Clinical trial NCT03742973
Conditions: Primary Biliary Cholangitis
Keywords: Janus kinase inhibitor JAK
Sponsor: Eli Lilly and Company
Start date: 2019-03-28; Completion date: 2019-09-26
Enrollment: 2 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
This study evaluates the safety and efficacy of baricitinib in participants with primary biliary cholangitis (PBC) who do not respond or are unable to take ursodeoxycholic acid (UDCA).

Detailed description:

Arms: arm 1: Participants received 2 milligram (mg) of Baricitinib tablet orally once a day for 12 weeks. Cohort A is not reported due to protection of personal identifiable information based on enrollment futility. arm 2: Participants received placebo orally once a day for 12 weeks. Cohort A is not reported due to protection of personal identifiable information based on enrollment futility. arm 3: Participants received 4 mg of Baricitinib orally once a day for 12 weeks. Cohort B was planned, but due to enrollment futility, the strategic decision was made to terminate the study. arm 4: Placebo administered orally. Cohort B was planned, but due enrollment futility, the strategic decision was made to terminate the study.
Interventions: intervention 1: Baricitinib intervention 2: Placebo
Intervention descriptions: intervention 1: Administered orally. intervention 2: Administered orally.

Protocol documents:
Prot_000.pdf: 
 I4V-MC-JAIV Protocol b 
 
A Randomized, Double-Blind, Placebo-Controlled, Proof-of-Concept Study Evaluating the 
Efficacy and Safety of Baricitinib (LY3009104) in Patients with Primary Biliary 
Cholangitis Who Have an Inadequate Response or Are Intolerant to UDCA 
 
NCT03742973 
 
Approval Date: 24-Apr-2019 
 
 
 


I4V-MC-JAIV(b) Clinical Protocol
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LY3009104
Protocol I4V-MC-JAIV(b)
A Randomized, Double-Blind, Placebo-Controlled, 
Proof-of-Concept Study Evaluating the Efficacy and Safety 
of Baricitinib (LY3009104) in Patients with Primary Biliary 
Cholangitis Who Have an Inadequate Response or Are 
Intolerant to UDCA
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)
Eli Lilly and Company
Indianapolis, Indiana USA 46285
Initial Protocol Electronically Signed and Approved by Lilly on 20 July 2018.
Protocol Amendment (a) was approved on 28-Sep-2018
Protocol Amendment (b) was Electronically Signed and Approved by Lilly on date 
provided below.
Approval Date: 24-Apr-2019 GMT


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Table of Contents
Section
Page
Protocol I4V-MC-JAIV(b)  A Randomized, Double-Blind, 
Placebo-Controlled, Proof-of-Concept Study Evaluating the Efficacy 
and Safety of Baricitinib (LY3009104) in Patients with Primary 
Biliary Cholangitis Who Have an Inadequate Response or Are 
Intolerant to UDCA.............................................................................................................1
Table of Contents........................................................................................................................2
1.
Synopsis .............................................................................................................................8
2.
Schedule of Activities .......................................................................................................10
3.
Introduction ......................................................................................................................14
3.1.
Study Rationale............................................................................................................14
3.2.
Background..................................................................................................................15
3.3.
Benefit/Risk Assessment..............................................................................................16
4.
Objectives and Endpoints..................................................................................................18
5.
Study Design.....................................................................................................................19
5.1.
Overall Design .............................................................................................................19
5.2.
Number of Participants.................................................................................................21
5.3.
End of Study Definition ...............................................................................................21
5.4.
Scientific Rationale for Study Design...........................................................................21
5.5.
Justification for Dose ...................................................................................................22
6.
Study Population...............................................................................................................23
6.1.
Inclusion Criteria..........................................................................................................23
6.2.
Exclusion Criteria ........................................................................................................24
6.3.
Lifestyle Restrictions....................................................................................................30
6.4.
Screen Failures.............................................................................................................30
7.
Treatments........................................................................................................................31
7.1.
Treatments Administered .............................................................................................31
7.1.1.
Packaging and Labelling ......................................................................................31
7.2.
Method of Treatment Assignment ................................................................................31
7.2.1.
Selection and Timing of Doses.............................................................................32
7.3.
Blinding .......................................................................................................................32
7.4.
Preparation/Handling/Storage/Accountability...............................................................33
7.5.
Treatment Compliance .................................................................................................33
7.6.
Concomitant Therapy...................................................................................................33
7.6.1.
Permitted Medications and Procedures.................................................................33
7.6.2.
Prohibited Medications and Procedures................................................................34


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7.7.
Treatment after the End of the Study............................................................................34
7.7.1.
Treatment after Study Completion........................................................................34
8.
Discontinuation Criteria ....................................................................................................35
8.1.
Discontinuation from Study Treatment.........................................................................35
8.1.1.
Interruption of Investigational Product .................................................................35
8.1.2.
Permanent Discontinuation from Study Treatment ...............................................36
8.1.3.
Discontinuation of Inadvertently Enrolled Patients...............................................38
8.2.
Discontinuation from the Study....................................................................................38
8.3.
Lost to Follow-up.........................................................................................................38
9.
Study Assessments and Procedures ...................................................................................39
9.1.
Efficacy Assessments...................................................................................................39
9.1.1.
Primary Efficacy Assessments .............................................................................39
9.1.2.
Secondary and Exploratory Efficacy Assessments................................................39
9.1.3.
Appropriateness of Assessments ..........................................................................40
9.2.
Adverse Events ............................................................................................................40
9.2.1.
Serious Adverse Events........................................................................................41
9.2.1.1.
Suspected Unexpected Serious Adverse Reactions..........................................42
9.2.2.
Adverse Events of Special Interest .......................................................................42
9.2.3.
Complaint Handling.............................................................................................42
9.3.
Treatment of Overdose.................................................................................................42
9.4.
Safety...........................................................................................................................42
9.4.1.
Electrocardiograms ..............................................................................................42
9.4.2.
Vital Signs ...........................................................................................................43
9.4.3.
Physical Examination...........................................................................................43
9.4.4.
Laboratory Tests ..................................................................................................43
9.4.5.
Chest x-Ray and Tuberculosis Testing..................................................................43
9.4.6.
Quick Inventory of Depressive Symptomatology Self-Rated–
16.........................................................................................................................44
9.4.7.
Hepatic Safety Monitoring ...................................................................................44
9.4.8.
Safety Monitoring ................................................................................................45
9.4.8.1.
Venous Thromboembolic Event Assessment ..................................................46
9.4.8.2.
Data Monitoring Committee ...........................................................................46
9.5.
Pharmacokinetics .........................................................................................................47
9.6.
Pharmacodynamics ......................................................................................................48
9.7.
Biomarkers...................................................................................................................48
10.
Statistical Considerations ..................................................................................................49
10.1. Sample Size Determination ..........................................................................................49
10.2. Populations for Analyses..............................................................................................49


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10.3. Statistical Analyses ......................................................................................................49
10.3.1.
General Statistical Considerations ........................................................................49
10.3.1.1.
Analysis Methods...........................................................................................50
10.3.1.2.
Missing Data Imputation ................................................................................50
10.3.2.
Treatment Group Comparability...........................................................................51
10.3.2.1.
Patient Disposition..........................................................................................51
10.3.2.2.
Patient Characteristics ....................................................................................51
10.3.2.3.
Concomitant Therapy .....................................................................................51
10.3.2.4.
Treatment Compliance....................................................................................51
10.3.3.
Efficacy Analyses ................................................................................................52
10.3.3.1.
Primary Analyses ...........................................................................................52
10.3.3.2.
Secondary Analyses........................................................................................52
10.3.4.
Safety Analyses....................................................................................................52
10.3.5.
Pharmacokinetic/Pharmacodynamic Analyses......................................................52
10.3.6.
Other Analyses.....................................................................................................53
10.3.6.1.
Subgroup Analyses.........................................................................................53
10.3.7.
Interim Analyses..................................................................................................53
11.
References ........................................................................................................................54
12.
Appendices .......................................................................................................................57


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List of Tables
Table
Page
Table JAIV.1.
Schedule of Activities for Cohorts A and B....................................................10
Table JAIV.2.
Objectives and Endpoints...............................................................................18
Table JAIV.3.
Treatment Regimens......................................................................................31
Table JAIV.4.
Criteria for Interruption of Investigational Product.........................................35


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List of Figures
Figure
Page
Figure JAIV.1.
Illustration of study design for Clinical Protocol I4V-MC-JAIV. ...................21


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List of Appendices
Appendix
Page
Appendix 1.
Abbreviations and Definitions........................................................................58
Appendix 2.
Clinical Laboratory Tests...............................................................................61
Appendix 3.
Study Governance Considerations..................................................................63
Appendix 4.
Hepatic Monitoring Tests for Treatment-Emergent Abnormality....................67
Appendix 5.
Monitoring Tests for Confirmed VTE............................................................68
Appendix 6.
Protocol Amendment History.........................................................................69


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1. Synopsis
Title of Study:
A Randomized, Double-Blind, Placebo-Controlled, Proof-of-Concept Study Evaluating the 
Efficacy and Safety of Baricitinib (LY3009104) in Patients with Primary Biliary Cholangitis 
Who Have an Inadequate Response or Are Intolerant to UDCA.
Rationale:  
Baricitinib (LY3009104) is an oral Janus kinase 1 (JAK1)/Janus kinase 2 (JAK2) selective 
inhibitor, representing a potentially effective therapy for the treatment of patients with primary 
biliary cholangitis (PBC). The current study will evaluate the safety and tolerability of 
baricitinib 2-mg and, if acceptable, will continue to evaluate the efficacy and safety profile of 
baricitinib 4-mg when administered once daily to patients with primary biliary cholangitis (PBC) 
who have had an inadequate response or who are intolerant to ursodeoxycholic acid (UDCA).  
The efficacy, safety, and tolerability data from this study are intended to inform the benefit-risk 
relationship of baricitinib in patients with PBC.
Objective(s)/Endpoints:
Objectives
Endpoints
Primary

To evaluate the effect of baricitinib 4-mg QD 
compared to placebo on PBC disease 

Change from baseline in ALP at Week 12
Secondary

To evaluate the effect of baricitinib 4-mg QD 
compared to placebo on PBC disease

Proportion of patients with ALP <1.67 x ULN
(and at least 15% decrease from baseline) and 
total bilirubin<ULN at Week 12

To evaluate the effect of baricitinib 2-mg QD 
compared to placebo on PBC disease

Change from baseline in ALP at Week 12

Proportion of patients with ALP<1.67 x ULN 
(and at least 15% decrease from baseline) and 
total bilirubin < ULN at Week 12

To evaluate the effect of baricitinib 4-mg and 
2-mg QD compared to placebo on PBC 
symptoms

Change from baseline in itch as measured by 
Itch NRS at Week 12

Change from baseline in fatigue as measured 
by Fatigue NRS at Week 12
Abbreviations:  ALP = alkaline phosphatase; NRS = Numeric Rating Scale; PBC = primary biliary cholangitis; 
QD = once daily; ULN = upper limit of normal.


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Summary of Study Design:
Study I4V-MC-JAIV is a multicenter, randomized, double-blind, parallel, placebo-controlled 
study with 3 study periods in patients with PBC who have an inadequate response or who are 
intolerant to UDCA that will be conducted in 2 cohorts
Cohort A is a randomized, double-blind, parallel, placebo-controlled cohort comprised of the 
first group of patients.  This Cohort will randomize at least twelve patients to baricitinib 2-mg 
and at least eight patients to placebo.  
Cohort B is a randomized, double-blind, parallel, placebo-controlled cohort comprised of the 
second group of patients.  This Cohort will randomize at least twenty patients to baricitinib 4 mg 
and twelve patients to placebo.  
Enrollment in Cohort B will begin only after the DMC review of Cohort A is complete and Lilly 
has received and accepted a recommendation to proceed.  
Patients in Cohort A and Cohort B will follow the same study schedule.
Number of Patients:
The study will include approximately 52 patients with PBC.
Statistical Analysis:
Unless otherwise specified, the efficacy, health outcomes, and safety analyses will be conducted 
on the modified intent-to-treat (mITT) population.  The mITT population is defined as all 
randomized patients who take at least one dose of study treatment.
Comparisons between baricitinib and placebo will be performed for all analyses in the treatment 
period. Baseline will be defined as the last available value before the first dose of investigational 
product for both efficacy and safety analyses, unless otherwise specified.
Treatment comparisons of continuous efficacy and health outcome variables will be made using 
mixed-effects models for repeated measures (MMRM) with treatment,
An unstructured covariance matrix 
will be used to model the within-patient variance-covariance errors.  Type III sums of squares for 
the least-squares (LS) means will be used for the statistical comparison and the 90% confidence 
interval (CI) will also be reported. Treatment group comparisons with placebo at Week 12 and 
other visits will be tested.
Treatment comparisons of categorical efficacy variables will be made using a logistic regression 
analysis with treatment, cohort, baseline ALP (≤2.5X ULN, >2.5X ULN) and baseline UDCA
use (yes/no) in the model. The proportions and 90% CI will be reported.


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2. Schedule of Activities
Table JAIV.1. Schedule of Activities for Cohorts A and B
Procedure
Screening
Treatment Period
Follow-up
Visit Number
V1
V2
V3a
V4
V5
V6
V7
ET
V801
(up to 49 days 
prior to V3)
(at least 4 
weeks after V1)
Week 0
Week 1
(±2 days)
Week 4
(±4 days)
Week 8
(±4 days)
Week 12
(±4 days)
28 days post last 
dose (±4 days)
Informed consent
X
Inclusion and exclusion criteria
review
X
X
Patient demography
X
Physical examinationb
X
Pre-existing conditions and 
medical history (includes substance 
usage)c
X
Randomization 
X
Investigational product dispensed
X
X
X
Investigational product returned 
and compliance assessed
X
X
X
X
X
Study Procedures
TB testd
X
Read PPD if applicable (48-72 
hours post PPD)
Xe
Chest x-rayf
X
ECGg
X
AE/SAE review
X
X
X
X
X
X
X
X
Concomitant medication review
X
X
X
X
X
X
X
X
Symptom-directed physical 
examination
X
X
X
X
X
X
X
Targeted event historyh
X
X
X
X
X
X
X
Vital signs (blood pressure, pulse, 
and temperature)
X
X
X
X
X
X
X
X
Waist circumference
X
X
X


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Procedure
Screening
Treatment Period
Follow-up
Visit Number
V1
V2
V3a
V4
V5
V6
V7
ET
V801
(up to 49 days 
prior to V3)
(at least 4 
weeks after V1)
Week 0
Week 1
(±2 days)
Week 4
(±4 days)
Week 8
(±4 days)
Week 12
(±4 days)
28 days post last 
dose (±4 days)
Height
X
Weight
X
X
X
X
X
X
X
Itch NRS
X
X
X
X
X
X
X
X
PBC-40
X
X
X
X
X
X
X
X
FACIT-F
X
X
X
X
X
X
X
X
Fatigue NRS
X
X
X
X
X
X
X
X
Physician Global Assessment
X
X
X
X
X
X
X
X
QIDS-SR16  
X
X
X
X
X
X
Laboratory Tests
FSHi
X
TSH
X
Serum pregnancy testj
X
Urine pregnancy testj
X
X
X
X
X
X
HIV
X
Hepatitis B testing (HBsAg, 
HBcAb, HBsAb)
X
Hepatitis C virus (HCV) antibody
testing
X
ANA
X
ASMA
X
CK-18 M30 and M65
X
X
X
X
ELF:  hyaluronic acid (HA), 
procollagen type III amino 
N-terminal peptide (P3NP), and 
tissue inhibitor of 
metalloproteinase 1 (TIMP-1)
X
X
X
X
Immunoglobulins (IgG, IgA, IgM)
X
X
X
X
X
X
X
X
hsCRP 
X
X
X
X
X
X
X
X
ESRk
X
X
X
X
X
X
X
X
FGF 19 
X
X
X
X
X
Cytokine panell
X
X
X
X
X


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Procedure
Screening
Treatment Period
Follow-up
Visit Number
V1
V2
V3a
V4
V5
V6
V7
ET
V801
(up to 49 days 
prior to V3)
(at least 4 
weeks after V1)
Week 0
Week 1
(±2 days)
Week 4
(±4 days)
Week 8
(±4 days)
Week 12
(±4 days)
28 days post last 
dose (±4 days)
INR
X
Clinical chemistrym
X
X
X
X
X
X
X
X
X
ALP isoenzyme
X
X
X
X
X
X
X
Hematologym
X
X
X
X
X
X
X
X
Fasting lipid paneln
X
X
X
X
Baricitinib plasma concentrations
(PK sample)o
X
X
X
X
X
X
Urinalysis
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
Exploratory samples for storage 
(RNA)
X
X
X
X
X
Abbreviations:  AE = adverse event; ANA = antinuclear antibody ; ASMA = anti-smooth-muscle antibody; CK-18 = cytokeratin 18; ECG = electrocardiogram; 
ELF = enhanced liver fibrosis; ESR = erythrocyte sedimentation rate; ET = early termination; FACIT-F = Functional Assessment of Chronic Illness 
Therapy-Fatigue; FGF = fibroblast growth factor; FSH = follicle-stimulating hormone; HBcAb = hepatitis B core antibody; HBsAb = hepatitis B surface 
antibody test; HBsAg = hepatitis B surface antigen; HIV = human immunodeficiency virus; hsCRP = high-sensitivity C-reactive protein; INR = International 
Normalized Ratio; NRS = Numeric Rating Scale; PBC-40 = Quality of Life for Primary Biliary Cirrhosis; PK = pharmacokinetics; PPD = purified protein 
derivative; QIDS-SR = Quick Inventory of Depressive Symptomatology-Self-Report–16; RNA = ribonucleic acid; SAE = serious adverse event; 
TB = tuberculosis; TSH = Thyroid-stimulating hormone.
Footnotes on next page.


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LY3009104
a
At Visit 3, all baseline assessments must be performed and baseline laboratory samples (except postdose PK sample [Section 9.5]) must be drawn prior to 
administration of the first dose of investigational product for randomized patients.
b
One complete physical examination (excluding pelvic and rectal examinations) will be performed at Visit 1.  All subsequent physical examinations may be
symptom-directed.  A complete physical examination may be repeated at the investigator’s discretion any time.
c
Substances include drugs, alcohol, tobacco, and caffeine.
d
TB test(s) including PPD, QuantiFERON®-TB Gold, and T-SPOT®.  See Exclusion Criterion [23] for description of TB testing.  In countries where the 
QuantiFERON-TB Gold test or T-SPOT is available, either test may be used instead of the PPD TB test.  The QuantiFERON-TB Gold test may be performed 
locally or centrally; the T-SPOT must be performed locally.  (Note:  Exception:  Patients with a history of active or latent TB who have documented evidence 
of appropriate treatment, have no history of re-exposure since their treatment was completed, and have a screening chest x-ray with no evidence of active TB 
may be enrolled if other entry criteria are met.  Such patients would not be required to undergo the protocol-specific TB testing but must have a chest x-ray at 
screening.)
e
If PPD testing was chosen to test for TB, then the patient must return and PPD test read 48 to 72 hours after Visit 1 (post-PPD).
f
A chest x-ray (posterior-anterior view) will be performed at screening unless one has been performed within the past 6 months and the x-ray and reports are 
available for review by the investigator.  
g
12-lead ECGs (single) will be performed locally and will be locally (machine) read.
h
The targeted event history will assess for signs and symptoms of thromboembolic events, serious infections, and malignancies.  
i
For female patients aged 50 to ≤55 years with an intact uterus, not on hormone therapy, with 6 to ≤12 months of spontaneous amenorrhea, an FSH test will be 
performed to confirm nonchildbearing potential (FSH >40 mIU/mL).
j
For all women of childbearing potential, a serum pregnancy test (central laboratory) will be performed at Visit 1.  Urine pregnancy tests (local laboratory) will 
be performed at Visit 2 and at all subsequent study visits during the treatment period.  Visit 2 results must be known prior to first dose of investigational 
product.
k
ESR to be performed locally.
l
The cytokine panel will include IL-12 (Appendix 2).
m See Appendix 2 for details.
n
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, the sample should still be collected.  
o
See Section 9.5 for details
.


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3. Introduction
3.1.
Study Rationale
Baricitinib belongs to the pharmacological class of Janus kinase (JAK) inhibitors.  Janus kinases 
are a family of 4 protein tyrosine kinases (JAK1, JAK2, JAK3, and tyrosine kinase 2 [TYK2]) 
that play an important role in cytokine signal transduction.  Baricitinib is a JAK1/JAK2 inhibitor 
that demonstrates selectivity for and inhibition of JAK1 and JAK2 with lower potency towards 
inhibition of JAK3 or TYK2 (Fridman et al. 2010).
In isolated enzyme assays, baricitinib inhibited the activities of JAK1, JAK2, TYK2, and JAK3 
with half-maximal inhibitory concentration values of 5.9, 5.7, 53, and >400 nM, respectively 
(Fridman et al. 2010).  Janus kinases are enzymes that transduce intracellular signals from cell 
surface receptors for a number of cytokines and growth factors involved in hematopoiesis, 
inflammation, and immune function (e.g., interleukin [IL]-2, IL-6, IL-12, IL-15, IL-23, 
interferons, and granulocyte-macrophage colony-stimulating factor signal through the JAK 
family) (O’Shea et al. 2015).  Within the intracellular signaling pathway, JAKs phosphorylate 
and activate signal transducers and activators of transcription (STATs), which activate gene 
expression within the cell.  Baricitinib modulates these signaling pathways by partially inhibiting 
JAK1 and JAK2 enzymatic activity, then reducing the phosphorylation and activation of STATs 
and thereby reducing inflammation, cellular activation, and proliferation of key immune cells 
(O’Shea et al. 2013).
The current study will evaluate the safety and tolerability of baricitinib 2-mg and, if acceptable,
will continue to evaluate the efficacy and safety profile of baricitinib 4-mg when administered 
once daily to patients with primary biliary cholangitis (PBC) who have had an inadequate 
response or who are intolerant to ursodeoxycholic acid (UDCA).  The efficacy, safety, and 
tolerability data from this study are intended to inform the benefit-risk relationship of baricitinib 
in patients with PBC.
Associations between PBC and common genetic variants at the human leukocyte antigen class II, 
IL-12A, and IL-12RB2 loci have been established and suggest that the IL-12 immunoregulatory 
signaling axis is relevant to the pathophysiology of PBC (Hirschfield et al. 2009).  More recent 
data have identified a relationship between the interferon (IFN), IL-12, and IL-23 pathways and 
the pathogenesis of PBC (Kawata et al. 2013).  The mechanism of action of baricitinib suggests 
that it will inhibit the activity of cytokines implicated in PBC, most notably type I IFN 
(JAK1/TYK2), IL-12, and IL-23 (JAK1/TYK2).
Baricitinib 2- and 4-mg have been studied in patients with autoimmune diseases (rheumatoid 
arthritis [RA] and systemic lupus erythematosus [SLE]), atopic dermatitis (AD), and 
autoinflammatory diseases (Chronic Atypical Neutrophilic Dermatosis with Lipodystrophy and 
Elevated temperatures [CANDLE] syndrome and stimulator of interferon genes-associated 
vasculopathy with onset in infancy [SAVI]).  Clinical efficacy and safety have been shown in 
4 completed Phase 3 studies in patients with RA (Genovese et al. 2016; Dougados et al. 2017; 
Fleischmann et al. 2017; Taylor et al. 2017).  Completed Phase 2 studies of baricitinib also 


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LY3009104
demonstrated efficacy in patients with moderate-to-severe plaque psoriasis (Papp et al. 2016) and 
diabetic kidney disease (Tuttle et al. 2018).
 
 
  
Baricitinib undergoes little liver metabolism (<10% of the administered oral dose); the main 
elimination pathway is renal (75%) through glomerular filtration and active secretion. 
 
