A Randomized, Double-Blind, Placebo-Controlled, Phase 3 Study Evaluating the Efficacy and Safety of Baricitinib in Patients With Moderately to Severely Active Rheumatoid Arthritis Who Have Had an Inadequate Response to Methotrexate Therapy
Phase: PHASE3
Conditions: Rheumatoid Arthritis
Sponsor: Eli Lilly and Company

Protocol (c) I4V-CR-JAGS 
 
Randomized, Double-Blind, Placebo-Controlled, Phase 3 Study Evaluating the Efficacy and 
Safety of Baricitinib in Patients with Moderately to Severely Active Rheumatoid Arthritis Who 
Have Had an Inadequate Response to Methotrexate Therapy 
 
NCT02265705 
 
Approval Date: 07-Dec-2016 
 
 
 

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1. Protocol I4V-CR-JAGS(c)
A Randomized, Double-Blind, Placebo-Controlled, Phase 3 
Study Evaluating the Efficacy and Safety of Baricitinib in 
Patients with Moderately to Severely Active Rheumatoid 
Arthritis Who Have Had an Inadequate Response to 
Methotrexate Therapy
Confidential Information
The information contained in this protocol is confidential and is intended for the use of 
clinical investigators.  It is the property of Eli Lilly and Company or its subsidiaries and 
should not be copied by or distributed to persons not involved in the clinical investigation of 
baricitinib, unless such persons are bound by a confidentiality agreement with Eli Lilly and 
Company or its subsidiaries.  This document and its associated attachments are subject to 
United States Freedom of Information Act (FOIA) Exemption 4. 
Baricitinib (LY3009104)
A Phase 3, randomized, double-blind, placebo-controlled, parallel-group study of baricitinib 
for the treatment of moderately to severely active rheumatoid arthritis during a 52-week 
treatment period in patients with inadequate response to methotrexate therapy.
Eli Lilly and Company
Indianapolis, Indiana USA 46285
Protocol Electronically Signed and Approved by Lilly: 05-Nov-2013.
Amendment (a) Electronically Signed and Approved by Lilly
on 03-Apr-2014.
Amendment (b) Electronically Signed and Approved by Lilly
on 27-Feb-2015.
Amendment (c) Electronically Signed and Approved by Lilly
on approval date provided below
Approval Date: 07-Dec-2016 GMT

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2.
Synopsis
Study Rationale
Baricitinib (LY3009104) is an oral Janus kinase 1 (JAK1)/Janus kinase 2 (JAK2) selective 
inhibitor representing a potentially effective therapy for treatment of patients with moderately to 
severely active rheumatoid arthritis (RA).  The rationale for the current study is to confirm the 
efficacy and to continue to define the safety profile of 4 mg baricitinib when administered once 
daily (QD) to patients with RA who have had an inadequate response to methotrexate (MTX) 
therapy.  The safety and tolerability data from this study are intended to inform the current 
understanding of the benefit-risk relationship for baricitinib in patients with RA.

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Clinical Protocol Synopsis:  Study I4V-CR-JAGS(b)
Name of Investigational Product:
Baricitinib (LY3009104)
Title of Study:  A Randomized, Double-Blind, Placebo- Controlled, Phase 3 Study Evaluating the Efficacy and 
Safety of Baricitinib in Patients with Moderately to Severely Active Rheumatoid Arthritis Who Have Had an 
Inadequate Response to Methotrexate Therapy
Number of Planned Patients:
   Entered:  411
   Enrolled/Randomized:  288 (144 on baricitinib,
144 on placebo)
   Completed:  Approximately 245
Phase of Development:  3
Length of Study:  2 years 
Planned first patient visit:  Jun 2014
Planned last patient visit:  Jun 2016
Objectives:  The primary objective of the study is to determine whether baricitinib is superior to placebo in the 
treatment of patients with moderately to severely active rheumatoid arthritis (RA) despite methotrexate treatment 
(that is, inadequate response to methotrexate [MTX-IR]), as assessed by the proportion of patients achieving a 20% 
improvement in American College of Rheumatology criteria (ACR20) at Week 12.
The secondary objectives of the study are to evaluate the efficacy of baricitinib versus placebo as assessed by:

change from baseline to Week 12 in Health Assessment Questionnaire-Disability Index (HAQ-DI) score 
compared to placebo

change from baseline to Week 12 in Disease Activity Score modified to include the 28 diarthroidal joint 
count (DAS28)-high-sensitivity C-reactive protein (hsCRP) compared to placebo

proportion of patients achieving a Simplified Disease Activity Index (SDAI) score ≤3.3 at Week 12
compared to placebo

mean duration of morning joint stiffness in the 7 days prior to Week 12 compared to placebo as collected 
in diaries

mean severity of morning joint stiffness in the 7 days prior to Week 12 compared to placebo as collected 
in diaries 

mean Worst Tiredness numeric rating scale (NRS) in the 7 days prior to Week 12 compared to placebo as 
collected in diaries

mean Worst Joint Pain NRS in the 7 days prior to Week 12 compared to placebo as collected in diaries
The exploratory objectives in the study include:

change from baseline at Weeks 16, 24 and 52 in structural joint damage as measured by modified Total 
Sharp Score (mTSS; van der Heijde 2000)

proportion of patients with mTSS change ≤0 from baseline at Weeks 16, 24, and 52

change from baseline to Weeks 16, 24, and 52 in joint space narrowing and bone erosion scores

proportion of patients achieving DAS28-hsCRP ≤3.2 and DAS28-hsCRP <2.6 at Weeks 12, 24, and 52

proportion of patients achieving HAQ-DI improvement ≥0.22 and ≥0.3 at Weeks 12, 24, and 52

proportion of patients achieving ACR20 at Week 24 and Week 52 

proportion of patients achieving 50% improvement in American College of Rheumatology criteria 
(ACR50) at Weeks 12, 24, and 52

proportion of patients achieving 70% improvement in American College of Rheumatology criteria 
(ACR70) at Weeks 12, 24, and 52

percentage change from baseline to Weeks 12, 24, and 52 in individual components of the ACR Core Set

change from baseline through Week 52 in DAS28-hsCRP

change from baseline through Week 52 in DAS28-erythrocyte sedimentation rate (ESR)

proportion of patients achieving DAS28-ESR ≤3.2 and DAS28-ESR <2.6 at Weeks 12, 24, and 52

change from baseline to Week 24 and Week 52 in HAQ-DI score

change from baseline to Weeks 12, 24, and 52 in Clinical Disease Activity Index (CDAI) score

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
change from baseline to Weeks 12, 24, and 52 in SDAI score

proportion of patients achieving a CDAI score ≤2.8 at Weeks 12, 24, and 52

proportion of patients achieving an SDAI score ≤3.3, Week 24, and Week 52

proportion of patients achieving ACR/European League Against Rheumatism (EULAR) remission 
according to the Boolean-based definition at Weeks 12, 24, and 52

proportion of patients achieving moderate and good EULAR responses based on the DAS28 at Weeks 12, 
24, and 52

evaluation of hybrid ACR (bounded) response at Weeks 12, 24 and 52

change from baseline to Weeks 12, 24, and 52 in Functional Assessment of Chronic Illness Therapy 
Fatigue (FACIT-F) scale scores

change from baseline to Weeks 12, 24 and 52 in European Quality of Life-5 Dimensions-5 Level (EQ-5D-
5L) scores

change from baseline to Weeks 12, 24 and 52 in Work Productivity and Activity Impairment-Rheumatoid 
Arthritis (WPAI-RA) scores

evaluation of healthcare resource utilization through Week 52

change from baseline to Weeks 12, 24 and 52 in duration of morning joint stiffness assessed at the visit 
using an electronic patient-reported outcomes (ePRO) tablet

change from baseline to Weeks 12, 24 and 52 in Worst Tiredness NRS assessed at the visit using an ePRO 
tablet

change from baseline to Weeks 12, 24 and 52 in Worst Joint Pain NRS assessed at the visit using an 
ePRO tablet.
Study Design:  Study I4V-CR-JAGS(b) (JAGS) will be a 52-week, Phase 3, multicenter, randomized, double-
blind, placebo- controlled, parallel-group, study comparing the efficacy of baricitinib versus placebo in patients 
with moderately to severely active RA who have had an insufficient response to MTX and who have never been
treated with a biologic disease-modifying antirheumatic drug (DMARD) (that is, MTX-IR patients).  Baricitinib 
will be administered as a 4-mg tablet QD. The dose for patients with renal impairment, defined as estimated 
glomerular filtration rate (eGFR) <60 mL/min/1.73 m2, will be 2 mg baricitinib QD. Patients not assigned to the 
baricitinib treatment arm will receive either a 4-mg or 2-mg matching placebo tablet.  
A total of 288 patients are planned for enrollment in this study (144 to receive baricitinib, and 144 to receive 
placebo).  After the Week 52 study visit, eligible patients may proceed to a separate extension study (Study I4V-
MC-JADY [JADY]) lasting for up to 2 years or to the posttreatment follow-up period of this study (Part C).
Study JAGS will consist of 4 parts:

Screening:  Screening period lasting from 3 to 42 days prior to Visit 2 (Week 0)

Part A:  double-blind, placebo-controlled period from Week 0 through Week 24

Part B:  open-label period from Week 24 through Week 52

Part C:  posttreatment follow-up period.
Diagnosis and Main Criteria for Inclusion and Exclusions:  The proposed patient population for Study I4V-CR-
JAGS(b) (JAGS) will be ambulatory adult patients with moderately to severely active RA who have had an 
insufficient response to MTX and who have never been treated with a biologic DMARD.  Patients will be eligible 
for participation only if they have an inadequate response to MTX as evidenced by the presence of at least 6/68 
tender joints and 6/66 swollen joints and an hsCRP measurement ≥6 mg/L.
Investigational Product, Dosage, and Mode of Administration or Intervention:  
Baricitinib 4 mg administered orally QD
Planned Duration of Treatment:  52 weeks.
Screening period:  3 to 42 days
Treatment period:  52 weeks
Follow-up period:  28 days
Reference Therapy, Dose, and Mode of Administration or Comparative Intervention:  

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Placebo tablets matching baricitinib will be administered orally QD.
Patients will continue to take their background MTX therapy during the course of the study.
Criteria for Evaluation:
Efficacy
The following efficacy measures will be assessed in this study:

ACR20, ACR50, and ACR70 indices

HAQ-DI

DAS28-hsCRP and DAS28-ESR

Hybrid ACR (bounded) response measure

SDAI

CDAI

EULAR responses based on DAS28

mTSS (includes joint space narrowing score and bone erosion score)
Health Outcomes
The following health outcome measures will be administered in this study:

duration and severity of morning joint stiffness

recurrence of joint stiffness during the day

tiredness severity numeric rating scale (Worst Tiredness NRS)

pain severity numeric rating scale (Worst Joint Pain NRS)

FACIT-F

WPAI-RA

EQ-5D-5L

Quick Inventory of Depressive Symptomatology Self-Rated-16 (QIDS-SR16)

healthcare resource utilization
Safety
The following safety measures will be assessed in this study:

adverse events (AEs)

adverse events of special interest (AESIs)

serious adverse events (SAEs)

suspected unexpected serious adverse reactions (SUSARs)

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
physical examinations

electrocardiograms (ECGs)

chest x-ray and tuberculosis (TB) testing

vital signs (blood pressure and heart rate) and physical characteristics

standard laboratory tests (including hematology, clinical chemistry, urinalysis, lipid profile, eGFR, iron 
studies, hsCRP, and ESR)

concomitant medications
AESIs will include:

severe or opportunistic infections

myelosuppressive events of anemia, leukopenia, neutropenia, lymphopenia, and thrombocytopenia

thrombocytosis

elevations in alanine aminotransferase (ALT) or aspartate aminotransferase (AST) (>3 times ULN) with 
total bilirubin (>2 times ULN)
Patients with these laboratory value specified events will be identified using the same criteria for the interruption of 
investigational product with the exception of anemia, which will be identified using the same criteria for the 
discontinuation of investigational product, and thrombocytosis, which will be defined as a platelet count 
>600,000/μL.
Pharmacogenetics
Samples will be stored, and analysis may be performed on genetic variants thought to play a role in active RA and 
the JAK/signal transducers and activators of transcription (STAT) signaling pathways.
Statistical Methods:
Stratification:
Randomization will be stratified at the country level and joint erosion status (1-2 joint erosions plus seropositivity 
versus at least 3 joint erosions)
Sample size:
288 patients (144 in baricitinib, 144 in placebo) will provide:

99% power to detect a difference between the baricitinib and placebo treatment groups in ACR20 response 
rate (60% versus 35%) at Week 12 based on a 2-sided chi-square test at a significance level of 0.05.
The above sample size and power estimates are based on nQuery advisor 7.0.
General considerations:  
All statistical tests of treatment effects will be performed at 2-sided significance levels of 0.05, unless otherwise 
stated.  Treatment comparisons of discrete efficacy variables will be made using a logistic regression analysis with 
country, treatment groups and joint erosion status in the model.  The proportions and 95% confidence interval (CI)
will be reported.  Treatment comparisons of continuous efficacy variables will be made using analysis of 
covariance (ANCOVA) with country, treatment groups, joint erosion status and baseline value in the model.  Type 
III sums of squares for the least-squares (LS) means will be used for the statistical comparison; the 95% CI will 
also be reported.
When a restricted maximum likelihood (REML)-based mixed model for repeated measures (MMRM) is used, the 
model will include the fixed, categorical effects of treatment, country, joint erosion status, visit, treatment-by-visit-
interaction, as well as the continuous, fixed covariates of baseline score and baseline score-by-visit-interaction.  An 
unstructured (co)variance structure will be used to model the within-patient errors.  If this analysis fails to 
converge, other structures will be tested.  Type III sums of squares for the LS means will be used for the statistical 
comparison; the 95% CI will also be reported.  Treatment group comparisons with placebo at Week 12 and all 
other visits will be tested.  Further details on the MMRM will be described in the statistical analysis plan (SAP).
Fisher's exact test will be used for all AEs, discontinuation, and other categorical safety variables.  Continuous vital 

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signs and other continuous safety variables including laboratory parameters will be analyzed by using ANCOVA 
with treatment and baseline value in the model.  
Analysis population:
Unless otherwise specified, the efficacy and safety analyses will be conducted on a modified intent-to-treat basis 
(Gillings and Koch 1991).  This analysis set includes all data from all randomized patients who received at least 
1 dose of study drug.  Patients will be analyzed according to the treatment to which they were assigned.
Sensitivity analyses of the primary endpoints may be conducted and will be described in the statistical analysis 
plan.
Missing data imputation:
In accordance with precedent set with other Phase 3 RA trials (Cohen et al. 2006; Keystone et al. 2004, 2008, 
2009; Smolen et al. 2008, 2009), the following methods for imputation of missing data will be used:

Nonresponder imputation (NRI):  All patients who discontinue the study or the study treatment at any time for 
any reason will be defined as nonresponders for the NRI analysis for categorical variables, such as 
ACR20/50/70, from the time of discontinuation and onward.  Patients who receive rescue therapy at Week 16 
will be analyzed as nonresponders after Week 16 and onward.  Randomized patients without available data at 
a postbaseline visit will be defined as nonresponders for the NRI analysis at that visit. 

Linear extrapolation method:  The linear extrapolation method will be used for analysis of the structural 
progression endpoint (van der Heijde mTSS) to impute missing data at time points when analyses are 
conducted (including the analyses at Week 24 and Week 52).  For patients who discontinue the study or the 
study treatment or for patients who miss a radiograph for any reason, baseline data and the most recent 
radiographic data prior to discontinuation or the missed radiograph, adjusted for time, will be used for linear 
extrapolation to impute missing data at subsequent time points.  For patients who receive rescue therapy 
starting at Week 16 or at any time point thereafter, baseline data and the most recent radiographic data prior to 
initiation of rescue therapy, adjusted for time, will be used for linear extrapolation.  All patients originally 
randomized to placebo will be switched to active treatment at Week 24; thus, there will be no observed data 
for the placebo arm for the structural comparison at subsequent time points.  Therefore, baseline data and the 
most recent radiographic data prior to initiation of the new therapy, adjusted for time, will be used for linear 
extrapolation at Week 52.  The linear extrapolation method has been established as an appropriate missing data 
imputation method in other Phase 3 RA trials (Keystone et al. 2004, 2008, 2009; Cohen et al. 2006; Smolen et 
al. 2008, 2009).  Missing postbaseline values will be imputed only if both a baseline value and a postbaseline 
value from another time point are available, as long as the patient was on the same treatment at each applicable 
time point.

Multiple imputation:  Other methods than linear extrapolation that include multiple imputation will be 
employed for analysis of the structural progression endpoint (van der Heijde mTSS) to impute missing data at 
Week 24.  Details will be provided in the SAP.

Modified baseline observation carried forward (mBOCF):  The mBOCF method will be used for the analysis 
of secondary continuous endpoints (unless otherwise stated).  For patients who discontinue the study or the 
study treatment because of an AE, including death, the baseline observation will be carried forward to the 
corresponding endpoint for evaluation.  For patients who discontinue the study for reason(s) other than an AE, 
the last nonmissing postbaseline observation prior to discontinuation will be carried forward to the 
corresponding endpoint for evaluation.  For patients who receive rescue therapy starting at Week 16, the last 
nonmissing observation at or before rescue will be carried forward to subsequent time points for evaluation.  

Modified last observation carried forward (mLOCF):  For all continuous measures including safety analyses, 
the mLOCF will be a general approach to impute missing data unless otherwise specified.  For patients who 
receive rescue therapy starting at Week 16, the last nonmissing observation at or before rescue will be carried 

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forward to subsequent time points for evaluation.  For all other patients discontinuing from the study or the 
study treatment for any reason, the last nonmissing postbaseline observation before discontinuation will be 
carried forward to subsequent time points for evaluation.  After mLOCF imputation, data from patients with 
nonmissing baseline and postbaseline observations will be included in the analyses.  The mLOCF will be used 
as a sensitivity method to the mBOCF method with respect to the secondary endpoints.  

Other methods for data imputation for analysis of endpoints other than mTSS may be used and will be 
described in the SAP.
Analyses methods:
Primary analysis:
A logistic regression model with treatment, country and joint erosion status in the model will be used to test the 
treatment difference between baricitinib and placebo in the proportion of patients achieving ACR20 response at 
Week 12.  The NRI method as described above will be used to impute missing data.
Secondary analyses:

Comparison between baricitinib and placebo in change from baseline to Week 12 in HAQ-DI score:  An 
ANCOVA analysis with treatment, country, joint erosion status and baseline score in the model will be used to 
test the treatment difference between baricitinib and placebo in change from baseline to Week 12 in HAQ-DI.  
The mBOCF and mLOCF approaches as described above will be used to impute missing data.

Comparison between baricitinib and placebo in change from baseline to Week 12 in DAS28-hsCRP:  An 
ANCOVA model with treatment, country, joint erosion status, and baseline score in the model will be used to 
test the treatment difference between baricitinib and placebo in change from baseline to Week 12 in 
DAS28-hsCRP.  The mBOCF and mLOCF approaches as described above will be used to impute missing 
data.

Comparison between baricitinib and placebo in proportion of patients achieving an SDAI score ≤3.3 at 
Week 12: A logistic regression model with treatment, country, and joint erosion status in the model will be 
used to test the treatment difference between baricitinib and placebo in the proportion of patients achieving an 
SDAI score ≤3.3 response at Week 12.  The NRI method as described above will be used to impute missing 
data.

Comparison between baricitinib and placebo in mean duration of morning stiffness in the 7 days prior to 
Week 12:  An ANCOVA analysis with treatment, country, joint erosion status and baseline score (Day 1 on 
the diaries) in the model will be used to test the treatment difference between baricitinib and placebo in mean 
duration of morning stiffness.  

Comparison between baricitinib and placebo in mean severity of morning joint stiffness in the 7 days prior to 
Week 12:  An ANCOVA analysis with treatment, country, joint erosion status and baseline score (Day 1 on 
the diaries) in the model will be used to test the treatment difference between baricitinib and placebo in mean
severity of morning joint stiffness. 

Comparison between baricitinib and placebo in mean “Worst Tiredness” NRS in the 7 days prior to Week 12:  
An ANCOVA model with treatment, country, joint erosion status, and baseline score (Day 1 on the diaries) in 
the model will be used to test the treatment difference between baricitinib and placebo in mean “Worst 
Tiredness” NRS. 

Comparison between baricitinib and placebo in mean “Worst Joint Pain” NRS in the 7 days prior to Week 12:  
An ANCOVA model with treatment, country, joint erosion status, and baseline score (Day 1 on the diaries) in 
the model will be used to test the treatment difference between baricitinib and placebo in mean “Worst Joint 
Pain” NRS. 
Besides the analyses listed in the objective section, the following analyses will be performed as well.

change from baseline in mTSS

proportion of patients with mTSS change ≤0 

change from baseline in joint space narrowing and bone erosion scores

proportion of patients achieving DAS28-hsCRP ≤3.2 and <2.6

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
proportion of patients achieving HAQ-DI improvement ≥0.22 and ≥0.3

proportions of patients achieving ACR20 (other than primary), ACR50, and ACR70

percentage change from baseline in individual components of the ACR Core Set

change from baseline in DAS28-hsCRP

change from baseline in DAS28-ESR

proportion of patients achieving DAS28-ESR ≤3.2 and <2.6

change from baseline in HAQ-DI

change from baseline in CDAI score

change from baseline in SDAI score

proportion of patients achieving CDAI score ≤2.8

proportion of patients achieving SDAI score ≤3.3 (ACR/EULAR remission according to the Index-based 
definition)

proportion of patients achieving ACR/EULAR remission according to the Boolean-based definition

proportion of patients achieving moderate response and good response based on EULAR response criteria

hybrid ACR (bounded) response measure

change from baseline in fatigue score in the FACIT-F

change from baseline in health states, VAS score, and index score of EQ-5D-5L

change from baseline in absenteeism, presenteeism, work productivity loss, and activity impairment scores of 
WPAI-RA

individual items and total score in healthcare resource utilization

change from baseline in duration of morning joint stiffness assessed at the visit using an ePRO tablet

change from baseline in Worst Tiredness NRS assessed at the visit using an ePRO tablet

change from baseline in Worst Joint Pain NRS assessed at the visit using an ePRO tablet.
Approaches similar to the primary and above secondary analyses will be used to analyze other exploratory and 
health outcome measures.  Analysis methods will consist of ANCOVA and logistic regression, as described above, 
using mBOCF, linear extrapolation, NRI, and mLOCF missing data imputation methods, as applicable.
In addition, continuous parameters that are collected at repeated visits throughout the double-blind period may be 
analyzed using a MMRM approach as described in the general consideration section.
Safety:
All safety data will be descriptively summarized by treatment groups and analyzed using the mITT population.
For the purposes of calculating changes from baseline during Part A and Part B treatment, baseline may be 
considered as the original baseline for Part A – prior to any study drug received – or at the visits that mark the 
transition between treatments received, depending on the purpose of the summary or comparison being made.  
Summaries within Parts A and B will be conducted by treatment group used within each respective part.  
Additional summaries by treatment group that continue unchanged across multiple parts of the study will be 
conducted, as appropriate.
Treatment-emergent adverse events are defined as AEs that first occurred or worsened in severity after the first 
dose of study treatment.  AEs will be considered treatment emergent for nonresponders assigned to baricitinib if 
the AEs first occurred or worsened in severity after the visit at which rescue therapy is assigned.  The number of 
TEAEs as well as the number and percentage of patients who experienced at least 1 TEAE will be summarized 
using Medical Dictionary for Regulatory Activities (MedDRA) for each system organ class (SOC) (or a body 
system) and each preferred term by treatment group.  TEAEs will also be summarized by relationship to treatment 
and by severity within each treatment group.  Serious adverse events (SAEs) and AEs that lead to study drug 
discontinuation will also be summarized by treatment group.  Fisher’s exact test will be used to perform the 

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statistical comparisons between baricitinib and placebo.  
All clinical laboratory results will be descriptively summarized by treatment group.  Individual results that are 
outside of normal range will be flagged in data listings.  Quantitative clinical hematology, chemistry, and urinalysis 
variables obtained at the baseline to postbaseline visits will be summarized as changes from baseline by treatment 
group and analyzed using ANCOVA with treatment and baseline value in the model.  Categorical variables, 
including the incidence of abnormal values and incidence of AESIs, will be summarized by frequency and 
percentage of patients in corresponding categories.  Shift tables will be presented for selected measures.  
Observed values and changes from baseline (predose or screening if missing) for vital signs and physical 
characteristics will be descriptively summarized by treatment group and time point.  Change from baseline to 
postbaseline in vital signs, QIDS-SR16, and body weight will be analyzed using ANCOVA with treatment and
baseline value in the model.
The incidence and average duration of study drug interruptions will be summarized and compared descriptively 
among treatment groups.  Various techniques may be used to estimate the effects of study drug interruptions on 
safety measures.  Further analyses may be performed and will be planned in the SAP.  
Data collected after initiation of rescue therapy will be summarized as appropriate.

