section of the SAP or a separate 
unblinding plan document.
For Part A, two interim analyses are planned.  The first interim will take place at least 2 weeks 
after all subjects have had their last dose. The second will take place when all data from Part A 
are available.  Since all safety data for the primary objective in the Part A treatment period will 
be completed at the first interim, the study team will be unblinded to all available results for both 
interims in Part A.
For Part B, an interim efficacy analysis is planned when approximately 40% of the subjects have 
completed the Week 12 visit.  This interim analysis will be conducted for internal decision 
making to trigger planning activities for future studies associated with LY3337641.  The study 
will not be stopped early for efficacy. No adjustment of type I error will be performed. The 
PK/PD data will also be reviewed as part of the interim analysis to initiate model development 
processes.  Based on emerging data, additional interim analyses may be conducted by an 
Assessment Committee to review unblinded safety data.
A second interim analysis in Part B is planned when all subjects in Part B have completed (or 
discontinued early from) Part B. This interim analysis is planned to be the final analysis for 
Part B for CSR writing. This interim will include all planned analyses of available data. The 
study team will be unblinded to all available results for Part B.
If the Assessment Committee determines that an additional efficacy interim analysis may be 
needed before the Part B final analysis for internal decision-making for future studies, then an 
additional efficacy interim analysis may be conducted. This study will not be stopped early for 
efficacy reasons. No adjustment of type I error will be performed. The PK/PD data may be 
reviewed, and the model may be updated.
Subjects participating in Part B who are positive for HBcAb will continue to have HBV DNA 
monitoring every 3 months (for 6 months) after the last dose of study drug. Once subjects test 
positive for HBV DNA, they should be managed as clinically indicated and discontinued from 
the study (HBV monitoring is no longer required within the study at that point).  The final 
database will be locked when these subjects complete all HBV DNA monitoring. The analyses 
for HBV DNA will be rerun on the final data.
Details of the planned interim data analyses and the Assessment Committee data review process 
will be included in an Assessment Committee charter.

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10. Study Governance Considerations
10.1. Regulatory and Ethical Considerations, Including the Informed 
Consent Process
10.1.1. 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.  This includes 
obtaining the appropriate signatures and dates on the ICF prior to the 
performance of any protocol procedures and prior to the administration of 
study drug.

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.
10.1.2. Ethical Review
The investigator or an appropriate local representative must give assurance that the ERB was 
properly constituted and convened as required by International Conference on 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, 
including any changes made by the ERBs, before it is used at the investigative site(s).  All ICFs 
must be compliant with the ICH guideline on GCP.
The study site’s ERB(s) should be provided with the following:

the current IB and updates during the course of the study

ICF

relevant curricula vitae
10.1.3. Regulatory Considerations
This study will be conducted in accordance with

consensus ethics principles derived from international ethics guidelines, including 
the Declaration of Helsinki and Council for International Organizations of
Medical Sciences International Ethical Guidelines

applicable ICH GCP Guidelines

applicable laws and regulations
Some of the obligations of the sponsor will be assigned to a third-party.

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10.1.4. Investigator Information
Physicians with a specialty in rheumatology or internal medicine will participate as investigators 
in this clinical trial.  Other specialties may be acceptable with approval by the sponsor.
10.1.5. 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.
10.1.6. Final Report Signature
The CSR-coordinating investigator will sign the final CSR for this study, indicating agreement 
that, to the best of his or her knowledge, the report accurately describes the conduct and results 
of the study.
The sponsor’s responsible medical officer and statistician will approve the final CSR for this 
study, confirming that, to the best of his or her knowledge, the report accurately describes the 
conduct and results of the study.
10.2. Data Quality Assurance
To ensure accurate, complete, and reliable data, Lilly or its representatives will do the following:

provide instructional material to the study sites, as appropriate

sponsor start-up training to instruct the investigators and study coordinators.  This 
training will give instruction on the protocol, the completion of the eCRFs, and 
study procedures.

