A Phase 3, Multicenter Study to Evaluate the Long-Term Safety and Efficacy of Baricitinib in Patients With Rheumatoid Arthritis
Phase: PHASE3
Conditions: Rheumatoid Arthritis
Sponsor: Eli Lilly and Company

Protocol I4V-MC-JADY (i) 
 
A Phase 3, Multicenter Study to Evaluate the Long-Term Safety and Efficacy of Baricitinib in 
Patients with Rheumatoid Arthritis 
 
NCT01885078 
 
Approval Date: 10-Dec-2019 

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1. Protocol I4V-MC-JADY(i)
A Phase 3, Multicenter Study to Evaluate the Long-Term 
Safety and Efficacy of Baricitinib in Patients with 
Rheumatoid Arthritis
Confidential Information
The information contained in this document is confidential and is intended for the use of 
clinical investigators.  It is the property of Eli Lilly and Company or its subsidiaries and 
should not be copied by or distributed to persons not involved in the clinical investigation of 
baricitinib (LY3009104), unless such persons are bound by a confidentiality agreement with 
Eli Lilly and Company or its subsidiaries.  
Note to Regulatory Authorities:  This document may contain protected personal data 
and/or commercially confidential information exempt from public disclosure.  Eli Lilly and 
Company requests consultation regarding release/redaction prior to any public release.  In 
the United States, this document is subject to Freedom of Information Act (FOIA) 
Exemption 4 and may not be reproduced or otherwise disseminated without the written 
approval of Eli Lilly and Company or its subsidiaries.
Baricitinib (LY3009104)
Study I4V-MC-JADY is a Phase 3, multicenter, outpatient long-term safety and efficacy 
extension study.  Patients who completed a Phase 2 or Phase 3 baricitinib RA trial may be 
eligible to enter this trial.
Eli Lilly and Company
Indianapolis, Indiana USA 46285
Protocol Electronically Signed and Approved by Lilly:  13 December 2012
Amendment (a) Electronically Signed and Approved by Lilly:  14 February 2013
Amendment (b) Electronically Signed and Approved by Lilly:  28 May 2013
Amendment (c) Electronically Signed and Approved by Lilly:  31 May 2013
Amendment (d) Electronically Signed and Approved by Lilly: 21 March 2014
Amendment (e) Electronically Signed and Approved by Lilly:  30 October 2014
Amendment (f) Electronically Signed and Approved by Lilly:  30 January 2017
Amendment (g) Electronically Signed and Approved by Lilly:  11 December 2017
Amendment (h) Electronically Signed and Approved by Lilly:  20 December 2018
Amendment (i) Electronically Signed and Approved by Lilly 
on approval date provided below.
Approval Date: 10-Dec-2019 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 evaluate the 
safety profiles and durability of effect of 2-mg and 4-mg baricitinib doses when administered 
once daily (QD) over an extended time period to patients with RA who have completed a 
previous Phase 2 or Phase 3 study of baricitinib.  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.
Clinical Protocol Synopsis:  Study I4V-MC-JADY
Name of Investigational Product:
Baricitinib (LY3009104)
Title of Study:  A Phase 3, Multicenter Study to Evaluate the Long-Term Safety and Efficacy of Baricitinib in 
Patients with Rheumatoid Arthritis
Number of Planned Patients/Subjects:
   Entered:  approximately 2400–3500
   Planned Enrollment:  2400–3500
   Completed:  1200–1700
Phase of Development:  3
Length of Study:  10 years
Planned first patient visit:  May 2013               Planned last patient visit:  July 2024
Objectives:  The primary objective of the study is to evaluate the long-term safety and tolerability of baricitinib in 
patients who have completed a previous baricitinib RA study.  Safety and tolerability assessments will include:

Treatment-emergent adverse events (TEAEs), adverse events of special interest, and serious adverse 
events (SAEs)

Temporary investigational product interruptions and permanent investigational product discontinuations

Vital signs and laboratory evaluations (including chemistry and hematology)
The secondary objective(s) of the study are:
To evaluate in patients initially randomized to receive baricitinib in the originating study, the effect of long-term 
administration of baricitinib as assessed by:

Proportion of patients who maintain an ACR20, ACR50, and ACR70 response through each 12 months of 
treatment

Proportion of patients who maintain a Disease Activity Score modified to include the 28 diarthrodial joint 
count (DAS28)-high sensitivity C-reactive protein (hsCRP) ≤3.2, DAS28-erythrocyte sedimentation rate 
(ESR) ≤3.2, DAS28-hsCRP <2.6, and DAS28-ESR <2.6; Clinical Disease Activity Index (CDAI) ≤10 and 
CDAI ≤2.8; Simplified Disease Activity Index (SDAI) ≤11 and SDAI ≤3.3; ACR/EULAR remission 
according to the Boolean-based definition; and Health Assessment Questionnaire–Disability Index (HAQ-
DI) improvement ≥0.22 and ≥0.3 from Month 6 (of the originating study) through each 12 months of 
treatment

Change from baseline of originating study through each 12 months of treatment up to 5 years in structural 
joint damage as measured by modified Total Sharp Score (mTSS) (van der Heijde method) 

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
Proportion of patients with mTSS change ≤0 from baseline of originating study through each 12 months 
of treatment up to 5 years

Change from baseline of originating study through each 12 months of treatment up to 5 years in joint 
space narrowing and bone erosion score

Change from baseline in duration of morning stiffness through each 12 months of treatment

Change from baseline through each 12 months of treatment in European Quality of Life-5 Dimensions-5 
Level (EQ-5D-5L) scores 

Evaluation of healthcare resource utilization through each 12 months of treatment

To determine if treatment with baricitinib 2 mg QD maintains the low disease activity level achieved with 
the 4-mg QD dose (i.e., step-down dosing) on the following outcomes:
o
Proportion of patients who maintain a CDAI score of ≤10 from Studies JADV, JADW, and 
JADX after 3 months of treatment with baricitinib 2 mg QD and with patients continuing 
treatment with the 4-mg QD dose
o
Time to relapse (where relapse is defined as a CDAI score >10 from Studies JADV, JADW, 
and JADX) after randomization to the baricitinib 2-mg and 4-mg QD doses
Similar analyses will be conducted on patients who initiated treatment with baricitinib as rescue therapy at some 
time during the originating study.
The exploratory objective(s) of the study are:

To determine if treatment with baricitinib 2 mg QD maintains the low disease activity level or remission 
achieved with the 4-mg QD dose (i.e., step-down dosing) on the following outcomes:
o
Proportion of patients who maintain a CDAI score of ≤2.8 from Study JADZ after 3 months of 
treatment with baricitinib 2 mg QD and with patients continuing treatment with the 4-mg QD 
dose
o
Time to relapse after randomization to the baricitinib 2-mg and 4-mg QD doses where relapse is 
defined as:

a CDAI score >2.8 from Study JADZ

loss of CDAI categorization at randomization (a CDAI score >2.8 if CDAI score at 
randomization is 2.8 or a CDAI score > 10 if CDAI score at randomization is >2.8 and 
10)

having been rescued

To describe the clinical course of patients initiating baricitinib at the time of enrollment in Study JADY as 
assessed by DAS28-hsCRP, DAS28-ESR, and CDAI at 3, 6, 12, and at each 12 months of treatment 
allocation in the originating study
o
From placebo in Study JADW or JADX to baricitinib in Study JADY
o
From MTX in Study JADZ to baricitinib in Study JADY 
o
From adalimumab in Study JADV to baricitinib in Study JADY

To describe the clinical course of patients switching from MTX + baricitinib in Study JADZ to baricitinib 
monotherapy in Study JADY as assessed by DAS28-hsCRP, DAS28-ESR, and CDAI at 3, 6, 12, and at 
each 12 months of treatment

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Study Design:  Study I4V-MC-JADY (JADY) is a Phase 3, multicenter, long-term extension study evaluating the 
safety and efficacy of baricitinib (2 mg QD and 4 mg QD) in patients with rheumatoid arthritis for up to 
84 months.  Patients who completed an originating study (Study JADA, JADZ, JADV, JADX, JADW, or JAGS) 
may be eligible for enrollment into Study JADY.  Patients from future baricitinib RA studies may also be enrolled 
into Study JADY.  Planned enrollment will be approximately 2400 to 3500 patients.
This study will consist of 3 parts:  a screening period that will occur during the last visit of the originating study; 
Part A:  treatment period lasting up to 84 months from enrollment into Study JADY; and Part B:  posttreatment 
follow-up period.
Patients will receive baricitinib 4 mg QD or baricitinib 2 mg QD.
Diagnosis and Main Criteria for Inclusion and Exclusions:  Male or female patients at least 18 years of age who 
have been diagnosed with RA and have completed the final study visit in a previous baricitinib RA study
Investigational Product, Dosage, and Mode of Administration or Intervention: Patients who have completed 
Study JADV, JADZ, JADX, JADW, or JAGS will be assigned to blinded baricitinib treatment (2 mg QD or 4 mg 
QD), and all patients who have completed Study JADA will be assigned to receive open-label baricitinib 4 mg QD.  
Patients with renal impairment at baseline of the originating study (defined as estimated glomerular filtration rate 
[eGFR] <60 mL/min/1.73 m2) will only be eligible for dosing with baricitinib 2 mg QD.  Baricitinib tablets will be 
administered orally.
Planned Duration of Treatment: 84 months
Screening period:  1 day (should occur during the last visit of the originating study.  However, in particular 
circumstances, this duration may be extended after consultation with the sponsor.)
Treatment period:  84 months
Follow-up period:  28 days
Reference Therapy, Dose, and Mode of Administration or Comparative Intervention:  Patients originating 
from Study JADV, JADZ, JADX, JADW, or JAGS and who were not previously rescued will receive either a 
4-mg or 2-mg matching placebo tablet to maintain the blind of the step-down.
Criteria for Evaluation:  
Efficacy:  
The following efficacy measures will be assessed in this study:

ACR20, ACR50, and ACR70 indices

Hybrid ACR (bounded) response measure

DAS28-ESR and DAS28-hsCRP

EULAR28

mTSS (includes joint space narrowing score and bone erosion score) 

HAQ-DI

Simplified Disease Activity Index (SDAI)

CDAI

ACR/EULAR remission (according to the Boolean-based definition)
Safety:  
The following safety measures will be assessed in this study:

adverse events (AEs)

Adverse events of special interest

SAEs

suspected unexpected serious adverse reactions (SUSARs) 

concomitant medications

physical examinations

vital signs (blood pressure and pulse) and physical characteristics

standard laboratory tests (including hematology, clinical chemistry, urinalysis, lipid profile, eGFR, iron 
studies, hsCRP, and ESR)

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Adverse events of special interest or laboratory results of special interest will include:

severe or opportunistic infections

myelosuppressive events of anemia, leukopenia, neutropenia, lymphopenia, or thrombocytopenia

thrombocytosis

elevations in alanine aminotransferase or aspartate aminotransferase (>3 times the upper limit of normal 
[ULN]) with total bilirubin (>2 times the 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/L.
Health Outcomes:  
The following health outcome measures will be administered in this study:

duration of morning joint stiffness

EQ-5D-5L

Quick Inventory of Depressive Symptomatology Self-Rated-16 (QIDS-SR16)

healthcare resource utilization
Statistical Methods:
Sample Size: It is expected that 80% of patients will complete Study JADV, JADZ, JADX, JADW, JADA, or 
JAGS; therefore, planned enrollment for JADY will be approximately 2400 to 3500 patients.
Analysis Population: The efficacy and health outcome analyses will be conducted on an intention-to-treat (ITT) 
basis. The ITT analysis set will include all data from all enrolled patients treated with at least 1 dose of the 
investigational product in Study JADY.  The ITT population will be subcategorized based on baricitinib exposure 
in the originating study and whether the patient required rescue therapy.  Analysis of structural progression (van 
der Heijde mTSS) will be conducted on the ITT population using patients with available baseline (from the 
originating study) and at least 1 postbaseline x-ray assessment (collected in JADY).  Safety analyses will be 
performed on the safety population, defined as all enrolled patients who received at least 1 dose of the 
investigational product in Study JADY.
Missing Data Imputation:
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 are eligible for rescue therapy 
starting at 3 months (all studies except JADZ) or at any time point (JADZ) will be analyzed as nonresponders 
after rescue therapy and onward.  Enrolled patients without available data at a postbaseline visit will be 
defined as nonresponders for the NRI analysis at that visit. The time period used for the NRI analysis will be
defined in the statistical analysis plan (SAP) and in the integrated efficacy analysis plan (IEAP).
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.  The time period used for the linear 
extrapolation method will be defined in the SAP.
3.
Multiple imputation:  Methods other 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.  
Details will be provided in the SAP and IEAP.
4.
Modified last observation carried forward (mLOCF):  For all continuous measures including safety endpoints, 
the mLOCF will be a general approach to impute missing data unless otherwise specified.  For patients who 
are eligible for rescue therapy starting at 3 months (all studies except JADZ) or at any time point (JADZ), 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.  If the postbaseline observation is missing, then it will not be included in the analysis even if 
the baseline observation is not missing.  The time period used for the mLOCF method will be defined in the 

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SAP and IEAP.
5.
Supportive methods to the NRI and mLOCF will be used.
Efficacy Analyses:  Change from baseline of originating studies to postbaseline visits in JADY in mTSS will be 
summarized by treatment and analyzed using a t-test.  Within-treatment changes from baseline along with 
95% confidence interval (CI) will be assessed using the t-test.  The linear extrapolation method as described above 
will be used to impute missing mTSS.  Mixed model for repeated measures (MMRM) will also be used to analyze 
structural progression data and other continuous endpoints.  Joint space narrowing and bone erosion score analysis 
will follow the same model specification described for mTSS.  Proportion of patients with mTSS change ≤0 from 
baseline of originating studies to postbaseline visits in JADY, the proportion of patients maintaining a 
CDAI score ≤10, CDAI score ≤2.8, DAS28-hsCRP ≤3.2, DAS28-ESR ≤3.2, DAS28-hsCRP <2.6, DAS28-ESR 
<2.6, SDAI ≤11, SDAI ≤3.3; HAQ-DI improvement from baseline (of originating studies) of ≥0.22 and ≥0.3;
ACR20/50/70 response; and ACR/EULAR remission (according to the Boolean-based definition) at applicable 
visits in JADY will be summarized by treatment and study cohort.  The 95% CI for single proportion will be 
provided using the Wilson Score method (Wilson 1927; Newcombe 1998).  Categorical repeated measure analyses 
such as pseudo-likelihood-based mixed effects model for repeated measures (categorical MMRM) will be 
explored.  The Kaplan Meier method will be used to assess durability of effect using time to relapse by treatment 
group.  Cox regression model might be explored for time to relapse. Graphical presentations of median time to 
relapse will be provided.  Mean change from baseline to postbaseline visits in continuous efficacy variables 
(including DAS28-C-reactive protein [CRP] and DAS28-ESR) will be summarized.  The t-test will be used to 
summarize within-group changes from baseline.  Within treatment changes from baseline will be assessed by the t-
test along with 95% CI.
Safety:  All safety data will be descriptively summarized by cohort and treatment group (step-down) and analyzed 
using the safety population.  Treatment-emergent AEs (TEAEs) are defined as AEs that first occurred or worsened 
in severity on or after the first dose of study treatment in JADY.  The number and percentage of TEAEs will be 
summarized using MedDRA (Medical Dictionary for Regulatory Activities) for each system organ class and each 
preferred term by cohort and treatment group (step-down).  TEAEs will also be summarized by relationship to 
treatment and by severity within each cohort and treatment group (step-down).  SAEs and AEs that lead to 
investigational product discontinuation will also be summarized by cohort and treatment group (step-down).  
Fisher exact test will be used for statistical comparisons.  Change from baseline in quantitative clinical chemistry 
will be analyzed using analysis of covariance (ANCOVA) with treatment (or cohort) and baseline value in the 
model or the t-test where applicable.  Categorical variables, including the incidence of abnormal values and 
incidence of adverse events of special interest, will be summarized by frequency and percentage of patients in 
corresponding categories.  Shift tables will be presented for selected measures and analyzed by treatment (or 
cohort).  Change from baseline to postbaseline in vital signs, QIDS-SR16, and body weight will be analyzed using 
ANCOVA with treatment (or cohort) and baseline value in the model or the t-test where applicable.
Health Outcomes:  Health outcome measures will be analyzed using methods described for the continuous or 
categorical data as described for the efficacy measures.  More details are provided in the IEAP.
Planned Analyses:  Several analyses for regulatory purposes, such as safety updates (including the 120-day safety 
update), regulatory responses, yearly analyses for disclosure purposes, and a 2-year and a 5-year analysis of x-ray 
(radiographic progression of structural joint damage) data for publication purposes and/or to provide to regulatory 
agencies are planned for this study.  The first analysis is planned after all of the Phase 3 original studies (JADV, 
JADZ, JADX, or JADW) are analyzed and a final analysis after all patients complete the study.
Unblinding details will be specified in the unblinding plan section of the SAP.
Interim Analyses:  A DMC oversaw the conduct of all the Phase 3 clinical trials evaluating baricitinib in patients 
with RA.  The DMC consisted of members external to Lilly.  This DMC followed the rules defined in the DMC 
charter, focusing on potential and identified risks for this molecule and for this class of compounds.  DMC 
membership included, at a minimum, specialists with expertise in rheumatology, statistics, and other appropriate 
specialties.  This DMC for studies of patients with RA was coordinated with the DMC(s) for other ongoing studies 
of baricitinib in other indications, and this coordination did not alter the number and timing of the interim analyses.

