Conditions: Cutaneous Lichen Planus
Allocation: NON_RANDOMIZED | Intervention model: SEQUENTIAL
Enrollment: 12
Healthy volunteers: no

Brief summary:
This research study is evaluating the safety and efficacy of Baricitinib in treating Cutaneous Lichen Planus (LP).

Detailed description:

Arms:
arm 1: Subjects with a diagnosis of cutaneous LP will receive Baricitinib (LY3009104) for a 16 weeks treatment period arm 2: Subject that demonstrate a response to the 16 weeks of treatment with 2 mg of Baricitinib (LY3009104), but have not achieved a PGA 0 will receive 4 mg of Baricitinib (LY3009104) for 12 weeks

Interventions: intervention 1: Baricitinib (LY3009104) 2 mg intervention 2: Baricitinib (LY3009104) 4 mg
Intervention descriptions: intervention 1: 2 mg orally administered once daily for 16 weeks intervention 2: 4 mg orally administered once daily for 12 weeks

Protocol document:
Prot_SAP_000.pdf: 
 
Baricitinib (LY3009104) in the 
Treatment of Cutaneous Lichen 
Planus 
 
NCT# 05188521 
 
June 17, 2022 


 
 
 
Baricitinib (LY3009104) in the Treatment of Cutaneous Lichen Planus 
 
 
 
 
 
 
Regulatory Sponsor: 
Mayo Clinic  
Aaron Mangold, M.D.   
Department of Dermatology  
13400 E Shea Blvd 
Scottsdale, AZ 85259  
(480) 301-5686 
 
Funding Sponsor: 
(Optional) 
Eli Lilly and Company 
Indianapolis, Indiana 46285 
   
Study Product: 
Baricitinib (LY3009104) oral medication 
Protocol Number: (IRBe) 
  
21-003075 
 
IND Number: 
156046  
 
 
 
 
 
 
Version Date 
Major Changes 
1.0 
 
Initial Protocol 
1.1 
4.30.21 
Dose modified (4mg changed to 2mg once daily); patients of childbearing 
age will receive monthly pregnancy tests (starting at day 0); patients with 
moderate-to-severe renal impairment will be excluded from study 
1.2 
11.16.21 
Added single-cell RNA sequencing; will require two additional skin biopsies 
and one additional blood draw at both the week 0 and week 2 visits to obtain 
tissue; collaboration with University of Michigan for single-cell RNA 
processing 
1.3  
2.14.2022 
Adding ability for remote visits 
1.4 
3.17.2022 
Adding LPQOL assessment into study visits  
1.5 
6.07.2022 
Removing clinical assessments during remote visits  
1.6 
6.17.2022 
Adding dose escalation and extension for patients and removing CRC visit 
during remote visits 
 
 
Table of Contents 
 
STUDY SUMMARY ............................................................................................................................................ 5 


2 
INTRODUCTION ........................................................................................................................................ 5 
2.1 
BACKGROUND ................................................................................................................................................ 5 
2.2 
INVESTIGATIONAL AGENT .............................................................................................................................. 7 
2.3 
PRECLINICAL DATA ........................................................................................................................................ 7 
2.4 
CLINICAL DATA TO DATE ............................................................................................................................. 10 
2.5 
DOSE RATIONALE ......................................................................................................................................... 15 
2.6 
RISKS AND BENEFITS .................................................................................................................................... 15 
3 
STUDY OBJECTIVES ............................................................................................................................... 17 
4 
STUDY DESIGN ........................................................................................................................................ 18 
4.1 
GENERAL DESCRIPTION ................................................................................................................................ 18 
4.2 
NUMBER OF SUBJECTS .................................................................................................................................. 20 
4.3 
DURATION OF PARTICIPATION ...................................................................................................................... 20 
4.4 
PRIMARY STUDY ENDPOINTS ....................................................................................................................... 22 
4.5 
SECONDARY STUDY ENDPOINTS................................................................................................................... 22 
4.6 
PRIMARY SAFETY ENDPOINTS ...................................................................................................................... 22 
4.7 
IDENTIFICATION OF SOURCE DATA ............................................................................................................... 23 
5 
SUBJECT SELECTION ENROLLMENT AND WITHDRAWAL .......................................................... 23 
5.1 
INCLUSION CRITERIA .................................................................................................................................... 23 
5.2 
EXCLUSION CRITERIA ................................................................................................................................... 23 
5.3 
SUBJECT RECRUITMENT, ENROLLMENT AND SCREENING ............................................................................. 25 
5.4 
EARLY WITHDRAWAL OF SUBJECTS ............................................................................................................. 25 
5.4.1 
When and How to Withdraw Subjects .................................................................................................. 25 
5.4.2 
Data Collection and Follow-up for Withdrawn Subjects ..................................................................... 26 
6 
STUDY DRUG ............................................................................................................................................ 26 
6.1 
DESCRIPTION (INVESTIGATOR’S BROCHURE) ............................................................................................... 26 
6.2 
TREATMENT REGIMEN .................................................................................................................................. 28 
6.3 
PREPARATION AND ADMINISTRATION OF STUDY DRUG ............................................................................... 28 
6.4 
SUBJECT COMPLIANCE MONITORING ........................................................................................................... 28 
6.5 
PRIOR AND CONCOMITANT THERAPY ........................................................................................................... 28 
6.6 
PACKAGING .................................................................................................................................................. 28 
6.7 
RECEIVING, STORAGE, DISPENSING AND RETURN ........................................................................................ 29 
6.7.1 
Receipt of Drug Supplies ..................................................................................................................... 29 
6.7.2 
Storage ................................................................................................................................................. 29 
6.7.3 
Dispensing of Study Drug .................................................................................................................... 29 
6.7.4 
Return or Destruction of Study Drug ................................................................................................... 29 
7 
STUDY PROCEDURES ............................................................................................................................. 29 
7.1 
VISIT 1 .......................................................................................................................................................... 29 
7.2 
VISIT 2 .......................................................................................................................................................... 30 
7.3 
VISIT 3 .......................................................................................................................................................... 30 
8 
STATISTICAL PLAN ................................................................................................................................ 33 
8.1 
SAMPLE SIZE DETERMINATION ..................................................................................................................... 33 
8.2 
STATISTICAL METHODS ................................................................................................................................ 33 
8.3 
SUBJECT POPULATION(S) FOR ANALYSIS ...................................................................................................... 34 
9 
SAFETY AND ADVERSE EVENTS ......................................................................................................... 35 
9.1 
DEFINITIONS ................................................................................................................................................. 35 
9.2 
RECORDING OF ADVERSE EVENTS ................................................................................................................ 39 
9.3 
REPORTING OF SERIOUS ADVERSE EVENTS AND UNANTICIPATED PROBLEMS ............................................. 39 
9.3.1 
Sponsor-Investigator reporting: notifying the Mayo IRB .................................................................... 39 
9.3.2 
Sponsor-Investigator reporting: Notifying the FDA and Funding Sponsor ......................................... 41 
9.4 
STOPPING RULES .......................................................................................................................................... 42 
9.5 
MEDICAL MONITORING ................................................................................................................................ 42 
10 
DATA HANDLING AND RECORD KEEPING ................................................................................... 43 
10.1 
CONFIDENTIALITY ........................................................................................................................................ 43 
10.2 
SOURCE DOCUMENTS ................................................................................................................................... 44 


10.3 
CASE REPORT FORMS ................................................................................................................................... 44 
10.4 
RECORDS RETENTION ................................................................................................................................... 44 
11 
STUDY MONITORING, AUDITING, AND INSPECTING ................................................................. 45 
11.1 
STUDY MONITORING PLAN ........................................................................................................................... 45 
11.2 
AUDITING AND INSPECTING .......................................................................................................................... 45 
12 
ETHICAL CONSIDERATIONS ............................................................................................................ 45 
13 
STUDY FINANCES ................................................................................................................................ 45 
13.1 
FUNDING SOURCE ......................................................................................................................................... 45 
13.2 
SUBJECT STIPENDS OR PAYMENTS ................................................................................................................ 45 
14 
PUBLICATION PLAN ........................................................................................................................... 46 
15 
REFERENCES ....................................................................................................................................... 46 
16 
ATTACHMENTS ................................................................................................................................... 47 
Pruritus Visual Analogue Scale ............................................................................................................................ 50 
 
 
 
 
 
 
 
 
 
 
 


 
List of Abbreviations 
 
 
LIST OF ABBREVIATIONS 
AE 
BSA 
mCAILS 
 
 
Adverse Event/Adverse Experience 
Body Surface Area  
Modified Clinical Assessment Scale of Severity for Index Lesion 
Signs & Symptoms 
CFR 
Code of Federal Regulations 
CRF 
CXCR3 
CXCL9 
DEGs 
Case Report Form 
Chemokine Receptor-3 
Chemokines Ligands 9 
Differentially Expressed Genes  
DSMB 
Data and Safety Monitoring Board 
FDA 
Food and Drug Administration 
GCP 
GVHD 
Good Clinical Practice 
Graft Versus Host Disease  
HIPAA 
Health Insurance Portability and Accountability Act 
IB 
IL-1 
Investigator’s Brochure 
Interleukin-1 
IND 
IFNα 
IFNγ 
Investigational New Drug Application 
Interferon Alpha 
Interferon Gamma 
IRB 
JAK 
LP 
LTR 
MDC 
NRS 
PDC 
PGA 
Institutional Review Board 
Janus Kinase  
Lichen Planus 
Lichenoid Tissue Reaction 
Myeloid Dendritic Cells   
Numerical Rating Scale  
Plasmacytoid Dendritic Cells  
Physician Global Assessment  
PHI 
Protected Health Information 
PI 
Principal Investigator 
SAE 
Serious Adverse Event/Serious Adverse Experience 
SOP 
Standard Operating Procedure 
 
 
 
 
. 
 
 
 


Study Summary 
Title 
Baricitinib (LY3009104) in the Treatment of Cutaneous Lichen 
Planus 
 
Running Title 
Baricitinib (LY3009104) in LP 
Protocol Number 
21-003075 
Phase 
Phase II 
Methodology 
Open-Label, Single Arm  
Overall Study 
Duration 
21 to 24 weeks  
Subject Participation 
Duration 
20 weeks  
Single or Multi-Site  
Single Site  
Objectives 
To evaluate the safety and efficacy of Baricitinib (LY3009104) in 
cutaneous LP as assessed by the change in Physician Global Assessment 
(PGA) of skin, oral mucosa, and hair, Body Surface Area (BSA), Index 
Treatment and Control Lesion by Modified Clinical Assessment Scale 
of Severity for Index Lesion Signs and Symptoms (mCAILS) score, 
Pruritus Visual Analog Scale (VAS), Verbal Rating Scale (VRS), 
Pruritus Numerical Rating Scale (NRS), and Skindex-16. To predict 
responses through the identification of unique biomarkers of LP at week 
0 and utilizing RNA sequencing on responsive and non-responsive 
tissue at week 2.   
Number of Subjects 
12 
Diagnosis and Main 
Inclusion Criteria 
Non-pregnant adults with cutaneous LP  
Study Product, Dose, 
Route, Regimen 
Baricitinib (LY3009104) 2 mg orally administrated, once daily. 
Duration of 
Administration 
Drug will be administered from Day 0 through Week 16.  
Reference therapy 
Baricitinib (LY3009104) is currently being used to treat subjects with 
rheumatoid arthritis and under investigation for atopic dermatitis and 
psoriasis.  
Statistical 
Methodology 
The statistical analysis will provide descriptive summary statistics for 
categorical and continuous outcomes.  Categorical variables will be 
described by their count and proportion of occurrence while continuous, 
normally distributed variables will be described by their mean and 
standard deviation; and continuous, non-normally distributed variables 
will be described by their median and range 
 
1 
Introduction 
 
This document is a protocol for a human research study. This study will be carried out in accordance with the 
applicable United States government regulations and Mayo Clinic research policies and procedures.  
1.1 
Background 
 
Baricitinib (LY3009104) is an oral selective inhibitor of the Janus kinase (JAK) 


family of protein tyrosine kinases with selectivity for JAK1 and JAK2, and less selectivity for 
JAK3 with potent activity on the cytokine IFN-γ. IFN-γ is a critical cytokine in the signaling of LP. This study 
is aimed at evaluating the effects of baricitinib (LY3009104) 2 mg once daily in subjects with cutaneous LP; 
however, other forms of LP including mucosal and scalp disease may also be present.  
 
Lichenoid tissue reaction (LTR) includes lichen planus (LP), cutaneous lupus, dermatomyositis (DM), and 
graft versus host disease (GVHD). The pathogenesis of LP is incompletely understood; however, it is clearly 
T-cell mediated without a known auto-antigen. Lichen Planus (LP) is an inflammatory skin condition 
characterized by purple, polygonal, pruritic, papules and plaques. LP can affect any ectodermally derived 
tissues including: the skin (most commonly), nails, and mucous membranes. LP is thought to affect 
approximately 1-2% of the general population. Most cutaneous LP resolves within one to two years. Disease 
duration, in ascending order, is generalized cutaneous, non-generalized cutaneous, cutaneous and mucosal, 
mucosal, hypertrophic, and Lichen Planopilaris (hair LP). LP is the prototypical lichen tissue reaction (LTR). 
Modern theories of LP encompass three major stages: antigen recognition, lymphocyte activation, and 
keratinocyte apoptosis. A fourth stage, resolution, is a new and emerging topic. The occurrence of triggering 
factors in a genetically predisposed individual carrying LP-associated genes, results in disease development. 
During the initiation phase, damage to keratinocytes results in the release of DNA, RNA, and cathelicidin 
(LL37). These proteins can stimulate plasmacytoid dendritic cells (PDC) via toll like receptors 7, 9 (TLR7,9) 
which result in the release of interferon alpha (IFNα). IFNα can have both local and distant effects upon 
myeloid dendritic cells (MDC) as well as keratinocytes. Stimulated MDC interact with CD4+ T-helper cells 
and with the correct antigen. The antigen remains unknown but may represent a viral derived peptide. 
Signaling receptors on MDC will stimulate CD4+ T-helper cells via the release of Tumor necrosis factor alpha 
(TNFα), Interleukin-1 (IL-1), and -12. In addition, cluster of differentiation- (CD40) and CD40 ligand 
(CD40L) will result in the co-stimulation of the T-helper/MDC interaction. Stimulated CD4+ T-helper cells 
then release of interferon gamma (IFNγ) and IL-2. These cytokines stimulate CD8+ T-cytotoxic cells. The 
stimulated CD8+ cells expressing Chemokine receptor-3 (CXCR3) will migrate to the dermal-epidermal 
junction following the release of chemokines ligands 9 (CXCL9), -10, -11. These chemokines are released by 
stressed and stimulated keratinocytes. The stimulated CD8+ cells will interact with the stressed keratinocytes 
and can induce apoptosis in with the proper and signaling receptors. This antigen also remains unknown but 
may be a self-antigen released by local stress. The major kill signals are TNFα, granzyme, and perforin. Fas 
and Fas ligand (FasL) are expressed on both keratinocytes and lymphocytes. Local CXCR3+ DC and T-
regulatory cells may also modulate the local lichenoid response.  
 
Based upon the critical role of CD8+ T-cytotoxic cells and IFNα and IFNγ signaling in LP, inhibition with 
Janus Kinase (JAK) 1, 2 inhibitors have significant therapeutic potential. Fitting with this, recent data has been 
published showing that IFNγ primed keratinocytes are vulnerable to CD8+ cytotoxic T-cells.1 This axis is 
dependent upon JAK inhibitors. Interestingly, this study also showed that the cytotoxic immune response was 
mediated by JAK2. The use of baricitinib in vitro was able to protect keratinocytes from cell mediated toxicity.  
 
The current topical therapeutic options for LP are limited to topical corticosteroids, calcineurin inhibitors, and 
retinoids. Topical therapies are effective with limited disease but refractory disease is frequently encountered. 
Specific variants of LP, such as hypertrophic LP and localized cutaneous disease, are often refractory to all 
topical therapies and require systemic or skin-directed treatment with oral acitretin, methotrexate, 
glucocorticoids or light therapy. Long-term therapy with some of these oral medications is less desired due to 
adverse effects.  
 
Therefore, additional oral and topical therapies would be highly desirable in hypertrophic and refractory 
localized cutaneous LP. As proof of principle, systemic JAK1, 2 inhibition with ruxolitinib was highly 
effective in steroid refractory graft versus host disease (GVHD).2 Additionally, there was a recent case report 
of an exceptional responder to JAK1, 2 inhibition with ruxolitinib in refractory dermatomyositis (DM).3 As 
stated above, DM, GVHD, and LP share a similar histological pattern as well as signaling mechanism and, 
therefore, we would expect LP to respond similarly with systemic treatment. To test this concept, we would 
propose a single-center, exploratory, open-label, single-arm design study using systemic JAK1, 2 inhibitor for 
lesions of LP. 
 


1.2 
Investigational Agent 
 
Baricitinib (LY3009104) is an inhibitor of the JAK family of protein tyrosine kinases. Mitogenic and 
inflammatory cytokines are strongly implicated in the pathogenesis of psoriasis, alopecia areata, atopic 
dermatitis, and lichenoid tissue reactions of the skin including LP. Baricitinib (LY3009104) inhibits the 
phosphorylation of STAT proteins and the production of pro-inflammatory factors induced by cytokines such 
as IL-23 and IFNγ, and has the potential to simultaneously reduce inflammation, cellular activation and 
proliferation of key immune cells (Investigator’s Brochure). IFNγ is a key cytokine in the pathogenesis of LP.1 
 
Baricitinib (LY3009104) 2 mg orally administered, once daily in subjects cutaneous LP. 
1.3 
Preclinical Data 
 
All preclinical data below is referenced from the IB. Please refer to the IB for more details.  
 
Baricitinib represents a selective inhibitor of JAKs with excellent potency and selectivity for 
JAK2 (half-maximal inhibitory concentration [IC50] = 5.7 nM) and JAK1 (IC50 = 5.9 nM), and 
less potency for JAK3 (IC50 = >400 nM), or TYK2 (IC50 = 53 nM).4 
Although baricitinib potently inhibits JAKs, it does not significantly inhibit (<30% inhibition) a broad panel of 
26 other kinases when tested at 200 nM (approximately 50 times the average IC50 JAK potency of baricitinib). 
Moreover, baricitinib demonstrates excellent potency in cell-based assays (IC50 values of 3 to 30 nM) relevant 
to the pathogenesis of autoimmune disease such as IL-2 stimulated phosphorylation of JAKs and STATs and 
IL-2 induced proliferation of T cells. This effect is not due to general cytotoxicity. Baricitinib also potently 
inhibited the phosphorylation of STAT proteins and the production of proinflammatory factors (IL-17 or 
monocyte chemotactic protein- [MCP-] 1, for example) induced by other important cytokines such as IL-23 
and IL-6 with IC50 values in the range of 20 to 60 nM. 
 
To estimate baricitinib potency in blocking JAK activity in hematopoietic cells in vivo where 
serum protein binding can be a significant factor, a whole blood assay was established that 
measures STAT3 phosphorylation in response to cytokine stimulation. Baricitinib blocked 
IL-6-induced STAT3 phosphorylation in human whole blood with an IC50 value of 104 ± 14 nM 
(n = 5). No effects on total STAT3 levels were observed at any concentration tested. 
 
Baricitinib has been administered orally to CD-1 mice, Sprague Dawley rats, beagle dogs, and 
New Zealand white rabbits. In all toxicology species, exposures generally increased with 
increasing dose and were largely dose proportional to slightly greater than dose proportional. In 
general, exposures following repeated dosing were similar to single dose exposures, with some 
accumulation (approximately 2-fold) occurring in gravid rabbits. Gender differences were 
minimal. 
 
Following administration of [14C]-baricitinib, minimal metabolism was observed in all species, 
as parent compound was the primary circulating entity in plasma and the bulk of radioactivity in 
urine and feces from all species was also attributed to parent compound. Furthermore, the 
toxicology species used to evaluate baricitinib are exposed to metabolites observed in humans. 
In mouse, rat, rabbit, dog, and human plasma, baricitinib had moderate protein binding with in 
vitro values ranging from approximately 45% to 56%. 
 