 
 
 
Given the efficacy of baricitinib demonstrated in clinical trials for treating
autoimmune/autoinflammatory diseases, the acceptable safety profile of baricitinib observed 
through the current stage of development, and a continuing unmet medical need in patients with 
PBC, there is a compelling rationale for the initiation of a proof of concept study to evaluate 
baricitinib in the treatment of PBC.  Baricitinib has not been studied in patients with PBC, so the 
study will be conducted in 2 cohorts.  In cohort A patients will be randomized to placebo or 
baricitinib 2-mg once daily. If the safety and tolerability profile is acceptable, the study will 
continue to Cohort B, which will randomize patients to placebo and baricitinib 4-mg once daily.
3.2.
Background
Primary biliary cholangitis is a chronic and progressive cholestatic liver disease thought to be 
autoimmune in nature and is characterized by a T-lymphocyte-mediated attack on small 
intralobular bile ducts (Webb et al. 2015; Hirschfield et al. 2018).  It is an orphan disease with a 
diagnosed prevalence in North America and Europe of about 40 per 100,000 persons (Boonstra 
et al. 2011).  Primary biliary cholangitis is diagnosed frequently from routine liver biochemical 
tests obtained for other reasons (i.e., increased ALP) while the patient is still asymptomatic or in 
early-stage disease when a patient seeks treatment for pruritus or fatigue (Hirschfield et al. 
2018). Untreated PBC typically progresses over several years to liver cirrhosis resulting in liver 
transplant or death. Currently, proposed treatments are directed toward 2 approaches
(Hirschfield et al. 2018). The first is to manage the production and disposal of bile acids that 
accumulate in the liver because of progressive destruction and impaired function of the bile ducts 
caused by chronic inflammation. The second approach is to modify the autoimmune process that 
drives the disease.  


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Ursodeoxycholic acid was approved for treating PBC in 1997 and is now the standard of care for 
treating this disease (UDCA USPI; Hirschfield et al. 2018). Ursodeoxycholic acid works by 
facilitating bile flow through the liver and protecting liver cells.  It is thought that UDCA is 
concentrated in bile and decreases biliary cholesterol by suppressing hepatic synthesis and 
secretion of cholesterol and by inhibiting its intestinal absorption (UDCA Drugbank [WWW]).  
Ursodeoxycholic acid is credited with significantly reducing disease progression, liver transplant,
and death (Kowdley 2000).  Treatment with UDCA is recommended at diagnosis, regardless of 
disease stage.  About 40% to 50% of patients have an inadequate response to UDCA, as assessed 
by lack of improvement in liver biochemistry (Corpechot et al. 2008; Carbone et al. 2013).  A 
second medication, obeticholic acid, was approved as a treatment for PBC in 2016 (USPI; 
Nevens et al. 2016).  The mechanism of treating PBC is by decreasing the intracellular 
hepatocyte concentrations of bile acids by suppressing de novo synthesis from cholesterol, as 
well as by increasing transport of bile acids out of the hepatocytes. Obeticholic acid treatment is 
approved as an add-on to UDCA in patients with an inadequate response or as monotherapy in 
patients who are intolerant to UDCA.  Among these patients and according to efficacy data, 
approximately 55% will have an ALP less than 1.67 times ULN after 12 months of treatment.
However, neither of these treatments effectively address other major symptoms of PBC such as 
itch or fatigue. In fact, obeticholic acid is associated with increased pruritus, and achieving and 
maintaining an effective dose is limited by this adverse effect (Nevens et al. 2016).
Several groups have shown that survival in patients who respond to UDCA is comparable to that 
of the general population, whereas liver transplant-free survival in UDCA nonresponders is 
substantially reduced (Zhu et al. 2015).  In a recent study of 2300 patients enrolled in the 
UK-PBC Research Cohort, it was confirmed that UDCA response strongly predicted prognosis.  
UDCA nonresponders by the Paris-I definition had a hazard ratio (HR) of 2.2 for liver transplant
or death from liver failure, compared with responders (PBC Genetics Study [WWW]). New 
treatment options that reduce symptoms and treat the underlying disease are needed for patients 
with PBC.
3.3.
Benefit/Risk Assessment
Potential benefits are discussed in the study rationale section (Section 3.1) and known risks from 
the baricitinib clinical program are discussed here.
Serious infections, venous thromboembolism, hepatotoxicity, and fetal malformations were
identified as important potential risks with baricitinib.  Inclusion/Exclusion criteria in the
protocol limit enrolment of patients who are at risk for these important potential risks.  Although 
infections were seen in about half of the RA study population, the incidence rate of serious 
infection in patients exposed to baricitinib in the RA program was 3.0 per 100 patient-years.  
During the controlled period (through 16 weeks), rates were similar in both baricitinib- and 
placebo-treated patients.  The nonserious infections (upper respiratory tract infections, herpes 
zoster, and herpes simplex) associated with baricitinib in the RA program are readily diagnosed, 
manageable, and typically resolve without long-term sequelae.  It is recommended that where 
indicated, herpes zoster vaccination be offered to patients prior to receiving baricitinib.


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Increases in levels of ALT, AST, and total bilirubin have been observed in patients with RA.  
Most of these increases improved with continued use or temporary discontinuation of baricitinib 
with no long-term effects.  No cases of severe drug-induced liver injury were observed with 
baricitinib treatment.
Fetal malformations were reported in animal toxicology studies at higher doses than those used 
in human patients.  Only a small number of patients have become pregnant in baricitinib clinical
trials and there have been no reports of fetal malformations in these pregnancies.
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.  With long-term exposures, the exposure-adjusted incidence rate of 
VTE for baricitinib-treated patients with RA was similar to the background rates published in the 
literature for the target population.  There was no pattern of increased or decreased risk during 
long-term exposures. An analysis of risk factors showed that prior VTE, age, body mass index, 
and use of a cyclooxygenase-2 inhibitor were associated with the risk for a VTE observed during 
treatment with baricitinib.  To mitigate risk of venous thromboembolism, exclusion and 
discontinuation criteria have been added to the protocol to limit participation of patients who are 
at an increased risk of VTE.
Safety reports from postmarketing surveillance of the use of baricitinib in RA have been 
consistent with the safety profile reported from clinical trials.  
More information about the known and expected benefits, risks, serious adverse events (SAEs) 
and reasonably anticipated adverse events (AEs) of baricitinib are to be found in the 
Investigator’s Brochure (IB).


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4.
Objectives and Endpoints
Table JAIV.2 shows the objectives and endpoints of the study.
Table JAIV.2.
Objectives and Endpoints
Objectives
Endpoints
Primary

To evaluate the effect of baricitinib 4-mg QD 
compared to placebo on PBC disease 

Change from baseline in ALP at Week 12
Secondary

To evaluate the effect of baricitinib 4-mg QD 
compared to placebo on PBC disease

Proportion of patients with ALP <1.67 x ULN
(and at least 15% decrease from baseline) and 
total bilirubin<ULN at Week 12

To evaluate the effect of baricitinib 2-mg QD 
compared to placebo on PBC disease

Change from baseline in ALP at Week 12

Proportion of patients with ALP<1.67 x ULN 
(and at least 15% decrease from baseline) and 
total bilirubin < ULN at Week 12

To evaluate the effect of baricitinib 4-mg and 
2-mg QD compared to placebo on PBC 
symptoms

Change from baseline in itch as measured by 
Itch NRS at Week 12

Change from baseline in fatigue as measured 
by Fatigue NRS at Week 12
Abbreviations:  ALP = alkaline phosphatase; NRS = Numeric Rating Scale; PBC = primary biliary cholangitis; QD 
= once daily; ULN = upper limit of normal.


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5. Study Design
5.1.
Overall Design
Study I4V-MC-JAIV (JAIV) is a multicenter, randomized, double-blind, parallel, 
placebo-controlled, proof-of-concept Phase II study in patients with primary biliary cholangitis 
(PBC) who have an inadequate response or are intolerant to UDCA that will be conducted in 2 
cohorts.  Both cohorts will follow the same study schedule.
Cohort A
Cohort A is a randomized, double-blind, parallel, placebo-controlled cohort comprised of 
the first group of patients.  At least twelve patients will be randomized to baricitinib 2-mg 
and at least eight patients will be randomized to placebo.  Once Cohort A has fully 
enrolled, enrollment will be suspended.
Once all Cohort A patients have completed the 12 week treatment period their data will 
be reviewed by an external DMC.  
The primary goal of Cohort A will be to assess the tolerability and safety of baricitinib 2-
mg compared to placebo through Week 12.  Efficacy measures, such as change in ALP 
will also be assessed to provide context for the benefit:risk ratio.  
A DMC will oversee this study (Section 9.4.8.2).
Cohort B
Cohort B is a randomized, double-blind, parallel, placebo-controlled phase comprised of 
the second group of patients.  At least twenty patients will be randomized to baricitinib 4-
mg and at least twelve patients will be randomized to placebo.  
Enrollment in Cohort B will begin only after the DMC review of Cohort A is complete 
and Lilly has received and accepted a recommendation to proceed.  
Figure JAIV.1 illustrates the study design.
All procedures to be conducted during the study, including timing of all procedures, are indicated 
in the Schedule of Activities (Section 2).  Section 7.6 describes permitted concomitant therapy.  
Study governance considerations are described in detail in Appendix 3.
Each cohort of the study consists of 3 periods:
Screening Period: The screening period is up to 49 days and begins when the patient signs the 
informed consent form (ICF).  In exceptional circumstances, the screening window can be 
extended after consultation with the sponsor where local authorities permit.  During the 
screening period, the investigator must confirm the patient meets all inclusion and no exclusion 
criteria for the study (Section 6).  Two assessments of AST, ALT, ALP, and total bilirubin values 
are required prior to randomization (by at least two measurements obtained at least 4 weeks 
apart).  If the AST, ALT, ALP, or bilirubin values from the second sample are increased more 


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than 20% compared to the first sample (second test result/first test result >1.2) and the second 
sample exceeds the ULN, then the patient will be excluded (exclusion criterion 44).  Screening 
procedures will be performed according to the Schedule of Activities (Section 2).  Eligible 
patients will be randomized at Week 0 (Visit 3).
Treatment Period:  At Visit 3 (Week 0, baseline) all assessments are completed and baseline 
laboratory samples obtained according to the Schedule of Activities prior to the first dose of 
investigational product for both cohorts.  Randomized patients will take the first dose of 
investigational product at the clinic and pharmacokinetic (PK) samples will be drawn 15 minutes 
and 1 hour post dose.
Investigational product will be taken daily for 12 weeks.  Clinical assessments and laboratory 
samples, including additional PK sampling, will be obtained at scheduled visits according to the 
Schedule of Activities (Section 2).  Special timing considerations of administration of 
investigational product relative to PK sample collection at study visits are described in 
Section 9.5.
During the treatment period, in addition to randomized treatment, patients will also maintain 
their usual medication regimen for PBC (Section 7.6 for details on concomitant therapy).
Follow-up Period: Patients who complete the treatment period, as well as those who 
discontinue Study JAIV treatment early, will have a post-treatment follow-up visit (Visit 801) 
approximately 4 weeks after the last dose of investigational product.


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Abbreviations:  V = Visit; W = Week.
a  Patients able to tolerate ursodeoxycholic acid (UDCA) will take UDCA orally as 
background therapy during the study.  
Figure JAIV.1.
Illustration of study design for Clinical Protocol I4V-MC-JAIV.  
Patients in Cohort A and Cohort B will follow the same study schedule 
as outlined in this figure.  Cohort A will randomize 12 patients to
baricitinib 2-mg and 8 patients to placebo.  After a DMC review of 
Cohort A data, Cohort B will then randomize 20 patients to baricitinib 4-
mg and 12 patients to placebo.
5.2.
Number of Participants
Approximately 52 subjects are planned to be randomized in this study.  Approximately 12 
patients will receive baricitinib 2-mg, approximately 20 patients will receive baricitinib 4-mg,
and approximately 20 patients will receive placebo.
5.3.
End of Study Definition
End of the study is the date of the last visit or last scheduled procedure shown in the Schedule of 
Activities (Section 2) for the last patient.
5.4.
Scientific Rationale for Study Design
 
 


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5.5.
Justification for Dose
 
 
 
 
 
 
 
 
 
 
 
 
  


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6.
Study Population
Prospective approval of protocol deviations to recruitment and enrollment criteria, also known as 
protocol waivers or exemptions, are not permitted.
Note: The numbering system used for inclusion and exclusion criteria provides a unique number 
for each criterion which is maintained in the case of a protocol amendment. Specifically, if a 
criterion removed as a result of an amendment, the number and the criterion will be removed and 
will not be reused. If an amendment to the protocol adds a criterion, that criterion will receive 
the next available number, regardless of where it is located in the list.
6.1.
Inclusion Criteria
Subjects will be eligible for randomization only if they meet all of the following criteria within 
the screening period, which is ≤49 days prior to randomization, unless specifically defined:  
Type of Patient and Disease Characteristics
[1]
Male or female patients who are at least 18 years of age.
[2]
Have a diagnosis of PBC (consistent with American Association for the Study of Liver 
Disease [AASLD] and European Association for Study of the Liver [EASL] Practice 
Guidelines; [Lindor 2009; EASL 2017]), as demonstrated by the presence of at least 2 
of the following 3 diagnostic factors:

History of elevated ALP levels for at least 6 months

Positive antimitochondrial antibodies titer 

Liver biopsy consistent with PBC
[3]
Have ALP ≥1.67 x ULN but <6 x ULN
[4]
Taking UDCA for at least 52 weeks (stable dose for at least 12 weeks) prior to Visit 3 
(Week 0), or have previously taken, but are intolerant (in the opinion of the 
investigator) to UDCA and have not received UDCA for at least 12 weeks prior to Visit 
3 (Week 0).
Patient Characteristics
[5]
Nonpregnant, nonbreastfeeding female patients of childbearing potential:
a.
Patients who are abstinent (if this is complete abstinence, as their preferred 
and usual lifestyle) or in a same-sex relationship (as part of their preferred 
and usual lifestyle) must agree to either remain abstinent or stay in a 
same-sex relationship without sexual relationships with the opposite sex 
during the entirety of the study and for at least 1 week following the last 
dose of investigational product.


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Total abstinence is defined as refraining from intercourse during the entirety 
of the study and for at least 1 week following the last dose of investigational 
product.  Periodic abstinence such as calendar, ovulation, symptothermal, 
postovulation methods, and withdrawal are not acceptable methods of 
contraception.
b. Otherwise, patients must agree to use for the entirety of the study and for at 
least 1 week following the last dose of investigational product, 2 effective 
methods of contraception, where at least 1 form is highly effective (such as 
combination oral contraceptives, implanted contraceptives or intrauterine 
devices). Effective contraception (such as male or female condoms with 
spermicide, diaphragms with spermicide or cervical sponges) may be used 
as the second therapy. Barrier protection methods without concomitant use 
of a spermicide are not a reliable or acceptable method.
Female patients of nonchildbearing potential may participate without 
requirements for contraception.  This includes female patients who are:  
a.
Infertile due to surgical sterilization (hysterectomy, bilateral oophorectomy, 
or tubal ligation), congenital anomaly such as mullerian agenesis; or
b. Postmenopausal – defined as either
i. A woman at least 50 years of age with an intact uterus, not on 
hormone therapy, who has had either
1. Cessation of menses for at least 1 year, or
2. At least 6 months of spontaneous amenorrhea with a 
follicle-stimulating hormone (FSH) >40 mIU/mL; or
ii. A woman 55 years of age or older not on hormone therapy, who 
has had at least 6 months of spontaneous amenorrhea; or 
iii. A woman at least 55 years of age with a diagnosis of menopause 
prior to starting hormone replacement therapy.
Informed Consent
[6]
Must read and understand the informed consent approved by Eli Lilly and Company 
(Lilly), or its designee, and the institutional review board (IRB)/ethics review board 
(ERB) governing the site, and provide written informed consent.  
6.2.
Exclusion Criteria
Patients will be excluded from study enrollment if they meet any of the following criteria at
screening and/or enrollment:
Medical Conditions
[7]
History or presence of other concomitant liver diseases including:


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a.
Hepatitis C virus (HCV) infection (hepatitis C antibody-positive and HCV 
ribonucleic acid [RNA] positive).

Note:  Patients who have documented anti-HCV treatment for a past 
HCV infection AND are HCV RNA-negative with a sustained viral 
response may be enrolled in the study.
b. Hepatitis B virus (HBV) infection defined as:

positive for hepatitis B surface antigen (HBsAg), or

positive for hepatitis B core antibody (HBcAb) 
c.
Primary sclerosing cholangitis
d. Alcoholic liver disease
e.
Autoimmune liver disease other than PBC, such as overlap hepatitis
f.
Nonalcoholic steatohepatitis 
g. Gilbert’s syndrome
[8]
Presence of clinical complications of PBC or clinically significant hepatic 
decompensation, including:
a.
Liver transplantation, current placement on a liver transplant list or current 
Model for End Stage Liver Disease (MELD) score ≥ 15
b. Portal hypertension with complications, including known gastric or 
esophageal varices, ascites, history of variceal bleeds or related therapeutic 
or prophylactic interventions (e.g., beta blockers, insertion of variceal bands 
or transjugular intrahepatic portosystemic shunt), or hepatic encephalopathy
c.
Cirrhosis with complication, i.e., decompensated cirrhosis, including history 
or presence of one or more of the following:  

spontaneous bacterial peritonitis

hepatocellular carcinoma

hepatorenal or hepatopulmonary syndrome
[9]
Have an estimated glomerular filtration rate (eGFR) based on the most recent 
available serum creatinine of <90 mL/min/1.73 m2.
[10] Have screening electrocardiogram (ECG) abnormalities that in the opinion of 
the investigator or the sponsor are clinically significant and indicate an 
unacceptable risk for the patient’s participation in the study.
[11] Have experienced any of the following within 12 weeks of screening:  
myocardial infarction, unstable ischemic heart disease, stroke, or New York 
Heart Association Stage III/IV heart failure.


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[12] Have active fibromyalgia that in the investigator’s opinion, would make it 
difficult to appropriately assess fatigue for the purposes of this study.
[13] Have had any major surgery within 8 weeks prior to study entry or will require 
major surgery during the study that in the opinion of the investigator in 
consultation with Lilly or its designee, would pose an unacceptable risk to the 
patient.
[14] Have a diagnosis of any systemic inflammatory condition other than PBC such 
as, but not limited to, RA, spondyloarthropathy, Crohn’s disease, ulcerative 
colitis, psoriatic arthritis, active vasculitis, or gout.
[15] Have a history of VTE (deep vein thrombosis/pulmonary embolism [DVT/PE]).
[16] Have a history or presence of cardiovascular, respiratory, hepatic, 
gastrointestinal, endocrine, hematological, neurological, or neuropsychiatric 
disorders or any other serious and/or unstable illness that, in the opinion of the 
investigator, could constitute an unacceptable risk when taking investigational 
product or interfere with the interpretation of data.
[17] Have a history of lymphoproliferative disease; have signs or symptoms 
suggestive of possible lymphoproliferative disease, including lymphadenopathy 
or splenomegaly; have active primary or recurrent malignant disease; or have 
been in remission from clinically significant malignancy for <5 years prior to 
randomization.
a.
Patients with cervical carcinoma in situ that has been resected with no 
evidence of recurrence or metastatic disease for at least 3 years may 
participate in the study.
b. Patients with basal cell or squamous epithelial skin cancers that have been 
completely resected with no evidence of recurrence for at least 3 years may 
participate in the study.  
[18] Have a current or recent (<4 weeks prior to randomization) clinically serious 
infection or any other active or recent infection that, in the opinion of the 
investigator, would pose an unacceptable risk to the patient if participating in 
the study.
Note:  a recent viral upper respiratory tract infection or uncomplicated urinary 
tract infection need not be considered clinically serious.
[19] Have symptomatic herpes simplex at the time of randomization.  
[20] Have had symptomatic herpes zoster infection within 12 weeks prior to 
randomization.  
[21] Have a history of disseminated/complicated herpes zoster (for example, 
multidermatomal involvement, ophthalmic zoster, central nervous system 
involvement, or postherpetic neuralgia).


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[22] Have had household contact with a person with active tuberculosis (TB) and did 
not receive appropriate and documented prophylaxis for TB.
[23] Have active TB disease determined on the basis of a positive medical history, 
physical examination, or chest radiography (per local standard of care) or latent 
TB infection (LTBI) determined on the basis of:
a.
A positive tuberculin skin test (TST, also called a purified protein derivative 
[PPD] or Mantoux test) result (skin induration ≥5 mm at 48 to 72 hours after 
the test date, or 
b. A positive QuantiFERON®-TB Gold or T-Spot®.TB test
If the QuantiFERON-TB Gold is indeterminate or the T-Spot.TB is invalid or 
borderline, one retest is allowed.  Patients with 2 indeterminate QuantiFERON-TB 
Gold or 2 invalid or borderline T-Spot.TB assays are excluded from the study.  
The choice to perform either a TST or an interferon-gamma release assay 
(IGRA) test must be made by the investigator according to local licensing and 
standard of care.  Interferon-gamma release assay test is a preferred method in 
patients with a history of Bacillus Calmette-Guerin (BCG) vaccination, given 
the rate of false positive TST results in this population.
Patients who have a documented history of completing an appropriate TB 
treatment regimen for active TB or LTBI and with no risk of re-exposure since
their treatments were completed are eligible to participate in the study.  These 
patients should not undergo TST or IGRA testing.  
Patients with documentation of a “negative” IGRA or TST testing within 
3 months before initial screening may not need to repeat TB testing at 
screening, based on judgment of the investigator.  Source documentation must 
include the original laboratory report for IGRA or a record of size in millimeters 
of the induration response (for TST).  A TST recorded as “negative” without 
documenting the size of induration in millimeters will not be acceptable and 
will require a retest.
[24] Have been exposed to a live vaccine within 12 weeks of randomization or are 
expected to need/receive a live vaccine during the course of the study (with the 
exception of herpes zoster vaccination).  
Note:  All patients who have not previously received the herpes zoster vaccine by 
screening will be encouraged (per local guidelines) to do so prior to randomization; 
vaccination with live herpes zoster vaccine must occur >4 weeks prior to randomization 
and start of investigational product.  Patients will not be randomized if they were 
exposed to a live herpes zoster vaccination within 4 weeks of planned randomization.  
If a virus subunit, that is, Shingrix®, is used to vaccinate against herpes zoster, there is 
no requirement of a waiting period prior to randomization.  
Investigators should review the vaccination status of their patients and follow the local 
guidelines for vaccination.