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3. Table of Contents
A Randomized, Double-Blind, Placebo- Controlled, Phase 3 
Study Evaluating the Efficacy and Safety of Baricitinib in 
Patients with Moderately to Severely Active Rheumatoid 
Arthritis Who Have Had an Inadequate Response to 
Methotrexate Therapy
Section
Page
1.
Protocol I4V-CR-JAGS(c) A Randomized, Double-Blind, Placebo-
Controlled, Phase 3 Study Evaluating the Efficacy and Safety of 
Baricitinib in Patients with Moderately to Severely Active 
Rheumatoid Arthritis Who Have Had an Inadequate Response to 
Methotrexate Therapy.........................................................................................................1
2.
Synopsis .............................................................................................................................2
3.
Table of Contents..............................................................................................................11
4.
Abbreviations and Definitions...........................................................................................18
5.
Introduction ......................................................................................................................24
6.
Objectives.........................................................................................................................27
6.1.
Primary Objective ........................................................................................................27
6.2.
Secondary Objectives...................................................................................................27
6.3.
Exploratory Objective ..................................................................................................27
7.
Investigational Plan...........................................................................................................29
7.1.
Summary of Study Design............................................................................................29
7.1.1.
Screening Period..................................................................................................30
7.1.2.
Part A and Part B:  24-Week Double-Blind Placebo-
Controlled, (Part A) Period and 28-Week Open-Label (Part 
B) Period..............................................................................................................30
7.1.3.
Part C:  Posttreatment Follow-Up Period..............................................................31
7.1.4.
Study Extensions..................................................................................................31
7.2.
Discussion of Design and Control ................................................................................31
8.
Study Population...............................................................................................................33
8.1.
Entry Criteria ...............................................................................................................33
8.1.1.
Inclusion Criteria .................................................................................................33
8.1.2.
Exclusion Criteria ................................................................................................34
8.2.
Enrollment Criteria.......................................................................................................38
8.2.1.
Inclusion Criteria .................................................................................................38
8.2.2.
Exclusion Criteria ................................................................................................38

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8.2.3.
Rationale for Exclusion of Certain Study Candidates ...........................................41
8.3.
Discontinuations ..........................................................................................................41
8.3.1.
Discontinuation of Patients...................................................................................41
8.3.1.1.
Interruption of Study Drug..............................................................................41
8.3.1.2.
Discontinuation of Study Drug .......................................................................42
8.3.1.3.
Discontinuation from the Study ......................................................................43
8.3.2.
Discontinuation of Study Sites .............................................................................44
8.3.3.
Discontinuation of the Study................................................................................44
9.
Treatment..........................................................................................................................45
9.1.
Treatments Administered .............................................................................................45
9.2.
Materials and Supplies .................................................................................................45
9.3.
Method of Assignment to Treatment ............................................................................46
9.4.
Rationale for Selection of Doses in the Study...............................................................46
9.5.
Selection and Timing of Doses.....................................................................................47
9.5.1.
Special Treatment Considerations ........................................................................47
9.6.
Continued Access to Investigational Product................................................................48
9.7.
Blinding .......................................................................................................................48
9.8.
Concomitant Therapy...................................................................................................49
9.9.
Treatment Compliance .................................................................................................50
10.
Efficacy, Health Outcome Measures, Safety Evaluations, Sample 
Collection and Testing, and Appropriateness of Measurements .........................................52
10.1. Efficacy Measures........................................................................................................52
10.1.1.
Primary Efficacy Measure....................................................................................52
10.1.2.
Secondary Efficacy Measures...............................................................................52
10.1.2.1.
Disease Activity Score-Erythrocyte Sedimentation Rate 
and Disease Activity Score–High Sensitivity C-Reactive 
Protein............................................................................................................52
10.1.2.2.
ACR50 and ACR70 Indices............................................................................52
10.1.2.3.
Hybrid American College of Rheumatology Response 
Measure..........................................................................................................52
10.1.2.4.
ACR/EULAR Rheumatoid Arthritis Remission ..............................................53
10.1.2.5.
Simplified Disease Activity Index (SDAI)......................................................53
10.1.2.6.
Clinical Disease Activity Index (CDAI)..........................................................54
10.1.2.7.
European League Against Rheumatism Responder Index ...............................54
10.1.2.8.
Van der Heijde Modified Total Sharp Score (mTSS) ......................................54
10.2. Health Outcome Measures............................................................................................55
10.3. Safety Evaluations........................................................................................................57
10.3.1.
Adverse Events (AEs)..........................................................................................57
10.3.1.1.
Adverse Events of Special Interest..................................................................58

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10.3.1.2.
Serious Adverse Events (SAEs)......................................................................58
10.3.1.2.1.
Suspected Unexpected Serious Adverse Reactions 
(SUSARs).................................................................................................59
10.3.2.
Other Safety Measures .........................................................................................60
10.3.2.1.
Measures Evaluated During Screening Period.................................................60
10.3.2.2.
Measures Evaluated During Screening and Treatment 
Periods ...........................................................................................................60
10.3.3.
Safety Monitoring ................................................................................................61
10.3.4.
Complaint Handling.............................................................................................62
10.4. Sample Collection and Testing.....................................................................................62
10.4.1.
Samples for Standard Laboratory Testing.............................................................62
10.4.2.
Exploratory Stored Samples .................................................................................63
10.4.2.1.
Pharmacogenetics...........................................................................................63
10.4.2.2.
Nonpharmacogenetic/Biomarker Stored Samples............................................64
10.5. Appropriateness of Measurements................................................................................64
11.
Data Quality Assurance.....................................................................................................65
11.1. Data Capture System....................................................................................................65
12.
Sample Size and Statistical Methods .................................................................................66
12.1. Determination of Sample Size ......................................................................................66
12.2. Statistical and Analytical Plans.....................................................................................66
12.2.1.
General Considerations ........................................................................................66
12.2.2.
Patient Disposition...............................................................................................68
12.2.3.
Patient Characteristics..........................................................................................68
12.2.4.
Concomitant Therapy...........................................................................................68
12.2.5.
Treatment Compliance .........................................................................................69
12.2.6.
Primary Outcome and Methodology.....................................................................69
12.2.7.
Efficacy Analyses ................................................................................................69
12.2.8.
Health Outcome Analyses ....................................................................................71
12.2.9.
Safety Analyses....................................................................................................71
12.2.10. Subgroup Analyses ..............................................................................................72
12.2.11. Planned Analyses.................................................................................................72
13.
Informed Consent, Ethical Review, and Regulatory Considerations ..................................73
13.1. Informed Consent.........................................................................................................73
13.2. Ethical Review.............................................................................................................73
13.3. Regulatory Considerations ...........................................................................................73
13.3.1.
Investigator Information.......................................................................................74
13.3.2.
Protocol Signatures ..............................................................................................74
13.3.3.
Final Report Signature .........................................................................................74

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14.
References ........................................................................................................................75

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List of Tables
Table
Page
Table JAGS.8.1. Criteria for Temporary Discontinuation of Investigational Product ................42
Table JAGS.8.2. Criteria for Permanent Discontinuation of Investigational Product.................43
Table JAGS.9.1. Treatment Regimens......................................................................................45
Table JAGS.10.1.
Scoring Method for the Hybrid American College of Rheumatology 
Response Measure .........................................................................................53
Table JAGS.10.2.
Categorization of Patients as Nonresponders, Moderate Responders, 
or Good Responders ......................................................................................54

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List of Figures
Figure
Page
Figure JAGS.7.1.Illustration of study design for Clinical Protocol I4V-CR-JAGS. ...................30

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List of Attachments
Attachment
Page
Attachment 1.
Protocol JAGS Study Schedule......................................................................79
Attachment 2.
Protocol JAGS Clinical Laboratory Tests.......................................................86
Attachment 3.
Protocol JAGS Hepatic Monitoring Tests for Treatment-Emergent 
Abnormality ..................................................................................................88
Attachment 4.
Protocol Amendment I4V-CR-JAGS (c) Summary A Randomized, 
Double-Blind, Placebo-Controlled, Phase 3 Study Evaluating the 
Efficacy and Safety of Baricitinib in Patients with Moderately to 
Severely Active Rheumatoid Arthritis Who Have Had an Inadequate 
Response to Methotrexate Therapy................................................................89

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4. Abbreviations and Definitions
Term
Definition
ACR
American College of Rheumatology
ACR20
20% improvement in American College of Rheumatology criteria
ACR50
50% improvement in American College of Rheumatology criteria
ACR70
70% improvement in American College of Rheumatology criteria
adverse event (AE)
Any untoward medical occurrence in a patient or clinical investigation subject 
administered a pharmaceutical product and 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
ANCOVA
analysis of covariance
anti-CCP
anticyclic citrullinated peptide
AST
aspartate aminotransferase
audit
a systematic and independent examination of the trial-related activities and 
documents to determine whether the evaluated trial-related activities were 
conducted, and the data were recorded, analyzed, and accurately reported 
according to the protocol, applicable standard operating procedures (SOPs), 
good clinical practice (GCP), and the applicable regulatory requirement(s)
blinding
A procedure in which one or more parties to the trial are kept unaware of the 
treatment assignment(s).  Single-blinding usually refers to the patient(s) being 
unaware, and double-blinding usually refers to the patient(s), investigator(s), 
monitor(s), and in some cases, select sponsor personnel being unaware of the 
treatment assignment(s).
case report form 
(CRF) and 
electronic case 
report form (eCRF)
sometimes referred to as clinical report form:  a printed or electronic form for 
recording study participants’ data during a clinical study, as required by the 
protocol.  This study uses an electronic case report form.
CDAI
Clinical Disease Activity Index
cDMARD
conventional disease-modifying antirheumatic drugs
CI
confidence interval
CL
central compartment clearance

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clinical research 
physician
Individual responsible for the medical conduct of the study.  Responsibilities of 
the clinical research physician may be performed by a physician, clinical 
research scientist, global safety physician or other medical officer.
CNS
central nervous system
complaint
A complaint is any written, electronic, or oral communication that alleges 
deficiencies related to the identity, quality, purity, durability, reliability, safety 
or effectiveness, or performance of a drug or drug delivery system.
compliance
adherence to all the trial-related requirements, good clinical practice (GCP) 
requirements, and the applicable regulatory requirements
CRP
C-reactive protein
CSR
Clinical Study Report
DAS
Disease Activity Score
DAS28
Disease Activity Score modified to include the 28 diarthroidal joint count
DMARD
disease-modifying antirheumatic drug
DNA
deoxyribonucleic acid
ECG
Electrocardiogram
efficacy/
effectiveness
Efficacy is the ability of a treatment to achieve a beneficial intended result.
Effectiveness is the measure of the produced effect of an intervention when 
carried out in a clinical environment.
eGFR
estimated glomerular filtration rate
end of study (trial)
the date of the last visit or last scheduled procedure shown in the study schedule 
for the last active patient in the study
enroll/randomize
The act of assigning a patient to a treatment.  Patients who are 
enrolled/randomized in the trial are those who have been assigned to a 
treatment.
enter
The act of obtaining informed consent for participation in a clinical trial from 
patients deemed eligible or potentially eligible to participate in the clinical trial.  
Patients entered into a trial are those who sign the informed consent document 
directly or through their legally acceptable representatives.
ePRO
electronic Patient-Reported Outcome
EQ-5D-5L
European Quality of Life-5 Dimensions-5 Level
ESR
erythrocyte sedimentation rate
ethical review 
board (ERB)
a board or committee (institutional, regional, or national) composed of medical 
and nonmedical members whose responsibility is to verify that the safety, 
welfare, and human rights of the patients participating in a clinical trial are 

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protected
EULAR
European League Against Rheumatism
EULAR28
European League Against Rheumatism Responder Index based on the 28-joint 
count
FACIT-F
Functional Assessment of Chronic Illness Therapy Fatigue
FSH
follicle-stimulating hormone
GCP
good clinical practice
HAQ-DI
Health Assessment Questionnaire–Disability Index
HBsAb
hepatitis B surface antibody
HBV
hepatitis B virus
HCV
hepatitis C virus
HDL
high-density lipoprotein
HIV
human immunodeficiency virus
hsCRP
high-sensitivity C-reactive protein
IB
Investigator’s Brochure
IC50
inhibitory concentration of 50%
ICF
informed consent form
ICH
International Conference on Harmonisation
IL-6
interleukin-6
intention to treat 
(ITT)
The principle that asserts that the effect of a treatment policy can be best 
assessed by evaluating on the basis of the intention to treat a patient (that is, the 
planned treatment regimen) rather than the actual treatment given.  It has the 
consequence that patients 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.
investigator
A person responsible for the conduct of the clinical study at a study site.  If a 
study is conducted by a team of individuals at a study site, the investigator is the 
responsible leader of the team and may be called the principal investigator.
IWRS
interactive web-response system
JAK
Janus kinase
JAK1
1 of 4 identified members of the family of Janus kinases
JAK2
1 of 4 identified members of the family of Janus kinases

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JAK3
1 of 4 identified members of the family of Janus kinases
Ka
absorption rate constant
LC/MS/MS
liquid chromatography, tandem mass spectrometry
LDL
low-density lipoprotein
legal 
representative
an individual, judicial, or other body authorized under applicable law to consent 
on behalf of a prospective patient, to the patient’s participation in the clinical 
trial
LS means
least square means
mBOCF
modified baseline observation carried forward
MCS
Mental Component Score
MDRD
Modification of Diet in Renal Disease
MedDRA
Medical Dictionary for Regulatory Activities
mITT
modified intent-to-treat
mLOCF
modified last observation carried forward
MMRM
mixed model for repeated measures
MRI
magnetic resonance imaging
mRNA
messenger ribonucleic acid
mTSS
modified Total Sharp Score
MTX
Methotrexate
MTX-IR
patients who have had an inadequate response to methotrexate
NRI
nonresponder imputation
NRS
numeric rating scale
NSAID
nonsteroidal anti-inflammatory drug
patient
a study participant who has the disease or condition for which the 
investigational product is targeted
PCS
Physical Component Score
PI
principal investigator
PK
Pharmacokinetic
per-protocol (set)
the set of data generated by the subset of patients who sufficiently complied 

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(PP)
with the protocol to ensure that these data would be likely to exhibit the effects 
of treatment, according to the underlying scientific model
PPD
purified protein derivative
QD
once daily
QIDS-SR16
Quick Inventory of Depressive Symptomatology Self-Rated-16
RA
rheumatoid arthritis
REML
restricted maximum likelihood
SAE
serious adverse event
SAP
statistical analysis plan
screening
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
SD
standard deviation
SDAI
Simplified Disease Activity Index
SJC
swollen joint count
SOC
system organ class
STAT
signal transducers and activators of transcription
subject
An individual who is or becomes a participant in clinical research, either as a 
recipient of the investigational product(s) or as a control.  A subject may be 
either a healthy human or a patient.
SUSARs
suspected unexpected serious adverse reactions
TB
Tuberculosis
TJC
tender joint count
TNF
tumor necrosis factor
TNF-α
tumor necrosis factor-alpha
treatment-
emergent adverse 
event (TEAE)
any untoward medical occurrence that either occurs or worsens at any time after 
treatment baseline and which does not necessarily have to have a causal 
relationship with this treatment (also called treatment-emergent signs and 
symptoms [TESS])
TSH
thyroid-stimulating hormone
TYK2
tyrosine kinase 2
ULN
upper limit of normal
V1
central compartment volume of distribution

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V2
peripheral volume of distribution
VAS
visual analog scale
WBC
white blood cell
WPAI-RA
Work Productivity and Activity Impairment-Rheumatoid Arthritis

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A Randomized, Double-Blind, Placebo- Controlled, Phase 3 
Study Evaluating the Efficacy and Safety of Baricitinib in 
Patients with Moderately to Severely Active Rheumatoid 
Arthritis Who Have Had an Inadequate Response to 
Methotrexate Therapy
5. Introduction
Rheumatoid arthritis (RA) is a systemic inflammatory autoimmune disease.  The disease has 
variable expression and outcome ranging from mild, limited disease to severe disease associated 
with progressive joint destruction, significantly compromised quality of life, and reduced 
survival (Smolen and Steiner 2003; Colmegna et al. 2012).  Substantial comorbidity can be seen 
outside of the musculoskeletal system, with excess cardiovascular risk, dyslipidemia, and 
propensity for infection partially related to the need for treatment with immunomodulatory 
agents (Curtis et al. 2007; Kitas and Gabriel 2011).
Management of RA has improved substantially in recent years.  In addition to reduction of signs 
and symptoms, improvement of physical function, and inhibition of structural damage, better 
patient outcomes and clinical remission are now considered achievable goals.  Therefore, the 
current recommended primary target for treatment of RA should be a state of clinical remission 
(Smolen et al. 2010; Felson et al. 2011).  There are several definitions for clinical remission 
based on composite scores (commonly including: tender joint counts [TJCs]/swollen joint 
counts [SJCs], level of acute phase reactants, and assessment of a patient or physician global 
response).  These scores include the Disease Activity Score (DAS), DAS modified to include the 
28 diarthroidal joint count (DAS28), Simplified Disease Activity Index (SDAI), Clinical Disease 
Activity Index (CDAI), and a Boolean definition as recently proposed jointly by American 
College of Rheumatology (ACR)/European League Against Rheumatism (EULAR) (Felson et al.
2011).  The current focus on arresting disease activity results from an understanding that 
persistent joint inflammation leads to progressive joint destruction manifested by cartilage loss, 
erosive damage to juxta-articular bone, and resultant functional impairment; that erosive bone 
changes occur within months of disease onset; and that early and aggressive treatment increases 
the likelihood of disease control (Klareskog et al. 2009; Colmegna et al. 2012).
Despite a variety of approved agents for RA, complete or sustained disease remission is unusual.  
Conventional disease-modifying anti-rheumatic drugs (cDMARDs) have been used with some 
success.  Patients often receive 1 or more of these medications (for example, methotrexate
[MTX], sulfasalazine, hydroxychloroquine, leflunomide, azathioprine, gold salts, and 
cyclosporine), typically in combination with low-dose oral or intra-articular glucocorticoids.  In 
addition to cDMARDs, biological agents that block or antagonize critical inflammatory 
mediators, T cells, or B cells can reduce pain and swelling and provide joint protection against 
structural damage.  The efficacy of these biologics, particularly in combination with MTX, has 
been shown to have a clinically important effect on the signs and symptoms of RA
(Fleischmann 2005); however, a majority of patients do not go into remission or achieve a 50% 

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improvement in ACR criteria (ACR50) in a clinical trial setting.  During treatment with tumor 
necrosis factor-alpha (TNF-α) antagonists, approximately 30% of patients fail to achieve a 20%
improvement in ACR criteria (ACR20; primary failure), and more patients lose efficacy during 
therapy (secondary failure; Rubbert-Roth and Finckh 2009).  Disease progression can still occur 
even for patients who achieve apparent adequate control of their signs and symptoms with 
cDMARDs and/or biologic therapies (Klareskog et al. 2009; Rubbert-Roth and Finckh 2009).  
Accordingly, a significant unmet need remains for more effective and better tolerated treatments 
for RA.
Members of the Janus kinase (JAK) family of protein tyrosine kinases (JAK1, JAK2, JAK3, and 
tyrosine kinase 2 [TYK2]) play an important role in signal transduction following cytokine and 
growth factor binding to their receptors.  Aberrant production of cytokines and growth factors 
has been associated with a number of chronic inflammatory conditions, including RA.  Many of 
the pro-inflammatory cytokines implicated in the pathogenesis of RA, including interleukin-6 
(IL-6) and interferon-gamma, use cell signaling that involves the JAK/signal transducers and 
activators of transcription (STAT) pathways.  Inhibition of JAK-STAT signaling can target 
multiple RA-associated cytokine pathways and thereby reduce inflammation, cellular activation, 
and proliferation of key immune cells as demonstrated with other JAK inhibitors (Williams et al.
2008; Kremer et al. 2009).  
Baricitinib is an orally available, selective JAK inhibitor with excellent potency and selectivity 
for JAK1 (inhibitory concentration of 50% [IC50] = 5.9 nM) and JAK2 (IC50 = 5.7 nM) and less 
potency for JAK3 (IC50 ≥400 nM) or TYK2 (IC50 = 53 nM) (Fridman et al. 2010).  Baricitinib is 
being developed for treatment of patients with moderately to severely active RA who are either 
intolerant to MTX treatment or who have had an inadequate response to disease-modifying 
antirheumatic drugs (DMARDs), either conventional or biologic.  One completed and 2 currently 
ongoing Phase 2 studies have evaluated the clinical utility of baricitinib as treatment for patients 
with active RA.  In the completed study (I4V-MC-JADC [JADC], conducted by Incyte 
Corporation), administration of baricitinib at doses of 4, 7, or 10 mg daily for up to 24 weeks 
resulted in improved signs and symptoms in patients with an inadequate response to DMARDs, 
including biologics.  A relatively flat dose response was observed for the efficacy parameters,
with the 4-mg dose performing as well as the 7- and 10-mg doses.  The proportions of patients 
who were ACR responders generally decreased in the off-treatment follow-up period (from 
Week 24 to Week 28).  
In an ongoing Phase 2 study (I4V-MC-JADA [JADA]), administration of baricitinib at doses of 
1, 2, 4, and 8 mg daily for up to 12 weeks with continued administration of the 2-, 4-, and 8-mg 
doses for up to 24 weeks resulted in improved signs and symptoms in patients with an inadequate 
response to MTX.  The observed treatment effect in the 4- and 8-mg dose groups was similar,
confirming the flat dose response observed in Study JADC.  The treatment effect in these dose 
groups was larger than that observed in the 1- and 2-mg dose groups.  The 1- and 2-mg dose 
groups offered some clinical effectiveness relative to placebo treatment.  Patients completing 
24 weeks of treatment could enter an extension study that is currently ongoing.  A third Phase 2 
study (I4V-JE-JADN) is ongoing in Japan.  The safety profile for baricitinib has been informed 

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by results from nonclinical and clinical studies evaluating a wide range of doses (up to 20 mg 
once daily [QD]).  There are a number of potential risks recognized for baricitinib that will be 
followed carefully in the Phase 3 development program.  Important laboratory monitoring 
guidance for baricitinib include decreased hemoglobin; increased total cholesterol, high-density 
lipoprotein (HDL), low-density lipoprotein (LDL), and triglycerides; and decreased neutrophils 
and other phagocytic white cell lines (within the normal reference range).  More information 
about the known and expected benefits, risks, and reasonably anticipated adverse events (AEs) 
may be found in the investigator’s brochure (IB).  Information on AEs expected to be related to 
the study drug may be found in Section 7 (Development Core Safety Information) of the IB.  
Information on serious AEs (SAEs) expected in the study population independent of drug 
exposure will be assessed by the sponsor in aggregate periodically during the course of the study 
and may be found in Section 6 (Effects in Humans) of the IB.  
There are 6 Phase 3 Studies including I4V-CR-JAGS.  The remaining 5 Phase 3 studies are 
described below.  Study I4V-MC-JADV (JADV) is investigating the efficacy and safety of 
baricitinib in patients with active RA.  Study JADV is a double-blind, placebo- and 
active-controlled study investigating the efficacy and safety of baricitinib (4 mg QD) in patients 
with active RA who have had an inadequate response to MTX (MTX-IR).  The study is 52 weeks 
in duration and includes assessment of structural joint damage.  Study I4V-MC-JADZ is a 
double-blind, active-controlled study investigating the efficacy and safety of baricitinib (4 mg 
QD), administered as monotherapy or in combination with MTX, in patients with early RA who 
have had limited or no treatment with DMARDs.  Methotrexate, administered as monotherapy 
and titrated to the highest tolerated dose, serves as the active comparator.  Study I4V-MC-JADX 
(JADX) is a double-blind, placebo-controlled study investigating the efficacy and safety of 
baricitinib (2 mg QD or 4 mg QD) administered with background cDMARD(s) in patients with 
active RA who have had an inadequate response to conventional DMARDs.  Study I4V-MC-
JADW (JADW) is a double-blind, placebo-controlled study investigating the efficacy and safety 
of baricitinib (2 mg QD or 4 mg QD) administered with background cDMARD(s) in patients 
with active RA who have had an inadequate response to biologic DMARDs.  Patients completing 
any of the above studies are eligible for enrollment in Study I4V-MC-JADY (JADY), a long-
term extension study investigating the safety of baricitinib with prolonged administration (up to
2 additional years of treatment).  
Given the continuing unmet medical need in patients with moderately to severely active RA, the 
efficacy of baricitinib demonstrated in Phase 2 studies, and the acceptable safety profile for 
baricitinib observed through the current stage of development, Phase 3 testing is appropriate.  
Study I4V-CR-JAGS (JAGS) is a 52-week, double-blind, placebo-controlled study to assess the 
efficacy and safety of baricitinib (4 mg QD) in patients with moderately to severely active RA 
who have had an inadequate response to MTX (MTX-IR).