Regarding multiple-dose toxicokinetics, the plasma toxicokinetics of baricitinib were evaluated in gravid 
Sprague Dawley rats and New Zealand white rabbits. Gravid rats were given daily oral doses of baricitinib 
beginning on Gestation Day (GD) 6 continuing through GD17. In a separate fertility and early embryonic 
development study, the plasma toxicokinetics of baricitinib were also evaluated in gravid Sprague Dawley rats 
administered daily oral doses of baricitinib for 2 weeks prior to cohabitation (Study Day 14) through GD6. In 
both studies, the exposures generally increased proportional to dose and no accumulation was observed. 
Gravid rabbits were administered daily oral doses of baricitinib beginning on GD7 and continuing through 
GD20. Exposures (Cmax and AUC) increased in a greater than dose-proportional manner and were 


approximately 2-fold higher on GD20 compared to GD7, suggesting some accumulation of compound in 
rabbits. 
 
Regarding drug distribution, quantitative whole-body autoradiographic techniques were used to determine the 
tissue distribution of drug-derived radioactivity in male and female pigmented (Long-Evans) and male non-
pigmented (Sprague Dawley) rats following a single oral dose of [14C]-baricitinib. Distribution was extensive, 
with the highest concentrations of radioactivity being found in alimentary canal contents, bile, and urine. 
Distribution of drug-derived radioactivity was similar in pigmented and non-pigmented rats, with the 
exception of [14C]-baricitinib distributing to the uveal tract of the eye in pigmented rats, suggesting binding to 
melanin-containing tissues. 
 
Elimination was nearly complete by 168 hours postdose in non-pigmented rats and 672 hours 
postdose in pigmented rats, except for low levels of radioactivity detectable in the dorsal caudal 
nerve, aorta, and uveal tract in pigmented rats. Specifically in the brain, radioactivity was below 
quantifiable limits (BQL) at all time points in pigmented rats, while in non-pigmented male rats 
low levels of radioactivity were detected in the brain (cerebrum: 0.189 µg equivalents/g of 
tissue; medulla: 0.231 µg equivalents/g of tissue) at 2 hours postdose, but were BQL at all other 
time points out to 168 hours. The low levels of radioactivity detected in the brain were likely 
from the vascular system and not directly in the brain tissue, thus penetration of baricitinib across 
the blood brain barrier is unlikely. The predominant routes of elimination were feces (in mice, rats with oral 
administration,) and urine (in rats with IV administration). Routes of elimination were similar in feces and 
urine in dogs.  
 
The placental transfer and subsequent fetal exposure following a single oral dose of [14C]- 
baricitinib was evaluated in pregnant Sprague Dawley rats. [14C]-baricitinib-related 
radioactivity was widely distributed in fetal tissues at moderate levels through 8 hours postdose. 
Fetal tissues with the highest concentrations of drug-derived radioactivity were adrenal gland, 
gastrointestinal tract, myocardium, liver, and lung. Moderate to low levels of [14C]-baricitinib-related 
radioactivity were measurable in fetal brain and spinal cord through 8 hours postdose. All fetal tissue 
radioactivity concentrations were BQL by the final sampling time at 24 hours postdose. Lacteal excretion 
following a single oral administration of [14C]-baricitinib to lactating Sprague Dawley rats was also evaluated. 
Peak concentrations of [14C]-baricitinib-related radioactivity were observed at 4 hours postdose in milk and 
declined to low or BQL levels by 24 hours postdose. Exposure to radioactivity was approximately 39- and 18-
fold greater in milk than in plasma based on area under the concentration versus time curve from zero to 
infinity (AUC0-∞) and Cmax values, respectively. The elimination half-lives of radioactivity in plasma and 
milk were similar (2.61 and 2.72 hours, respectively). 
 
Following a single oral dose of [14C]-baricitinib, the in vivo metabolism was evaluated in mice, 
rats, and dogs. Minimal metabolism was observed in all species, as parent compound was the 
primary circulating entity in plasma and the bulk of radioactivity in urine and feces from all 
species was also attributed to parent compound. In all species, the major metabolic pathway for 
these low level (<10% of dose) metabolites was oxidation. A low-level sulfate conjugate and 
glucuronide conjugate were also identified in mouse and rat feces and mouse and dog urine, 
respectively. Additionally, 2 to 3 low level unidentified metabolites were observed in various 
matrices in all species. 
 
The toxicologic and toxicokinetic profiles of baricitinib were characterized in oral studies of up 
to 6 months in rats and 9 months in dogs. The safety of baricitinib was also characterized in juvenile rats. In 
the rat study, dose-limiting toxicity was identified at the high-dose level in both sexes. The high dose of 100 
mg/kg/day was lowered to 60 mg/kg/day for females due to mortality occurring within the first 3 weeks of 
dosing that was subsequently determined to have resulted from gavage errors and not baricitinib toxicity. In 
males, mortality in high-dose (100 mg/kg/day) animals was mainly attributed to cardiomyopathy. This is a 
common background lesion in aging male rats, and it is possible that repeated dosing with baricitinib 
exacerbated this lesion. The 100-mg/kg/day dose was associated with plasma drug levels (unbound AUC0-24h 
104.7µM*h) approximately 80-fold above those associated with a 4-mg once daily (QD) dose in subjects with 


RA. Crystals, degeneration/regeneration, and/or tubular dilatation were observed in the kidney of males at 100 
mg/kg/day and females at 100/60 mg/kg/day and considered adverse. Additional findings deemed adverse at 
≥25 mg/kg/day included significant but reversible decreases in lymphocytes, generalized lymphoid depletion, 
and bone marrow hypocellularity, all presumed pharmacological effects of JAK inhibition. The no-observed-
adverse-effect level (NOAEL) for QD administration of baricitinib for 26 weeks was 5 mg/kg/day (unbound 
AUC of 2.04 µM*h). Skeletal malformations (bent limbs and rib anomalies) and an increased incidence of 
skeletal development variations occurred in rat fetuses. Decreased pup weights were the dose-limiting effect in 
the rat pre-postnatal study. In juvenile rats, like adults, effects on body weight and the immune system were 
observed. Bone effects observed in the juvenile study included bacterial osteomyelitis with secondary fracture 
in one high dose animal, and exacerbation of femoral head and neck degeneration/atrophy. 
 
In a 9-month dog study, administration of doses ≥3 mg/kg/day resulted in baricitinib-related 
early termination of dogs, suspension of dosing, adverse clinical effects, and anatomic and 
clinical pathology changes associated with clinical development of demodicosis and 
pyogranulomatous dermatitis; a secondary effect of the immunomodulatory pharmacology of 
baricitinib. Liver lesions consisting of minimal to moderate inflammatory cell infiltrates and/or 
inflammation and minimal to slight biliary hyperplasia, and associated increases in serum liver 
enzymes (aspartate aminotransferase [AST], alanine aminotransferase [ALT], alkaline 
phosphatase [ALP], gamma-glutamyltransferase [GGT]) were observed in dogs given 
≥3 mg/kg/day. However, the relationship of the liver findings to baricitinib is uncertain because 
of the confounding severe demodectic mange and inflammation that were aggressively treated 
with Ivermectin and nonsteroidal anti-inflammatory drugs. Based on the adverse nature of the 
generalized demodicosis in animals given ≥3 mg/kg/day, the NOAEL is 0.5 mg/kg/day (unbound 
AUC of 0.74 µM*h). 
 
Overall, the major cell types affected by JAK inhibition in the nonclinical safety studies were lymphocytes and 
eosinophils. Decreases in lymphocytes and eosinophils in dogs were associated with clinical manifestations of 
immunosuppression including demodectic mange and bacterial, protozoal and/or yeast infections. Significant 
decreases in mean lymphocyte counts are generally not observed clinically. Given the general lack of 
correlation between nonclinical and clinical effects such as decreased lymphocyte counts with consequent 
infections, it seems useful to rely on the clinical safety database for consideration of safety margins, with the 
understanding that the consequences of immunosuppression may occur. 
 
Regarding developmental toxicity, maternal and embryo-fetal toxicity occurred at the highest doses evaluated. 
At the high dose of 30 mg/kg in rabbits, maternal effects included mortality and decreased body weight gain, 
and decreased weight and rib/vertebral anomalies were observed in the fetuses. The NOAEL in rabbits for 
both maternal and fetal toxicity was 10 mg/kg/day. In the rat, maternal effects were decreased body weight 
gain and lacrimation at the high dose of 40 mg/kg; skeletal malformations (bent limbs and rib anomalies) and 
an increased incidence of skeletal development variations occurred in fetuses at the mid and high doses. The 
maternal NOAEL was 10 mg/kg, and the fetal NOAEL in rats was 2 mg/kg. 
 
Regarding carcinogenicity, administration of baricitinib was well tolerated in both the 2-year rat and 6-month 
hRAS [001178-T (hemizygous), CByB6F1-Tg(HRAS)2Jic] transgenic mouse studies and did not produce 
neoplasms at any of the administered doses. Margins of safety based on unbound plasma exposure ranged 
from approximately 6-66-fold exposure at the maximum projected human dose. In rats, baricitinib 
administration was associated with increased survival and a decrease in proliferative changes, which included 
decreased incidences of neoplastic and 
hyperplastic lesions in the mammary gland and liver. 
 
In a variety of in vitro binding and kinase assays, baricitinib did not demonstrate cross-reactivity 
for any of approximately 50 different receptors, channels, and transporters; or against 
approximately 30 non-JAK family kinases evaluated at 0.1 and 1 µM, and 0.2 µM, respectively. 
Safety pharmacology studies indicate that, at clinical doses, baricitinib is not expected to produce 


effects related to central nervous system (CNS), cardiovascular (including human ether-à-go-go-related gene 
[hERG]), or respiratory function. At Cmax exposures approximately 21-(dog) to 
162-(rat) fold greater than the 4 mg clinical dose, the following findings were noted: altered 
autonomic activity, transient decreases in locomotor activity, and single occurrences of 
lacrimation at 100 mg/kg in a rat CNS evaluation; lower respiratory frequency and minute 
volume at 100 mg/kg in a rat respiratory evaluation; slight lowering of arterial pressure (2 to 3 
hours postdose) and pulse pressure (7 to 18 hours postdose), and slight increase in heart rate (0 
to 18 hours postdose) at 3 mg/kg in a dog cardiovascular evaluation; and no prolongation of the 
QTc interval in dogs. The IC50 for baricitinib on the hERG current was 161.5 µM. The 
exposure margin between expected human Cmax plasma baricitinib (unbound) concentrations 
after a 4-mg dose (108 nM) and hERG IC50 inhibition is approximately 1400-fold, thus, 
indicating a low probability of a QT prolongation effect at therapeutically relevant doses. 
 
1.4 
Clinical Data to Date 
 
Clinical data to date is referenced from the IB. Please refer to the IB for more details.  
 
As of 13 February 2019, 3 Phase 2 studies and 5 Phase 3 clinical studies have been completed in 
patients with RA, and an extension study to collect long-term data is ongoing. In addition, Lilly 
has completed 22 Phase 1 studies (1 in patients with rheumatoid arthritis (RA) and 21 clinical pharmacology 
studies) and 4 Phase 2 studies (1 in diabetic nephropathy (DN), 1 in psoriasis (Ps), 1 in systemic lupus 
erythematosus (SLE), and 1 in atopic dermatitis (AD)). Other studies are ongoing, including an expanded 
access (EA) program for rare autoinflammatory diseases, 7 Phase 3 studies in AD, 3 Phase 3 studies in SLE, 1 
Phase 2 study in primary biliary cholangitis (PBC), 2 Phase 3 studies in juvenile idiopathic arthritis (JIA), and 
1 Phase 2/3 
study and 1 Phase 3 study in alopecia areata (AA). As of this date, approximately 548 healthy 
volunteers/Phase 1 study participants and 6555 patients have received baricitinib since the start of clinical 
trials. 
 
Effects on QTc Interval 
A thorough QT (TQT) study (JADO) showed that a supratherapeutic single oral dose of 40 mg 
baricitinib did not prolong the electrocardiogram QT interval corrected for heart rate (QTc) 
based on ICH-E14 criteria. Single doses up to 40 mg and multiple doses of up to 20 mg daily for 10 days have 
been administered in clinical trials without dose-limiting toxicity. 
 
Rheumatoid Arthritis 
The primary efficacy measure in all completed Phase 3 studies was a 20% improvement in 
American College of Rheumatology (ACR) response criteria (ACR20). Other efficacy 
parameters evaluated include the following: ACR50, ACR70;5 the change in 
the individual components of the ACR core set (tender joint count, swollen joint count, patient’s 
assessment of pain as measured by Health Assessment Questionnaire-Disability Index [HAQDI], 
patient’s global assessment of disease activity, physician’s global assessment of disease 
activity, health assessment questionnaire, high sensitivity C-reactive protein [CRP]); van der 
Heijde Modified Total Sharp Score (mTSS);6 and the Disease Activity 
Score 28 (DAS28).7 In addition, the Simplified Disease Activity Index 
(SDAI), Clinical Disease Activity Index (CDAI), and the Boolean-based definition of remission 
were evaluated.8  
 
The primary efficacy objective (based on ACR20) was met in each completed Phase 3 study, and 
most major (gated) secondary objectives were also met. Across the completed Phase 3 studies, baricitinib 
consistently demonstrated significant improvements compared to comparators (placebo, MTX, adalimumab) 
with respect to relevant domains of efficacy. Across measures, improvements were generally seen with 
baricitinib from the earliest weeks of treatment (in many instances as early as Week 1) and sustained through 
the duration of each study. 


 
Baricitinib demonstrated statistically significant inhibition of radiographic progression of 
structural joint damage (mTSS) in each of the 3 completed studies which incorporated this 
measure (Studies JADZ, JADV, and JADX). 
 
In Study JADZ, baricitinib 4 mg used as monotherapy demonstrated significantly larger 
treatment effects across relevant efficacy measures compared to the active comparator, MTX 
monotherapy. In most respects, the treatment effects observed for baricitinib monotherapy were 
comparable in magnitude to those associated with the combination of baricitinib plus MTX. 
Consistent with these findings, in subgroup analyses of Study JADX, treatment effects for 
baricitinib appeared comparable whether it was used alone, on a background of MTX, or on a 
background of other cDMARDs. 
 
In Study JADV, all patients received background MTX during the study, a measure introduced to 
afford the active bDMARD comparator adalimumab the opportunity to exert optimum efficacy. 
Baricitinib 4 mg demonstrated significantly larger treatment effects across relevant efficacy 
measures compared to both placebo and to the active comparator adalimumab. 
 
In Studies JADX and JADW, baricitinib 4- and 2-mg doses were evaluated compared to placebo. 
Study JADW included a substantial proportion of patients who had failed multiple bDMARDs 
with various mechanisms of action. In each study, both baricitinib dose groups demonstrated 
treatment effects that were superior to placebo. Treatment effects were more rapid, more 
consistently statistically significant, and larger in magnitude across important efficacy measures 
for the baricitinib 4-mg dose than for baricitinib 2 mg. These observations were consistent with 
findings from completed Phase 2 studies, and were supported by exposure and exposure– 
response analyses. 
 
In the long-term extension Study JADY, a variety of analyses demonstrated that for patients who 
had completed 24 to 128 weeks of treatment with baricitinib in an originating study, 
effectiveness was sustained across measures during an additional 48 weeks of treatment. 
 
Patients who had received other active study drug regimens (MTX, adalimumab, or baricitinib 
plus MTX) in an originating study and switched study drug to baricitinib upon entering 
Study JADY did not experience loss of disease control during 48 weeks of treatment. Among patients who had 
achieved satisfactory and sustained disease control after 
at least 15 months of treatment with baricitinib 4 mg QD, patients who reduced their dose to 
2 mg QD in a randomized, double-blind manner exhibited statistically significant increases in 
disease activity compared to patients who continued to receive baricitinib 4 mg. However, most 
patients (in both the groups who continued 4 mg and whose dose was reduced to 2 mg) retained 
the state of low disease activity or remission that led to their re-randomization. 
 
Safety: In the RA clinical development program, no increased risk for serious adverse events (SAEs) 
(including serious infections, malignancies, or major adverse cardiac events [MACE]) was observed for either 
the baricitinib 4-mg or baricitinib 2-mg group compared to placebo control. In baricitinib-treated patients, 
there were no SAE preferred terms that were reported by >1% of patients. In the baricitinib 2-mg versus 4-mg 
comparison, there were no differences in the proportion of patients with SAEs through 16 weeks. Deaths have 
been reported 
infrequently in patients taking baricitinib and are not considered a risk with baricitinib use. Serious infections 
were not different from placebo and no differences were noted between doses for serious or opportunistic 
infections in the placebo-controlled data. 
 
Regarding TEAEs, treatment-emergent infections were more commonly observed in baricitinib-treated 
patients. The most frequently reported infections were upper respiratory tract infections (URTI), viral URTI, 
urinary tract infections (UTI), bronchitis, pharyngitis, gastroenteritis, herpes zoster, influenza, sinusitis, and 
herpes simplex. The majority of the commonly reported AEs were anticipated events in the RA population (for 


example, infections including upper respiratory tract infections) or laboratory abnormalities consistent with the 
pharmacology of JAK inhibitors (for example, increases in creatine phosphokinase [CPK] and lipids including 
total cholesterol, low density lipoproteincholesterol (LDL-C), high density lipoprotein-cholesterol (HDL-C) 
and triglycerides). Of these AEs, upper respiratory tract infections (including viral upper respiratory tract 
infections and bronchitis), herpes zoster, lipid increases, and increased CPK were considered adverse drug 
reactions (ADRs). 
 
Psoriasis 
The primary efficacy parameter evaluated were the Psoriasis Area and Severity Index (PASI) 
75 (EMEA [WWW]).9 Additional efficacy parameters evaluated included 
PASI 50 and PASI 90. 
 
Study JADP: The primary efficacy analysis was to investigate whether at least 1 baricitinib dose group was 
superior to placebo at Week 12 as measured by the proportion of patients with PASI 75. At 12 weeks, both the 
8- and 10-mg groups had significantly greater improvement compared to placebo.  
 
For those patients achieving a PASI 75 response at 12 weeks who stayed on the same dose, this 
level of efficacy was largely maintained at 24 weeks. For those patients who did not achieve a 
PASI 75 at 12 weeks, it was possible to achieve additional benefit by increasing the dose, or for 
partial responders, staying on the same dose for an additional 12 weeks. For the 10-mg group, 
maximal PASI response was seen at 12 weeks; however, additional benefit was apparent in the 
4- and 8-mg groups at 16 weeks. The predicted PASI 75 response at 16 weeks was 42.5% and 
48.6% for the 4- and 8-mg groups, respectively. 
 
Safety: In Study JADP, there was a low incidence of SAEs reported during the 4 parts of the study. The SAEs 
were assessed by the phase of study and if they occurred when switched from a high dose (8 mg or 10 mg) to a 
low dose (2 mg to 4 mg). In Part A, the incidence of SAEs was the same in all treatment groups, with 1 SAE 
per group. Events occurring in baricitinib-treated 
patients included pneumonia, esophageal carcinoma, squamous cell carcinoma of skin, and 
psoriasis.10 Three SAEs were reported in Part B, with a gastrointestinal 
hemorrhage and pulmonary embolism occurring in patients receiving high doses in Parts A and 
B, and a diabetic foot reported initially in part A in a patient who received placebo and then 
taking baricitinib 10 mg in Part B. In Part C, an SAE of abdominal pain was reported in a patient 
receiving a high dose switched to a low dose from Part B to C, and 1 SAE of cellulitis was 
reported in a patient switched from a high dose to placebo in Part B to C. In Part D, 2 SAEs were reported, 
arteriosclerosis coronary artery in a patient receiving baricitinib 8 mg and ovarian 
adenoma in a patient receiving baricitinib 10 mg. 
 
From baseline through the first 12 weeks of treatment, the percentages of patients who experienced at least one 
TEAE were similar in the placebo, 2- and 4- mg dose groups (44.1%, 50.0% and 47.2%, respectively) but were 
higher for the 8- and 10-mg dose groups (57.8% and 63.8%, respectively). The most common TEAEs were 
infestations and infections where the incidence rate was 26.5% for patients treated with placebo and 21.1% for 
the combined baricitinib groups. The most common occurrence of TEAEs in all groups was nasopharyngitis. 
 