make periodic visits to the study site

be available for consultation and stay in contact with the study site personnel by 
mail, telephone, and/or fax

review and evaluate eCRF data and use standard computer edits to detect errors in 
data collection

conduct a quality review of the database
In addition, Lilly or its representatives will periodically check a sample of the subject data 
recorded against source documents at the study site.  The study may be audited by Lilly or its 
representatives and/or regulatory agencies at any time.  Investigators will be given notice before 
an audit occurs.
To ensure the safety of participants in the study and accuracy, completeness, and reliability of 
data, the investigator will keep records of laboratory tests, clinical notes, and subject medical 
records in the subject files as original source documents for the study.  If requested, the 

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investigator will provide the sponsor, applicable regulatory agencies, and applicable ERBs with 
direct access to original source documents.
10.2.1. Data Capture System
An electronic data capture system will be used in this study.  The site maintains a separate source 
for the data entered by the site into the sponsor-provided electronic data capture system.
Case report form data will be encoded and stored in a clinical trial database.  Data managed by a 
central vendor, such as laboratory test data, will be stored electronically in the central vendor’s 
database system.  Data will subsequently be transferred from the central vendor to the Lilly data 
warehouse.
Any data for which paper documentation provided by the subject will serve as the source 
document will be identified and documented by each site in that site’s study file.  
Data from complaint forms submitted to Lilly will be encoded and stored in the global product 
complaint management system.
10.3. Study and Site Closure
10.3.1. Discontinuation of Study Sites
Study site participation may be discontinued if Lilly or its designee, the investigator, or the ERB 
of the study site judges it necessary for medical, safety, regulatory, or other reasons consistent 
with applicable laws, regulations, and GCP.
10.3.2. Discontinuation of the Study
The study will be discontinued if Lilly or its designee judges it necessary for medical, safety, 
regulatory, or other reasons consistent with applicable laws, regulations, and GCP.

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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.
Aletaha D, Neogi T, Silman AJ, Funovits J, Felson DT, Bingham CO 3rd, Birnbaum NS, 
Burmester GR, Bykerk VP, Cohen MD, Combe B, Costenbader KH, Dougados M, Emery P, 
Ferraccioli G, Hazes JM, Hobbs K, Huizinga TW, Kavanaugh A, Kay J, Kvien TK, Laing T, 
Mease P, Ménard HA, Moreland LW, Naden RL, Pincus T, Smolen JS, Stanislawska-Biernat 
E, Symmons D, Tak PP, Upchurch KS, Vencovský J, Wolfe F, Hawker G. 2010 Rheumatoid 
arthritis classification criteria: an American College of Rheumatology/European League 
Against Rheumatism Collaborative Initiative. Arthritis Rheum. 2010;62(9):2569–2581.
Brazier JE, Harper R, Jones NM, O’Cathain A, Thomas KJ, Usherwood T, Westlake L. 
Validating the SF-36 health survey questionnaire: new outcome measure for primary care. 
BMJ. 1992;305(6846):160-164.
Burger JA. Bruton’s tyrosine kinase (BTK) inhibitors in clinical trials. Curr Hematol Malig Rep. 
2014;9(1):44-49.
Cella D, Webster K. Linking outcomes management to quality-of-life measurement. Oncology
(Williston Park). 1997;11(11A):232-235.
Chakravarty SD, Poulikakos PI, Ivashkiv LB, Salmon JE, Kalliolias GD. Kinase inhibitors: anew 
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.
[FDA] Food and Drug Administration. Guidance for industry rheumatoid arthritis: developing 
drug products for treatment 2013. Available at: 
http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances
/UCM354468.pdf. Accessed September 22, 2015.
Felson D and American College of Rheumatology Committee to Reevaluate Improvement 
Criteria. A proposed revision to the ACR20: the hybrid measure of American College of 
Rheumatology response. Arthritis Rheum. 2007;57(2):193-202.
Fries JF, Spitz P, Kraines RG, Holman HR. Measurement of patient outcome in arthritis. 
Arthritis Rheum. 1980;23(2):137-145.
Fries JF, Spitz PW, Young DY. The dimensions of health outcomes: the health assessment 
questionnaire, disability and pain scales. J Rheumatol. 1982;9(5):789-793.
Horwood NJ, Urbaniak AM, Danks L. Tec family kinases in inflammation and disease. Int Rev 
Immunol. 2012;31(2):87–103.
Klareskog L, Catrina AI, Paget S. Rheumatoid arthritis. Lancet. 2009;373(9664):659-672.