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6. Objectives
6.1.
Primary Objective
The primary objective of the study is to determine whether baricitinib is superior to placebo in 
the treatment of patients with moderately to severely active RA despite methotrexate treatment 
(that is, MTX-IR), as assessed by the proportion of patients achieving ACR20 at Week 12.
6.2.
Secondary Objectives
The secondary objectives of the study are to evaluate the efficacy of baricitinib versus placebo as 
assessed by:

change from baseline to Week 12 in Health Assessment Questionnaire-Disability Index 
(HAQ-DI) score 

change from baseline to Week 12 in DAS28-high-sensitivity C-reactive protein (hsCRP)

proportion of patients achieving an SDAI score ≤3.3 at Week 12 

mean duration of morning joint stiffness in the 7 days prior to Week 12  as collected in 
diaries

mean severity of morning joint stiffness in the 7 days prior to Week 12 as collected in 
diaries 

mean Worst Tiredness numeric rating scale (NRS) in the 7 days prior to Week 12 as 
collected in diaries

mean Worst Joint Pain NRS in the 7 days prior to Week 12 as collected in diaries.
6.3.
Exploratory Objective
The exploratory objectives in the study include efficacy evaluation of baricitinib as assessed by:

change from baseline at Weeks 16, 24 and 52 in structural joint damage as measured by 
modified Total Sharp Score (mTSS; van der Heijde 2000)

proportion of patients with mTSS change ≤0 from baseline at Weeks 16, 24, and 52

change from baseline to Weeks 16, 24, and 52 in joint space narrowing and bone erosion 
scores

proportion of patients achieving DAS28-hsCRP ≤3.2 and DAS28-hsCRP <2.6 at 
Weeks 12, 24, and 52

proportion of patients achieving HAQ-DI improvement ≥0.22 and ≥0.3 at Weeks 12, 24, 
and 52

proportion of patients achieving ACR20 at Week 24 and Week 52

proportion of patients achieving ACR50 at Weeks 12, 24, and 52

proportion of patients achieving 70% improvement in ACR criteria (ACR70) at 
Weeks 12, 24, and 52

percentage change from baseline to Weeks 12, 24, and 52 in individual components of the 
ACR Core Set

change from baseline through Week 52 in DAS28-hsCRP

change from baseline through Week 52 in DAS28-erythrocyte sedimentation rate (ESR)

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
proportion of patients achieving DAS28-ESR ≤3.2 and DAS28-ESR <2.6 at Weeks 12, 
24, and 52

change from baseline to Week 24 and Week 52 in HAQ-DI score

change from baseline to Weeks 12, 24, and 52 in CDAI score

change from baseline to Weeks 12, 24, and 52 in SDAI score

proportion of patients achieving a CDAI score ≤2.8 at Weeks 12, 24, and 52

proportion of patients achieving an SDAI score ≤3.3 at 24, and Week 52

proportion of patients achieving ACR/EULAR remission according to the Boolean-based 
definition at Weeks 12, 24, and 52

proportion of patients achieving moderate and good EULAR responses based on the 
DAS28 at Weeks 12, 24, and 52

evaluation of hybrid ACR (bounded) response at Weeks 12, 24 and 52

change from baseline to Week 12, Week 24, and Week 52 in Functional Assessment of 
Chronic Illness Therapy Fatigue (FACIT-F) scale scores

change from baseline to Weeks 12, 24 and 52 in European Quality of Life-5 Dimensions-
5 Level (EQ-5D-5L) scores

change from baseline to Weeks 12, 24 and 52 in Work Productivity and Activity 
Impairment-Rheumatoid Arthritis (WPAI-RA) scores

evaluation of healthcare resource utilization through Week 52

change from baseline to Weeks 12, 24 and 52 in duration of morning joint stiffness 
assessed at the visit using an electronic patient-reported outcomes (ePRO) tablet

change from baseline to Weeks 12, 24 and 52 in Worst Tiredness NRS assessed at the 
visit using an ePRO tablet

change from baseline to Weeks 12, 24 and 52 in Worst Joint Pain NRS assessed at the 
visit using an ePRO tablet.

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7. Investigational Plan
7.1.
Summary of Study Design
Study JAGS will be a 52-week, Phase 3, multicenter, randomized, double-blind, placebo-
controlled, parallel-group study comparing the efficacy of baricitinib versus placebo in patients 
with moderately to severely active RA who have had an insufficient response to MTX and who 
have never been treated with a biologic DMARD (that is, MTX-IR patients).  
Baricitinib will be administered as a 4-mg tablet QD.  The dose for patients with renal 
impairment, defined as estimated glomerular filtration rate (eGFR) <60 mL/min/1.73 m
2, will be 
2 mg baricitinib QD. Patients not assigned to the baricitinib treatment arm will receive either a 
4-mg or 2-mg matching placebo tablet.  
Planned enrollment is approximately 288 randomized patients: 144 to receive baricitinib, and 
144 to receive placebo. After the Week 52 study visit, eligible patients may proceed to a 
separate extension study (Study JADY) lasting for up to 49 months or to the posttreatment 
follow-up period of this study (Part C).
Study JAGS will consist of 4 parts:  

Screening:  Screening period lasting from 3 to 42 days prior to Visit 2 (Week 0)

Part A:  double-blind, placebo-controlled period from Week 0 through Week 24

Part B:  open-label period from the end of Week 24 through Week 52

Part C:  posttreatment follow-up period

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Figure JAGS.7.1 illustrates the study design.
Abbreviations:  MTX = methotrexate, V = visit, W = week.
Note:
Diagonal dashed arrows indicate an option for rescue therapy.  The diagonal solid arrow indicates a 
mandatory change to baricitinib treatment (at Week 24 for placebo-treated patients).
Figure JAGS.7.1.
Illustration of study design for Clinical Protocol I4V-CR-JAGS.
7.1.1. Screening Period
This is a screening period of not less than 3 days and not more than 42 days. In exceptional
circumstances, the screening window can be extended after consultation with the Sponsor.  
Patients will be screened for study eligibility at Visit 1 and will be randomized at Visit 2 to 
continue in Part A.
7.1.2. Part A and Part B:  24-Week Double-Blind Placebo- Controlled,
(Part A) Period and 28-Week Open-Label (Part B) Period
Patients on a background of MTX will be randomized at a 1:1 ratio to 1 of 2 treatment arms 
(baricitinib or placebo):

Patients randomized to baricitinib will be administered a 4-mg tablet QD (or 2 mg 
baricitinib tablet QD if eGFR <60 mL/min/1.73 m2) starting at Week 0 (Visit 2) through 
Week 52 (Visit 15).

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
Patients randomized to placebo will be administered a placebo tablet QD starting at 
Week 0 (Visit 2) through Week 24 (the morning of Visit 11).  At Week 24, patients will 
be administered baricitinib 4 mg QD (or 2 mg baricitinib QD if eGFR
<60 mL/min/1.73 m2) through Week 52 (Visit 15).  Patients will be eligible for rescue 
treatment beginning at Week 16 (Visit 9).  Details of the rescue are listed in Section 
9.5.1.  
Patients will remain on background MTX, nonsteroidal anti-inflammatory drugs (NSAIDs), 
analgesics, and/or corticosteroids (see Section 9.8 for guidelines on adjustments to concomitant 
therapy).  Patients will take their assigned doses of study drugs as directed.  The primary efficacy 
endpoint will be at Week 12, and the final visit during Part A will be at Week 24.  The final visit 
during Part B will be at Week 52 (Visit 15).  The structural joint damage endpoints will be at 
Weeks 16, 24, and 52.  All patients who complete the Week 52 study visit will be eligible for 
inclusion in extension Study JADY.  
7.1.3. Part C:  Posttreatment Follow-Up Period
Patients who are not enrolled in the extension Study JADY will have a Follow-Up Visit 
(Visit 801) approximately 28 days after the last dose of study drug.  
Patients who discontinue from the study prior to Week 52 for any reason will have an Early 
Termination Visit performed, including x-rays.  The Early Termination Visit should be 
performed as soon as logistically possible because this visit includes assessment of safety.  
Infrequently, patient and investigator availability may be such that the Early Termination Visit 
and the Follow-Up Visit may occur on or about the same date.  In this instance, the visits may be 
combined and should occur approximately 28 days after the last dose of study drug.  All 
activities required for the Early Termination Visit should be completed according to the Study 
Schedule (Attachment 1).
7.1.4. Study Extensions
Patients who complete this study through Visit 15 will be eligible to participate in Study JADY, 
if enrollment criteria for Study JADY are met.
7.2.
Discussion of Design and Control
Based on efficacy, safety, and pharmacokinetic (PK) data from the Phase 2 studies (JADC and 
JADA), Eli Lilly and Company (Lilly) has selected a single dose of 4 mg QD baricitinib (with 
dose adjustment for renal dysfunction) for evaluation in this study (see Section 9.4 for rationale).
The Week 12 primary efficacy endpoint was chosen based on the results of Studies JADC and 
JADA.  In these studies, efficacy as measured by ACR20 response was observed as early as 
2 weeks after initial administration of baricitinib followed by near-maximum efficacy response 
achieved by Week 12.  The 52-week treatment period will allow evaluation of the long-term 
effect of baricitinib on structural joint damage.
All patients will be required to be on background MTX treatment at baseline.  Other background 
therapies, including NSAIDs and low dose oral corticosteroids, are permitted during the study 

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for patients who are on stable doses of these treatments at baseline.  Patients should remain on 
the same dose of MTX throughout the study; however, the MTX dose may be adjusted for safety 
reasons.
To prevent potential unblinding due to observed efficacy or laboratory changes, a “dual assessor” 
approach will be used to evaluate efficacy and safety.  The Joint Assessor (or designee) should 
be a rheumatologist or skilled arthritis assessor.  The Joint Assessor will be responsible for 
completing the joint counts.  To ensure consistent joint evaluation throughout the trial, individual 
patients should be evaluated by the same Joint Assessor for all study visits.  The Joint Assessor 
must not access or discuss with the patient the patient-reported assessments, Physician’s Global 
Assessment of Disease Activity (visual analog scale [VAS]), and safety assessments.
The Safety Assessor (or designee) should be a rheumatologist (or medically qualified physician) 
and will have access to both safety and efficacy data.  The Safety Assessor may be the Principal 
Investigator (PI).  The Safety Assessor will be responsible for completing the Physician’s Global 
Assessment of Disease Activity (VAS).  To ensure consistent Physician’s Global Assessment of 
Disease Activity (VAS) throughout the trial, the instrument should be evaluated by the same 
physician at all study visits.  The Safety Assessor will have access to source documents, 
laboratory results, and case report forms (CRFs) and will be responsible for making treatment 
decisions based on a patient’s clinical response and laboratory parameters.
All patients in Study JAGS will be offered rescue therapy starting at Week 16 in line with 
precedent from recent clinical trials.  Patients who are determined to be nonresponders to their 
originally assigned treatment will be reassigned to treatment with baricitinib at Week 16.  
Patients originally assigned to baricitinib will be rescued to the same dose of baricitinib to 
maintain the study blind.  Patients not rescued at Week 16 may be rescued to treatment with 
baricitinib at the discretion of the investigator anytime thereafter.  Patients initially randomized 
to placebo and not rescued will be reassigned to receive baricitinib at Week 24 to limit exposure 
to inactive treatment.  Patients not experiencing improvement in signs and symptoms following 
approximately 4 weeks of rescue treatment should be discontinued from the study. Patients may 
be rescued only once.  See Section 9.5.1 for details of rescue treatment.

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8. Study Population
The study population will be comprised of patients diagnosed with RA with active disease who 
have failed to adequately respond to MTX.  Study investigator(s) will review patient records and 
screening test results to determine that the patient meets all inclusion and exclusion criteria to 
qualify for participation in the study.
Individuals who do not meet the criteria for participation in this study (screen failure) may be re-
screened.  Individuals may be re-screened up to 1 time.  The interval between re-screenings 
should be approximately 30 days.  Each time re-screening is performed, the individual must sign 
a new informed consent form (ICF) and will be assigned a new identification number.
8.1.
Entry Criteria
Patients may enter into the study once they have signed the ICF.  Patients may be assessed for 
study entry on the basis of readily available information (that is, information that does not 
require informed consent from the subject).
8.1.1. Inclusion Criteria
Patients are eligible for entry into the study (ie, eligible to sign consent) only if they meet all of 
the following criteria:
[1]
are at least 18 years of age
[2]
have a diagnosis of adult-onset RA as defined by the ACR/EULAR 2010
Criteria for the Classification of RA (Aletaha et al. 2010)
[3]
have moderately to severely active RA defined as the presence of at least 
6/68 tender joints and at least 6/66 swollen joints
a.
If significant surgical treatment of a joint has been performed, that
joint cannot be counted in the TJC and SJC for entry or enrollment 
purposes.
[4]
have a C-reactive protein (CRP) (or hsCRP) measurement ≥6mg/L based on 
the most recent data (if available)
[5]
have had regular use of MTX for at least the 12 weeks prior to study entry at a 
dose that, in accordance with local clinical practice, is considered acceptable 
to adequately assess clinical response.  The dose of MTX must have been a 
stable, unchanging oral dose of 7.5 to 25 mg/week (or the equivalent 
injectable dose) for at least the 8 weeks prior to study entry.  The dose of 
MTX is expected to remain stable throughout the study and may be adjusted 
only for safety reasons.
a.
For patients entering the trial on MTX doses <15 mg/week, there 
must be clear documentation in the medical record that higher doses 
of MTX were not tolerated or that the dose of MTX is the highest 
acceptable dose based on local clinical practice guidelines.

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b. Local standard of care should be followed for concomitant 
administration of folic acid.
[6]
are able to read, understand, and give written informed consent.
8.1.2. Exclusion Criteria
Patients will be excluded from participating in the study if they meet any of the following 
criteria:
[7]
are currently receiving corticosteroids at doses >10 mg of prednisone per day 
(or equivalent) or have been receiving an unstable dosing regimen of 
corticosteroids within 2 weeks of study entry or within 6 weeks of planned 
randomization
[8]
have started treatment with NSAIDs (for which the NSAID use is intended for 
treatment of signs and symptoms of RA) within 2 weeks of study entry or 
within 6 weeks of planned randomization or have been receiving an unstable 
dosing regimen of NSAIDs within 2 weeks of study entry or within 6 weeks 
of planned randomization
[9]
are currently receiving concomitant treatment with MTX, 
hydroxychloroquine, and sulfasalazine or combination of any 3 cDMARDs
[10] are currently receiving or have received cDMARDs (for example, gold salts, 
cyclosporine, azathioprine, or any other immunosuppressives) other than
MTX, hydroxychloroquine (up to 400 mg/day), or sulfasalazine (up to 
3000 mg/day) within 8 weeks prior to study entry
a.
Doses of hydroxychloroquine or sulfasalazine should be stable for at 
least 8 weeks prior to study entry; if either has been recently 
discontinued, the patient must not have taken any dose within 4 
weeks prior to study entry.
b. Immunosuppression related to organ transplantation is not 
permitted.
[11] have received leflunomide in the 12 weeks prior to study entry (or within 
4 weeks prior to study entry if the standard 11 days of cholestyramine is used 
to washout leflunomide)
[12] have started a new physiotherapy treatment for RA in the 2 weeks prior to 
study entry
[13] have ever received any biologic DMARD (such as tumor necrosis factor 
(TNF), interleukin-1, interleukin-6 (IL-6), or T-cell- or B-cell-targeted 
therapies)
[14] have received interferon therapy (such as Roferon-A, Intron-A, Rebetron, 
Alferon-N, Peg-Intron, Avonex, Betaseron, Infergen, Actimmune, Pegasys) 
within 4 weeks prior to study entry or are anticipated to require interferon 
therapy during the study

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[15] have received any parenteral corticosteroid administered by intramuscular or 
intravenous injection within 2 weeks prior to study entry or within 6 weeks 
prior to planned randomization or are anticipated to require parenteral 
injection of corticosteroids during the study
[16] have had 3 or more joints injected with intraarticular corticosteroids or 
hyaluronic acid within 2 weeks prior to study entry or within 6 weeks prior to 
planned randomization
a.
Joints injected with intraarticular corticosteroids or hylarunic acid 
within 2 weeks prior to study entry or within 6 weeks prior to 
planned randomization cannot be counted in the TJC and SJC for 
entry or enrollment purposes.
[17] have active fibromyalgia that, in the investigator’s opinion, would make it 
difficult to appropriately assess RA activity for the purposes of this study
[18] have a diagnosis of any systemic inflammatory condition other than RA such 
as, but not limited to, juvenile chronic arthritis, spondyloarthropathy, Crohn’s 
disease, ulcerative colitis, psoriatic arthritis, active vasculitis or gout
a.
Patients with secondary Sjögren’s syndrome are not excluded.
[19] have a diagnosis of Felty’s syndrome
[20] have had any major surgery within 8 weeks prior to study entry or will require 
major surgery during the study that, in the opinion of the investigator in 
consultation with Lilly or its designee, would pose an unacceptable risk to the 
patient
[21] have experienced any of the following within 12 weeks of study entry:  
myocardial infarction, unstable ischemic heart disease, stroke, or New York 
Heart Association Stage IV heart failure
[22] have a history or presence of cardiovascular, respiratory, hepatic, 
gastrointestinal, endocrine, hematological, neurological, or neuropsychiatric 
disorders or any other serious and/or unstable illness that, in the opinion of the 
investigator, could constitute a risk when taking investigational product or 
could interfere with the interpretation of data
[23] are largely or wholly incapacitated permitting little or no self-care, such as 
being bedridden or confined to a wheelchair
[24] have an eGFR based on the most recent available serum creatinine using the 
Modification of Diet in Renal Disease (MDRD) method of 
<40 mL/min/1.73 m2
[25] have a history of chronic liver disease with the most recent available aspartate 
aminotransferase (AST) or alanine aminotransferase (ALT) >1.5 times the 
ULN or the most recent available total bilirubin 1.5 times the ULN

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[26] have a history of lymphoproliferative disease; or have signs or symptoms 
suggestive of possible lymphoproliferative disease, including 
lymphadenopathy or splenomegaly; or have active primary or recurrent 
malignant disease; or have been in remission from clinically significant 
malignancy for <5 years
a.
Patients with cervical carcinoma in situ that has been resected with 
no evidence of recurrence or metastatic disease for at least 3 years 
may participate in the study.
b. Patients with basal cell or squamous epithelial skin cancers that have
been completely resected with no evidence of recurrence for at least 
3 years may participate in the study.
[27] have been exposed to a live vaccine within 12 weeks prior to planned 
randomization or are expected to need/receive a live vaccine during the course 
of the study (with the exception of herpes zoster vaccination)
a.
All patients who have not received the herpes zoster vaccine at study 
entry will be encouraged to do so prior to randomization; 
vaccination must occur >30 days prior to randomization and start of 
study drug.  Patients will be excluded if they were exposed to herpes
zoster vaccination within 30 days of planned randomization.
b. Investigators should review the vaccination status of their patients 
and follow the local guidelines for adult vaccination with nonlive 
vaccines intended to prevent infectious disease prior to entering 
patients into the study.
[28] have a current or recent (<30 days prior to study entry) clinically serious viral, 
bacterial, fungal, or parasitic infection
[29] have had symptomatic herpes zoster infection within 12 weeks prior to study 
entry
[30] have a history of disseminated/complicated herpes zoster (for example, 
multidermatomal involvement, ophthalmic zoster, central nervous system
(CNS) involvement, or postherpetic neuralgia)
[31] are immunocompromised and, in the opinion of the investigator, are at an 
unacceptable risk for participating in the study
[32] have a history of active hepatitis B virus (HBV), hepatitis C virus (HCV), or 
human immunodeficiency virus (HIV)
[33] have had household contact with a person with active tuberculosis (TB) and 
did not receive appropriate and documented prophylaxis for TB
[34] have evidence of active TB or have previously had evidence of active TB and 
did not receive appropriate and documented treatment
[35] are pregnant or nursing at the time of study entry