Atopic Dermatitis 
Study JAHG was a randomized, double-blind, parallel, placebo-controlled, 16-week Phase 2 study comparing 
the efficacy and safety of baricitinib to placebo in patients with moderate-to-severe AD. Patients were 
randomized 4:3:3 to placebo (n=49), baricitinib 2 mg QD (n=37), or 
baricitinib 4 mg QD (n=38). Background therapy of mid-potency topical corticosteroids (TCS 
[triamcinolone 0.1% cream]) was used during the 28-day standardization period prior to 
randomization and continued throughout the study. The study was positive for the primary 
outcome of the proportion of patients achieving a 50% improvement from baseline in Eczema 
Area and Severity Index (EASI-50) score in the baricitinib 4-mg QD treatment arm compared to 
placebo at Week 16. Differences in EASI-50 response compared to placebo were significant in 
both the 4- and 2-mg groups at Week 4 and remained significant to Week 16 in the 4-mg group 


and Week 12 in the 2-mg group. To assess if efficacy was impacted by baseline disease severity, subgroup 
analysis of response for patients with EASI baseline scores above and 
below median EASI score at baseline was conducted. This analysis showed that most of the 
placebo (background TCS) response observed during the trial was observed in the population 
with lower EASI baseline scores. Given these findings and given that the proposed entry 
criterion for Phase 3 studies is patients with an EASI score of ≥16, analyses were also performed 
on the population with EASI scores at baseline ≥16. It is of note that, in general, the 
overall effect of examining the higher disease severity subgroups (EASI above median, or EASI 
≥16) across a range of efficacy measures (particularly more stringent endpoints, e.g., Investigator 
Global Assessment [IGA] 0,1 and EASI-75) is a lowering of the observed response for the 
placebo group and to a lesser degree the 2-mg group, whereas the efficacy in the 4-mg groups 
appears to be largely maintained.  
 
The 4–mg group, and on some analyses to a lesser degree the 2-mg group, was also able to 
demonstrate significant improvements compared to placebo across a range of other physician and 
patient-reported outcomes that are clinically relevant to the assessment of AD, for example, 
Scoring Atopic Dermatitis (SCORAD), Patient Oriented Efficacy Measure (POEM), 
Dermatology Life Quality Index (DLQI), and also assessments of itch and sleep. A number of 
these assessments were statistically significant as early as Week 1, and generally reached a 
maximal effect by Week 4. 
 
There are currently 5 outpatient, multicenter, double-blind, placebo-controlled, Phase 3 studies 
(I4V-MC-JAHL [JAHL], I4V-MC-JAHM [JAHM], I4V-MC-JAIN [JAIN], I4V-MC-JAIW 
[JAIW], and I4V-MC-JAIY [JAIY]) and 2 long-term extension studies (I4V-MC-JAHN and 
I4V-MC-JAIX) evaluating the safety and efficacy of baricitinib in adult patients with moderate to-severe AD 
who have responded inadequately to or who are intolerant to topical therapy (i.e., TCS or topical calcineurin 
inhibitors). Based on preliminary results from Phase 3 Studies JAHL and JAHM, baricitinib met the primary 
endpoint in both studies. In both studies, a statistically significantly larger proportion of patients treated with 
baricitinib than placebo patients achieved the primary endpoint at Week 16 defined by the Investigator’s 
Global Assessment (IGA) score for AD of clear or almost clear (IGA 0,1). 
 
Safety: In study JAHG, there were 3 treatment-emergent SAEs reported, 2 in the 
baricitinib 2-mg dose group and 1 in the 4-mg dose group. One SAE occurred in the treatment 
period in the 4-mg dose group, which was a benign large intestine polyp that was discovered 
after 21 days of treatment. Two SAEs were reported after treatment discontinuation in patients 
treated with baricitinib 2 mg. One patient had an uncontrolled flare of AD and the second patient 
had a case of acute bronchitis in association with underlying alpha-1 antitrypsin deficiency, 
which was not disclosed at screening. 
 
Treatment-emergent AEs occurring in 4 or more patients in Study JAHG included headache, 
blood CPK increased, nasopharyngitis, and dermatitis atopic. The events of headache, CPK 
increased, and nasopharyngitis occurred numerically more often with baricitinib than 
with placebo. For AEs that have been declared of special interest for baricitinib, there was a numerically 
higher proportion of patients with an event in the 4-mg group compared to the 2-mg and placebo groups 
(placebo: 11/49; 22%; baricitinib 2 mg: 10/37; 27%; baricitinib 4 mg: 17/38; 45%). The numerical increase 
seemed to be driven mostly by an increase in the number of nasopharyngitis and upper respiratory tract 
infections. One case of herpes zoster was reported for a patient in the placebo group. The percentage of 
patients discontinuing the study (including the washout, including worsening AD during washout) because of 
an AE was highest in the 4-mg group (6/38; 16%) compared to the placebo group (5/49; 10%) and the 2-mg 
group (3/37; 8%). 
 
In preliminary results from Phase 3 Studies I4V-MC-JAHL (JAHL) and I4V-MC-JAHM 
(JAHM), SAEs were reported by 3%, 4%, 1%, and 1% of patients treated with placebo, 1 mg 
baricitinib, 2 mg baricitinib, and 4 mg baricitinib, respectively. No serious venous 
thromboembolic events (VTEs), major adverse cardiovascular events (MACE), or deaths were 


reported in the 16-week placebo-controlled period. There were 4 serious events of eczema 
herpeticum reported in 2 patients receiving placebo and 2 patients receiving baricitinib 1 mg. TEAEs were 
reported by 55%, 54%, 58% and 56% of patients treated with placebo, 1 mg baricitinib, 2 mg baricitinib, and 4 
mg baricitinib, respectively. The most common TEAEs were headache and nasopharyngitis, and 
nasopharyngitis and upper respiratory tract infections were the most common treatment-emergent infections. 
No TEAEs of VTEs or MACE were reported in the 16-week placebo-controlled portion of the studies. 
 
Systemic Lupus Erythematosus 
Study JAHH was a Phase 2, multicenter, randomized, double-blind, placebo-controlled, parallel, 
outpatient, 24-week study evaluating the efficacy and safety of baricitinib 4 mg and 2 mg QD in 
adult patients with SLE receiving standard therapy. A total of 314 patients were randomized to 
placebo (n=105), baricitinib 2-mg QD (n=105), or baricitinib 4-mg QD (n=104). 
 
The study was positive for the primary efficacy measure, the percentage of patients achieving 
remission of SLE arthritis and/or rash, as defined by SLE Disease Activity Index 2000 
(SLEDAI-2K) at Week 24. A significantly greater percentage of patients treated 
with baricitinib 4 mg QD (67.3%) achieved remission at Week 24 compared to placebo (53.3%) 
(p<0.05). In contrast, there was no statistically significant effect of baricitinib 2 mg (58.1%) 
compared to placebo on the percentage of patients achieving remission. 
 
The study was also positive also for the secondary efficacy measures that included SLE 
Responder Index (SRI-4), occurrence of flare as measured by SLEDAI Flare Index (SFI), and 
Lupus Low Disease Activity State (LLDAS). The percentage of patients achieving an SRI-4 response at Week 
24 was significantly greater for those treated with baricitinib 4-mg QD (64.4%) compared to placebo (47.6%) 
(p<0.05). In contrast, there was no statistically significant effect of baricitinib 2 mg (51.4%) compared to 
placebo on the percentage of patients achieving SRI-4 response. 
 
The percentage of patients with flare (any severity) during the 24-week treatment period, as 
assessed with the SFI, was reduced for those treated with baricitinib 4-mg QD (32.7%) compared 
to placebo (51.4%) (p<0.05). The SFI uses the SLEDAI-2K score, disease activity scenarios, 
treatment changes, and the Physician’s Global Assessment (PGA) of Disease Activity to define 
mild/moderate and severe flares. The index considers the absolute change in total 
scores, new or worsening symptoms, and increases in medication use or hospitalization due to 
the disease activity. There was no statistically significant difference between baricitinib 
2 mg QD (42.9%) and placebo. A similar dose-associated trend was observed for severe flare but 
the effect was not statistically significant (11.4% for placebo, 9.5% for baricitinib 2 mg, and 
5.8% for baricitinib 4 mg). 
 
There was a statistically significant difference in the percentage of patients treated with 
baricitinib 4-mg QD who achieved LLDAS at Week 24 compared to placebo (p<0.05). In contrast, there was 
no statistically significant effect of baricitinib 2-mg compared to placebo on the percentage of patients 
achieving LLDAS. 
 
There are currently 2 ongoing Phase 3, multicenter, randomized, double-blind, 
placebo-controlled, outpatient clinical trials (I4V-MC-JAHZ and I4V-MC-JAIA) evaluating 
the safety and efficacy of baricitinib 4 mg and 2 mg in adult patients with SLE receiving 
standard of care (SOC). The primary objective is to evaluate the effect of baricitinib 4 mg plus SOC compared 
to placebo plus SOC as measured by the proportion of patients achieving an SRI-4 response at Week 52. 
 
Safety: In study JAHH, the proportions of patients who reported a SAE through a 24-week treatment period 
and up to 30 days post-treatment were higher in the baricitinib groups (10.5% and 9.6% for baricitinib 2-mg 
and 4-mg, respectively) compared to placebo (4.8%). Although the numbers were small, infections contributed 
the most to the imbalance in SAEs, with 6 (5.8%) reported in the baricitinib 4-mg group and 2 (1.9%) in the 
baricitinib 2-mg group, as compared to 1 (1.0%) in the placebo group. There were no cases of serious herpes 
zoster or opportunistic infection and no reports of tuberculosis (TB). There were no deaths in the study. There 


were no malignancies or MACE reported. One SAE of deep vein thrombosis (DVT) was reported in the 
baricitinib 4-mg group, in a patient with preexisting antiphospholipid antibodies and pain in the affected limb 
(right calf) prior to study entry, who was taking a concomitant oral corticosteroid and celecoxib during the 
study. 
 
The proportion of patients who reported at least 1 TEAE was similar across treatment groups 
(64.8% for placebo, 71.4% for baricitinib 2 mg QD, and 73.1% for baricitinib 4 mg QD) in the 
JAHH study during the 24-week treatment period and up to 30 days after treatment. The 
proportions of patients who reported viral upper respiratory tract infections were higher for 
baricitinib-treated patients (9.6%) compared to placebo (3.8%) with similar proportions for the 
baricitinib 2-mg and 4-mg dose groups (9.5% vs. 9.6%, respectively). 
 
Compared to placebo or baricitinib 2-mg, a higher proportion of patients had a treatment 
interruption due to AE in the baricitinib 4-mg group: 10.5% for placebo, 6.7% for baricitinib 
2 mg, and 20.2% for baricitinib 4 mg. Adverse events in the infections and infestations system 
organ class were the most common reason for treatment interruption in all 3 treatment groups 
and made the largest contribution among the system organ classes to the difference between 
baricitinib 4-mg and placebo. 
 
 
Diabetic Nephropathy 
Study I4V-MC-JAGQ was a Phase 2 study in patients with diabetic nephropathy (DN). This 
study primarily tested the hypothesis that at least 1 baricitinib dose group was superior to 
placebo in decreasing urinary albumin/creatinine ratio (UACR) from baseline to Week 24. A 
statistically significant decrease from baseline was observed in the UACR ratio of Week 24 to baseline in the 
baricitinib 4-mg QD treatment group (least-squares mean difference as a ratio 
[LSMD]=0.59; p=0.022) when compared with placebo. 
 
Additional analyses of UACR using values obtained from the 24-hour urine collection were 
supportive of the results observed in the primary and secondary efficacy analyses of UACR that 
were obtained from the first morning urine (FMU) collection. Statistically significant treatment 
differences were observed during the treatment period for the decrease from baseline in 24-hour 
UACR ratio at Week 12 in the baricitinib 1.5-mg QD (LSMD as a ratio=0.71; p=0.040) and 
baricitinib 4-mg QD (LSMD as a ratio=0.61; p=0.004) treatment groups when compared with 
placebo, and at Week 24 in the baricitinib 1.5-mg QD treatment group when compared with 
placebo (LSMD as a ratio=0.67; p=0.031). Analysis of UACR results from both FMU and 24-hour urine 
collections at Week 28 indicated that the UACR reductions compared with placebo, that were noted at Week 
24, were largely maintained after 4 weeks of washout, at Week 28. 
 
No additional efficacy data from ongoing or completed Phase 2 or Phase 3 studies in other inflammatory 
conditions are currently available.  
 
1.5 
Dose Rationale  
 
Balancing the safety risks and efficacy data of varying baricitinib doses from prior studies, our study proposes 
oral Baricitinib (LY3009104) 2 mg QD dosing for 16 weeks (primary endpoint) in LP study subjects. If the 
patient opts into the extension portion of the study, the dose will escalate to 4 mg.  
 
 
1.6 
Risks and Benefits 
 
Benefits: 
 


Others with LP may benefit in the future from what we learn in this research study.  It is possible their 
symptoms could also improve while being treated with this study drug  
 
      Risks: 
 
The following adverse events were reported as common side effects associated with the use of Baricitinib 
(LY3009104): 
 
• Very common (occurring in greater than or equal to 10% of subjects), common (occurring in 1-10% of 
subjects), and rare but serious (occurring in < 1% of subjects) side effects occurring in subjects. As of 
the clinical data cutoff date, approximately 548 healthy volunteers/Phase 1 study participants and 6555 
patients have received baricitinib since the start of clinical trials. The most frequently reported TEAEs 
in healthy participants and participants with RA, Ps, AD, and SLE receiving 4-mg dose or lower are 
listed below. 
 
Very Common (affecting more than 10 in every 100 patients) 
No adverse event was seen in more than 10% of the rheumatoid arthritis, psoriasis, atopic dermatitis or 
systemic lupus erythematosus subjects treated with baricitinib (LY3009104). 
 
Common (affecting less than 10 in every 100 patients) 
Upper respiratory tract infection / nasopharyngitis (common cold) 
Bronchitis / pharyngitis  
Urinary tract infection (UTI) 
Gastroenteritis (upset stomach) 
Herpes zoster / herpes simplex activation (shingles / cold sore, respectively) 
Influenza (flu) 
Increase in blood chemistry labs (including lipids and CPK) 
Headache 
Atopic Dermatitis (treatable skin condition) 
Thrombocytosis (increased blood platelets) 
Nausea 
 
 
Rare but Serious  
Pulmonary embolism (blood clot in lung)  
Deep vein thrombosis (blood clot typically in leg) 
Cellulitis (severe skin infection) 
Anemia 
 
 
Hematologic and clinical chemistry lab abnormalities: 
Baricitinib (LY3009104) taken systemically can inhibit the growth of blood cells. Low blood cells can make 
subjects more susceptible to infections by bacteria, virus, and fungi. The risk is low with systemic therapy and 
subjects will be monitored for any signs of inhibition of their blood counts.  
 
Treatment with Baricitinib (LY3009104) has been associated with dose-related increases in CPK and total 
cholesterol, triglycerides, LDL-cholesterol (C), and HDL-C with stable LDL/HDL ratio. Observed increases 
have not led serious events or discontinuation of Baricitinib (LY3009104) in prior clinical trial participants. 
These lipid counts will be monitored throughout the study.  
 
Infection risk: 
There is an increased risk of infection with use of Baricitinib (LY3009104). This will be monitored for. 
Baricitinib (LY3009104) may increase the risk of infections and reactivation of latent infections such as 
Tuberculosis, Valley Fever or viral infections such as herpes zoster (shingles) or herpes simplex (cold sore). 
Please seek medical advice if signs or symptoms suggestive of infection occur.  


 
Allergy: 
It is possible that some people could have an allergic reaction to Baricitinib (LY3009104). 
   
Venous thromboembolism: 
Events of deep venous thrombosis (DVT) and pulmonary embolism (PE) have been reported in rare 
occurrences with patients taking Baricitinib (LY3009104). While we do not expect such events to occur, 
patients should seek medical advice if they experience signs or symptoms of DVT/PE such as significant 
shortness of breath, bloody cough or lower leg swelling, redness and pain.  
Cancer Risk: 
Baricitinib (LY3009104) may have the potential to affect the subject’s immune system; they may be at 
increased risk for infections and possibly cancer. Live vaccines should not be given concurrently with 
Baricitinib (LY3009104).  
 
Pregnancy Risk: 
The effect of the study drug on a fetus (developing baby still in the womb), or on a breastfeeding infant, is 
unknown and may be harmful. Because of these risks, women cannot take part in this study if they are 
pregnant or breastfeeding. 
 
Skin biopsy: 
A skin biopsy is generally a safe procedure, but some potential risks may include local pain, mild local 
bruising, bleeding, scarring, and an infection at the site where the skin biopsy was performed.  If a topical 
antibiotic is used afterwards, then there is a small risk of an allergic reaction. 
 
Chest X-ray: 
Subjects will be exposed to radiation from the chest x-ray. The amount of radiation has a low risk of harmful 
effects. 
 
ECG: 
There may be mild discomfort from the sticky pads and a possibility of the skin being irritated by the adhesive 
on the sticky pads. Chest hair may need to be shaved prior to the placement of the sticky pads. 
 
Blood draw:  
The risks of drawing blood include pain, bruising, lightheadedness, and/or fainting, or rarely, infection at the 
site of the needle stick.   
 
Other: 
As with all research, there is a chance that confidentiality could be compromised; however, we take 
precautions to minimize this risk.  
 
2 Study Objectives 
 
Primary Objective: 
To determine the efficacy of Baricitinib (LY3009104) as measured by PGA of skin overall response at week 
16, 
 
 
Secondary Objective: 
To determine the efficacy of Baricitinib (LY3009104) as measured by the change in modified CAILS score of 
the cutaneous index treatment (weeks 0 and 16) and changes in lesion count (week 0 and 16), the change in 
Pruritus VAS, VRS, & NRS,  (week 0 to week 2, weeks 0 to 4, weeks 4 to 8, weeks 0 to 8, weeks 8 to 12, 
weeks 0 to 12, weeks 12 to 16, weeks 0 to 16, weeks 16 to 20 and weeks 0 to 20), change in Skindex-16 (week 
0 to week 2, weeks 0 to 4, weeks 4 to 8, weeks 0 to 8, weeks 8 to 12, weeks 0 to 12, weeks 12 to 16, weeks 0 
to 16, weeks 16 to 20 and weeks 0 to 20), change in Physician Global Assessment (PGA) of oral mucosa and 


hair (week 0 to week 2, weeks 0 to 4, weeks 4 to 8, weeks 0 to 8, weeks 8 to 12, weeks 0 to 12, weeks 12 to 
16, weeks 0 to 16, weeks 16 to 20 and weeks 0 to 20), change in BSA (week 0 to week 2, weeks 0 to 4, weeks 
4 to 8, weeks 0 to 8, weeks 8 to 12, weeks 0 to 12, weeks 12 to 16, weeks 0 to 16, weeks 16 to 20 and weeks 0 
to 20), change in Modified CAILS (week 0 to week 2, weeks 0 to 4, weeks 4 to 8, weeks 0 to 8, weeks 8 to 12, 
weeks 0 to 12, weeks 12 to 16, weeks 16 to 20 and weeks 0 to 20), and change in lesion count (week 0 to week 
2, weeks 0 to 4, weeks 4 to 8, weeks 0 to 8, weeks 8 to 12, weeks 0 to 12, weeks 12 to 16, weeks 16 to 20 and 
weeks 0 to 20).  
 
Exploratory Objectives:  
To predict responses and examine the pharmacodynamics of treatment through the identification of unique 
biomarkers and transcriptomic changes of LP at week 0 and utilizing RNA sequencing on responsive and non-
responsive tissue at week 2 to correlate these biomarkers with measures of global response: Modified CAILS, 
PGA, BSA, and lesion count.  
 
If the patient chooses to participate in the extension, all of the objectives listed above will be observed through 
to week 32.  
 
3 Study Design 
 
3.1 
General Description 
 
This is a single center, exploratory, open-label, single-arm design study of 12 patients. Treatment naïve and 
treatment refractory patients with LP will be treated Baricitinib (LY3009104). Patients who are non-
responders to physician choice standard of care will undergo a washout period and will be enrolled in the 
study. 
 
Multiple safety studies have been conducted with Baricitinib (LY3009104) (see Safety) and a dose of 2 mg 
QD is deemed safe. (Investigator’s Brochure) We propose a single center, exploratory, open-label, single-arm 
design study of 12 patients. Treatment naïve and treatment refractory patients with LP will be treated with 
Baricitinib (LY3009104) for 16 weeks. 
 
Individuals with cutaneous LP will be eligible. Individuals must have 4 lesions at baseline; however, a 
minimum of 8 lesions which are at least 5mm in diameter is ideal. All lesions will be annotated, photographed, 
and scored. The rationale for a minimum of 8 lesions is based upon the assumption of a 50% response rate at 2 
weeks. With 8 lesions, there would be a less than 1% chance that all 8 lesions would resolve spontaneously. 
Prior treatment will be allowed; however, a washout period of 2 weeks for topical and 4 weeks for systemic 
agents is required. At the washout period, individuals will undergo evaluation with a PGA and BSA 
calculation. The indexed lesions will be photographed, measured, scored, and recorded with Modified CAILS 
scores as well. The Modified CAILS calculations will be used for the determination of responsive and non-
responsive lesions. Additional Pruritus measures using the VRS, VAS, NRSSkindex-16, and LPQOL will be 
collected at that time.  
 