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Koenders MI, van den Berg WB. Novel therapeutic targets in rheumatoid arthritis. Trends 
Pharmacol Sci. 2015;36(4):189-195.
Ramey DR, Fries JF, Singh G. The Health Assessment Questionnaire 1995–status and review. 
In: Spilker B, editor. Quality of life and pharmacoeconomics in clinical trials. 2nd ed. 
Philadelphia: Lippincott-Raven, 1996: p 227-237.
Scott DL, Wolfe F, Huizinga TW. Rheumatoid arthritis. Lancet. 2010;376(9746):1094-1108.
Smolen JS, Breedveld FC, Eberl G, Jones I, Leeming M, Wylie GL, Kirkpatrick J. Validity and 
reliability of the twenty-eight-joint count for the assessment of rheumatoid arthritis activity. 
Arthritis Rheum. 1995;38(1):38-43.
Stoll JG, Yasothan U. Rheumatoid arthritis market. Nat Rev Drug Discov. 2009;8(9):693-694.
Vander Cruyssen B, Van Looy S, Wyns B, Westhovens R, Durez P, Van den Bosch F, Veys EM, 
Mielants H, De Clerck L, Peretz A, Malaise M, Verbruggen L, Vastesaeger N, Geldhof A, 
Boullart L, De Keyser F. DAS28 best reflects the physician’s clinical judgment of response to 
infliximab therapy in rheumatoid arthritis patients: validation of the DAS28 score in patients 
under infliximab treatment. Arthritis Res Ther. 2005;7(5):R1063-R1071.
Ware JE Jr, Sherbourne CD. The MOS 36-item short-form health survey (SF-36), I: conceptual 
framework and item selection. Med Care. 1992;30(6):473-483.

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Appendix 1.
Abbreviations and Definitions
Term
Definition
ACPA
anti-citrullinated peptide antibodies
ACR
American College of Rheumatology
ACR20
20% improvement in the American College of Rheumatology criteria
ACR50
50% improvement in the American College of Rheumatology criteria
ACR70
70% improvement in the American College of Rheumatology criteria
ACR90
90% improvement in the American College of Rheumatology criteria
ACR-N
continuous measure of percentage improvement from baseline in American College of 
Rheumatology criteria:  this index is defined operationally as the lowest of either (a) the 
percentage change in TJC, (b) the percentage change in SJC, or (c) the median 
percentage change in the remaining 5 ACR core criteria (eg, a patient with an ACR-N 
of “X” has improvement of at least “X%” in tender and swollen joints and a median 
improvement of at least “X%” in the 5 remaining ACR core criteria)
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 adverse event can therefore be any unfavorable and 
unintended sign (including an abnormal laboratory finding), symptom, or disease 
temporally associated with the use of a medicinal (investigational) product, whether or 
not related to the medicinal (investigational) product.
AESI
adverse event of special interest
ALT
alanine aminotransferase
AST
aspartate aminotransferase
blinding
A double-blind study is one in which neither the subject nor any of the investigator or 
sponsor staff who are involved in the treatment or clinical evaluation of the subjects are 
aware of the treatment received.
BTK
Bruton’s tyrosine kinase
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.
CSR
clinical study report
DAS28
Disease Activity Score modified to include the 28 diarthrodial joint count
DMARD
disease-modifying antirheumatic drug