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[25] Are currently enrolled in or have discontinued within 4 weeks of screening from 
any other clinical trial involving an investigational product or nonapproved use 
of a drug or device or any other type of medical research judged not to be 
scientifically or medically compatible with this study.
[26] Have previously completed or been randomized and withdrawn from any other 
study investigating baricitinib.  
Diagnostics Assessments
[27] Have evidence of human immunodeficiency virus (HIV) infection and/or 
positive HIV antibodies.
[28] Have a thyroid-stimulating hormone (TSH) outside the reference range for the 
population that in the opinion of the investigator poses an unacceptable risk for 
the patient’s participation in the study or is suggestive of an additional or 
another hepatic disorder.
Patients who are receiving thyroxine as replacement therapy may participate in 
the study, provided stable therapy has been administered for ≥12 weeks and 
TSH is within the laboratory’s reference range.  Patients who have TSH 
marginally outside the laboratory’s normal reference range and are receiving 
stable thyroxine replacement therapy may participate if the treating physician 
has documented that the thyroxine replacement therapy is adequate for the 
patient.
[29] Have any of the following specific abnormalities based on screening central lab 
test results:

Hemoglobin <10 g/dL (100.0 g/L)

ALT >3 x ULN

AST >3 x ULN

ALP >6 x ULN

Total bilirubin level (TBL) >ULN

Creatine phosphokinase (CPK) > ULN

Serum albumin < LLN

International Normalized Ratio of Prothrombin Time (INR) > ULN

Total white blood cell (WBC) count <LLN

Absolute neutrophil count [ANC] <LLN

Lymphocyte count <LLN

Platelet (thrombocyte) count < LLN


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In the case of any of the aforementioned laboratory abnormalities, the tests may 
be repeated once during screening, and values resulting from repeat testing may 
be accepted for enrollment eligibility if they meet the eligibility criterion.
[44] The second set of screening values for ALT, AST, or total bilirubin are above 
the upper limit of normal and > 20% higher than the first values obtained 
during screening
[45] The second screening value for ALP is > 20% higher than the first value
obtained during screening
Prior/Concomitant Therapy
[30] Are receiving unstable treatment for pruritus within 6 weeks prior to Visit 3 
(Week 0).
[31] Have been treated with systemic (oral or parenteral) corticosteroids within 6 
weeks prior to Visit 3 (Week 0).
Note:  the use of topical, ophthalmic, intranasal, and inhaled corticosteroids will be 
permitted.
[32] Have received biologic treatments for an immunologic disease within 4 weeks 
of screening such as etanercept, infliximab, certolizumab, adalimumab, 
golimumab, tocilizumab, abatacept, ustekinumab, ixekizumab, secukinumab, or 
anakinra.
[33] Have received a JAK inhibitor.
[34] Have received obeticholic acid.  
[35] Have received fenofibrate or other fibrates for the treatment of PBC.  
[36] Are currently treated with probenecid that cannot be discontinued for the 
duration of the study.
Other Exclusions
[37] Are largely or wholly incapacitated permitting little or no self-care, such as 
being bedridden.
[38] In the opinion of the investigator, are at an unacceptable risk for participating in 
the study.
[39] Have donated more than a single unit of blood within 4 weeks prior to screening 
or intend to donate blood during the course of the study.


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[40] Have a history of IV drug abuse, other illicit drug abuse, or chronic alcohol 
abuse within the 2 years prior to screening or are concurrently using, or 
expected to use during the study, illicit drugs (including marijuana).  Alcohol 
abuse is defined as consumption of more than 210 mL of alcohol per week (i.e., 
the equivalent of 14 four-ounce (125 mL) glasses of wine or 14 twelve-ounce 
(330 mL) cans/bottles of beer), or other substance abuse within 1 year prior to 
Visit 3 (Week 0).
[41] Are unable or unwilling to make themselves available for the duration of the 
study and/or are unwilling to follow study restrictions/procedures.
[42] Are investigator site personnel directly affiliated with this study and/or their 
immediate families.  Immediate family is defined as a spouse, parent, child, or 
sibling, whether biological or legally adopted.
[43] Are Lilly or Incyte employees.
6.3.
Lifestyle Restrictions
Study participants should be instructed not to donate blood or blood products during the study, 
and for 30 days following the last dose of investigational product.
6.4.
Screen Failures
Individuals who do not meet the criteria for participation in this study (screen failure) may be
rescreened.  Individuals may be rescreened 1 time.  The interval to rescreening should be at least 
2 weeks.  The individual must sign a new ICF and will be assigned a new identification number
at the time of the second screening.


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7. Treatments
7.1.
Treatments Administered
This study involves a comparison between baricitinib administered once daily and placebo.  
Patients able to tolerate UDCA will continue to take a stable dose of UDCA orally as 
background therapy during the study. Table JAIV.3 shows the treatment regimens.
Table JAIV.3.
Treatment Regimens
Cohort A
Regimen
Dose
Week 1 through 12
Baricitinib
2 mg Baricitinib (2 x 1-mg tablets)
Placebo 
PTM 2 mg (2 x PTM 1-mg tablets)
Cohort B
Regimen
Dose
Week 1 through 12
Baricitinib
4-mg Baricitinib (1 x 4-mg tablet)
Placebo 
PTM 4 mg (1 x PTM 4-mg tablet)
Abbreviation:  PTM = placebo to match.
The investigator or his or her designee is responsible for the following:

explaining the correct use of the investigational agent(s) to the patient

verifying that instructions are followed properly

maintaining accurate records of investigational product dispensing and collection

at the end of the study returning all unused medication to Lilly, or its designee, 
unless the sponsor and sites have agreed that all unused medication is to be 
destroyed by the site, as allowed by local law.
7.1.1. Packaging and Labelling
The sponsor (or its designee) will provide the following investigational product:

tablets containing 1-mg of baricitinib 

tablets containing 4-mg of baricitinib

tablets containing placebo to match 1-mg of baricitinib

tablets containing placebo to match 4-mg of baricitinib.
Clinical trial materials will be labeled according to the country’s regulatory requirements.  
Patients will be instructed to take the tablet(s) each day as assigned.
7.2.
Method of Treatment Assignment
 
 


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Assignment to treatment groups will be determined by a computer-generated random sequence 
using an interactive web-response system (IWRS).  The IWRS will be used to assign 
double-blind investigational product to each patient.  Site personnel will confirm that they have 
located the correct package by entering a confirmation number found on the package into the 
IWRS.
7.2.1. Selection and Timing of Doses
Investigational product will be provided to patients following randomization at Visit 3 (Week 0).
The tablet(s) should be taken orally each day, without regard to food and if possible, at 
approximately the same time every day. Special timing considerations of administration of 
investigational product relative to PK sample collection at study visits are described in 
Section 9.5.
For patients taking concomitant cholestyramine it is recommended that patients take baricitinib 
at least 1 hour before or 4 to 6 hours after cholestyramine.  
7.3.
Blinding
This is a double-blind study. To preserve the blinding of the study, a minimum number of Lilly 
personnel will see the randomization table and treatment assignments before the study is 
complete.  All study assessments will be performed by study personnel who are blinded to the 
patient’s treatment group.  Except in clinical circumstances where unblinding is required, the 
patients, investigators, Lilly study team, and any personnel interacting directly with patients or 
investigative sites will remain blinded to baricitinib and placebo assignment.  Every effort should 
be made to preserve the blind unless there is a compelling reason that knowledge of the specific 
treatment would alter the medical care of the patient.  
In case of an emergency, the investigator has the sole responsibility for determining if unblinding 
of a patient’s treatment assignment is warranted for medical management of the event.  Patient’s
safety must always be the first consideration in making such a determination.  Where feasible 
and when the timing of the emergent situation permits, the investigator should attempt to contact 
the Lilly medical monitor before unblinding a subject’s treatment assignment. If a patient’s 
treatment assignment is unblinded, Lilly must be notified immediately.  If the investigator 
decides that unblinding is warranted, it is the responsibility of the investigator to promptly 
document the decision and rationale and notify Lilly as soon as possible.
Emergency unblinding for AEs may be performed through the IWRS.  This option may be used 
ONLY if the patient’s well-being requires knowledge of the patient’s treatment assignment.  All 
unblinding events are recorded and reported by the IWRS.  If an investigator, site personnel 
performing assessments, or patient is unblinded, the patient must be discontinued from the study.  
In cases where there are ethical reasons to have the patient remain in the study, the investigator 
must obtain specific approval from a Lilly designated medical monitor for the patient to continue 
in the study.


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7.4.
Preparation/Handling/Storage/Accountability
All investigational product (used and partially used) will be returned to the sponsor or destroyed 
at the site level with the sponsor’s written approval.  In some cases, sites may destroy the 
material if, during the investigative site selection, the evaluator has verified and documented that 
the site has appropriate facilities and written procedures to dispose of clinical trial materials.
Follow storage and handling instructions on the investigational product packaging.
7.5.
Treatment Compliance
Patient compliance with study medication will be assessed at Visit 4 through Visit 7 and at Early 
Termination during the treatment period by counting returned tablets and direct questioning.  
Deviation(s) from the prescribed dosage regimen should be recorded in the electronic case report 
form (eCRF).
The patient will be considered significantly noncompliant if he or she misses more than 20% of 
study medication 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.
7.6.
Concomitant Therapy
Patients will maintain their usual medication regimen for PBC and for any other concomitant 
diseases throughout the study unless specifically excluded in the protocol (Section 6.2, Exclusion 
Criteria).  Patients taking these medications should be on chronic stable doses at the time of 
randomization, as specified by the Inclusion Criteria (Section 6.1, Inclusion Criteria).
All concomitant medication, whether prescription or over the counter, used at baseline and/or 
during the course of the study must be recorded on the relevant eCRF.  Any changes to the 
patient’s medication must be discussed with the investigator.  Patients should be instructed to 
consult the investigator or other appropriate study personnel at the site before taking any new 
medications or supplements during the study.
7.6.1. Permitted Medications and Procedures
 
 


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7.6.2. Prohibited Medications and Procedures
 
 
 
 
 
 
 
 
t
 
7.7.
Treatment after the End of the Study
7.7.1. Treatment after Study Completion
Baricitinib will not be made available to patients after conclusion of the study.


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8.
Discontinuation Criteria
8.1.
Discontinuation from Study Treatment
8.1.1. Interruption of Investigational Product
In some circumstances, it may be necessary to temporarily interrupt treatment as a result of AEs 
or abnormal laboratory values that may have an unclear relationship to investigational product.  
It is recommended that the investigator consult with Lilly (or its designee) before temporarily 
interrupting therapy for reasons other than those defined in Table JAIV.4.  Unless otherwise 
specified, retest timing and frequency is at the investigator’s discretion.
Investigational product that was temporarily interrupted because of an AE or abnormal 
laboratory value not specifically covered in Table JAIV.4 may be restarted at the discretion of 
the investigator.  Investigational product must be held in the following situations and may only 
be resumed as noted in the table.
Table JAIV.4.
Criteria for Interruption of Investigational Product
Hold Investigational Product if the Following 
Abnormalities Occur:
Investigational Product May be Resumed When:
WBC count <2000 cells/L
(<2.00 x 103/L or <2.00 GI/L)
WBC count 2500 cells/L
(≥2.50 x 103/L or ≥2.50 GI/L)
ANC <1000 cells/L 
(<1.00 x 103/L or <1.00 GI/L) 
ANC ≥1200 cells/L
(≥1.2 x 103/L or ≥1.2 GI/L)
Lymphocyte count <500 cells/L
(<0.50 x 103/L or <0.50 GI/L)
Lymphocyte count 750 cells/L
(≥0.75 x 103/L or ≥0.75 GI/L)
Platelet count <75,000/L
(<75 x 103/L or <75 GI/L)
Platelet count 100,000/L
(≥100 x 103/L or ≥100 GI/L)
ALT or AST>3X ULN for patients with normal 
ALT or AST at baseline 
ALT and AST return to ≤3X ULN and investigational 
product is not considered the cause of enzyme elevation.
ALT or AST > 3X baseline value for patients with 
ALT or AST >ULN at baseline
ALT and AST return to ≤3X baseline value for patients 
with increased baseline and investigational product is not 
considered the cause of enzyme elevation.
Hemoglobin <8 g/dL (<80.0 g/L)
Hemoglobin 9 g/dL (≥90.0 g/L)
eGFR <50 mL/min/1.73 m2
eGFR ≥60 mL/min/1.73 m2
Symptomatic herpes zoster
All skin lesions have crusted and are resolving
Infection that, in the opinion of the investigator, 
merits the IP being withhelda
Resolution of infection that, in the opinion of the 
investigator, merits the IP being restarted
Clinical features of VTE (deep vein thrombosis or 
pulmonary embolism) are present
After diagnosis of VTE has been excluded.  If diagnosis of 
VTE is confirmed, study treatment must be permanently 
discontinued
Abbreviations:  ALT = alanine aminotransferase; ANC = absolute neutrophil count; AST = aspartate 
aminotransferase; eGFR = estimated glomerular filtration rate; IP = investigational product; ULN = upper limit 
of normal; VTE = venous thromboembolism; WBC = white blood cell.
a
Permanent discontinuation of IP should be considered for patients who develop a serious infection that, in the 
opinion of the investigator, would pose an unacceptable risk if IP were resumed.


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8.1.2. Permanent Discontinuation from Study Treatment
Possible reasons leading to permanent discontinuation of investigational product:

Subject Decision
o
the patient requests to discontinue investigational product.

Investigator Decision
o
the investigator decides that the patient should be discontinued from investigational 
product

Discontinuation due to a hepatic event or liver test abnormality:  Patients who are 
discontinued from investigational product because of a hepatic event or liver test 
abnormality should have additional hepatic safety data collected via eCRF.  Details on 
continued hepatic monitoring are provided in Section 9.4.7.
If multiple values are obtained during screening, the highest value prior to receipt of 
investigational product will be used as baseline.  Discontinuation of the investigational 
product for abnormal liver tests should be considered by the investigator when a patient
meets one of the following conditions after consultation with the Lilly designated medical 
monitor:  
a.
For patients with baseline normal ALT and/or AST, the following will result in 
discontinuation:
single laboratory test
ALT or AST >8 x ULN
single laboratory test
ALT or AST >3 x ULN and TBL >2 x ULN or 
International Normalized Ratio (INR) >1.5
single laboratory test
ALT or AST >3 x ULN with the appearance of fatigue, 
nausea, vomiting, right upper-quadrant pain or 
tenderness, fever, rash, and/or eosinophilia (>5%)
confirmed laboratory test (2 tests)
ALT or AST >2 x ULN and no other known cause.
during temporary interruption of IP
ALT or AST >5 x ULN for more than 2 weeks after 
temporary interruption of investigational product
b. For patients with baseline elevated ALT and/or AST, the following will result in 
discontinuation:
confirmed laboratory test (2 tests)
ALT >5 x baseline, or >400 U/L (whichever occurs first)
confirmed laboratory test (2 tests)
ALT >3 x baseline and TBL >2 x ULN or INR >1.5
confirmed laboratory test (2 tests)
ALT >3 x baseline with appearance of severe fatigue, 
nausea, vomiting, right upper-quadrant abdominal pain, 
fever, rash, and/or eosinophilia (>5%)
confirmed laboratory test (2 tests)
ALT or AST >2 x ULN and no other known cause
confirmed laboratory test (2 tests)
TBL >1.5 x baseline upon retesting and no other known 
cause
during temporary interruption of IP 
ALT >4 x baseline or >300 U/L (whichever occurs first) 
for more than 2 weeks after temporary interruption of 
investigational product


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c.
For all patients, the following will result in discontinuation:
confirmed laboratory test (2 tests)
ALP >3 x baseline and >6 x ULN
confirmed laboratory test (2 tests)
ALP >2.5 x baseline and TBL >2 x ULN or INR >1.5
confirmed laboratory test (2 tests)
ALP >2.5 x baseline with appearance of severe fatigue, 
vomiting, right upper-quadrant pain, fever, rash, and/or 
eosinophilia (>5%)

Discontinuation due to other laboratory abnormalities:

White blood cell count <1000 cells/L (1.00 x 103/L or 1.00 GI/L)

Absolute neutrophil count <500 cells/L (0.50 x 103/L or 0.50 GI/L)

Lymphocyte count <200 cells/L (0.20 x 103/L or 0.20 GI/L)

Hemoglobin <6.5 g/dL (<65.0 g/L)

Creatine phosphokinase >5x ULN

eGFR ≤40mL/min/1.73m2.
Temporary interruption rules (Section 8.1.1) must be followed where applicable.  For laboratory 
values that meet permanent discontinuation thresholds, investigational product should be 
discontinued.  However, if in the opinion of the investigator, the laboratory abnormality is due to 
intercurrent illness or another identified factor, laboratory tests may be repeated.  The 
investigator may be able to restart investigational product after consultation with the Lilly 
designated medical monitor, only when the laboratory value meets resumption thresholds 
(Table JAIV.4) following the resolution of the intercurrent illness or other identified factor.

Discontinuation due to other circumstances:

pregnancy

malignancy (except for successfully treated basal cell or squamous epithelial 
skin cancers)

occurrence of a VTE (DVT/PE) 

serious infection that, in the opinion of the investigator, merits the 
investigational product being discontinued

if the patient, for any reason, requires treatment with another therapeutic agent 
that may be effective for treatment of PBC that is listed in the exclusion 
criteria (Section 6.2) or is noncompliant to the concomitant therapy 
requirements (Section 7.6) during the study.  Discontinuation from the 
investigational product must occur prior to introduction of the new agent.
Throughout the study, investigators should continue to assess benefit/risk for patients to remain 
in the trial and should consider discontinuing patients if sufficient clinical benefit is not observed 
with protocol allowed concomitant treatments.
Patients discontinuing from the investigational product prematurely for any reason should 
complete AE and other follow-up procedures per Section 2 (Schedule of Activities), Section 9.2
(Adverse Events), and Section 9.4 (Safety) of this protocol.


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8.1.3. Discontinuation of Inadvertently Enrolled Patients
If the sponsor or investigator identify a patient who did not meet enrollment criteria and was 
inadvertently enrolled, then the patient should be discontinued from study treatment unless there 
are extenuating circumstances that make it medically necessary for the patient to continue on 
study treatment.  If the investigator and the sponsor designated medical monitor agree it is 
medically appropriate to continue, the investigator must obtain documented approval from the 
sponsor designated medical monitor to allow the inadvertently enrolled patient to continue in the 
study with or without treatment with investigational product. Safety follow-up is as outlined in 
Section 2 (Schedule of Activities), Section 9.2 (Adverse Events), and Section 9.4 (Safety) of the 
protocol.
8.2.
Discontinuation from the Study
Patients will be discontinued in the following circumstances:  

enrollment in any other clinical study involving an investigational product or 
enrollment in any other type of medical research judged not to be scientifically or 
medically compatible with this study

participation in the study needs to be stopped for medical, safety, regulatory, or 
other reasons consistent with applicable laws, regulations, and good clinical 
practice (GCP)

investigator decision
o
the investigator decides that the patient should be discontinued from the study
o
if the patient, for any reason, requires treatment with another therapeutic agent 
that has been demonstrated to be effective for treatment of the study
indication, discontinuation from the study occurs prior to introduction of the 
new agent

subject decision
o
the patient requests to be withdrawn from the study
Patients discontinuing from the study prematurely for any reason should complete AE and other 
safety follow-up per Section 2 (Schedule of Activities), Section 9.2 (Adverse Events), and 
Section 9.4 (Safety) of this protocol.
8.3.
Lost to Follow-up
A patient will be considered lost to follow-up if he or she repeatedly fails to return for scheduled 
visits and is unable to be contacted by the study site.  Site personnel are expected to make 
diligent attempts to contact patients who fail to return for a scheduled visit or were otherwise 
unable to be followed up by the site.


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9.
Study Assessments and Procedures
Section 2 lists the Schedule of Activities, with the study procedures and their timing (including 
tolerance limits for timing).
Appendix 2 lists the laboratory tests that will be performed for this study.
Unless otherwise stated in the subsections below, all samples collected for specified laboratory 
tests will be destroyed within 60 days of receipt of confirmed test results.  Certain samples may 
be retained for a longer period, if necessary, to comply with applicable laws, regulations, or 
laboratory certification standards.
9.1.
Efficacy Assessments
9.1.1. Primary Efficacy Assessments
The primary efficacy assessment in Study JAIV will be change in ALP at Week 12.
9.1.2. Secondary and Exploratory Efficacy Assessments
Secondary efficacy assessments will include the proportion of patients with ALP <1.67 x ULN 
(and at least 15% decrease from baseline), Itch NRS, fatigue NRS.  Exploratory efficacy 
assessments will include Functional Assessment of Chronic Illness Therapy-Fatigue (FACIT-F), 
PBC-40, and total bilirubin.
The Itch NRS is a patient-administered, 11-point horizontal scale anchored at 0 and 10, with 0 
representing “no itch” and 10 representing “worst itch imaginable.” Overall severity of a 
patient’s itching is indicated by selecting the number that describes the worst level of itching in 
the past 7 days.
The Fatigue NRS is a single-item, patient-administered, 11-point horizontal scale anchored at 0 
and 10, with 0 representing “no fatigue” and 10 representing “as bad as you can imagine.” 
Overall severity of a patient’s fatigue is indicated by selecting the number that describes the 
worst level of fatigue during the past 7 days.
The FACIT-F measures an individual’s self-reported level of fatigue during their usual daily 
activities over the past 7 days.  The scale is composed of 13 items measured on a 4-point Likert 
scale (4 = very much to 0 = not at all).  The total score ranges from 0 to 52, and higher scores 
representing less fatigue.  A score of less than 30 indicates severe fatigue (Webster et al. 2003).
The PBC-40 is a disease-specific, 40-item, patient-reported survey containing 6 domains:  
overall symptoms, itch, fatigue, cognition, social, and emotional.  Response options for overall 
symptoms, itch, fatigue, and cognition are on a 5-point scale: “Never,” “Rarely,” “Sometimes,”
“Most of the time,” and “Always.”  Response options are also on a 5-point scale for social and 
emotional: “Not at all,” “A little,” “Somewhat,” “Quite a bit,” and “Very much.”  Items are 
scored from 1 to 5 and the individual item scores are summed to give a total domain score where 
high scores represent high impact of PBC on quality of life (Jacoby et al. 2005).


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The Physician’s Global Assessment of Disease Activity is the physician’s assessment of the 
patient’s overall disease activity due to PBC, as compared with all possible patients with PBC. 
The Physician’s Global Assessment of Disease Activity is scored using a 100-mm visual analog 
scale (VAS), where 0 mm (measured from the left starting point of the line) indicates no disease 
activity and 100 mm (measured from the left starting point of the line) indicates the most severe 
disease activity possible for all patients with PBC.  The Physician’s Global Assessment of 
Disease Activity score is indicated by making a vertical tick mark on the line between 0 and 
100 mm. There are benchmarks of 0 (0 mm), 1 (33 mm), 2 (67 mm), and 3 (100 mm) on the line 
corresponding to no, mild, moderate, and severe PBC disease activity, respectively.
9.1.3. Appropriateness of Assessments
Itch and fatigue are 2 prevalent and bothersome symptoms to PBC patients.  The PBC-40 is a 
disease-specific quality of life measure developed for PBC.  
9.2.
Adverse Events
Investigators are responsible for monitoring the safety of patients who have entered this study 
and for alerting Lilly or its designee to any event that seems unusual, even if this event may be 
considered an unanticipated benefit to the patient.
The investigator is responsible for the appropriate medical care of patients during the study.
Investigators must document their review of each laboratory safety report.
The investigator remains responsible for following, through an appropriate health care option, 
AEs that are serious or otherwise medically important, considered related to the investigational 
product or the study, or that caused the patient to discontinue the investigational product before 
completing the study.  The patient should be followed until the event resolves, stabilizes with 
appropriate diagnostic evaluation, or is reasonably explained.  The frequency of follow-up
evaluations of the AE is left to the discretion of the investigator.
Lack of drug effect is not an AE in clinical studies, because the purpose of the clinical study is to 
establish treatment effect.
After the ICF is signed, study site personnel will record via eCRF the occurrence and nature of 
each patient’s preexisting conditions, including clinically significant signs and symptoms of the 
disease under treatment in the study.  In addition, site personnel will record any change in the 
condition(s) and any new conditions as AEs. Investigators should record the following via the 
eCRF for each AE:  time of onset, time of termination, severity and their assessment of the 
potential relatedness of each AE to protocol procedure or investigational product.  
The investigator will interpret and document whether or not an AE has a reasonable possibility 
of being related to study treatment, or a study procedure, taking into account the disease, 
concomitant treatment or pathologies.  
A “reasonable possibility” means that there is a cause and effect relationship between the 
investigational product and/or study procedure and the AE.


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The investigator answers yes/no when making this assessment.
Planned surgeries and nonsurgical interventions should not be reported as AEs unless the 
underlying medical condition has worsened during the course of the study.
If a patient’s investigational product is discontinued as a result of an AE, study site personnel 
must report this to Lilly or its designee via eCRF, clarifying if possible, the circumstances 
leading to any dosage modifications, or discontinuations of treatment.  
9.2.1. Serious Adverse Events
An SAE is any AE from this study that results in one of the following outcomes:

death

initial or prolonged inpatient hospitalization

a life-threatening experience (that is, immediate risk of dying)

persistent or significant disability/incapacity

congenital anomaly/birth defect

important medical events that may not be immediately life-threatening or result in 
death or hospitalization but may jeopardize the patient or may require intervention 
to prevent one of the other outcomes listed in the definition above.  