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Access to the unblinded interim data was limited to the statisticians who conducted the interim analyses and the 
DMC.  The statisticians conducting the interim analyses were independent from the study team.  The study team 
did not have access to the unblinded data.  Study sites received information about interim results ONLY if they 
needed to know for the safety of their patients.
The DMC reviewed study discontinuation data, AEs including SAEs, clinical laboratory data, vital sign data, and 
so on.  The DMC recommended continuation of the study, as designed.  The DMC reviewed efficacy data to 
investigate the benefit/risk relationship in the context of safety observations for ongoing patients in the study.  The 
study was not stopped for positive efficacy results, and there was no planned futility assessment.  Hence, there was 
no alpha adjustment for these interim analyses.  Details of the DMC and interim safety analyses were documented 
in a DMC charter and DMC analysis plan, and all documentation is archived in the sponsor trial master file.
Besides DMC members, a limited number of preidentified individuals may gain access to the safety data, as 
specified in the unblinding plan, prior to the final database lock, to initiate the exploration for safety data (e.g., 
neutropenia, anemia).  Information that may unblind the study during the analyses will not be reported to study 
sites or the blinded study team until the database is locked. 
The DMC fulfilled the responsibilities of the Charter and have been disbanded.  Ongoing safety monitoring is 
being conducted by the Global Patient Safety and RA-BEYOND Study team according to company policy.

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3. Table of Contents
A Phase 3, Multicenter Study to Evaluate the Long-Term 
Safety and Efficacy of Baricitinib in Patients with Rheumatoid 
Arthritis
Section
Page
1.
Protocol I4V-MC-JADY(i) A Phase 3, Multicenter Study to Evaluate 
the Long-Term Safety and Efficacy of Baricitinib in Patients with 
Rheumatoid Arthritis...........................................................................................................1
2.
Synopsis .............................................................................................................................2
3.
Table of Contents................................................................................................................8
4.
Abbreviations and Definitions...........................................................................................14
5.
Introduction ......................................................................................................................19
5.1.
Background..................................................................................................................19
5.2.
Benefit/Risk .................................................................................................................20
6.
Objectives.........................................................................................................................24
6.1.
Primary Objective ........................................................................................................24
6.2.
Secondary Objectives...................................................................................................24
6.3.
Exploratory Objectives.................................................................................................25
7.
Investigational Plan...........................................................................................................26
7.1.
Summary of Study Design............................................................................................26
7.1.1.
Design Overview .................................................................................................26
7.1.2.
Treatment Duration, Treatment Assignment, and 
Maintenance of Study Blind in Study JADY ........................................................26
7.1.3.
Baricitinib Dose Titration.....................................................................................28
7.1.4.
Rescue Therapy....................................................................................................28
7.2.
Discussion of Design and Control ................................................................................31
8.
Study Population...............................................................................................................33
8.1.
Inclusion Criteria..........................................................................................................33
8.2.
Exclusion Criteria ........................................................................................................33
8.2.1.
Rationale for Exclusion of Certain Study Candidates ...........................................34
8.3.
Discontinuations ..........................................................................................................34
8.3.1.
Discontinuation of Patients...................................................................................34
8.3.1.1.
Interruption of Investigational Product............................................................34
8.3.1.2.
Discontinuation of Investigational Product .....................................................35
8.3.1.3.
Discontinuation from the Study ......................................................................36
8.3.2.
Discontinuation of Study Sites .............................................................................37

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8.3.3.
Discontinuation of the Study................................................................................37
9.
Treatment..........................................................................................................................38
9.1.
Treatments Administered .............................................................................................38
9.2.
Materials and Supplies .................................................................................................38
9.3.
Method of Assignment to Treatment ............................................................................39
9.4.
Rationale for Selection of Doses in the Study...............................................................39
9.5.
Selection and Timing of Doses.....................................................................................39
9.5.1.
Special Treatment Considerations ........................................................................39
9.6.
Continued Access to Investigational Product................................................................40
9.7.
Blinding .......................................................................................................................40
9.8.
Concomitant Therapy...................................................................................................40
9.9.
Treatment Compliance .................................................................................................42
10.
Efficacy, Health Outcome Measures, Safety Evaluations, Sample 
Collection and Testing, and Appropriateness of Measurements .........................................43
10.1. Efficacy Measures........................................................................................................43
10.1.1.
ACR20, ACR50, and ACR70 Indices...................................................................43
10.1.1.1.
Hybrid American College of Rheumatology Response 
Measure..........................................................................................................43
10.1.1.2.
Disease Activity Score-Erythrocyte Sedimentation Rate 
and Disease Activity Score–High-Sensitivity C-Reactive 
Protein............................................................................................................44
10.1.1.3.
European League Against Rheumatism Responder Index ...............................44
10.1.1.4.
van der Heijde Modified Total Sharp Score ....................................................45
10.1.1.5.
Simplified Disease Activity Index ..................................................................45
10.1.1.6.
Clinical Disease Activity Index.......................................................................46
10.1.1.7.
ACR/EULAR Rheumatoid Arthritis Remission ..............................................46
10.2. Health Outcome Measures............................................................................................46
10.3. Safety Evaluations........................................................................................................48
10.3.1.
Adverse Events ....................................................................................................48
10.3.1.1.
Adverse Events of Special Interest..................................................................49
10.3.1.2.
Serious Adverse Events ..................................................................................49
10.3.1.2.1.
Suspected Unexpected Serious Adverse Reactions....................................50
10.3.2.
Other Safety Measures .........................................................................................50
10.3.3.
Venous Thromboembolism Assessment ...............................................................51
10.3.4.
Safety Monitoring ................................................................................................51
10.3.5.
Complaint Handling.............................................................................................53
10.4. Sample Collection and Testing.....................................................................................53
10.4.1.
Samples for Standard Laboratory Testing.............................................................53
10.4.2.
Exploratory Work ................................................................................................54

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10.4.2.1.
Nonpharmacogenetic/Biomarker Stored Samples............................................54
10.5. Appropriateness of Measurements................................................................................54
11.
Data Quality Assurance.....................................................................................................55
11.1. Data Capture System....................................................................................................55
12.
Sample Size and Statistical Methods .................................................................................57
12.1. Determination of Sample Size ......................................................................................57
12.2. Statistical and Analytical Plans.....................................................................................57
12.2.1.
General Considerations ........................................................................................57
12.2.2.
Patient Disposition...............................................................................................59
12.2.3.
Patient Characteristics..........................................................................................59
12.2.4.
Concomitant Therapy...........................................................................................59
12.2.5.
Treatment Compliance .........................................................................................59
12.2.6.
Primary Outcome and Methodology.....................................................................59
12.2.7.
Efficacy Analyses ................................................................................................59
12.2.8.
Health Outcome Analyses ....................................................................................60
12.2.9.
Safety Analyses....................................................................................................60
12.2.10. Subgroup Analyses ..............................................................................................61
12.2.11. Planned Analyses.................................................................................................61
12.2.12. Interim Analyses..................................................................................................62
13.
Informed Consent, Ethical Review, and Regulatory Considerations ..................................63
13.1. Informed Consent.........................................................................................................63
13.2. Ethical Review.............................................................................................................63
13.3. Regulatory Considerations ...........................................................................................63
13.3.1.
Protocol Signatures ..............................................................................................64
13.3.2.
Final Report Signature .........................................................................................64
14.
References ........................................................................................................................65

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List of Tables
Table
Page
Table JADY.1.
Criteria for Temporary Discontinuation of Investigational Product ................35
Table JADY.2.
Criteria for Permanent Discontinuation of Investigational Product.................36
Table JADY.3.
Treatment Regimens......................................................................................38
Table JADY.4.
Scoring Method for the Hybrid American College of Rheumatology 
Response Measure .........................................................................................44
Table JADY.5.
Categorization of Patients as Nonresponders, Moderate Responders, or 
Good Responders...........................................................................................45

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List of Figures
Figure
Page
Figure JADY.1. Illustration of study design for Clinical Protocol I4V-MC-JADY –
patients enrolled after completing Study JADA, JADV, JADZ, JADX, 
JADW, or JAGS. ...........................................................................................30

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List of Attachments
Attachment
Page
Attachment 1.
Protocol JADY Study Schedule .....................................................................69
Attachment 2.
Protocol JADY Clinical Laboratory Tests......................................................81
Attachment 3.
Protocol JADY Hepatic Monitoring Tests for Treatment-Emergent 
Abnormality ..................................................................................................83
Attachment 4.
Monitoring Tests for Confirmed VTE............................................................84
Attachment 5.
Protocol Amendment
I4V-MC-JADY(i) Summary..........................................................................85

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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.
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)
sometimes referred to as clinical report form:  an electronic form for recording 
study participants’ data during a clinical study, as required by the protocol
CDAI
Clinical Disease Activity Index
cDMARD
conventional disease-modifying antirheumatic drugs
CI
confidence interval
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.

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Term
Definition
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
COX-2
cyclooxygenase-2
CRP
C-reactive protein
DAS
Disease Activity Score
DAS28
Disease Activity Score modified to include the 28 diarthrodial joint count
DMARD
disease-modifying antirheumatic drug
DMC
data monitoring committee
DVT
deep vein thrombosis
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 
protected
EULAR
European League Against Rheumatism

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Term
Definition
EULAR28
European League Against Rheumatism Responder Index based on the 28-joint 
count
FSH
follicle-stimulating hormone
GCP
good clinical practice
HAQ-DI
Health Assessment Questionnaire–Disability Index
HBcAb
hepatitis B core antibody
HBsAb
hepatitis B surface antibody
HBV DNA
hepatitis B virus deoxyribonucleic acid
HDL
high-density lipoprotein
hsCRP
high-sensitivity C-reactive protein
IB
Investigator’s Brochure
IC50
inhibitory concentration of 50%
ICF
informed consent form
ICH
International Council for Harmonisation
IEAP
integrated efficacy analysis plan
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 (i.e., 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.
interim analysis
an analysis of clinical study data, separated into treatment groups, that is 
conducted before the final reporting database is created/locked
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.
IVRS
interactive voice-response system
IWRS
interactive web-response system
JAK
Janus kinase
JAK1
1 of 4 identified members of the family of Janus kinases

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Term
Definition
JAK2
1 of 4 identified members of the family of Janus kinases
JAK3
1 of 4 identified members of the family of Janus kinases
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
least squares
MedDRA
Medical Dictionary for Regulatory Activities
MI
myocardial infarction
mLOCF
modified last observation carried forward
MMRM
mixed model for repeated measures
month
a period of 28 days
mTSS
modified Total Sharp Score
MTX
methotrexate
MTX-IR
patients who have had an inadequate response to methotrexate
NRI
nonresponder imputation
NSAID
nonsteroidal anti-inflammatory drug
patient
a study participant who has the disease or condition for which the 
investigational product is targeted
PE
pulmonary embolism
PK
pharmacokinetic(s)
PPD
purified protein derivative
PSAP
program safety analysis plan
QD
once daily
QIDS-SR16
Quick Inventory of Depressive Symptomatology Self-Rated-16
RA
rheumatoid arthritis
SAE
serious adverse event
SAP
statistical analysis plan

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Term
Definition
SC
subcutaneous
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
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])
TYK2
tyrosine kinase 2, 1 of 4 identified members of the family of Janus kinases
ULN
upper limit of normal
V1
central compartment volume of distribution
VAS
visual analog scale
VTE
venous thromboembolic event (deep vein thrombosis or pulmonary embolism)

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A Phase 3, Multicenter Study to Evaluate the Long-Term 
Safety and Efficacy of Baricitinib in Patients with Rheumatoid 
Arthritis
5. Introduction
5.1.
Background
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 diarthrodial 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 (e.g., 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% improvement in ACR criteria 
(ACR50) in a clinical trial setting.  During treatment with tumor necrosis factor-alpha (TNF-α) 

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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).  Achieving remission is the first treatment hierarchical 
objective of the Treat to Target RA recommendations (Smolen et al. 2010).  As RA is a chronic 
condition, patients are usually treated with long-term cDMARDs and/or biologics.  Therefore,
there is interest in assessing whether doses can be decreased slowly once disease activity has 
been controlled.  For patients who do achieve remission or low disease state, the EULAR 
recommendations for the management of RA is to consider tapering ± withdrawal of background 
cDMARDs (Smolen et al. 2017).
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).
5.2.
Benefit/Risk
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 DMARDs, either 
conventional or biologic.  Three completed Phase 2 studies, four completed Phase 3 studies, and 
one ongoing Phase 3 study (Study I4V-CR-JAGS [JAGS]) have evaluated the clinical utility of 
baricitinib as treatment for patients with active RA.  In the Phase 2 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 another 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 

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24 weeks of treatment could enter the extension period of Study JADA that provided treatment 
for up to an additional 24 months.
The primary efficacy objective (based on ACR20) was met in each completed Phase 3 study, and
most major (gated) secondary objectives were also met.  Baricitinib also demonstrated 
significant improvements compared to comparators (placebo, MTX, adalimumab) with respect to 
relevant domains of efficacy. Across measures, improvements were generally seen with 
baricitinib from the earliest weeks of treatment (in many instances as early as Week 1) and 
sustained through the duration of each study.  Baricitinib demonstrated statistically significant 
inhibition of radiographic progression of structural joint damage in each of the three completed 
studies which incorporated this measure. For additional details regarding efficacy, see 
Section 6.3 of Investigator’s Brochure (IB).
Consistent with prior cumulative data, baricitinib continued to be well-tolerated through 52 and 
128 weeks of treatment. The data were consistent with the safety profile observed in the first 
24 weeks and, in particular, the data do not demonstrate new signals for events occurring after 
long-term administration of baricitinib. There were few discontinuations, and no new signals of 
concern with regard to overall adverse events (AEs), serious adverse events (SAEs), infections, 
malignancies, cardiovascular events, or other aspects of clinical safety.
The safety profile for baricitinib has been informed by results from nonclinical and clinical 
studies evaluating a wide range of doses (up to 40 mg once daily [QD]).  There are potential 
risks recognized for baricitinib that will be followed carefully in the Phase 3 development 
program.  The potential risks for baricitinib include increased AEs due to increased exposures in 
patients with renal impairment, myelosuppression, increased infections (including opportunistic 
infections and herpes zoster), increased cardiovascular events due to changes in lipids, fetal
malformations, emergence of malignancies previously contained by the immune system, and 
pharmacologic interaction between nonsteroidal anti-inflammatory drugs (NSAIDs) and 
baricitinib to decrease the capacity of the kidneys to respond to hemodynamic changes.  
Venous thromboembolism (VTE), including deep vein thrombosis (DVT) and pulmonary 
embolism (PE), had been determined to be an important potential risk for baricitinib.  Based on 
the 2019 updated review of reported events from clinical trials and spontaneous postmarketing 
cases, as well as the evolving external landscape acknowledging an association with JAK 
inhibitors as a class, DVT and PE are proposed to be considered as adverse drug reactions 
(ADRs) in baricitinib labeling for United States, Europe, Canada, and Japan.  Globally, labels for 
baricitinib carry the following warning and precaution: “Events of deep venous thrombosis 
(DVT) and pulmonary embolism (PE) have been reported in patients receiving baricitinib.  
Baricitinib should be used with caution in patients with risk factors for DVT/PE.  If clinical 
features of DVT/PE occur, interrupt baricitinib, evaluate promptly, and institute appropriate 
treatment.”
More information about the known and expected benefits, risks, and reasonably anticipated AEs
may be found in the investigator’s brochure (IB).  Information on AEs expected to be related to 

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the investigational product may be found in Section 7 (Development Core Safety Information) of 
the IB.  Information on 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.  For additional details regarding risks, see 
Section 6.2 of the IB.
Study I4V-MC-JADY (JADY) is a Phase 3 long-term extension (up to 84 months) study
investigating the efficacy and safety of baricitinib in patients with RA.  Patients who have 
completed a Phase 2 or Phase 3 study of baricitinib (i.e., an originating study) are eligible for 
enrollment into Study JADY.  Originating studies include but are not limited to Studies JADA, 
JADZ, JADV, JADX, JADW, and JAGS:

Study I4V-MC-JADA (JADA), as described above, is a Phase 2b, double-blind, 
placebo-controlled study investigating the efficacy and safety of baricitinib doses of 1, 2, 
4, and 8 mg QD in patients with active RA despite ongoing MTX therapy.  Study JADA 
consists of a 12-week double-blind treatment period, a 12-week blinded extension period, 
and 2 optional 52-week open-label extension periods.  At the time of study completion, 
all patients in Study JADA will be receiving baricitinib 4 mg QD.