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ECG
electrocardiogram
eCRF
electronic case report form (sometimes referred to as a clinical report form):  an 
electronic form for recording study participants’ data during a clinical study, as required 
by the protocol
EDV
early discontinuation visit
enroll
the act of assigning a subject to a treatment.  Subjects who are enrolled in the trial are 
those who have been assigned to a treatment.
enter
Subjects entered into a trial are those who sign the informed consent form.
ERB
ethical review board
FACIT-F
Functional Assessment of Chronic Illness Therapy–Fatigue
GCP
good clinical practice
HAQ-DI
Health Assessment Questionnaire–Disability Index
HBcAb
hepatitis B core antibody
HBsAb
hepatitis B surface antibody
HBV
hepatitis B virus
HCV
hepatitis C virus
HCVAb
hepatitis C antibody
hsCRP
high-sensitivity C-reactive protein
hybrid ACR
the hybrid ACR (bounded) response measure will be obtained as described by the ACR 
Committee to Reevaluate Improvement Criteria (Felson et al. 2007)
IB
Investigator’s Brochure
ICF
informed consent form
ICH
International Conference on Harmonisation
Ig
immunoglobulin
interim analysis
An interim analysis is an analysis of clinical study data, separated into treatment groups, 
that is conducted before the final reporting database is created/locked.
IP
Investigational product:  a pharmaceutical form of an active ingredient or placebo being 
tested or used as a reference in a clinical trial, including products already on the market 
when used or assembled (formulated or packaged) in a way different from the 
authorized form, or marketed products used for an unauthorized indication, or marketed 
products used to gain further information about the authorized form.
IWRS
interactive web-response system

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LDA
low disease activity
Listing of Excluded 
and Restricted 
Medications tool
a tabular listing of allowed and excluded/restricted concomitant medications and 
applicable conditions for use  
medical monitor
individual responsible for the medical conduct of the study:  Responsibilities of the 
medical monitor may be performed by a clinical research physician or other medical 
officer.
MMRM
mixed model repeated measures
modified intent-to-
treat
The intent-to-treat principle asserts that the effect of a treatment policy can be best
assessed by evaluating on the basis of the intention to treat a subject (that is, the planned 
treatment regimen) rather than the actual treatment given.  It has the consequence that 
subjects allocated to a treatment group should be followed up, assessed, and analyzed as 
members of that group irrespective of their compliance to the planned course of 
treatment.  The modified intent-to-treat population includes all randomized subjects 
receiving at least 1 dose of study drug. The analysis population (for applicable 
treatment outcomes measures) will be all subjects with both a baseline and at least 
1 postbaseline data measurement.
MTX
methotrexate
per-protocol set
all subjects randomly assigned to the study drug and using the study drug for 12 weeks 
(ie, the subset of subjects who sufficiently complied with the protocol); results from this 
population would be likely to exhibit the effects of treatment, according to the
underlying scientific model.
PK/PD
pharmacokinetics/pharmacodynamics
qd
once daily
RA
rheumatoid arthritis
SAE
serious adverse event
safety population
all randomized subjects receiving at least 1 dose of the study drug
SAP
statistical analysis plan
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 study
SF-36
Medical Outcomes Study 36-Item Short Form Health Survey
SJC
swollen joint count
study drug
LY3337641 and/or placebo used in the current study
subject
an individual who is or becomes a participant in clinical research, either as a recipient 
of the investigational product(s) or as a control. A subject may be either a healthy 
human or a patient.