Individuals will then initiate treatment for all lesions of LP once daily and will be evaluated weekly and 
assessed by PGA of skin, oral mucosa, and hair, BSA, lesion count, Modified CAILS, Pruritus VRS, VAS and 
NRS scales,Skindex-16, and LPQOL between weeks 0-16 (see Appendix). Week 16 will be the primary 
endpoint. Therapy will be stopped and the individuals will be evaluated at week 20 after an observation period 
of 4 weeks and assessed by PGA, BSA, lesion count, mCAILS, Pruritus VRS, VAS and NRS scales,Skindex-
16, and LPQOL. Laboratory and safety monitoring will occur at weeks 1, 2, 3, 4, 8, 12, 16, 20, 24, 28, and 32. 
3D Photographs will be taken at weeks 0, 1, 2, 3, 4, 8, 12, 16, 20, 24, 28, and 32. Individual lesions will be 
circled at each visit and the exact area of each lesion will be measured. Up close photos will be taken of the 
disease.  
 


Tissue will be collected for bulk RNA sequencing and single cell RNA sequencing (for patients who opt in) at 
week 0 and 2. Blood collection will include the isolation at week 0, 1, 2, 3, 4, 8, 12, 16, 20, 24, 28, and 32. 
Blood will be drawn into 5mL vials and subsequently separated. The serum and cell pellet will be stored for 
future analysis. At weeks 0 and 2, an additional 5mL vial of blood will be drawn from patients who agree to 
provide single-cell RNA sequencing samples. For these samples, the buffy coat (containing peripheral blood 
mononuclear cells, PBMCs) will be isolated from whole blood, then immediately placed into cryopreservation 
medium and stored in a -80°C biobank freezer. Up to five skin biopsies will be taken during the study for all 
patients. At week 0, up to two, 3mm tissue biopsies will be taken from LP lesional skin and one biopsy will be 
taken from normal appearing skin for bulk RNA sequencing. The initial biopsy of lesional tissue and control 
will be annotated. At week 2, up to two, 3mm biopsies will be taken – one from normal appearing skin, one 
from lesional responsive tissue, and/or one from lesional non-responsive tissue. An additional two, 6-8mm 
biopsies of lesional tissue for single-cell RNA sequencing will be taken– one at week 0 and one at week 2 –
from patients who opt in. The week 2 biopsy will be obtained from an annotated lesion, whether responsive or 
non-responsive. Responsive and non-responsive lesions will be determined by the change in mCAILS between 
week 0 and 2. Responsive tissue will require at least 50% reduction in mCAILS while non-responsive tissue 
can have progression, no change, or up to a 50% reduction in mCAILS. The lesions will be chosen utilizing 
full body photographs taken previously at week 0. Up to 60 of the 3mm biopsy samples will be snap frozen 
and stored in the tissue biobank. Once completed, RNA sequencing will be performed on the tissue samples 
and analysis will be performed. Paired analysis of treatment responsive and refractory lesions will be made as 
well as treated and untreated lesions.  
 
Nucleic Acid Extractions: RNA will be extracted from a total of 50 µm of fresh tissue using the Qiagen FFPE 
RNeasy Micro extraction Kit according to manufacturer’s recommendation.  
 
Bulk RNA Transcriptome Sequencing: RNA transcriptome sequencing will be carried out using commercially 
available techniques.  Briefly, RNA Libraries will be created using up to 100ng of RNA as starting material 
using the Illumina RNA Exome Library kit according to manufacturer’s recommendation. Libraries will 
undergo quality control for quality and quantity using the Agilent BioAnalyzer High Sensitivity Chip. Pair-
End sequencing will then be carried out on the Illumina HiSeq 4000 using 101bp insert fragments.   
 
Single-cell RNA Transcriptome Sequencing: Samples will be prepped and analyzed per single-cell RNA 
sequencing standard operating procedures of the University of Michigan genomics lab.  
 
Primary and Secondary Measures: 
 
All efficacy assessments will be performed prior to the administration of study treatment at each visit. The 
recommended order and the overall outline of measurements for the efficacy assessments are described below.  
 
Efficacy measures: PGA, BSA, mCAILS, Pruritus VRS, VAS and NRS,Skindex-16, and LPQOLto determine 
the efficacy of Baricitinib (LY3009104) as measured by the change in Modified CAILS score of the index 
lesion (weeks 0 and 16) and changes in lesion count (week 0 and 16). 
 
Secondary Outcome Measures: To determine the efficacy of Baricitinib (LY3009104) as measured by the 
change in Pruritus VAS, VRS, & NRS,  (week 0 to week 2, weeks 0 to 4, weeks 4 to 8, weeks 0 to 8, weeks 8 
to 12, weeks 0 to 12, weeks 12 to 16, weeks 0 to 16, weeks 16 to 20,weeks 0 to 20, weeks 0 to 24, week 20 to 
24, week 0 to 28, week 24 to 28, weeks 0 to 32, week 28 to 32), change in Skindex-16 (week 0 to week 2, 
weeks 0 to 4, weeks 4 to 8, weeks 0 to 8, weeks 8 to 12, weeks 0 to 12, weeks 12 to 16, weeks 0 to 16, weeks 
16 to 20,weeks 0 to 20,weeks 0 to 24, week 20 to 24, week 0 to 28, week 24 to 28, weeks 0 to 32, week 28 to 
32), change in LPQOL (week 0 to week 2, weeks 0 to 4, weeks 4 to 8, weeks 0 to 8, weeks 8 to 12, weeks 0 to 
12, weeks 12 to 16, weeks 0 to 16, weeks 16 to 20, weeks 0 to 20,weeks 0 to 24, week 20 to 24, week 0 to 28, 
week 24 to 28, weeks 0 to 32, week 28 to 32), change in Physician Global Assessment (PGA) of skin, oral 
mucosa, and hair (week 0 to week 2, weeks 0 to 4, weeks 4 to 8, weeks 0 to 8, weeks 8 to 12, weeks0 to 12, 
weeks 12 to 16, weeks 0 to 16, weeks 16 to 20,weeks 0 to 20, weeks 0 to 24, week 20 to 24, week 0 to 28, 
week 24 to 28, weeks 0 to 32, week 28 to 32), change in BSA (week 0 to week 2, weeks 0 to 4, weeks 4 to 8, 
weeks 0 to 8, weeks 8 to 12, weeks 0 to 12, weeks 12 to 16, weeks 0 to 16, weeks 16 to 20,weeks 0 to 20, 


weeks 0 to 24, week 20 to 24, week 0 to 28, week 24 to 28, weeks 0 to 32, week 28 to 32), change in Modified 
CAILS (week 0 to week 2, weeks 0 to 4, weeks 4 to 8, weeks 0 to 8, weeks 8 to 12, weeks 0 to 12, weeks 12 to 
16, weeks 16 to 20,weeks 0 to 20,weeks 0 to 24, week 20 to 24, week 0 to 28, week 24 to 28, weeks 0 to 32, 
week 28 to 32), and change in lesion count (week 0 to week 2, weeks 0 to 4, weeks 4 to 8, weeks 0 to 8, weeks 
8 to 12, weeks 0 to 12, weeks 12 to 16, weeks 16 to 20,weeks 0 to 20,weeks 0 to 24, week 20 to 24, week 0 to 
28, week 24 to 28, weeks 0 to 32, week 28 to 32).  
 
 
 
Exploratory Outcome Measures: To predict responses and examine the pharmacodynamics of treatment 
through the identification of unique biomarkers and trasnscriptomic changes of LP at week 0, and utilizing 
RNA sequencing on responsive and non-responsive tissue at week 2 to correlate these biomarkers with 
measures of global response: Modified CAILS, PGA, BSA, and lesion count. 
3.2 
Number of Subjects 
 
12 subjects will be enrolled in this study. 
 
3.3 
Duration of Participation 
 
The study consists of 3 epochs: screening/washout period (at least 1 week and up to 4 weeks), treatment epoch 
(16 weeks from screen/washout), and follow up epoch (4 weeks). The screening and washout period will allow 
for treatment naïve/ new diagnosis LP to undergo evaluation and diagnosis and for treatment refractory to 
undergo a washout. The total duration of the study will be 21-24 weeks, with the option to enroll in a 3 month 
extension with a dose escalation to 4 mg for patients who demonstrate response to treatment, but have not yet 
achieved PGA 0 
 
Tables: 
• 
Table-1: Prohibited treatment 
Prohibited treatments†, ‡  
 
Washout period  
(before Randomization 
Visit) 
Any concomitant oral or topical JAK inhibitor 
Any biologic drug  
Prohibited 
Stable dose for 3 months  
Immunomodulation treatments for LP§ 
[e.g., methotrexate, cyclosporine A, corticosteroids (oral, i.v., 
intramuscular, s.c., intra-articular, transdermal), 
mycophenolate mofetil, azathioprine]  
4 weeks 
Topical treatment that is likely to impact signs and symptoms 
of LP (e.g., pimecrolimus, tacrolimus) 
2 weeks 
Non-immunosuppressive agents (tetracycline antibiotics & 
niacinamide) 
2 weeks 
 
Prohibited regimen of Topical Corticosteroids (TCS) 
 
TCS on any location on body (including face, scalp and/or 
genitoanal area) 
2 weeks 
 
 
†If the prohibited treatment is being used during the study for any indication, the subject must discontinue use 
of the prohibited treatment if he/she wishes to continue in the study.  
‡ In case of undue safety risk for the subject, the subject should discontinue study treatment at the discretion of 
the investigator/qualified site staff. If the subject received a live virus vaccination during the study, the subject 
must discontinue study treatment. 


§Inhalative CS with only a topical effect (e.g., to treat asthma) are not considered “systemic 
immunomodulation treatments” and are therefore acceptable as co-medication. Immunosuppressive 
medication for conditions other than LP will be allowed.   
 
Table 2: Washout Periods for Monoclonal Antibodies (Biologic Drugs) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Table-3: Screening and Visits (+/- 3-day window) 
 
 
Screening 
Day 
0 
Week 
1 
Week 
2 
Week 
3 
Week 
4 
Week 
8 
Week 
12 
Week 
16 
Week 
20 
Week 
24  
Week 
28 
Week 
32 
Baricitinib 
(LY3009104) 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
Physical Exam 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Adverse Event 
Assessment 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Chest X-ray 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Assessments: PGA, 
BSA, lesion number, 
mCAILS, Skindex-16, 
Pruritus VAS, VRS & 
NRS, LPQOL  
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Photographer 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Skin Biopsy 
(tissue/serum bank) 
 
X 
 
X 
 
 
 
 
 
 
 
 
 
ECG 
X 
 
 
 
 
X 
 
 
 
 
 
 
 
Urine Pregnancy Test 
X 
X 
 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
Venipuncture 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Biomarker/RNAseq 
blood (tissue/serum 
bank) 
 
X 
x 
X 
x 
X 
x 
x 
X 
x 
X 
X 
X 
CMP 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Lipid Panel 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
CPK 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
CBC 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Quantiferon Gold 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Hepatitis B 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Hepatitis C 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Brand 
Name 
Generic Name 
Recommended 
Minimum 
Washout 
(approximately 
5 
half-lives) 
ACTEMRA 
Tocilizumab 
8 weeks 
CIMZIA 
Certolizumab 
pegol 
10 weeks 
COSENTYX Secukinumab 
16 weeks 
DUPIXENT 
Dupilumab 
12 weeks 
ENBREL 
Etanercept 
4 weeks 
HUMIRA 
Adalimumab 
8 weeks 
KEVZARA 
Sarilumab 
7 weeks 
ORENCIA 
Abatacept 
8 weeks 
REMICADE Infliximab 
6 weeks 
RITUXIN 
Rituximab 
6 months 
SIMPONI 
Golumimab 
10 weeks 
STELARA 
Ustekinumab 
16 weeks 
TALTZ 
Ixekizumab 
10 weeks 
TREMFYA 
Guselkumab 
12 weeks 
XOLAIR 
Omalizumab 
16 weeks 


HIV 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Coccidioidomycosis 
X 
 
 
 
 
 
 
 
 
 
 
 
 
3.4 
Primary Study Endpoints 
 
Overall response by PGA of skin at week 16.  
 
3.5 
Secondary Study Endpoints 
Change in modified CAILS of index treatment lesion (week 0 and 16) and change in lesion count (week 0 and 
week 16). Change in Pruritus VAS, VRS, & NRS,  (week 0 to week 2, weeks 0 to 4, weeks 4 to 8, weeks 0 to 8, 
weeks 8 to 12, weeks 0 to 12, weeks 12 to 16, weeks 0 to 16, weeks 16 to 20,weeks 0 to 20, weeks 0 to 24, week 
20 to 24, week 0 to 28, week 24 to 28, weeks 0 to 32, week 28 to 32), change in Skindex-16 (week 0 to week 2, 
weeks 0 to 4, weeks 4 to 8, weeks 0 to 8, weeks 8 to 12, weeks 0 to 12, weeks 12 to 16, weeks 0 to 16, weeks 
16 to 20,weeks 0 to 20, weeks 0 to 24, week 20 to 24, week 0 to 28, week 24 to 28, weeks 0 to 32, week 28 to 
32), change in LPQOL (week 0 to week 2, weeks 0 to 4, weeks 4 to 8, weeks 0 to 8, weeks 8 to 12, weeks 0 to 
12, weeks 12 to 16, weeks 0 to 16, weeks 16 to 20, weeks 0 to 20, weeks 0 to 24, week 20 to 24, week 0 to 28, 
week 24 to 28, weeks 0 to 32, week 28 to 32), change in Physician Global Assessment (PGA)of oral mucosa, 
and hair (week 0 to week 2, weeks 0 to 4, weeks 4 to 8, weeks 0 to 8, weeks 8 to 12, weeks 0 to 12, weeks 12 to 
16, weeks 0 to 16, weeks 16 to 20,weeks 0 to 20, weeks 0 to 24, week 20 to 24, week 0 to 28, week 24 to 28, 
weeks 0 to 32, week 28 to 32), change in BSA (week 0 to week 2, weeks 0 to 4, weeks 4 to 8, weeks 0 to 8, 
weeks 8 to 12, weeks 0 to 12, weeks 12 to 16, weeks 0 to 16, weeks 16 to 20, weeks 0 to 20, weeks 0 to 24, week 
20 to 24, week 0 to 28, week 24 to 28, weeks 0 to 32, week 28 to 32), change in Modified CAILS (week 0 to 
week 2, weeks 0 to 4, weeks 4 to 8, weeks 0 to 8, weeks 8 to 12, weeks 0 to 12, weeks 12 to 16, weeks 16 to 
20,weeks 0 to 20, weeks 0 to 24, week 20 to 24, week 0 to 28, week 24 to 28, weeks 0 to 32, week 28 to 32), 
and change in lesion count (week 0 to week 2, weeks 0 to 4, weeks 4 to 8, weeks 0 to 8, weeks 8 to 12, weeks 0 
to 12, weeks 12 to 16, weeks 16 to 20 and weeks 0 to 20, weeks 0 to 24, week 20 to 24, week 0 to 28, week 24 
to 28, weeks 0 to 32, week 28 to 32). 
3.6 
Primary Safety Endpoints 
 
A thorough baseline screening will be followed for all patients and is outlined in Table-2. A detailed list of the 
methods in which baseline screening will be performed is outlined in Supplemental 2. All blood draws and 
safety assessments must be performed prior to study treatment administration. Appropriate safety assessments 
(e.g., evaluation of AEs and SAEs) should be repeated after dosing with study treatment. A physical 
examination, including general appearance and vital signs, will be performed as indicated in Table-2. If 
indicated, based on medical history and/or symptoms, additional exams will be performed at the discretion of 
the investigator. If possible, the same member of the study site staff throughout the study will perform 
assessments for an individual subject. Information for all physical examinations will be included in the source 
documentation at the study site. Significant findings that are present prior to the subject signing informed 
consent will be included in the Medical History. Significant findings made after the signing of the informed 
consent, which meet the definition of an AE, must be recorded as an AE. Vital signs (blood pressure, pulse, 
height, weight) will be assessed at each physical examination as indicated in Table-2 (see Supplemental 2 for 
details on how to acquire vital signs). Whether action needs to be taken to address notable vital signs will be 
decided by the investigator, considering the overall status of the subject. Laboratory studies will be drawn as 
indicated in Table-2. Whether action needs to be taken to address notable laboratory values will be decided by 
the investigator, considering the overall status of the subject. Hematology assessments will be measured at all 
scheduled study visits specified in Table-2. Serum chemistry will be a comprehensive metabolic and lipid 
panels that will be measured at all scheduled study visits specified in Table-2. 
 
If the prohibited treatment is being used during the study for any indication, the subject must discontinue use of 
the prohibited treatment if he/she wishes to continue in the study.  In case of undue safety risk for the subject, 
the subject should discontinue study treatment at the discretion of the investigator/qualified site staff. If the 
subject received a live virus vaccination during the study, the subject must discontinue study treatment. 
 


3.7 
Identification of Source Data 
 
All data in the study will be captured in the case report forms including: 
• Safety measures 
• Efficacy measures 
• Laboratory studies 
• Vital Signs 
• 
Exploratory measures 
4 Subject Selection Enrollment and Withdrawal 
4.1 
Inclusion Criteria 
 
Subjects eligible for inclusion in this study must fulfill all the following criteria: 
 
• Subjects must be able to understand and comply with the requirements of the study and communicate with 
the investigator. Subjects must give written, signed, and dated informed consent before any study related 
activity is performed. When appropriate, a legal representative will sign the informed consent according to 
local laws and regulation 
• Both men and women must be at least 18 years of age at the time of screening 
• Subjects must have clinical and histological features of LP 
• LP requiring systemic treatment 
• Subjects must have treatment naïve cutaneous LP or treatment refractory disease, as defined by failure of at 
least one established treatment for LP 
o Failure of prior therapy 
 Topical treatment 
 Systemic immunosuppressant 
 Oral metronidazole 
 Oral sulfasalazine 
 Oral retinoid 
4.2 
Exclusion Criteria 
 