Study I4V-MC-JADZ (JADZ) is a Phase 3, double-blind, active-controlled study 
investigating the efficacy and safety of baricitinib (4 mg QD) administered as 
monotherapy or in combination with MTX, during a 52-week treatment period, in 
patients with early RA who have had limited or no treatment with DMARDs.  MTX, 
administered as monotherapy and titrated to the highest tolerated dose specified in the 
protocol, serves as the active comparator.  At the time of study completion, all patients in 
Study JADZ will be receiving baricitinib 4 mg QD, MTX (at highest tolerated dose), or 
the combination of baricitinib plus MTX.

Study I4V-MC-JADV (JADV) is a Phase 3, 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.  As tumor necrosis factor 
(TNF) inhibitors are the most commonly used biologic class of therapies for the treatment 
of moderately to severely active RA in MTX-IR patients, Humira® (adalimumab) was 
selected as an appropriate active comparator to baricitinib.  At the time of study 
completion, all patients in Study JADV will be receiving either baricitinib 4 mg QD or 
adalimumab.

Study I4V-MC-JADX (JADX) is a Phase 3, double-blind, placebo-controlled study 
investigating the efficacy and safety of baricitinib (2 mg QD or 4 mg QD) administered 
with background cDMARD(s), during a 24-week treatment period, in patients with active 
RA who have had an inadequate response to cDMARDs.  At the time of study 
completion, all patients in Study JADX will be receiving baricitinib 2 mg QD, baricitinib 
4 mg QD, or placebo.

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
Study I4V-MC-JADW (JADW) is a Phase 3, double-blind, placebo-controlled study 
investigating the efficacy and safety of baricitinib (2 mg QD or 4 mg QD) administered 
with background cDMARD(s), during a 24-week treatment period, in patients with active 
RA who have had an inadequate response to biologic DMARDs.  At the time of study 
completion, all patients in Study JADW will be receiving baricitinib 2 mg QD, baricitinib 
4 mg QD, or placebo.

Study I4V-CR-JAGS (JAGS) is a Phase 3, double-blind, placebo-controlled study 
investigating the efficacy and safety of baricitinib (4 mg QD) administered with 
background MTX, during a 52-week treatment period, in patients with moderately to 
severely active RA who have had an inadequate response to MTX therapy.  At the time 
of study completion, all patients in Study JAGS will be receiving baricitinib 4 mg QD.
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 exposures to date, continued administration of baricitinib in this 
extension of the ongoing Phase 3 studies is appropriate.

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6. Objectives
6.1.
Primary Objective
The primary objective of the study is to evaluate the long-term safety and tolerability of 
baricitinib. Safety and tolerability assessments will include:

Treatment-emergent adverse events (TEAEs), adverse events of special interest, and 
serious adverse events (SAEs)

Temporary investigational product interruptions and permanent investigational product
discontinuations

Vital signs and laboratory evaluations (including chemistry and hematology)
6.2.
Secondary Objectives
To evaluate in patients initially randomized to receive baricitinib in the originating study, the 
effect of long-term administration of baricitinib as assessed by:

Proportion of patients who maintain an ACR20, ACR50, and ACR70 through each 
12 months of treatment

Proportion of patients who maintain a Disease Activity Score modified to include the 
28 diarthrodial joint count (DAS28)-high sensitivity C-reactive protein (hsCRP) ≤3.2, 
DAS28-erythrocyte sedimentation rate (ESR) ≤3.2, DAS28-hsCRP <2.6, and DAS28-
ESR <2.6; Clinical Disease Activity Index (CDAI) ≤10 and CDAI ≤2.8; Simplified 
Disease Activity Index (SDAI) ≤11 and SDAI ≤3.3; ACR/EULAR remission according 
to the Boolean-based definition; and Health Assessment Questionnaire–Disability Index 
(HAQ-DI) improvement ≥0.22 and ≥0.3 from Month 6 (of the originating study) through 
each 12 months of treatment

Change from baseline of originating study through each 12 months of treatment up to 5 
years in structural joint damage as measured by modified Total Sharp Score (mTSS) (van 
der Heijde method) 

Proportion of patients with mTSS change ≤0 from baseline of originating study through
each 12 months of treatment up to 5 years

Change from baseline of originating study through each 12 months of treatment up to 5 
years in joint space narrowing and bone erosion score

Change from baseline in duration of morning stiffness through each 12 months of 
treatment

Change from baseline through each 12 months of treatment in European Quality of Life-5 
Dimensions-5 Level (EQ-5D-5L) scores

Evaluation of healthcare resource utilization through 12 months of treatment

To determine if treatment with baricitinib 2 mg QD maintains the low disease activity 
level achieved with the 4-mg QD dose (i.e., step-down dosing) on the following 
outcomes:

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o
Proportion of patients who maintain a CDAI score of ≤10 from Studies JADV, 
JADW, and JADX after 3 months of treatment with baricitinib 2 mg QD and with
patients continuing treatment with the 4-mg QD dose
o
Time to relapse (where relapse is defined as a CDAI score >10 from Studies 
JADV, JADW, and JADX) after randomization to the baricitinib 2-mg and 4-
mg QD doses
Similar analyses will be conducted on patients who initiated treatment with baricitinib as rescue 
therapy at some time during the originating study.
6.3.
Exploratory Objectives

To determine if treatment with baricitinib 2 mg QD maintains the low disease activity 
level or remission achieved with the 4-mg QD dose (i.e., step-down dosing) on the 
following outcomes:
o
Proportion of patients who maintain a CDAI score of ≤2.8 from Study JADZ after 
3 months of treatment with baricitinib 2 mg QD and with patients continuing 
treatment with the 4-mg QD dose
o
Time to relapse after randomization to the baricitinib 2-mg and 4-mg QD doses 
where relapse is defined as:

a CDAI score >2.8 from Study JADZ

loss of CDAI categorization at randomization (a CDAI score >2.8 if CDAI 
score at randomization is 2.8 or a CDAI score > 10 if CDAI score at 
randomization is >2.8 and 10)

having been rescued

To describe the clinical course of patients initiating baricitinib at the time of enrollment 
in Study JADY as assessed by DAS28-hsCRP, DAS28-ESR, and CDAI at 3, 6, 12, and at
each 12 months of treatment by initial treatment allocation in the originating study
o
From placebo in Study JADW or JADX to baricitinib in Study JADY
o
From MTX in Study JADZ to baricitinib in Study JADY 
o
From adalimumab in Study JADV to baricitinib in Study JADY

To describe the clinical course of patients switching from MTX + baricitinib in 
Study JADZ to baricitinib monotherapy in Study JADY as assessed by DAS28-hsCRP, 
DAS28-ESR, and CDAI at 3, 6, 12, and at each 12 months of treatment

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7. Investigational Plan
7.1.
Summary of Study Design
7.1.1. Design Overview
Study I4V-MC-JADY (JADY) is a Phase 3, multicenter, long-term extension study evaluating 
the safety and efficacy of baricitinib (2 mg QD and 4 mg QD) in patients with RA.  Patients who 
completed an originating study (Study JADA, JADZ, JADV, JADX, JADW, or JAGS) may be 
eligible for enrollment into Study JADY.  Patients from future baricitinib RA studies may also be 
enrolled into Study JADY.  Planned enrollment will be approximately 2400 to 3500 patients.
Study JADY will consist of 3 parts:

Screening:  Screening should occur during the last visit of the originating study.  
However, in particular circumstances, this duration may be extended after 
consultation with the sponsor.

Part A:  treatment period lasting up to 84 months from enrollment into Study 
JADY

Part B:  posttreatment follow-up period of 28 days.
Patients may continue to receive the background non-investigational, open-label cDMARD, 
NSAID, corticosteroid, and other analgesic therapies they were receiving at completion of the
originating study.  If, after final analysis of the Phase 2 and Phase 3 studies, it is determined that 
either dose of baricitinib does not have a positive benefit/risk profile, then that dose arm may be 
discontinued and all patients transferred to the remaining dose arm.  However, patients with renal 
impairment at baseline of the originating study will not receive doses higher than 2 mg 
baricitinib QD.
7.1.2. Treatment Duration, Treatment Assignment, and Maintenance 
of Study Blind in Study JADY
As Studies JADA, JADZ, JADV, JADX, JADW, and JAGS vary in duration; patients enrolling 
in Study JADY will enter the study at different visits. Timing of assessments in Study JADY is 
described in terms of 28-day months of treatment since randomization in the originating study. 
This study construct allows the activities required at each visit to be the same for all patients 
enrolled in Study JADY regardless of the originating study.

Patients completing Studies JADX and JADW will have had approximately 6 months of 
treatment with investigational product (baricitinib or placebo) and will enter Study JADY
at Visit 1.

Patients completing Studies JADV, JADZ, and JAGS will have had approximately 
12 months of treatment with investigational product (baricitinib, adalimumab [JADV], or 
MTX [JADZ]) and will enter Study JADY at Visit 4.

Patients completing Study JADA will have had approximately 30 months of treatment 
with baricitinib and will enter Study JADY at Visit 11.

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Studies JADA, JADZ, JADV, JADX, JADW, and JAGS also vary by whether patients are 
receiving open-label baricitinib or blinded investigational product at the time of study 
completion.  Therefore, treatment assignments and blinding in Study JADY vary depending on 
the originating study. In all cases, however, patients and investigators will remain blind as to 
their original (initial) blinded treatment assignment in the originating study.

Patients completing Study JADA will have been receiving open-label baricitinib 
4 mg QD and will receive open-label baricitinib 4 mg QD in Study JADY.

Patients enrolled in Studies JADW and JADX were initially randomized to baricitinib 
2 mg QD, 4 mg QD, or placebo and had the option of rescue therapy beginning at 
Week 16.  Patients completing these studies without requiring rescue therapy are still 
blinded to treatment allocation.  To maintain the study blinds, these patients will receive 
blinded therapy in Study JADY.  Patients who had been receiving baricitinib 2 mg QD 
will receive the 2-mg dose in Study JADY.  Patients who had been receiving either 
baricitinib 4 mg QD or placebo will receive the 4-mg dose.  Patients who received rescue 
therapy during Studies JADW and JADX will be receiving baricitinib 4 mg QD at study 
completion.  These patients will continue to receive baricitinib 4 mg QD in Study JADY.  
Patients with renal impairment will receive baricitinib 2 mg QD.

Patients enrolled in Study JADV were initially randomized to baricitinib 4 mg QD, 
adalimumab 40 mg subcutaneous (SC) Q2 weeks, or placebo (both placebo tablet and SC 
injection).  Patients had the option of rescue therapy beginning at Week 16.  Patients 
initially randomized to placebo received baricitinib 4 mg QD beginning at Week 24.  
Patients completing the study without rescue therapy are still blinded to treatment 
allocation.  To maintain the study blind and to avoid administering a SC placebo injection 
for an extended period, these patients will receive baricitinib 4 mg QD, and adalimumab 
investigational product (i.e., adalimumab and matching adalimumab placebo) will be 
discontinued.  Patients who had received rescue therapy during Study JADV will be 
receiving open-label 4 mg QD baricitinib at study completion.  These patients will 
continue to receive baricitinib 4 mg QD in Study JADY.  Patients with renal impairment
will receive baricitinib 2 mg QD.

Patients enrolled in Study JADZ were initially randomized to baricitinib 4 mg QD, MTX 
monotherapy, or baricitinib plus MTX.  Patients had the option of rescue therapy 
beginning at Week 24.  Patients completing the study without rescue therapy are still 
blinded to treatment allocation.  To maintain the study blind, these patients will receive 
baricitinib 4 mg QD and MTX investigational product (i.e., MTX or matching MTX 
placebo) will be discontinued.  Patients who had received rescue therapy during Study 
JADZ will be receiving open-label baricitinib 4 mg QD and open-label MTX at study 
completion.  These patients will continue to receive baricitinib 4 mg QD, and open-label 
MTX will be discontinued.  Patients with renal impairment will receive 2 mg baricitinib 
QD.

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
Patients enrolled in Study JAGS were initially randomized to baricitinib 4 mg QD or 
placebo.  At Week 24, all patients entered the open-label period and received a dose of 
baricitinib 4 mg QD.  Patients will continue to receive baricitinib 4 mg QD in Study 
JADY.  Patients with renal impairment will receive baricitinib 2 mg QD.
7.1.3. Baricitinib Dose Titration
An exploratory objective of this study is to evaluate the effectiveness of a reduced dose of 
baricitinib (step-down from baricitinib 4 mg QD to baricitinib 2 mg QD) in patients who achieve 
a sustained (at least 3 months in JADY) low disease activity level (CDAI score ≤10; for patients 
originating in Studies JADV, JADX, JADW, and JAGS) or a sustained remission (CDAI score 
≤2.8; for patients originating in Study JADZ).  Patients achieving these disease activity criteria
will be randomized following a 1:1 ratio allocation to continue baricitinib 4 mg QD or receive 
the 2-mg QD dose in a blinded fashion.  Patients eligible for randomization to step-down must 
have received at least 15 months of treatment with baricitinib 4 mg QD and have not received 
rescue therapy in the originating study or JADY.  Patients from Study JADA are not eligible for 
participation in step-down dosing.
If a patient experiences worsening of disease symptoms (either CDAI >10 or CDAI >2.8, 
depending on originating study) following step-down, a change in analgesics/NSAIDs dosing or 
the addition of an analgesics/NSAIDs may be considered to manage transient flares.  An 
unscheduled study visit may be needed to assess response to NSAIDs/analgesics and need for 
rescue therapy.  If the patient fails to achieve low disease activity or remission, they may be 
returned to baricitinib 4 mg QD, and an alteration in cDMARD or corticosteroid therapy may be 
considered.  Patients will be eligible for step-down dosing only once.  If after rescue therapy and 
adjustment of concomitant medications, in the opinion of the investigator the patient is unable to 
derive adequate benefit (e.g., achieving a CDAI ≤10 (patients originating in Studies JADV, 
JADX, JADW, and JAGS) or CDAI ≤2.8 (patients originating in Study JADZ)) from treatment 
with baricitinib over an appropriate time period (e.g., 3 months), the patient should be 
discontinued from the study.
7.1.4. Rescue Therapy
For patients originating in Studies JADA, JADV, JADW, JADX, and JAGS rescue therapy may 
be provided to any patient who has a CDAI score >10 at or after 3 months following enrollment
into Study JADY. Patients receiving baricitinib 2 mg QD and who have normal renal function 
(defined as estimated glomerular filtration rate [eGFR] ≥60 mL/min/1.73 m2) will be rescued to 
baricitinib 4 mg QD. Patients receiving baricitinib 4 mg QD and patients receiving a baricitinib 
2-mg QD dose due to renal impairment will continue to receive these doses.
Furthermore, addition or increase in dose of cDMARDs may occur only after rescue.
For patients originating in Study JADZ, MTX or other cDMARDs may be prescribed at the 
discretion of the investigator and according to local clinical practice, at any time point during 
Study JADY (including prior to 3 months since enrollment).

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Patients originating from any study who initiate/increase MTX or other cDMARDs above the 
maintenance dose in the originating study during Study JADY will be considered as having 
received rescue therapy.
Patients who experience worsening symptoms between scheduled visits should contact the 
investigator to arrange an unscheduled study visit and should be assessed for rescue therapy, as 
appropriate.  If after 3 months of rescue therapy and adjustment of concomitant medications (e.g., 
cDMARDs), patients are considered nonresponders (defined as failure to reach CDAI ≤22 for 
patients originating in Studies JADV, JADX, JADW, or JAGS and as failure to reach CDAI ≤10 
for patients originating in Study JADZ), it is recommended that they should be discontinued 
from the study.  If after 6 months of rescue therapy and adjustment of concomitant medications 
(e.g., cDMARDs), patients have responded but have not reached low disease activity (defined as 
CDAI ≤10 for patients originating in any study), it is recommended that they should be 
discontinued from the study.
Section 12.2.12 outlines information regarding the data monitoring committee (DMC) and 
interim analyses.
Figure JADY.1 illustrates the study design.