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SUSARs
suspected unexpected serious adverse reactions
TB
tuberculosis
TEAE
treatment-emergent adverse event:  any untoward medical occurrence that either occurs 
or worsens at any time after treatment baseline and that does not necessarily have to 
have a causal relationship with this treatment
TJC
tender joint count
TST
tuberculin skin test
type I error
rejection of the null hypothesis when it is, in fact, true
ULN
upper limit of normal
VAS
visual analog scale

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Appendix 2.
Schedule of Activities
Tables presenting the Schedule of Activities for Part A and Part B are provided after the 
summary of study periods presented below.
Part A:
Screening Period (Visit 1, Weeks –4 to 0)
A screening period to assess subject eligibility will begin at Visit 1 and can last up to 28 days.  
Subjects will sign the ICF before any study assessments, examinations, or procedures are
performed.  Details regarding inclusion/exclusion criteria are in Sections 5.1 and 5.2.  Refer to 
the Schedule of Activities table for details regarding screening procedures.  
Dosing Period (Visits 2 to 5; Weeks 0 to 4; Study Days 1 to 29)
Subjects will be randomly assigned at baseline (Visit 2) in a 1:1:1:1 ratio to 1 of 4 arms:  
3 experimental arms in which LY3337641 will be dosed orally at 5, 10, or 30 mg and 1 placebo 
comparator arm.  Study drug will be administered qd in a blinded fashion from Week 0 through 
Week 4.  Four clinic visits are planned during this period (Visits 2 to 5) at Weeks 0, 1, 2, and 4.  
At these visits, subjects will undergo safety evaluations, clinical assessments, PK samplings, and 
other laboratory assessments according to the Schedule of Activities table.
Safety Follow-Up Period (Visit 801, Week 6, Study Day 43)
All subjects will have a safety visit (Visit 801) at least 2 weeks after the final dose of study drug.  
For subjects who discontinue the study early, an additional safety visit is only required if the 
EDV occurs less than 2 weeks after the last dose of study drug.
Part B:
Screening Period (Visit 101, Weeks –4 to 0)
A screening period to assess subject eligibility will begin at Visit 101 and can last up to 28 days.  
Subjects will sign the ICF before any study assessments, examinations, or procedures are
performed.  Details regarding inclusion/exclusion criteria are in Sections 5.1 and 5.2.  Refer to 
the Schedule of Activities table for details regarding screening procedures.  
Dosing Period (Visits 102 to 106; Weeks 0 to 12; Study Days 1 to 85)
Subjects will be randomly assigned at baseline (Visit 102) in a 1:1:1:1 ratio to 1 of 4 arms:  
3 experimental arms in which LY3337641 will be dosed orally at 5, 10, or 30 mg and 1 placebo 
comparator arm.  Study drug will be administered qd in a blinded fashion from Week 0 through 
Week 12.  Five clinic visits are planned during this period (Visits 102 to 106) at 
Weeks 0, 2, 4, 8, and 12.  At these visits, subjects will undergo safety evaluations, clinical
assessments, PK samplings, and other laboratory assessments according to the Schedule of 
Activities table.

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Safety Follow-Up Period (Visit 802, Week 14, Study Day 99)
All subjects will have a safety visit (Visit 802) at least 2 weeks after the final dose of study drug.  
For subjects who discontinue the study early, an additional safety visit is only required if the 
EDV occurs less than 2 weeks after the last dose of study drug.
Additional HBV DNA Monitoring (Visits 803 and 804, Study Days 169 to 253)
HBV DNA will be monitored every 3 months (for 6 months) after the last dose of study drug for 
those subjects who are HBcAb+ and HBV DNA negative (undetectable) at screening.