Subjects fulfilling any of the following criteria are not eligible for inclusion in this study. To ensure the 
recruitment of a representative sample of all eligible subjects, the investigator may apply no additional 
exclusions. 
• On excluded therapies, not on a stable dose of a therapy, or incompletely washed out for a therapy (Table-
1.) 
• Known hypersensitivity or other adverse reaction to Baricitinib (LY3009104) 
• Variants of LP deemed by the investigators to be inappropriate for Baricitinib (LY3009104) including but 
not limited to: 
o Drug-induced LP  
o Predominant non-cutaneous variants of LP, note that individuals can have disease in non-cutaneous 
areas; however, they must also have cutaneous disease. 
 Lichen Planopilaris 
 Oral Lichen planus 
• Pregnant or nursing (lactating) women (pregnancy is defined as the state of a female after conception and 
until the termination of gestation, confirmed by a positive human chorionic gonadotropin (hCG) laboratory 
test) 
• Women of childbearing potential [Post-menopausal or not of child-bearing potential is defined by 1 year of 
natural (spontaneous) amenorrhea or surgical bilateral oophorectomy (with or without hysterectomy), total 
hysterectomy or tubal ligation at least 6 weeks ago. Oophorectomy alone must be confirmed by follow up 
hormone level assessment to be considered not of child-bearing potential, defined as all women 


p h ysi ol o gicall y ca pa ble of bec o mi n g pre g n a nt, u nless t he y are usi n g b asic met h o ds of c o ntrace pti o n w hic h 
i ncl u des: 
o  T otal a bsti ne nce ( Peri o dic a bsti ne nce a n d wit h dra wal are n ot acce pta ble m et h o ds of c o ntrace pti o n) 
o  Fe male sterilizati o n ( bilateral o o p h orect o m y wit h or wit h o ut h ysterect o m y), t otal h ysterect o m y, or 
t u bal li gati o n at least 6 wee ks bef ore ta ki n g st u d y treat me nt. O o p h orect o m y al o ne re q uires f oll o w 
u p h or m o ne le vel assess me nt f or fertilit y.  
o  Male sterilizati o n (at least 6 m o nt hs pri or t o scree ni n g). T he vasect o mize d male part ner s h o ul d be 
t he s ole part ner f or t hat s u bject. 
o  Barrier met h o ds of c o ntr ace pti o n: c o n d o m or occl usi ve ca p.  
o  Use of or al, i njecte d or i m pla nte d h or m o nal met h o ds of c o ntrace pti o n or ot her f or ms or h or m o n al 
c o ntrace pti o n t hat ha ve c o m plete efficac y (fail ure < 1 %). ( T h e d ose of t h e c o ntrace pti ve s h o ul d be 
sta ble f or 3 m o nt hs) 
•  Acti ve o n g oi n g i nfla m mat or y diseases of t he s ki n ot her t ha n L P t hat mi g ht c o nf o u n d t he e v al uati o n of t he 
be nefit of Bari citi ni b ( L Y 3 0 0 9 1 0 4) 
•  U n derl yi n g c o n diti o n (i ncl u di n g, b ut n ot li mite d t o meta b olic, he mat ol o gic, re nal, he p atic, p ul m o nar y, 
ne ur ol o gic, e n d ocri ne, car diac, i nfecti o us or gastr oi ntesti nal c o n diti o ns) w hic h, i n t he o pi ni o n of t he 
i n vesti gat or, si g nifica ntl y i m m u n oc o m pr o mises t he s u bject a n d/ or places t h e s u bject at u nacce pt a ble ris k 
f or recei vi n g a n i m m u n o m o d ulat or y t hera p y 
•  M o derate -t o-se vere r e nal i m pair me nt i ncl u di n g patie nts wit h esti mate d gl o mer ular filtrati o n rate (e G F R) 
< 6 0 m L/ mi n/ 1. 7 3 m 2 
•  Acti ve s yste mic i nfecti o ns d uri n g t he 2 wee ks pri or t o ra n d o mizati o n (c o m m o n c ol d vir uses e xcl u de d ) or 
a n y i nfecti o n t hat r e occ urs o n a re g ular basis.  
•  
C urre nt se ver e pr o gressi ve or u nc o ntr olle d diseas e w hic h t he i n vesti gat or re n ders t he s u bject u ns uita ble f or 
t he trial or p uts t he s u bject at i ncrease d ris k  
•  Ha ve h a d a n y maj or s ur g er y wit hi n 8 w ee ks pri or t o scree ni n g or will re q uire maj or s ur g er y d uri n g t h e st u d y 
t hat, i n t he o pi ni o n of t he i n vesti gat or w o ul d p ose a n u nacce pta ble ris k t o t he patie nt. 
•  Ha ve e x p erie nce d a n y of t he f oll o wi n g wit hi n 1 2 wee ks of scree ni n g: V T E ( D V T/ p ul m o nar y e m b olis m 
[ P E]), m y ocar di al i nfarcti o n ( MI), u nsta ble isc he mic heart disease, str o k e, or Ne w Y or k H eart Ass ociati o n 
Sta ge III/I V h eart fail ure.  
•  Ha ve a hist or y of rec urr e nt ( ≥ 2) V T E ( D V T/ P E).  
•  Ha ve  a  hist or y  of  l y m p h o pr oliferati ve  dis ease;  ha ve  si g ns  or  s y m pt o ms  s u g gesti ve  of  p ossi ble  
l y m p h o pr oliferati ve disease, i ncl u di n g l y m p ha de n o pat h y or s ple n o me gal y; ha ve acti ve pri mar y or rec urre nt 
mali g na nt disease; or ha ve bee n i n re missi o n fr o m cli nicall y si g nifica nt mali g na nc y f or < 5 years pri or t o 
ra n d o mizati o n. 
•  Ha ve ha d s y m pt o matic h er pes z oster i nfecti o n wit hi n 1 2 wee ks pri or t o ra n d o mizati o n. 
•  Ha ve  a  hist or y  of  diss e mi nate d/c o m plicate d  h er pes  z oster  (f or  e x a m ple,  o p ht hal mic  z oster  or  C N S  
i n v ol ve me nt). 
•  A L T or A S T > 2 x u p p er li mits of n or mal ( U L N); al kali ne p h os p hatase ( A L P) ≥2 x U L N; t otal bilir u bi n ≥1. 5 
x U L N; he m o gl o bi n < 1 0 g/ d L ( 1 0 0. 0 g/ L); t otal w hite bl o o d cell c o u nt < 3 0 0 0 cells/ μ L ( < 3. 0 0 x 1 0 3/ μ L or 
< 3. 0 0 billi o n/ L); ne utr o pe nia (a bs ol ute ne utr o p hil c o u nt [ A N C] < 1 5 0 0 cells/ L) ( < 1. 5 0 x 1 0 3/ L or < 1. 5 0 
billi o n/ L);  l y m p h o pe nia  (l y m p h oc yte  c o u nt  < 1 0 0 0  cells/ μ L)  ( < 1. 0 0  x  1 0 3/ μ L  or  < 1. 0 0  bili o n/ L); 
t hr o m b oc yt o pe nia ( platel ets < 1 0 0, 0 0 0 cells/ μ L) ( < 1 0 0 x 1 0 3/ μ L or < 1 0 0 billi o n/ L) 
•  Ha ve a p ositi ve test f or h e patitis B vir us ( H B V) defi ne d as:  
  
a. p ositi ve f or he patitis B s urface a nti ge n ( H Bs A g), or 
 
b.  p ositi ve  f or  he p atitis  B  c ore  a nti b o d y  ( H Bc A b)  a n d  p ositi ve  f or  h e patitis  B  vir us  
  
de o x yri b o n ucleic aci d ( H B V D N A) 
N ote: Patie nts w h o ar e H Bc A b -p ositi ve a n d H B V D N A -n e gati ve m a y b e e nr olle d i n t h e st u d y b ut will 
re q uire a d diti o nal H B V D N A m o nit ori n g d uri n g t he st u d y. 
•  Ha ve he p atitis C vir us ( H C V) i nfecti o n ( h e patitis C a nti b o d y -p ositi ve a n d H C V ri b o n ucleic aci d [ R N A] -
p ositi ve). 
N ote: Patie nts w h o h a ve d oc u me nte d a nti -H C V treat me nt f or a past H C V i nfecti o n A N D are H C V R N A -
ne gati ve ma y be e nr olle d i n t he st u d y. 
•  Ha ve e vi d e nce of HI V i nfecti o n a n d/ or p ositi ve HI V a nti b o dies. 


• Have had household contact with a person with active TB and did not receive appropriate and documented 
prophylaxis for TB. 
• Have evidence of active TB or latent TB 
• Have evidence of active TB, defined in this study as the following: 
o Positive purified protein derivative (PPD) test (≥5 mm induration between approximately 2 and 3 
days after application, regardless of vaccination history), medical history, clinical features, and 
abnormal chest x-ray at screening. 
o QuantiFERON®-TB Gold test or T-SPOT®.TB test (as available and if compliant with local TB 
guidelines) may be used instead of the PPD test. Patients are excluded from the study if the test is 
not negative and there is clinical evidence of active TB. 
Exception: patients with a history of active TB who have documented evidence of appropriate treatment, 
have no history of re-exposure since their treatment was completed, have no clinical features of active 
TB, and have a screening chest x-ray with no evidence of active TB may be enrolled if other entry criteria 
met. Such patients would not be required to undergo the protocol-specific TB testing for PPD, 
QuantiFERON®-TB Gold test, or T-SPOT®.TB test but must have a chest x-ray at screening (i.e., chest 
imaging performed within the past 6 months will not be accepted). 
• Have evidence of untreated/inadequately or inappropriately treated latent TB, defined in this study as the 
following: 
o Positive PPD test, no clinical features consistent with active TB, and a chest x-ray with no evidence 
of active TB at screening; or 
o If the PPD test is positive and the patient has no medical history or chest x-ray findings consistent 
with active TB, the patient may have a QuantiFERON®-TB Gold test or T-SPOT®.TB test (as 
available and if compliant with local TB guidelines).  If the test results are not negative, the patient 
will be considered to have latent TB (for purposes of this study); or 
o QuantiFERON®-TB Gold test or T- SPOT®.TB test (as available and if compliant with local TB 
guidelines) may be used instead of the PPD test. If the test results are positive, the patient will be 
considered to have latent TB. If the test is not negative, the test may be repeated once within 
approximately 2 weeks of the initial value. If the repeat test results are again not negative, the patient 
will be considered to have latent TB (for purposes of this study). 
• 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). 
• 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. 
• Have a history of intravenous 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). 
 
 
4.3 
Subject Recruitment, Enrollment and Screening 
 
• From the Principal Investigator or Co-Investigator clinical practices 
• Screening requirements or qualifying lab values 
• Evaluation and documentation of inclusion/exclusion criteria 
 
4.4 
Early Withdrawal of Subjects 
4.4.1 When and How to Withdraw Subjects 
• Subject safety issues 
• Failure of subject to adhere to protocol requirements 
• Disease progression 
• Subject decision to withdraw from the study (withdrawal of consent) 


Subjects who withdraw from the study for any reason will have their information recorded at the time of 
withdrawal. At the time of withdrawal, the subject will be considered at the final treatment date and will move 
into the treatment observation phase (4 weeks). Subjects will not be replaced. Follow up for subjects will 
continue to follow the normal follow up (Table-2) 
4.4.2 Data Collection and Follow-up for Withdrawn Subjects 
At the time of withdrawal, the reason for withdrawal will be recorded in the CRF. Individuals who withdraw 
will go into the observation phase for 4 weeks. If a subject withdraws consent, attempts will be made to obtain 
permissions to collect follow up information.  
5 Study Drug  
5.1 
Description (Investigator’s Brochure) 
 
The chemical name of Baricitinib (LY3009104) is 2-(3-(4-(7H-pyrrolo[2,3-d]pyrimidin-4-yl)- 
1H-pyrazol-1-yl)-1-(ethylsulfonyl)azetidin-3-yl)acetonitrile (Figure 1). Baricitinib (LY3009104) has a 
molecular formula of C16H17N7O2S and a molecular weight of 371.42. 
 
Baricitinib (LY3009104) Structural Formula   
 
 
Baricitinib (LY3009104) drug substance is a white to practically white to light pink powder. Baricitinib 
(LY3009104) has been formulated in 3 strengths (1 mg, 2 mg, or 4 mg) that are actively being investigated.  
 
Baricitinib (LY3009104) is an oral formulation of an investigational product under development for the 
treatment of patients with rheumatoid arthritis, alopecia areata, atopic dermatitis, psoriasis, systemic lupus 
erythematosus and other potential autoimmune diseases of the skin. Baricitinib (LY3009104) is an oral 
selective inhibitor of the Janus kinase (JAK) family of protein tyrosine kinases with selectivity for JAK1 and 
JAK2, and less selectivity for JAK3 with potent activity on the cytokine IFN-γ.  JAK1 and JAK2 mediate the 
signaling of a number of cytokines and growth factors that are important for hematopoiesis and immune 
function. JAK signaling involves recruitment of STATs (signal transducers and activators of transcription) to 
cytokine receptors, activation and subsequent localization of STATs to the nucleus leading to modulation of 
gene expression. Mitogenic and inflammatory cytokines are strongly implicated in the pathogenesis of 
psoriasis, alopecia areata, atopic dermatitis, and other potential autoimmune diseases of the skin. Inhibition of 
specific cytokine function using antibodies directed against the common p40 subunit of interleukin (IL)-12 and 
IL-23 has demonstrated proof-of-concept validating cytokine signaling as a therapeutic target for the treatment 
of psoriasis.  
 
Pharmacodynamics: 
The decrease in the cytokine-stimulated pSTAT3 formation in response to single- and multiple dose baricitinib 
was measured in 3 clinical pharmacology studies. Data showed a dose dependent 
inhibition of pSTAT3 formation in response to cytokine stimulation in the single dose range of 1-mg to 20-mg 
(Study JADF) and multiple once-daily doses of 2-mg to 20-mg for 
10 days (Study JADE). Similar levels of inhibition were observed using either IL-6 or TPO as 


the stimulus. Maximal inhibition of pSTAT3 formation occurred approximately 1 to 2 hours 
post-dose, coincident with tmax. The pSTAT3 levels returned approximately to baseline levels by 
24 hours for all dose groups following single and multiple doses. Based on the results from Study JADF and 
Study JADE, a PK/PD relationship was established for baricitinib-induced inhibition of IL-6 stimulated 
pSTAT3 formation. The calculated IC50 value was 75 nM (27.9 ng/mL) from Study JADF and 100 nM (37.1 
ng/mL) from Study JADE (for a combined value of 90 nM (33.3ng/mL). These results are similar to the IC50 
value of 104 nM (38.6 ng/mL) estimated from in vitro data. These data suggest that QD dosing of 4-mg, but 
not 2-mg, results in a period of time when the baricitinib concentration in the central compartment is above the 
ex vivo IC50 for IL-6-stimulated pSTAT3 formation. 
 
Pharmacokinetics: 
Baricitinib is rapidly absorbed with a median time of maximum observed drug concentration 
(tmax) of 1 hour (range: 0.5 to 3 hours). Over a single-dose range of 1 mg to 30 mg in healthy 
subjects, mean estimates of baricitinib Cmax and AUC(0-∞) increased approximately 
proportionally to dose. Baricitinib PK after multiple doses were predictable from single dose 
data. Accumulation during QD dosing was minimal, with an accumulation ratio of 1.11- and 
1.15-fold for Cmax and AUC, respectively. Steady state was typically reached between the 
second and third doses. 
 
Renal elimination of parent is the principal clearance mechanism for baricitinib, and baricitinib apparent 
clearance (CL/F) is directly related to baseline glomerular filtration rate (GFR). The differences in CL/F 
between populations are likely due to differences in renal function, which affects apparent renal clearance 
(CLr/F). Pharmacokinetic parameter estimates are 
also available for patients with atopic dermatitis based on Phase 2 Study I4V-MC-JAHG 
(JAHG), although a different PK model was applied. The estimated values of CL/F and apparent 
total volume of distribution were 12.3 L/h and 105 L, respectively for this patient population. 
 
The mean absolute bioavailability of baricitinib was 79%. The protein binding of baricitinib was 
50 ± 2% in plasma and 55 ± 3% in serum. Mean volume of distribution following IV 
administration was 75.7 L (21% coefficient of variation [CV]), suggesting distribution of 
baricitinib into tissues. About 75% of the baricitinib dose is excreted in the urine predominately 
as parent, and about 20% of the dose is excreted in the feces. 
 
Bioequivalence was demonstrated between the baricitinib 4-mg commercial oral tablet and a 
4-mg dose (2 mL of 2 mg/mL suspension) of a pediatric suspension in Study I4V-MC-JAGU. 
There was no statistically significant difference in exposure to baricitinib based on AUC and 
Cmax between the tablet and suspension formulation when administered in the fasted state. When 
the suspension was administered with a high-fat, high-calorie meal, the Cmax of baricitinib was 
reduced by 32.5% compared to the fasted state. The median tmax of baricitinib was also delayed 
by 2 hours in the fed compared to the fasted state; however, the overall exposure based on AUC 
was similar in the fed and fasted states. 
 
Potential for Baricitinib (LY3009104) to Affect Other Drugs: 
Cytochrome P450 Enzymes: In vitro, baricitinib did not significantly inhibit nor induce the 
activity of CYP enzymes (CYPs 3A, 1A2, 2B6, 2C8, 2C9, 2C19, and 2D6). In clinical 
pharmacology studies, coadministration of baricitinib with the CYP3A substrates simvastatin, 
ethinyl estradiol, or levonorgestrel resulted in no clinically meaningful changes to these drugs. 
 
Transporters: In vitro, baricitinib did not inhibit the transporters Pgp or OATP 1B1. In vitro, 
baricitinib does inhibit OAT1, OAT2, OAT3, OCT1, OCT2, OATP1B3, BCRP, MATE1, and 
MATE2-K, but clinically meaningful changes to drugs that are substrates for these transporters 
are unlikely. In clinical pharmacology studies, there were no clinically meaningful effects when 
baricitinib was coadministered with digoxin (Pgp substrate) or MTX (substrate of several 
transporters). 
 


Potential for Other Drugs to Affect Baricitinib: 
Cytochrome P450 Enzymes: In vitro, baricitinib is a CYP3A4 substrate. In clinical 
pharmacology studies, coadministration of baricitinib with ketoconazole (CYP3A inhibitor) 
resulted in no clinically meaningful effect. Coadministration of baricitinib with fluconazole 
(CYP3A/CYP2C19/CYP2C9 inhibitor) or rifampin (CYP3A inducer) resulted in no clinically 
meaningful changes to baricitinib. 
 
Transporters: In vitro, baricitinib is a substrate for OAT3, Pgp, BCRP, and MATE2-K. In a 
clinical pharmacology study, probenecid (OAT3 inhibitor with strong inhibition potential) 
dosing resulted in approximately a 2-fold increase in AUC(0-∞) with no change in Cmax of 
baricitinib. Simulations with diclofenac and ibuprofen (OAT3 inhibitors with less inhibition 
potential) predicted minimal effect on baricitinib. Coadministration of baricitinib with 
cyclosporine (Pgp/BCRP inhibitor) or MTX (substrate of several transporters) resulted in no 
clinically meaningful effects on baricitinib exposure. 
 
5.2 
Treatment Regimen 
 
Subjects will administer Baricitinib (LY3009104) 2 mg tablet once daily on an empty stomach. Treatment will 
take place from Day 0 to Week 16.    
5.3 
Preparation and Administration of Study Drug 
 
The study drug will be supplied by Eli Lilly to the Mayo Clinic Pharmacy, attn. Todd Luckritz, Pharm D, 
R.Ph. 13400 E Shea BLVD, Scottsdale, AZ 85259. The study drug will be stored in the Mayo Clinic 
Pharmacy. The study drug will be labelled in the Mayo Clinic Pharmacy and will be dispensed to the subjects. 
The subjects will be given sufficient quantity of tablets at each visit for use between subsequent study visits. 
Instructions on proper use will be provided to each subject. 
 
5.4 
Subject Compliance Monitoring 
 
Compliance will be assessed through direct questioning of subjects as well as through drug use diaries.   
5.5 
Prior and Concomitant Therapy 
 
Individuals on stable doses of medications for chronic illnesses will be allowed. Individuals on 
immunosuppressive agents for LP will not be allowed; however, individuals on stable doses of 
immunosuppressant for other conditions will be allowed if deemed to be safe by the treating physicians. 
Additional exclusionary drugs are included in Table-1. 
 
Individuals using Baricitinib (LY3009104) should use topical broad-spectrum sunscreens with a minimum of 
SPF30, avoid excess sunlight, and wear sun protective clothing.  
 
5.6 
Packaging 
 
The drug will be packaged in bottles with 30 tablets of Baricitinib (LY3009104) 2 mg per bottle.   The entire 
quantity needed for the study will be provided in one shipment.   The study drug bottles will be labeled with a 
diaper label that fully surrounds the bottle.  All applicable US FDA required text will be included on the label, 
included Caution: Limited by U.S. Law to Investigational Use.         


5.7 
Receiving, Storage, Dispensing and Return 
5.7.1 Receipt of Drug Supplies 
 
The drug will be obtained or delivered from Eli Lilly and Company to the pharmacy at each investigative site. 
 
Upon receipt of the of the study treatment supplies, an inventory must be performed and a drug receipt log 
filled out by the person accepting the shipment.  It is important that the designated study staff counts and 
verifies that the shipment contains all the items noted in the shipping invoice. Any discrepancies, damaged or 
unusable study drug in a given shipment (active drug or comparator) will be documented in the study files. 
The sponsor-investigator must be notified immediately of any discrepancies, damaged or unusable products 
that are received. 
5.7.2 Storage 
The Baricitinib (LY3009104) drug product should be stored between 15°C and 30°C (59°F and 86°F). The 
supplies will be stored in the Mayo Clinic Pharmacy.  
5.7.3 Dispensing of Study Drug 
 
Regular study drug reconciliation will be performed to document drug assigned, drug dispensed, drug returns, 
and drug remaining.  This reconciliation will be logged on the drug reconciliation form and signed and dated 
by the study team. A three month extension and dose excalation to 4mg will be available to all patients who 
demonstrate response to treatment, but have not yet achieved PGA 0 
 
5.7.4 Return or Destruction of Study Drug 
 
At the completion of the study, there will be a final reconciliation of drug shipped, drug dispensed, drug 
returns, and drug remaining.  This reconciliation will be logged on the drug reconciliation form, signed and 
dated.  Any discrepancies noted will be documented and investigated, prior to return or destruction of unused 
study drug.  Drug destroyed on site will be documented in the study files. 
 