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Figure JADY.1.
Illustration of study design for Clinical Protocol I4V-MC-JADY – patients enrolled after completing 
Study JADA, JADV, JADZ, JADX, JADW, or JAGS.
Visit
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
Months of 
Treatment Since 
Randomization 
in Originating 
Study
JADW
and 
JADX
6
7
9
12
--
15
18
21
24
27
30
33
36
39
42
45
48
51
54
--
60
--
66
--
72
--
78
84
90
--
--
--
--
JADV 
and
JADZ
--
--
--
13
14
16
19
22
25
28
31
34
37
40
43
46
49
52
55
58
61
--
67
--
73
--
79
85
91
97
--
--
--
JAGS
--
--
--
13
--
16
19
22
25
28
31
34
37
40
43
46
49
52
55
58
61
--
67
--
73
--
79
85
91
97
--
--
--
JADA
--
--
--
--
--
--
--
--
--
--
32
35
38
41
44
47
50
53
56
59
62
65
68
71
74
77
80
86
92
98 104 110 116
The duration of an individual patient’s participation in Study JADY will be 
approximately 84 months 
First opportunity 
for randomization 
to step-down for 
qualifying patients 
First patient 
visit for patients 
originating from 
JADA
First patient visit for 
patients originating 
from JADV, JADZ, 
and JAGS
First patient 
visit for patients 
originating from 
JADX and JADW
Last patient visit 
for patients 
originating from 
JADX and JADW
Last patient 
visit for 
patients 
originating 
from JADA
Last patient visit 
for patients 
originating from 
JADV, JADZ, and 
JAGS

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7.2.
Discussion of Design and Control
Baricitinib doses of 4 mg QD or 2 mg QD will be provided in this extension study.  Patients 
receiving baricitinib during the originating study will continue on the baricitinib dose 
administered at the end of that study.  Patients enrolling in Study JADY from Studies JADW and 
JADX will receive blinded investigational product (either baricitinib 4 mg QD or 2 mg QD) in 
order to preserve the blind of the originating study.  Patients previously receiving placebo will 
receive the baricitinib 4-mg dose.  For patients enrolling in JADY from Studies JADV and 
JADZ, the adalimumab investigational product (Study JADV) and MTX investigational product 
(Study JADZ) will be discontinued in order to preserve the blind of the originating study and to 
avoid the long-term administration of placebo injections.  Patients previously receiving a 
comparator investigational product will receive the baricitinib 4-mg dose (see Section 9.4 for 
rationale) in Study JADY.  Patients with renal impairment at baseline of the originating study
will not receive doses higher than 2 mg baricitinib QD.
Background cDMARDs, NSAIDs, and low-dose oral corticosteroids are permitted during the 
study (see Section 9.8 for concomitant medications).  For patients originating in Studies JADA, 
JADV, JADW, JADX, and JAGS rescue therapy may be provided after 3 months following 
enrollment into Study JADY. For patients originating in Study JADZ, MTX or other cDMARDs 
may be prescribed at the discretion of the investigator and according to local clinical practice, at 
any time point during Study JADY (including prior to 3 months since enrollment) to ensure 
adequate control of disease activity in these patients with early RA.
Safety assessment of baricitinib will be based on the total duration of baricitinib exposure 
including exposure during the originating study.  Efficacy assessments will also be based on the 
total duration of baricitinib exposure using disease severity measures obtained at the time of 
initial randomization in the originating study as baseline values.  The outcomes for patients 
switching from adalimumab plus MTX to baricitinib plus MTX (originating Study JADV), from 
MTX monotherapy to baricitinib monotherapy (originating Study JADZ), from MTX plus 
baricitinib to baricitinib monotherapy (originating Study JADZ) and from placebo plus 
MTX/cDMARD to baricitinib plus MTX/cDMARD (Studies JADW and JADX) will be 
described.
The effectiveness of a reduced dose of baricitinib (step-down from baricitinib 4 mg QD to 
baricitinib 2 mg QD) in patients who achieve a sustained low disease activity level (CDAI score 
≤10) (or a sustained remission [CDAI score ≤2.8] for patients from Study JADZ) will be 
assessed.  For patients with early RA originating in Study JADZ, more stringent eligibility 
criteria for step-down dosing are applied as the goal of therapy in these patients is to achieve 
remission.  For patients originating in Studies JADV, JADW, and JADX, less stringent criteria 
are applied as a more reasonable goal of treatment would be attainment of low disease activity.  
Fifteen months of treatment with baricitinib prior to step-down was selected to allow adequate 
study duration (>1 year) on stable doses of baricitinib 4 mg QD to thoroughly assess the 
benefit/risk profile of the dose regimen, including assessment of key endpoints such as 
radiographic progression at 12 months.  Allowing step-down after a minimum of 15 months 
treatment with baricitinib also ensures that patients have been on stable doses of baricitinib for at 

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least 3 months in the context of the JADY study prior to step-down.  Both the investigator and 
patient will be blinded to if or when randomization to step-down dosing occurs.

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8. Study Population
The study population will be comprised of patients diagnosed with RA who have completed any 
of the ongoing baricitinib studies listed in the inclusion criteria.  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.
8.1.
Inclusion Criteria
Patients are eligible to be included in the study only if they meet the following criterion:
[1] Have completed the final active treatment study visit in Study JADV, JADZ, JADX, 
JADW, JADA, or JAGS
8.2.
Exclusion Criteria
Patients will be excluded from the study if they meet any of the following criteria:
[2] have significant uncontrolled cerebro-cardiovascular (e.g., myocardial infarction [MI], 
unstable angina, unstable arterial hypertension, severe heart failure, or cerebrovascular 
accident), respiratory, hepatic, renal, gastrointestinal, endocrine, hematologic, 
neuropsychiatric disorders, or abnormal laboratory values that developed during a 
previous baricitinib study that, in the opinion of the investigator, pose an unacceptable 
risk to the patient if investigational product continues to be administered
[3] have a known hypersensitivity to baricitinib or any component of this investigational
product
[4] had investigational product permanently discontinued at any time during a previous 
baricitinib study
[5] had temporary investigational product interruption at the final study visit of a previous 
baricitinib study and, in the opinion of the investigator, this poses an unacceptable risk 
for the patient’s participation in the study
[6] have any other condition that, in the opinion of the investigator, renders the patient 
unable to understand the nature, scope, and possible consequences of the study or 
precludes the patient from following and completing the protocol
[7] are females of childbearing potential who do not agree to use 2 forms of highly effective 
birth control when engaging in sexual intercourse while enrolled in the study and for at 
least 28 days following the last dose of 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 (i.e, 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 methods to be used with their partner):

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
oral, injectable, implanted, or other hormonal contraceptives 
(including contraceptive pills, implants, transdermal 
patches, hormonal vaginal devices, or injections with 
prolonged release)

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 (e.g., progestin-releasing coil)

vasectomized male (with appropriate postvasectomy 
documentation of the absence of sperm in the ejaculate)
[8] 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 investigational product
8.2.1. Rationale for Exclusion of Certain Study Candidates
The rationale for the exclusion criteria is as follows:  Exclusion Criteria [2] through [6] exclude 
individuals with previous or concomitant medical conditions that increase the risk for their 
participation in the study.  Exclusion Criteria [7] and [8] exclude individuals who are pregnant, 
breastfeeding, at risk for becoming pregnant, or at risk for impregnating their partner during the 
study.
8.3.
Discontinuations
8.3.1. Discontinuation of Patients
8.3.1.1.
Interruption of Investigational Product
In some circumstances, it may be necessary to temporarily interrupt treatment as a result of AEs 
or abnormal laboratory values as described in Table JADY.1 that may have an unclear 
relationship to investigational product.  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 
investigational product that was temporarily discontinued because of an AE or abnormal 
laboratory value.  Investigational product must be held in the following situations involving 
laboratory abnormalities and may be resumed as noted in Table JADY.1.

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Table JADY.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/L
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 without documented renal impairment at 
baseline of originating study
eGFR 50 mL/min/1.73 m2
eGFR <30 mL/min/1.73 m2 (from serum creatinine) 
for patients with documented renal impairment at 
baseline of originating study
eGFR 40 mL/min/1.73 m2
ALT or AST >5 times the ULN
ALT and AST return to <2 times the ULN, and 
investigational product is not considered to be the cause of 
enzyme elevation
Hemoglobin <8 g/dL
Hemoglobin 10 g/dL
Symptomatic herpes zoster
All skin lesions have crusted and are resolving
Severe infection that, in the opinion of the 
investigator, merits the investigational product being 
discontinued
Resolution of infection
Clinical features of VTE (deep vein thrombosis or
pulmonary embolism [DVT/PE]) are present
After confirmation that DVT/PE is not present
Abbreviations:  ALT = alanine aminotransferase; ANC = absolute neutrophil count; AST = aspartate
aminotransferase; DVT/PE = deep vein thrombosis or pulmonary embolism; eGFR = estimated glomerular 
filtration rate; min = minute; ULN = upper limit of normal; VTE = venous thromboembolic event; WBC = white 
blood cell.
Although temporary interruption of investigational product is not a requirement at times of 
increased potential risk of VTE (e.g., surgery, significant air travel, or other situations involving 
prolonged immobilization), following appropriate VTE prophylaxis guidelines is recommended 
to help manage the VTE risk under these circumstances.
8.3.1.2.
Discontinuation of Investigational Product
Any patient who is permanently discontinued from investigational product for an AE or 
abnormal laboratory result should have the reason for investigational product discontinuation 
reported as the AE or abnormal laboratory value.  If any of the criteria listed in Section 8.3.1.1
above recur after investigational product is restarted, the investigator must obtain approval from 
Lilly (or its designee) before restarting investigational product. In addition, patients will be 
permanently discontinued from investigational product if they experience any of the criteria 
listed in Table JADY.2.

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Table JADY.2.
Criteria for Permanent Discontinuation of Investigational Product
Permanently Discontinue Investigational Product if Any of the Following Is 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/L
ANC <500 cells/L
Lymphocyte count <200 cells/L
Hemoglobin <6.5 g/dL
Pregnancy
Malignancy (except for successfully treated basal cell or squamous epithelial skin cancers)
HBV DNA ≥29 IU/mLa
Develop a VTE (DVT/PE) since first receiving baricitinib (including originating study)
b with exception
c
Abbreviations:  ALT = alanine aminotransferase; ANC = absolute neutrophil count; AST = aspartate 
aminotransferase; HBV DNA = hepatitis B virus deoxyribonucleic acid; ULN = upper limit of normal; 
VTE = venous thromboembolic event; WBC = white blood cell.
a
If a 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 for additional instruction on HBV DNA monitoring.
b
Patients who develop a VTE may have additional follow-up and testing recommended (see Section 10.3.3 and 
Attachment 4).
c
Patients who had a single occurrence of VTE (occurrence includes a DVT, PE, or DVT and PE combination at 
roughly the same time) prior to the protocol amendment (i) effective date may continue receiving baricitinib in 
Study JADY at the investigtor’s discretion.
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 investigational product.  If the patient 
is discontinued from investigational product, the patient should remain in the study to complete
study procedures listed in the Early Termination Visit and enter the posttreatment follow-up 
period.
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 classified as non-responder after 3 months of rescue therapy (as described 
in Section 7.1.4).

Patient failed to reach low disease activity within 6 months after response to 
rescue therapy (as described in Section 7.1.4).

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
Patient enrolls in any other clinical trial involving an investigational product or 
enrolls 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 
investigational product is to be discontinued and appropriate measures are to be 
taken.  Lilly (or designee) is to be notified immediately.

Lilly (or designee) decides that the patient should be withdrawn.

Patient is noncompliant with protocol procedures to the extent that the 
noncompliance interferes with the patient’s safety monitoring or hinders 
interpretation of study data.

Patient requests to be withdrawn from the study.

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).  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.
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
Patients in this long-term extension study will receive baricitinib doses of 2 mg or 4 mg 
administered orally QD according to the study they completed before entering Study JADY and 
as shown in Table JADY.3.  Patients with renal impairment who received a baricitinib dose of 
2 mg QD in the originating study will continue to receive a 2 mg QD dose of baricitinib in Study 
JADY.  For details regarding step-down and rescue dosing, see Section 7.1.3 and Section 7.1.4.
Table JADY.3.
Treatment Regimens
Originating Study
Treatment at End of Originating 
Study
Treatment at Start of JADY
JADV
Baricitinib 4 mg QD
Baricitinib 4 mg QD
Adalimumab 40 mg SC biweekly
JADZ
Baricitinib 4 mg QD + MTX weekly
Baricitinib 4 mg QD
Baricitinib 4 mg QD monotherapy
MTX monotherapy weekly
JADX
Baricitinib 4 mg QD 
Baricitinib 4 mg QD
Baricitinib 2 mg QD
Baricitinib 2 mg QD
Placebo QD
Baricitinib 4 mg QD
JADW
Baricitinib 4 mg QD
Baricitinib 4 mg QD
Baricitinib 2 mg QD
Baricitinib 2 mg QD
Placebo QD
Baricitinib 4 mg QD
JADA
Baricitinib 4 mg QD
Baricitinib 4 mg QD
JAGS
Baricitinib 4 mg QD
Baricitinib 4 mg QD
Abbreviations:  MTX = methotrexate; QD = once daily.
The investigator or his/her designee will be responsible for explaining the correct use of the 
investigational agent 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 2 mg of baricitinib

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
tablets containing placebo to match 2 mg baricitinib tablets

tablets containing 4 mg of baricitinib

tablets containing placebo to match 4 mg baricitinib tablets
Investigational product will be dispensed to the patient at the principal investigator’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 
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
At the start of Study JADY, patients who meet all criteria for enrollment and who have 
completed Study JADV, JADZ, JADX, JADW, or JAGS will be assigned to baricitinib treatment
(2 mg QD or 4 mg QD) according to the study they have just completed, as outlined in 
Table JADY.3.  Patients who meet all criteria for enrollment and who have completed Study 
JADA will be assigned to receive open label baricitinib 4 mg QD for the duration of Study 
JADY.  Patients with renal impairment will receive baricitinib 2 mg QD.
Patients eligible for step-down will be assigned to step-down treatment by a computer-generated 
random sequence using an interactive voice-response system (IVRS) or interactive web-response 
system (IWRS).  Randomization to baricitinib 2 mg QD or 4 mg QD will follow a 1:1 ratio 
allocation and will be stratified by region and originating study.  The IVRS or IWRS will be used 
to assign packages containing double-blind investigational product to each patient.  Site 
personnel will confirm that they have located the correct packages by entering a confirmation 
number found on the packages into the IVRS or IWRS before dispensing to the patient.
9.4.
Rationale for Selection of Doses in the Study
Based on efficacy, safety, and pharmacokinetics data from the Phase 2 studies (JADC and 
JADA), Lilly has selected doses of 4 mg QD and 2 mg QD baricitinib for evaluation in Phase 3 
studies and will continue those doses in this study.
9.5.
Selection and Timing of Doses
Investigational product should be dispensed to the patient at the first visit of Study JADY.  
Baricitinib dosing will continue daily for 84 months.  Oral investigational product should be 
taken at home at approximately the same time each day.
9.5.1. Special Treatment Considerations
Step-down dosing and rescue therapy will be available (see Section 7.1.3 and Section 7.1.4).