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[36] are females of childbearing potential who do not agree to use 2 forms of 
highly effective birth control when engaging in intercourse while enrolled in 
the study and for at least 28 days following the last dose of orally 
administered investigational product
a.
Females of nonchildbearing potential are defined as women 
60 years of age, women 40 and <60 years of age who have had a 
cessation of menses for at least 12 months, or women who are 
congenitally or surgically sterile (that is, have had a hysterectomy or 
bilateral oophorectomy or tubal ligation).
b. The following birth control methods are considered highly effective 
(the patient should choose 2 to be used with their partner):

oral, injectable, or implanted hormonal contraceptives

condom with a spermicidal foam, gel, film, cream, or 
suppository

occlusive cap (diaphragm or cervical/vault caps) with a 
spermicidal foam, gel, film, cream, or suppository

intrauterine device

intrauterine system (for example, progestin-releasing coil)

vasectomized male (with appropriate postvasectomy 
documentation of the absence of sperm in the ejaculate)
[37] are males who do not agree to use 2 forms of highly effective birth control 
(see above) while engaging in sexual intercourse with female partners of 
childbearing potential while enrolled in the study and for at least 28 days 
following the last dose of orally administered investigational product
[38] have donated >500 mL of blood within 30 days prior to study entry or intend 
to donate blood during the course of the study
[39] have a history of chronic alcohol abuse, intravenous drug abuse, or other illicit 
drug abuse within the 2 years prior to study entry
[40] have previously been randomized in this study or any other study 
investigating baricitinib
[41] are unable or unwilling to make themselves available for the duration of the 
study and/or are unwilling to follow study restrictions and procedures
[42] have received prior treatment with an oral JAK inhibitor
[43] are investigator site personnel directly affiliated with this study and/or their 
immediate families.  Immediate family is defined as a spouse, parent, child, or 
sibling, whether biological or legally adopted
[44] are Lilly or Incyte employees or either’s designee

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[45] are currently enrolled in or have discontinued within 30 days of study entry 
from a clinical trial involving an investigational product or nonapproved use 
of a drug or device or are concurrently enrolled in any other type of medical 
research judged not to be scientifically or medically compatible with this 
study.
8.2.
Enrollment Criteria
8.2.1. Inclusion Criteria
Entered patients are eligible for enrollment into the study (that is, eligible for randomization) 
only if they continue to meet all entry criteria (see above) at the time of randomization and meet
the following enrollment criteria:
[46] have moderately to severely active RA defined as the presence of at least 
6/68 tender joints and at least 6/66 swollen joints assessed at Visit 1 and Visit 
2 at the time of randomization
[47] have an hsCRP measurement ≥6mg/L based on Visit 1 laboratory results by 
central laboratory testing
The hsCRP measurement may be repeated once within approximately 2 weeks 
of the initial value, and the value resulting from repeat testing may be 
accepted for enrollment eligibility if it meets the eligibility criterion.
[48] have at least 1 joint erosion in hand, wrist, or foot joints based on radiographic 
interpretation by the central reader and be rheumatoid factor or anticyclic 
citrullinated peptide (anti-CCP) antibody positive; or have at least 3 joint 
erosions in hand, wrist, or foot joints based on radiographic interpretation by 
the central reader regardless of rheumatoid factor or anti-CCP antibody status
(radiographic images acquired within 4 weeks of study entry may be 
submitted to the central reader to confirm eligibility). If a patient undergoes 
rescreening, radiographic images acquired as part of initial screening and 
within 10 weeks of randomization may be used.
8.2.2. Exclusion Criteria
Entered patients are ineligible for enrollment (that is, ineligible for randomization) and should be 
discontinued from the study if they meet any of the following criteria:
[49] have screening laboratory test values, including thyroid-stimulating hormone 
(TSH), outside the reference range for the population or investigative site that, 
in the opinion of the investigator, pose an unacceptable risk for the patient’s 
participation in the study
a.
Patients who are receiving thyroxine as replacement therapy may 
participate in the study provided stable therapy has been 
administered for ≥12 weeks and TSH is within the laboratory’s 
reference range.

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The TSH test may be repeated once within approximately 2 weeks of the 
initial value, and the value resulting from repeat testing may be accepted for 
enrollment eligibility if it meets the eligibility criterion.
[50] have any of the following specific abnormalities on screening laboratory tests:

AST or ALT >1.5 times the ULN

total bilirubin ≥1.5 times the ULN

hemoglobin <10.0 g/dL (100.0 g/L)

total white blood cell count <2500 cells/L

neutropenia (absolute neutrophil count <1200 cells/L)

lymphopenia (lymphocyte count <750 cells/L)

thrombocytopenia (platelets <100,000/L)

eGFR <40 mL/min/1.73 m2
In the case of any of the aforementioned laboratory abnormalities, the tests 
may be repeated once within approximately 2 weeks of the initial values, and 
values resulting from repeat testing may be accepted for enrollment eligibility 
if they meet the eligibility criterion.
[51] have screening electrocardiogram (ECG) abnormalities that, in the opinion of 
the investigator or the sponsor, are clinically significant and indicate an 
unacceptable risk for the patient’s participation in the study (for example, 
Fridericia’s corrected QT interval >500 msec)
[52] have symptomatic herpes simplex at the time of study enrollment
[53] have evidence of active TB as documented by a positive purified protein 
derivative (PPD) test (≥5-mm induration between approximately 2 and 3 days 
after application, regardless of vaccination history), medical history, clinical 
symptoms, and abnormal chest x-ray at screening
a.
The QuantiFERON®-TB Gold or the T-SPOT®.TB test (if available) 
may be used instead of the PPD test.  Patients are excluded from the 
study if the test is not negative and there is clinical evidence of 
active TB.
[54] have evidence of latent TB (as documented by a positive PPD, no clinical 
symptoms consistent with active TB, and a normal chest x-ray at screening)
unless patients complete at least 4 weeks of appropriate treatment prior to 
randomization and agree to complete the remainder of treatment while in the 
trial

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a.
If the PPD test is positive and the patient has no medical history or 
chest x-ray findings consistent with active TB, the patient may have 
a QuantiFERON-TB Gold or T-SPOT.TB test (if available).  If the 
test results are not negative, the patient will be considered to have 
latent TB (for purposes of this study).
b. The QuantiFERON-TB Gold or T-SPOT.TB test (if available) may 
be used instead of the PPD test.  If the test results are positive, the 
patient will be considered to have latent TB.  If the test is not 
negative, the test may be repeated once within approximately 
2 weeks of the initial value.  If the repeat test results are again not 
negative, the patient will be considered to have latent TB (for 
purposes of this study).
c.
Exceptions include patients with a history of active or latent TB who 
have documented evidence of appropriate treatment.
[55] have a positive test for HBV defined as:
a.
positive for hepatitis B surface antigen, or
b. positive for anti-hepatitis B core antibody but negative for hepatitis 
B surface antibody (HBsAb), or
c.
for patients enrolled in other countries, if required, positive for 
anti-HBsAb and positive for HBV deoxyribonucleic acid (DNA).
If any of the HBV tests have an indeterminate result, confirmatory testing will 
be performed by an alternate method.
[56] have HCV (positive for anti-hepatitis C antibody with confirmed presence of 
HCV)
[57] have evidence of human HIV infection and/or positive HIV antibodies
[58] Are women ≥40 and <60 years of age who have had a cessation of menses for 
at least 12 months, have a follicle-stimulating hormone (FSH) value 
<40 mIU/mL, and do not agree to use 2 forms of highly effective methods of 
birth control when engaging in intercourse while enrolled in the study and for 
at least 28 days following the last dose of orally administered investigational 
product, unless they are congenitally or surgically sterile (that is, have had a 
hysterectomy, bilateral oophorectomy, or tubal ligation)
[59] Have received treatment with traditional medicine that has known 
immunosuppressant or immunomodulatory effects, such as Pafulin or 
Leigongteng (Common Threewingnut Root) within 30 days before Visit 2
[60] Have a current or recent (during screening period) clinically serious viral, 
bacterial, fungal, or parasitic infection

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If patients are entered into the study while taking medications that require discontinuation before 
randomization, those patients should only be asked to discontinue these medications after it has 
been determined that they will be eligible for randomization.
Patients who are entered into the study but do not meet enrollment criteria should be 
discontinued from the study.  These patients can be re-entered into the trial (ie, give repeat 
consent) if the investigator believes that the patient might meet enrollment criteria at a future 
date.  The investigator should wait approximately 1 month before re-entering a patient into the 
study.
8.2.3. Rationale for Exclusion of Certain Study Candidates
The rationale for the entry Exclusion Criteria is as follows:  Exclusion Criteria [7] to [16] 
exclude individuals who are taking or who may take RA medications or treatments that interfere 
with the ability to assess the safety and efficacy of baricitinib.  Exclusion Criteria [17] to [26] 
exclude individuals with previous or concomitant medical conditions that increase the risk for 
their participation in the study.  Exclusion Criteria [27] to [34] exclude individuals who are at an 
increased risk for infections or infectious complications.  Exclusion Criteria [35] to [37] exclude 
individuals who are pregnant, breastfeeding, at risk for becoming pregnant, or at risk for 
impregnating their partner during the study.  Exclusion Criteria [38] to [45] exclude individuals 
who may not be compliant with study-related procedures or whose participation in the study may 
introduce bias.
The rationale for the enrollment Exclusion Criteria is as follows:  Exclusion Criteria [49] to [52] 
exclude individuals with concomitant medical conditions that increase the risk for their 
participation in the study.  Exclusion Criteria [53] to [57] and [60] exclude individuals who are at 
an increased risk for infections or infectious complications.  Exclusion Criterion [58] excludes 
individuals who are at risk for becoming pregnant during the study.  Exclusion Criterion [59] 
excludes individuals who are taking or who may take traditional medicines that may interfere 
with the ability to assess the safety and efficacy of baricitinib.  
8.3.
Discontinuations
8.3.1. Discontinuation of Patients
8.3.1.1.
Interruption of Study Drug
In some circumstances it may be necessary to temporarily interrupt treatment as a result of AEs
or abnormal laboratory values as described in Table JAGS.8.1 that may have an unclear 
relationship to study drug.  Except in cases of emergency, it is recommended that the investigator 
consult with Lilly (or its designee) before temporarily interrupting therapy.
The investigator must obtain approval from Lilly (or its designee) before restarting study drug 
that was temporarily discontinued because of an AE or abnormal laboratory value.  Study drug 
must be held in the following situations involving laboratory abnormalities and may be resumed 
as noted in Table JAGS.8.1.

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Table JAGS.8.1.
Criteria for Temporary Discontinuation of Investigational Product
Hold Investigational Product if the Following 
Laboratory Test Results Occur:
Investigational Product May Be Resumed after 
Approval from Lilly (or its Designee) and When:
WBC count <2000 cells/µL
WBC count 2500 cells/µL
ANC <1000 cells/µL
ANC >2000 cells/µL
Lymphocyte count <500 cells/µL
Lymphocyte count 750 cells/µL
Platelet count <75,000/µL
Platelet count 100,000/µL
eGFR <40 mL/min/1.73 m2 (from serum creatinine) for 
patients receiving the baricitinib 4 mg QD dose
eGFR 50 mL/min/1.73 m2
eGFR <30 mL/min/1.73 m2 (from serum creatinine) for 
patients receiving the baricitinib 2 mg QD dose
eGFR 40 mL/min/1.73 m2
ALT or AST >5 times ULN
ALT and AST return to <2 times ULN and 
investigational product is not considered to be the cause 
of enzyme elevation
Hemoglobin <8 g/dL
Hemoglobin 10 g/dL
Abbreviations:  ALT = alanine aminotransferase; ANC = absolute neutrophil count; AST = aspartate 
aminotransferase; eGFR = estimated glomerular filtration rate; min = minute; QD = once daily; ULN = upper 
limit of normal; WBC = white blood cell.
8.3.1.2.
Discontinuation of Study Drug
Any patient who is permanently discontinued from study drug for an AE or abnormal laboratory 
result should have the AE or abnormal laboratory value reported as an SAE (reported as Other 
Reason Serious).  If any of the criteria listed in Section 8.3.1.1 above recur after study drug is 
restarted, the patient should be permanently discontinued from study drug.  In addition, patients 
will be permanently discontinued from study drug if they experience any of the criteria listed in
Table JAGS.8.2.

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Table JAGS.8.2.
Criteria for Permanent Discontinuation of Investigational Product
Permanently Discontinue Investigational Product if any of the Following are Observed:
ALT or AST >8 times the ULN
ALT or AST >5 times the ULN persisting for more than 2 weeks after temporary interruption of investigational 
product
ALT or AST >3 times the ULN and total bilirubin level >2 times the ULN
ALT or AST >3 times the ULN with the appearance of fatigue, nausea, vomiting, right upper quadrant pain or 
tenderness, fever, rash, and/or eosinophilia (>5%)
WBC count <1000 cells/µL
Absolute neutrophil count <500 cells/µL
Lymphocyte count <200cells/µL
Hemoglobin <6.5 g/dL
Symptomatic herpes zoster
Pregnancy
Malignancy
HBV DNA ≥29 IU/mLa
Severe infection that, in the opinion of the investigator, merits the investigational product being discontinued
Abbreviations:  ALT = alanine aminotransferase; AST = aspartate aminotransferase; ULN = upper limit of normal; 
WBC = white blood cell.
a.
If an HBV DNA result of “target detected” 29 IU/mL or greater, then the patient should be referred to a 
hepatology specialist immediately.  In selected cases, investigators may temporarily continue study drug in 
accordance with current immunomodulator management in the setting of HBV DNA positivity.  This option 
may be considered in consultation with Lilly (or its designee) and evaluation of individual patient risks and 
benefits.  Refer to Section 10.3.2.2 for additional instruction on HBV DNA monitoring.
8.3.1.3.
Discontinuation from the Study
The criteria for enrollment must be followed explicitly.  If a patient who does not meet 
enrollment criteria is inadvertently enrolled, the investigator should contact Lilly or its designee 
to discuss whether the patient should be discontinued from study drug.  If the patient is 
discontinued from study drug, the patient should remain in the study to provide the follow-up 
data needed for the primary analysis (Week 12) of the entire intention-to-treat (ITT) population.
Patients may choose to withdraw from the study for any reason at any time, and the reason for 
early withdrawal will be documented.
In addition, patients will be discontinued from the study in the following circumstances:

Patient enrolls in any other clinical trial involving an investigational product or 
enrollment in any other type of medical research judged not to be scientifically or 
medically compatible with this study.

Investigator decides that the patient should be withdrawn.  If this decision is made 
because of an intolerable AE or a clinically significant laboratory value, the study 
drug is to be discontinued and appropriate measures are to be taken.  Lilly (or 
designee) is to be notified immediately.

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
Lilly (or designee) decides that the patient should be withdrawn.

Patient is noncompliant with protocol procedures.

Patient withdraws consent.

Investigator or Lilly (or designee), for any reason, stops the study.
Patients who discontinue the study early will have Early Termination procedures and follow-up 
performed as shown in the study schedule (Attachment 1).
8.3.2. Discontinuation of Study Sites
Study site participation may be discontinued if Lilly, the investigator, or the ethical review board 
(ERB) of the study site judges it necessary for medical, safety, regulatory, or other reasons 
consistent with applicable laws, regulations, and good clinical practice (GCP).
8.3.3. Discontinuation of the Study
The study will be discontinued if Lilly judges it necessary for medical, safety, regulatory, or 
other reasons consistent with applicable laws, regulations, and GCP.

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9. Treatment
9.1.
Treatments Administered
This study involves a comparison of baricitinib 4 mg administered orally QD, and placebo 
administered orally QD.  Patients will continue to take background MTX therapy during the 
course of the study. Table JAGS.9.1 shows the treatment regimens.
Table JAGS.9.1.
Treatment Regimens
Treatment 
Group
Treatments Administered
during Part A
Treatments Administered
during Part B
(Patients Not Rescued)
Treatments Administered
during Part B
(after Rescuea)
Baricitinib 
treatment

Baricitinib 4 mgb oral 
once-daily tablet
Baricitinib 4 mgb oral 
once-daily tablet 
Baricitinib 4 mgb oral 
once-daily tablet
Placebo 
comparator

Baricitinib placebo oral
once-daily tablet

Baricitinib 4 mgb oral 
once-daily tablet 
Baricitinib 4 mgb oral 
once-daily tablet
a
See Section 9.5.1 for details of rescue medication.
b
The dose for patients with renal impairment, defined as estimated glomerular filtration rate <60 mL/min/1.73 m2, 
will be 2 mg once daily.
The investigator or his/her designee will be responsible for explaining the correct use of 
investigational agent(s) to the patient, verifying that instructions are followed properly, 
maintaining accurate records of investigational product dispensing and collection, and returning 
all unused medication to Lilly or its designee at the end of the study.
In some cases, sites may destroy the material if, during the investigator site selection, the 
evaluator has verified and documented that the site has appropriate facilities and written 
procedures to dispose of clinical trial materials.
Patients will be instructed to contact the investigator as soon as possible if they have a complaint 
or problem with the investigational product so that the situation can be assessed.
9.2.
Materials and Supplies
Lilly (or designee) will provide the following primary study materials:

tablets containing 4 mg of baricitinib

tablets containing 2 mg of baricitinib

tablets containing placebo to match 4 mg baricitinib

tablets containing placebo to match 2 mg baricitinib
Investigational product will be dispensed to the patient at the PI’s study site.  Investigational 
product packaging will contain enough tablets for the longest possible interval between visits.
Investigational product will be labeled according to the country’s regulatory requirements.  All 
investigational products will be stored, inventoried, reconciled, and destroyed according to 

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applicable regulations.  Investigational products will be supplied by Lilly or its representative in 
accordance with current Good Manufacturing Practices, and will be supplied with lot numbers, 
expiry dates, and certificates of analysis (as applicable).
9.3.
Method of Assignment to Treatment
Patients who meet all criteria for enrollment will be randomized in a 1:1 ratio 
(baricitinib:placebo) to double-blind treatment at Week 0 (Visit 2). Randomization will be 
stratified by country and joint erosion status (1-2 joint erosions plus seropositivity versus at least 
3 joint erosions). 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 of baricitinib/placebo containing double-blind 
investigational product to each patient.  Each package of clinical trial material will supply 
sufficient medication for the number of weeks between visits.  Site personnel will confirm that 
they have located the correct package by entering a confirmation number found on the packages 
of investigational product into the IWRS before dispensing the package to the patient.
9.4.
Rationale for Selection of Doses in the Study
Clinical Efficacy Considerations
A single initial dose of 4 mg QD baricitinib in this study was selected based on the efficacy, 
safety, and PK data from Phase 2 Studies JADC and JADA.  In Study JADC, baricitinib doses of 
4, 7, and 10 mg QD were studied and found to produce similar degrees of efficacy across the 
measured parameters at both the Week 12 and Week 24 time points.  Study JADA included 
lower doses of baricitinib (1 and 2 mg QD) to find the minimum clinically effective dose and to 
confirm the flat dose-response curve in the dose range of 4 to 8 mg QD.  In Study JADA, a 
relatively flat dose-response curve was observed in the 4-and 8-mg QD dose groups at Week 12
across almost all measured efficacy parameters.  The 1- and 2-mg QD dose groups are 
biologically active but did not produce adequate response at Week 12 as assessed by ACR50, 
ACR70, and low disease activity and remission rates when compared to placebo and the 4- and 
8-mg dose groups.  All 4 doses were associated with reductions in hsCRP and ESR values over 
time.  Assessment of the Week 12 magnetic resonance imaging (MRI) data suggests the potential 
for the 4- and 8-mg QD baricitinib doses to have a favorable impact on reducing structural 
damage given the observed significant improvement in osteitis.
Week 24 data from Study JADA demonstrated persistence of the flat dose response between the 
4- and 8-mg QD doses.  Over the second 12-week period, continued administration of the 2-mg 
QD dose did not result in further improvement in the clinically important endpoints of ACR50, 
ACR70, DAS28-hsCRP ≤3.2, DAS28-hsCRP <2.6, and CDAI and SDAI remission rates.  
Week 24 MRI data further support the potential for the 4- and 8-mg QD doses to have a 
beneficial effect on prevention of structural damage.
Clinical Safety Considerations
Baricitinib was generally safe and well tolerated in single doses ranging from 1 to 20 mg and in 
repeat oral doses ranging from 2 to 20 mg. The most commonly reported treatment-emergent 

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AEs (TEAEs) were in the infections and infestations system organ class (SOC). The most 
common alterations in laboratory values involved decreases in hemoglobin, hematocrit, total red 
blood cells, and white blood cells (neutrophils and other white cell lines), and increases in 
platelet counts, HDL, LDL, total cholesterol, and triglycerides. Patients with RA experienced a 
mean increase in ALT/AST compared to placebo, with the mean values remaining within the 
normal reference range and clinically significant increases in ALT/AST occurring uncommonly.
Patients with impaired renal function have increased exposure to baricitinib.
Dose Adjustment for Renal Impairment
The therapeutic dose range for baricitinib was identified from concentration-efficacy 
relationships for ACR20 and DAS28-hsCRP as well as concentration-safety relationships 
identified for absolute neutrophil counts and hemoglobin.  The starting dose for this Phase 3 
study will be 4 mg QD.  As demonstrated in a study of subjects with normal renal function 
versus those with mild to end-stage renal disease (Study I4V-MC-JADL), baricitinib exposure 
increases with decreased renal function.  Based on PK simulations of baricitinib exposures for 
the mild and moderate categories of renal function (stratified as eGFR 60 to 
<90 mL/min/1.73 m2 and eGFR 30 to <60 mL/min/1.73 m2, respectively) dose adjustment is not 
required for patients with eGFR ≥60 mL/min/1.73 m2.  Patients with eGFR <60 mL/min/1.73 m2
will receive a dose of 2 mg QD, which will ensure that exposures are comparable to, but do not 
exceed, those of the 4-mg QD dose.  Lilly intends to enroll patients with eGFR no lower than 
40 mL/min/1.73 m2 in the Phase 3 trials.  Baricitinib will be discontinued if eGFR falls below 
30 mL/min/1.73 m2.  Baricitinib administration to patients with severe renal impairment (eGFR
<30 mL/min/1.73 m2) is not intended.
Summary
The clinical data known to date suggest a dosing strategy using a 4-mg QD dose as having the 
potential for providing clinically relevant efficacy response while minimizing potential risks of 
AEs.
9.5.
Selection and Timing of Doses
Each patient will receive blinded investigational product (baricitinib 4 mg or baricitinib placebo 
tablets orally QD) beginning on the day of Visit 2 (Week 0).  Baricitinib 4-mg oral dosing will 
continue daily through Visit 15 (Week 52).  Baricitinib placebo oral dosing will continue daily 
through Visit 11 (Week 24); at Visit 11 (Week 24), all patients randomized to placebo will be 
reassigned to baricitinib.
Oral investigational product should be taken at home at approximately the same time each day, 
as much as possible:

At Visit 2 (Week 0), patients will take their investigational product in the clinic.
9.5.1. Special Treatment Considerations
In consideration of the disease severity, all patients in Study JAGS will be offered rescue therapy 
starting at Week 16 if they are determined to be nonresponders.