All AEs occurring after signing the ICF are recorded in the eCRF and assessed for 
serious criteria.  The SAE reporting to the sponsor begins after the patient has 
signed the ICF and has received investigational product.  However, if an SAE 
occurs after signing the ICF, but prior to receiving investigational product, the 
SAE should be reported to the sponsor as per SAE-reporting requirements and 
timelines (Section 9.2) if it is considered reasonably possibly related to study 
procedure.
Study site personnel must alert Lilly or its designee of any SAE within 24 hours of investigator 
awareness of the event via a paper SAE form.  If alerts are issued via telephone, they are to be 
immediately followed with official notification on study specific SAE forms.  The SAE form 
should be completed by the investigator, and submitted via fax to the Sponsor’s global patient 
safety department.  This form includes a fax cover page that is prepopulated with the appropriate 
fax number.  The 24-hour notification requirement refers to the initial SAE information and all 
follow-up SAE information.  Patients with a serious hepatic AE should have additional data 
collected using the eCRF.
Pregnancy (during maternal or paternal exposure to investigational product) does not meet the 
definition of an AE.  However, to fulfill regulatory requirements any pregnancy should be 
reported following the SAE process to collect data on the outcome for both mother and fetus.
Investigators are not obligated to actively seek AEs or SAEs in subjects once they have 
discontinued and/or completed the study (the patient disposition eCRF has been completed).  
However, if the investigator learns of any SAE, including a death, at any time after a subject has 


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been discharged from the study, and he or she considers the event reasonably possibly related to 
the study treatment or study participation, the investigator must promptly notify Lilly.
9.2.1.1.
Suspected Unexpected Serious Adverse Reactions
Suspected unexpected serious adverse reactions (SUSARs) are serious events that are not listed 
in the IB and that the investigator identifies as related to investigational product or procedure.  
United States 21 CFR 312.32 and European Union Clinical Trial Directive 2001/20/EC and the 
associated detailed guidances or national regulatory requirements in participating countries 
require the reporting of SUSARs. Lilly has procedures that will be followed for the 
identification, recording and expedited reporting of SUSARs that are consistent with global 
regulations and the associated detailed guidances.
9.2.2. Adverse Events of Special Interest
Adverse events of special interest will include the following:

Infections (including TB, herpes zoster, or opportunistic infections)

Malignancies

Hepatic events (Section 9.4.7)

Major adverse cardiovascular events (MACE) (Section 9.4.8)

Arterial thrombotic events

Thrombotic events (DVT and PE) (Section 9.4.8.1).
Sites will provide details on these AEs as instructed on the eCRF and may be asked for 
additional description by Lilly.
9.2.3. Complaint Handling
Lilly collects product complaints on investigational products and drug delivery systems used in 
clinical studies in order to ensure the safety of study participants, monitor quality, and to 
facilitate process and product improvements.
Patients will be instructed to contact the investigator as soon as possible if he or she has a 
complaint or problem with the investigational product so that the situation can be assessed.
9.3.
Treatment of Overdose
Refer to the IB.
9.4.
Safety
9.4.1. Electrocardiograms
A single 12-lead standard ECG will be obtained locally at Visit 1 and read by a qualified 
physician (the investigator or qualified designee) at the site to determine whether the patient 
meets entry criteria.
Electrocardiograms may be obtained at additional times, when deemed clinically necessary.


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9.4.2. Vital Signs
For each patient, vital signs measurements should be conducted according to the Schedule of 
Activities (Section 2).  Subjects should be seated and relaxed with both feet on the floor for at 
least 5 minutes prior to taking measurements.
Three replicate blood pressure readings should be made at each time point at approximately 
30- to 60-second intervals.  A single-pulse measurement should be taken simultaneously with at 
least one of the blood pressure readings.  Blood pressure and pulse measurements should be 
made using either automated or manual equipment.  If measurements are machine averaged, the 
average blood pressure reading should be recorded on the CRF.  If measurements are manual or 
the machine does not provide an average reading, then each individual reading should be 
recorded on the CRF.  Measurements should be made before any scheduled blood draws.
Additional measurements of vital signs may be performed at the discretion of the investigator.
Any clinically significant findings from vital signs measurement that result in a diagnosis and 
that occur after the patient receives the first dose of study treatment should be reported to Lilly or 
its designee as an AE via eCRF.
9.4.3. Physical Examination
For each patient, physical examinations will be conducted according to the Schedule of 
Activities (Section 2).  One complete physical examination (excluding pelvic and rectal 
examinations) will be performed at Visit 1 (Screening).  All remaining physical examinations 
throughout the study should include a symptom-directed physical examination.  A complete 
physical examination may be repeated at the investigator’s discretion at any time a patient 
presents with physical complaints.
9.4.4. Laboratory Tests
For each patient, laboratory tests detailed in (Appendix 2) should be conducted according to the 
Schedule of Activities (Section 2).  
With the exception of laboratory test results that may unblind the study, Lilly or its designee will 
provide the investigator with the results of laboratory tests analyzed by a central vendor, if a 
central vendor is used for the clinical trial.  
Any clinically significant findings from laboratory tests that result in a diagnosis and that occur 
after the patient receives the first dose of investigational product should be reported to Lilly or its 
designee as an AE via eCRF.
9.4.5. Chest x-Ray and Tuberculosis Testing
A posterior anterior view chest x ray will be obtained locally at screening (Visit 1), unless results 
from a chest x-ray obtained within 6 months prior to the study are available.  The chest x-ray will 
be reviewed by the investigator or his or her designee to exclude patients with active TB 
infection.  In addition, patients will be tested at screening (Visit 1) for evidence of active or 
latent TB as described in the exclusion criteria, Section 6.2.


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9.4.6. Quick Inventory of Depressive Symptomatology Self-Rated–16
The Quick Inventory of Depressive Symptomatology Self-Rated–16 (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, with higher scores denoting greater symptom severity.  The domains 
assessed by the instrument include sad mood, concentration, self-criticism, suicidal ideation, 
interest, energy/fatigue, sleep disturbance (initial, middle, and late insomnia or hypersomnia), 
decrease/increase in appetite/weight, and psychomotor agitation/retardation.  Additional 
information and the QIDS-SR16 questions may be found on the University of Pittsburgh 
Epidemiology Data Center web site (Inventory of Depressive Symptomatology/Quick Inventory 
of Depressive Symptomatology [WWW]) (Rush et al. 2003; Trivedi et al. 2004).
9.4.7. Hepatic Safety Monitoring
If a study patient with ALT and AST within the normal range at baseline experiences elevated 
transaminases greater than 2x ULN, then a repeat measurement should be performed within 48 -
72 hours.  If elevations greater than 2x ULN persist, then subjects should be evaluated for other 
causes of transaminase elevation and with additional tests of hepatic status.  Close observation 
for suspected DILI will be conducted.  If no other cause is found, then investigational product
should be discontinued (see guidelines in Section 8.1).  
If a study patient with ALT and AST above the normal range at baseline develops further 
elevations of ALT or AST >2x the baseline value or a bilirubin >2x ULN during the study, then 
repeat testing should be performed within 48 - 72 hours.  If there are persistent elevations (ALT 
or AST >2x baseline or bilirubin >2x ULN), then close observation for suspected DILI will be 
conducted.  If no other cause is found, then discontinuation of investigational product should be 
considered (see guidelines in Section 8.1).
The decision to discontinue or temporarily interrupt investigational product should be considered 
based on factors that include how much higher than baseline ALT and AST were relative to the 
upper limit of normal (ULN) and how much the on-study ALT and AST levels have increased 
relative to baseline, in addition to whether there is concomitant elevation of bilirubin or INR (see 
guidelines in Section 8.1).
If the patient lives in a remote area, repeat laboratory testing and close monitoring can be 
performed locally and the results should be promptly communicated to the investigator.
Close Observation for Suspected DILI 

Repeat liver enzyme and serum bilirubin tests two or three times weekly. Frequency of 
repeat testing can decrease to once a week or less if abnormalities stabilize or the trial 
drug has been discontinued and the subject is asymptomatic.

Obtain a more detailed history of symptoms and prior or concurrent diseases.


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
Obtain a history of concomitant drug use (including nonprescription medications and 
herbal and dietary supplement preparations), alcohol use, recreational drug use, and 
special diets.

Rule out acute viral hepatitis types A, B, C, D, and E; autoimmune or alcoholic hepatitis; 
NASH; hypoxic/ischemic hepatopathy; and biliary tract disease.

Obtain a history of exposure to environmental chemical agents.

Obtain additional tests to evaluate liver function, as appropriate (e.g., INR, direct 
bilirubin).  
Follow up testing may include ALT, AST, ALP, TBL, direct bilirubin, gamma-glutamyl 
transferase, and creatine phosphokinase to confirm the abnormality and to determine if it is 
increasing or decreasing.  If the abnormality persists or worsens, clinical and laboratory 
monitoring should be initiated by the investigator and in consultation with the study medical 
monitor.  Monitoring of ALT, AST, TBL, and ALP should continue until levels normalize or 
return to approximate baseline levels.  
Hepatic Safety Data Collection
Additional safety data should be collected via the eCRF if 1 or more of the following conditions 
occur:  

Elevation of serum ALT to ≥5 x ULN for patients with normal/near-normal 
baseline ALT or to ≥5 x baseline value for patients with baseline ALT 
>1.5 x ULN on 2 or more consecutive blood tests

Elevated serum TBL to ≥2 x ULN 

Elevation of serum ALP to ≥2 x baseline value on 2 or more consecutive blood 
tests

Patient discontinued from treatment due to a hepatic event or abnormality of liver 
tests

Hepatic event considered to be a SAE.
9.4.8. Safety Monitoring 
Lilly will periodically review evolving aggregate safety data within the study by appropriate 
methods.
The Lilly designated medical monitor will monitor safety data throughout the course of the 
study.  Lilly will review SAEs within time frames mandated by company procedures.  The Lilly 
designated medical monitor 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 study.  If a death or a 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


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preserve the integrity of the data collected during this trial and minimize any potential for bias
while providing for appropriate safety monitoring.
Investigators will monitor vital signs and carefully review findings that may be associated with 
cardiovascular events.  Adverse event reports and vital signs will be collected at each study visit.
The cardiovascular monitoring plan includes the following:

Regular monitoring of lipid levels

Potential MACE (cardiovascular death, myocardial infarction, and stroke), other
cardiovascular events (such as hospitalization for unstable angina, hospitalization for 
heart failure, serious arrhythmia, resuscitated sudden death, cardiogenic shock, and 
coronary interventions), and noncardiovascular deaths will be identified by the 
investigative site or through medical review and will be sent to a blinded Clinical Event
Committee for adjudication at regular intervals.  
9.4.8.1.
Venous Thromboembolic Event 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 is recommended as outlined in Appendix 5. All suspected DVT or 
PE will be independently adjudicated by a blinded Clinical Event Committee.  
9.4.8.2.
Data Monitoring Committee
A DMC will oversee the conduct of this study. The DMC will consist of members external to 
Lilly. This DMC will be guided by the DMC charter. At a minimum the DMC will include the 
following who have previous DMC experience:

a specialist with expertise in hepatology and

a statistician.  
The DMC will review and evaluate data from the 12 week treatment period from patients in 
Cohort A.
In addition, the DMC may be convened if 2 or more patients permanently discontinue due to 
safety.  The DMC chair will determine if the full DMC needs to convene.  
The DMC chair will have access to all SAEs as reported to regulatory authorities and may 
convene a meeting at any time.
Access to the unblinded interim data will be limited to the statisticians who conduct the interim
analyses and the DMC. The statisticians conducting the interim analyses will be independent
from the study team.  The study team will not have access to the unblinded data. 
Data that the DMC will review include, but are not limited to, reasons for study discontinuation, 
AEs including SAEs, clinical laboratory data and vital signs. The DMC may recommend 
continuation of the study as designed, temporary suspension of enrollment, or discontinuation of 
a particular dose regimen or discontinuation of the entire study. The DMC may request to 
review efficacy data to investigate the benefit/risk relationship in the context of safety 


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observations for ongoing patients in the study. Details of the DMC and interim safety analyses 
will be documented in a DMC charter.
In addition to the DMC members, a limited number of prespecified individuals may gain access
to the unblinded PK, safety, and efficacy data (as specified in the unblinding plan) prior to the
final database lock to initiate the exploration and/or final population of the PK/PD model
development processes.  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.
9.5.
Pharmacokinetics
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 


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9.6.
Pharmacodynamics
 
 
 
 
 
9.7.
Biomarkers
Biomarker research is performed to address questions of relevance to drug disposition, target 


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10. Statistical Considerations
10.1. Sample Size Determination
Approximately 20 patients will be randomized to the baricitinib 2-mg and placebo treatment 
groups for Cohort A.  Twelve patients will be randomly assigned to the 2-mg treatment group 
and 8 patients to the placebo treatment group.  This sample size is appropriate to provide 
sufficient preliminary safety and tolerability information for baricitinib 2-mg dose in patients 
with PBC prior to studying 4-mg baricitinib.
For Cohort B, 32 patients will be randomized to the baricitinib 4-mg and placebo treatment 
groups. Twenty patients will be randomized to the baricitinib 4-mg treatment group and 12 
patients to placebo.  
Overall, 20 patients per group will be assigned to the baricitinib 4-mg and placebo dose groups.  
Based on this sample size, this study will have approximately 81% power to detect a difference 
in ALP change from baseline between baricitinib 4-mg and placebo at Week 12 assuming that 
the true difference is 65 U/L. The sample size was determined based on a 2-sample t-test with 
2-sided alpha level of 0.1 and a standard deviation of 80 U/L for the change from baseline in 
ALP.  The sample size calculation was performed using nQuery® Advisor 7.0 software.
10.2. Populations for Analyses
For purposes of analysis, the following populations are defined:
Population
Description
Enrolled 
All patients who sign informed consent
Randomized
All patients who are randomized at Week 0.
Modified Intent-to-Treat (mITT)
The mITT population is defined as all randomized patients who take at least one 
dose of study treatment.  Patients will be included if they do not receive the 
correct treatment, or otherwise do not follow the protocol.  Subjects will be 
analyzed according to the treatment to which they were randomized.
Safety
The safety population is defined as all randomized patients who receive at least
1 dose of study treatment and who did not discontinue from the study for the 
reason ‘Lost to Follow-up’ at the first postbaseline visit with no safety 
post-baseline data.  Patients will be analyzed according to the treatment to 
which they were randomized.
Additional subpopulations may be identified. Full details will be provided in the study statistical 
analysis plan (SAP).
10.3. Statistical Analyses
10.3.1. General Statistical Considerations
Statistical analysis of this study will be the responsibility of Lilly or its designee.
Unless otherwise specified, the efficacy, health outcomes, and safety analyses will be conducted 
on the modified intent-to-treat (mITT) population.


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All tests of treatment effects will be conducted at a 2-sided alpha level of 0.1, unless otherwise 
stated.  No multiplicity adjustment will be used in this study.
Baseline will be defined as the last available value before the first dose of investigational product 
for both efficacy and safety analyses.  In most cases, this will be the measure recorded at Week 0 
(Visit 3).  Change from baseline will be calculated as the visit value of interest minus the 
baseline value.
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 clinical study report (CSR).  Additional exploratory analyses of the data will be conducted 
as deemed appropriate.
10.3.1.1. Analysis Methods
The primary analysis for all continuous efficacy and health outcomes variables will use a 
mixed-effects models for repeated measures (MMRM) with treatment,
 
  An unstructured covariance matrix will 
be used to model the within-patient variance-covariance errors.  If the unstructured covariance 
matrix results in a lack of convergence, the heterogeneous Toeplitz covariance structure, 
followed by the heterogeneous autoregressive covariance structure will be used.  The 
Kenward-Roger method will be used to estimate the denominator degrees of freedom.  Type III 
sums of squares for the least-squares (LS) means will be used for all the statistical comparisons; 
the 90% confidence interval (CI) will also be reported.  The LS mean difference, standard error, 
p-value, and CIs will also be reported.  Treatment group comparisons at specific study visits will 
be tested using the t-test obtained from the MMRM results.  Additional details of the MMRM 
method are described in Section 10.3.1.2.  
The primary analysis for all categorical efficacy and health outcomes variables will use a logistic 
regression analysis with treatment, cohort,
 
The p-value and 90% (unless otherwise specified) CI for the 
odds ratio from the logistic regression model will be used for primary statistical inference.  When 
logistic regression sample size requirements are not met, (<5 responders in any category for any 
factor), the p-value from the Cochran-Mantel-Haenszel (CMH) test with 
 
as factors will be used instead of the 
odds ratio and CI.  Missing data imputation is described in Section 10.3.1.2.
10.3.1.2. Missing Data Imputation
As with any clinical study, patient dropouts and consequently missing data are expected.  While 
every effort will be made to reduce missing data, the missing data imputation methods described 
below will be used to provide a conservative approach for assessing efficacy endpoints when 
patients have missing data.
The following imputation rules will be used:


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
Last-observed-value-carried forward (LOCF): For analysis of categorical efficacy and 
health outcomes variables, LOCF will be used to assess a patient’s response when data 
are missing at that endpoint.  Randomized subjects without at least 1 postbaseline 
observation will be defined as non-responders for this analysis.

Mixed-model repeated measures (MMRM): For continuous variables, the primary
analysis will be a MMRM analysis with a missing-at-random assumption for handling
missing data.  This analysis takes into account both missingness of data and the
correlation of the repeated measurements. No additional imputation methods will be
applied to the MMRM analysis.  Any observed data after permanent discontinuation of 
investigational product will be excluded from the MMRM analysis.
Full details of these analyses including missing data imputation methods and covariates will be 
provided in the SAP.  Additional sensitivity analyses will be described in the SAP.
10.3.2. Treatment Group Comparability
10.3.2.1. Patient Disposition
All patients who discontinue from the study or the study treatment will be identified, along with 
their reason for discontinuation. Reasons for discontinuation from the study will be summarized 
by treatment group.  
A detailed description of patient disposition will be provided at the end of the study.  
10.3.2.2. Patient Characteristics
Demographic and baseline characteristics will be summarized descriptively by treatment group. 
Descriptive statistics including the number of patients, mean, standard deviation, median, 
minimum, and maximum will be provided for continuous measures, and frequency counts and 
percentages will be tabulated for categorical measures. No formal statistical comparisons will be 
made among treatment groups unless otherwise stated.
10.3.2.3. Concomitant Therapy
Concomitant medications will be descriptively summarized by treatment group in terms of 
frequencies and percentages using the safety population. The medications will be coded 
accordingly.
10.3.2.4. Treatment Compliance 
Treatment compliance with the randomly assigned study medication will be evaluated at every 
clinic visit through the counts of returned investigational product tablets.  A patient will be 
considered significantly noncompliant if he or she misses more than 20% (i.e., compliance 
<80%) 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 medication.


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10.3.3. Efficacy Analyses
10.3.3.1. Primary Analyses
The primary efficacy measure is the change from baseline in ALP at Week 12. An MMRM (as 
described in Section 10.3.1.1) will be used to test the treatment difference between baricitinib 
and placebo.  
10.3.3.2. Secondary Analyses
Secondary efficacy and health outcomes variables will be assessed using the methods stated in 
Sections 10.3.1.1 and 10.3.1.2.  
10.3.4. Safety Analyses
All safety data will be descriptively summarized by treatment groups and analyzed using the 
safety population.
Treatment-emergent adverse event (TEAEs) are defined as AEs that first occurred or worsened 
in severity after the first dose of study treatment. The number of TEAEs as well as the number 
and percentage of patients who experienced at least 1 TEAE will be summarized using the 
Medical Dictionary for Regulatory Activities for each system organ class (or a body system) and 
each preferred term by treatment group. SAEs and AEs that lead to discontinuation of 
investigational product will also be summarized by treatment group. Fisher’s exact test will be 
used to perform comparisons between the baricitinib and placebo groups.
All clinical laboratory results will be descriptively summarized by treatment group. Individual 
results that are outside of normal reference ranges will be flagged in data listings. Quantitative
clinical hematology, chemistry, and urinalysis variables obtained at the baseline to postbaseline
visits will be summarized as changes from baseline by treatment group and analyzed using
analysis of covariance (ANCOVA) with treatment and baseline value in the model. Categorical 
variables, including the incidence of abnormal values and incidence of AEs of special interest, 
will be summarized by frequency and percentage of patients in corresponding categories. Shift 
tables will be presented for selected measures.
Observed values and changes from baseline (predose or screening if missing) for vital signs and
physical characteristics will be descriptively summarized by treatment group and time point.  
Change from baseline to postbaseline in vital signs and body weight will be analyzed using 
ANCOVA with treatment and baseline value in the model.
The incidence and average duration of investigational product interruptions will be summarized 
and compared descriptively among treatment groups. Further analyses may be performed and 
will be planned in the SAP.
10.3.5. Pharmacokinetic/Pharmacodynamic Analyses
All plasma baricitinib concentration-time data will be pooled and evaluated using population PK 
methods.  A covariate screen of patient and study-specific factors will be included in the analyses 
based on factors investigated in previous and (if any) ongoing PK analyses, and on their 
relevance to the target population.  Exploratory and/or model-based analyses, examining the 


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relationships between baricitinib exposure and efficacy and response endpoints will be 
conducted.  Other analyses of efficacy and safety outcome measures may also be assessed as 
scientifically appropriate and warranted by available data.  Details about the analyses to be 
conducted will be contained in the PK/PD analysis plan.
10.3.6. Other Analyses
Not Applicable.
10.3.6.1. Subgroup Analyses 
Not Applicable.
10.3.7. Interim Analyses
A limited number of preidentified individuals may gain access to the limited unblinded data, as 
specified in the unblinding plan, prior to the final database lock, in order to initiate the final 
population PK/PD model development processes for final analyses.  Information that may 
unblind the study during the analyses will not be reported to study sites or blinded study team 
until the study has been unblinded; this applies to Cohort A and Cohort B.
Data from patients in Cohort A will be summarized after all the patients have completed the 
study.  These data will be available to Lilly and the DMC.  No additional interim analyses are 
planned.  
Unblinding details are specified in the unblinding plan section of the SAP or a separate 
unblinding plan document.