6 
Study Procedures 
 
6.1 
Visit 1 
 
Screening visit:   
 
During this visit, we will do some tests and procedures to see if subjects are eligible to take part in this 
research study.  The study staff will review the results of these tests and procedures.  If subjects aren’t eligible, 
the Principal Investigator will tell them why.  At this visit we will:  
 
 Patients will have the ability to conduct this visit remotely. If done remotely, vitals and a physical exam 
will not be conducted. The patient will need to do the blood sample, chest x-ray and electrocardiogram 
at their local laboratory and send the results to the PI prior to their Day 0 visit. The patient will give the 
receipts for the tests to the CRC who will process the reimbursements. 
 Ask about medical history 
 Perform a physical exam, including height, weight, and “vital signs” (blood pressure, temperature, 
heart and breathing rates) 
 Perform a chest x-ray  
 Perform an electrocardiogram (ECG)  
 Draw a blood sample 
 We may take swabs to test for certain fungal and bacterial infections 


 Test urine for pregnancy if female subject is able to become pregnant 
 
If it isn’t known if subject has HIV, Hepatitis B or C, blood tests will need to be done.   
6.2 
Visit 2 
 
Day 0 Visit we will: 
 
• Perform a physical exam, check vital signs and ask about side effects or health problems since last 
visit 
• Exam skin lesions to note any changes 
• Take photographs of skin lesions to document any changes 
• Draw blood sample(s) 
• Perform skin biopsies (up to three, 3mm and up to one, 6-8mm tissue samples will be taken)  
• Dispense study drug  
• Test urine for pregnancy if female subject is able to become pregnant 
 
6.3 
Visit 3  
 
Week 1 Visit we will:   
  
• Patients will have the ability to conduct this visit via video visit with the provider. If being conducted 
remotely, vitals, physical exam, skin lesion assessments, and labs will not be conducted. The patient will 
need to send photos and the PI will conduct the IGA assessment via video visit.  
• Perform a physical exam, check vital signs and ask about side effects or health problems since last visit 
• Exam skin lesions to note any changes 
• Take photographs of skin lesions to document any changes 
• Draw a blood sample 
• Dispense study drug  
 
7.4      Visit 4  
 
Week 2 Visit we will:  
 
• Perform a physical exam, check vital signs and ask about side effects or health problems since last 
visit 
• Exam skin lesions to note any changes 
• Take photographs of skin lesions to document any changes 
• Draw blood sample(s) 
• Perform skin biopsies (up to two, 3mm and up to one, 6-8mm tissue samples will be taken)  
• Dispense study drug  
 
7.5       Visit 5 
 
Week 3 Visit we will:  
 
• Patients will have the ability to conduct this visit via video visit with the provider. If being conducted 
remotely, vitals, physical exam, skin lesion assessments, and labs will not be conducted. The patient will 
need to send photos and the PI will conduct the IGA assessment via video visit.  
• Give subject a physical exam, check vital signs and ask about side effects or health problems since last 
visit 
• Exam skin lesions to note any changes 


• Take photographs of skin lesions to document any changes 
• Draw a blood sample 
• Dispense study drug  
 
7.6       Visit 6 
 
Week 4 Visit we will:  
 
• Perform a physical exam, check vital signs and ask about side effects or health problems since last visit 
• Exam skin lesions to note any changes 
• Take photographs of skin lesions to document any changes 
• Draw a blood sample 
• Perform an ECG  
• Dispense study drug  
• Test urine for pregnancy if female subject is able to become pregnant 
 
7.7         Visit 7 
 
Week 8 Visit we will:  
 
• Perform a physical exam, check vital signs and ask about side effects or health 
      problems since last visit 
• Exam skin lesions to note any changes 
• Take photographs of skin lesions to document any changes 
• Draw a blood sample 
• Dispense study drug 
• Test urine for pregnancy if female subject is able to become pregnant 
 
7.8        Visit 8 
 
Week 12 Visit we will:  
 
• Perform a physical exam, check vital signs and ask about side effects or health 
      problems since last visit 
• Exam skin lesions to note any changes 
• Take photographs of skin lesions to document any changes 
• Draw a blood sample 
• Dispense study drug 
• Test urine for pregnancy if female subject is able to become pregnant 
 
7.9         Visit 9 
 
Week 16 Visit we will:  
 
• Perform a physical exam, check vital signs and ask about side effects or health 
      problems since last visit 
• Exam skin lesions to note any changes 
• Take photographs of skin lesions to document any changes 
• Draw a blood sample 
• Dispense study drug 
• Test urine for pregnancy if female subject is able to become pregnant 
 
7.10        Visit 10 


 
Week 20 Visit we will:  
 
• Perform a physical exam, check vital signs and ask about side effects or health 
      problems since last visit 
• Exam skin lesions to note any changes 
• Take photographs of skin lesions to document any changes 
• Draw a blood sample 
• Dispense study drug 
• Test urine for pregnancy if female subject is able to become pregnant 
 
 
7.11       Visit 11 
 
Week 24 Visit we will:  
 
• Perform a physical exam, check vital signs and ask about side effects or health 
      problems since last visit 
• Exam skin lesions to note any changes 
• Take photographs of skin lesions to document any changes 
• Draw a blood sample 
• Dispense study drug 
• Test urine for pregnancy if female subject is able to become pregnant 
 
 
 
7.12       Visit 12 
 
Week 28 Visit we will:  
 
• Perform a physical exam, check vital signs and ask about side effects or health 
      problems since last visit 
• Exam skin lesions to note any changes 
• Take photographs of skin lesions to document any changes 
• Draw a blood sample 
• Test urine for pregnancy if female subject is able to become pregnant 
 
 
7.13       Visit 13 
 
Week 32 Visit we will:  
 
• Perform a physical exam, check vital signs and ask about side effects or health 
      problems since last visit 
• Exam skin lesions to note any changes 
• Take photographs of skin lesions to document any changes 
• Draw a blood sample 
• Test urine for pregnancy if female subject is able to become pregnant 
 
 


 
7 Statistical Plan 
7.1 
Sample Size Determination 
 
 Data analysis: Assuming a medium effect size (0.3) and a target power of 80%, a two-armed study would need 
about 108 subjects and a single arm about 88 subjects. Due to the costs associated with a study, we propose a 
single armed study of 12 subjects with corollary science including RNA sequencing. This will reduce costs and 
provide biomarkers predictive of response. Effect sizes will be estimated for the appropriate statistical tests that 
will be used for group comparisons in future studies. This will enable more accurate power and sample size 
estimates moving forward. 
 
7.2 
Statistical Methods 
 
Descriptive Statistics 
 
Sample Size Computation and Power Analysis: 
The sample size for this pilot study is set at 12 subjects for logistical and financial reasons. This is similar in size 
to other exploratory studies and will provide adequate data for estimation purposes for planning future studies.  
With 12 subjects, the study is intended to be for estimation purposes only.    
 
Statistical Analysis Plan: 
Data Analysis - The statistical analysis will provide descriptive summary statistics for categorical and 
continuous outcomes.  Categorical variables will be described by their count and proportion of occurrence 
while continuous, normally distributed variables will be described by their mean and standard deviation; and 
continuous, non-normally distributed variables will be described by their median and range. The paired or 
unpaired Wilcoxon tests will be used to quantify differences in numerical outcomes while the Fisher’s exact 
test and the McNemar’s or Bowker’s tests will be used to quantify changes in categorical variables.  
If missingness occurs at random a mixed model will be utilized to assess the change in the lesion over time. A 
sensitivity analysis will be performed using the last observation carried forward and the results will be 
compared to that of the mixed model. 
Effect sizes will be estimated for the appropriate statistical tests that will be used for group comparisons in 
future studies. This will enable more accurate power and sample size estimates moving forward. 
 
Bioinformatic Analysis:  
Bulk RNA-seq analysis: We will use our recently developed LinNorm program 
(https://www.bioconductor.org/packages/release/bioc/html/Linnorm.html) to process RNA-seq data and detect 
differentially expressed genes (DEGs) by comparing the RNA-seq profiles. We will first find DEG between 
responsive and non-responsive samples from the same individual by using paired or unpaired Wilcoxon rank-
sum test (depending on how the samples are collected). We will then rank each gene in the DEGs based on the 
occurrence frequencies in all 12 subjects to find common DEGs for responsiveness (use permutation test to 
determine the p value).  For the top ranked genes (common DEGs), we will use DAVID11 and GSEA12 
software to find enriched inflammatory pathways and GO terms for the DEGs. By comparing the normal tissue 
with the pathogenic tissue (responsive + non-responsible) using the above approach, we will detect a common 
DEGs for LP pathogenesis. Hierarchical clustering13 and Principal Component Analysis (PCA)14 will be 
applied to samples for their hierarchical relationship and clustering properties. Ideally normal, responsive and 
non-responsible tissues should form three distinct groups. The PCA analysis will provide us a set of gene 
signatures that can distinguish these three types of tissues. The common DEGs for responsiveness and 
pathogenesis, as well as gene signature from PCA will be used for our pathogenesis or survival prediction. We 
will perform structure variants calling from RNA-seq data with SNPiR,15 and reconstruct gene co-expression 
networks with ARACHNE.16 Additionally, we will perform de-convolutional analysis, to compare the immune 
profiles of responsive and non-responsive tissue and to correlate immune profiles. Predictive biomarkers will 
be correlated with lesional and global responses.  


Single-cell RNA Seq analysis: will be performed according to standard operating procedures of University of 
Michigan genomics lab and bioinformatics 
 
7.3 
Subject Population(s) for Analysis 
• All-completed population:  All subjects that receive at least one dose will be considered for analysis.  


 
8 Safety and Adverse Events 
8.1 
Definitions 
Unanticipated Problems Involving Risk to Subjects or Others (UPIRTSO) 
Any unanticipated problem or adverse event that meets the following three criteria:  
• Serious: Serious problems or events that results in significant harm, (which may be physical, 
psychological, financial, social, economic, or legal) or increased risk for the subject or others (including 
individuals who are not research subjects). These include: (1) death; (2) life threatening adverse 
experience; (3) hospitalization - inpatient, new, or prolonged; (4) disability/incapacity - persistent or 
significant; (5) birth defect/anomaly; (6) breach of confidentiality and (7) other problems, events, or 
new information (i.e. publications, DSMB reports, interim findings, product labeling change) that in the 
opinion of the local investigator may adversely affect the rights, safety, or welfare of the subjects or 
others, or substantially compromise the research data, AND 
• Unanticipated: (i.e. unexpected) problems or events are those that are not already described as potential 
risks in the protocol, consent document, not listed in the Investigator’s Brochure, or not part of an 
underlying disease. A problem or event is "unanticipated" when it was unforeseeable at the time of its 
occurrence. A problem or event is "unanticipated" when it occurs at an increased frequency or at an 
increased severity than expected, AND 
• Related: A problem or event is "related" if it is possibly related to the research procedures. 
 
Adverse Event 
An untoward or undesirable experience associated with the use of a medical product (i.e. drug, device, 
biologic) in a patient or research subject. 
Serious Adverse Event 
Adverse events are classified as serious or non-serious.  Serious problems/events can be well defined and 
include; 
• death 
• life threatening adverse experience 
• hospitalization 
• inpatient, new, or prolonged; disability/incapacity 
• persistent or significant disability or incapacity 
• birth defect/anomaly 
 
and/or per protocol may be problems/events that in the opinion of the sponsor-investigator may have adversely 
affected the rights, safety, or welfare of the subjects or others, or substantially compromised the research data. 
 
.  
 
All adverse events that do not meet any of the criteria for serious, should be regarded as non-serious adverse 
events.  
 
Adverse Event Reporting Period 
 
For this study, the study treatment follow-up period is defined as 30 days following the last administration of 
study treatment.  
 
Preexisting Condition 
A preexisting condition is one that is present at the start of the study.  A preexisting condition should be 
recorded as an adverse event if the frequency, intensity, or the character of the condition worsens during the 
study period. 
 


Ge ner al P h ysic al E x a mi n ati o n Fi n di n gs 
 
At scree ni n g, a n y cli nicall y si g nifica nt a b n or malit y s h o ul d be rec or de d as a pree xisti n g c o n diti o n.  At t he e n d 
of t he st u d y, a n y ne w cli nicall y si g nifica nt fi n di n gs/a b n or malities t hat meet t he defi niti o n of a n a d verse e v e nt 
m ust als o be rec or d e d a n d d oc u m e nte d as a n a d verse e ve nt.   
 
A t h or o u g h baseli ne scree ni n g will be f oll o we d f or all s u bjects a n d is o utli ne d i n Ta ble - 2. A d etaile d list of t he 
met h o ds i n w hic h baseli ne scree ni n g will be perf or me d is o utli ne d i n S u p ple me ntal 2 . All bl o o d dra ws a n d 
safet y assess me nts m ust be perf or me d pri or  t o st u d y treat me nt a d mi nistrati o n. A p pr o priate safet y assess me nts 
(e. g., e val u ati o n of A Es a n d S A Es) s h o ul d be re peate d after d osi n g wit h st u d y treat me nt. A p h ysical 
e xa mi nati o n, i ncl u di n g ge neral a p peara n ce a n d vit al si g ns, will be perf or me d as i n dicate d i n Ta ble -2.  If 
i n dicate d, base d o n me di cal hist or y a n d/ or s y m pt o ms, a d diti o nal e xa ms will be perf or m e d at t he discreti o n of 
t he i n vesti gat or. If p ossi ble, t he sa me me m ber of t he st u d y site staff t hr o u g h o ut t he st u d y will perf or m 
assess me nts f or a n i n di vi d ual s u bject. I nf or m ati o n f or all p h ysical e x a mi nati o ns will be i ncl u de d i n t he s o urce 
d oc u me ntati o n at t he st u d y site. Si g nifica nt fi n di n gs t hat are prese nt pri or t o t he s u bject si g ni n g i nf or me d 
c o nse nt will be i ncl u de d i n t he Me dical Hist or y. Si g nifica nt fi n di n gs ma de after t he si g ni n g of t he i nf or me d 
c o nse nt, w hic h meet t he defi niti o n of a n A E, m ust be rec or de d as a n A E. Vital si g ns ( bl o o d press ure, p ulse, 
hei g ht, wei g ht) will be assesse d at eac h p h ysical e xa mi nati o n as i n dicate d i n Ta ble - 2 (s ee S u p ple me ntal 2  f or 
details o n h o w t o ac q uire vital si g ns). W het her acti o n nee ds t o be ta ke n t o a d dress n ota ble vital si g ns will be 
deci de d b y t he i n vesti gat or, c o nsi deri n g t he o verall stat us of t he s u bject. 
 
T e m p or ar y I nterr u pti o n  of I n vesti gati o nal Pr o d uct: I n s o me circ u msta nces, patie nts ma y nee d t o t e m p oraril y 
i nterr u pt treat me nt as a r es ult of A Es or a b n or mal la b orat or y val u es t hat ma y ha ve a n u nclear rel ati o ns hi p t o 
i n vesti gati o nal pr o d uct. F or t he a b n or mal l a b orat or y fi n di n gs a n d cli nical e ve nts (re gar dl ess of relate d ness), 
s pecific g ui da nce is pr o vi de d f or te m p oraril y i nterr u pti n g treat me nt a n d w he n treat me nt ma y be restarte d.  Retest 
fre q ue n c y a n d ti mi n g of f oll o w u p la b orat or y tests t o m o nit or t he a b n or mal fi n di n g is at t he discreti o n of t he 
i n vesti gat or.  I n vesti gati o nal pr o d uct t hat was te m p oraril y i nterr u pte d beca use of a n A E or a b n or mal la b orat or y 
val ue ma y be r estarte d at t he discreti o n of t he i n vesti gat or. 
•  A bs ol ute Ne utr o p hil C o u nt ( A N C): Treat me nt s h o ul d be i nterr u pte d if A N C < 1 x 1 0 9 cells/ L a n d ma y 
be restart e d o nce A N C ret ur n a b o ve t his val ue 
•  A bs ol ute L y m p h oc yte C o u nt ( A L C): Treat me nt s h o ul d be i nterr u pte d if A L C < 0. 5 x 1 0 9 cells/ L a n d 
ma y be restarte d o nce A L C ret ur n a b o ve t his val u e 
•  He m o gl o bi n ( H b): Treat me nt s h o ul d be i nterr u pte d if H b < 8 g/ d L a n d ma y be restarte d o n ce H b ret ur n 
a b o ve t his val ue 
•  He patic tra nsa mi nas es:  Treat me nt  s h o ul d be te m p oraril y i nterr u pte d if dr u g -i n d uce d li ver i nj ur y is 
s us pecte d 
 
Per m a ne nt Disc o nti n u ati o n  fr o m I n vesti gati o nal Pr o d uct: I n v esti gati o nal pr o d uct m ust be per m a ne ntl y 
disc o nti n ue d  if  t he  patie nt  or  t he  patie nt’s  desi g nee  re q uests  t o  disc o nti n ue  i n vesti gati o nal  pr o d uct.  
Disc o nti n uati o n of t he i n vesti gati o nal pr o d uct f or a b n or mal li ver t ests s h o ul d be c o nsi dere d b y t h e i n vesti ga t or 
w he n a patie nt meets 1 of t he f oll o wi n g c o n diti o ns: 
•  A L T or A S T > 8 x U L N  
•  A L T or A S T > 5 x U L N f or m ore t ha n 2 w ee ks after te m p orar y i nterr u pti o n of i n vesti gati o nal pr o d uct 
•  A L T or A S T > 3 x U L N a n d t otal bilir u bi n le vel ( T B L) > 2 x U L N or i nter nati o nal n or malize d rati o 
(I N R) > 1. 5 
•  A L T or A S T > 3 x U L N wit h t he a p peara nce of fati g ue, na usea, v o miti n g, ri g ht u p per q ua dra nt p ai n or 
te n der ness, f e ver, ras h, a n d/ or e osi n o p hilia ( > 5 %) 
•  A L P > 3 x U L N t hat is dee me d t o be of li ver ori gi n a n d dr u g- relate d  
•  A L P > 2. 5 x U L N a n d T B L > 2 x U L N 
•  A L P > 2. 5 x U L N wit h t he a p peara n ce of fati g ue, na usea, v o miti n g, ri g ht u p per- q ua dra nt pai n or 
te n der ness, f e ver, ras h, a n d/ or e osi n o p hilia ( > 5 %) 
•  I n v esti gati o nal pr o d uct s h o ul d be per ma ne ntl y dis c o nti n ue d if a n y of t he f oll o wi n g la b orat or y 
a b n or malities are o bs er v e d:  
•  W hite bl o o d cell c o u nt < 1 0 0 0 cells/ L ( 1. 0 0 x 1 0 3/ L or 1. 0 0 billi o n/ L)  


•  A N C < 5 0 0 cells/ L ( 0. 5 0 x 1 0 3/ L or 0. 5 0 billi o n/ L) 
•  L y m p h oc yte c o u nt < 2 0 0 cells/ L ( 0. 2 0 x 1 0 3/ L or 0. 2 0 billi o n/ L) 
•  He m o gl o bi n < 6. 5 g/ d L ( < 6 5. 0 g/ L) 
 
 
He p atitis B vir us  D N A testi n g will be p erf or m e d i n e nr olle d p atie nts w h o teste d p ositi ve f or H Bc A b at 
scree ni n g. Patie nts w h o are H Bc A b -p ositi ve a n d H B V D N A -ne g ati ve ( u n detecta ble) at Visit 1 will re q uire H B V 
D N A m o nit ori n g e ver y 3 m o nt hs a n d at t he patie nt’s last visit, re gar dless of t heir he patitis B s urface a nti b o d y 
( H Bs A b) stat us. T he f oll o wi n g acti o ns s h o ul d be ta ke n i n res p o ns e t o H B V D N A test res ults: 
•  If a si n gle r es ult is o btai ne d wit h a val ue “ bel o w li mit of q ua ntitati o n,” t he test s h o ul d be re peate d 
wit hi n a p pr o xi matel y 2 wee ks. 
•  If t he re p eat test r es ult is “tar get n ot detecte d,” m o nit ori n g ma y res u me acc or di n g t o t he st u d y 
sc he d ule. 
•  If t he patie nt has 2 or m ore test res ults wit h a val u e “ bel o w li mit of q ua ntitati o n” d uri n g t he st u d y, 
H B V D N A testi n g s h o ul d be perf or me d a p pr o xi matel y o nce p er m o nt h f or t he re mai n der of t he st u d y 
a n d ref err al t o a he p at ol o gist is rec o m me n de d.  
•  If a r es ult is o btai ne d wit h a val ue a b o v e li mit of q ua ntitati o n at a n y ti me d uri n g t he st u d y, t he patie nt 
will be per ma ne ntl y disc o nti n ue d fr o m i n vesti gati o nal pr o d uct a n d s h o ul d be referre d t o a he p at ol o g y 
s pecialist i m me diatel y 
 
 
S u p ple m e nt al 1: A p pr o pri ate ness of Me as ures  
 
S ki n Sc ori n g:  
T here are n o v ali date d s ki n sc ori n g s yste ms f or L P. T heref ore, w e will use si m ple meas ures of B S A w hic h is 
o bjecti ve a n d P G A w hic h is well vali date d i n ot her i nfla m mat or y s ki n c o n diti o ns. A d diti o nall y, we will si m pl y 
a n n otate t he n u m ber of lesi o ns o n t he i n di vi d ual as a mar ker of t otal disease b ur de n. T he lat ter meas ure, 
m C AI L S  was d e vise d f or e val uati o n of c uta n e o us T-cell l y m p h o ma lesi o ns f or trial p ur p oses. T his s yste m 
pr o vi des acc urate m eas ur e me nts of C T C L patc hes, pla q ues, a n d t u m ors. T his sc ori n g s yste m ca pt ures lesi o n 
re d ness, size, t e xt ure, pi g me ntati o n a n d ele vati o n  c haracteristics . We will use a M o difie d C AI L S sc ori n g 
s yste m t hat discar ds pi g me ntati o n sc ori n g as res ol vi n g L P lesi o n i n here ntl y lea ve be hi n d h y p er pi g me nte d s ki n 
c ha n ges w hic h ma y c o nf o u n d acti ve lesi o n sc ori n g. T his will pr o vi de a c o m p osite a nal ysis of t he i n de x lesi o ns 
as well as t he ge n eral b o d y i n v ol ve me nt of t he i n di vi d ual. T he M o difie d C AI L S s yste m is a d va nta g e o us o ver 
t he P A SI or E A SI s yst e m i n t hat i n all o ws f or m ore acc urate calc ul ati o n of s urface area a n d i nc or p orates t hat 
i nt o t he fi nal sc ore.  
 