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All patients who are non-responders (in both baricitinib and placebo arm) will receive rescue 
therapy at Week 16.  Patients who are nonresponders and who were randomized to placebo will 
be rescued with baricitinib.  To maintain study integrity through investigational product blinding, 
patients who were originally randomized to baricitinib will continue to receive baricitinib, with 
appropriate ongoing assessment of response and use of concomitant medication as needed.  
Nonresponse at Week 16 is defined as lack of improvement of at least 20% in both TJC and SJC 
at both Week 14 and Week 16 compared to baseline.  At Week 16, the IWRS will assign rescue 
treatment based on TJC and SJC values.
After Week 16, rescue therapy will be offered to patients at the discretion of the investigator 
based on TJCs and SJCs.  Once a patient has been rescued, new NSAIDS, corticosteroids, and/or 
analgesics may be added or doses of ongoing concomitant NSAIDs, corticosteroids, and/or 
analgesics may be increased at the discretion of the investigator.
A patient may only be rescued once.  If a patient continues to meet nonresponse criteria for 
4 weeks after rescue or at any time point thereafter, that patient should be discontinued from the 
study.
Nonresponders who are rescued will receive an oral tablet daily for the remainder of the study.  
Rescue therapy will be administered through Week 52.
9.6.
Continued Access to Investigational Product
After the Week 52 study visit, eligible patients may proceed to a separate extension study 
(Study JADY) lasting for up to 48 months.
9.7.
Blinding
This is a double-blind 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.  Emergency unblinding for AEs may be performed through an IWRS, which may 
supplement or take the place of emergency codes generated by a computer drug-labeling system.  
This option may be used ONLY if the patient’s well-being requires knowledge of the patient’s 
treatment assignment.  All operations resulting in an unblinding event are recorded and reported 
by the IWRS.
The investigator should make every effort to contact the Lilly clinical research physician prior to 
unblinding a patient’s treatment assignment.  If a patient’s treatment assignment is unblinded, 
Lilly must be notified immediately by telephone.
If an investigator, site personnel performing assessments, or patient is unblinded, the patient 
must be discontinued from the study.  In cases for which there are ethical reasons to have the 
patient remain in the study, the investigator must obtain specific approval from a Lilly clinical 
research physician for the patient to continue in the study.

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9.8.
Concomitant Therapy
Patients will be instructed to consult the investigator or other appropriate study personnel at the 
site before taking any new medications or supplements during the study.
As listed below, all patients will continue to take the background MTX therapy at a stable dose 
throughout the study.
Additional drugs are to be avoided during the study unless required to treat an AE or for the 
treatment of an ongoing medical condition.  Investigators should follow local guidelines for the 
management of lipid disorders.  If the need for other concomitant medications arises, 
discontinuation of the patient from study drug or the study will be at the discretion of the 
investigator in consultation with Lilly (or designee).
Patients will not be permitted to have received a live vaccination up to 12 weeks prior to baseline 
or at any time during the study (with the exception of herpes zoster vaccination, which is not 
permitted within 30 days of planned randomization or at any time during the study).
Treatment with concomitant DMARDs during the study is permitted as outlined below and in the 
inclusion/exclusion criteria:

Use of concomitant oral MTX for at least 12 weeks with treatment at a stable dose of 
7.5 to 25 mg/week (or the equivalent injectable dose) for at least 8 weeks prior to entry 
into the study is required for study participation.  Patients should remain on the same 
dose of MTX throughout Part A and Part B of the study; however, the MTX dose may be 
adjusted for safety reasons.

Patients may also be on concomitant hydroxychloroquine or sulfasalazine.  If receiving 
hydroxychloroquine (up to 400 mg/day) or sulfasalazine (up to 3000 mg/day), the patient 
must be receiving a stable dose for at least 8 weeks prior to entry into the study, and the 
dose must remain stable throughout the study.

Concomitant use of NSAIDs is permitted during Part A of the study only if the patient 
was on a stable dose for at least 6 weeks before planned randomization.  An increase of 
NSAID dose and/or introduction of new NSAIDs are not permitted during Part A of the 
study unless a patient receives rescue therapy.  After rescue or during Part B of the study, 
new NSAIDs or increases in doses of ongoing concomitant NSAIDs are permitted.  Dose 
reductions and/or termination of NSAIDs are permitted at any time.

During the study, concomitant use of analgesics is permitted.  Increase of an analgesic 
dose and/or introduction of a new analgesic is not permitted during Part A of the study 
unless a patient receives rescue therapy.  After rescue, new analgesics or increases in 
doses of ongoing concomitant analgesics are permitted.  Dose reductions and/or 
termination of analgesics are permitted at any time.

Prednisone (or equivalent) at doses up to 10 mg per day is allowed during this study but 
must be maintained at stable levels from 6 weeks prior to randomization through the 
treatment phase of the study, unless a patient receives rescue therapy.  After rescue, new 
corticosteroids or increases in doses of ongoing concomitant corticosteroids are 
permitted.  Patients who were not previously on prednisone (or equivalent) prior to 

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randomization should not initiate corticosteroid therapy during the study.  Patients should 
not receive other systemic corticosteroids during the study including intra-muscular or 
intra-articular corticosteroids.  Topical, intranasal, intra-ocular, and inhaled 
corticosteroids are permitted.

If an unforeseen intra-articular glucocorticoid injection is required during the study, it 
will be noted as a protocol deviation.

It is strongly encouraged to avoid hyaluronic acid injections during the course of the 
study.  If required, use should be minimized and discussed with the Sponsor.

Local standard of care should be followed for concomitant administration of folic acid.
The following concomitant medications are prohibited after randomization:

Live vaccines, including herpes zoster vaccination.  Nonlive seasonal vaccinations and/or 
emergency vaccination, such as rabies or tetanus vaccinations, are allowed.

Any DMARDs, other than stable doses of background DMARDs being used at the time 
of study entry

Any biologic therapy (such as TNF, interleukin-1, IL-6, T-cell-, or B-cell-targeted 
therapies) for any indication

Any interferon therapy (such as Roferon-A, Intron-A, Rebetron, Alferon-N, Peg-Intron, 
Avonex, Betaseron, Infergen, Actimmune, Pegasys)

Any parenteral corticosteroid administered by intramuscular or IV injection

Any traditional medicine that is known to have immunosuppressant and/or 
immunomodulatory effects, such as Pafulin or Leigongteng (Common Three
Threewingnut Root)
In addition to the concomitant medications guidelines outlined above, all patients who have not 
already received the herpes zoster vaccine at study entry will be encouraged to do so.  Lilly will 
provide this vaccine where available.  After receiving the herpes zoster vaccine, all patients must 
wait at least 30 days before randomization to study treatment.  
Any joints that had been injected with intraarticular corticosteroids within 6 weeks prior to 
randomization will be censored from the TJCs and SJCs for the duration of the study.
All concomitant medications taken during the study must be recorded in the Concomitant 
Medication sections of the CRF.
9.9.
Treatment Compliance
Patient compliance with study medication will be assessed at Visits 5 through 7 and Visits 9 
through 15 (and, if necessary, at Early Termination) during the treatment period by counting 
returned tablets.  Deviations from the prescribed dosage regimen should be recorded in the CRF.
For baricitinib or oral placebo, a patient will be considered significantly noncompliant if he or 
she misses >20% of the prescribed doses during the study unless the patient’s investigational 
product was withheld by the investigator for safety reasons.  

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Similarly, a patient 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.  Patients found to be noncompliant with the investigational product should be 
assessed to determine the reason for noncompliance and educated and/or managed as deemed 
appropriate by the investigator to improve compliance.

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10.
Efficacy, Health Outcome Measures, Safety Evaluations, 
Sample Collection and Testing, and Appropriateness of 
Measurements
Study procedures and their timing (including tolerance limits for timing) are summarized in the 
Study Schedule (Attachment 1).
10.1. Efficacy Measures
10.1.1. Primary Efficacy Measure
The primary efficacy measure will be the proportion of patients achieving ACR20 at Week 12.  
ACR20 is defined as at least 20% improvement in the following ACR Core Set values:

TJC (68 joint count)

SJC (66 joint count)

An improvement of ≥20% in at least 3 of the following 5 assessments:
1. Patient’s Assessment of Pain (VAS)
2. Patient’s Global Assessment of Disease Activity (VAS)
3. Physician’s Global Assessment of Disease Activity (VAS)
4. Patient’s Assessment of Physical Function as measured by the HAQ-DI
5. Acute phase reactant as measured by hsCRP.
10.1.2. Secondary Efficacy Measures
The secondary efficacy measures described below will be collected at the times shown in the 
Study Schedule (Attachment 1).
10.1.2.1. Disease Activity Score-Erythrocyte Sedimentation Rate and Disease 
Activity Score–High Sensitivity C-Reactive Protein
The DAS28 is a measure of disease activity in 28 joints that consists of a composite numeric 
score of the following variables:  TJC, SJC, hsCRP or ESR, and Patient’s Global Assessment of 
Disease Activity (Vander Cruyssen et al. 2005).  The 28 joints to be examined and assessed as 
tender or not tender for TJC and as swollen or not swollen for SJC include 14 joints on each side 
of the patient’s body:  the 2 shoulders, the 2 elbows, the 2 wrists, the 10 metacarpophalangeal 
joints, the 2 interphalangeal joints of the thumb, the 8 proximal interphalangeal joints, and the 
2 knees (Smolen et al. 1995).
10.1.2.2. ACR50 and ACR70 Indices
The ACR50 and ACR70 responses are secondary efficacy measures that are calculated as 
improvements of at least 50% and of at least 70%, respectively, in the ACR Core Set values
identified in Section 10.1.1.
10.1.2.3. Hybrid American College of Rheumatology Response Measure
The hybrid ACR (bounded) response measure will be obtained as described by the ACR 
Committee to Reevaluate Improvement Criteria (2007); see Table JAGS.10.1.

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Table JAGS.10.1.
Scoring Method for the Hybrid American College of Rheumatology 
Response Measure
Mean % Change in Core Set Measuresa
ACR Status
<20
≥20, <50
≥50, <70
≥70
Not ACR20
Mean % change
19.99
19.99
19.99
ACR20 but not ACR50
20
Mean % change
49.99
49.99
ACR50 but not ACR70
50
50
Mean % change
69.99
ACR70
70
70
70
Mean % change
Abbreviations:  ACR = American College of Rheumatology; ACR20 = 20% improvement in ACR criteria; 
ACR50 = 50% improvement in ACR criteria; ACR70 = 70% improvement in ACR criteria.
a 1) Calculate the average percentage change in core set measures.  For each core set measure, subtract score 
after treatment from baseline score and determine percentage improvement in each measure.  Next, if a core 
set measure worsened by >100%, limit that percentage change to 100% (set equal to -100% bound).  Then, 
average the percentage changes for all core set measures. 2) Determine whether the patient has achieved 
ACR20, ACR50, or ACR70. 3)  Using the table above, obtain the hybrid ACR response measure.  To use 
the table, take the ACR20, ACR50, or ACR70 status of the patient (left column) and the mean percentage 
improvement in core set items; the hybrid ACR score is where they intersect in the table.
10.1.2.4. ACR/EULAR Rheumatoid Arthritis Remission
Two ACR/EULAR definitions of RA remission will be evaluated, a “Boolean-based definition” 
and an “index-based definition” (Felson et al. 2011).

Boolean-based Definition of Remission:  All 4 criteria below must be met:
o
TJC28 ≤ 1 
o
SJC28 ≤ 1
o
hsCRP ≤ 1 mg/dL (10 mg/L)
o
patient global DAS on VAS (0 to 10.0) ≤ 1

Index-based Definition of Remission (see Section 10.1.2.5):
o
SDAI ≤ 3.3
10.1.2.5. Simplified Disease Activity Index (SDAI)
The SDAI is a tool for measurement of disease activity in RA that integrates measures of 
physical examination, acute phase response, patient self-assessment, and evaluator assessment.  
The SDAI is calculated by adding together scores from the following assessments:

number of swollen joints (0 to 28), 

number of tender joints (0 to 28), 

CRP in mg/dL (0.1 to 10.0), 

patient global DAS on VAS (0 to 10.0), and

evaluator global health score on VAS (0 to 10.0) (Aletaha and Smolen 2005)
Disease remission according to ACR/EULAR index-based definition of remission is defined as 
an SDAI score of ≤3.3 (Felson et al. 2011).

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10.1.2.6. Clinical Disease Activity Index (CDAI)
The CDAI is similar to the SDAI, but it allows for immediate scoring because it does not use a 
laboratory result.  The CDAI is calculated by adding together scores from the following 
assessments:

number of swollen joints (0 to 28),

number of tender joints (0 to 28),

patient global DAS on VAS (0 to 10.0), and

evaluator global health score on VAS (0 to 10.0) (Aletaha and Smolen 2005)
Remission is defined as a CDAI score of ≤2.8 (Felson et al. 2011).
10.1.2.7. European League Against Rheumatism Responder Index
Assessments of patients with RA by EULAR response criteria will be used to categorize patients 
as nonresponders, moderate responders, good responders, or responders (moderate + good 
responders) according to Table JAGS.10.2 (van Gestel et al. 1998).
Table JAGS.10.2.
Categorization of Patients as Nonresponders, Moderate 
Responders, or Good Responders
Postbaseline Level of 
DAS28
Improvement Since Baseline in DAS28
>1.2
≤1.2 and >0.6
≤0.6
DAS28 ≤3.2
Good response
3.2 < DAS28 ≤5.1
Moderate response
DAS28 >5.1
No response
Abbreviation:  DAS28 = Disease Activity Score modified to include the 28 diarthroidal joint count.
10.1.2.8. Van der Heijde Modified Total Sharp Score (mTSS)
Structural progression will be measured using the mTSS (van der Heijde 2000). During 
screening, all patients meeting entry criteria will have a single posteroanterior radiographic 
assessment of the left and right hand/wrist and a single dorsoplantar radiographic image taken of 
the left and right foot.  Alternatively, images taken within 4 weeks prior to baseline may be used.  
Images taken at screening (or within 4 weeks of screening) will be reviewed centrally by 
qualified readers for evidence of erosive bony change(s).  These initial radiographs will serve as 
the baseline radiographs for comparison throughout the study.  If a patient undergoes 
rescreening, radiographic images acquired as part of initial screening and within 10 weeks of 
randomization may be used. Radiographs (that is, a single posteroanterior view of each hand and 
a single dorsolantar view of each foot) will be obtained at Weeks 16, 24, and 52. 
For patients who discontinue prematurely from the study, x-rays will be performed at the early 
termination visit only if the previous x-rays were taken more than 12 weeks earlier.
The mTSS (van der Heijde 2000) quantifies the extent of bone erosions and joint space 
narrowing for 44 and 42 joints, respectively, of the hands/wrists and feet with higher scores 

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representing greater damage. X-rays will also be assessed for joint space narrowing and bone 
erosions. 
Quality control will be performed for proper imaging examination technique prior to allocation
of the images to the central readers. The independent read of x-ray images will be performed by
2 primary readers and 1 adjudicator, when necessary, based on predefined criteria. The
2 primary readers will each read 100% of the study patients.  All time points will be displayed in
random order for a given patient. The reader will have no knowledge of the true chronologic
order, patient identity, or treatment group. To ensure a consistent read by the independent
readers, an inter-/intrareader variability assessment will be included in the central imaging core
laboratory independent read. Repeat x-rays will be requested for all images obtained that are of
poor quality as defined in the Image Acquisition Guidelines.
10.2. Health Outcome Measures
The health outcome measures listed below will be administered.  Country-specific translations of 
each measure will be available in this study.  Items being measured using a paper diary should be 
completed at the end of the patient’s day (typically their bedtime).

Morning Joint Stiffness Severity Numeric Rating Scale (NRS):  The Morning Joint 
Stiffness NRS is a patient-administered, single-item, 11-point horizontal scale anchored 
at 0 and 10, with 0 representing “no joint stiffness” and 10 representing “joint stiffness as 
bad as you can imagine.” Patients rate their morning joint stiffness each day (using a 
paper diary) by selecting the one number that describes their overall level of joint 
stiffness at the time they woke up.

Duration of morning joint stiffness:  
o
Patient diary:  The duration of morning joint stiffness is a patient-administered 
item that allows for the patients to enter the length of time in hours and minutes 
that their morning joint stiffness lasted each day.
o
Electronic PRO (tablet):  The duration of morning joint stiffness is a patient-
administered item that allows for the patients to enter the length of time in 
minutes (using 15-minute increments) that their morning joint stiffness lasted on 
the day prior to that visit (using an electronic patient-reported outcomes [ePRO] 
tablet).  

Recurrence of joint stiffness:  The recurrence of joint stiffness throughout the day is a 
patient-administered single-item question assessed each day (using a paper diary) that 
asks “Did you have any joint stiffness throughout today, other than when you woke up?”
(Yes/No)

Tiredness Severity Numeric Rating Scale (Worst Tiredness NRS):  
o
Patient diary:  The Worst Tiredness NRS is a patient-administered, single-item, 
11-point horizontal scale anchored at 0 and 10, with 0 representing “no tiredness” 
and 10 representing “as bad as you can imagine.”  Patients rate their tiredness 
each day (using a paper diary) by selecting the one number that describes their 
worst level of tiredness.

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o
Electronic PRO (tablet):  The Worst Tiredness NRS is a patient-administered, 
single-item, 11-point horizontal scale anchored at 0 and 10, with 0 representing 
“no tiredness” and 10 representing “as bad as you can imagine.”  Patients rate 
their tiredness by selecting the one number that describes their worst level of 
tiredness during the past 24 hours.

Severity of joint pain Numeric Rating Scale (Worst Joint Pain NRS):  
o
Patient diary:  The Worst Joint Pain NRS is a patient-administered, single-item, 
11-point horizontal scale anchored at 0 and 10, with 0 representing “no pain” and 
10 representing “pain as bad as you can imagine.”  Patients rate their joint pain 
each day (using a paper diary) by selecting the one number that describes their 
worst level of joint pain.
o
Electronic PRO (tablet):  The Worst Joint Pain NRS is a patient-administered, 
single-item, 11-point horizontal scale anchored at 0 and 10, with 0 representing 
“no pain” and 10 representing “joint pain as bad as you can imagine.”  Patients 
rate their joint pain by selecting the one number that describes their worst level of 
joint pain during the past 24 hours.

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 activities (Fries et al. 1980, 1982; Ramey et al. 1996). The 
disability section of the questionnaire scores the patient’s self-perception on the degree of 
difficulty (0 = without any difficulty, 1 = with some difficulty, 2 = with much difficulty, 
and 3 = unable to do) when dressing and grooming, arising, eating, walking, hygiene, 
reach, grip, and performing other daily activities. 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.  

FACIT-F scale:  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.

WPAI-RA:  The WPAI-RA questionnaire was developed to measure the effect of general 
health and symptom severity on work productivity and regular activities.  It contains 
6 items covering overall work productivity (health), overall work productivity 
(symptom), impairment of regular activities (health), and impairment of regular activities 
(symptom).  Scores are calculated as impairment percentages (Reilly et al. 1993).

EQ-5D-5L:  The EQ-5D-5L is a standardized measure of health status that provides a 
simple, generic measure of health for clinical and economic appraisal.  The EQ-5D-5L 
consists of 2 components:  a descriptive system of the respondent’s health and a rating of 
his or her current health state using a 0- to 100-mm VAS.  The descriptive system 
comprises the following 5 dimensions: mobility, self-care, usual activities, 
pain/discomfort, and anxiety/depression.  Each dimension has 5 levels:  no problems, 

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slight problems, moderate problems, severe problems, and extreme problems.  The 
respondent is asked to indicate his/her health state by ticking (or placing a cross) in the 
box associated with the most appropriate statement in each of the 5 dimensions. It should 
be noted that the numerals 1 to 5 have no arithmetic properties and should not be used as 
a cardinal score. The VAS records the respondent’s self-rated health on a vertical VAS 
in which the endpoints are labeled “best imaginable health state” and “worst imaginable 
health state.”  This information can be used as a quantitative measure of health outcome.  
The EQ-5D-5L health states, defined by the EQ-5D-5L descriptive system, may be 
converted into a single summary index by applying a formula that essentially attaches a 
value (also called weights) to each of the levels in each dimension (Brooks 1996; 
EuroQol Group 2011 [WWW]; Herdman et al. 2011).

Quick Inventory of Depressive Symptomatology Self-Rated-16 (QIDS-SR16):  The 
QIDS-SR16 is a 16-item, self-report instrument intended to assess the existence and 
severity of symptoms of depression as listed in the American Psychiatric Association's 
Diagnostic and Statistical Manual of Mental Disorders, 4th Edition (APA 1994).  
Patients are asked to consider each statement as it relates to the way they have felt for the 
past 7 days.  There is a 4-point scale for each item ranging from 0 to 3.  The 16 items 
corresponding to 9 depression domains are summed to give a single score ranging from 
0 to 27.  Additional information and the QIDS-SR16 questions may be found on the 
University of Pittsburgh Epidemiology Data Center web site (Inventory of Depressive 
Symptomatology/Quick Inventory of Depressive Symptomatology [WWW]) (Rush et al. 
2003; Trivedi et al. 2004).

Healthcare resource utilization:  The healthcare resource utilization data will be collected 
by site staff regarding the number of visits to medical care providers such as general 
practitioners, specialists, physical or occupational therapists, and other non-physical care 
providers for services outside of the clinical study; emergency room admissions; hospital 
admissions; and concomitant medications related to the treatment of RA. These data will 
be collected to support economic evaluations of treatment.
10.3. Safety Evaluations
Investigators will be responsible for monitoring the safety of patients who enter 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 patient.
The investigator will be responsible for the appropriate medical care of patients during the study.
The investigator remains responsible for following, through an appropriate health care option, 
AEs that are serious or that cause the patient to discontinue before completing the study.  The 
patient should be followed until the event is resolved or explained.  Frequency of follow-up 
evaluation will be left to the discretion of the investigator.
10.3.1. Adverse Events (AEs)
Lilly has standards for reporting AEs that are to be followed regardless of applicable regulatory 
requirements that may be less stringent.  