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12.
Appendices


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Appendix 1.
Abbreviations and Definitions
Term
Definition
AASLD
American Association for the Study of Liver Disease
AD
atopic dermatitis
AE
adverse event:  Any untoward medical occurrence in a patient or clinical investigation 
subject administered a pharmaceutical product that does not necessarily have a causal 
relationship with this treatment.  An adverse event can therefore be any unfavorable and 
unintended sign (including an abnormal laboratory finding), symptom, or disease 
temporally associated with the use of a medicinal (investigational) product, whether or 
not related to the medicinal (investigational) product.
ALP
alkaline phosphatase
ALT
alanine aminotransferase
ANA
antinuclear antibody
ANC
absolute neutrophil count
ANCOVA
analysis of covariance
AST
aspartate aminotransferase
blinding
A single-blind study is one in which the investigator and/or his staff are aware of the 
treatment but the patient is not, or vice versa, or when the sponsor is aware of the 
treatment but the investigator and/his staff and the patient are not.
A double-blind study is one in which neither the patient nor any of the investigator or 
sponsor staff who are involved in the treatment or clinical evaluation of the subjects are 
aware of the treatment received.
CANDLE
Chronic Atypical Neutrophilic Dermatosis With Lipodystrophy and Elevated 
Temperatures
CI
confidence interval
CIOMS
Council for International Organizations of Medical Sciences
CK-18
cytokeratin 18
CMH
Cochran-Mantel-Haenszel
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 study-related, good clinical practice (GCP), and applicable regulatory 
requirements.
CRP
C-reactive protein
DN
diabetic nephropathy
DNA
deoxyribonucleic acid
DVT
deep vein thrombosis
EASL
European Association for Study of the Liver
ECG
electrocardiogram
eCRF
electronic case report form
eGFR
estimated glomerular filtration rate
ELF
enhanced liver fibrosis
enroll
The act of assigning a patient to a treatment.  Patients who are enrolled in the study are 
those who have been assigned to a treatment.
enter
Patients entered into a study are those who sign the informed consent form directly or 
through their legally acceptable representatives.
FACIT-F
Functional Assessment of Chronic Illness Therapy-Fatigue
FGF
fibroblast growth factor
GCP
good clinical practice
HBcAb
hepatitis B core antibody


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HBsAb
hepatitis B surface antibody 
HBsAg
hepatitis B surface antigen
HBV
hepatitis B virus
HCV
hepatitis C virus
HIV
human immunodeficiency virus
hsCRP
high-sensitivity C-reactive protein
IB
Investigator’s Brochure
ICF
informed consent form
ICH
International Council for Harmonisation
IFN
interferon
IgG
immunoglobulin G
IgM
immunoglobulin M
IGRA
interferon-gamma release assay
IL
interleukin
Informed consent
A process by which a patient voluntarily confirms his or her willingness to participate 
in a particular study, after having been informed of all aspects of the study that are 
relevant to the patient’s decision to participate.  Informed consent is documented by 
means of a written, signed and dated informed consent form.
INR
International Normalized Ratio
interim analysis
An interim analysis is an analysis of clinical study data, separated into treatment groups, 
that is conducted before the final reporting database is created/locked.
investigational 
product
A pharmaceutical form of an active ingredient or placebo being tested or used as a 
reference in a clinical trial, including products already on the market when used or 
assembled (formulated or packaged) in a way different from the authorized form, or 
marketed products used for an unauthorized indication, or marketed products used to 
gain further information about the authorized form.
IRB/ERB
institutional review board /ethics review board
ITT
intention to treat:  The principle that asserts that the effect of a treatment policy can be 
best assessed by evaluating on the basis of the intention to treat a patient (that is, the 
planned treatment regimen) rather than the actual treatment given.  It has the 
consequence that patients allocated to a treatment group should be followed up, 
assessed, and analyzed as members of that group irrespective of their compliance to the 
planned course of treatment.
IV
intravenous 
IWRS
interactive web-response system
JAK
Janus kinase
LOCF
last-observed-value-carried forward
LS mean
least squares mean
MELD
Model for End Stage Liver Disease
mITT
modified intent-to-treat
MMRM
mixed-effects models for repeated measures
NRI
nonresponder imputation
NRS
Numeric Rating Scale
PBC
primary biliary cholangitis
PBC-40
Quality of Life for Primary Biliary Cirrhosis
PE
pulmonary embolism
PK/PD
pharmacokinetics/pharmacodynamics
PPD
purified protein derivative
PTM
placebo to match
QD
once daily
QIDS-SR16
Quick Inventory of Depressive Symptomatology
RA
rheumatoid arthritis
RNA
ribonucleic acid
SAE
serious adverse event


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SAP
statistical analysis plan
screen
The act of determining if an individual meets minimum requirements to become part of 
a pool of potential candidates for participation in a clinical study.  
SoC
Standard of care
SAVI
stimulator of interferon genes-associated vasculopathy with onset in infancy
SLE
systemic lupus erythematosus
STAT
signal transducers and activators of transcription
SUSARs
suspected unexpected serious adverse reactions
TB
tuberculosis
TBL
total bilirubin level
TEAE
Treatment-emergent adverse event:  An untoward medical occurrence that emerges 
during a defined treatment period, having been absent pretreatment, or worsens relative 
to the pretreatment state, and does not necessarily have to have a causal relationship 
with this treatment.
TNF
Tumor necrosis factor
TSH
thyroid-stimulating hormone
TST
tuberculin skin test
TYK
tyrosine kinase
UDCA
ursodeoxycholic acid
ULN
upper limit of normal
VAS
visual analog scale
VTE
venous thromboembolic events
WBC
white blood cell


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Appendix 2.
Clinical Laboratory Tests
Clinical Laboratory Tests
Hematologya
Clinical Chemistrya,b
Hemoglobin
Serum Concentrations of:
Hematocrit
Sodium
Erythrocyte count (RBC)
Potassium
Mean cell volume
Total bilirubin
Mean cell hemoglobin concentration
Direct bilirubin
Leukocytes (WBC)
Alkaline phosphatase (ALP)
Neutrophils, segmented
Alanine aminotransferase (ALT)
Lymphocytes
Aspartate aminotransferase (AST)
Monocytes
Blood urea nitrogen (BUN)
Eosinophils
Creatinine
Basophils
Uric acid
Platelets
Calcium
Mean Platelet Volume
TSH
INR (prothrombin time)c
Glucosed
ESR
Albumin
Creatine phosphokinase (CPK)
Urinalysisa
Specific gravity
Markers
pH
IgM, IgG, IgA
Protein
CRP
Glucose
FGF 19
Ketones
CK-18 M30
Blood
CK-18 M65
Urine leukocyte esterase
Cytokine Panel
Hepatitis Serology
IL-1 beta
HBsAgc, HBcAbc, HBsAbc
IL-2
HCV antibodyc
IL-4
HIV serologyc
IL-6
ANAc and ASMAc
IL-8
IL-10
Lipid Profiled
IL-12 (p70)
Total Cholesterol
IL-13
High-density lipoprotein
TNF alpha
Low-density lipoprotein
IFN gamma
Triglycerides
ELF
Pregnancy Test (females only)e
Hyaluronic acid (HA)
Procollagen type III amino N-terminal peptide (P3NP)
Alkaline Phosphatase Isoenzymesf
Tissue inhibitor of metalloproteinase 1 (TIMP-1)


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Abbreviations:  ANA = antinuclear antibody; ASMA = antismooth muscle antibody; CK= cytokeratin; CRP = C 
reactive protein; ELF = enhanced liver fibrosis; ESR = erythrocyte sedimentation rate; FGF = fibroblast growth 
factor; HBcAb = hepatitis B core antibody; HBsAb = hepatitis B surface antibody test; HBsAg = hepatitis B 
surface antigen; HBV DNA = hepatitis B virus deoxyribonucleic acid; HCV antibody = hepatitis C virus 
antibody; HIV = human immunodeficiency virus; IFN = interferon; Ig = Immunoglobulin; IL = interleukin; INR 
= International Normalized Ratio.; RBC = red blood cells; TNF = tumor necrosis factor; TSH = thyroid 
stimulating hormone; WBC = white blood cells.
a
All laboratories will be assayed/calculated by a Lilly-designated laboratory unless otherwise noted.
b
Refer to the Schedule of Activities:  Abbreviated chemistry includes total bilirubin, direct bilirubin, ALT, BUN, 
and serum creatinine.
c
Only at screening visit.
d
Fasting laboratory values for glucose and lipids will be required at baseline and Week 12.  Patients should not eat 
or drink anything except water for 12 hours prior to test.  Lipid panel consists of direct HDL-C, triglycerides, 
cholesterol, and LDL-C (calculation from Friedewald et al. 1972).
e
For all women of child-bearing potential, a serum pregnancy test (central laboratory) will be performed at 
Visit 1.  Urine pregnancy tests (local laboratory) will also be performed at each subsequent study visit per the 
Schedule of Activities.
f  Assayed by Lilly-designated laboratory.


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Appendix 3.
Study Governance Considerations
Appendix 3.1.
Regulatory and Ethical Considerations, Including the 
Informed Consent Process
Appendix 3.1.1.
Informed Consent
The investigator is responsible for:

ensuring that the patient understands the nature of the study, the potential risks 
and benefits of participating in the study, and that their participation is voluntary.

ensuring that informed consent is given by each patient or legal representative.  
This includes obtaining the appropriate signatures and dates on the informed 
consent form (ICF) prior to the performance of any protocol procedures and prior 
to the administration of investigational product.

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 study.

ensuring that a copy of the ICF is provided to the participant or the participant’s 
legal representative and is kept on file.

ensuring that the medical record includes a statement that written informed 
consent was obtained before the participant was enrolled in the study and the date 
the written consent was obtained. The authorized person obtaining the informed 
consent must also sign the ICF.  
Appendix 3.1.2.
Recruitment
Lilly or its designee is responsible for the central recruitment strategy for patients.  Individual 
investigators may have additional local requirements or processes.
Investigator(s) will be responsible for subject recruitment through local requirements or 
processes.  
Appendix 3.1.3.
Ethical Review
The investigator or an appropriate local representative must give assurance that the ethical 
review board (ERB) was properly constituted and convened as required by International Council
for Harmonization (ICH) guidelines and other applicable laws and regulations.
Documentation of ERB approval of the protocol and the ICF must be provided to Lilly before the 
study may begin at the investigative site(s).  Lilly or its representatives must approve the ICF, 
including any changes made by the ERBs, before it is used at the investigative site(s).  All ICFs 
must be compliant with the ICH guideline on Good Clinical Practice (GCP).
The study site’s ERB(s) should be provided with the following:


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
the protocol and related amendments and addenda, current Investigator Brochure 
(IB) and updates during the course of the study

informed consent form 

other relevant documents (for example, curricula vitae, advertisements)
Appendix 3.1.4.
Regulatory Considerations
This study will be conducted in accordance with the protocol and with the:

consensus ethics principles derived from international ethics guidelines, including 
the Declaration of Helsinki and Council for International Organizations of
Medical Sciences (CIOMS) International Ethical Guidelines

applicable ICH GCP Guidelines

applicable laws and regulations
Some of the obligations of the sponsor will be assigned to a third party.
Appendix 3.1.5.
Investigator Information
Physicians with a specialty in gastroenterology or hepatology will participate as investigators in 
this clinical trial.
Appendix 3.1.6.
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.
Appendix 3.1.7.
Final Report Signature
The CSR coordinating investigator will sign the final CSR for this study, indicating agreement 
that, to the best of his or her knowledge, the report accurately describes the conduct and results 
of the study.
The sponsor’s responsible medical officer and statistician will approve the final CSR for this 
study, confirming that, to the best of their knowledge, the report accurately describes the conduct 
and results of the study.
Appendix 3.2.
Data Quality Assurance
To ensure accurate, complete, and reliable data, Lilly or its representatives will do the following:

provide instructional material to the study sites, as appropriate

sponsor start-up training to instruct the investigators and study coordinators.  This 
training will give instruction on the protocol, the completion of the eCRFs, and 
study procedures.


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
make periodic visits to the study site

be available for consultation and stay in contact with the study site personnel by 
mail, telephone, and/or fax

review and verify data reported to detect potential errors
In addition, Lilly or its representatives will 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.
The investigator will keep records of all original source data.  This might include laboratory 
tests, medical records, and clinical notes.  If requested, the investigator will provide the sponsor, 
applicable regulatory agencies, and applicable ERBs with direct access to original source 
documents.
Appendix 3.2.1.
Data Capture System
The investigator is responsible for ensuring the accuracy, completeness, legibility, and timeliness 
of the data reported to the sponsor.  
An electronic data capture system (EDC) will be used in this study for the collection of CRF 
data.  The investigator maintains a separate source for the data entered by the investigator or 
designee into the sponsor-provided EDC system.  The investigator is responsible for the 
identification of any data to be considered source and for the confirmation that data reported are 
accurate and complete by signing the CRF.
Additionally, clinical outcome assessment (COA) data (questionnaires, scales, rating scales etc.) 
will be collected by the patient and investigator site personnel, via a paper source document and 
will be transcribed by the investigator site personnel into the EDC system.
Data collected via the sponsor-provided data capture system will be stored at a third-party.  The 
investigator will have continuous access to the data during the study and until decommissioning 
of the data capture system.  Prior to decommissioning, the investigator will receive an archival 
copy of pertinent data for retention.
Data managed by a central vendor, such as laboratory test data, will be stored electronically in 
the central vendor’s database system and reports/electronic transfers will be provided to the 
investigator for review and retention.  Data will subsequently be transferred from the central 
vendor to the Lilly data warehouse.
Data from complaint forms submitted to Lilly will be encoded and stored in the global product 
complaint management system.


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Appendix 3.3.
Study and Site Closure
Appendix 3.3.1.
Discontinuation of Study Sites
Study site participation may be discontinued if Lilly, the investigator, or the ERB of the study 
site judges it necessary for medical, safety, regulatory, or other reasons consistent with 
applicable laws, regulations, and GCP.
Appendix 3.3.2.
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.
Appendix 3.4.
Publication Policy
The publication policy for Study F1K-MC-JAIV is described in Clinical Trial Agreement.


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Appendix 4.
Hepatic Monitoring Tests for 
Treatment-Emergent Abnormality
Selected tests may be obtained in the event of a treatment-emergent hepatic abnormality and may 
be required in follow-up with patients in consultation with the Lilly, or its designee, 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
Alkaline Phosphatase Isoenzymesa
CPK
Anti-smooth muscle antibody (or anti-actin 
antibody)a
Abbreviations:  ALT = alanine aminotransferase; AST = aspirate aminotransferase; CPK = creatinine 
phosphokinase; GGT = gamma-glutamyl transferase; Ig = immunoglobulin; INR = International Normalized 
Ratio; RBC = red blood cells; WBC = white blood cells.
a
Assayed by Lilly-designated or local laboratory.
b
Reflex/confirmation dependent on regulatory requirements and/or testing availability.


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Appendix 5.
Monitoring Tests for Confirmed VTE
Selected tests may be obtained in the event of a confirmed venous thromboembolic event (VTE) 
and may be required in follow-up with patients in consultation with Eli Lilly and Company, its 
designee, or the designated medical monitor.  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.
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; MTHFR = methylene 
tetrahydrofolate reductase; PT = prothrombin time; PTT = partial thromboplastin time.


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Appendix 6.
Protocol Amendment History
Overview
Protocol I4V-MC-JAIV, A Randomized, Double Blind, Placebo Controlled, Proof of Concept 
Study Evaluating the Efficacy and Safety of Baricitinib (LY3009104) in Patients with Primary 
Biliary Cholangitis Who Have an Inadequate Response or Are Intolerant to UDCA, has been 
amended.  The new protocol is indicated by amendment (b) and will be used to conduct the study 
in place of any preceding version of the protocol.
The overall changes and rationale for the changes made to this protocol are described in the 
following table:
Section # and Name
Description of Change
Brief Rationale
Section 6. Study Population
Added a note on number system 
used for inclusion and exclusion 
criteria 
To avoid confusion for the reader 
who may think there has been a 
mistake with numbering.
Section 6.2 Exclusion Criteria
Exclusion Criterion 8c
Added clarifying language that 
cirrhosis should include 
complications
Without this language the reader 
could interpret this as cirrhosis 
without complications was an 
exclusion criterion – it is not.
Section 7.2 Method of Treatment 
Assignment
Changed method from stratification 
to dynamic minimization
The method was changed to increase 
the likelihood of balanced 
randomization.
Section 8.1.2 Permanent 
Discontinuation from Study 
Treatment
Added the discontinuation criterion 
of eGFR ≤40mL/min/1.73m2
The study team intended for this to 
be added in amendment (a); 
however, it was inadvertently not 
included.
Throughout
Minor editorial changes
Changes made for clarity.
The following section includes content changes to Protocol JAIV. The following section does 
not include minor edits to grammar, capitalization, and formatting.


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Revised Protocol Sections
Note:
Deletions have been identified by strikethroughs.
Additions have been identified by the use of underscore.
6.
Study Population
Note: The numbering system used for inclusion and exclusion criteria provides a unique number 
for each criterion which is maintained in the case of a protocol amendment. Specifically, if a 
criterion removed as a result of an amendment, the number and the criterion will be removed and 
will not be reused.  If an amendment to the protocol adds a criterion, that criterion will receive 
the next available number, regardless of where it is located in the list.  
6.2.
Exclusion Criteria
Medical Conditions
[8]
Presence of clinical complications of PBC or clinically significant hepatic 
decompensation, including:
c.
Cirrhosis with complication, i.e., decompensated cirrhosis, including history 
or presence of one or more of the following:  

spontaneous bacterial peritonitis

hepatocellular carcinoma

hepatorenal or hepatopulmonary syndrome
d. Hepatorenal syndrome (type I or II)
7.2.
Method of Treatment Assignment
 
 
  
8.1.2.
Permanent Discontinuation from Study Treatment
Discontinuation due to other laboratory abnormalities:

White blood cell count <1000 cells/L (1.00 x 103/L or 1.00 GI/L)

Absolute neutrophil count <500 cells/L (0.50 x 103/L or 0.50 GI/L)

Lymphocyte count <200 cells/L (0.20 x 103/L or 0.20 GI/L)

Hemoglobin <6.5 g/dL (<65.0 g/L)

Creatine phosphokinase >5x ULN

eGFR ≤40mL/min/1.73m2.

SAP_001.pdf: 
I4V-MC-JAIV Statistical Analysis Plan   
 
I4V-MC-JAIV: A Randomized, Double-Blind, Placebo-Controlled, Proof-of-Concept Study 
Evaluating the Efficacy and Safety of Baricitinib (LY3009104) in Patients with Primary Biliary 
Cholangitis Who Have an Inadequate Response or Are Intolerant to UDCA 
 
NCT03742973 
 
Approval Date: 14-May-2019 
 
 
 


I4V-MC-JAIV Statistical Analysis Plan Version 1
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LY3009104
1.
Statistical Analysis Plan:  
I4V-MC-JAIV:  A Randomized, Double-Blind, 
Placebo-Controlled, Proof-of-Concept Study Evaluating 
the Efficacy and Safety of Baricitinib (LY3009104) in 
Patients with Primary Biliary Cholangitis Who Have an 
Inadequate Response or Are Intolerant to UDCA
Confidential Information
The information contained in this document is confidential and the information contained 
within it may not be reproduced or otherwise disseminated without the approval of 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) Primary Biliary Cholangitis
Study I4V-MC-JAIV (JAIV) is a proof-of-concept, Phase II, multicenter, randomized, double-
blind, parallel, placebo-controlled study to evaluate the safety and efficacy of baricitinib 2-
mg and 4-mg compared to placebo in adult patients with primary biliary cholangitis (PBC) 
who have an inadequate response or are intolerant to UDCA.  
Eli Lilly and Company
Indianapolis, Indiana USA 46285
Protocol I4V-MC-JAIV
Phase II
Statistical Analysis Plan electronically signed and approved by Lilly on date provided 
below.
Approval Date: 14-May-2019 GMT


I4V-MC-JAIV Statistical Analysis Plan Version 1
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2.
Table of Contents
Section
Page
1.
Statistical Analysis Plan:   I4V-MC-JAIV:  A Randomized, 
Double-Blind, Placebo-Controlled, Proof-of-Concept Study 
Evaluating the Efficacy and Safety of Baricitinib (LY3009104) in 
Patients with Primary Biliary Cholangitis Who Have an Inadequate 
Response or Are Intolerant to UDCA..................................................................................1
2.
Table of Contents................................................................................................................2
3.
Revision History .................................................................................................................6
4.
Study Objectives.................................................................................................................7
4.1.
Primary Objective ..........................................................................................................7
4.2.
Secondary Objectives.....................................................................................................8
5.
Study Design.......................................................................................................................9
5.1.
Summary of Study Design..............................................................................................9
5.2.
Determination of Sample Size ........................................................................................9
5.3.
Method of Assignment to Treatment ............................................................................10
6.
A Priori Statistical Methods ..............................................................................................11
6.1.
General Considerations ................................................................................................11
6.1.1.
Analysis Populations............................................................................................11
6.1.2.
Definition of Baseline and Postbaseline Measures................................................12
6.1.3.
Analysis Methods.................................................................................................12
6.2.
Covariate Adjustment...................................................................................................13
6.3.
Handling of Dropouts or Missing Data.........................................................................14
6.3.1.
Last Observation Carried Forward........................................................................14
6.3.2.
Mixed Model for Repeated Measures...................................................................14
6.3.3.
Nonresponder Imputation.....................................................................................15
6.4.
Multicenter Studies ......................................................................................................15
6.5.
Multiple Comparisons/Multiplicity...............................................................................15
6.6.
Patient Disposition .......................................................................................................15
6.7.
Patient Characteristics ..................................................................................................16
6.7.1.
Historical Illness and Pre-existing Conditions ......................................................18
6.8.
Treatment Compliance .................................................................................................18
6.9.
Concomitant and Previous Therapy..............................................................................19
6.10. Efficacy Analyses ........................................................................................................19
6.10.1.
Primary Outcome and Methodology.....................................................................23
6.10.2.
Secondary Efficacy Analyses ...............................................................................23
6.10.3.
Supplementary Analyses ......................................................................................23


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6.11. Health Outcomes/Quality-of-Life Analyses..................................................................23
6.12. Bioanalytical and Pharmacokinetic/Pharmacodynamic Methods...................................28
6.13. Safety Analyses............................................................................................................28
6.13.1.
Extent of Exposure...............................................................................................29
6.13.2.
Adverse Events ....................................................................................................29
6.13.3.
Deaths, Other Serious Adverse Events, and Other Notable 
Adverse Events ....................................................................................................30
6.13.4.
Adverse Events of Special Interest .......................................................................30
6.13.4.1.
Abnormal Hepatic Tests .................................................................................30
6.13.4.2.
Hematologic Changes.....................................................................................31
6.13.4.3.
Lipid Effects...................................................................................................32
6.13.4.4.
Renal Function Effects ...................................................................................32
6.13.4.5.
Evaluations in Creatine Phosphokinase (CPK)................................................33
6.13.4.6.
Infections........................................................................................................33
6.13.4.7.
Major Adverse Cardiovascular Events (MACE) and 
Other Cardiovascular Events...........................................................................34
6.13.4.8.
Venous and Pulmonary Artery Thromboembolic (VTE) 
Events ............................................................................................................35
6.13.4.9.
Arterial Thromboembolic (ATE) Events.........................................................35
6.13.4.10. Malignancies ..................................................................................................36
6.13.4.11. Allergic Reactions/Hypersensitivities .............................................................36
6.13.4.12. Gastrointestinal Perforations...........................................................................37
6.13.4.13. Depression and Suicide...................................................................................37
6.13.5.
Clinical Laboratory Evaluation.............................................................................38
6.13.6.
Vital Signs and Other Physical Findings...............................................................38
6.14. Subgroup Analyses.......................................................................................................39
6.15. Protocol Violations.......................................................................................................39
6.16. Interim Analyses and Data Monitoring.........................................................................40
6.16.1.
Interim Analysis Plan...........................................................................................40
6.17. Planned Exploratory Analyses......................................................................................41
6.18. Annual Report Analyses...............................................................................................41
6.19. Clinical Trial Registry Analyses...................................................................................41
7.
Unblinding Plan................................................................................................................42
8.
References ........................................................................................................................43


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Table of Contents
Table
Page
Table JAIV.4.1. Primary Objective and Endpoint ......................................................................7
Table JAIV.4.2. Secondary Objectives and Endpoints ...............................................................8
Table JAIV.6.1. Patient Characteristics....................................................................................17
Table JAIV.6.2. Description and Derivation of Primary and Secondary Efficacy 
Outcomes ......................................................................................................21
Table JAIV.6.3. Description of Primary and Secondary Efficacy Analyses..............................22
Table JAIV.6.4. Description and Derivation of Health Outcomes and Quality-of-Life 
Measures .......................................................................................................24
Table JAIV.6.5. Description of Health Outcomes and Quality-of-Life Measures 
Analyses........................................................................................................27
Table JAIV.6.6. Definition of Analysis Sets ............................................................................28
Table JAIV.6.7. Summary Tables Related to Adverse Events..................................................30
Table JAIV.6.8. Summary Tables and Figures Related to Hepatic Safety ................................31
Table JAIV.6.9. Summary Tables Related to Hematologic Changes ........................................32
Table JAIV.6.10. Summary Tables Related to Lipid Effects......................................................32
Table JAIV.6.11. Summary Tables Related to Effects on Renal Function..................................33
Table JAIV.6.12. Summary Tables Related to Effects on Renal Function..................................33
Table JAIV.6.13. Summary Tables Related to Infections...........................................................34
Table JAIV.6.14. Summary Tables Related to MACE and Other Cardiovascular Events ...........35
Table JAIV.6.15. Summary Tables Related to VTE Events .......................................................35
Table JAIV.6.16. Summary Tables Related to ATE Events .......................................................36
Table JAIV.6.17. Summary Tables Related to Malignancies .....................................................36
Table JAIV.6.18. Summary Tables Related to Allergic Reactions/Hypersensitivities.................37
Table JAIV.6.19. Summaries Related to Depression and Suicide...............................................37
Table JAIV.6.20. Summary Tables Related to Clinical Laboratory Evaluations.........................38
Table JAIV.6.21. Summary Tables Related to Vital Signs.........................................................39


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Table of Contents
Figure
Page
Figure JAIV.5.1. Illustration of study design for Clinical Protocol I4V-MC-JAIV. .....................9


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3.
Revision History
Statistical Analysis Plan (SAP) Version 1 is based on Protocol I4V-MC-JAIV(b) and was 
approved prior to unblinding.  