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9.6.
Continued Access to Investigational Product
Baricitinib will not be made available at the conclusion of the study.
9.7.
Blinding
For patients who enroll into this study after completing Study JADV, JADZ, JADA, or JAGS, 
the known treatment assignment at the start of JADY will be baricitinib 4 mg QD.  For patients 
who enroll into this study after completing Study JADX or JADW and who received rescue
therapy during the originating study, the known treatment assignment at the start of JADY will 
be baricitinib 4 mg QD.  For patients who enroll from Study JADX or JADW and who did not 
receive rescue therapy during the originating study, baricitinib 2 mg QD or baricitinib 4 mg QD 
will continue to be assigned in a blinded manner at entry into JADY.  Patients with renal 
impairment at baseline of the originating studies (defined as eGFR <60 mL/min/1.73 m2) will 
not receive doses higher than 2 mg baricitinib QD.
Patients who qualify for the randomized step-down evaluation will receive blinded therapy upon 
randomization so that they are no longer aware of the baricitinib dose they are receiving.  To 
preserve the blinding of the randomized step-down, a minimum number of Lilly personnel will 
see the randomization table and treatment assignments before the primary analysis of this study 
phase is conducted.
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.
Processes to maintain blinding during the interim analysis conducted by the DMC are described 
in Section 12.2.12.
9.8.
Concomitant Therapy
Patients may continue to receive concomitant treatments for RA used during the study in which 
they were previously enrolled.  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.
Concomitant DMARDs for patients who completed Study JADZ:
During Study JADZ, concomitant MTX treatment was blinded.  Therefore, MTX or other 
cDMARDs may be prescribed at the discretion of the investigator and according to local clinical 
practice, at any time point during Study JADY.
Concomitant cDMARDs for patients who completed Study JADW, JADX, JADV, JADA, 
or JAGS:
MTX or other cDMARDs may be prescribed for patients having a CDAI score >10 at or after 
3 months following enrollment into Study JADY.
Patients who initiate MTX or other cDMARDs during Study JADY will be considered as having 
received rescue therapy.

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For all patients in Study JADY:

All biologic DMARD therapies are prohibited.

cDMARDs may be added or the dose increased only after rescue.  Maximum doses for 
the following cDMARDs are specified: hydroxychloroquine up to 400 mg/day; 
sulfasalazine up to 3000 mg/day; leflunomide (Arava®, Sanofi-Aventis) up to 20 mg/day; 
and azathioprine up to 150 mg/day or 2 mg/kg/day.
o
For patients who achieve sustained remission or low disease activity, it is 
recommended to consider tapering ± withdrawal of background cDMARDs in 
accordance with professional treatment guidelines (Singh et. al. 2016; Smolen et 
al. 2017)
Analgesics and NSAID use, including cyclooxygenase-2 (COX-2) inhibitors, is permitted up to 
the maximum recommended dose according to local clinical practice.  Addition of analgesics or 
NSAIDs, or change of dose of ongoing analgesics and NSAIDs may occur at any time point 
during Study JADY. The choice and dose of analgesics and NSAID are at the discretion of the 
investigator. Dose adjustments are permitted for safety reasons and, if required, to treat 
worsening of symptoms. Aspirin (acetylsalicylic acid, maximum 350 mg/day) use is allowed to 
reduce cardiovascular risk.
Oral corticosteroid use is permitted as follows:  

Oral corticosteroids for treatment of RA may be initiated, and the dose may be increased 
to an average daily dose equivalent to 10 mg/day of prednisone for patients not 
previously on corticosteroid therapy at the discretion of the investigator.

Increasing/decreasing the oral corticosteroid dose will be allowed at the investigator’s 
discretion up to an average daily dose equivalent to 10 mg of prednisone per day for the 
management of RA.

In addition, burst and taper of corticosteroids will be allowed at the discretion of the 
investigator so that an average daily dose equivalent to 10 mg prednisone is not exceeded 
over a 30-day period for management of conditions other than RA.

To treat non-RA conditions, increased doses of oral corticosteroids may be considered on 
a case-by-case basis with the provision that the corticosteroid dose be reduced to previous 
levels when possible. For example, a non-RA condition, such as asthma, requiring an 
increase in oral corticosteroid dose of up to 40 mg of prednisone per day for 2 weeks or 
less is permitted.
Intra-articular joint injections and bursal injections may be given at doses and intervals at
the investigator’s discretion.
Proton pump inhibitors and H2 receptor blockers or equivalent local standard of care may be
given at the recommended dose as prophylactic treatment to patients receiving NSAIDs or 
corticosteroids.

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Additional drugs are to be avoided during the study unless required to treat an AE or for the
treatment of an ongoing medical condition. If the need for other concomitant medications arises,
discontinuation of the patient from investigational product or the study will be at the discretion 
of the investigator in consultation with Lilly (or designee).
Live vaccines, including herpes zoster vaccination, are prohibited during the study.  Nonlive 
seasonal vaccinations and/or emergency vaccination, such as rabies or tetanus vaccinations, are 
allowed.
All concomitant medications taken during the study must be recorded in the Concomitant 
Medication sections of the case report form (CRF).
9.9.
Treatment Compliance
Patient compliance with study medication will be assessed at Visits 2 through 33 when specified 
in the study schedule (Attachment 1) (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.
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.
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
The efficacy measures described below will be collected at the times shown in the study 
schedule (Attachment 1).
10.1.1. ACR20, ACR50, and ACR70 Indices
ACR20 is defined as at least 20% improvement from baseline of originating study in the 
following ACR Core Set values:

TJC (68 joint count)

SJC (66 joint count)

An improvement of at least 20% in at least 3 of the following 5 assessments:
1. Patient Assessment of Pain (visual analog scale [VAS])
2. Patient Global Assessment of Disease Activity (VAS)
3. Physician Global Assessment of Disease Activity (VAS)
4. Patient Assessment of Physical Function as measured by the HAQ-DI
5. acute phase reactant as measured by hsCRP
ACR50 and ACR70 responses are efficacy measures that are calculated as improvements of at 
least 50% and of at least 70%, respectively, in the ACR Core Set values listed above.
10.1.1.1. 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 JADY.4.

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Table JADY.4.
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 (baseline of originating study) 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 (bounded) 
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.
10.1.1.2. 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 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 thumbs, the 8 proximal interphalangeal joints, and the 
2 knees (Smolen et al. 1995).
10.1.1.3. European League Against Rheumatism Responder Index
Assessments of patients with RA by European League Against Rheumatism Responder Index 
based on the 28-joint count (EULAR28) will be used to categorize patients as nonresponders, 
moderate responders, good responders, or responders (moderate + good responders) according to 
Table JADY.5 (van Gestel et al. 1998).

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Table JADY.5.
Categorization of Patients as Nonresponders, Moderate 
Responders, or Good Responders
Postbaseline Level of 
DAS28
Improvement since Baseline of Originating Study 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 diarthrodial joint count.
10.1.1.4. van der Heijde Modified Total Sharp Score
For patients who had radiographs of left and right hands/wrists and left and right feet taken 
during their originating study, structural progression will be measured using the mTSS.  The 
baseline initial radiographs taken in the originating study will serve as the baseline radiographs 
for comparison throughout Study JADY.
For patients who completed enrollment in a previous study (JADV, JADZ, JADA, JADX, or
JAGS), additional radiographs (i.e, a single posteroanterior view of each hand and a single 
dorsoplantar view of each foot) will be obtained as shown in the study schedule (Attachment 1).
X-rays of the hands/wrists and feet will be scored using the structural progression as measured 
using a modification of the mTSS (van der Heijde 2000).  This methodology quantifies the extent 
of bone erosions and joint space narrowing for 44 and 42 joints, respectively, with higher scores 
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.
10.1.1.5. Simplified Disease Activity Index
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)

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
hsCRP in mg/dL (0.1 to 10.0)

patient global DAS on VAS (0 to 10.0 cm), and 

evaluator global health score on VAS (0 to 10.0 cm) (Aletaha and Smolen 2005)
Disease remission is defined as an SDAI score of ≤3.3 (Felson et al. 2011).
Low disease activity is defined as a SDAI score ≤11 (Aletaha and Smolen 2005).
10.1.1.6. Clinical Disease Activity Index
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 cm), and 

evaluator global health score on VAS (0 to 10.0 cm) (Aletaha and Smolen 2005)
Remission is defined as a CDAI score of ≤2.8 (Felson et al. 2011).
Low disease activity is defined as a CDAI score ≤10 (Aletaha and Smolen 2005).
10.1.1.7. ACR/EULAR Rheumatoid Arthritis Remission
Two new ACR/EULAR definitions of RA remission will be evaluated, a “Boolean-based 
definition” and an “index-based definition” (Felson et al. 2011).  The “index-based definition” 
was discussed in Section 10.1.1.5.
For the ACR/EULAR, according to the “Boolean-based definition” of remission, all 4 criteria 
below must be met at the same visit:  

Tender joint counts (0 to 28) ≤1

Swollen joint counts (0 to 28) ≤1

hsCRP ≤1 mg/dL (10 mg/L)

Patient global DAS on VAS (using 0 to 10.0 cm) ≤1
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.

Duration of morning joint stiffness:  The duration of morning joint stiffness is a 
patient-administered item that allows for the patients to enter the length of time in 
minutes that their morning joint stiffness lasted the day prior to the visit (using an 
electronic patient-reported outcomes [ePRO] tablet).

HAQ-DI:  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, 

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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, performing 
hygiene, reaching, gripping, 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.

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, 
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; 
Herdman et al. 2011; The EuroQol Group 2013 [WWW]).

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’s web site (University of Pittsburgh 
IDS/QIDS page [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 nonphysical care 
providers for services outside of the clinical study; emergency room admissions; hospital 

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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 record all relevant 
AE/SAE information in the CRF. 
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
Lilly has standards for reporting AEs that are to be followed regardless of applicable regulatory 
requirements that may be less stringent.
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 informed consent form (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 data entry.
Any clinically significant findings from electrocardiogram, 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, and/or investigational 
product via electronic data 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.

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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 data 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 or laboratory results of special interest will include:

severe or opportunistic infections

venous thromboembolism (DVT/PE)

myelosuppressive events of anemia, leukopenia, neutropenia, lymphopenia, or 
thrombocytopenia

thrombocytosis

elevations in alanine aminotransferase (ALT) or aspartate aminotransferase (AST)
(>3 times the upper limit of normal [ULN]) and total bilirubin (>2 times the 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/L.
10.3.1.2. Serious Adverse Events
SAE collection in Study JADY will begin after the patient has signed informed consent.  SAEs 
reported prior to signing of informed consent should be reported to the study in which the patient 
was previously enrolled.
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 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 (i.e, immediate risk of dying)

persistent or significant disability/incapacity

congenital anomaly/birth defect

considered significant by the investigator for any other reason
Important medical events that may not result in death, be life-threatening, or require 
hospitalization may be considered serious 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.

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SAEs 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 either 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, MI, hospitalization for unstable angina, 
hospitalization for heart failure, serious arrhythmia, resuscitated sudden death, cardiogenic shock 
due to MI, 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
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.  
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
Physical examination:  A focused physical examination will be performed prior to study 
enrollment to assure that the patient has not developed any condition that would meet the 
exclusion criteria.  The focused physical examination may be repeated at the investigator’s 
discretion any time a patient presents with physical complaints (Attachment 1).
Tuberculosis testing:  Investigators should follow local guidelines for monitoring patients for 
tuberculosis (TB) if a patient is at high risk for acquiring TB or reactivation of latent TB.
Vital signs and physical characteristics:  Vital signs (sitting blood pressure and pulse) will be 
measured at times indicated in the study schedule (Attachment 1).  Patients should be seated and 
relaxed with both feet on the floor for at least 5 minutes prior to taking measurements.  
Simultaneous blood pressure and pulse measurements should be made using either automated or 
manual equipment.  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 1 of the blood pressure readings.  If measurements are machine 
averaged, the average 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).

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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).
Pregnancy tests:  Patients should be counseled not to become pregnant during the study and to 
contact the investigator immediately if pregnancy is suspected.  Urine pregnancy tests should be 
performed as needed at the discretion of the investigator.
Hepatitis B virus (HBV) DNA monitoring:  Patients who were hepatitis B core antibody 
(HBcAb) positive at screening for the originator study will require HBV DNA monitoring 
approximately every 3 to 6 months, regardless of their hepatitis B surface antibody (HBsAb) 
status.
If 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 JADY.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
during Study JADY and the preceding originator baricitinib study, HBV testing should be 
conducted approximately once per month for the remainder of the study and referral to a 
hepatologist is recommended.

Patients who met criteria for monthly HBV DNA testing in the preceding originator 
baricitinib study should continue with monthly testing in Study JADY.
10.3.3. Venous Thromboembolism Assessment
If a patient develops the signs and symptoms of a DVT or PE, appropriate local laboratory tests 
and imaging should be performed, as necessary, for diagnosis of the event.  For confirmed cases, 
additional laboratory testing may be performed, as outlined in Attachment 4. The choice and 
optimal timing of these tests will be directed by the patient’s management and may require 
ongoing follow-up after study discontinuation.  
10.3.4. Safety Monitoring
The Lilly clinical research physician will monitor safety data throughout the course of the study.

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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 times the ULN or elevated total bilirubin ≥2 times the 
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 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.  AE 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 MIs, 
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 to detect any clinically significant imbalance in the 
occurrence of these events between treatment groups

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
A DMC (an advisory group for this study formed to protect the patients; refer to Interim 
Analyses, Section 12.2.12) oversaw the conduct of all of the baricitinib Phase 3 clinical trials.  In 
the event that safety monitoring was to uncover an issue that needed to be addressed by 
unblinding at the group level, only members of the DMC were to be able to conduct additional 
analyses of the safety data.

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10.3.5. 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 will be reported directly to the manufacturers 
of those drugs/devices in accordance with the package insert.
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 will be 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.  Urine pregnancy tests will be performed as needed at the discretion of the 
investigator.  Blood and urine samples will be collected 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.
Routine 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 will be run and confirmed promptly whenever scientifically 
appropriate.  When scientific circumstances warrant, however, it will be 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.

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10.4.2. Exploratory Work
10.4.2.1. Nonpharmacogenetic/Biomarker Stored Samples
Collection of samples for nonpharmacogenetic biomarker research is a required part of this 
study.  Where local regulations allow, serum, plasma, 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 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 email, 
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 patient-reported outcome measures or other data reported directly by the subject will 
be entered into an ePRO instrument at the time that the information is obtained.  Electronic 
physician-reported outcome measures will be directly entered by the physician or designee 
(Physician Global Assessment of Disease Activity) or by the joint assessor (TJC/SJC) into the 
electronic site tablet.  In these instances for which there is no prior written or electronic source 
data at the site, the ePRO instrument record will serve as the source.
Assessments/procedures conducted during the final visit of the patient’s originating study will be 
replicated from the originating study datasets to the JADY study datasets.  For example, Study 
JADX Week 24/V11 data will be replicated as Month 6/V1 data.  The originating study data will 
be the source data.  Assessments with ongoing data in the originating study will be re-entered in 
the electronic data capture system such as continuing AEs and concomitant medications.
The ePRO records will be stored by a third party, and investigator sites will have continuous 
access to the source documents during the study and will receive an archival copy at the end of 
the study for retention.

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Any data for which the ePRO instrument record will serve to collect source data will be 
identified and documented by each site in that site’s study file.
CRF 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
It is expected that 80% of patients will complete Study JADV, JADZ, JADX, JADW, JADA, or 
JAGS; therefore, planned enrollment into JADY will be approximately 2400 to 3500 patients.
12.2. Statistical and Analytical Plans
12.2.1. General Considerations
Statistical analysis of this study will be the responsibility of Eli Lilly and Company, although 
implementation of the SAP and IEAP may be delegated to a third party.  A detailed SAP and 
IEAP describing the statistical methodologies will be developed or amended by Lilly or its 
designee.
Collected data will be presented using summary tables by treatment cohort and by treatment 
group for step-down.  Continuous data will be summarized using the mean, median, standard 
deviation (SD), and range (minimum and maximum).  Categorical data will be summarized in 
terms of frequency counts and percentages.  Graphical presentations will be used to support the 
presentation of selected data using, but not limited to, Kaplan Meier time to event analyses 
(e.g., time to relapse).  All statistical tests will be performed at a 2-sided significance level of 
0.05, unless otherwise stated.  Interaction effects, where applicable, will be performed at a 2-
sided significance level of 0.1.  Statistical comparisons will be made using Fisher exact test 
where applicable, and t-test or ANCOVA for continuous data, whichever is appropriate, unless 
otherwise stated. If a restricted maximum likelihood-based mixed model for repeated measures 
(MMRM) is used (e.g., structural progression data and other continuous endpoints), the model 
will include treatment, visit, and treatment-by-visit-interaction as fixed categorical effects and 
baseline score and baseline score-by-visit-interaction as fixed continuous effects.  An 
unstructured (co)variance structure will be used to model the between- and within-patient errors.  
If this analysis fails to converge, other structures will be tested. The Kenward-Roger method 
will be used to estimate the degrees of freedom.  Type III sums of squares for the least squares 
(LS) means will be used; p-values and 95% confidence interval (CI) will also be reported for 
each treatment group.  Further details on the use of MMRM will be described in the SAP and 
IEAP.
Baseline collected at the originating studies will be used as baseline for all ACR categorical and 
HAQ-DI improvement from baseline analyses in this study unless otherwise specified.  For 
patients who switch after randomization (step-down) to a different dose, analyses will be based 
on their random assignment to treatment unless otherwise specified.  Details will be provided in 
the SAP and IEAP.
Analysis Populations:
The efficacy and health outcome analyses will be conducted on an intention-to-treat (ITT) basis 
unless otherwise specified.  The ITT analysis set will include all data from all enrolled patients 
treated with at least 1 dose of the investigational product in Study JADY.  The ITT population 

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will be subcategorized based on baricitinib exposure in the originating study and whether the 
patient required rescue therapy.  Analysis of structural progression (van der Heijde mTSS) will 
be conducted on the ITT population using patients with available baseline (from the originating
study) and at least 1 postbaseline x-ray assessment (collected in JADY).  Safety analyses will be 
performed on the safety population, which is defined as all enrolled patients who received at 
least 1 dose of the investigational product in Study JADY.  Patients will be analyzed for efficacy, 
health outcomes, and safety according to the treatment to which they were assigned.  Further 
details will be described in the SAP and IEAP.
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 are eligible for rescue therapy starting at 3 months (all studies 
except JADZ) or at any time point (JADZ) will be analyzed as nonresponders after rescue 
therapy and onward.  Enrolled patients without available data at a postbaseline visit will 
be defined as nonresponders for the NRI analysis at that visit. The time period used for 
the NRI analysis will be defined in the SAP and IEAP.
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.
The time period used for the linear extrapolation method will be defined in the SAP.
3. Multiple imputation:  Methods other 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.  Details will be provided in the SAP and 
IEAP.
4. Modified last observation carried forward (mLOCF):  For all continuous measures 
including safety endpoints, the mLOCF will be a general approach to impute missing data 
unless otherwise specified.  For patients who are eligible for rescue therapy starting at 
3 months (all studies except JADZ) or at any time point (JADZ), 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.  If the postbaseline observation 
is missing, then it will not be included in the analysis even if the baseline observation is 
not missing.  The time period used for the mLOCF method will be defined in the SAP 
and IEAP.
5. Supportive methods to the NRI and mLOCF will be used.