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Appendix 3.
Clinical Laboratory Tests

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Clinical Laboratory Testsa
Hematologyb,c
CBC with differential:
Clinical Chemistryb,c
Serum concentrations of the following:
Hemoglobin
Sodium
Hematocrit
Potassium
Erythrocyte count (RBC)
Total bilirubin
Mean cell volume
Direct bilirubin
Mean cell hemoglobin
Alkaline phosphatase
Mean cell hemoglobin concentration
ALT
Leukocytes (WBC) with absolute counts:
AST
Neutrophils, segmented
Blood urea nitrogen
Lymphocytes
Bicarbonate
Monocytes
Chloride
Eosinophils
Creatinine with calculated eGFRd
Basophils
Calcium
Platelets
Glucose (nonfasting)
Cell morphology
Albumin
Flow cytometry (lymphocyte subsets)
Total protein
Amylase
Lipase
Creatine kinase
Urinalysisb,c
Specific gravity
Lipid panel (nonfasting)
pH
Cholesterol (total)
Protein
HDL-C
Glucose
LDL-C
Color
Triglycerides
Bilirubin
Urobilinogen
Endocrine
Urinary nitrate 
TSH
Ketones
FSH
Blood
Urine leukocyte esterase
Pregnancy Test (female subjects only)
Microscopic exam of sediment (when indicated)e
Pregnancy urinef
Pregnancy serumb
Hepatitis
Hepatitis B surface antigen
Other Tests
Hepatitis B surface antibody
ACPA
Hepatitis B core antibody
Rheumatoid factor
Hepatitis B virus DNA
pBTKg
Hepatitis C antibody
BTK occupancyg
Hepatitis C virus RNA h
hsCRP
Human immunodeficiency virus 
Exploratory storage samples (serum, plasma, 
Whole Blood, and RNA)
LY pharmacokinetics samples
Tuberculosis
Pharmacogenetic sample
QFTi or T-Spot.TBf or TSTf
Total Ig, IgG, IgM, and IgA
Hemoglobin A1C

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Clinical Laboratory Testsa
Abbreviations:  ACPA = anti-citrullinated peptide antibodies; ALT = alanine aminotransferase; AST = aspartate 
aminotransferase; BTK = Bruton’s tyrosine kinase; eGFR = estimated glomerular filtration rate; 
FSH = follicle-stimulating hormone; hsCRP = high-sensitivity C-reactive protein; HDL-C = high-density 
lipoprotein cholesterol; Ig = immunoglobulin; LDL-C = low-density lipoprotein cholesterol; LY = LY3337641; 
pBTK = phosphorylated BTK; QFT = QuantiFERON-TB Gold; RBC = red blood cell count; TB = tuberculosis; 
TSH = thyroid-stimulating hormone; WBC = white blood cells.
a
Refer to the Schedule of Activities (Appendix 2).  
b
Assayed by the Lilly-designated (central) laboratory.
c
Unscheduled blood chemistry (including creatine kinase), hematology, and urinalysis panels may be performed 
at the discretion of the investigator.  If tests are done to evaluate laboratory results for resuming study drug, 
samples must be assayed centrally.  
d
Estimated glomerular filtration rate for serum creatinine will be calculated by the central laboratory using the 
Modification of Diet in Renal Disease method.
e
Microscopic examination of sediment will be performed only if abnormalities are noted on the routine urinalysis.
f
Testing will be performed by a local or investigator-designated laboratory.
g
Samples will be drawn only at sites that meet assay requirements.  
h
Hepatitis C Virus RNA will only be measured to confirm positive Hepatitis C virus antibody.
i
QFT to be performed by a local laboratory but may be performed at the Lilly-designated (central) laboratory.

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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 requested for subject follow-up after consultation with the Lilly medical monitor or designee.
Hepatic Monitoring Tests
Hepatic Hematologya
Haptoglobina
Hemoglobin
Hematocrit
Hepatic Coagulationa
RBC
Partial thromboplastin time
WBC
Prothrombin time, INR
Neutrophils, segmented
Lymphocytes
Hepatic Serologiesa,b
Monocytes
Hepatitis A antibody, total
Eosinophils
Hepatitis A antibody, IgM
Basophils
Hepatitis B surface antigen
Platelets
Hepatitis B surface antibody
Hepatitis B Core antibody
Hepatic Chemistrya
Hepatitis C antibody
Total bilirubin
Hepatitis E antibody, IgG
Direct bilirubin
Hepatitis E antibody, IgM
Alkaline phosphatase
ALT
Anti-nuclear antibodya
AST
GGT
Alkaline phosphatase isoenzymesa
CK
Anti–smooth muscle antibody (or anti-actin 
antibody)a
Abbreviations:  ALT = alanine aminotransferase; AST = aspartate aminotransferase; CK = creatine kinase; 
GGT = -glutamyl transferase; Ig = immunoglobulin; INR = international normalized ratio; RBC = red blood 
cells; WBC = white blood cells.
a
Assayed by Lilly-designated or local laboratory.
b
Reflex/confirmation dependent on regulatory requirements and/or testing availability.