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4.
Study Objectives
4.1.
Primary Objective
The primary objective of Study I4V-MC-JAIV (JAIV) is:
Table JAIV.4.1.
Primary Objective and Endpoint
Objectives
Endpoints

To evaluate the effect of baricitinib 4-mg QD 
compared to placebo on PBC disease

Change from baseline in ALP at Week 12
Abbreviations:  ALP = alkaline phosphatase; PBC = primary biliary cholangitis; QD = once daily.
According to ICH E9R1 guidelines, the objectives of a study should be translated into precise 
definition of estimands.  Estimands are defined using the following four attributes:

The population of interest consists of the patients targeted by the scientific question;

The variable (or endpoint) of evaluation that is obtained for each patient, required to 
address the scientific question; 

The population-level summary of variable, a basis for treatment evaluation;

The specification of how to account for intercurrent events to reflect the scientific 
question of interest. 
In particular, for Study JAIV, the estimands are defined by:

Population:  The population of interest is patients with primary biliary cholangitis (PBC)
who have had an inadequate response or intolerance to ursodeoxycholic acid (UDCA).  
Analysis populations are defined in Section 6.1.1.  The analysis population corresponding 
to each of the efficacy and health outcome endpoints is specified in Table JAIV.6.3 and 
Table JAIV.6.5.

Variables:  The primary endpoint/variable is listed in Table JAIV.4.1 and secondary 
endpoints/variables are listed in Table JAIV.4.2.  A full list of efficacy and health 
outcome endpoints/variables is given in Table JAIV.6.2 and Table JAIV.6.4.

Population-level Summary:  The summary measure for binary variables will be 
proportion and the summary measure for continuous variables will be average.  The 
primary comparison of interest will be the difference of proportions between baricitinib 
dose groups and placebo.  Details are given in Section 6.7.

Intercurrent Event(s) Strategy:  Intercurrent events are defined as certain events occurring 
during the course of the study which complicate the interpretation of the treatment 
effects, such as treatment discontinuation and death.  Intercurrent events will be handled 
by the while-on-treatment strategy and the hypothetical strategy approaches as primary 
strategies. For the while-on treatment strategy, the variable of interest is the response 
prior to the occurrence of the event, i.e., while the subject was on treatment, whereas the 


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hypothetical strategy aims to estimate the effect in the hypothetical situation that all the 
patients continue in the study to the time point of interest and adhere to their randomized 
treatment for the entire time.  The composite strategy, which incorporates the occurrence 
of an intercurrent event as a component of the response of interest, will also be used in 
supplementary analysis.  An example of composite strategy might be if early treatment 
discontinuation is considered a form of treatment failure. Specific statistical methods to 
be used for handling intercurrent events under different strategies are described in Section 
6.3.  Statistical methods corresponding to each of the efficacy and health outcome 
variables are summarized in Table JAIV.6.2 and Table JAIV.6.4.
4.2.
Secondary Objectives
The secondary objectives of the study are the following:
Table JAIV.4.2.
Secondary Objectives and Endpoints
Objectives
Endpoints

To evaluate the effect of baricitinib 4-mg QD 
compared to placebo on PBC disease

Proportion of patients with ALP <1.67 x ULN
(and at least 15% decrease from baseline) and 
total bilirubin<ULN at Week 12

To evaluate the effect of baricitinib 2-mg QD 
compared to placebo on PBC disease

Change from baseline in ALP at Week 12

Proportion of patients with ALP<1.67 x ULN 
(and at least 15% decrease from baseline) and 
total bilirubin < ULN at Week 12

To evaluate the effect of baricitinib 4-mg and 
2-mg QD compared to placebo on PBC 
symptoms

Change from baseline in itch as measured by 
Itch NRS at Week 12

Change from baseline in fatigue as measured 
by Fatigue NRS at Week 12
Abbreviations:  ALP = alkaline phosphatase; NRS = Numeric Rating Scale; PBC = primary biliary cholangitis; 
QD = once daily; ULN = upper limit of normal.


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5.
Study Design 
5.1.
Summary of Study Design
Study JAIV is a multicenter, randomized, double-blind, parallel, placebo-controlled, 
proof-of-concept, Phase II study in patients with primary biliary cholangitis (PBC) who have an 
inadequate response or are intolerant to UDCA.  The study will be conducted in 2 cohorts.  
Cohort A will randomize patients to placebo and baricitinib 2-mg.  Cohort B will randomize 
patients to placebo and baricitinib 4-mg.  Enrollment in Cohort B will begin only after the data 
monitoring committee (DMC) review of Cohort A is complete and Lilly has received and 
accepted a recommendation to proceed.  Both cohorts will follow the same study schedule.
Figure JAIV.5.1 illustrates the study design.
Abbreviations:  V = Visit; W = Week.
a  Patients able to tolerate ursodeoxycholic acid (UDCA) will take UDCA orally as 
background therapy during the study.  
Figure JAIV.5.1.
Illustration of study design for Clinical Protocol I4V-MC-JAIV.  
  Patients in Cohort A and Cohort B will follow the same study schedule 
as outlined in this figure.  Cohort A will randomize 12 patients to
baricitinib 2-mg and 8 patients to placebo.  After a DMC review of 
Cohort A data, Cohort B will then randomize 20 patients to baricitinib 4-
mg and 12 patients to placebo.
5.2.
Determination of Sample Size
Approximately 20 patients will be randomized to the baricitinib 2-mg and placebo treatment 
groups for Cohort A.  Twelve patients will be randomly assigned to the 2-mg treatment group 
and 8 patients to the placebo treatment group.  This sample size is appropriate to provide 


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sufficient preliminary safety and tolerability information for baricitinib 2-mg in patients with 
PBC prior to studying 4-mg baricitinib.
For Cohort B, 32 patients will be randomized to the baricitinib 4-mg and placebo treatment 
groups.  Twenty patients will be randomized to the baricitinib 4-mg treatment group and 
12 patients to placebo.  
Overall, 20 patients per group will be assigned to the baricitinib 4-mg (Cohort B) and placebo 
(Cohorts A and B) dose groups.  Based on this sample size, this study will have approximately 
81% power to detect a difference in ALP change from baseline between baricitinib 4-mg and 
placebo at Week 12 assuming that the true difference is 65 U/L.  The sample size was 
determined based on a 2-sample t-test with 2-sided alpha level of 0.1 and a standard deviation of 
80 U/L for the change from baseline in ALP.  The sample size calculation was performed using 
nQuery® Advisor 7.0 software.
5.3.
Method of Assignment to Treatment
 
 
Assignment to treatment groups will be determined by a computer-generated random sequence 
using an interactive web-response system (IWRS).  The IWRS will be used to assign 
double-blind investigational product to each patient.  Site personnel will confirm that they have 
located the correct package by entering a confirmation number found on the package into 
the IWRS.


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6.
A Priori Statistical Methods
6.1.
General Considerations
This plan describes a priori statistical analyses for efficacy, health outcome, and safety that will 
be performed.  
Statistical analysis of this study will be the responsibility of Eli Lilly and Company (Lilly) or its 
designee.  The statistical analyses will be performed using SAS
® Version 9.4 or a more recent 
version. 
Not all displays described in this SAP will necessarily be included in the clinical study report 
(CSR).  Not all displays will necessarily be created as a “static” display.  Some may be 
incorporated into interactive display tools instead of or in addition to a static display.  Any 
display described in this SAP and not included in the CSR would be available upon request.
Incidence rates and 95% confidence interval (CI) will be displayed for select safety endpoints.
Statistical tests of treatment effects and CIs will be performed at a 2-sided significance level of 
0.1, unless otherwise stated. No multiplicity adjustment will be used in this study.  
Data collected at early termination visits will be mapped to the next scheduled visit number for 
that patient if it falls within the visit window.  For by-visit summaries, only visits in which a 
measure was scheduled to be collected will be summarized.  Any unscheduled visit data will be 
included at the patient-level listings.  However, the data will be included in other analyses, 
including shift analyses for safety analytes, change from baseline to endpoint using last
observation carried forward (LOCF) analyses, and other categorical analyses.
6.1.1. Analysis Populations
Modified intent-to-treat (mITT) population: The mITT population is defined as all 
randomized patients who take at least 1 dose of investigational product
Safety population: The safety population is defined as all randomized patients who receive at 
least 1 dose of investigational product and who did not discontinue from the study for the reason 
“lost to follow-up” at the first postbaseline visit.
Unless otherwise specified, the efficacy and health outcome analyses will be conducted on the 
mITT population. Patients will be analyzed according to the treatment to which they were 
randomized.  The analysis populations will include patients from both Cohort A and Cohort B.
Concomitant medications will be descriptively summarized by treatment group in terms of 
frequencies and percentages using the safety population. The medications will be coded 
accordingly.
All safety data will also be descriptively summarized by treatment groups and analyzed using the 
safety population.


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In the rare situation where a patient is lost to follow-up at the first postbaseline visit, but some 
safety data exist (e.g., unscheduled laboratory assessments) after first dose of study drug, a 
listing of the data or a patient profile will be provided. 
6.1.2. Definition of Baseline and Postbaseline Measures
Baseline will be defined as the last available value before the first dose of investigational product 
for both efficacy and safety analyses.  In most cases, this will be the measure recorded at Week 0 
(Visit 3).  Change from baseline will be calculated as the visit value of interest minus the 
baseline value.
Postbaseline measurements are collected after study drug administration through Visit 7 (Week 
12) or an early discontinuation visit.
6.1.3. Analysis Methods
The primary analysis for all continuous efficacy and health outcome variables will use a 
mixed-effects models for repeated measures (MMRM) with 
 
 An unstructured covariance matrix will 
be used to model the within-patient variance-covariance errors.  If the unstructured covariance 
matrix results in a lack of convergence, the heterogeneous Toeplitz covariance structure, 
followed by the heterogeneous autoregressive covariance structure will be used.  The 
Kenward-Roger method will be used to estimate the denominator degrees of freedom.  Type III 
tests will be used for all the statistical comparisons; the 90% confidence interval (CI) will also be 
reported.  The LS mean difference, standard error, p-value, and CI will also be reported.  
Treatment group comparisons at specific study visits will be tested using the t-test obtained from 
the MMRM results.  Data will be censored as described in Section 6.3.
The primary analysis for all categorical efficacy and health outcome variables will use a logistic 
regression analysis
 
  The p-value and 90% (unless otherwise specified) CI for the 
odds ratio from the logistic regression model will be used for primary statistical inference.  When 
logistic regression sample size requirements are not met, (<5 responders in any category for any 
factor), the p-value from the Cochran-Mantel-Haenszel (CMH) test with 
 
In addition, all primary and secondary continuous efficacy and health outcome variables will use 
analysis of covariance (ANCOVA) models
 
and cohort in the model as a 
supplementary analysis. Type III sums of squares for the least-squares mean (LSM) will be used 
for the statistical comparison of treatment groups, and the LSM difference, standard error, p-
value and 90% CI will also be reported. The last observation carried forward (LOCF) approach 
will be used to impute missing data. 


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All safety data will be descriptively summarized by treatment groups and analyzed using the 
safety population.
Treatment-emergent adverse event (TEAEs) are defined as AEs that first occurred or worsened 
in severity after the first dose of study treatment. The number of TEAEs as well as the number 
and percentage of patients who experienced at least 1 TEAE will be summarized using the 
Medical Dictionary for Regulatory Activities (MedDRA) for each system organ class (or a body 
system) and each preferred term by treatment group. SAEs and AEs that lead to discontinuation 
of investigational product and discontinuation from the study will also be summarized by 
treatment group. The Fisher exact test will be used to perform comparisons between the
baricitinib and placebo groups.
All clinical laboratory results will be descriptively summarized by treatment group. Individual 
results that are outside of normal reference ranges will be flagged in data listings. Quantitative
clinical hematology, chemistry, and urinalysis variables obtained at the baseline and postbaseline
visits will be summarized as changes from baseline by treatment group and analyzed using
analysis of covariance (ANCOVA) with treatment and baseline value in the model. The 
significance of within-treatment group changes from baseline will be evaluated by testing 
whether or not the treatment group least-squares mean (LSM) changes from baseline are 
different from zero; the p-value and standard error for the LSM change will be displayed.  
Differences in LSM will be displayed, with the p-value associated with the LSM comparison to 
placebo and a 95% CI on the LSM difference also provided.  Treatment-emergent high/low for 
categorical laboratory safety analyses will also be produced.  Categorical variables, including the
incidence of abnormal values and incidence of AEs of special interest, will be summarized by 
frequency and percentage of patients in corresponding categories. Shift tables will be presented 
for selected measures.
Observed values and changes from baseline (predose or screening if predose is missing) for vital 
signs and physical characteristics will be descriptively summarized by treatment group and visit.  
Change from baseline to postbaseline in vital signs and body weight will be analyzed using 
ANCOVA with treatment and baseline value in the model.
The incidence and average duration of investigational product interruptions will be summarized 
and compared descriptively among treatment groups.
6.2.
Covariate Adjustment
The randomization to treatment groups at Week 0 (Visit 3) is stratified by
 
  
The covariates used in the ANCOVA model for continuous data generally will include the 
parameter value at baseline. Inclusion of baseline in the ANCOVA model ensures that treatment 
LSMs are estimated at the same baseline value.  When an MMRM analysis is performed, 
baseline value and baseline-by-visit interactions will be included as covariates.  


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6.3.
Handling of Dropouts or Missing Data
Last-observed-value-carried forward (LOCF) (for categorical variables) and MMRM (for 
continuous variables) will be the primary methods used to handle missing data.  Nonresponder 
imputation (NRI) will also be used as a supplementary analysis method for categorical data.  The 
censoring rules along with their associated estimator assumptions are described in Sections 6.3.1
through 6.3.3.  
As efficacy and health outcome data can accrue after a patient permanently discontinues study 
drug, general censoring rules to the data will be applied to all efficacy and health outcome 
observations subsequent to these events. 
The censoring rule will censor efficacy and health outcome results after permanent study drug 
discontinuation.  This censoring rule will be applied to all continuous and categorical efficacy 
and health outcome endpoints.  Sections 6.3.1 through 6.3.3 summarize the imputation methods 
for the various efficacy and health outcome endpoints. 
6.3.1. Last Observation Carried Forward
Categorical data will primarily be imputed by carrying forward the last post-baseline assessment
for the measure. According to ICH E9 R1, the while-on-treatment strategy could be applied 
based on the last post-baseline value (scheduled or unscheduled visits) at or before the visit of 
interest while the patient was still on study drug. Patients in the analysis population without at 
least 1 postbaseline observation will be defined as non-responders for this analysis. After last 
observation carried forward (LOCF) imputation is applied, data from patients with nonmissing 
baseline and at least 1 postbaseline observation will be included in the analyses.  These LOCF 
analyses help ensure the maximum number of randomized patients who were assessed post-
baseline will be included in the analyses.
All categorical endpoints will utilize LOCF methodology after censoring efficacy and health 
outcome results for those who permanently discontinued study drug. For all patients who 
permanently discontinue study treatment or discontinue from the study for any reason at any 
time, the last nonmissing postbaseline observation on or prior to discontinuation will be carried 
forward to subsequent time points for evaluation. If a patient does not have a nonmissing 
observed record (or one imputed by other means) for a postbaseline visit prior to discontinuation, 
the last postbaseline record prior to the missed visit will be used for the visit.
Further, all continuous primary and secondary efficacy and health outcome variables will be 
imputed using LOCF as a supplementary analysis.
6.3.2. Mixed Model for Repeated Measures
For the continuous primary, secondary, and exploratory efficacy and health outcome variables, 
such as ALP and Itch NRS, MMRM analyses will be performed to mitigate the impact of 
missing data.  This approach assumes that missing observations are missing-at-random 
(missingness is related only to observed data and not to any unobserved data) during the study 
and takes into account both the missingness of data and the correlation of the repeated 


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measurements. An MMRM method can be justified based on the hypothetical strategy (ICH E9 
R1) for handling intercurrent events.
All continuous endpoints will utilize MMRM after censoring efficacy and health outcome results 
for those who permanently discontinued study drug.
6.3.3. Nonresponder Imputation
For the analysis of all categorical efficacy and health outcome variables, the nonresponder 
imputation (NRI) method will be used as a supplementary analysis.  NRI can be justified based 
on the composite strategy (ICH E9R1) for handling intercurrent events. In this strategy a patient 
is defined as a responder only if (i) they meet the clinical requirements for response at the 
predefined time and (ii) they remain on the assigned study treatment.  Failing either criteria by 
definition makes them a non-responder.
All secondary categorical endpoints will utilize the NRI method after censoring efficacy and 
health outcome results for those who permanently discontinued study drug.  Patients in the 
analysis population without at least 1 post-baseline observation will also be defined as 
nonresponders for all visits.  As well, patients who are missing a value prior to discontinuation 
(ie, the patient is missing an intermediate visit) will be imputed as nonresponders at that visit.
6.4.
Multicenter Studies
This study will be conducted by multiple investigators at multiple sites internationally.  
However, since the number of patients at each site is expected to be very small, no further 
sensitivity analysis will be performed for the sites or countries.
6.5.
Multiple Comparisons/Multiplicity
No multiplicity adjustment will be used in this study.
6.6.
Patient Disposition
An overview of patient populations will be summarized by treatment group. Frequency counts 
and percentages of patients excluded prior to randomization by primary reason for exclusion will 
be provided for patients who failed to meet study entry requirements during screening.
Patient disposition through Week 12 will be summarized using the mITT population.  Frequency 
counts and percentages of patients who complete the study treatment visits or discontinue early 
from the study along with whether they completed follow-up or did not complete follow-up will 
be summarized separately by treatment group for patients along with their reason for study 
discontinuation.  Frequency counts and percentages of patients who complete the treatment or 
discontinue treatment early will also be summarized separately by treatment group for patients
along with their reason for treatment discontinuation.  
A listing of patient disposition will be provided for all randomized patients, with the extent of 
their participation in the study and the reason for discontinuation.  A listing of all randomized 
patients with their treatment assignment will also be provided.


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6.7.
Patient Characteristics
Patient characteristics including demographics and baseline characteristics will be summarized 
descriptively by treatment group for the mITT population. Historical illnesses and pre-existing 
conditions will be summarized descriptively by treatment group for the safety population.  
Descriptive statistics including number of patients (n), mean, SD, minimum, 1st quartile, median, 
3rd quartile, and maximum will be provided for continuous measures, and frequency counts and 
percentages will be tabulated for categorical measures.  A listing of patient demographics will 
also be provided for the mITT population. No formal statistical comparisons will be made 
among treatment groups unless otherwise stated.
Table JAIV.6.1 describes the specific variables and how they will be summarized.  


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Table JAIV.6.1. 
Patient Characteristics 
Variable 
Continuous 
measure 
Summary 
Categorical Summary 
Age a 
Yes 
None 
Sex 
No 
Male, Female 
Race 
No 
American Indian/Alaska Native, Asian, Black/African American, 
Native Hawaiian or other Pacific Islander, White, or Multiple 
Geographic region 
No 
By Country 
Height (cm) 
Yes 
None 
Weight (kg) 
Yes 
None 
BMIb 
Yes 
<18.5 kg/m2, ≥18.5 and <25 kg/m2, ≥25 and <30 kg/m2, ≥30 and 
<35 kg/m2 , ≥35 and <40 kg/m2, ≥40 kg/m2 
Alcohol use 
No 
Never, Current, Former 
Tobacco use 
No 
Never, Current, Former 
Age at PBC diagnosis (years)c 
Yes 
<18 years, ≥18 years 
Duration of PBC diagnosisd 
Yes 
0 to <2 years, 2 to <5 years, 5 to <10 years, 10 to <20 years, ≥20 
years 
Current UDCA use 
No 
Yes, No 
Baseline ALP level 
Yes 
Baseline ALP ≤2.5xULN, Baseline ALP >2.5xULN 
Quality of Life for Primary 
Biliary Cirrhosis (PBC-40) at 
baseline 
Yes 
None 
Functional Assessment of 
Chronic Illness 
Therapy-Fatigue (FACIT-F) at 
baseline 
Yes 
None 
Itch Numeric Rating Scale 
(NRS) at baseline 
Yes 
No pruritus (0), Mild pruritus (>0 to <4), Moderate pruritus (≥4 to 
<7), Severe pruritus (≥7 to <9), Very severe pruritus (≥9) 
Frequency table for each value 
Fatigue NRS 
Yes 
None 
Physician’s Global 
Assessment of Disease 
Activity at baseline 
Yes 
None 
Total bilirubin at baseline  
Yes 
None 
Abbreviations:  ALP = alkaline phosphatase; BMI = body mass index; NRS = Numeric Rating Scale; PBC = 
primary biliary cholangitis; UDCA = ursodeoxycholic acid. 
a Age in years will be calculated as (number of months between first dose date and July 1st of birth year) / 12, and 
truncated to a whole-year (integer) age. 
b Body Mass Index (BMI) will be calculated as:  ܤܯܫ ሺ݇݃ / ݉ଶሻൌܹ݄݁݅݃ݐ ሺ݇݃ሻ /ሺܪ݄݁݅݃ݐ ሺ݉ሻሻଶ. 
c Age at diagnosis in years will be calculated as (number of months between date of PBC diagnosis and July 1st of 
birth year) / 12, and truncated to a whole-integer age. 
d The duration of PBC from diagnosis (year) = [(Date of informed consent – Date of PBC diagnosis )+1]/ 365.25.  
If year of onset is missing, duration of PBC will be set as missing.  Otherwise, unknown month will be taken as 
January, and unknown day will be taken as 01.  The duration of PBC will be rounded to 1 decimal place.  
 