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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 IEAP and the clinical study report.  Additional exploratory analyses of the data 
will be conducted as deemed appropriate.
12.2.2. Patient Disposition
The number of enrolled patients along with ITT population will be summarized by treatment 
cohort and randomized patients by treatment group for the step-down.  Frequency counts and 
percentages will be presented for each treatment cohort and treatment group (step-down). 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 cohort and 
treatment group (step-down).
12.2.3. Patient Characteristics
Baseline characteristics will be summarized descriptively by treatment cohort and treatment 
group (step-down).  Descriptive statistics including the number of patients, mean, 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 the different cohorts or treatment groups unless otherwise stated.
12.2.4. Concomitant Therapy
Concomitant medications will be descriptively summarized in terms of frequency counts and 
percentages using the safety population prior to and after step-down.  The medications will be 
coded accordingly.
12.2.5. Treatment Compliance
Compliance to investigational product treatment for baricitinib will be assessed through counts 
of returned investigational product tablets.  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 investigational product 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 investigational 
product.  Patient compliance will be further defined in the SAP and IEAP.
12.2.6. Primary Outcome and Methodology
Refer to Section 12.2.9.
12.2.7. Efficacy Analyses
Change from baseline of originating studies to postbaseline visits in JADY in structural joint 
damage as measured by mTSS will be summarized by treatment and analyzed using a t-test.  
Within-treatment changes from baseline along with 95% CI will be assessed using the t-test.  The 

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linear extrapolation method as described above will be used to impute missing mTSS.  MMRM 
(defined in Section 12.2.1) will be used to analyze structural progression data and other 
continuous endpoints.  Joint space narrowing and bone erosion score analysis will follow the 
same model specification described for mTSS.
Categorical efficacy variables including the proportion of patients with mTSS change ≤0 from 
baseline of originating studies to postbaseline visits in JADY; the proportion of patients 
maintaining a CDAI score ≤10, CDAI ≤2.8, DAS28-hsCRP ≤3.2, DAS28-ESR ≤3.2, 
DAS28-hsCRP <2.6, DAS28-ESR <2.6, SDAI ≤11, SDAI ≤3.3; HAQ-DI improvement from 
baseline (of originating studies) of ≥0.22 and ≥0.3; ACR20/50/70 response; and ACR/EULAR 
remission (according to the Boolean-based definition) at applicable visits in JADY will be 
summarized by treatment and study cohort.  The 95% CI for single proportion will be provided 
using the Wilson Score method (Wilson 1927; Newcombe 1998).  Categorical repeated measure 
analyses such as pseudo-likelihood-based mixed effects model for repeated measures 
(categorical MMRM) will be explored.  The Kaplan Meier method will be used to assess 
durability of effect using time to relapse by treatment group.  Cox regression model might be 
explored for time to relapse.  Graphical presentations of median time to relapse will be provided.
Mean change from baseline (last assessment in originating studies) to postbaseline visits in 
continuous efficacy variables (including DAS28-hsCRP and DAS28-ESR) will be summarized.  
The t-test will be used to summarize within-group changes from baseline. Within treatment 
changes from baseline will be assessed by the t-test along with 95% CI. More details will be 
provided in the SAP and IEAP.
12.2.8. Health Outcome Analyses
The health outcome measures will be analyzed using methods described for the continuous or 
categorical data as described for the efficacy measures in Section 12.2.7.  More details are 
provided in the IEAP.
12.2.9. Safety Analyses
Safety data including TEAEs, adverse events of special interest, SAEs, laboratory analytes 
(chemistry, hematology, etc.), and vital signs will be descriptively summarized by cohort and by 
treatment group (step-down) and analyzed using the safety population.
TEAEs are defined as AEs that first occurred or worsened in severity on or after the first dose of 
study treatment in JADY.  The number of TEAEs as well as the number and percentage of 
patients who experience at least 1 TEAE will be summarized using MedDRA (Medical 
Dictionary for Regulatory Activities) for each system organ class (or a body system) and each 
preferred term by cohort and treatment group (step-down).  Exposure-adjusted incidence rates 
will be provided.  TEAEs will also be summarized by relationship to treatment and by severity 
within each cohort and treatment group (step-down).  SAEs and AEs that lead to investigational 
product discontinuation will also be summarized by cohort and treatment group (step-down).  
Fisher exact test will be used for the statistical comparisons.

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All clinical laboratory results will be descriptively summarized by cohort and treatment group
(step-down).  Individual results that are outside of normal reference ranges will be flagged in 
data listings.  Quantitative clinical hematology, chemistry, and urinalysis variables obtained at 
baseline to postbaseline visits will be summarized as changes from baseline by cohort and 
treatment group (step-down) and evaluated using an ANCOVA with treatment (or cohort) and 
baseline value in the model or the t-test where applicable. Within group changes from baseline 
will be assessed by the t-test. Categorical variables, including the incidence of abnormal values 
and incidence of adverse events of special interest, will be summarized by frequency and 
percentage of patients in corresponding categories.  Shift tables will be presented for selected 
measures and analyzed by treatment (or cohort).
Observed values and changes from baseline (predose or screening if missing) for vital signs and 
physical characteristics will be descriptively summarized by cohort and treatment group 
(step-down) and time point.  Change from baseline to postbaseline in vital signs, QIDS-SR16, 
and body weight will be analyzed using ANCOVA with treatment (or cohort) and baseline value 
in the model or the t-test where applicable. Within-group changes from baseline will be assessed 
by the t-test.
The incidence and average duration of investigational product interruptions will be descriptively 
summarized by treatment (or cohort).  Various techniques may be used to estimate the effects of 
investigational product interruptions on safety measures.  Further analyses may be performed 
and will be planned in the program safety analysis plan (PSAP) and the SAP.
Data collected after initiation of rescue therapy will be summarized as appropriate.
12.2.10.
Subgroup Analyses
Subgroup analysis will be conducted for selected safety, efficacy, and health outcome measures 
by gender, age, race, country, region, originating study (JADV, JADX, etc.), and so on.
Definitions for the levels of the subgroup variables, the analysis methodology, and any subgroup 
analyses will be defined in details in the SAP, IEAP, and the PSAP.  Because this study is not 
powered for subgroup analyses, all subgroup analyses will be treated as exploratory.
12.2.11.
Planned Analyses
Several analyses for regulatory purposes, such as safety updates (including the 120-day safety 
update), regulatory responses, yearly analyses for disclosure purposes, and a 2-year and a 5-year 
analysis of x-ray (radiographic progression of structural joint damage) data for publication
purposes and/or to provide to regulatory agencies are planned for this study. The first analysis is 
planned after all of the Phase 3 original studies (JADV, JADZ, JADX, or JADW) are analyzed 
and a final analysis after all patients complete the study.
Unblinding details will be specified in the unblinding plan section of the SAP.

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12.2.12.
Interim Analyses
A DMC oversaw the conduct of all the Phase 3 clinical trials evaluating baricitinib in patients 
with RA.  The DMC consisted of members external to Lilly.  This DMC followed the rules 
defined in the DMC charter, focusing on potential and identified risks for this molecule and for 
this class of compounds.  DMC membership included, at a minimum, specialists with expertise 
in rheumatology, statistics, and other appropriate specialties.  This DMC for studies of patients 
with RA was coordinated with the DMC(s) for other ongoing studies of baricitinib in other 
indications, and this coordination did not alter the number and timing of the interim analyses.
Access to the unblinded interim data was limited to the statisticians who conducted the interim 
analyses and the DMC.  The statisticians conducting the interim analyses were independent from 
the study team.  The study team did not have access to the unblinded data.  Study sites received
information about interim results ONLY if they needed to know for the safety of their patients.
The DMC reviewed study discontinuation data, AEs including SAEs, clinical laboratory data, 
vital sign data, and so on.  The DMC recommended continuation of the study, as designed.  The 
DMC reviewed efficacy data to investigate the benefit/risk relationship in the context of safety 
observations for ongoing patients in the study.  The study was not stopped for positive efficacy 
results, and there was no planned futility assessment.  Hence, there was no alpha adjustment for 
these interim analyses.  Details of the DMC and interim safety analyses were documented in a 
DMC charter and DMC analysis plan, and all documentation is archived in the sponsor trial 
master file.
Besides DMC members, a limited number of preidentified individuals may gain access to the 
safety data, as specified in the unblinding plan, prior to the final database lock, to initiate the 
exploration for safety data (e.g., neutropenia, anemia).  Information that may unblind the study 
during the analyses will not be reported to study sites or the blinded study team until the database
is locked.
The DMC fulfilled the responsibilities of the Charter and have been disbanded. Ongoing safety 
monitoring is being conducted by the Global Patient Safety and RA-BEYOND Study team 
according to company policy.

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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 Council for
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. 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.
13.3.2. 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.
References
Aletaha D, Smolen J. The Simplified Disease Activity Index (SDAI) and the Clinical Disease 
Activity Index (CDAI): a review of their usefulness and validity in rheumatoid arthritis. Clin 
Exp Rheumatol. 2005;23(suppl 39):S100-S108.
American College of Rheumatology Committee to Reevaluate Improvement Criteria. A 
proposed revision to the ACR20: the hybrid measure of American College of Rheumatology 
response. Arthritis Rheum. 2007;57(2):193-202.
[APA] American Psychiatric Association’s Diagnostic and Statistical Manual of Mental 
Disorders, 4th Edition. Washington, DC; American Psychiatric Association. 1994. 
Brooks R. EuroQol: The current state of play. Health Policy. 1996;37(1):53–72.
Cohen SB, Emery P, Greenwald MW, Dougados M, Furie RA, Genovese MC, Keystone EC, 
Loveless JE, Burmester GR, Cravets MW, Hessey EW, Shaw T, Totoritis MC: REFLEX Trial 
Group. Rituximab for rheumatoid arthritis refractory to anti-tumor necrosis factor therapy. 
Results of a multicenter, randomized, double-blind, placebo-controlled phase III trial 
evaluating primary efficacy and safety at twenty-four weeks. Arthritis Rheum. 
2006;54(9):2793-2806.
Colmegna I, Ohata BR, Menard HA. Current understanding of rheumatoid arthritis therapy. Clin 
Pharmacol Ther. 2012;91(4):607-620.
Curtis JR, Patkar N, Xie A, Martin C, Allison JJ, Saaq M, Shatin D, Saaq KG. Risk of serious 
bacterial infections among rheumatoid arthritis patients exposed to tumor necrosis factor alpha 
antagonists. Arthritis Rheum. 2007;56(4):1125-1133.
The EuroQol Group. EQ-5D-5L User Guide. Version 5.0. October 2013. Available at:
http://www.euroqol.org/fileadmin/user_upload/Documenten/PDF/Folders_Flyers/EQ-5D-
3L_UserGuide_2013_v5.0_October_2013.pdf. Accessed September 9, 2014.
Felson DT, Smolen JS, Wells G, Zhang B, van Tuyl LH, Funovits J, Aletaha D, Allaart CF, 
Bathon J, Bombardieri S, Brooks P, Brown A, Matucci-Cerinic M, Choi H, Combe B, 
de Wit M, Dougados M, Emery P, Furst D, Gomez-Reino J, Hawker G, Keystone E, Khanna 
D, Kirwan J, Kvien TK, Landewé R, Listing J, Michaud K, Martin-Mola E, Montie P, Pincus 
T, Richards P, Siegel JN, Simon LS, Sokka T, Strand V, Tugwell P, Tyndall A, van der Heijde 
D, Verstappen S, White B, Wolfe F, Zink A, Boers M. American College of 
Rheumatology/European League against Rheumatism provisional definition of remission in 
rheumatoid arthritis for clinical trials. Ann Rheum Dis. 2011;70:404-413.
Fleischmann RM. Is there a need for new therapies for rheumatoid arthritis? J Rheum Suppl. 
2005;73):3S-7S.
Fridman JS, Scherle PA, Collins R, Burn TC, Li Y, Li J, Covington MB, Thomas B, Collier P, 
Favata MF, Wen X, Shi J, McGee R, Haley PJ, Shepard S, Rodgers JD, Yeleswaram S, 
Hollis G, Newton RC, Metcalf B, Friedman SM, Vaddi K. Selective inhibition of JAK1 and 
JAK2 is efficacious in rodent models of arthritis: preclinical characterization of INCB028050. 
J Immunol. 2010;184(9):5298–5307.