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Lack of drug effect is not an AE in clinical studies because the purpose of the clinical study is to 
establish drug effect.
Cases of pregnancy that occur during maternal or paternal exposures to investigational product 
or drug delivery system should be reported.  Data on fetal outcome and breastfeeding are 
collected for regulatory reporting and drug safety evaluation.
Study site personnel will record the occurrence and nature of each patient’s preexisting 
conditions, including clinically significant signs and symptoms of the disease under treatment in 
the study.
After the ICF is signed, site personnel will record any change in the condition(s) and the 
occurrence and nature of any AEs.  All AEs related to protocol procedures will be reported to 
Lilly or its designee.
In addition, all AEs occurring after the patient receives the first dose of investigational product 
must be reported to Lilly or its designee via electronic entry.
Any clinically significant findings from ECGs, laboratory tests, vital sign measurements, or other 
procedures that result in a diagnosis should be reported to Lilly or its designee.
Investigators will be instructed to report to Lilly or its designee their assessment of the potential 
relatedness of each AE to protocol procedure, studied disease state, investigational product, 
and/or drug delivery system via electronic entry.
Study site personnel must alert Lilly or its designee within 24 hours of the investigator 
unblinding a patient’s treatment group assignment for any reason.
If a patient’s dosage is reduced or treatment is discontinued as a result of an AE, study site 
personnel must clearly report to Lilly or its designee via electronic entry the circumstances and 
data leading to any such dosage reduction or discontinuation of treatment.
10.3.1.1. Adverse Events of Special Interest
Adverse events of special interest (AESIs) will include:

severe or opportunistic infections

myelosuppressive events of anemia, leukopenia, neutropenia, lymphopenia, and 
thrombocytopenia

thrombocytosis

elevations in ALT or AST (>3 times ULN) with total bilirubin (>2 times ULN)
Patients with these laboratory value specified events will be identified using the same criteria for 
the interruption of investigational product with the exception of anemia, which will be identified 
using the same criteria for the discontinuation of investigational product, and thrombocytosis, 
which will be defined as a platelet count >600,000/μL.
10.3.1.2. Serious Adverse Events (SAEs)
Serious adverse event collection will begin after the patient has signed informed consent and has 
received investigational product.  If a patient experiences an SAE after signing informed consent 

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but prior to receiving investigational product, the event will NOT be collected unless the 
investigator feels the event may have been caused by a protocol procedure.
Previously planned (prior to signing the ICF) surgeries should not be reported as SAEs unless the 
underlying medical condition has worsened during the course of the study.
Study site personnel must alert Lilly or its designee of any serious adverse event (SAE) within 
24 hours of investigator awareness of the event via a sponsor-approved method.  Alerts issued 
via telephone are to be immediately followed with official notification on study-specific SAE
forms.  An SAE is any AE from this study that results in one of the following outcomes:

death

initial or prolonged inpatient hospitalization

a life-threatening experience (that is, immediate risk of dying)

persistent or significant disability/incapacity

congenital anomaly/birth defect

considered significant by the investigator for any other reason
In addition, any patient who is permanently discontinued from study drug for an AE or abnormal 
laboratory result should have the AE or abnormal laboratory value reported as an SAE (reported 
as ‘Other Reason Serious’).
Important medical events that may not result in death, be life-threatening, or require 
hospitalization may be considered serious adverse drug events when, based on appropriate
medical judgment, they may jeopardize the patient and may require medical or surgical 
intervention to prevent one of the outcomes listed in this definition.
Serious adverse event occurring after a patient has taken the last dose of investigational product 
will be collected in the pharmacovigilance system and the clinical data collection database for 28 
days after the last dose of investigational product, regardless of the investigator’s opinion of 
causation.  Thereafter, SAEs are not required to be reported unless the investigator feels the 
events were related to investigational product, drug delivery system, or protocol procedure.
Information on SAEs expected in the study population independent of drug exposure and that 
will be assessed by the sponsor in aggregate periodically during the course of the trial may be 
found in the IB.  In the RA population, the occurrence of malignancies, major 
cerebrocardiovascular events (including death, myocardial infarction, hospitalization for unstable 
angina, hospitalization for heart failure, serious arrhythmia, resuscitated sudden death, 
cardiogenic shock due to myocardial infarction, coronary revascularization procedure; 
neurologic-stroke; and peripheral vascular events), and serious infections is reasonably 
anticipated because of the age of the population, comorbid conditions, disease state, and 
concomitant medications.
10.3.1.2.1.Suspected Unexpected Serious Adverse Reactions (SUSARs)
Suspected unexpected serious adverse reactions (SUSARs) are serious events that are not listed 
in the IB and that the investigator identifies as related to investigational product or procedure.  

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Lilly has procedures, which are consistent with global regulations and the associated detailed 
guidances that will be followed for the recording and expedited reporting of SUSARs.
10.3.2. Other Safety Measures
10.3.2.1. Measures Evaluated During Screening Period
Physical examination.  One complete physical examination (excluding pelvic and rectal 
examinations) will be performed at screening.  This examination will determine whether the 
patient meets the criteria required to participate in the study and will also serve as a monitor for 
preexisting conditions and as a baseline for TEAE assessment.  Body weight and height will also 
be recorded.
Electrocardiograms.  A single 12-lead ECG will be obtained at screening to determine whether 
the patient meets entry criteria for the study.  Electrocardiograms (ECGs) will be locally 
(machine) read and interpreted by a qualified physician (the investigator or qualified designee) at 
the site.
Chest x-ray and tuberculosis testing.  A posterior-anterior view chest x-ray will be obtained 
locally, unless results from a chest x-ray obtained within 6 months prior to the study are 
available.  The chest x-ray will be reviewed by the investigator or his/her designee to exclude 
patients with active TB infection.
In addition, patients will be tested at screening and entry for evidence of active or latent TB as 
described in exclusion criteria, Section 8.2.2.  
10.3.2.2. Measures Evaluated During Screening and Treatment Periods
Vital signs and physical characteristics.  Vital signs (sitting blood pressure and heart rate) will 
be measured at times indicated in the Study Schedule (Attachment 1).  Subjects should be seated 
and relaxed with both feet on the floor for at least 5 minutes prior to taking measurements.  
Three replicate blood pressure readings should be made at each time point at approximately 30-
to 60-second intervals.  A single pulse measurement should be taken simultaneously with at least 
one of the blood pressure readings.  Blood pressure and pulse measurements should be made 
using either automated or manual equipment.  If measurements are machine averaged, the 
average blood pressure reading should be recorded on the CRF.  If measurements are manual or 
the machine does not provide an average reading, then each individual reading should be 
recorded on the CRF.  Measurements should be made before any scheduled blood draws.  Any 
clinically significant findings that result in a diagnosis should be captured on the CRF and 
reported as an AE.  Additional measurements of vital signs may be performed at the discretion of 
the investigator.  Physical characteristics including weight and waist circumference will be 
measured at times indicated in the Study Schedule (Attachment 1).
Standard laboratory tests.  Hematology, clinical chemistry, urinalysis, lipid profile, eGFR, iron 
studies, hsCRP, and ESR will be measured at times indicated in the Study Schedule (Attachment 
1).

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Hepatitis B virus (HBV) DNA monitoring:  Patients who were hepatitis B core antibody 
(HBcAb) positive at screening will require HBV DNA monitoring as indicated in the study 
schedule (Attachment 1).  If an HBV DNA result of “target detected” ≥29 IU/mL, then the 
patient should be referred to a hepatology specialist immediately.  In selected cases, investigators 
may temporarily continue study drug in accordance with current immunomodulator management
in the setting of HBV DNA positivity.  This option may be considered in consultation with Lilly 
(or its designee) and evaluation of individual patient risks and benefits.
The following actions should be taken in response to HBV DNA test results:

If a result of “target detected” is obtained at any time during the study with a value of ≥29 
IU/mL, refer to Table JAGS.8.2

If a single result of “target detected” is obtained with a value of <29 IU/mL, the test should 
be repeated within approximately 2 weeks. 
o
If the repeat test result is “target not detected,” monitoring may resume according to the 
study schedule.

If the patient has two or more test results of “target detected” with a value of <29 IU/mL at 
any time, HBV testing should be conducted approximately once per month for the remainder 
of the study and referral to a hepatologist is recommended. 
The additions to the Study Schedule and table of Clinical Laboratory Tests are shown in 
Attachment 1 and Attachment 2.
10.3.3. Safety Monitoring
The Lilly clinical research physician will monitor safety data throughout the course of the study.  
Lilly will review SAEs within time frames mandated by company procedures. The Lilly clinical 
research physician will, as is appropriate, consult with the functionally independent Global
Patient Safety therapeutic area physician or clinical scientist and periodically review trends in 
safety data and laboratory analytes.  Any concerning trends in frequency or severity noted by an 
investigator and/or Lilly (or designee) may require further evaluation.
All deaths and SAE reports will be reviewed in a blinded manner by Lilly during the clinical 
trial.  These reports will be reviewed to ensure completeness and accuracy but will not be 
unblinded to Lilly during the clinical trial.  If a death or clinical AE is deemed serious, 
unexpected, and possibly related to investigational product, only Lilly Global Patient Safety will 
be unblinded for regulatory reporting and safety monitoring purposes.  These measures will 
preserve the integrity of the data collected during this trial and minimize any potential for bias 
while providing for appropriate safety monitoring.  
Liver function monitoring will occur frequently throughout the study.  If a study patient 
experiences elevated ALT or AST 3 × ULN or elevated total bilirubin 2 × ULN, clinical and 
laboratory monitoring should be initiated by the investigator.  Details for hepatic monitoring 
depend on the severity and persistence of observed laboratory test abnormalities.  To ensure 
patient safety and comply with regulatory guidance, the investigator is to consult with the Lilly 

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designated medical monitor regarding collection of specific recommended clinical information 
and follow-up laboratory tests (see Attachment 3).
Investigators will monitor vital signs and carefully review findings that may be associated with 
cardiovascular events.  Adverse event reports and vital signs will be collected at each study visit.  
The cardiovascular monitoring plan includes, in addition, the following:

regular monitoring of lipid levels

adjudication of major adverse cardiovascular events (all deaths and nonfatal 
myocardial infarctions, hospitalization for unstable angina, hospitalization for heart 
failure, coronary interventions [such as coronary artery bypass graft or percutaneous 
coronary intervention], stroke, and transient ischemic attack) by a Cardiovascular 
Safety Committee at regular intervals 

estimation of relative rates of occurrence of select AEs using observations obtained 
from a matched, observational, comparator cohort of RA patients using existing RA
registry/registries.
10.3.4. Complaint Handling
Lilly collects product complaints on investigational products and drug delivery systems used in 
clinical studies to ensure the safety of study participants, monitor quality, and facilitate process 
and product improvements.  Complaints related to unblinded concomitant drugs or drug delivery 
systems are reported directly to the manufacturers of those drugs/devices in accordance with the 
package inserts.  For blinded studies, all product complaints associated with material packaged, 
labeled, and released by Lilly or its delegate will be reported.
The investigator or his/her designee is responsible for handling the following aspects of the 
product complaint process in accordance with the instructions provided for this study:

recording a complete description of the product complaint reported and any associated 
AEs using the study-specific complaint forms provided for this purpose

faxing the completed product complaint form within 24 hours to Lilly or its designee
If the investigator is asked to return the product for investigation, he/she will return a copy of the 
product complaint form with the product.
10.4. Sample Collection and Testing
Attachment 1 lists the schedule for sample collections in this study, and Attachment 2 lists the 
specific tests that will be performed for this study.
10.4.1. Samples for Standard Laboratory Testing
Standard laboratory tests, including chemistry, hematology, and urinalysis panels, will be 
performed.  Specifically, hsCRP results will be blinded after Visit 2.  Serum and/or urine 
pregnancy tests will be performed at each visit as described in the study schedule (Attachment 
1).  Blood and urine samples will be collected for other laboratory tests at the times specified in 
the study schedule (Attachment 1).  Blood will be collected by venipuncture.  Attachment 2 lists 
the specific tests that will be performed for this study.  

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Routine and other clinical laboratory tests will be analyzed by a central laboratory selected by 
Lilly.
Investigators must document their review of each laboratory safety report.
Samples collected for specified laboratory tests will be destroyed within 60 days of receipt of 
confirmed test results.  Tests are run and confirmed promptly whenever scientifically 
appropriate.  When scientific circumstances warrant, however, it is acceptable to retain samples 
to batch the tests run or to retain the samples until the end of the study to confirm that the results
are valid.  Certain samples may be retained for a longer period, if necessary, to comply with 
applicable laws, regulations, or laboratory certification standards.
10.4.2. Exploratory Stored Samples
10.4.2.1. Pharmacogenetics
There is growing evidence that genetic variation may impact a patient’s response to therapy.  
Variable response to therapy may be due to genetic determinants that affect drug absorption, 
distribution, metabolism, and excretion; the mechanism of action of the drug; the disease 
etiology; and/or the molecular subtype of the disease being treated.  Therefore, where local 
regulations allow, blood samples will be collected for pharmacogenetic analysis, as noted in the 
Study Schedule (Attachment 1).
Samples will be stored, and analysis may be performed on genetic variants thought to play a role 
in active RA including, but not limited to, the cluster of immune response genes on 
chromosome 6, such as HLA-DRB1, HLA-DQA1, HLA-DPA1, HLA-DPB1, TNF-α, and TNF 
receptors; RANK-Ligand; the JAK signaling pathways; MTX metabolizing genes such as 
methylene tetrahydrofolate reductase and other folate reductases; PTPN22 and related signaling 
molecules; IL-6 pathway members; and the STAT signaling family members, including STAT4, 
to evaluate their association with observed response to baricitinib.
In the event of an unexpected AE or the observation of unusual response, the samples may be 
genotyped and analysis may be performed to evaluate a genetic association with response to 
baricitinib.  These investigations may be limited to a focused candidate gene study or, if 
appropriate, genome-wide association studies may be performed to identify regions of the 
genome associated with the variability observed in drug response.  Samples will only be used for 
investigations related to disease and drug or class of drugs under study in the context of this 
clinical program.  They will not be used for broad exploratory unspecified disease or population 
genetic analysis.
The sample will be identified by the patient number (coded) and stored for up to a maximum of 
15 years after the last patient visit for the study at a facility selected by the sponsor.  The sample 
and any data generated from it can be linked back to the patient only by investigator site 
personnel.  The duration allows the Sponsor to respond to regulatory requests related to the study 
drug.

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10.4.2.2. Nonpharmacogenetic/Biomarker Stored Samples
Collection of samples for nonpharmacogenetic biomarker research is a part of this study where 
local regulations allow.  Serum, plasma, whole blood RNA, and urine samples will be collected
at the times specified in the Study Schedule (Attachment 1).
Samples may be used for research on the drug target, disease process, pathways associated with 
disease state, mechanism of action of baricitinib, and/or research method or in validating 
diagnostic tools or assay(s) related to RA.
Samples will be identified by the patient number (coded) and stored for up for a maximum of 
15 years after the last patient visit for the study at a facility selected by the sponsor.
10.5. Appropriateness of Measurements
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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11.
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 a start-up training session to instruct the investigators and study coordinators.  
This session will give instruction on the protocol, the completion of the CRFs, and study 
procedures

make periodic visits to the study site

be available for consultation and stay in contact with the study site personnel by mail, 
telephone, and/or fax

review and evaluate CRF data and use standard computer edits to detect errors in data 
collection
In addition, Lilly or its representatives may periodically check a sample of the patient 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 to ensure accurate, complete, and reliable 
data, the investigator will keep records of laboratory tests, clinical notes, and patient medical 
records in the patient files as original source documents for the study.  If requested, the 
investigator will provide the sponsor, applicable regulatory agencies, and applicable ERBs with 
direct access to original source documents.
11.1. Data Capture System
An electronic data capture system will be used in this study.  The site will maintain a separate 
source for the data entered by the site into the sponsor-provided electronic data capture system.
Electronic physician-reported outcome measures will be directly entered by the physician or 
designee (Physician global assessment of disease activity) or by the blinded joint assessor 
(TJC/SJC) into the electronic 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 or x-ray data, will be stored electronically in the 
central vendor’s database system.  Data will subsequently be transferred from the central vendor 
to the Lilly generic laboratories system.
Data from complaint forms submitted to Lilly will be encoded and stored in the global product 
complaint management system.

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12.
Sample Size and Statistical Methods
12.1. Determination of Sample Size
Approximately 288 patients (144 in baricitinib, 144 in placebo) will provide:

99% power to detect a difference between the baricitinib and placebo treatment groups in 
ACR20 response rate (60% versus 35%) at Week 12 based on a 2-sided chi-square test at 
a significance level of 0.05.
The sample size and power estimates were obtained using nQuery® Advisor 7.0.
12.2. Statistical and Analytical Plans
12.2.1. General Considerations
All statistical tests of treatment effects will be performed at 2-sided significance levels of 0.05, 
unless otherwise stated. Treatment comparisons of discrete efficacy variables will be made using 
a logistic regression analysis with country, joint erosion status (1-2 joint erosions plus 
seropositivity vs at least 3 joint erosions) and treatment group in the model. The proportions and 
95% CI will be reported. Treatment comparisons of continuous efficacy variables will be made 
using analysis of covariance (ANCOVA) with country, treatment group, joint erosion status and 
baseline value in the model.  Type III sums of squares for the least-squares (LS) means will be 
used for the statistical comparison; the 95% CI will also be reported.
When a restricted maximum likelihood (REML)-based mixed model for repeated measures 
(MMRM) is used, the model will include the fixed, categorical effects of treatment, country, 
joint erosion status, visit, treatment-by-visit-interaction, as well as the continuous, fixed 
covariates of baseline score and baseline score-by-visit-interaction.  An unstructured 
(co)variance structure will be used to model the within-patient errors.  If this analysis fails to 
converge, other structures will be tested. Type III sums of squares for the LS means will be used 
for the statistical comparison; the 95% CI will also be reported.  Treatment group comparisons at 
Week 12 and all other visits will be tested.  Further details on the MMRM will be described in 
the statistical analysis plan (SAP).
Fisher's exact test will be used for all AEs, discontinuation, and other categorical safety data.  
Continuous vital signs and other continuous safety variables including laboratory parameters will 
be analyzed using ANCOVA with treatment and baseline value in the model.  
Analysis Population:
Unless otherwise specified, the efficacy and safety analyses will be conducted on a modified 
intent-to-treat basis (mITT) (Gillings and Koch 1991).  This analysis set includes all data from 
all randomized patients who received at least 1 dose of study drug.  In addition, the primary and 
secondary efficacy analyses for the double-blind period will be repeated in a subset of mITT
analysis set, the per protocol (PP) set, which is defined as all randomized patients who are 
compliant with treatment, who do not have significant protocol violations, and whose 
investigator site does not have significant GCP issues that require a report to the regulatory 

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agencies.  Analysis of structural progression (van der Heijde mTSS) will be conducted on the 
mITT population using patients with available baseline and at least 1 postbaseline value.
Sensitivity analyses of the primary endpoints may be conducted and will be described in the SAP.
Missing Data Imputation:
In accordance with precedent set with other Phase 3 RA trials (Keystone et al. 2004, 2008, 2009; 
Cohen et al. 2006; Smolen et al. 2008, 2009), the following methods for imputation of missing 
data will be used:
1. Nonresponder imputation (NRI):  All patients who discontinue the study or the study 
treatment at any time for any reason will be defined as nonresponders for the NRI 
analysis for categorical variables, such as ACR20/50/70, from the time of discontinuation 
and onward.  Patients who receive rescue therapy at Week 16 will be analyzed as 
nonresponders after Week 16 and onward.  Randomized patients without available data at 
a postbaseline visit will be defined as nonresponders for the NRI analysis at that visit.
2. Linear extrapolation method:  The linear extrapolation method will be used for analysis 
of the structural progression endpoint (van der Heijde mTSS) to impute missing data at 
time points when analyses are conducted (including the analyses at Week 24 and 
Week 52).  For patients who discontinue the study or the study treatment or for patients 
who miss a radiograph for any reason, baseline data and the most recent radiographic 
data prior to discontinuation or the missed radiograph, adjusted for time, will be used for
linear extrapolation to impute missing data at subsequent time points.  For patients who 
receive rescue therapy starting at Week 16 or at any time point thereafter, baseline data 
and the most recent radiographic data prior to initiation of rescue therapy, adjusted for 
time, will be used for linear extrapolation.  All patients originally randomized to placebo 
will be switched to active treatment at Week 24; thus, there will be no observed data for 
the placebo arm for the structural comparison at subsequent time points.  Therefore, 
baseline data and the most recent radiographic data prior to initiation of the new therapy, 
adjusted for time, will be used for linear extrapolation at Week 52.  The linear 
extrapolation method has been established as an appropriate missing data imputation 
method in other Phase 3 RA trials (Keystone et al. 2004, 2008, 2009; Cohen et al. 2006; 
Smolen et al. 2008, 2009).  Missing postbaseline values will be imputed only if both a 
baseline value and a postbaseline value from another time point are available, as long as 
the patient was on the same treatment at each applicable time point.
3. Multiple imputation:  Other methods than linear extrapolation that include multiple 
imputation will be employed for analysis of the structural progression endpoint (van der 
Heijde mTSS) to impute missing data at Week 24. Details will be provided in the SAP.
4. Modified baseline observation carried forward (mBOCF):  The mBOCF method will be 
used for the analysis of secondary continuous endpoints (unless otherwise stated).  For 
patients who discontinue the study or the study treatment because of an AE, including 
death, the baseline observation will be carried forward to the corresponding endpoint for 
evaluation. For patients who discontinue the study for reason(s) other than an AE, the 
last nonmissing postbaseline observation prior to discontinuation will be carried forward 

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to the corresponding endpoint for evaluation.  For patients who receive rescue therapy 
starting at Week 16, the last nonmissing observation at or before rescue will be carried 
forward to subsequent time points for evaluation.  
5. Modified last observation carried forward (mLOCF):  For all continuous measures 
including safety analyses, the mLOCF will be a general approach to impute missing data 
unless otherwise specified.  For patients who receive rescue therapy starting at Week 16, 
the last nonmissing observation at or before rescue will be carried forward to subsequent 
time points for evaluation.  For all other patients discontinuing from the study or the 
study treatment for any reason, the last nonmissing postbaseline observation before 
discontinuation will be carried forward to subsequent time points for evaluation. After 
mLOCF imputation, data from patients with nonmissing baseline and postbaseline 
observations will be included in the analyses.  The mLOCF will be used as a sensitivity 
method to the mBOCF method with respect to the secondary endpoints.  
6. Other methods for data imputation for analysis of endpoints other than mTSS may be 
used and will be described in the 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 SAP and the clinical study report (CSR).  Additional exploratory analyses of the data will 
be conducted as deemed appropriate.
12.2.2. Patient Disposition
The number of randomized patients along with mITT and PP set populations will be summarized 
by treatment group.  Frequency counts and percentages in different study parts will be presented 
for each treatment group.  All patients who discontinue from the study or the study treatment will 
be identified, and the extent of their participation in the study will be reported along with their 
reason for discontinuation.  Reasons for discontinuation from the study will be summarized by 
treatment group.
12.2.3. Patient Characteristics
Demographic and baseline characteristics will be summarized descriptively by treatment group.  
Descriptive statistics including number of patients, mean, standard deviation (SD), median, 
minimum, and maximum will be provided for continuous measures, and frequency counts and 
percentages will be tabulated for categorical measures.  No formal statistical comparisons will be 
made among treatment groups unless otherwise stated.
12.2.4. Concomitant Therapy
Concomitant medications will be descriptively summarized by treatment group in terms of 
frequencies and percentages using the mITT population.  The medications will be coded 
accordingly.  