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6.7.1. Historical Illness and Pre-existing Conditions 
Historical illnesses are defined as those conditions recorded in the Pre-existing Conditions and 
Medical History electronic case report form (eCRF) or from the Prespecified Medical History:  
Comorbidities eCRF with an end date prior to the informed consent date.  The number and 
percentage of patients with selected historical diagnoses will be summarized by treatment group 
using the safety population.  Historical diagnoses will be categorized using the Medical 
Dictionary for Regulatory Activities (MedDRA®, most current available version) algorithmic 
standardized MedDRA queries (SMQs) or similar pre-defined lists of preferred terms (PTs) of 
interest. 
Pre-existing conditions are defined as those conditions recorded in the Pre-existing Conditions 
and Medical History eCRF, the Prespecified Medical History:  Comorbidities eCRF, or the 
Adverse Events eCRF with a start date prior to the date of informed consent and an end date on 
or after informed consent or no end date (that is, the event is ongoing).  For events occurring on 
the day of the first dose of study treatment, the date and time of the onset of the event will both 
be used to determine if the event was pre-existing.  Conditions with a partial or missing start date 
(or time if needed) will be assumed to be “not pre-existing” unless there is evidence, through 
comparison of partial dates, to suggest otherwise.  Pre-existing conditions will be categorized 
using the MedDRA SMQs or similar pre-defined lists of PTs of interest.  Frequency counts and 
percentages of patients with selected pre-existing conditions will be summarized by treatment 
group using the safety population.  If a preexisting condition worsens in severity on or after date 
of first dose of study treatment, it will be considered a TEAE from the date of worsening 
onwards. 
6.8. Treatment Compliance 
Compliance with investigational product treatment for baricitinib and placebo 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 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. 
Compliance ൌtotal number of tablets dispensed –  total number of tablets returned
expected number of total tablets
 
where  
 Total number of tablets dispensed:  sum of tablets dispensed in the period of interest prior 
to Visit x;  
 Total number of tablets returned:  sum of the tablets returned in the period of interest 
prior to and including Visit x; 


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
Expected number of tablets:  number of days in the period of interest*number of tablets 
taken per day = [(date of visit – date of first dose + 1) – number of days of temporary 
drug interruption]*number of tablets taken per day 
Descriptive statistics for percent compliance and non-compliance rate will be summarized for the 
mITT population by treatment group for Week 0 through Week 12.  Sub-intervals of interest, 
such as compliance between visits, may also be presented.  The number of expected doses, 
tablets dispensed, tablets returned, and percent compliance will be listed by patient for Week 0 
through Week 12.
6.9.
Concomitant and Previous Therapy
Concomitant medications will be coded and descriptively summarized by treatment group in 
terms of frequencies and percentages using the mITT population.
At screening, previous and current PBC treatments are recorded for each patient.  A summary of 
previous medications used for PBC, including zoster immunization and TB vaccine and 
medications that are discontinued after screening and before the first dose of study drug, will be 
prepared using frequency counts and percentages by preferred medication name, with preferred 
medication names sorted by frequency in the baricitinib 4-mg group.  Concomitant therapy will 
be recorded at each visit and will be classified similarly.  An additional summary for previous 
medications used for PBC will be created containing the reason for discontinuation.
Concomitant therapy for the treatment period is defined as therapy that starts before or during the 
treatment period and ends during the treatment period or is ongoing (has no end date or ends 
after the treatment period).  Should there be insufficient data to make this comparison (for 
example, the concomitant therapy stop year is the same as the treatment start year, but the 
concomitant therapy stop month and day are missing), the medication will be considered as 
concomitant for the treatment period.  
Summaries of previous medications will be provided for the following categories:

Previous PBC therapies

Previous PBC therapies including reason for discontinuation
Summaries of concomitant medications will be provided for the following categories:

Concomitant medications for PBC

Concomitant medications for non-PBC
6.10. Efficacy Analyses
The general methods used to summarize efficacy data, including the definition of baseline value 
for assessments are described in Section 6.1.
Efficacy will generally be analyzed from Week 0 to Week 12, and patients will be analyzed 
according to the investigational product to which they were randomized at Week 0 (Visit 3):


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Table JAIV.6.2 includes the descriptions and derivations of the primary and secondary efficacy 
outcomes.
Table JAIV.6.3 provides the detailed analyses including analysis type, method and imputation, 
population, time point, and comparisons for efficacy analyses.


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Table JAIV.6.2. 
Description and Derivation of Primary and Secondary Efficacy Outcomes 
Measure 
Description 
Variable 
Derivation / Comment 
Definition of Missing 
Alkaline 
Phosphatase 
(ALP) 
Laboratory measurement of the 
enzymatic (catalytic) activity of ALP 
enzyme within the blood. 
 Change from baseline 
in ALP 
Change from baseline: observed ALP – 
baseline ALP 
Missing if baseline or 
observed value is missing. 
Total 
Bilirubin and 
Alkaline 
Phosphatase 
(ALP) 
Measurement of concentration of total 
bilirubin in the blood and measurement 
of the enzymatic (catalytic) activity of 
ALP enzyme within the blood. 
 Proportion of patients 
with ALP 
<1.67 x ULN (and at 
least 15% decrease 
from baseline) and 
total bilirubin < ULN 
If  observed ALP < 1.67 x ULN and 
௕௔௦௘௟௜௡௘ ஺௅௉ି ௢௕௦௘௥௩௘ௗ஺௅௉
௕௔௦௘௟௜௡௘ ஺௅௉
ൈ100 ൒15,
and observed total bilirubin ൏ULN 
then conclude that the patient has ALP 
<1.67 x ULN (and at least 15% decrease 
from baseline) and total bilirubin < 
ULN. 
Missing if any one of 
baseline ALP, observed 
ALP, or observed total 
bilirubin is missing. 
 


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Table JAIV.6.3.
Description of Primary and Secondary Efficacy Analyses
Measure
Variable
Analysis Method
(Section 6.1.3)
Population
(Section
6.1.1)
Comparison/Time Point
Analysis Type
Alkaline 
Phosphatase 
(ALP) and 
Total 
Bilirubin
Change from baseline in ALP
MMRM
mITT
Bari 4-mg vs PBO; Week 12
Primary analysis
Bari 2-mg vs PBO; Week 12
Secondary analysis
ANCOVA using 
LOCF
mITT
Bari 4-mg vs PBO; Week 12
Supplementary analysis
Bari 2-mg vs PBO; Week 12
Supplementary analysis
Proportion of patients with ALP 
<1.67 x ULN (and at least 15% decrease
from baseline) and total bilirubin<ULN 
at Week 12
Logistic regression 
using LOCF
mITT
Bari 4-mg vs PBO; Week 12
Secondary analysis
Bari 2-mg vs PBO; Week 12
Secondary analysis
Logistic regression 
using NRI
mITT
Bari 4-mg vs PBO; Week 12
Supplementary analysis
Bari 2-mg vs PBO; Week 12
Supplementary analysis
Abbreviations:  ANCOVA = analysis of covariance; Bari = baricitinib; mITT = modified intent-to-treat; LOCF = last observation carried forward; MMRM = 
mixed model repeated measures; NRI = nonresponder imputation; PBO = placebo.


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6.10.1. Primary Outcome and Methodology
The primary efficacy assessment in Study JAIV will be change in ALP at Week 12. The primary 
analysis of the study is to test the hypothesis that baricitinib 4-mg is superior to placebo for PBC 
disease based on the mITT population. MMRM described in Section 6.3.2 will be the primary 
method of analysis. The treatment difference along with the p-value and 90% confidence 
intervals will be reported.
6.10.2. Secondary Efficacy Analyses
There will be no adjustment for multiple comparisons for Study JAIV.  The secondary efficacy 
analyses are detailed in Table JAIV.6.3.  Health outcome analyses are described in Section 6.11.
6.10.3. Supplementary Analyses
Supplementary analyses for select outcomes have been previously described and include the 
following:

Non-responder imputation (NRI) (Section 6.3.3) for categorical secondary outcomes.

Analysis of continuous outcomes with ANCOVA (Section 6.1.3), with missing data 
imputed using LOCF (Section 6.3.1) for continuous primary and secondary outcomes. 
6.11. Health Outcomes/Quality-of-Life Analyses
The general methods used to summarize health outcomes and quality-of-life measures, including 
the definition of baseline value for assessments, are described in Section 6.1.
Health outcomes and quality-of-life measures will generally be analyzed according to the 
formats discussed in Section 6.10.
Table JAIV.6.4 includes the descriptions and derivations of the health outcomes and quality-of-
life measures. 
Table JAIV.6.5 provides the detailed analyses including analysis type, method and imputation, 
population, time point, and comparisons for health outcomes and quality-of-life measures.


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Table JAIV.6.4.
Description and Derivation of Health Outcomes and Quality-of-Life Measures
Measure
Description
Variable
Derivation / Comment
Definition of Missing
Itch Numeric 
Rating Scale 
(NRS)
The Itch NRS is a patient administered, 
11 point horizontal scale anchored at 0 
and 10, with 0 representing “no itch” 
and 10 representing “worst itch 
imaginable.”  Overall severity of a 
patient’s itching is indicated by selecting 
the number that describes the worst level 
of itching in the past 7 days.

Change from baseline 
in Itch NRS
Change from baseline: observed Itch 
score – baseline Itch score
Missing if baseline or 
observed value is missing.
Fatigue 
Numeric 
Rating Scale 
(NRS)
The Fatigue NRS is a single item, 
patient administered, 11 point horizontal 
scale anchored at 0 and 10, with 0 
representing “no fatigue” and 10 
representing “as bad as you can 
imagine.” Overall severity of a patient’s 
fatigue is indicated by selecting the 
number that describes the worst level of 
fatigue during the past 7 days.

Change from baseline 
in Fatigue NRS
Change from baseline: observed Fatigue
score – baseline Fatigue score
Missing if baseline or 
observed value is missing.
Functional 
Assessment 
of Chronic 
Illness 
Therapy 
Fatigue 
(FACIT-F)
The FACIT-F measures an individual’s 
self-reported level of fatigue during their 
usual daily activities over the past 
7 days.  The scale is composed of 13 
items measured on a 4-point Likert scale 
(4 = very much to 0 = not at all).  The 
total score ranges from 0 to 52, and 
higher scores represent less fatigue.  A 
score of less than 30 indicates severe 
fatigue (Webster et al. 2003).

Change from baseline 
in FACIT-F total 
score
Change from baseline: observed FACIT-
F total score – baseline FACIT-F total 
score according to version 4 of the 
scoring guidelines. 
(http://www.ser.es/wp-
content/uploads/2015/03/FACIT-
F_INDICE.pdf)
Individual item scoring will be done for 
exploratory purposes.
Missing individual items 
within the questionnaire are 
acceptable as long as more 
than 50% of the items are 
answered, e.g. 7 of 13. If
less than 7 items are 
answered baseline or 
observed value is missing.


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Measure
Description
Variable
Derivation / Comment
Definition of Missing
Quality of 
Life for 
Primary 
Biliary 
Cirrhosis
(PBC-40)
The PBC-40 is a disease-specific, 
40-item, patient-reported survey 
containing 6 domains:  overall 
symptoms, itch, fatigue, cognition, 
social, and emotional.  Response options 
for overall symptoms, itch, fatigue, and 
cognition are on a 5-point scale:  
“Never,” “Rarely,” “Sometimes,” “Most 
of the time,” and “Always.”  Response 
options are also on a 5-point scale for 
social and emotional:  “Not at all,” “A 
little,” “Somewhat,” “Quite a bit,” and 
“Very much.”  Items are scored from 1 
to 5 and the individual item scores are 
summed to give a total domain score 
where high scores represent high impact 
of PBC on quality of life (Jacoby et al. 
2005).

Change from baseline 
in PBC-40 for each of 
the 6 domain scores
Change from baseline: observed PBC-40
score – baseline PBC-40 score for each 
of the 6 domains
Missing if baseline or 
observed value is missing.


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Measure
Description
Variable
Derivation / Comment
Definition of Missing
Physician’s 
Global 
Assessment 
of Disease 
Activity
The Physician’s Global Assessment of 
Disease Activity is the physician’s 
assessment of the patient’s overall 
disease activity due to PBC, as 
compared with all possible patients with 
PBC.  The Physician’s Global 
Assessment of Disease Activity is scored 
using a 100-mm visual analog scale 
(VAS), where 0 mm (measured from the 
left starting point of the line) indicates 
no disease activity and 100 mm 
(measured from the left starting point of 
the line) indicates the most severe 
disease activity possible for all patients 
with PBC.  The Physician’s Global 
Assessment of Disease Activity score is 
indicated by making a vertical tick mark 
on the line between 0 and 100 mm.  
There are benchmarks of 0 (0 mm), 1 
(33 mm), 2 (67 mm), and 3 (100 mm) on 
the line corresponding to no, mild, 
moderate, and severe PBC disease 
activity, respectively.

Change from baseline 
in Physician’s Global 
Assessment of 
Disease Activity
Change from baseline: observed 
Physician’s Global Assessment of
Disease Activity score – baseline 
Physician’s Global Assessment of 
Disease Activity score
Missing if baseline or 
observed value is missing.


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Table JAIV.6.5.
Description of Health Outcomes and Quality-of-Life Measures Analyses
Measure
Variable
Analysis Method
(Section 6.1.3)
Population
(Section
6.1.1)
Comparison/Time Point
Analysis Type
Itch Numeric 
Rating Scale 
(NRS)
Change from baseline in itch
MMRM
mITT
Bari 4-mg and Bari 2-mg vs 
PBO; Week 12
Secondary analysis
ANCOVA using 
LOCF
mITT
Bari 4-mg and Bari 2-mg vs 
PBO; Week 12
Supplementary analysis
Fatigue 
Numeric 
Rating Scale 
(NRS)
Change from baseline in fatigue
MMRM
mITT
Bari 4-mg and Bari 2-mg vs 
PBO; Week 12
Secondary analysis
ANCOVA using 
LOCF
mITT
Bari 4-mg and Bari 2-mg vs 
PBO; Week 12
Supplementary analysis
Functional 
Assessment 
of Chronic 
Illness 
Therapy 
Fatigue 
(FACIT-F)
Change from baseline in FACIT-F total 
score
MMRM
mITT
Bari 4-mg and Bari 2-mg vs 
PBO; Week 12
Exploratory analysis
Quality of 
Life for 
Primary 
Biliary 
Cirrhosis
(PBC-40)
Change from baseline in PBC-40 domain 
scores
MMRM
mITT
Bari 4-mg and Bari 2-mg vs 
PBO; Week 12
Exploratory analysis
Physician’s 
Global 
Assessment 
of Disease 
Activity
Change from baseline in Physician’s 
Global Assessment of Disease Activity
MMRM
mITT
Bari 4-mg and Bari 2-mg vs 
PBO; Week 12
Exploratory analysis
Abbreviations:  ANCOVA = analysis of covariance; Bari = baricitinib; mITT = modified intent-to-treat; LOCF = last observation carried forward; MMRM = 
mixed model repeated measures; NRI = nonresponder imputation; PBO = placebo.


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6.12. Bioanalytical and Pharmacokinetic/Pharmacodynamic Methods
Pharmacokinetic, Pharmacodynamic and Biomarker analyses to address exploratory objectives 
of this study will be described by Lilly in separate PK/PD and Biomarker analysis plans.
6.13. Safety Analyses
Analysis populations are defined in Section 6.1.1. Table JAIV.6.6 describes the analysis sets.  
“Analysis set” is a broad term used to define a set of definitions including the population, the 
treatment group(s), the time period(s), and the comparison(s) where applicable.  
Table JAIV.6.6.
Definition of Analysis Sets
Analysis Set
Analysis 
Population
Treatment 
Groups (Short 
Label)
Baseline Time 
Period
Postbaseline 
Time Period
Inferential 
Comparisons
Treatment (T)
Safety
Population
Placebo, Bari 2 
mg, Bari 4 mg
From screening 
to just before
first study drug 
administration
From 
immediately 
after first dose of 
study drug to up 
to 30 days off 
drug follow-up 
time 
When used:  Bari 2 
mg vs. placebo; Bari 
4 mg vs. placebo 
Treatment plus 
follow-up (T + 
FU)
Safety
Population
Placebo, Bari 2 
mg, Bari 4 mg
From screening 
to just before
first study drug 
administration
From 
immediately 
after first dose of 
study drug to end 
of study 
participation.
When used:  Bari 2 
mg vs. placebo; Bari 
4 mg vs. placebo
Abbreviation:  Bari = baricitinib.
The planned safety analyses are consistent with compound-level safety standards, which are 
based on multiple sources, including company standards, internal and external subject matter 
experts, and cross-industry initiatives (e.g., white papers produced by a PhUSE Computational 
Science Working Group (a collaboration with FDA and PhUSE), published in the PhUSE 
Deliverables Catalog at https://www.phuse.eu/white-papers).  Descriptions of the safety analyses 
are provided in this SAP; however, additional details (such as handling of unscheduled visits, 
missing data, etc.) are in compound-level safety standards. 
The following statistical methods will be used for safety unless otherwise noted:

The Fisher exact test will be used for treatment comparisons of proportions, and odds 
ratios with corresponding 95% confidence intervals will be presented where specified.

Treatment differences in mean change for continuous measurements will be assessed 
using an analysis of covariance (ANCOVA) model fitting “baseline” as a covariate.  
Type 3 sums of squares will be used. In addition, the crude mean, standard deviation 
(SD), minimum, median, and maximum will be displayed.


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Tests with two-sided p-values less than or equal to 0.05 will be referred to as having strong 
statistical evidence for a treatment difference, unless otherwise noted.  However, p-values should 
not be over-interpreted, except for those associated with pre-specified hypotheses, since they 
correspond to data-driven hypotheses and hence are only useful as a flagging mechanism.
Additional safety analyses will be performed as part of the integrated safety analyses.  
6.13.1. Extent of Exposure
Duration of exposure (in days) to study drug will be summarized for the safety population by 
treatment group using descriptive statistics (n, mean, SD, minimum, 1st quartile, median, 3rd
quartile, maximum).  Cumulative exposure and duration of exposure will be summarized in 
terms of frequency counts and percentages by category and treatment group. 
Duration of exposure will be calculated as follows:

Duration of exposure to investigational product:  date of last dose of treatment – date of 
first dose of study drug + 1.
Last dose of treatment is calculated as last date on treatment.
Total patient-years (PY) of exposure will be reported for each treatment group for overall 
duration of exposure. Descriptive statistics (n, mean, SD, minimum, 1st quartile, median, 3rd
quartile and maximum) will be provided for patient-days of exposure and the frequency of 
patients falling into different exposure ranges will be summarized.  Exposure ranges will 
generally be reported in weeks using the following as a general guide:  

≥4 weeks, ≥8 weeks, and ≥12 weeks

>0 to <4 weeks, ≥4 weeks to <8 weeks, ≥8 to <12 weeks, and ≥12 weeks
Overall exposure will be summarized in total PY which is calculated according to the following 
formula:
PYE = sum of duration of exposure in days (for all patients in treatment group) / 365.25
These are described in detail in compound-level safety standards.
6.13.2. Adverse Events
Adverse events are recorded in the eCRFs.  The planned summaries are provided in 
Table JAIV.6.7 and are described more fully in compound-level safety standards and in the 
adverse event-related PhUSE white paper (Analysis and Displays Associated with Adverse 
Events:  Focus on Adverse Events in Phase 2-4 Clinical Trials and Integrated Summary 
Document [PhUSE 2017]).  The analysis population and period are defined in Table JAIV.6.7.


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Table JAIV.6.7.
Summary Tables Related to Adverse Events
Analysis
Analysis Set
An overview table, with the number and percentage of patients with death, an 
SAE, any TEAE, discontinuation from the study due to an AE, permanent 
discontinuation from study drug due to an AE, or a severe TEAE  
T, T+FU
The percentages of patients with TEAEs will be summarized by treatment using 
MedDRA Preferred Term nested within System Organ Class.  
T
The percentages of patients with TEAEs will be summarized by treatment using 
MedDRA Preferred Term (without regard to System Organ Class).  
T
The percentages of patients with TEAEs will be summarized by treatment using 
MedDRA Preferred Term for the common TEAEs (occurred in >=2% [before 
rounding] of treated patients).  
T
The percentages of patients with TEAEs by maximum severity will be 
summarized by treatment using MedDRA Preferred Term for the common 
TEAEs. Only counts and percentages will be included for the TEAEs by 
maximum severity.  
T
A listing of all deaths from randomization to end of study participation in each 
study will be provided.  Additional deaths that are reported outside of the study 
period will be obtained from the Lilly Safety System (LSS). 
Enrolled
The number and percentage of patients who experienced a SAE (including 
deaths and SAEs temporally associated or preceding deaths) during the 
treatment period will be summarized by treatment using MedDRA Preferred 
Term nested within System Organ Class.  
T
A listing of SAEs will be provided.  
Enrolled
The number and percentage of patients who permanently discontinued from 
study drug due to an adverse event (including adverse events that led to death) 
during the treatment period will be summarized by treatment using MedDRA 
Preferred Term nested within System Organ Class.  
T
The number and percentage of patients who temporarily interrupted study drug
due to an adverse event during the treatment period will be summarized by 
treatment using MedDRA Preferred Term nested within System Organ Class.  
T
Abbreviations:  AE = adverse event; PT = preferred term; SAE = serious adverse event; T = treatment; T+FU = 
treatment plus follow-up; TEAE = treatment-emergent adverse event.
6.13.3. Deaths, Other Serious Adverse Events, and Other Notable
Adverse Events
The planned table and listing for SAEs are included in the previous section.  A listing of deaths, 
regardless of when they occurred during the study, will also be provided.
6.13.4. Adverse Events of Special Interest
6.13.4.1.
Abnormal Hepatic Tests
Hepatic labs include alanine aminotransferase (ALT) and aspartate transaminase (AST), total 
bilirubin (TBL) and serum alkaline phosphatase (ALP). When criteria are met for hepatic 
evaluations, investigators will complete a follow-up hepatic safety eCRF. The planned 


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summaries are provided in Table JAIV.6.8 and are described more fully in compound-level 
safety standards.
Table JAIV.6.8.
Summary Tables and Figures Related to Hepatic Safety
Analysis
Analysis Set
ALT and AST:  The percentages of patients with a measurement greater than or 
equal to 3 times (3X), 5 times (5X), and 10 times (10X) the central lab upper 
limit of normal (ULN) during the treatment period for all patients with a post-
baseline value and for subsets based on various levels of baseline value.  
T
TBL:  The percentages of patients with a measurement greater than or equal to 2 
times (2X) the central lab ULN during the treatment period will be summarized 
for all patients with a post-baseline value and for subsets based on various levels 
of baseline value.  
T
ALP:  The percentages of patients with a measurement greater than or equal to 2
times (2X) the baseline value and a measurement greater than or equal to 3 times 
(3X) the baseline value during the treatment period will be summarized for all 
patients with a post-baseline value and for subsets based on various levels of 
baseline value.  
T
eDISH plot of maximum post-baseline ALT divided by ULN vs. maximum post-
baseline total bilirubin divided by ULN.
T+FU
Patient profiles including demographics, disposition, information collected on 
the hepatic-safety CRF (where applicable) and a display of study drug exposure, 
adverse events, medications, blood pressure, heart rate, and the liver-related 
measurements over time will be provided for patients with information collected 
on the hepatic-safety CRF and any additional patients meeting ALT or AST
measurement greater than or equal to 5X ULN (on a single measurement), or 
ALP measurement greater than or equal to 3X baseline ALP (on a single 
measurement), or ALP measurement greater than or equal to 2X baseline ALP 
on two or more consecutive measurements.
T+FU
Abbreviations:  ALP = alkaline phosphatase; ALT = alanine aminotransferase; AST = aspartate transaminase; T = 
treatment; T+FU = treatment plus follow-up; TBL = total bilirubin.
6.13.4.2.
Hematologic Changes
Hematologic changes will be assessed through analysis of hemoglobin, white blood cell count, 
absolute neutrophil count, lymphocyte count, and platelet count.  The planned summaries are 
provided in Table JAIV.6.9, and are described more fully in compound-level safety standards. 