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Appendix 5.
Protocol Amendment I8K-MC-JPDA(d) 
Summary 
A Randomized, Double-Blind, Placebo-Controlled, 2-Part 
Phase 2 Study to Evaluate the Safety and Efficacy of 
LY3337641 in Adult Subjects with Rheumatoid Arthritis:  
The RAjuvenate Study
Overview
Protocol I8K-MC-JPDA (A Randomized, Double-Blind, Placebo-Controlled, 2-Part Phase 2 
Study to Evaluate the Safety and Efficacy of LY3337641 in Adult Subjects with Rheumatoid 
Arthritis:  The RAjuvenate Study) has been amended.  The new protocol is indicated by 
amendment (d) 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 described in the 
following table:
Amendment Summary for Protocol I8K-MC-JPDA Amendment (d)
Section # and Name
Description of Change
Brief Rationale
Section 4.5 (Benefit/Risk 
Assessment)
Removed renal effects from a list of 
observed nonclinical effects
There was no evidence of significant 
renal effects in the 26-week rat 
(Study 31488) and 39-week monkey 
(Study 31489) repeat-dose studies, 
conducted at doses up to 120 mg/kg 
and 24 mg/kg.  This  change is an 
update to be consistent with the 
Investigator’s Brochure, which has 
already had the possible risk of renal 
injury removed.
Section 5.1 (Inclusion Criteria)
Modified inclusion criterion [2] to 
clarify that pregnancy testing is 
required only for women of 
childbearing potential
Pregnancy testing is required only 
for women of childbearing potential.
Section 5.1 (Inclusion Criteria)
Updated inclusion criterion [3] to 
require that women of childbearing 
potential agree to use a reliable 
method of birth control for 28 days 
(instead of 2 weeks) after the last 
dose of study drug.  
This revision is based on a new 
internal recommendation that 
contraception requirements for 
current and future clinical trials of 
LY3337641 be guided by duration 
of BTK occupancy by LY3337641 
instead of the pharmacologic 
half-life of LY3337641 .  The 
overall risk/benefitbenefit/risk 
assessment of LY3337641 has not 
changed.

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Appendix 2 (Schedule of Activities)
Modified to clarify that pregnancy 
testing is required only for women 
of childbearing potential
Pregnancy testing is required only 
for women of childbearing potential.
Appendix 2 (Schedule of Activities)
Modified to clarify that FSH testing 
is required only to confirm post-
menopausal status.
FSH testing is required only to 
confirm post-menopausal status.
Section 9.8 (Interim Analyses)
Added an optional additional 
efficacy interim analysis in Part B 
before the final analysis.
An optional additional efficacy 
interim analysis was added in Part B 
before the final analysis if the 
Assessment Committee determines 
that this the information may be 
needed for internal decision-making 
purposes for future studies prior to 
the Part B final analysis.  