I n cases w her e s o me or all of t he affecte d b o d y re gi o ns c o ntai n s uc h e xte nsi ve L P disease t hat ma k e c o u nti n g 
i n di vi d ual L P lesi o ns u nfeasi ble, t he lesi o n c o u nt i n t hese areas will be esti mate d.  T he pal mar s urface of t he 
ha n d e q uates t o a p pr o xi matel y 1 % B S A. T o esti mate t he lesi o n c o u nt  i n a b o d y re gi o n of e xte nsi ve disease, 
t he n u m ber of lesi o ns c o u nte d wit hi n a n area e q ui vale nt t o area  t he pal mar s urface of t he h a n d wit h i n t hat 
e xte nsi vel y disease d b o d y re gi o n will be m ulti plie d b y t he re prese ntati ve B S A of t hat b o d y re gi o n t o 
deter mi ne t he esti mate d l esi o n c o u nt c o ntai ne d i n t hat b o d y re gi o n. Re pres e ntati ve B S As of b o d y re gi o ns are 
defi ne d  as f oll o ws: hea d ( 7 %), nec k ( 2 %), a nteri or tr u n k ( 1 3 %), ar ms ( 8 %), f orear ms ( 6 %), h a n ds ( 5 %), 
p osteri or tr u n k ( 1 3 %), b utt oc ks ( 5 %), t hi g hs ( 1 9 %), le gs ( 1 4 %), feet ( 7 %) a n d gr oi n ( 1 %).  
 
Itc h Sc ori n g: 
 
T he  V A S, V R S,  N R S a n d S ki n de x-1 6 are all well vali date d meas ure of itc h. T he V A S, V R S a n d N R S  sc ores 
f oc us o n a gest alt of itc h. T he S ki n de x- 1 6 sc ori n g s yste m f oc uses o n itc h a n d its i m pact u p o n q ualit y of life.  
 
S u p ple m e nt al 2: S afet y Me as ures  
 
B aseli ne Scree ni n g:  
 


A serum β-hCG test will be performed in all pre-menopausal women as indicated. All pre-menopausal women 
who are not sterile at screening will also have a urine pregnancy test performed locally as indicated. Any woman 
with a confirmed positive pregnancy test during screening is not eligible for the study. A positive urine 
pregnancy test during the treatment periods of the study requires immediate interruption of study treatment until 
serum β-hCG is performed and found to be negative. If the serum β-hCG test is positive, study treatment must 
be definitively discontinued. 
 
Blood Pressure and Pulse: 
 
Height and Weight: 
Height and body weight will be measured in indoor clothing, but without shoes. If possible, body weight 
assessments should be performed by the same study site staff member and using the same scale throughout the 
study. 
 
Blood Draws: 
Subjects should avoid smoking within the hour preceding the blood draws. All laboratory studies will be 
conducted within the Mayo Clinic Health Systems (Mayo Clinic Arizona and Mayo Clinic Rochester). Details 
on the collections, shipment of samples and reporting of results will follow Mayo Clinic’s current protocols. For 
the identification of notable values, the Mayo Clinic reference laboratory should be consulted. 
 
Supplemental 3: Safety Monitoring 
 
Infection monitoring: 
Study subjects will be evaluated at each visit for signs or symptoms of infection.  
• Vitals signs as well as constitutional symptoms will be assessed.  
• Assessment for common infections such as cellulitis as well as oral, vaginal, and cutaneous candidiasis 
will be performed 
 
 
 
Post-study Adverse Event 
All unresolved adverse events should be followed by the sponsor-investigator until the events are resolved, the 
subject is lost to follow-up, or the adverse event is otherwise explained.  At the last scheduled visit, the 
sponsor-investigator should instruct each subject to report, to the sponsor-investigator, any subsequent event(s) 
that the subject, or the subject’s personal physician, believes might reasonably be related to participation in 
this study.  
 
Abnormal Laboratory Values 
A clinical laboratory abnormality should be documented as an adverse event if  
 
• they induce clinical signs or symptoms,  
• they are considered clinically significant,  
• they require therapy.  
 
Laboratory studies will be drawn as indicated in Table-2. Whether action needs to be taken to address notable 
laboratory values will be decided by the investigator, considering the overall status of the subject. Hematology 
assessments will be measured at all scheduled study visits specified in Table-2. Serum chemistry will be a 
comprehensive metabolic panel will be measured at all scheduled study visits specified in Table-2. 
 
Hospitalization, Prolonged Hospitalization or Surgery 
Any adverse event that results in hospitalization or prolonged hospitalization should be documented and 
reported as a serious adverse event unless specifically instructed otherwise in this protocol.  Any condition 
responsible for surgery should be documented as an adverse event if the condition meets the criteria for an 
adverse event.  
 


Neither the condition, hospitalization, prolonged hospitalization, nor surgery are reported as an adverse event 
in the following circumstances:  
 
• Hospitalization or prolonged hospitalization for diagnostic or elective surgical procedures for a 
preexisting condition.  Surgery should not be reported as an outcome of an adverse event if the purpose 
of the surgery was elective or diagnostic and the outcome was uneventful. 
8.2 
Recording of Adverse Events 
At each contact with the subject, the study team must seek information on adverse events by specific 
questioning and, as appropriate, by examination.  Information on all adverse events should be recorded 
immediately in the source document, and also in the appropriate adverse event section of the case report form 
(CRF).  All clearly related signs, symptoms, and abnormal diagnostic, laboratory or procedure results should 
recorded in the source document. 
 
All adverse events occurring during the study period must be recorded.  The clinical course of each event 
should be followed until resolution, stabilization, or until it has been ultimately determined that the study 
treatment or participation is not the probable cause.  Serious adverse events that are still ongoing at the end of 
the study period must be followed up, to determine the final outcome.  Any serious adverse event that occurs 
during the Adverse Event Reporting Period and is considered to be at least possibly related to the study 
treatment or study participation should be recorded and reported immediately. 
 
8.3 
Reporting of Serious Adverse Events and Unanticipated Problems 
 
When an adverse event has been identified, the study team will take appropriate action necessary to protect the 
study participant and then complete the Study Adverse Event Worksheet and log.  The sponsor-investigator 
will evaluate the event and determine the necessary follow-up and reporting required. 
 
Relationship of adverse events to study drug 
For all AEs, the investigator will assess the causal relationship between the study drug and the AE using his/her 
clinical expertise and judgment according to the following algorithm that best fits the circumstances of the AE. 
The investigator will interpret and document whether or not an AE has a reasonable possibility of being related 
to study treatment, study device, 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, study device and/or study procedure and the AE. 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. 
 
8.3.1 Sponsor-Investigator reporting: notifying the Mayo IRB 
 
The sponsor-investigator will report to the Mayo IRB any UPIRTSOs and Non-UPIRTSOs according to the 
Mayo IRB Policy and Procedures. 
 
Action taken regarding treatment  
 
AE Action: 
All adverse events should be treated appropriately. Treatment may include one or more of the following:  
• No action taken (i.e. further observation only)  
• [study/investigational] treatment dosage adjusted/temporarily interrupted  
• [study/investigational] treatment permanently discontinued due to this adverse event  
• concomitant medication given  
• non-drug therapy given  


• patient hospitalized/patient’s hospitalization prolonged  
 
AE Outcome: 
• All AE outcomes should be recorded (not recovered/not resolved; recovered/resolved; 
recovering/resolving, recovered/resolved with sequelae; fatal; or unknown) 
 
 
Serious Adverse Events (SAE) 
An SAE is defined as any adverse event (appearance of (or worsening of any pre-existing) undesirable sign(s), 
symptom(s) or medical conditions(s) which meets any one of the following criteria (Life-threatening in the 
context of a SAE refers to a reaction in which the patient was at risk of death at the time of the reaction; it does 
not refer to a reaction that hypothetically might have caused death if more severe.): 
• Is fatal or life-threatening  
• Results in persistent or significant disability/incapacity 
• Constitutes a congenital anomaly/birth defect 
• Requires inpatient hospitalization or prolongation of existing hospitalization, unless hospitalization is for: 
o Routine treatment or monitoring of the studied indication, not associated with any deterioration in 
condition (specify what this includes) 
o Elective or pre-planned treatment for a pre-existing condition that is unrelated to the indication 
under study and has not worsened since signing the informed consent 
o Treatment on an emergency outpatient basis for an event not fulfilling any of the definitions of a 
SAE given above and not resulting in hospital admission  
o Social reasons and respite care in the absence of any deterioration in the patient’s general condition 
• Is medically significant, i.e. defined as an event that jeopardizes the patient or may require medical or 
surgical intervention. 
 
SAE Reporting: 
 
To ensure patient safety, every SAE, regardless of causality, occurring after the patient has provided informed 
consent and until 30-days after the subject stopped study participation must be reported to Eli Lilly and Company 
as soon as possible but no later than 5 days from learning of its occurrence according to the Mayo Clinic IRB 
policy. Any SAEs experienced after the 30-days period should only be reported to Eli Lilly and Company and 
the Mayo Clinic IRB if the investigator suspects a causal relationship to study treatment. Recurrent episodes, 
complications, or progression of the initial SAE must be reported as follow-up to the original episode, regardless 
of when the event occurs. This report must be submitted as soon as possible but no later than 5 days from the 
investigator receiving the follow-up information. SAE should be followed up until resolution or until it is judged 
to be permanent. An SAE that is considered completely unrelated to a previously reported one should be reported 
separately as a new event. 
 
Information collected on the adverse event worksheet (and entered in the research database):  
• Subject’s name:  
• Medical record number:  
• Disease/histology (if applicable):  
• The date the adverse event occurred:  
• Description of the adverse event:  
• Relationship of the adverse event to the research (drug, procedure, or intervention*):  
• If the adverse event was expected:  
• The severity of the adverse event: (use a table to define severity scale 1-5**) 
• If any intervention was necessary:  
• Resolution: (was the incident resolved spontaneously, or after discontinuing treatment) 
• Date of Resolution:  
 
AE Reporting: 
Its relationship to the:  


• Study treatment (no/yes), or 
• Investigational treatment (no/yes), or 
• The other study treatment (non-investigational) (no/yes), or 
• Both or indistinguishable 
The relationship will be categorized as follows: 
• Unrelated- Clearly due only to extraneous causes and does not meet criteria listed under possible or 
probable. 
• Unlikely- Does not follow a reasonable temporal sequence from administration. May have been produced 
by the patient’s clinical state or by environmental factors or other therapies administered. 
• Possible- Follows a reasonable temporal sequence from administration but may have been also produced 
by the patient’s clinical state, environmental factors or other therapies administered. 
• Probable- Clear-cut temporal association with administration with improvement on cessation of 
investigational medicinal product or reduction in dose. Reappears upon rechallenge. Follows a known 
pattern of response to the investigational medicinal product. 
Its duration (start and end dates) or if the event is ongoing an outcome of not recovered/not resolved should be 
reported. 
Whether it constitutes a serious adverse event (SAE) 
 
Adverse Events (AE): 
The severity grade/Common Toxicity Criteria (CTC) AE Version 5.0 grade 
• Mild: usually transient in nature and generally not interfering with normal activities 
• Moderate: sufficiently discomforting to interfere with normal activities 
• Severe: prevents normal activities 
 
If CTCAE grading does not exist for an adverse event, use  
1=mild, 2=moderate, 3=severe, 4=life-threatening, CTCAE Grade 5 (death) is not used, but is collected in other 
CRFs (Study Completion, Death/Survival). 
 
8.3.2 Sponsor-Investigator reporting: Notifying the FDA and Funding Sponsor  
 
The sponsor-investigator will report to the FDA all unexpected, serious suspected adverse reactions according 
to the required IND Safety Reporting timelines, formats and requirements. 
 
Unexpected fatal or life threatening suspected adverse reactions where there is evidence to suggest a causal 
relationship between the study drug/placebo and the adverse event, will be reported as a serious suspected 
adverse reaction.  This will be reported to the FDA on FDA Form 3500A, no later than 7 calendar days after 
the sponsor-investigator’s initial receipt of the information about the event. 
 
Other unexpected serious suspected adverse reactions where there is evidence to suggest a causal relationship 
between the study drug/placebo and the adverse event, will be reported as a serious suspected adverse reaction.  
This will be reported to the FDA on FDA Form 3500A, no later than 15 calendar days after the sponsor-
investigator’s initial receipt of the information about the event. 
 
Any clinically important increase in the rate of serious suspected adverse reactions over those listed in the 
protocol or product insert will be reported as a serious suspected adverse reaction.  This will be reported to the 
FDA on FDA Form 3500A no later than 15 calendar days after the sponsor-investigator’s initial receipt of the 
information about the event. 
 
Findings from other studies in human or animals that suggest a significant risk in humans exposed to the drug 
will be reported.  This will be reported to the FDA on FDA Form 3500A, no later than 15 calendar days after 
the sponsor-investigators initial receipt of the information about the event. 
 
SAE Reporting to the Sponsor (Eli Lilly and Company) 


 
All Serious Adverse Events (“SAE”) required to be reported pursuant to the Protocol shall be provided to Eli 
Lilly and Company and its representatives by Institution or Principal Investigator within twenty-four (24) 
hours of learning of the event as well as provide any additional reports agreed upon by the Institution or 
Principal Investigator and Eli Lilly and Company’s contact  below.  SAE Reports will be sent to the email 
address provided below.  By sending to this e-mail address, the Eli Lilly and Company Pharmacovigilance 
group and the Eli Lilly and Company clinical operations project manager will receive copies of the reports. 
This process will be tested and established before the first patient is enrolled in the trial. Notwithstanding 
anything to the contrary herein, Institution or Principal Investigator will have the primary responsibility of 
reporting adverse events (“AE”) to regulatory authorities. 
 
Copies of IND safety reports submitted to the FDA by the Institution will be shared with the contact below so 
that these reports can be evaluated and included in investigator brochure or Incyte IND safety submissions as 
required to ensure safety of other patients who are receiving the product from Eli Lilly and Company for 
sponsored trials. 
 
Eli Lilly and Company contact for e-mail transmission of individual SAE reports.: 
 
Safety Contacts:  
 
Procedure for Reporting of Pregnancy and Lactation to the Sponsor (Eli Lilly and Company) 
 
Data on fetal outcome are collected for regulatory reporting and drug safety evaluation.  Follow-up should be 
conducted for each pregnancy to determine outcome, including spontaneous or voluntary termination, details of 
the birth, and the presence or absence of any birth defects, congenital abnormalities, or maternal and/or newborn 
complications. 
 
8.4 
Stopping Rules  
 
The stopping rules specified below are based on the knowledge available at study development. The stopping 
rule applies to the overall study. We note that the Adverse Event Stopping Rule may be adjusted in the event 
of either (1) the study re-opening to accrual or (2) at any time during the conduct of the trial and in 
consideration of newly acquired information regarding the adverse event profile of the treatment(s) under 
investigation. The study team may choose to suspend accrual because of unexpected adverse event profiles 
that have not crossed the specified rule below. 
 
Accrual will be temporarily suspended to this study if at any time we observe events considered at least 
possibly related to study treatment (i.e. an adverse event with attribute specified as “possible”, “probable”, or 
“definite”) that satisfy the following: 
 
• If 2 or more patients in the first 6 treated patients (or 30% after the first 6 treated patients have been accrued) 
experience a grade 3 or higher non-hematologic adverse event. 
 
We note that we will review grade 4 and 5 adverse events deemed “unrelated” or “unlikely to be related”, to 
verify their attribution and to monitor the emergence of a previously unrecognized treatment-related adverse 
event. 
8.5 
Medical Monitoring 
 
It is the responsibility of the Principal Investigator to oversee the safety of the study at his/her site.  This safety 
monitoring will include careful assessment and appropriate reporting of adverse events as noted above, as well 
as the construction and implementation of a site data and safety-monitoring plan (see section 10 “Study 
Monitoring, Auditing, and Inspecting”).  Medical monitoring will include a regular assessment of the number 
and type of serious adverse events. 


 
The occurrence of adverse events will be sought by non-directive questioning of the patient at each visit during 
the study. Adverse events also may be detected when the patient volunteers them during or between visits or 
through physical examination, laboratory test, or other assessments. Please see Supplemental 3 for a detailed 
description of safety monitoring. Clinically significant abnormal laboratory values or test results will be 
identified through a review of values outside of normal ranges/clinically notable ranges, significant changes 
from baseline or the previous visit, or values which are non-typical in patient with underlying disease. 
Investigators have the responsibility for managing the safety of individual patient and identifying adverse 
events. Alert ranges for labs and other test abnormalities are included determined by the Mayo Clinic Arizona 
and Mayo Medical Laboratory. Adverse events will be recorded in the Adverse Events Case Report Form 
(CRF) under the signs, symptoms or diagnosis associated with them, and severity. All adverse events will be 
treated appropriately. Once an adverse event is detected, it should be followed until its resolution or until it is 
judged to be permanent, and assessment should be made at each visit (or more frequently, if necessary) of any 
changes in severity, the suspected relationship to the study drug, the interventions required to treat it, and the 
outcome (see Supplemental 3). Information about common side effects already known about the 
investigational drug can be found in the package insert. This information will be included in the patient 
informed consent and should be discussed with the patient during the study as needed. The investigator will 
also instruct each patient to report any new adverse event (beyond the protocol observation period) that the 
patient, or the patient’s personal physician, believes might reasonably be related to study treatment. This 
information should be recorded in the investigator’s source documents, however, if the AE meets the criteria 
of an SAE. To ensure patient safety, every SAE (see Supplemental 3 for definition), regardless of suspected 
causality, occurring after the patient has provided informed consent and after the patient begins taking study 
drug and until 30 days after the patient has stopped study participation will be recorded and reported to Incyte. 
Any SAEs experienced after this 30-day period should only be reported to Incyte if the investigator suspects a 
causal relationship to the study drug. All malignant neoplasms will be assessed as serious under “medically 
significant” if other seriousness criteria are not met. Medical and scientific judgment will be exercised in 
deciding whether other situations should be considered serious reactions, such as important medical events that 
might not be immediately life threatening or result in death or hospitalization but might jeopardize the patient 
or might require intervention to prevent one of the outcomes listed in SAE. Any suspected transmission via a 
medicinal product of an infectious agent is also considered a serious adverse reaction. All AEs (serious and 
non-serious) are captured and recorded, SAEs also require individual reporting (see Supplemental 3). To 
ensure patient safety, each pregnancy occurring while the patient is on study treatment must be reported to the 
sponsor-investigator within 24 hours of learning of its occurrence. The pregnancy should be followed up to 
determine outcome, including spontaneous or voluntary termination, details of the birth, and the presence or 
absence of any birth defects, congenital abnormalities, or maternal and/or newborn complications. Pregnancy 
follow-up should be recorded on the same form and should include an assessment of the possible relationship 
to the study treatment. Any SAE experienced during the pregnancy and unrelated to the pregnancy must be 
reported on a SAE form.  
 