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Fries JF, Spitz P, Kraines RG, Holman HR. Measurement of patient outcome in arthritis. 
Arthritis Rheum. 1980;23(2):137-145.
Fries JF, Spitz PW, Young DY. The dimensions of health outcomes: the health assessment 
questionnaire, disability and pain scales. J Rheumatol. 1982;9(5):789-793.
Herdman M, Gudex C, Lloyd A, Janssen MF, Kind P, Parkin D, Bonsel G, Badia X. 
Development and preliminary testing of the new five-level version of EQ-5D (EQ-5D-5L). 
Qual Life Res. 2011;20(10):1727-1736.
Holm S. A simple sequentially rejective multiple test procedure. Scand J Statist. 1979;6:65-70.
Keystone EC, Kavanaugh AF, Sharp JT, Tannenbaum H, Hua Y, Teoh LS, Fischkoff SA, 
Chartash EK. Radiographic, clinical, and functional outcomes of treatment with adalimumab 
(a human anti–tumor necrosis factor monoclonal antibody) in patients with active rheumatoid 
arthritis receiving concomitant methotrexate therapy: a randomized, placebo-controlled, 
52-week trial. Arthritis Rheum. 2004;50(5):1400-1411.
Keystone E, van der Heijde D, Mason D Jr, Landewé R, van Vollenhoven R, Combe B, Emery P, 
Strand V, Mease P, Desai C, Pavelka K. Certolizumab pegol plus methotrexate is significantly 
more effective than placebo plus methotrexate in active rheumatoid arthritis: findings of a 
fifty-two-week, phase III, multicenter, randomized, double-blind, placebo-controlled, parallel-
group study. Arthritis Rheum. 2008;58(11):3319-3329.
Keystone E, Emery P, Peterfy CG, Tak PP, Cohen S, Genovese MC, Dougados M, Burmester 
GR, Greenwald M, Kvien TK, Williams S, Hagerty D, Cravets MW, Shaw T. Rituximab 
inhibits structural joint damage in patients with rheumatoid arthritis with an inadequate 
response to tumour necrosis factor inhibitor therapies. Ann Rheum Dis. 2009;68(2):216-221.
Kitas GD, Gabriel SE. Cardiovascular disease in rheumatoid arthritis: state of the art and future 
perspectives. Ann Rheum Dis. 2011;70(1):8-14. Erratum in Ann Rheum Dis. 2011;70(8):1520.
Klareskog L, Catrina AI, Paget S. Rheumatoid arthritis. Lancet. 2009;373(9664):659-672.
Kremer JM, Bloom BJ, Breedveld FC, Coombs JH, Fletcher MP, Gruben D, Krishnaswami S, 
Burgos-Vargas R, Wilkinson B, Zerbini CA, Zwillich SH. The safety and efficacy of a JAK 
inhibitor in patients with active rheumatoid arthritis: results of a double-blind, placebo-
controlled phase IIa trial of three dosage levels of CP-690,550 versus placebo. Arthritis 
Rheum. 2009;60(7):1895-1905.
Newcombe RG. Interval estimation for the difference between independent proportions: 
comparison of eleven methods. Stat Med. 1998;17:873-890. Erratum in Stat Med. 
1999;18:1293.
Ramey DR, Fries JF, Singh G. The Health Assessment Questionnaire 1995: status and review. 
In: Spiker B, editor. Quality of life and pharmacoeconomics in clinical trials. 2nd ed. 
Philadelphia: Lippincott-Raven, 1996: p 227-237.
Rubbert-Roth A, Finckh A. Treatment options in patients with rheumatoid arthritis failing initial 
TNF inhibitor therapy: a critical review. Arthritis Res Ther. 2009;11(suppl 1):S1.
Rush AJ, Trivedi MH, Ibrahim HM, Carmody TJ, Arnow B, Klein DN, Markowitz JC, 
Ninan PT, Kornstein S, Manber R, Thase ME, Kocsis JH, Keller MB. The 16-Item quick 
inventory of depressive symptomatology (QIDS), clinician rating (QIDS-C), and self-report 

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Psychiatry. 2003;54(5):573-583. Erratum in Biol Psychiatry. 2003;54(5);585.
Singh JA, Saag KG, Bridges SL Jr, Akl EA, Bannuru RR, Sullivan MC, Vaysbrot E, 
McNaughton C, Osani M, Shmerling RH, Curtis JR, Furst DE, Parks D, Kavanaugh A, 
O'Dell J, King C, Leong A, Matteson EL, Schousboe JT, Drevlow B, Ginsberg S, Grober J, 
St Clair EW, Tindall E, Miller AS, McAlindon T; American College of Rheumatology.
2015 American College of Rheumatology guideline for the treatment of rheumatoid arthritis.
Arthritis Care Res (Hoboken). 2016;68(1):1-25.
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.
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 J, Landewé RB, Mease P, Brzezicki J, Mason D, Luijtens K, van Vollenhoven RF, 
Kavanaugh A, Schiff M, Burmester GR, Strand V, VencovskỳJ, 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, 
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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, Landewé R, Bijlsma J, Burmester G, Chatzidionysiou K, Dougados M, Nam J, 
Ramiro S, Voshaar M, van Vollenhoven R, Aletaha D, Aringer M, Boers M, Buckley CD, 
Buttgereit F, Bykerk V, Cardiel M, Combe B, Cutolo M, van Eijk-Hustings Y, Emery P, 
Finckh A, Gabay C, Gomez-Reino J, Gossec L, Gottenberg JE, Hazes JMW, Huizinga T, 
Jani M, Karateev D, Kouloumas M, Kvien T, Li Z, Mariette X, McInnes I, Mysler E, Nash P, 
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Takeuchi T, Westhovens R, de Wit M, van der Heijde D. EULAR recommendations for the 
management of rheumatoid arthritis with synthetic and biological disease-modifying 
antirheumatic drugs: 2016 update. Ann Rheum Dis. 2017;76(6):960-977.
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 
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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 
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University of Pittsburgh Epidemiology Data Center; IDS/QIDS website. 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, 
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Moreland L. Initial efficacy of INCB018424, a selective Janus kinase 1& 2 (JAK 1&2) 
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Wilson, E. B. Probable inference, the law of succession, and statistical inference. Journal of the 
American Statistical Association. 1927;22:209-212.

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Attachment 1.Protocol JADY Study Schedule

I4V-MC-JADY(i) Clinical Protocol
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Study Schedule, Protocol I4V-MC-JADY
Long-term Treatment Extension
Part A, Visits 1 to 19l,m
Visit
1a
2
3
4a
5b
6
7
8
9
10
11a
12
13
14
15
16
17
18
19
Months of 
Treatment 
Since 
Randomizat
ion in 
Originating 
Study
JADW 
and
JADX
6
7
9
12
--
15
18
21
24
27
30
33
36
39
42
45
48
51
54
JADV 
and 
JADZ
--
--
--
13
14
16
19
22
25
28
31
34
37
40
43
46
49
52
55
JAGS
--
--
--
13
--
16
19
22
25
28
31
34
37
40
43
46
49
52
55
JADA
--
--
--
--
--
--
--
--
--
--
32
35
38
41
44
47
50
53
56
Visit window (days)
---c
± 5
± 5
± 9c
± 5
± 9
± 9
± 9
± 9
± 9
± 9c
± 9
± 9
± 9
± 9
± 9
± 9
± 9
± 9
Informed consent
Informed consent must be obtained before any JADY study procedures
Inclusion/exclusion 
review
Inclusion/exclusion must be reviewed before JADY study procedures
Clinical assessments
Patient demographics
Xk
Xk
Xk
Symptom-directed 
physical examinationd
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Height
Xk
Xk
Xk
Weight
X
X
X
X
X
X
X
X
X
Waist circumference
X
X
X
X
X
X
X
X
X
Vital signs (BP and 
pulse)e
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Adverse events
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X

I4V-MC-JADY(i) Clinical Protocol
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LY3009104
Long-term Treatment Extension
Part A, Visits 1 to 19l,m
Visit
1a
2
3
4a
5b
6
7
8
9
10
11a
12
13
14
15
16
17
18
19
Months of 
Treatment 
Since 
Randomizat
ion in 
Originating 
Study
JADW 
and
JADX
6
7
9
12
--
15
18
21
24
27
30
33
36
39
42
45
48
51
54
JADV 
and 
JADZ
--
--
--
13
14
16
19
22
25
28
31
34
37
40
43
46
49
52
55
JAGS
--
--
--
13
--
16
19
22
25
28
31
34
37
40
43
46
49
52
55
JADA
--
--
--
--
--
--
--
--
--
--
32
35
38
41
44
47
50
53
56
Visit window (days)
---c
± 5
± 5
± 9c
± 5
± 9
± 9
± 9
± 9
± 9
± 9c
± 9
± 9
± 9
± 9
± 9
± 9
± 9
± 9
Concomitant 
medications
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Randomizationf
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Call IVRS or use 
IWRS
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Investigational 
product dispensed
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Xn
Investigational 
products returned and 
assess compliance
X
X
X
X
X
X
X
X
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
X
X
Patient Assessment of 
Pain VAS
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X

I4V-MC-JADY(i) Clinical Protocol
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LY3009104
Long-term Treatment Extension
Part A, Visits 1 to 19l,m
Visit
1a
2
3
4a
5b
6
7
8
9
10
11a
12
13
14
15
16
17
18
19
Months of 
Treatment 
Since 
Randomizat
ion in 
Originating 
Study
JADW 
and
JADX
6
7
9
12
--
15
18
21
24
27
30
33
36
39
42
45
48
51
54
JADV 
and 
JADZ
--
--
--
13
14
16
19
22
25
28
31
34
37
40
43
46
49
52
55
JAGS
--
--
--
13
--
16
19
22
25
28
31
34
37
40
43
46
49
52
55
JADA
--
--
--
--
--
--
--
--
--
--
32
35
38
41
44
47
50
53
56
Visit window (days)
---c
± 5
± 5
± 9c
± 5
± 9
± 9
± 9
± 9
± 9
± 9c
± 9
± 9
± 9
± 9
± 9
± 9
± 9
± 9
Patient Global 
Assessment of Disease 
Activity
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Physician Global 
Assessment of Disease 
Activity
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Hand and foot x-raysg
X
X
X
X
X
HAQ-DI
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Morning joint stiffness 
duration
X
X
X
X
X
X
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
X
X
X
X
QIDS-SR16
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Healthcare resource 
use
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X

I4V-MC-JADY(i) Clinical Protocol
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LY3009104
Long-term Treatment Extension
Part A, Visits 1 to 19l,m
Visit
1a
2
3
4a
5b
6
7
8
9
10
11a
12
13
14
15
16
17
18
19
Months of 
Treatment 
Since 
Randomizat
ion in 
Originating 
Study
JADW 
and
JADX
6
7
9
12
--
15
18
21
24
27
30
33
36
39
42
45
48
51
54
JADV 
and 
JADZ
--
--
--
13
14
16
19
22
25
28
31
34
37
40
43
46
49
52
55
JAGS
--
--
--
13
--
16
19
22
25
28
31
34
37
40
43
46
49
52
55
JADA
--
--
--
--
--
--
--
--
--
--
32
35
38
41
44
47
50
53
56
Visit window (days)
---c
± 5
± 5
± 9c
± 5
± 9
± 9
± 9
± 9
± 9
± 9c
± 9
± 9
± 9
± 9
± 9
± 9
± 9
± 9
Laboratory tests
Clinical chemistryh
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Lipid paneli
X
X
X
X
X
X
X
X
X
Hematology
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
HBV DNAo
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Iron studies
(iron, TIBC, and 
ferritin)
X
X
X
X
X
Urinalysis
X
X
X
X
X
hsCRP
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Erythrocyte 
sedimentation ratej
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Immunoglobulin 
levels 
(IgG, IgA, IgM)
X
X
X
X
X

I4V-MC-JADY(i) Clinical Protocol
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LY3009104
Long-term Treatment Extension
Part A, Visits 1 to 19l,m
Visit
1a
2
3
4a
5b
6
7
8
9
10
11a
12
13
14
15
16
17
18
19
Months of 
Treatment 
Since 
Randomizat
ion in 
Originating 
Study
JADW 
and
JADX
6
7
9
12
--
15
18
21
24
27
30
33
36
39
42
45
48
51
54
JADV 
and 
JADZ
--
--
--
13
14
16
19
22
25
28
31
34
37
40
43
46
49
52
55
JAGS
--
--
--
13
--
16
19
22
25
28
31
34
37
40
43
46
49
52
55
JADA
--
--
--
--
--
--
--
--
--
--
32
35
38
41
44
47
50
53
56
Visit window (days)
---c
± 5
± 5
± 9c
± 5
± 9
± 9
± 9
± 9
± 9
± 9c
± 9
± 9
± 9
± 9
± 9
± 9
± 9
± 9
Lymphocyte subsets 
(T, B, NK, and T-cell 
subsets)
X
X
X
X
X
Exploratory storage 
samples (serum and 
plasma)
X
X
X
X
X
Exploratory storage 
samples (urine)
X
X
X
X
X

I4V-MC-JADY(i) Clinical Protocol
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LY3009104
Long-term Treatment Extension
Part A, Visits 20 to 33
Follow
-up 
Part B
Visit
20
21
22
23
24
25
26
27
28
29
30
31
32
33
ETl
801m
Months of 
Treatment 
Since 
Randomiz
ation in 
Originatin
g Study
JADW 
and
JADX
--
60
--
66
--
72
--
78
84
90
--
--
--
--
--
--
JADV 
and JADZ
58
61
--
67
--
73
--
79
85
91
97
--
--
--
--
--
JAGS
58
61
--
67
--
73
--
79
85
91
97
--
--
--
--
--
JADA
59
62
65
68
71
74
77
80
86
92
98
104
110
116
--
--
Visit window (days)
± 9
± 9
± 9
± 9
± 9
± 9
± 9
± 9
± 9
± 9
± 9
± 9
± 9
± 9
Any 
day
28 ± 9
after 
last 
dose
Clinical assessments
Symptom-directed 
physical examinationd
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Weight
X
X
X
X
X
X
X
X
X
X
X
X
Waist circumference
X
X
X
X
X
X
X
X
X
X
X
X
Vital signs (BP and 
pulse)e
X
X
X
X
X
X
X
X
X
X
X
X
X
X
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
Randomizationf
X
X
X
X
X
X
X
X
X
Call IVRS or use IWRS
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X

I4V-MC-JADY(i) Clinical Protocol
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LY3009104
Long-term Treatment Extension
Part A, Visits 20 to 33
Follow
-up 
Part B
Visit
20
21
22
23
24
25
26
27
28
29
30
31
32
33
ETl
801m
Months of 
Treatment 
Since 
Randomiz
ation in 
Originatin
g Study
JADW 
and
JADX
--
60
--
66
--
72
--
78
84
90
--
--
--
--
--
--
JADV 
and JADZ
58
61
--
67
--
73
--
79
85
91
97
--
--
--
--
--
JAGS
58
61
--
67
--
73
--
79
85
91
97
--
--
--
--
--
JADA
59
62
65
68
71
74
77
80
86
92
98
104
110
116
--
--
Visit window (days)
± 9
± 9
± 9
± 9
± 9
± 9
± 9
± 9
± 9
± 9
± 9
± 9
± 9
± 9
Any 
day
28 ± 9
after 
last 
dose
Investigational product 
dispensed
X
X
X
X
X
X
X
X
X
Xn
Xn
X
X
Investigational products 
returned and assess 
compliance
X
X
X
X
X
X
X
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
Patient Assessment of 
Pain VAS
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

I4V-MC-JADY(i) Clinical Protocol
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LY3009104
Long-term Treatment Extension
Part A, Visits 20 to 33
Follow
-up 
Part B
Visit
20
21
22
23
24
25
26
27
28
29
30
31
32
33
ETl
801m
Months of 
Treatment 
Since 
Randomiz
ation in 
Originatin
g Study
JADW 
and
JADX
--
60
--
66
--
72
--
78
84
90
--
--
--
--
--
--
JADV 
and JADZ
58
61
--
67
--
73
--
79
85
91
97
--
--
--
--
--
JAGS
58
61
--
67
--
73
--
79
85
91
97
--
--
--
--
--
JADA
59
62
65
68
71
74
77
80
86
92
98
104
110
116
--
--
Visit window (days)
± 9
± 9
± 9
± 9
± 9
± 9
± 9
± 9
± 9
± 9
± 9
± 9
± 9
± 9
Any 
day
28 ± 9
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-raysg
X
X
HAQ-DI
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Morning joint stiffness 
duration
X
X
X
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
X
X
X
QIDS-SR16
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Healthcare resource use
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X

I4V-MC-JADY(i) Clinical Protocol
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Long-term Treatment Extension
Part A, Visits 20 to 33
Follow
-up 
Part B
Visit
20
21
22
23
24
25
26
27
28
29
30
31
32
33
ETl
801m
Months of 
Treatment 
Since 
Randomiz
ation in 
Originatin
g Study
JADW 
and
JADX
--
60
--
66
--
72
--
78
84
90
--
--
--
--
--
--
JADV 
and 
JADZ
58
61
--
67
--
73
--
79
85
91
97
--
--
--
--
--
JAGS
58
61
--
67
--
73
--
79
85
91
97
--
--
--
--
--
JADA
59
62
65
68
71
74
77
80
86
92
98
104
110
116
--
--
Visit window (days)
± 9
± 9
± 9
± 9
± 9
± 9
± 9
± 9
± 9
± 9
± 9
± 9
± 9
± 9
Any 
day
28 ± 9
after 
last 
dose
Laboratory tests
Clinical chemistryh
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Lipid paneli
X
X
X
X
X
X
X
X
X
X
X
X
Hematology
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
HBV DNAo
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Xp
X
Iron studies
(iron, TIBC, and 
ferritin)
X
X
X
X
X
Urinalysis
X
X
X
X
X
hsCRP
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Erythrocyte 
sedimentation ratej
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X