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12.2.5. Treatment Compliance
Compliance to study treatment for baricitinib and placebo will be assessed through counts of 
returned study drug tablets.  For baricitinib or placebo, a patient will be considered significantly 
noncompliant if he or she misses more than 20% of the prescribed doses during the study, unless 
the patient’s study drug is withheld by the investigator for safety reasons.  Similarly, a patient 
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 study drug. Patients who 
are significantly noncompliant will be excluded from the PP set.
Patient compliance will be further defined in the SAP.
12.2.6. Primary Outcome and Methodology
A logistic regression model with treatment, country and joint erosion status in the model will be 
used to test the treatment difference between baricitinib and placebo in the proportion of patients 
achieving ACR20 response at Week 12.  The NRI method as described above will be used to 
impute missing data.
12.2.7. Efficacy Analyses
Secondary analyses:
1. Comparison between baricitinib and placebo in change from baseline to Week 12 in 
HAQ-DI score:  An ANCOVA model with treatment, country, joint erosion status, and 
baseline score in the model will be used to test the treatment difference between 
baricitinib and placebo in change from baseline to Week 12 in HAQ-DI.  The mBOCF
and mLOCF approaches as described above will be used to impute missing data.
2. Comparison between baricitinib and placebo in change from baseline to Week 12 in 
DAS28-hsCRP: An ANCOVA model with treatment, country, joint erosion status, and 
baseline score in the model will be used to test the treatment difference between 
baricitinib and placebo in change from baseline to Week 12 in DAS28-hsCRP.  The 
mBOCF and mLOCF approaches as described above will be used to impute missing data.
3. Comparison between baricitinib and placebo in proportion of patients achieving an SDAI 
score ≤3.3 at Week 12: A logistic regression model with treatment, country, and joint 
erosion status in the model will be used to test the treatment difference between 
baricitinib and placebo in the proportion of patients achieving an SDAI score ≤3.3 
response at Week 12.  The NRI method as described above will be used to impute 
missing data.
4. Comparison between baricitinib and placebo in mean duration of morning joint stiffness
in the 7 days prior to Week 12:  An ANCOVA model with treatment, country, joint 
erosion status, and baseline score (Day 1 on the diaries) in the model will be used to test 
the treatment difference between baricitinib and placebo in mean duration of morning 
joint stiffness in the 7 days prior to Week 12.  Refer to the SAP for more details.
5. Comparison between baricitinib and placebo in mean severity of morning joint stiffness
in the 7 days prior to Week 12:  An ANCOVA model with treatment, country, joint 

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erosion status, and baseline score (Day 1 on the diaries) in the model will be used to test 
the treatment difference between baricitinib and placebo in mean severity of morning 
joint stiffness in the 7 days prior to Week 12.  Refer to the SAP for more details.
6. Comparison between baricitinib and placebo in mean Worst Tiredness NRS in the 7 days 
prior to Week 12:  An ANCOVA model with treatment, country, joint erosion status, and 
baseline score (Day 1 on the diaries) in the model will be used to test the treatment 
difference between baricitinib and placebo in mean Worst Tiredness NRS in the 7 days 
prior to Week 12.  Refer to the SAP for more details.
7. Comparison between baricitinib and placebo in mean Worst Joint Pain NRS in the 7 days 
prior to Week 12:  An ANCOVA model with treatment, country, joint erosion status, and 
baseline score (Day 1 on the diaries) in the model will be used to test the treatment 
difference between baricitinib and placebo in mean Worst Joint Pain NRS in the 7 days 
prior to Week 12.  Refer to the SAP for more details.
Other efficacy and health outcome analyses:
Besides the analyses listed in the objective section, the following analyses will be performed:

change from baseline in mTSS

proportion of patients with mTSS change ≤0 

change from baseline in joint space narrowing and bone erosion scores

proportion of patients achieving DAS28-hsCRP ≤3.2 and <2.6

proportion of patients achieving HAQ-DI improvement ≥0.22 and ≥0.3

proportions of patients achieving ACR20 (other than primary),  ACR50, and ACR70

percentage change from baseline in individual components of the ACR Core Set

change from baseline in DAS28-hsCRP

change from baseline in DAS28-ESR

proportion of patients achieving DAS28-ESR ≤3.2 and <2.6

change from baseline in HAQ-DI

change from baseline in CDAI score

change from baseline in SDAI score

proportion of patients achieving CDAI score ≤2.8

proportion of patients achieving SDAI score ≤3.3 (ACR/EULAR remission according to 
the Index-based definition) 

proportion of patients achieving ACR/EULAR remission according to the Boolean-based 
definition

proportion of patients achieving moderate response and good response based on EULAR 
response criteria

hybrid ACR (bounded) response measure

change from baseline in fatigue score in the FACIT-F 

change from baseline in health states, VAS score, and index score of EQ-5D-5L

change from baseline in absenteeism, presenteeism, work productivity loss, and activity 
impairment scores of WPAI-RA

individual items and total score in healthcare resource utilization

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
change from baseline in duration of morning joint stiffness assessed at the visit using an 
ePRO tablet

change from baseline in Worst Tiredness NRS assessed at the visit using an ePRO tablet

change from baseline in Worst Joint Pain NRS assessed at the visit using an ePRO tablet.
Approaches similar to the primary and above secondary analyses will be used to analyze other 
efficacy and health outcome measures.  Analysis methods will consist of ANCOVA and logistic 
regression, as described above, using mBOCF, linear extrapolation, NRI, and mLOCF missing 
data imputation methods, where applicable.  In addition, continuous secondary parameters that 
are collected at repeated visits throughout the double-blind period may be analyzed using a 
MMRM approach as described in Section 12.2.1.  The MMRM will be considered as a 
sensitivity approach to ANCOVA results.
The Study JAGS data of mTSS, joint space narrowing and bone erosion scores will be pooled 
with JADV data for further analyses.
Data collected after initiation of rescue therapy will be summarized as appropriate.  Further 
details will be provided in the SAP.
12.2.8. Health Outcome Analyses
The health outcomes will be analyzed using methods described for continuous or categorical data 
as described for efficacy measures in Section 12.2.7.  More detailed analytical methods will be 
described in the SAP.
12.2.9. Safety Analyses
All safety data will be descriptively summarized by treatment groups and analyzed using the 
mITT population.
For the purposes of calculating changes from baseline during Part A and Part B treatment,
baseline may be considered as the original baseline for Part A – prior to any study drug received 
– or at the visits that mark the transition between treatments received, depending on the purpose 
of the summary or comparison being made.  Summaries within Parts A and B will be conducted 
by treatment group used within each respective part.  Additional summaries by treatment group 
that continue unchanged across multiple parts of the study will be conducted, as appropriate.
Treatment-emergent adverse events are defined as AEs that first occurred or worsened in 
severity after the first dose of study treatment.  AEs will be considered treatment emergent for 
nonresponders assigned to baricitinib if the AEs first occurred or worsened in severity after the 
visit at which rescue therapy is assigned. The number of TEAEs as well as the number and 
percentage of patients who experienced at least 1 TEAE will be summarized using Medical 
Dictionary for Regulatory Activities (MedDRA) for each system organ class (SOC) (or a body 
system) and each preferred term by treatment group.  TEAEs will also be summarized by 
relationship to treatment and by severity within each treatment group.  Serious adverse events 
(SAEs) and AEs that lead to study drug discontinuation will also be summarized by treatment 

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group. Fisher’s exact test will be used to perform the statistical comparisons between baricitinib 
and placebo.  
All clinical laboratory results will be descriptively summarized by treatment group.  Individual 
results that are outside of normal range will be flagged in data listings.  Quantitative clinical 
hematology, chemistry, and urinalysis variables obtained at the baseline to postbaseline visits 
will be summarized as changes from baseline by treatment group and analyzed using ANCOVA
with treatment and baseline value in the model.  Categorical variables, including the incidence of 
abnormal values and incidence of AESIs, will be summarized by frequency and percentage of 
patients in corresponding categories.  Shift tables will be presented for selected measures.  
Observed values and changes from baseline (predose or screening if missing) for vital signs and 
physical characteristics will be descriptively summarized by treatment group and time point.  
Change from baseline to postbaseline in vital signs, QIDS-SR16, and body weight will be 
analyzed using ANCOVA with treatment and baseline value in the model.
The incidence and average duration of study drug interruptions will be summarized and 
compared descriptively among treatment groups.  Various techniques may be used to estimate 
the effects of study drug interruptions on safety measures.  Further analyses may be performed 
and will be planned in the SAP.  
Data collected after initiation of rescue therapy will be summarized as appropriate.
12.2.10.
Subgroup Analyses
Subgroups analyses comparing baricitinib to placebo will be performed using ACR20, ACR50, 
HAQ-DI and DAS28-hsCRP at Week 12, Week 24, and mTSS at Week 24. Subgroups to be 
evaluated will include country, renal function, background therapy, joint erosion status, gender, 
age, race, etc.  Any other additional subgroups will be defined in the SAP.
For ACR20 and ACR50 analyses at Week 12 and Week 24, a logistic regression model will be 
used with treatment, subgroup, and treatment by subgroup interaction included as factors.
For the change from baseline to Weeks 12 and Week 24 in HAQ-DI score and DAS28-hsCRP 
and to Week 24 in mTSS, an ANCOVA model will be used with treatment, baseline score, 
subgroup, and treatment by subgroup interaction included as factors.
Further definitions for the levels of the subgroup variables, the analysis methodology, and any 
additional subgroup analyses will be defined in the SAP.  Because this study is not powered for 
subgroup analyses, all subgroup analyses will be treated as exploratory.
12.2.11.
Planned Analyses
Two database locks are planned for the study. The first database lock and a blinded review of 
data will occur after all patients complete the Week 24 study visit.  The final database lock and 
unblinded analysis will occur at the end of the study.
Unblinding details will be specified in the unblinding plan section of the SAP.

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13.
Informed Consent, Ethical Review, and Regulatory 
Considerations
13.1. Informed Consent
The investigator is responsible for ensuring that the patient understands the potential risks and 
benefits of participating in the study, including answering any questions the patient may have 
throughout the study and sharing in a timely manner any new information that may be relevant to 
the patient’s willingness to continue his or her participation in the trial.
The ICF will be used to explain the potential risks and benefits of study participation to the 
patient in simple terms before the patient is entered into the study and to document that the 
patient is satisfied with his or her understanding of the risks and benefits of participating in the 
study and desires to participate in the study.
The investigator is responsible for ensuring that informed consent is given by each patient.  This 
includes obtaining the appropriate signatures and dates on the ICF prior to the performance of 
any protocol procedures and prior to the administration of investigational product.
13.2. Ethical Review
Lilly or its representatives must approve all ICFs before they are submitted to the ERB and are 
used at investigative sites(s).  All ICFs must be compliant with the International Conference on 
Harmonisation (ICH) guideline on GCP.  
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).  The ERB(s) will review the protocol as required.
Any member of the ERB who is directly affiliated with this study as an investigator or as site 
personnel must abstain from the ERB’s vote on the approval of the protocol.
The study site’s ERB(s) should be provided with the following:

the current IB or package labeling and updates during the course of the study

ICF

relevant curricula vitae
13.3. Regulatory Considerations
This study will be conducted in accordance with:
1. consensus ethics principles derived from international ethics guidelines, 
including the Declaration of Helsinki and Council for International
Organizations of Medical Sciences International Ethical Guidelines
2. the ICH GCP Guideline [E6]
3. applicable laws and regulations
The investigator or designee will promptly submit the protocol to the applicable ERB(s).

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An identification code assigned by the investigator to each patient will be used in lieu of the 
patient’s name to protect the patient’s identity when reporting AEs and/or other trial-related data.
13.3.1. Investigator Information
Physicians with a specialty in RA will participate as investigators in this clinical trial.
13.3.2. 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.
13.3.3. Final Report Signature
The clinical study report coordinating investigator will sign the final clinical study report 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.  
Lilly will select a qualified investigator from among investigators participating in the design, 
conduct, and/or analysis of the study to serve as the clinical study report coordinating 
investigator.
The sponsor’s responsible medical officer will approve the final clinical study report for this 
study, confirming that, to the best of his or her knowledge, the report accurately describes the 
conduct and results of the study.

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14.
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Kavanaugh A, Schiff M, Burmester GR, Strand V, Vencovskỳ J, van der Heijde D.  Efficacy 
and safety of certolizumab pegol plus methotrexate in active rheumatoid arthritis:  the RAPID 
2 study. A randomised controlled trial. Ann Rheum Dis. 2009;68(6):797-804.
Smolen JS, Aletaha D, Bijlsma JW, Breedveld FC, Boumpas D, Burmester G, Combe B, 
Cutolo M, de Wit M, Dougados M, Emery P, Gibofsky A, Gomez-Reino JJ, Haraoui B, 
Keystone EC, Kvien TK, McInnes I, Martin-Mola E, Montecucco C, Schoels M, 
van der Heijde D, T2T Expert Committee. Treating rheumatoid arthritis to target: 
recommendations of an international task force. Ann Rheum Dis. 2010;69(4):631-637.
Smolen JS, Beaulieu A, Rubbert-Roth A, Ramos-Remus C, Rovensky J, Alecock E, 
Woodworth T, Alten R, OPTION investigators. Effect of interleukin-6 receptor inhibition with 
tocilizumab in patients with rheumatoid arthritis (OPTION study):  a double-blind, placebo-
controlled, randomised trial. Lancet. 2008;371(9617):987–997.
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.
Smolen J, Steiner G. Therapeutic strategies for rheumatoid arthritis. Nat Rev Drug Discov. 
2003;2(6):473-488. 
Trivedi MH, Rush AJ, Ibrahim HM, Carmody TJ, Biggs MM, Suppes T, Crismon ML, 
Shores-Wilson K, Toprac MG, Dennehy EB, Witte B, Kashner TM. The Inventory of 
Depressive Symptomatology, Clinician Rating (IDS-C) and Self-Report (IDS-SR), and the 
Quick Inventory of Depressive Symptomatology, Clinician Rating (QIDS-C) and Self-Report 
(QIDS-SR) in public sector patients with mood disorders: a psychometric evaluation. Psychol 
Med. 2004;34(1):73-82.
University of Pittsburgh Epidemiology Data Center; IDS/QIDS web site. Available at: 
http://www.ids-qids.org. Accessed June 13, 2012.
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):R1063-1071.

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van der Heijde D. How to read radiographs according to the Sharp/van der Heijde method. 
J Rheumatol. 2000; 27(1):261-263.
van Gestel AM, Haagsma CJ, van Riel PL. Validation of rheumatoid arthritis improvement 
criteria that include simplified joint counts. Arthritis Rheum. 1998;41(10):1845-1850.
Williams WV, Scherle P, Shi J, Newton R, McKeever E, Fridman J, Vaddi K, Levy R, 
Moreland L. Initial efficacy of INCB018424, a selective Janus kinase 1& 2 (JAK 1&2) 
inhibitor in rheumatoid arthritis (RA). Ann Rheum Dis. 2008;67(suppl II):62.

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Attachment 1.Protocol JAGS Study Schedule

LY3009104
I4V-CR-JAGS(c) Clinical Protocol Amendment
Page 80
Study Schedule, Protocol I4V-CR-JAGS
Screening
Blinded, Placebo- Controlled Treatment 
Part A
Open-label
Part B
Follow-
up 
Part Ca
Visit
1
1a
2
3
4
5
6
7
8
9
10
11
12
13
14
15
ET
801
Week of Treatment
Base-
line
0
1
2
4
8
12
14
16
20
24
28
32
40
52
Any 
week
Days from Visit 2
-42
to -3
days
0
7 
± 2 
days
14 
± 2 
days
28 
± 2 
days
56 
± 3 
days
84 
± 3 
days
98
± 3 
days
112 
± 3 
days
140
± 3 
days
168
± 3 
days
196
± 3 
days
224
± 5 
days
280
± 5 
days
365
± 5 
days
Any 
day
28 ± 5
days 
after 
last 
dose
Informed consent
X
Clinical assessments:
History
X
Physical examination
X
Symptom-directed physical 
examinationb
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Previous therapy/previous RA
therapy
X
Patient demographics
X
Height
X
Weight
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Waist circumference
X
X
X
X
Vital signs (BP and pulse)
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Habitsc
X
Electrocardiogramd
X
Inclusion/exclusion review for 
entry
X
Inclusion/exclusion review for 
enrollment
X

LY3009104
I4V-CR-JAGS(c) Clinical Protocol Amendment
Page 81
Screening
Blinded, Placebo- Controlled Treatment 
Part A
Open-label
Part B
Follow-
up 
Part Ca
Visit
1
1a
2
3
4
5
6
7
8
9
10
11
12
13
14
15
ET
801
Week of Treatment
Base-
line
0
1
2
4
8
12
14
16
20
24
28
32
40
52
Any 
week
Days from Visit 2
-42
to -3
days
0
7 
± 2 
days
14 
± 2 
days
28 
± 2 
days
56 
± 3 
days
84 
± 3 
days
98
± 3 
days
112 
± 3 
days
140
± 3 
days
168
± 3 
days
196
± 3 
days
224
± 5 
days
280
± 5 
days
365
± 5 
days
Any 
day
28 ± 5
days 
after 
last 
dose
Administer PPD or 
QuantiFERON®-TB Gold or T 
SPOT® TB teste
X
Read PPD or 
QuantiFERON-TB Golde
X
Chest x-rayf
X
Preexisting conditions
X
X
Adverse events 
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Concomitant medications
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Randomization
X
IWRS
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Investigational product 
dispensed
Xg
X
X
X
X
X
X
X
X
X
Investigational products 
returned and assess 
compliance
Xh
Xh
X
X
X
Xh
X
X
X
X
X
X
X
X
Tender/swollen joint count 
(68/66 joints)
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Patient’s assessment of pain 
visual analog scale
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Patient global assessment of 
disease activity
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X

LY3009104
I4V-CR-JAGS(c) Clinical Protocol Amendment
Page 82
Screening
Blinded, Placebo- Controlled Treatment 
Part A
Open-label
Part B
Follow-
up 
Part Ca
Visit
1
1a
2
3
4
5
6
7
8
9
10
11
12
13
14
15
ET
801
Week of Treatment
Base-
line
0
1
2
4
8
12
14
16
20
24
28
32
40
52
Any 
week
Days from Visit 2
-42
to -3
days
0
7 
± 2 
days
14 
± 2 
days
28 
± 2 
days
56 
± 3 
days
84 
± 3 
days
98
± 3 
days
112 
± 3 
days
140
± 3 
days
168
± 3 
days
196
± 3 
days
224
± 5 
days
280
± 5 
days
365
± 5 
days
Any 
day
28 ± 5
days 
after 
last 
dose
Physician global assessment of 
disease activity
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Hand and foot x-raysi
Xi
X
X
X
Xj
HAQ-DI
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Morning joint stiffness - diary
Xk
Morning joint stiffness - tablet l
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
FACIT-F
X
X
X
X
X
X
X
X
X
X
X
X
X
EQ-5D-5L
X
X
X
X
X
X
X
X
X
X
X
X
X
Worst tiredness NRS-diary
Xk
Worst tiredness NRS-tabletl
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
WPAI-RA
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Worst joint pain NRS-diary
Xk
Worst joint pain NRS-tabletl
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
QIDS-SR16
X
X
X
X
X
X
Healthcare resource use
X
X
X
X
X
X
X
X
X
X
X
X
X
Laboratory tests
TSH
X
HIV
X
Hepatitis C antibody testing
X
Hepatitis B testing 
(HBsAg, HBcAb, HBsAb)
X

LY3009104
I4V-CR-JAGS(c) Clinical Protocol Amendment
Page 83
Screening
Blinded, Placebo- Controlled Treatment 
Part A
Open-label
Part B
Follow-
up 
Part Ca
Visit
1
1a
2
3
4
5
6
7
8
9
10
11
12
13
14
15
ET
801
Week of Treatment
Base-
line
0
1
2
4
8
12
14
16
20
24
28
32
40
52
Any 
week
Days from Visit 2
-42
to -3
days
0
7 
± 2 
days
14 
± 2 
days
28 
± 2 
days
56 
± 3 
days
84 
± 3 
days
98
± 3 
days
112 
± 3 
days
140
± 3 
days
168
± 3 
days
196
± 3 
days
224
± 5 
days
280
± 5 
days
365
± 5 
days
Any 
day
28 ± 5
days 
after 
last 
dose
Serum pregnancy testm
X
X
Urine pregnancy testm
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
FSHn
X
Clinical chemistryo
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Lipid panelp
X
X
X
X
Lipid NMRq
X
X
Hematology
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
HBV DNA r
X
X
X
X
X
Xs
X
Iron studies
(iron, TIBC, and ferritin)
X
X
X
X
X
Urinalysis
X
X
X
X
X
X
X
X
Rheumatoid factor
X
X
X
X
X
X
hsCRP
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Erythrocyte sedimentation ratet
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Anti-CCP
X
X
X
X
X
X
Immunoglobulin levels 
(IgG, IgA, IgM)
X
X
X
X
X
X
X
X
Lymphocyte subsets 
(T, B, NK, and T-cell subsets)
X
X
X
X
X
X
X
X
Exploratory storage samples 
(serum and plasma)
X
X
X
X
X
X
X

LY3009104
I4V-CR-JAGS(c) Clinical Protocol Amendment
Page 84
Screening
Blinded, Placebo- Controlled Treatment 
Part A
Open-label
Part B
Follow-
up 
Part Ca
Visit
1
1a
2
3
4
5
6
7
8
9
10
11
12
13
14
15
ET
801
Week of Treatment
Base-
line
0
1
2
4
8
12
14
16
20
24
28
32
40
52
Any 
week
Days from Visit 2
-42
to -3
days
0
7 
± 2 
days
14 
± 2 
days
28 
± 2 
days
56 
± 3 
days
84 
± 3 
days
98
± 3 
days
112 
± 3 
days
140
± 3 
days
168
± 3 
days
196
± 3 
days
224
± 5 
days
280
± 5 
days
365
± 5 
days
Any 
day
28 ± 5
days 
after 
last 
dose
Exploratory storage samples 
(urine)
X
X
X
X
X
X
X
Exploratory storage samples 
(RNA)
X
X
X
X
X
X
X
DNA collection
X
X
Abbreviations:  Anti-CCP = anticyclic citrullinated peptide; BP = blood pressure; DNA = deoxyribonucleic acid; eGFR = estimated glomerular filtration rate; 
EQ-5D-5L = European Quality of Life-5 Dimensions-5 Level; ET = early termination; FACIT-F = Functional Assessment of Chronic Illness Therapy Fatigue 
scale; FSH = follicle-stimulating hormone; HAQ-DI = Health Assessment Questionnaire-Disability Index; HBcAb = hepatitis B core antibody; HBsAb = 
hepatitis B surface antibody; HBsAg = hepatitis B surface antigen; HBV DNA = hepatitis B virus deoxyribonucleic acid; HIV = human immunodeficiency 
virus; hsCRP = high-sensitivity C-reactive protein; Ig = immunoglobulin; IWRS = interactive web-response system; NK = natural killer; NMR = nuclear 
magnetic resonance; NRS = numeric rating scale; PPD = purified protein derivative; QIDS-SR16 = Quick Inventory of Depressive Symptomatology-Self-
Rated (16 items); RA = rheumatoid arthritis; RNA = ribonucleic acid; TB = tuberculosis; TIBC = total iron binding capacity; TSH = thyroid stimulating 
hormone; WPAI-RA = Work Productivity and Activity Impairment-Rheumatoid Arthritis.
a
Those patients who complete the study and do not enroll in extension Study JADY should return for a safety follow-up visit 28 days after their last dose of 
study drug.  Those patients who do enroll in Study JADY do not need to return for a follow-up visit.
b
Symptom-directed physical examinations may be conducted at the investigator’s discretion at any visit and any time a patient presents with physical 
complaints.
c
Include recording of habits such as caffeine, alcohol, and tobacco consumption.
d
Electrocardiograms will be performed locally and will be locally (machine) read.