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Table JAIV.6.9.
Summary Tables Related to Hematologic Changes
Analysis
Analysis Set
Shift tables showing the number and percentage of patients based on baseline to 
maximum during the treatment period will be created, with baseline depicted by 
the most extreme CTCAE grade during the baseline period.  With each shift 
table, a summary displaying the number and percentage of patients who 
decreased, increased, or stayed the same in CTCAE grade category will be 
presented.  
T
The percentages of patients with treatment-emergent laboratory abnormalities at 
any time during the treatment period will be summarized, based on any increase 
in postbaseline CTCAE grade, increase to CTCAE Grade 1 or above, Grade 2 or 
above, Grade 3 or above, and Grade 4.
T
The percentages of patients with treatment-emergent thrombocytosis will be 
summarized, defined as an increase in platelet count from a maximum baseline 
value ≤600 billion/L to any postbaseline value >600 billion/L.
T
Listing of patients with treatment-emergent thrombocytosis may be provided
T+FU
Abbreviations: CTCAE = Common Terminology Criteria for Adverse Events; T = treatment; T+FU = treatment 
plus follow-up.
6.13.4.3.
Lipid Effects
Lipid effects will be assessed through analysis of elevated total cholesterol, elevated LDL 
cholesterol, decreased and increased HDL cholesterol, and elevated triglycerides. The planned 
summaries are provided in Table JAIV.6.10 and are described more fully in compound-level 
safety standards.  
Table JAIV.6.10.
Summary Tables Related to Lipid Effects
Analysis
Analysis Set
Shift tables showing the number and percentage of patients based on baseline to 
maximum during the treatment period will be created, with baseline depicted by 
the most extreme NCEP-based level during the baseline period.  With each shift 
table, a summary displaying the number and percentage of patients who 
decreased, increased, or stayed the same in NCEP-based level will be presented.  
T
The percentages of patients with treatment-emergent shifts at any time during the 
treatment period will be summarized, based on increases to various levels of 
NCEP-based categories.
T
Abbreviation:  NCEP = National Cholesterol Education Programme.
6.13.4.4.
Renal Function Effects
Effects on renal function will be assessed through analysis of elevated creatinine.  Renal events 
will be identified using terms from the acute renal failure SMQ.  The planned summaries are 
provided in Table JAIV.6.11 and are described more fully in compound-level safety standards.
  


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Table JAIV.6.11.
Summary Tables Related to Effects on Renal Function
Analysis
Analysis Set
Shift tables showing the number and percentage of patients based on baseline to 
maximum during the treatment period will be created, with baseline depicted by 
the most extreme CTCAE grade during the baseline period.  With each shift 
table, a summary displaying the number and percentage of patients who 
decreased, increased, or stayed the same in CTCAE grade category will be 
presented.  
T
The percentages of patients with treatment-emergent laboratory abnormalities at 
any time during the treatment period will be summarized, based on any increase
in postbaseline CTCAE grade, increase to CTCAE Grade 1 or above, Grade 2 or 
above, Grade 3 or above, and Grade 4.
T
Abbreviations:  CTCAE = Common Terminology Criteria for Adverse Events; T = treatment; T+FU = treatment 
plus follow-up.
6.13.4.5.
Evaluations in Creatine Phosphokinase (CPK)
The planned summaries are provided in Table JAIV.6.12 and are described more fully in 
compound-level safety standards.  
Table JAIV.6.12.
Summary Tables Related to Effects on Renal Function
Analysis
Analysis Set
Shift tables showing the number and percentage of patients based on baseline to 
maximum during the treatment period will be created, with baseline depicted by 
the most extreme CTCAE grade during the baseline period.  With each shift 
table, a summary displaying the number and percentage of patients who 
decreased, increased, or stayed the same in CTCAE grade category will be 
presented.  
T
The percentages of patients with treatment-emergent laboratory abnormalities at 
any time during the treatment period will be summarized, based on any increase
in postbaseline CTCAE grade, increase to CTCAE Grade 1 or above, Grade 2 or 
above, Grade 3 or above, and Grade 4.
T
Abbreviations:  CTCAE = Common Terminology Criteria for Adverse Events; T = treatment; T+FU = treatment 
plus follow-up.
6.13.4.6.
Infections
Infections will be defined using all the PTs from the MedDRA Infections and Infestations SOC.  
The MedDRA terms used to identify infections considered to be opportunistic infections (OIs) 
are based on Winthrop et al. (2015) and are listed in the compound-level safety standards.  The 
list contains narrow (more specific) and broad (less specific) PTs.  
The planned summaries are provided in Table JAIV.6.13 and are described more fully in 
compound-level safety standards.  


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Table JAIV.6.13.
Summary Tables Related to Infections
Analysis
Analysis Set
The number and percentage of patients with treatment-emergent infections, 
serious infections, and infections resulting in permanent study drug 
discontinuation using MedDRA PTs
T
The number and percentage of patients with TEAEs of infections by maximum 
severity using MedDRA PTs  
T
Listing of patients experiencing TEAE infections will be provided.  The listing 
will include patient demographics, treatment group, treatment start and stop 
dates, infectious PT event, event start and stop dates, total leukocytes, total 
lymphocytes, absolute neutrophils, event seriousness, and event outcome
T+FU
Listings and summary of OIs based on MedDRA PTs
T
A summary table of herpes zoster will be provided, including event maximum 
severity, seriousness, whether resulting in temporary study drug interruption, 
whether resulting in study drug discontinuation, whether treated with antiviral 
medication, and event outcome.  The incidence rate adjusted for observation 
time will also be provided.  
T
A listing of patients with detectable HBV DNA 
T+FU
Hepatitis B virus DNA status (not detectable, detectable but not quantifiable [ie, 
< lower limit of detection (LLOD)], quantifiable [ie, ≥LLOD]) stratified by 
applicable baseline HBV serology status
T
Abbreviations:  OIs = opportunistic infections; PTs = preferred terms; T = treatment; T+FU = treatment plus follow-
up; TEAE = treatment-emergent adverse events.
6.13.4.7.
Major Adverse Cardiovascular Events (MACE) and Other 
Cardiovascular Events
Major adverse cardiovascular events (MACE) and other cardiovascular events will be 
adjudicated by an independent, external adjudication committee.  All confirmed events after 
adjudication will be used for the analysis.  
The planned summaries are provided in Table JAIV.6.14 and are described more fully in 
compound-level safety standards.


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Table JAIV.6.14.
Summary Tables Related to MACE and Other Cardiovascular 
Events
Analysis
Analysis Set
The number and percentage of patients with MACE, other cardiovascular events, 
non-cardiovascular death, and all-cause death, as adjudicated, will be 
summarized by treatment group based on the categories and subcategories as 
defined in compound-level safety standards.
T
A listing of the events sent for cardiovascular adjudication will be provided to 
include data concerning the MedDRA PT related to the event, the seriousness of 
the event, and the event outcome, along with the adjudicated result.
T+FU
Abbreviations:  MACE = Major Adverse Cardiovascular Events; PT = preferred term ; T = treatment; T+FU = 
treatment plus follow-up.
6.13.4.8. Venous and Pulmonary Artery Thromboembolic (VTE) Events
Venous thromboembolism (VTE) events will be adjudicated by an independent, external 
adjudication committee.  Venous and pulmonary artery thromboembolic events will be classified 
as deep vein thrombosis (DVT), pulmonary embolism (PE), or other peripheral venous 
thrombosis.  All confirmed events after adjudication will be used for the analysis.  
The planned summaries are provided in Table JAIV.6.15 and are described more fully in 
compound-level safety standards.
Table JAIV.6.15.
Summary Tables Related to VTE Events
Analysis
Analysis Set
The number and percentage of patients with a VTE, DVT/PE, DVT, PE, and 
other peripheral venous thrombosis, as positively adjudicated, will be 
summarized by treatment group.  
T
A listing of the VTE events sent for adjudication will be provided to include data 
concerning the MedDRA PT related to the event, the seriousness of the event, 
and the event outcome, along with the adjudicated result.
T+FU
Abbreviations:  DVT = deep vein thrombosis; PE = pulmonary embolism; PT = preferred term; T = treatment; 
T+FU = treatment plus follow-up; VTE = venous thromboembolism.
6.13.4.9. Arterial Thromboembolic (ATE) Events
Standardized MedDRA Queries (SMQs) or predefined search methods will be used to identify 
the candidate cases.  These candidate cases will be confirmed by medical review assessment.
The planned summaries are provided in Table JAIV.6.16 and are described more fully in 
compound-level safety standards.


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Table JAIV.6.16.
Summary Tables Related to ATE Events
Analysis
Analysis Set
The number and percentage of patients with treatment emergent ATE will be 
summarized by treatment group.  
T
Patient profile reports and LSS summaries will be provided for all treatment-
emergent serious and non-serious ATE.
T
Abbreviations:  ATE = Arterial thromboembolic event; LSS = Lilly Safety System; T = treatment; T+FU = 
treatment plus follow-up.
6.13.4.10.
Malignancies
Malignancies will be identified using terms from the malignant tumors SMQ.  Malignancies 
excluding nonmelanoma skin cancers (NMSC) and NMSC will be reported separately.  All the 
cases identified by the malignant tumors SMQ will be assessed through medical review to 
determine confirmed NMSC cases.
The planned summaries are provided in Table JAIV.6.17 and are described more fully in 
compound-level safety standards.
Table JAIV.6.17.
Summary Tables Related to Malignancies
Analysis
Analysis Set
The number and percentage of patients with treatment-emergent malignancies 
excluding NMSC and NMSC will be summarized by treatment group.
T
Listing of all malignancy cases, with an NMSC flag.
T+FU
Abbreviation:  NMSC = nonmelanoma skin cancers; T = treatment; T+FU = treatment plus follow-up.
6.13.4.11.
Allergic Reactions/Hypersensitivities
A search for relevant events related to allergic reaction and hypersensitivity will be performed 
using the following SMQs:

Anaphylactic reaction SMQ (20000021)

Hypersensitivity SMQ (20000214)

Angioedema SMQ (20000024)
Events that satisfy the queries will be listed, by temporal order within patient ID, and will 
include SOC, PT, SMQ event categorization including detail on the scope (narrow, algorithmic,
or broad), reported AE term, AE onset and end dates, severity, seriousness, outcome, etc.
The summaries described in Table JAIV.6.18 will be created if there are sufficient numbers of 
events to warrant further examination beyond the listing specified above.  


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Table JAIV.6.18.
Summary Tables Related to Allergic Reactions/Hypersensitivities
Analysis
Analysis Set
The number and percentage of patients with TEAEs will be summarized by 
treatment using MedDRA Preferred Term for any narrow or algorithmic term 
from any one of the 3 SMQs (each SMQ and SMQs combined)  
T
The number and percentages of patients with TEAEs will be summarized by 
treatment using MedDRA Preferred Term for any narrow scope term (each SMQ 
separately)  
T
The number and percentages of patients with TEAEs will be summarized by 
treatment using MedDRA Preferred Term for any broad term (each SMQ 
separately)  
T
Abbreviations: TEAE = treatment-emergent adverse event; SMQ = standardized MedDRA queries; T = treatment.
6.13.4.12.
Gastrointestinal Perforations
Potential gastrointestinal perforations will be identified using terms from the GI perforations 
SMQ.  Potential GI perforations identified by the SMQ search will be provided as a listing for 
internal review by the medical safety team.  Each case will be assessed to determine whether it is 
GI perforation.  All confirmed events after medical review will be used for later analysis.  
6.13.4.13.
Depression and Suicide
During the study, suicidal ideation and behavior, and depression, will be assessed prospectively 
by the investigator via signs and symptoms and through the use of the Quick Inventory of 
Depressive Symptomatology Self Report (QIDS-SR16).  The QIDS-SR16 total scores will also 
be categorized into severity classes (none, mild, moderate, severe, very severe).  
The planned summaries are provided in Table JAIV.6.19 and are described more fully in 
compound-level safety standards.
Table JAIV.6.19.
Summaries Related to Depression and Suicide
Analysis
Analysis Set
Treatment differences in mean change QIDS-SR16 total score will be analyzed.  
T
Frequency counts and percentages will be used to summarize the QIDS-SR16 
total score severity categories at each visit by treatment group.  
T
Shift tables showing the number and percentage of patients based on baseline to 
maximum during the treatment period will be created, with baseline depicted by 
the most extreme QIDS-SR16 category during the baseline period.  With each 
shift table, a summary displaying the number and percentage of patients who 
decreased, increased, or stayed the same in QIDS-SR16 category will be 
presented.  
T
Shift tables will be created for the QIDS-SR16 suicidal ideation item responses.
T
The percentages of patients with treatment-emergent shifts at any time during the 
treatment period will be summarized, based on any increase to mild and above, 
moderate or above, severe or above, very severe.
T


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Abbreviation: QIDS-SR16 = Quick Inventory of Depressive Symptomatology Self Report; T = treatment.
6.13.5. Clinical Laboratory Evaluation
The planned summaries for clinical laboratory evaluations are provided in Table JAIV.6.20 and 
are described more fully in compound-level safety standards and in the laboratory-related 
PhUSE white papers [Analyses and Displays Associated with Measures of Central Tendency –
Focus on Vital Sign, Electrocardiogram, and Laboratory Analyte Measurements in Phase 2-4 
Clinical Trials and Integrated Submission Documents (PhUSE 2013) and Analyses and Displays 
Associated with Outliers or Shifts from Normal to Abnormal:  Focus on Vital Signs, 
Electrocardiogram, and Laboratory Analyte Measurements in Phase 2-4 Clinical Trials and 
Integrated Summary Documents (PhUSE 2015)].
Table JAIV.6.20.
Summary Tables Related to Clinical Laboratory Evaluations
Analysis
Analysis Set
Box plots for observed values by visit and change from baseline values by visit 
and at last observation.
T excluding visit 
801
Tables with percentages of patients who shift from normal/high to low (i.e., 
treatment-emergent low) and percentages of patients who shift from normal/low 
to high (i.e., treatment-emergent high)
T
Listing of abnormal findings for laboratory analyte measurements, including 
qualitative measures
T+FU
Abbreviations:  T = treatment; T+FU = treatment plus follow-up.
6.13.6. Vital Signs and Other Physical Findings
The planned summaries for vital signs and physical characteristics (systolic BP, diastolic BP, 
pulse, weight, BMI and waist circumference) are provided in Table JAIV.6.21 and are described 
more fully in compound-level safety standards and in the vitals-related PhUSE white papers 
[Analyses and Displays Associated with Measures of Central Tendency – Focus on Vital Sign, 
Electrocardiogram, and Laboratory Analyte Measurements in Phase 2-4 Clinical Trials and 
Integrated Submission Documents (PhUSE 2013) and Analyses and Displays Associated with 
Outliers or Shifts from Normal to Abnormal:  Focus on Vital Signs, Electrocardiogram, and 
Laboratory Analyte Measurements in Phase 2-4 Clinical Trials and Integrated Summary 
Documents (PhUSE 2015)]. 


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Table JAIV.6.21.
Summary Tables Related to Vital Signs
Analysis
Analysis Set
Box plots for observed values by visit and change from baseline values by visit 
and at last observation.
T excluding visit 
801
Tables with percentages of patients who shift from normal/high to low (i.e., 
treatment-emergent low) and percentages of patients who shift from normal/low 
to high (i.e., treatment-emergent high).  The limits are defined in the compound-
level safety standards and are based on literature.
T
Abbreviation:  T = treatment.
6.14. Subgroup Analyses
Subgroup analyses comparing each dose of baricitinib to placebo will be performed on the mITT 
population at Week 12, with data up to rescue for the following:

Change from baseline in alkaline phosphatase (ALP) at Week 12.
The following subgroups (but not necessarily limited to only these) will be evaluated:

Descriptive statistics will be provided for each treatment and stratum of a subgroup as outlined, 
regardless of sample size.  The analysis will be performed using MMRM.  The model will
include treatment, subgroup, and treatment-by-subgroup interaction as explanatory variables.  
The treatment-by-subgroup interaction comparing treatment groups will be tested at the 0.1 
significance level.  The p-value from the MMRM will be reported for the interaction test.  
Response counts and percentages will be summarized by treatment for each subgroup category.  
Type III tests will be used for all the statistical comparisons; the 90% confidence interval (CI)
will also be reported.  The LS mean difference, standard error, p-value, and CI will also be 
reported.  Treatment group comparisons at specific study visits will be tested using the t-test
obtained from the MMRM results.  Additionally, descriptive statistics will also be provided for 
each treatment and cohort (Cohort A and Cohort B) as a subgroup.
6.15. Protocol Violations
Protocol deviations will be tracked by the clinical team, and their importance will be assessed by 
key team members during protocol deviation review meetings.  
Potential examples of deviations include patients who receive excluded concomitant therapy, 
significant non-compliance with study medication (<80% of assigned doses taken, failure to take 
study medication and taking incorrect study medication), patients incorrectly enrolled in the 
study, and patients whose data are questionable due to significant site quality or compliance 
issues.  Refer to a separate document for the important protocol deviations.
The number and percentage of patients having IPD(s) will be summarized within category and 
subcategory of deviation by treatment group for Period 2 using the ITT population.  Individual 
patient listings of IPDs will be provided.


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6.16. Interim Analyses and Data Monitoring
An interim analysis will be conducted under the auspices of a DMC according to the 
specifications set forth in the protocol.
A DMC will oversee the conduct of this trial. The DMC will consist of members external to 
Lilly. This DMC will follow the rules defined in the DMC charter, focusing on potential and 
identified risks for this molecule and for this class of compounds.  The DMC will include at least 
3 individuals including a chairperson independent of Lilly (external to Lilly) and independent of 
any third party organization (TPO) contracted by Lilly to conduct the study. The DMC will 
include at least 2 physicians (at least one specialist with expertise in hepatology) with experience 
as a DMC member, as well as a biostatistician with DMC and clinical trial experience.
The DMC will be authorized to review unblinded results of analyses by treatment group prior to 
database lock, including study discontinuation data, AEs including SAEs, clinical laboratory 
data, vital sign data, etc.  The DMC may recommend to continue the study as designed;  
temporarily suspend enrollment, pending resolution of a specified issue; or discontinue the entire 
study. While the DMC may request to review efficacy data to investigate the benefit/risk 
relationship in the context of safety observations for ongoing patients in the study, no 
information regarding efficacy will be communicated. Moreover, the study will not be stopped 
for positive efficacy results nor will it be stopped for futility. Hence, no alpha is spent.  Details 
of the DMC, including its operating characteristics, are documented in the Baricitinib Data 
Monitoring Committee Charter for Protocol I4V-MC-JAIV, and further details are given in the 
Interim Analysis Plan in Section 6.16.1.
Besides DMC members, a limited number of pre-identified individuals may gain access to the 
limited unblinded data, as specified in the unblinding plan, prior to the interim or final database 
lock, to initiate the final population PK/PD model development processes.  Information that may 
unblind the study during the analyses will not be reported to study sites or blinded study team 
until the study has been unblinded.
Unblinding details are given in a separate blinding and unblinding plan document.
6.16.1. Interim Analysis Plan
Analyses for the DMC will include listings and/or summaries of the following information:

patient disposition, demographics, and baseline characteristics

exposure

timing of and reasons for study discontinuation and permanent study drug discontinuation

adverse events (AEs), to include the following:
o
treatment-emergent AEs
o
serious AEs, including deaths
o
selected special safety topics

clinical laboratory results

vital signs


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All listings will include patient ID and treatment group.  Summaries will include TEAEs, SAEs, 
special topics AEs, and treatment-emergent high and low laboratory and vital signs in terms of 
counts, percentages and incidence rates where applicable.  For continuous analyses, box plots of 
laboratory analytes will be provided by time point and summaries will include descriptive 
statistics such as mean, SD, minimum, 1st quartile, median, 3rd quartile, and maximum.
The DMC may request efficacy data if they feel there is value and to confirm a reasonable 
benefit/risk profile for ongoing patients in the study.  If efficacy data are requested, change from 
baseline in ALP will be provided.  Further details are given in the DMC charter.
6.17. Planned Exploratory Analyses
The planned exploratory analyses are described in Sections 6.10 and 6.11.  Additional 
exploratory analyses may be conducted, such as exploring inadequate or super responders and 
their baseline characteristics and will be documented in a supplemental SAP.
6.18. Annual Report Analyses
Annual report analyses, such as for the Development Safety Update Report (DSUR), will be 
documented in a separate document.
6.19. Clinical Trial Registry Analyses
Additional analyses will be performed for the purpose of fulfilling the Clinical Trial Registry 
(CTR) requirements.  
Analyses provided for the CTR requirements include the following:
Summary of adverse events, provided as a dataset which will be converted to an XML file.  
Both Serious Adverse Events and “Other” Adverse Events are summarized:  by treatment 
group, by MedDRA preferred term.

An adverse event is considered “Serious” whether or not it is a treatment-emergent 
adverse event (TEAE).

An adverse event is considered in the “Other” category if it is both a TEAE and is not 
serious.  For each Serious AE and “Other” AE, for each term and treatment group, the 
following are provided:
o
the number of participants at risk of an event
o
the number of participants who experienced each event term
o
the number of events experienced.

Consistent with www.ClinicalTrials.gov requirements, “Other” AEs that occur in fewer 
than 5% of patients/subjects in every treatment group may not be included if a 5% 
threshold is chosen (5% is the minimum threshold).

AE reporting is consistent with other document disclosures for example, the CSR, 
manuscripts, and so forth. 


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7.
Unblinding Plan
Refer to a separate blinding and unblinding plan document for details. 


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8.
References
[CTCAE] Common Terminology Criteria for Adverse Events, Cancer Therapy Evaluation 
Program, Version 3.0, DCTD, NCI, NIH, DHHS, March 31, 2003. Available at: 
https://ctep.cancer.gov/protocoldevelopment/electronic_applications/docs/ctcaev3.pdf. 
Accessed 25 July 2017.
[CTCAE] Common Terminology Criteria for Adverse Events, Version 4.03, DHHS NIH NCI, 
NIH Publication No. 09-5410, June 14, 2010. Available at: 
https://evs.nci.nih.gov/ftp1/CTCAE/CTCAE_4.03_2010-06-14_QuickReference_5x7.pdf. 
Accessed 25 July 2017.
FACIT Fatigue Scale (Version 4). Available at: http://www.ser.es/wp-
content/uploads/2015/03/FACIT-F_INDICE.pdf. Accessed 08 May 2019.
[ICH] International Conference on Harmonisation. Harmonised Tripartite Guideline: Clinical 
safety data management: definitions and standards for expedited reporting. E2A. 1994;Step 4. 
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[ICH E9 R1] Estimands and Sensitivity Analysis in Clinical Trials 
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R1EWG_Step2_Guideline_2017_0616.pdf
Jacoby A, Rannard A, Buck D, Bhala N, Newton JL, James OFW, Jones DEJ. Development, 
validation, and evaluation of the PBC-40, a disease specific health related quality of life 
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PhUSE Computational Science Deliverables Catalog. Analysis and Displays Associated with 
Adverse Events: Focus on Adverse Events in Phase 2-4 Clinical Trials and Integrated 
Summary Document. 2017. https://www.phuse.eu/documents//working-
groups/deliverables/adverse-events-white-paper-version-10-03-feb-17-11796-19835.pdf
PhUSE Computational Science Deliverables Catalog. Analyses and Displays Associated with 
Measures of Central Tendency – Focus on Vital Sign, Electrocardiogram, and Laboratory 
Analyte Measurements in Phase 2-4 Clinical Trials and Integrated Submissin Documents.
(2013).http://www.phusewiki.org/wiki/images/4/48/CSS_WhitePaper_CentralTendency_v1.0.
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PhUSE Computational Science Deliverables Catalog. Analyses and Displays Associated with 
Outliers or Shifts from Normal to Abnormal: Focus on Vital Signs, Electrocardiogram, and 
Laboratory Analyte Measurements in Phase 2-4 Clinical Trials and Integrated Summary 
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displays-associated-with-outliers-or-shifts-from-normal-to-abnormal-version-10-10-sept-15-
11815.pdf.
Program Safety Analysis Plan: Baricitinib (LY3009104) Version 6. Report on file, Eli Lilly and 
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Protocol I4V-MC-JAIV(b). A Randomized, Double-Blind, Placebo-Controlled, 
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Patients with Primary Biliary Cholangitis Who Have an Inadequate Response or Are Intolerant
to UDCA. Report on file, Eli Lilly and Company.
Webster K, Cella D, Yost K. The Functional Assessment of Chronic Illness Therapy (FACIT) 
measurement system: properties, applications, and interpretation. Health Qual Life Outcomes. 
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