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Revised Protocol Sections
Note:
Deletions have been identified by strikethroughs.
Additions have been identified by the use of underscore.
4.5. Benefit/Risk Assessment 
There are currently no human data regarding the efficacy of LY3337641 in RA.  Nonclinical data
and safety data in Phase 1 support further development of LY3337641 in RA at the proposed
doses. 
The safety profile for LY3337641 has been informed by the results from nonclinical toxicology 
and safety pharmacology studies and the Phase 1 clinical study (JPDD).  The primary toxicity 
observed in animal studies was gastrointestinal tract injury.  Pancreatic, renal, and immune 
system effects were also observed (see Section 5.2.1 of the IB).  In humans, the drug was 
generally well tolerated at dosages up to 40 mg per day.  At total daily dosages of 80 mg and 
higher in the multiple dose portion of the study, significant TEAEs were reported in some 
subjects.  The majority involved skin manifestations, the most common being skin rash.
Associated signs and symptoms ranged from pruritus to systemic features such as fever and 
elevated levels of acute phase reactants. The highest dosage in Study JPDA is 30 mg qd, which 
is below the doses at which skin rashes or significant TEAEs were reported in Study JPDD.
However, adverse events (AEs) of skin rash will be monitored over the course of the study by the 
medical monitor using blinded data.  In addition, skin rash will be monitored by an Assessment 
Committee using unblinded data.  The Assessment Committee members will be independent 
from the Lilly study team (Section 8.4.7).
More information about the known and expected benefits, risks, serious adverse events (SAEs), 
and reasonably anticipated AEs of LY3337641 can be found in the IB.
5.1. Inclusion Criteria
Subjects are eligible to be included in the study only if they meet all of the following criteria:
[1]
are male or female between the ages of 18 and 65 years (inclusive) at the time 
of initial screening and are able and willing to provide written informed 
consent as a legal adult according to local regulations
[2]
female subjects of childbearing potential (regardless of childbearing 
potential):  test negative for pregnancy at screening and agree not to 
breastfeed from the start of screening until 2 weeks after the last dose of study 
drug
[3]
female subjects:  agree to use a reliable method of birth control (eg, 
intrauterine contraceptive devices, hormonal contraceptives, or complete 
abstinence from sexual intercourse with men) from the start of screening until 
2 weeks 28 days after the last dose of study drug or be classified as female 
subjects of nonchildbearing potential, defined as meeting at least 1 of the 
following criteria:  

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
are postmenopausal with spontaneous amenorrhea for at least 12 months and have 
a follicle-stimulating hormone level >40 mIU/mL (>40 IU/L) at screening

have undergone bilateral tubal ligation, bilateral oophorectomy, and/or 
hysterectomy at least 6 weeks prior to screening

have another medical cause of female infertility that has been discussed with and 
accepted in writing by the sponsor
9.8. Interim Analyses
…
For Part B, an interim efficacy analysis is planned when approximately 40% of the subjects have 
completed the Week 12 visit.  This interim analysis will be conducted for internal decision 
making to trigger planning activities for future studies associated with LY3337641.  The study 
will not be stopped early for efficacy. No adjustment of type I error will be performed. The 
PK/PD data will also be reviewed as part of the interim analysis to initiate model development 
processes.  Based on emerging data, additional interim analyses may be conducted by an 
Assessment Committee (AC) to review unblinded safety data.
A second interim analysis in Part B is planned when all subjects in Part B have completed (or 
discontinued early from) Part B. This interim analysis is planned to be the final analysis for 
Part B for CSR writing. This interim will include all planned analyses of available data. The 
study team will be unblinded to all available results for Part B.
If the AC determines that an additional efficacy interim analysis may be needed before the Part B 
final analysis for internal decision-making for future studies, then an additional efficacy interim 
analysis may be conducted. This study will not be stopped early for efficacy. No adjustment of 
type I error will be performed. The PK/PD data may be reviewed, and the model may be 
updated.
…

Leo Document ID = e8d279d9-683b-40c8-bd70-11f4b4865141
Approver: 
Approval Date & Time: 05-Jul-2017 14:39:02 GMT
Signature meaning: Approved
Approver: 
Approval Date & Time: 05-Jul-2017 15:32:25 GMT
Signature meaning: Approved
PPD
PPD