LY3009104
I4V-CR-JAGS(c) Clinical Protocol Amendment
Page 85
e
If the PPD test is positive and the patient has no medical history or chest x-ray findings consistent with active TB, the patient may have a QuantiFERON TB 
Gold or T-SPOT.TB test (if available).  If the QuantiFERON-TB Gold or T-SPOT.TB test results are not negative, the patient will be considered to have 
latent TB.  If the QuantiFERON-TB Gold or T-SPOT.TB test is available and in the judgment of the investigator, preferred as an alternative to the PPD skin 
test for the evaluation of TB infection, it may be used instead of the PPD TB test.  If the QuantiFERON-TB Gold or T-SPOT.TB test is positive, the patient 
will be considered to have latent TB.  If the test is not negative, the test may be repeated once within 2 approximately weeks of the initial value.  If the repeat 
test results are again not negative, the patient will be considered to have latent TB.
f
A chest x-ray will be taken locally at screening unless one has been obtained within the past 6 months (provided the x-ray and/or report are available for 
review).
g
At Visit 2, the patient will take his/her oral investigational product at the clinic under the supervision of study staff.  
h
At Visits 3, 4, and 8, patients should bring their investigational product with them to the study visit, but no tablet counts need to be performed.
i
All the radiographic images of the hands and feet will be submitted to the central reader for reviewing.  At screening, radiographic images of the hands and 
feet acquired within 4 weeks prior to study entry may be submitted to the central reader to confirm eligibility.  If a patient undergoes rescreening, radiographic 
images acquired as part of initial screening and within 10 weeks of randomization may be used.
j
X-rays will only be taken at early termination if the most recent x-ray was more than 12 weeks earlier.
k    Morning joint stiffness, Worst Tiredness, and Worst Joint Pain assessments will be collected using paper patient diary through Week 12 to assess duration, 
severity of morning joint stiffness, recurrence of stiffness during the day, worst tiredness and worst joint pain.
l
Morning joint stiffness duration, Worst Tiredness, and Worst Joint Pain assessments will be collected using an electronic patient-reported outcomes [ePRO] 
tablet at each visit.  
m For all women of childbearing potential, a serum pregnancy test (central laboratory) will be performed at Visit 1 and Visit 2.  Urine pregnancy tests (local 
laboratory) will also be performed at Visit 2 and at all subsequent study visits.
n
To confirm postmenopausal status for women ≥40 and <60 years of age who have had a cessation of menses, an FSH test will be performed.  Nonchildbearing 
potential will be defined as an FSH ≥40 mIU/mL and a cessation of menses for at least 12 months.
o
Clinical chemistry will include the following values calculated from serum creatinine:  calculated creatinine clearance (Cockcroft-Gault equation) and eGFR 
(calculated using the Modification of Diet in Renal Disease isotope dilution mass spectrometry traceable method).
p
Fasting lipid profile.  Patients should not eat or drink anything except water for 12 hours prior to sample collection.  If a patient attends these visits in a 
nonfasting state, this will not be considered a protocol violation.
q
Lipid NMR tests will not be performed at sites in China. Other participated countries will have this tests.
r
HBV DNA monitoring will be performed in patients who tested positive for HBcAb at screening.
s
To be performed only if previous test was more than 3 months earlier.
t    Erythrocyte sedimentation rate will be performed locally using a kit provided by the sponsor.

I4V-CR-JAGS(c) Clinical Protocol Amendment
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LY3009104
Attachment 2.Protocol JAGS Clinical Laboratory Tests
Clinical Laboratory Tests
Hematologya,b
Clinical Chemistrya,b
Hemoglobin
Serum concentrations of
Hematocrit
    Sodium
Erythrocyte count (RBCs)
Absolute reticulocyte count
    Potassium
    Total bilirubin
Mean cell volume
    Direct bilirubin
Mean cell hemoglobin
    Alkaline phosphatase
Mean cell hemoglobin concentration
    Alanine aminotransaminase/serum glutamic
Leukocytes (WBCs)
      pyruvic transaminase (ALT/SGPT)
Absolute count of
    Neutrophils, segmented
    Aspartate aminotransferase/serum glutamic
      oxaloacetic transaminase (AST/SGOT)
    Neutrophils, juvenile (bands)
    Lymphocytes
    Monocytes
    Blood urea nitrogen
    Creatinine
   Estimated glomerular filtration ratec
    Eosinophils
    Basophils
   Calculated creatinine clearanced
    Uric acid
    Platelets
    Calcium
Cell morphology
CBC, including differential and blood smear
    Glucosee
    Albumin
   Creatine kinase
Urinalysisa,b
    Total protein
Color
Specific gravity 
pH
Lipid profile includinge:
      total cholesterol,
Protein 
      HDL-C, LDL-C, and triglycerides
Glucose
Ketones
      ApoA1, ApoB
Blood 
Bilirubin
Urobilinogen
Leukocyte esterase
Lipoprotein subfractions (NMR)
Pregnancy Test (females only)b,f
FSH (females only)g
Nitrite
Microscopic examination of sedimenti
Other Tests
Lymphocyte subsets (T, B, NK, and T-cell subsets)
Hepatitis B surface antigen
Hepatitis B surface antibody
Hepatitis B core antibody
Stored serum, plasma, urine, mRNA and DNA samples 
for possible exploratory biomarker analyses
Hepatitis C antibodyh
Human immunodeficiency virus
Iron studies (iron, TIBC, and ferritin)
Thyroid-stimulating hormone
PPD or QuantiFERON® -TB Gold
jor 
T-SPOT®.TB
Rheumatoid factor

I4V-CR-JAGS(c) Clinical Protocol Amendment
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LY3009104
High-sensitivity C-reactive protein
ESRk
Anticyclic citrullinated peptide
Immunoglobulins (IgG, IgA, IgM)
HBV DNA
Footnotes appear on the following page.
Abbreviations:  ApoA1 = apolipoprotein A1; ApoB = apolipoprotein B; CBC = complete blood count; CPK = 
creatine phosphokinase; DNA = deoxyribonucleic acid; ESR = erythrocyte sedimentation rate; FSH = follicle-
stimulating hormone; HBV DNA = hepatitis B virus deoxyribonucleic acid; HDL-C = high-density lipoprotein 
cholesterol; Ig = immunoglobulin; LDL-C = low-density lipoprotein cholesterol; mRNA = messenger ribonucleic 
acid; NK = natural killer; NMR = nuclear magnetic resonance; PPD = purified protein derivative; RBC = red 
blood cell; TIBC = total iron binding capacity; WBC = white blood cell.  
a
Assayed/calculated by a sponsor-designated laboratory.  
b
Unscheduled blood chemistry (including CPK), hematology, and urinalysis panels may be performed at the 
discretion of the investigator.  If tests are done to evaluate laboratory results to resume study drug, samples must 
be assayed centrally.  
c
Estimated glomerular filtration rate for serum creatinine calculated by the central laboratory using the 
Modification of Diet in Renal Disease isotope dilution mass spectrometry traceable method.  
d
The calculated creatinine clearance will be determined by the central laboratory each time a serum creatinine 
sample is collected using the Cockcroft-Gault equation:  Men:  ([140 – age] x [weight in kg]) / (72 x [serum 
creatinine in mg/dL]) or ([140 – age] x [weight in kg]) / (0.814 x [serum creatinine in μmol/L]).  Women:  (above 
formula) x 0.85.  
e
Fasting laboratory values for glucose and lipids will be required at baseline, Week 12, Week 24, and Week 52.  If 
a patient attends these visits in a nonfasting state, this will not be considered a protocol violation.  These tests 
may be performed nonfasting at all other visits.  
f
For all women of childbearing potential, a serum pregnancy test (central laboratory) will be performed at Visit 1 
and both urine (local laboratory) and serum pregnancy (central laboratory) tests will be performed at Visit 2 to 
determine study eligibility.  Urine pregnancy tests (local laboratory) will also be performed at each subsequent 
study visit per study schedule.  
g
To confirm postmenopausal status for women ≥40 and <60 years of age, an FSH test will be performed.  
Nonchildbearing potential is defined as an FSH ≥40 mIU/mL and a cessation of menses for at least 12 months.
h
A positive hepatitis C antibody result will be confirmed with a positive hepatitis C virus result.  
i
Microscopic examination of sediment will be performed only if abnormalities are noted on the routine urinalysis.  
j
Test will be required at Visit 1 only to determine eligibility of patient for the study.  In countries where the 
QuantiFERON-TB Gold or T-SPOT.TB test is available and, in the judgment of the investigator, medically 
preferred as an alternative to the PPD test for the evaluation of mycobacterium tuberculosis (MTB) infection, it 
may be used instead of the PPD test (positive tests excluded) and may be read locally.  
k
ESR analysis will be performed by the local laboratory.  

I4V-CR-JAGS(c) Clinical Protocol Amendment
Page 88
LY3009104
Attachment 3.Protocol JAGS Hepatic Monitoring Tests for 
Treatment-Emergent Abnormality
Selected tests may be obtained in the event of a treatment-emergent hepatic abnormality and may 
be required in follow up with patients in consultation with the Lilly designated medical monitor.
Hepatic Monitoring Tests
Hepatic hematologya
Haptoglobina
Hemoglobin
Hematocrit
Hepatic coagulationa
RBC
Prothrombin time
WBC
Prothrombin time, INR
Neutrophils, segmented
Lymphocytes
Hepatic serologiesa,b
Monocytes
Hepatitis A antibody, total
Eosinophils
Hepatitis A antibody, IgM
Basophils
Hepatitis B surface antigen
Platelets
Hepatitis B surface antibody
Hepatitis B core antibody
Hepatic chemistrya
Hepatitis C antibody
Total bilirubin
Hepatitis E antibody, IgG
Direct bilirubin
Hepatitis E antibody, IgM
Alkaline phosphatase
ALT
Anti-nuclear antibodya
AST
GGT
CPK 
Anti-smooth muscle antibodya
Abbreviations:  ALT = alanine aminotransferase; AST = aspartate aminotransferase; CPK = creatine phosphokinase; 
GGT = gamma glutamyl transferase; Ig = immunoglobulin; INR = international normalized ratio; RBC = red 
blood cell; WBC = white blood cell.
a
Assayed by Lilly-designated or local laboratory.
b
Reflex/confirmation dependent on regulatory requirements and/or testing availability.

I4V-CR-JAGS(c) Clinical Protocol Amendment
Page 89
LY3009104
Attachment 4.
Protocol Amendment I4V-CR-JAGS (c) 
Summary A Randomized, Double-Blind, Placebo-
Controlled, Phase 3 Study Evaluating the Efficacy and 
Safety of Baricitinib in Patients with Moderately to 
Severely Active Rheumatoid Arthritis Who Have Had an 
Inadequate Response to Methotrexate Therapy
Overview
Protocol I4V-CR-JAGS has been amended.  The new protocol is indicated by amendment (c) 
and will be used to conduct the study in place of any preceding version of the protocol.
The overall changes and rationale for the changes made to this protocol are as follows:
This protocol amendment clarifies the timepoint of each database lock (DBL), the blindness of 
each DBL, and the analysis after each DBL.

The relevant change is in the Section 12.2.11.
Besides, the duration for Study JADY is also updated.

The relevant change is in the Section 7.1.

I4V-CR-JAGS(c) Clinical Protocol Amendment
Page 90
LY3009104
Revised Protocol Sections
Note:
Deletions have been identified by strikethroughs.
Additions have been identified by the use of underscore.
2.
Synopsis
Objectives:
The secondary objectives of the study are to evaluate the efficacy of baricitinib versus placebo as assessed by:
…

mean Worst Joint Pain NRS in the 7 days prior to Week 12 compared to placebo as collected in diaries
The exploratory objectives in the study include:
…

change from baseline to Weeks 12, 24 and 52 in Worst Joint Pain NRS assessed at the visit using an 
ePRO tablet.
Criteria for Evaluation:
Health Outcomes
The following health outcome measures will be administered in this study:

duration and severity of morning joint stiffness

recurrence of joint stiffness during the day

tiredness severity numeric rating scale (Worst Tiredness NRS)

pain severity numeric rating scale (Worst Joint Pain NRS)

FACIT-F

WPAI-RA

EQ-5D-5L

Quick Inventory of Depressive Symptomatology Self-Rated-16 (QIDS-SR16)

healthcare resource utilization
Analyses methods:
Secondary analyses:
…

Comparison between baricitinib and placebo in mean “Worst Joint Pain” NRS in the 7 days prior to Week 12:  
An ANCOVA model with treatment, country, joint erosion status, and baseline score (Day 1 on the diaries) in 
the model will be used to test the treatment difference between baricitinib and placebo in mean “Worst Joint
Pain” NRS. 
Besides the analyses listed in the objective section, the following analyses will be performed as well.
…

change from baseline in Worst Joint Pain NRS assessed at the visit using an ePRO tablet.
6.
Objective
6.2.
Secondary Objectives
The secondary objectives of the study are to evaluate the efficacy of baricitinib versus placebo as 
assessed by:
…

mean Worst Joint Pain NRS in the 7 days prior to Week 12 as collected in diaries

I4V-CR-JAGS(c) Clinical Protocol Amendment
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LY3009104
6.3.
Exploratory Objective
The exploratory objectives in the study include efficacy evaluation of baricitinib as assessed by:
…

change from baseline to Weeks 12, 24 and 52 in Worst Joint Pain NRS assessed at the 
visit using an ePRO tablet.
7.
Investigational Plan
7.1.
Summary of Study Design
Planned enrollment is approximately 288 randomized patients: 144 to receive baricitinib, and 
144 to receive placebo. After the Week 52 study visit, eligible patients may proceed to a 
separate extension study (Study JADY) lasting for up to 2 years49 months or to the 
posttreatment follow-up period of this study (Part C).
10.
Efficacy, Health Outcome Measures, Safety Evaluations, Sample Collection and 
Testing, and Appropriateness of Measurements
10.2.
Health Outcome Measures

Severity of joint pain Numeric Rating Scale (Worst Joint Pain NRS):  
o
Patient diary:  The Worst Joint Pain NRS is a patient-administered, single-item, 
11-point horizontal scale anchored at 0 and 10, with 0 representing “no pain” and 
10 representing “pain as bad as you can imagine.”  Patients rate their joint pain 
each day (using a paper diary) by selecting the one number that describes their 
worst level of joint pain.
o
Electronic PRO (tablet):  The Worst Joint Pain NRS is a patient-administered, 
single-item, 11-point horizontal scale anchored at 0 and 10, with 0 representing 
“no pain” and 10 representing “joint pain as bad as you can imagine.”  Patients 
rate their joint pain by selecting the one number that describes their worst level of 
joint pain during the past 24 hours.
12.
Sample Size and Statistical Methods
12.2.
Statistical and Analytical Plans
12.2.7. Efficacy Analyses
Secondary analyses:
7.
Comparison between baricitinib and placebo in mean Worst Joint Pain NRS in the 
7 days prior to Week 12:  An ANCOVA model with treatment, country, joint erosion 
status, and baseline score (Day 1 on the diaries) in the model will be used to test the 
treatment difference between baricitinib and placebo in mean Worst Joint Pain NRS in 
the 7 days prior to Week 12.  Refer to the SAP for more details.
Other efficacy and health outcome analyses:

I4V-CR-JAGS(c) Clinical Protocol Amendment
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LY3009104
Besides the analyses listed in the objective section, the following analyses will be performed:
…

change from baseline in Worst Joint Pain NRS assessed at the visit using an ePRO 
tablet.
12.2.11.
Planned Analyses
The analysis of primary and secondary endpoints will occur when all patients complete the Week 
24 study visit.  A final analysis will occur when all patients complete the study.Two database 
locks are planned for the study. The first database lock and a blinded review of data will occur 
after all patients complete the Week 24 study visit.  The final database lock and unblinded 
analysis will occur at the end of the study.

LY3009104
I4V-CR-JAGS(c) Clinical Protocol Amendment
Page 93
Attachment 1.
Protocol JAGS Study Schedule
Study Schedule, Protocol I4V-CR-JAGS (c)
Screening
Blinded, Placebo- Controlled Treatment 
Part A
Open-label
Part B
Follow-
up 
Part Ca
Visit
1
1a
2
3
4
5
6
7
8
9
10
11
12
13
14
15
ET
801
Week of Treatment
Base-
line
0
1
2
4
8
12
14
16
20
24
28
32
40
52
Any 
week
Days from Visit 2
-42
to -3
days
0
7 
± 2 
days
14 
± 2 
days
28 
± 2 
days
56 
± 3 
days
84 
± 3 
days
98
± 3 
days
112 
± 3 
days
140
± 3 
days
168
± 3 
days
196
± 3 
days
224
± 5 
days
280
± 5 
days
365
± 5 
days
Any 
day
28 ± 5
days 
after 
last 
dose
Informed consent
X
Clinical assessments:
History
X
Physical examination
X
Symptom-directed physical 
examinationb
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Previous therapy/previous RA 
therapy
X
Patient demographics
X
Height
X
Weight
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Waist circumference
X
X
X
X
Vital signs (BP and pulse)
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Habitsc
X
Electrocardiogramd
X
Inclusion/exclusion review for 
entry
X
Inclusion/exclusion review for 
X

LY3009104
I4V-CR-JAGS(c) Clinical Protocol Amendment
Page 94
Screening
Blinded, Placebo- Controlled Treatment 
Part A
Open-label
Part B
Follow-
up 
Part Ca
Visit
1
1a
2
3
4
5
6
7
8
9
10
11
12
13
14
15
ET
801
Week of Treatment
Base-
line
0
1
2
4
8
12
14
16
20
24
28
32
40
52
Any 
week
Days from Visit 2
-42
to -3
days
0
7 
± 2 
days
14 
± 2 
days
28 
± 2 
days
56 
± 3 
days
84 
± 3 
days
98
± 3 
days
112 
± 3 
days
140
± 3 
days
168
± 3 
days
196
± 3 
days
224
± 5 
days
280
± 5 
days
365
± 5 
days
Any 
day
28 ± 5
days 
after 
last 
dose
enrollment
Administer PPD or 
QuantiFERON®-TB Gold or T 
SPOT® TB teste
X
Read PPD or 
QuantiFERON-TB Golde
X
Chest x-rayf
X
Preexisting conditions
X
X
Adverse events 
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Concomitant medications
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Randomization
X
IWRS
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Investigational product 
dispensed
Xg
X
X
X
X
X
X
X
X
X
Investigational products 
returned and assess 
compliance
Xh
Xh
X
X
X
Xh
X
X
X
X
X
X
X
X
Tender/swollen joint count 
(68/66 joints)
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Patient’s assessment of pain 
visual analog scale
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Patient global assessment of 
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X

LY3009104
I4V-CR-JAGS(c) Clinical Protocol Amendment
Page 95
Screening
Blinded, Placebo- Controlled Treatment 
Part A
Open-label
Part B
Follow-
up 
Part Ca
Visit
1
1a
2
3
4
5
6
7
8
9
10
11
12
13
14
15
ET
801
Week of Treatment
Base-
line
0
1
2
4
8
12
14
16
20
24
28
32
40
52
Any 
week
Days from Visit 2
-42
to -3
days
0
7 
± 2 
days
14 
± 2 
days
28 
± 2 
days
56 
± 3 
days
84 
± 3 
days
98
± 3 
days
112 
± 3 
days
140
± 3 
days
168
± 3 
days
196
± 3 
days
224
± 5 
days
280
± 5 
days
365
± 5 
days
Any 
day
28 ± 5
days 
after 
last 
dose
disease activity
Physician global assessment of 
disease activity
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Hand and foot x-raysi
Xi
X
X
X
Xj
HAQ-DI
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Morning joint stiffness - diary
Xk
Morning joint stiffness - tablet l
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
FACIT-F
X
X
X
X
X
X
X
X
X
X
X
X
X
EQ-5D-5L
X
X
X
X
X
X
X
X
X
X
X
X
X
Worst tiredness NRS-diary
Xk
Worst tiredness NRS-tabletl
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
WPAI-RA
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Worst joint pain NRS-diary
Xk
Worst joint pain NRS-tabletl
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
QIDS-SR16
X
X
X
X
X
X
Healthcare resource use
X
X
X
X
X
X
X
X
X
X
X
X
X
Laboratory tests
TSH
X
HIV
X
Hepatitis C antibody testing
X

LY3009104
I4V-CR-JAGS(c) Clinical Protocol Amendment
Page 96
Screening
Blinded, Placebo- Controlled Treatment 
Part A
Open-label
Part B
Follow-
up 
Part Ca
Visit
1
1a
2
3
4
5
6
7
8
9
10
11
12
13
14
15
ET
801
Week of Treatment
Base-
line
0
1
2
4
8
12
14
16
20
24
28
32
40
52
Any 
week
Days from Visit 2
-42
to -3
days
0
7 
± 2 
days
14 
± 2 
days
28 
± 2 
days
56 
± 3 
days
84 
± 3 
days
98
± 3 
days
112 
± 3 
days
140
± 3 
days
168
± 3 
days
196
± 3 
days
224
± 5 
days
280
± 5 
days
365
± 5 
days
Any 
day
28 ± 5
days 
after 
last 
dose
Hepatitis B testing 
(HBsAg, HBcAb, HBsAb)
X
Serum pregnancy testm
X
X
Urine pregnancy testm
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
FSHn
X
Clinical chemistryo
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Lipid panelp
X
X
X
X
Lipid NMRq
X
X
Hematology
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
HBV DNA r
X
X
X
X
X
Xs
X
Iron studies
(iron, TIBC, and ferritin)
X
X
X
X
X
Urinalysis
X
X
X
X
X
X
X
X
Rheumatoid factor
X
X
X
X
X
X
hsCRP
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Erythrocyte sedimentation ratet
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Anti-CCP
X
X
X
X
X
X
Immunoglobulin levels 
(IgG, IgA, IgM)
X
X
X
X
X
X
X
X
Lymphocyte subsets 
(T, B, NK, and T-cell subsets)
X
X
X
X
X
X
X
X

LY3009104
I4V-CR-JAGS(c) Clinical Protocol Amendment
Page 97
Screening
Blinded, Placebo- Controlled Treatment 
Part A
Open-label
Part B
Follow-
up 
Part Ca
Visit
1
1a
2
3
4
5
6
7
8
9
10
11
12
13
14
15
ET
801
Week of Treatment
Base-
line
0
1
2
4
8
12
14
16
20
24
28
32
40
52
Any 
week
Days from Visit 2
-42
to -3
days
0
7 
± 2 
days
14 
± 2 
days
28 
± 2 
days
56 
± 3 
days
84 
± 3 
days
98
± 3 
days
112 
± 3 
days
140
± 3 
days
168
± 3 
days
196
± 3 
days
224
± 5 
days
280
± 5 
days
365
± 5 
days
Any 
day
28 ± 5
days 
after 
last 
dose
Exploratory storage samples 
(serum and plasma)
X
X
X
X
X
X
X
Exploratory storage samples 
(urine)
X
X
X
X
X
X
X
Exploratory storage samples 
(RNA)
X
X
X
X
X
X
X
DNA collection
X
X
Abbreviations:
…
k    Morning joint stiffness, Worst Tiredness, and Worst Joint Pain assessments will be collected using paper patient diary through Week 12 to assess duration, 
severity of morning joint stiffness, recurrence of stiffness during the day, worst tiredness and worst joint pain.
l
Morning joint stiffness duration, Worst Tiredness, and Worst Joint Pain assessments will be collected using an electronic patient-reported outcomes [ePRO] 
tablet at each visit.

Leo Document ID = a7fca142-cda1-478c-a499-5a7a5bcc7c3d
Approver: 
Approval Date & Time: 07-Dec-2016 01:25:10 GMT
Signature meaning: Approved
Approver: 
Approval Date & Time: 07-Dec-2016 10:21:59 GMT
Signature meaning: Approved
PPD
PPD