I4V-MC-JADY(i) Clinical Protocol
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Long-term Treatment Extension
Part A, Visits 20 to 33
Follow
-up 
Part B
Visit
20
21
22
23
24
25
26
27
28
29
30
31
32
33
ETl
801m
Months of 
Treatment 
Since 
Randomiz
ation in 
Originatin
g Study
JADW 
and
JADX
--
60
--
66
--
72
--
78
84
90
--
--
--
--
--
--
JADV 
and 
JADZ
58
61
--
67
--
73
--
79
85
91
97
--
--
--
--
--
JAGS
58
61
--
67
--
73
--
79
85
91
97
--
--
--
--
--
JADA
59
62
65
68
71
74
77
80
86
92
98
104
110
116
--
--
Visit window (days)
± 9
± 9
± 9
± 9
± 9
± 9
± 9
± 9
± 9
± 9
± 9
± 9
± 9
± 9
Any 
day
28 ± 9
after 
last 
dose
Immunoglobulin 
levels 
(IgG, IgA, IgM)
X
X
X
X
X
Lymphocyte subsets 
(T, B, NK, and T-cell 
subsets)
X
X
X
X
X
Exploratory storage 
samples (serum and 
plasma)
X
X
X
X
X
Exploratory storage 
samples (urine)
X
X
X
X
X
Abbreviations:  BP = blood pressure; CDAI = Clinical Disease Activity Index; eGFR = estimated glomerular filtration rate; EQ-5D-5L = European Quality of 
Life-5 Dimensions-5 Level; ET = Early Termination; HAQ-DI = Health Assessment Questionnaire-Disability Index; HBcAb = hepatitis B core antibody;
HBsAb = hepatitis B surface antibody; HBV DNA = hepatitis B virus deoxyribonucleic acid; hsCRP = high-sensitivity C-reactive protein; Ig = 
immunoglobulin; IVRS = interactive voice-response system; IWRS = interactive web-response system; NK = natural killer; QIDS-SR16 = Quick Inventory of 

I4V-MC-JADY(i) Clinical Protocol
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LY3009104
Depressive Symptomatology-Self-Rated (16 items); TIBC = total iron binding capacity; VAS = visual analog scale.
a
Any assessments/procedures conducted during the final visit of the patient’s originating study should not be repeated during their first visit for Study JADY.
b
Visit 5 only applies to patients originating in Studies JADV and JADZ.
c
The 1-day screening period should occur during the last visit of the originating study.  However, in particular circumstances, this duration may be extended 
after consultation with the sponsor.  Therefore, there is no specified visit window for patients enrolled at Visits 1, 4, and 11 entering Study JADY from the 
originating studies.
d
A focused physical examination will be performed prior to study entry to assure that the patient has not developed any condition that would meet the 
exclusion criteria.  The focused physical examination may be repeated at the investigators discretion any time a patient presents with physical complaints.
e
At each time point, 3 replicate readings should be made at approximately 30- to 60-second intervals.  Blood pressure is recorded as the average of these 
3 readings.  A single pulse measurement should be taken simultaneously with at least 1 of the readings at each time point.
f
From this visit forward, patients from Study JADV, JADZ, JADW, JAGS, or JADX who never received rescue therapy, and who have received baricitinib 
4 mg QD on a stable background for at least 15 months, will be eligible for step-down dosing if they achieve a CDAI score ≤10 (≤2.8 for JADZ) for a 
minimum of 3 months.  Randomization is not performed at the final scheduled visit for each originating study.
g
Hand and foot x-rays are not required for patients originating in Study JADW.  Patients originating in studies other than JADW will have x-rays performed in 
Study JADY if they have an evaluable baseline x-ray from the originating study.  X-rays will be taken at the following visits depending on the originating 
study: Study JADX Visits 1, 4, 9, 13, 17, 21, ET; Studies JADV, JADZ, and JAGS Visits 4, 9, 13, 17, 21, ET; Study JADA Visits 13, 17, 21, ET. X-rays will 
only be taken at the first patient visit if the most recent x-ray was at least 8 weeks earlier. X-rays will only be taken at ET if the most recent x-ray was more 
than 12 weeks earlier. X-ray will only be taken at ET if termination occurs prior to Visit 21.
h
Clinical chemistry will include the following values calculated from serum creatinine:  calculated creatinine clearance (Cockcroft-Gault equation) 
(this calculation will be performed at the visits where both weight and serum creatinine are collected, according to the Protocol JADY Study Schedule 
[Attachment 1]) and eGFR (calculated using the Modification of Diet in Renal Disease isotope dilution mass spectrometry traceable method).
i
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.
j
Erythrocyte sedimentation rate to be performed locally using a kit provided by the sponsor.
k
Only required if this is a patient’s entry visit.
l
Patients who discontinue from the study prior to final scheduled visit for any reason will have an ET Visit performed.  All procedures required for the ET 
Visit should be completed according to the study schedule.  The ET visit will be done only once during the trial.  If the patient completes the study through
final scheduled visit, the patient will continue to Part B (Visit 801) without an ET.
m A Follow-up Visit (Visit 801) will be performed approximately 28 days after the last dose of investigational product is administered.
n
Investigational product is not dispensed to patients originating from Studies JADW and JADX at Visit 29.  Investigational product is not dispensed to patients 
originating from Studies JADV, JADZ, and JAGS at Visit 30.
o
HBV DNA will be performed in patients who tested positive for HBcAb at screening in the originating study.  HBV DNA monitoring approximately every 3
to 6 months, at an ET Visit, and at Visit 801, will be required, regardless of the patient’s HBsAb status.
p
To be performed only if previous test was more than 3 months earlier.

I4V-MC-JADY(i) Clinical Protocol
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Attachment 2.Protocol JADY 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
Absolute count of
    Neutrophils, segmented
    Aspartate aminotransferase/serum glutamic
      oxaloacetic transaminase
    Neutrophils, juvenile (bands)
    Lymphocytes
    Blood urea nitrogen
    Creatinine
   Estimated glomerular filtration rated
    Monocytes
   Calculated creatinine clearancee
   Uric acid
    Eosinophils
    Calcium
    Basophils
    Glucose
    Platelets
    Albumin
Cell morphology
CBC, including differential and blood smear
  Creatine kinase
    Total protein
Urinalysisa,b
Color 
Specific gravity
pH
Lipid profile includingf total cholesterol, HDL-C, 
LDL-C, and triglycerides, ApoA1, ApoB
Protein
Urine Pregnancy Test (females only)g
Glucose
Ketones
Other Tests
Blood 
Bilirubin
Urobilinogen 
Leukocyte esterase
Nitrite
Microscopic examination of sedimentc
Iron studies (iron, TIBC, and ferritin)
High-sensitivity C-reactive protein
Erythrocyte sedimentation rateh
Immunoglobulins (IgG, IgA, IgM)
HBV DNA
Lymphocyte subsets (T, B, NK, and T-cell subsets)
Stored serum, plasma, urine samples for possible 
exploratory biomarker analyses
(Abbreviations and footnotes follow on the next page.)

I4V-MC-JADY(i) Clinical Protocol
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LY3009104
Abbreviations:  ApoA1 = apolipoprotein A1; ApoB = apolipoprotein B; CBC = complete blood count; HBV DNA = 
hepatitis B virus deoxyribonucleic acid; HDL-C = high density lipoprotein cholesterol; Ig = immunoglobulin; 
LDL-C = low-density lipoprotein cholesterol; NK = natural killer; 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 done to evaluate laboratory results to resume investigational product, samples 
must be assayed centrally.
c
Microscopic examination of sediment performed only if abnormalities are noted on the routine urinalysis.
d
Estimated glomerular filtration rate for serum creatinine will be calculated by the central laboratory using the 
Modification of Diet in Renal Disease isotope dilution mass spectrometry traceable method.
e
The calculated creatinine clearance will be determined by the central laboratory 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 mol/L]).  Women:  (above formula) x 0.85.  This calculation will be 
performed at the visits where both weight and serum creatinine are collected, according to the Protocol JADY 
Study Schedule (Attachment 1).
f
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.
g
For all women of childbearing potential, urine pregnancy tests (local laboratory) will be performed at the 
discretion of the investigator.
h
Erythrocyte sedimentation rate analysis will be performed by the local laboratory.

I4V-MC-JADY(i) Clinical Protocol
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Attachment 3.Protocol JADY 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-MC-JADY(i) Clinical Protocol
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Attachment 4.
Monitoring Tests for Confirmed VTE
Selected tests may be obtained in the event of a confirmed VTE and may be required in 
follow-up with patients in consultation with Eli Lilly and Company, its designee, or the clinical 
research physician.  
Protein C Functional
Protein S Clottable
Antithrombin III
APC Resistance
PT
APTT
Fibrinogen
Cardiolipin Antibodies
PT Gene
Factor VIII C Assay
Hexagonal Phase Phospholipid Neutralization
C-Reactive Protein
PTT Incubated Mixing 
Dilute Russell Viper Venom 
Platelet Neutralization 
Factor V Leiden 
MTHFR 
Thrombin Time 
Reptilase 
Fibrinogen Antigen 
Protein C Immunologic 
Protein S Immunologic 
Heparin fXa Inhibition 
Abbreviations:  APC = activated protein C; APTT = activated partial thromboplastin time; fXa = clotting factor Xa; 
MTHFR = methylene tetrahydrofolate reductase; PT = prothrombin time; PTT = partial thromboplastin time; 
VTE = venous thromboembolic event.

I4V-MC-JADY(i) Clinical Protocol
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Attachment 5.Protocol Amendment
I4V-MC-JADY(i) Summary
Overview
Protocol I4V-MC-JADY has been amended.  The new protocol is indicated by amendment (i)
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:
Amendment Summary for Protocol I4V-MC-JADY Amendment (i)
Section # and Name
Description of Change
Brief Rationale
5.2. Benefit/Risk

Added text to address 
potential risk of VTE for 
baricitinib.

Deleted VTE incidence 
imbalance 
Updating text based on 2019 safety 
review, to include information that 
JAK inhibitors as a class have DVT 
and PE as known ADRs and 
warning label text.
8.3.1.1. Interruption of 
Investigational Product
Updated text in Table JADY.1.
Includes text stating that patients 
may resume study after confirmation 
that DVT/PE is not present.
8.3.1.2.  Discontinuation of 
Investigational Product
Updated text in Table JADY.2.
Based on the 2019 updated review 
of reported events from clinical trials 
and spontaneous postmarketing 
cases, as well as the evolving 
external landscape acknowledging 
an association between JAK 
inhibitors as a class and DVT/PE as 
uncommon ADRs.  
10.3.  Safety Evaluations
Updated to include text stating that 
investigators must record AE/SAEs 
in the CRF
Investigators must record AE/SAEs 
in the CRF.
Attachment 1.  Protocol JADY 
Study Schedule
Updated footnote g
Early termination participants will 
only receive an X-ray if termination 
occurs before Visit 21.

I4V-MC-JADY(i) Clinical Protocol
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Revised Protocol Sections
Note:
Deletions have been identified by strikethroughs.
Additions have been identified by the use of underscore.
1. Protocol I4V-MC-JADY (ih)
A Phase 3, Multicenter Study to Evaluate the Long-Term 
Safety and Efficacy of Baricitinib in Patients with 
Rheumatoid Arthritis
5.2. Benefit/Risk
The safety profile for baricitinib has been informed by results from nonclinical and clinical 
studies evaluating a wide range of doses (up to 40 mg once daily [QD]).  There are potential 
risks recognized for baricitinib that will be followed carefully in the Phase 3 development 
program.  The potential risks for baricitinib include increased AEs due to increased exposures in 
patients with renal impairment, myelosuppression, increased infections (including opportunistic 
infections and herpes zoster), increased cardiovascular events due to changes in lipids, fetal 
malformations, emergence of malignancies previously contained by the immune system, and 
pharmacologic interaction between nonsteroidal anti-inflammatory drugs (NSAIDs) and 
baricitinib to decrease the capacity of the kidneys to respond to hemodynamic changes.  
Venous thromboembolic events (VTEs) have been determined to be an important potential risk 
for baricitinib.  There was a numerical imbalance in reports of VTEs in the 24-week, placebo-
controlled period of the Phase 3 trials of patients with RA.  Available evidence does not establish 
a causal association.  The exposure-adjusted incidence rate of VTE for baricitinib-treated RA 
patients over long-term exposures was similar to the background rates published in the literature 
for the target population (ie, patients with RA).  There was no pattern of increased or decreased 
risk during long-term exposures, and cases observed with baricitinib were confounded by 1 or 
more recognized risk factors for a VTE (eg, history of VTE, increased body mass index, older 
age).  Venous thromboembolic event risk can be managed through risk mitigation strategies.  
Presymptomatic screening for hypercoagulable conditions is not currently recommended, even in 
the prescribing information for medications with known increased risk for VTEs.  
Venous thromboembolism (VTE), including deep vein thrombosis (DVT) and pulmonary 
embolism (PE), had been determined to be an important potential risk for baricitinib.  Based on 
the 2019 updated review of reported events from clinical trials and spontaneous postmarketing 
cases as well as the evolving external landscape acknowledging an association with JAK 
inhibitors as a class, DVT and PE are proposed to be considered as adverse drug reactions 
(ADRs) in baricitinib labeling for United States, Europe, Canada, and Japan.  Globally, labels for 
baricitinib carry the following warning and precaution: “Events of deep venous thrombosis 
(DVT) and pulmonary embolism (PE) have been reported in patients receiving baricitinib.  
Baricitinib should be used with caution in patients with risk factors for DVT/PE.  If clinical 

I4V-MC-JADY(i) Clinical Protocol
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LY3009104
features of DVT/PE occur, interrupt baricitinib, evaluate promptly, and institute appropriate 
treatment.”
8.3.1.  Discontinuation of Patients
Table JADY.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/L
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 without documented renal impairment at 
baseline of originating study
eGFR 50 mL/min/1.73 m2
eGFR <30 mL/min/1.73 m2 (from serum creatinine) 
for patients with documented renal impairment at 
baseline of originating study
eGFR 40 mL/min/1.73 m2
ALT or AST >5 times the ULN
ALT and AST return to <2 times the ULN, and 
investigational product is not considered to be the cause of 
enzyme elevation
Hemoglobin <8 g/dL
Hemoglobin 10 g/dL
Symptomatic herpes zoster
All skin lesions have crusted and are resolving
Severe infection that, in the opinion of the 
investigator, merits the investigational product being 
discontinued
Resolution of infection
Clinical features of VTE (deep vein thrombosis or
pulmonary embolism [DVT/PE]) are present
After confirmation that DVT/PE is not present evaluation
and instition of appropriate treatment
Abbreviations:  ALT = alanine aminotransferase; ANC = absolute neutrophil count; AST = aspartate
aminotransferase; DVT/PE = deep vein thrombosis or pulmonary embolism; eGFR = estimated glomerular 
filtration rate; min = minute; ULN = upper limit of normal; VTE = venous thromboembolic event; WBC = white 
blood cell.

I4V-MC-JADY(i) Clinical Protocol
Page 88
LY3009104
Table JADY.2.
Criteria for Permanent Discontinuation of Investigational Product
Permanently Discontinue Investigational Product if Any of the Following Is 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/L
ANC <500 cells/L
Lymphocyte count <200 cells/L
Hemoglobin <6.5 g/dL
Pregnancy
Malignancy (except for successfully treated basal cell or squamous epithelial skin cancers)
HBV DNA ≥29 IU/mLa
Develop a second VTE (DVT/PE) since first receiving baricitinib (including originating study)
b with exception
c
Abbreviations:  ALT = alanine aminotransferase; ANC = absolute neutrophil count; AST = aspartate 
aminotransferase; HBV DNA = hepatitis B virus deoxyribonucleic acid; ULN = upper limit of normal; 
VTE = venous thromboembolic event; WBC = white blood cell.
a
If a 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 for additional instruction on HBV DNA monitoring.
b
Patients who develop a VTE may have additional follow-up and testing recommended (see Section 10.3.3 and 
Attachment 4).
c
Patients who had a single occurrence of VTE (occurrence includes a DVT, PE, or DVT and PE combination at 
roughly the same time) prior to the protocol amendment (i) effective date may continue receiving baricitinib in 
Study JADY at the investigator’s discretion. 
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 record all relevant 
AE/SAE information in the CRF.  
Attachment 1.  Study Schedule, Protocol I4V-MC-JADY
g Hand and foot x-rays are not required for patients originating in Study JADW.  Patients 
originating in studies other than JADW will have x-rays performed in Study JADY if they 
have an evaluable baseline x-ray from the originating study.  X-rays will be taken at the 
following visits depending on the originating study: Study JADX Visits 1, 4, 9, 13, 17, 21,
ET; Studies JADV, JADZ, and JAGS Visits 4, 9, 13, 17, 21, ET; Study JADA Visits 13, 17,
21, ET. X-rays will only be taken at the first patient visit if the most recent x-ray was at least 
8 weeks earlier. X-rays will only be taken at ET if the most recent x-ray was more than 12 
weeks earlier.  X-ray will only be taken at ET if termination occurs prior to Visit 21.

Leo Document ID = f88baf61-a80f-40c9-a9a9-dcaf6f51ac57
Approver: 
Approval Date & Time: 10-Dec-2019 15:18:26 GMT
Signature meaning: Approved
Approver: 
Approval Date & Time: 10-Dec-2019 15:26:56 GMT
Signature meaning: Approved
PPD
PPD