9 Data Handling and Record Keeping 
9.1 
Confidentiality 
Information about study subjects will be kept confidential and managed according to the requirements of the 
Health Insurance Portability and Accountability Act of 1996 (HIPAA).  Those regulations require a signed 
subject authorization informing the subject of the following:  
• What protected health information (PHI) will be collected from subjects in this study 
• Who will have access to that information and why 
• Who will use or disclose that information 
The rights of a research subject to revoke their authorization for use of their PHI. (This information is contained 
within the Mayo IRB Informed Consent Template Section). Study data will be securely stored on a password 
protected computer that only the research study team will have access to.  Any study related paper documents 
will be stored in a locked cabinet that only the research study team will have access to.  
 


In the event that a subject revokes authorization to collect or use PHI, the investigator, by regulation, retains 
the ability to use all information collected prior to the revocation of subject authorization.  For subjects that 
have revoked authorization to collect or use PHI, attempts should be made to obtain permission to collect at 
least vital status (long term survival status that the subject is alive) at the end of their scheduled study period. 
9.2 
Source Documents 
Source data is all information, original records of clinical findings, observations, or other activities in a clinical 
trial necessary for the reconstruction and evaluation of the trial.  Source data are contained in source 
documents.  Examples of these original documents, and data records include: hospital records, clinical and 
office charts, laboratory notes, memoranda, subjects’ diaries or evaluation checklists, pharmacy dispensing 
records, recorded data from automated instruments, copies or transcriptions certified after verification as being 
accurate and complete, microfiches, photographic negatives, microfilm or magnetic media, x-rays, subject 
files, and records kept at the pharmacy, at the laboratories, and at medico-technical departments involved in 
the clinical trial. 
9.3 
Case Report Forms 
 
The study case report form (CRF) is the primary data collection instrument for the study.  All data requested 
on the CRF must be recorded.  All missing data must be explained.  If a space on the CRF is left blank because 
the procedure was not done or the question was not asked, write “N/D”.  If the item is not applicable to the 
individual case, write “N/A”.  All entries should be printed legibly in black ink.  If any entry error has been 
made, to correct such an error, draw a single straight line through the incorrect entry and enter the correct data 
above it.  All such changes must be initialed and dated.  Do not erase or use “white-out” for errors.  For 
clarification of illegible or uncertain entries, print the clarification above the item, then initial and date it.  If 
the reason for the correction is not clear or needs additional explanation, neatly include the details to justify the 
correction. 
 
 
Data Security and Confidentiality 
 
All study data will be collected by the research team, reviewed by the PI, and stored in secure, locked files 
and/or databases in order to protect it from inadvertent loss or improper access. All laboratory specimens, 
evaluation forms, reports, and other records will be identified by coded number only to maintain subject 
confidentiality. Information gained from this study that can be linked to the subject's identity will not be 
released to anyone other than the investigators, the subject and the subject's physician. All the information 
obtained in connection with these studies will remain confidential as far as possible within state and federal 
law. The results of these studies will be published in scientific journals without identifying the subjects by 
name. 
 
Data Quality Assurance 
 
Source document verification will be performed to ensure that the database accurately reflects data on the 
CRFs.  
 
Data Clarification Process 
 
9.4 
Records Retention 
 
The sponsor-investigator will maintain records and essential documents related to the conduct of the study.  
These will include subject case histories and regulatory documents. These will include subject case histories 
and regulatory documents. There will be a subject code master list that will be stored so as to protect subjects’ 
confidentiality. Case Report Forms will be coded. There will be no subject names or other directly identifiable 
information will not appear on any reports, publications, or other disclosures of clinical study outcomes. 
 


The sponsor-investigator will retain the specified records and reports for; 
1. Up to 2 years after the marketing application is approved for the drug; or, if a marketing application is 
not submitted or approved for the drug, until 2 years after shipment and delivery of the drug for 
investigational use is discontinued and the FDA has been so notified. OR 
2. As outlined in the Mayo Clinic Research Policy Manual –“Retention of and Access to Research Data 
Policy” http://mayocontent.mayo.edu/research-policy/MSS_669717   
Whichever is longer 
 
10 Study Monitoring, Auditing, and Inspecting 
10.1 Study Monitoring Plan 
 
The investigator will allocate adequate time for such monitoring activities.  The Investigator will also ensure 
that the monitor or other compliance or quality assurance reviewer is given access to all the study-related 
documents and study related facilities (e.g. pharmacy, diagnostic laboratory, etc.), and has adequate space to 
conduct the monitoring visit. 
10.2 Auditing and Inspecting 
The investigator will permit study-related monitoring, audits, and inspections by the IRB, the sponsor, and 
government regulatory agencies, of all study related documents (e.g. source documents, regulatory documents, 
data collection instruments, study data etc.).  The investigator will ensure the capability for inspections of 
applicable study-related facilities (e.g. pharmacy, diagnostic laboratory, etc.). 
 
Participation as an investigator in this study implies acceptance of potential inspection by government 
regulatory authorities and applicable compliance offices. 
11 Ethical Considerations 
This study is to be conducted according to United States government regulations and Institutional research 
policies and procedures. 
 
This protocol and any amendments will be submitted to a properly constituted local Institutional Review 
Board (IRB), in agreement with local legal prescriptions, for formal approval of the study.  The decision of the 
IRB concerning the conduct of the study will be made in writing to the sponsor-investigator before 
commencement of this study. 
 
All subjects for this study will be provided a consent form describing this study and providing sufficient 
information for subjects to make an informed decision about their participation in this study.  This consent 
form will be submitted with the protocol for review and approval by the IRB for the study.  The formal 
consent of a subject, using the Approved IRB consent form, must be obtained before that subject undergoes 
any study procedure.  The consent form must be signed by the subject or the subject’s legally authorized 
representative, and the individual obtaining the informed consent. 
12 Study Finances 
12.1 Funding Source 
 
Eli Lilly and Company is funding this research study.  
 
12.2 Subject Stipends or Payments 
 
Subjects will receive $50 for each biopsy visit they complete (Day 0 and Week 2).  They will receive $25 for 
all other visits that they complete.   If they complete all study visits they will receive a total of $300.    
 


13 Publication Plan 
 
The key design elements of this protocol will be posted in a publicly accessible database such as 
clinicaltrials.gov. In addition, upon study completion and finalization of the study report the results of this trial 
will be either submitted for publication and/or posted in a publicly accessible database of clinical trial results.   
 
14 References 
 
1. 
Shao, S., et al., IFN-gamma enhances cell-mediated cytotoxicity against keratinocytes via JAK2/STAT1 in lichen 
planus. Sci Transl Med, 2019. 11(511). 
2. 
Zeiser, R., et al., Ruxolitinib in corticosteroid-refractory graft-versus-host disease after allogeneic stem cell 
transplantation: a multicenter survey. Leukemia, 2015. 29(10): p. 2062-8. 
3. 
Hornung, T., et al., Remission of recalcitrant dermatomyositis treated with ruxolitinib. N Engl J Med, 2014. 
371(26): p. 2537-8. 
4. 
Fridman, J.S., et al., Selective inhibition of JAK1 and JAK2 is efficacious in rodent models of arthritis: preclinical 
characterization of INCB028050. J Immunol, 2010. 184(9): p. 5298-307. 
5. 
Felson, D.T., et al., American College of Rheumatology. Preliminary definition of improvement in rheumatoid 
arthritis. Arthritis Rheum, 1995. 38(6): p. 727-35. 
6. 
van der Heijde, D.M., Radiographic imaging: the 'gold standard' for assessment of disease progression in 
rheumatoid arthritis. Rheumatology (Oxford), 2000. 39 Suppl 1: p. 9-16. 
7. 
van Gestel, A.M., et al., Development and validation of the European League Against Rheumatism response 
criteria for rheumatoid arthritis. Comparison with the preliminary American College of Rheumatology and the 
World Health Organization/International League Against Rheumatism Criteria. Arthritis Rheum, 1996. 39(1): p. 
34-40. 
8. 
Felson, D.T., et al., American College of Rheumatology/European League against Rheumatism provisional 
definition of remission in rheumatoid arthritis for clinical trials. Ann Rheum Dis, 2011. 70(3): p. 404-13. 
9. 
Menter, A., et al., Guidelines of care for the management of psoriasis and psoriatic arthritis: Section 1. Overview 
of psoriasis and guidelines of care for the treatment of psoriasis with biologics. J Am Acad Dermatol, 2008. 
58(5): p. 826-50. 
10. 
Papp, K.A., et al., A randomized phase 2b trial of baricitinib, an oral Janus kinase (JAK) 1/JAK2 inhibitor, in 
patients with moderate-to-severe psoriasis. Br J Dermatol, 2016. 174(6): p. 1266-76. 
11. 
Huang, D.W., et al., The DAVID Gene Functional Classification Tool: a novel biological module-centric algorithm 
to functionally analyze large gene lists. Genome biology, 2007. 8(9): p. R183. 
12. 
Subramanian, A., et al., Gene set enrichment analysis: a knowledge-based approach for interpreting genome-
wide expression profiles. Proceedings of the National Academy of Sciences of the United States of America, 
2005. 102(43): p. 15545-50. 
13. 
Yeung, K.Y., D.R. Haynor, and W.L. Ruzzo, Validating clustering for gene expression data. Bioinformatics, 2001. 
17(4): p. 309-18. 
14. 
Yeung, K.Y. and W.L. Ruzzo, Principal component analysis for clustering gene expression data. Bioinformatics, 
2001. 17(9): p. 763-74. 
15. 
Piskol, R., G. Ramaswami, and J.B. Li, Reliable identification of genomic variants from RNA-seq data. Am J 
Hum Genet, 2013. 93(4): p. 641-51. 
16. 
Margolin, A.A., et al., ARACNE: an algorithm for the reconstruction of gene regulatory networks in a mammalian 
cellular context. BMC Bioinformatics, 2006. 7 Suppl 1: p. S7. 
17. 
Olsen, E.A., et al., Clinical end points and response criteria in mycosis fungoides and Sezary syndrome: a 
consensus statement of the International Society for Cutaneous Lymphomas, the United States Cutaneous 
Lymphoma Consortium, and the Cutaneous Lymphoma Task Force of the European Organisation for Research 
and Treatment of Cancer. J Clin Oncol, 2011. 29(18): p. 2598-607. 
18. 
Duvic, M., et al., Phase 2 and 3 clinical trial of oral bexarotene (Targretin capsules) for the treatment of 
refractory or persistent early-stage cutaneous T-cell lymphoma. Archives of dermatology, 2001. 137(5): p. 581-
93. 
19. 
Rogers, L.C., et al., Digital planimetry results in more accurate wound measurements: a comparison to standard 
ruler measurements. J Diabetes Sci Technol, 2010. 4(4): p. 799-802. 
20. 
Phan, N.Q., et al., Assessment of pruritus intensity: prospective study on validity and reliability of the visual 
analogue scale, numerical rating scale and verbal rating scale in 471 patients with chronic pruritus. Acta Derm 
Venereol, 2012. 92(5): p. 502-7. 
21. 
Reich, A., et al., Visual analogue scale: evaluation of the instrument for the assessment of pruritus. Acta Derm 
Venereol, 2012. 92(5): p. 497-501. 
22. 
Chren, M.M., et al., Measurement properties of Skindex-16: a brief quality-of-life measure for patients with skin 
diseases. J Cutan Med Surg, 2001. 5(2): p. 105-10. 
23. 
Atherton, P.J., et al., Using the Skindex-16 and Common Terminology Criteria for Adverse Events to assess 
rash symptoms: results of a pooled-analysis (N0993). Support Care Cancer, 2012. 20(8): p. 1729-35. 
 


15 Attachments 
 
Appendix: 
 
Physician Global Assessment: 17, 18 
Grade 0 Completely clear: no evidence of disease (100% improvement) CCR 
Grade 1 Almost clear: very significant clearance (≥90% to <100%) PR 
Grade 2 Marked Improvement: significant improvement (≥75% to <90%) PR 
Grade 3 Moderate improvement: intermediate between slight and marked (≥50% to <75%) PR 
Grade 4 Slight improvement: some improvement (≥25% to <50%); however, significant evidence of disease 
remains SD 
Grade 5 No change; disease has not changed from baseline condition (+/-<25%) SD 
Grade 6 Worse, disease is worse than at baseline evaluation by (≥25%) or more PD 
 
CCR- Complete clinical response 
PR- Partial response 
SD- Stable disease 
PD- Progressive Disease 
 
 
 
 


Modified CAILS- 
Clinical Assessment Scale of Severity for Index Lesion Signs and Symptoms (mCAILS) 17, 18 
 
Scale      Grade 
0             No evidence of sign or symptom 
1             Intermediate interval 
2             Mild: less than average presentation of sign or symptom 
3             Intermediate interval 
4             Moderate: average disease presentation of sign or symptom 
5             Intermediate interval 
6             Severe: greater than 25% worse than average severity of sign or symptom 
7             Intermediate interval 
8             Very severe: the near worst severity sign or symptom 
A scale of 0 to 18 was used to grade lesion size by square centimeter (0, 0 [no measurable area]; 1, >0 and ≤4; 
2, >4 and ≤10; 3, >10 and ≤16; 4, >16 and ≤25; 5, >25 and ≤35; 6, >35 and ≤45; 7, >45 and ≤55; 8, >55 and 
≤70; 9, >70 and ≤90; 10, >90 and ≤110; 11, >110 and ≤130; 12, >130 and ≤155; 13, >155 and ≤180; 14, >180 
and ≤210; 15, >210 and ≤240; 16, >240 and ≤270; 17, >270 and ≤300; and 18, >300). The area of the lesion will 
be measured with digital planimetry. 17-19 
 
 
mCAILS index lesion score: 
1. 
Erythema (0-8) 
2. 
Scaling (0-8) 
3. 
Plaque elevation (0-8) 
4. 
Size (0-18) 
o 
Trained clinical evaluators assessed the same patients throughout the study. 
o 
The CA (the ratio of summation (Σ) of all clinical signs for these index lesion at each visit compared 
with baseline) included cutaneous tumors and all extra cutaneous manifestations of disease.  
o 
Complete clinical remission (CCR) required a CA ratio of 0 with no evidence of disease  
o 
Partial remission (PR) was defined as a CA ratio of 0.5 or lower  
o 
Progressive disease was defined as a 25% or higher increase in CA ratio 
(Olsen et al., 2011b, Duvic et al., 2001b) 
 
 
 


Itch-  
Numerical Rating Scale (NRS) (bottom)- 20, 21 
 
0- No itch 
1-4 Mild itch 
4-7 Moderate itch 
7-9 Severe itch 
10- Very severe itch  
 
 
 
 
 


Pruritus Verbal Rating Scale (VRS) 
 
On average, please rate your itch over the past 24 hours: 
 
□ 0 (None) 
□ 1 (Mild) 
□ 2 (Moderate) 
□ 3 (Severe) 
 
At its worst, please rate your itch in the last 24 hours: 
 
□ 0 (None) 
□ 1 (Mild) 
□ 2 (Moderate) 
□ 3 (Severe) 
 
 
Pruritus Visual Analogue Scale 
 
Please rate your average itch level over the past day by placing a vertical mark on the line below. 
 
 
No Itch   
Worst Imaginable Itch 
 
  
.  
cm 
 
Please rate your worst itch level over the past day by placing a vertical mark on the line below. 
 
 
No Itch   
Worst Imaginable Itch 
 
 
 
.  
cm 
 
 
VAS score interpretation:  
 
VAS 0 = No itch 
VAS <3 = Mild itch 
VAS ≥3 <7 = Moderate itch 
VAS ≥7 <9 = Severe itch 
VAS ≥9 = Very severe itch 
 
Skindex-16- 
 


Skindex 16 22, 23- 
 
Scoring (0=never bothered to 6=always bothered), Total 0 to 96 
 
Symptom Subscale 
1. 
Skin itching 
2. 
Skin burning or stinging 
3. 
Skin hurting 
4. 
Skin irritated 
 
Emotional Subscale 
5. 
Persistence or recurrence of condition 
6. 
Worry about condition 
7. 
Appearance of skin 
8. 
Frustration about skin 
9. 
Embarrassment about skin 
10. 
Annoyed about skin 
11. 
Feeling depressed 
 
Functional Subscale 
12. 
Effect of skin on interaction with others 
13. 
Effect of skin on desire to be with people 
14. 
Skin making it hard to show affection 
15. 
Effect of skin on daily activity 
16. 
Skin making it hard to work/have enjoyment 
 
 
 
 
16 LICHEN PLANUS QUALITY OF LIFE QUESTIONNAIRE (LPQoL) v2.0 
 
MRN:
 
……………………………………
…………………… 
 
Name:  
……………………………………………
…………… 
Date: ………………………………………………………… 
 
Score: ………………………………………………………… 
 
17 This questionnaire aims to measure how much your lichen planus has 
affected your life over the LAST MONTH. Please check one box for each 
question. 
 
1. How much has your lichen planus affected your sleep? 
Very much  
A lot  
A little  
Not at all  
 
2. How much has your lichen planus affected your work or study? 


Very much  
A lot  
A little  
Not at all  
Not relevant  
 
3. How much has your lichen planus affected your hobbies and interests? 
Very much  
A lot  
A little  
Not at all  
Not relevant  
 
4. How much have you felt self-conscious because of your lichen 
planus? Very much  
A lot  
A little 
Not at all  
 
5. Have you felt lower in mood due to your lichen planus? 
Very much  
A lot  
A little  
Not at all  
 
6. Have you felt more irritable with other people due to your lichen 
planus? Very much  
A lot  
A little 
Not at all  
 
7. How much has applying the treatment for your lichen planus been 
troublesome? Very much  
A lot  
A little  
Not at 
all  
 
8. Have you felt unsupported for your lichen planus? 
Very much  
A lot  
A little  
Not at all  
 
18 Please answer the following questions if your lichen planus affects your SKIN. 
If it does not, please skip to the next section. 
 
9. How sore has your skin been? 
Very much  
A lot  
A little  
Not at all  
 
10. How itchy has your skin been? 
Very much  
A lot  
A little  
Not at all  
 
19 Please answer the following questions if your lichen planus affects your 
MOUTH or THROAT. If it does not, please skip to the next section. 
 
11. How much has your oral lichen planus stopped you from eating certain 
foods? Very much  
A lot  
A little  
Not 
at all  


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12. How much has your oral lichen planus affected your taste? 
Very much  
A lot  
A little  
Not at all  
 
13. How much has your oral lichen planus affected your ability to carry out dental 
hygiene e.g. brushing your teeth? 
Very much  
A lot  
A little  
Not at all  
 
14. How much has your mouth been sore or burning? 
Very much  
A lot  
A little  
Not at all  
 
20 Please answer the following questions if your lichen planus 
affects your GENITALIA (private parts). If it does not, please 
skip to the next section. 
 
15. How much has your genital lichen planus caused any sexual difficulties? 
Very much  
A lot  
A little  
Not at all  
Not relevant  
 
16. How much has your genital area been sore or burning? 
Very much  
A lot  
A little  
Not at all  
 
17. How much has your genital area been itchy? 
Very much  
A lot  
A little  
Not at all  
 
21 Please answer the following questions if your lichen planus affects 
your SCALP/HAIR (lichen planopilaris). If it does not, please skip to 
the next section. 
 
18. How sore or itchy has your scalp been due to 
your lichen planus? Very much  
A lot  
A little  
Not at all  
 
19. How much has the appearance of your scalp lichen planus e.g. 
hair loss bothered you? Very much  
A lot 
A little  
Not at all  
 
22 Please answer the following questions if your lichen planus affects 
your NAILS. If it does not, please skip to the next section. 
 
20. How sore has your nail lichen planus been? 
Very much  
A lot  
A little  
Not at all  
 


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Mayo Clinic- Aaron Mangold, M.D.   
 
CONFIDENTIAL 
21. How much has your nail lichen planus caused 
difficulty handling objects? Very much  
A lot  
A little  
Not at all  
 
22. Have any these areas been actively affected for you in 
the last month? Please circle [3 points for each 
affected]: Eyes 
Ears Nose 
Esophagus 
Larynx 
Perianal and Buttock 
Bladder 
 
23. Are there any other ways that lichen planus affects your quality of life that we have not 
addressed? 
……………………………………………………………………………………………………………………
………………….. 
 
Thank you for your time. Scoring (0-84): 
Very much = 3 
A lot = 2 A little = 
1 
Not at all = 0 The LPQoL is 
calculated by the sum of all the scores for each question. 
 
 
 


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