Baricitinib in Relapsing Giant Cell Arteritis (GCA): A Phase II, Single-institution, Open-label Pilot Study
Phase: PHASE2
Conditions: Arteritis, Giant Cell
Sponsor: Matthew J Koster

Baricitinib in Relapsing Giant Cell Arteritis (GCA): A Phase II, Single-institution, Open-
label Pilot Study 
 
NCT03026504 
 
30December2019 

 
Version: 7.0 
Revised 12/30/19 
 
 
Baricitinib in Relapsing Giant Cell Arteritis (GCA): 
A Phase II, Single-institution, Open-label Pilot Study 
 
 
Participating Institution/Investigators 
 
Mayo Clinic, Rochester, MN 
 
Principal Investigator Kenneth J. 
Warrington, M.D. Professor of 
Medicine 
warrington.kenneth@mayo.edu 
 
Co-principal Investigator 
Matthew J. Koster, M.D. Assistant 
Professor of Medicine 
koster.matthew@mayo.edu 
 
Co-investigators: 
Ashima Makol, M.B.B.S Assistant 
Professor of Medicine 
makol.ashima@mayo.edu 
 
Eric L. Matteson, M.D., M.P.H 
Professor of Medicine 
matteson.eric@mayo.edu 
 
Steven R. Ytterberg, M.D Associate 
Professor of Medicine 
ytterberg.steven@mayo.edu 
 
Statistician 
Cynthia S. Crowson, M.S. crowson@mayo.edu 
 
Research Coordinator Jane 
Jaquith, C.C.R.C 
jaquith.jane@mayo.edu 
 
Version 
Date 
Major Changes 
1 
25 Oct 2016 
Initial protocol 
2 
03 Nov 2016 
Added known evidence of hyperbilirubinemia to exclusions (Sect 7.2), clarified timing of study 
visit/schedule (Sect 9.6), added required information on study monitoring/auditing 
plan/inspection/ethical consideration following intraclinic regulatory review 
3 
25Jul 2017 
Removes screening patient global assessment; Excludes Probenecid within 2 weeks of baseline (Sect 
7.3), Additional study drug discontinuation criterion (Sect 10.2) 
4 
21Sept2017 
Change to excluded/prior medication (Sect 7.3) to allow patients having been exposed to IL-6 inhibitor 
to still be considered for study if they were intolerant of the medication and did not have primary 
failure of the medication for control of GCA. This is in response to increase use of tocilizumab for GCA 
following FDA approval of tocilizumab for GCA in May 2017  
5 
28Nov2017 
Change to excluded/prior medication (Sect 7.3) to clarify language about prior IL-6 inhibitor use before 
study entrance  
Changed tuberculosis screening to include option of different interferon gamma release assay (T-spot 
test) if initial QuantiFERON-TB Gold test is indeterminate 
6 
10Jul2018 
Changed timing of hepatitis and TB screening. If have had done within the last 6 months for other 
clinical reason and they were negative without evidence of exposure or symptoms then these 
negative results will be used for baseline negative and not repeated. This is consistent with clinical 
practice for patients being treated with biologics. See table 2  
7 
30Dec2019 
Clarification of Exclusion criteria (7.2) 

 
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Clarification for shingles vaccine. At time of initial drafting Zostavax was only option but now Shingrix 
is available which is okay to have administered while on immunosuppression and would not be 
exclusion to enrollment and can be done at any time prior to or during study.  (7.2.2) 
 
Clarification on exclusion language of vision changes. It has been the intent of the investigators that 
patients not be demonstrating any NEW features of vision loss to prevent this from being a feature of 
relapse because this is considered a severe relapse and such findings would not be advised to a 
rapid steroid taper as done in this study protocol. However, it was not the intent of the investigators to 
exclude patients with prior symptoms of visual ischemia (at time of diagnosis) if they are not having 
any NEW or worsening vision loss at the time of the documented relapse. We realize that “permanent 
vision loss” may be misleading if this was present at time of diagnosis (because it will always be 
present).Language is updated to clarify this point. (7.2.4) 
 
 
 

 
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Table of Contents 
 
1.   PROTOCOL OVERVIEW………………………………………………………………………………… 
4 
2.   STUDY RATIONALE / SPECIFIC AIMS…………………………………………………………… 
6 
3.   BACKGROUND/SIGNIFICANCE……………………………………………………………………        7 
3.1. 
Giant Cell Arteritis………………………………………………………………    
7 
3.2. 
Glucocorticoids…………………………………………………………………  
7 
3.3. 
Steroid-sparing Agents…………………………………………………………     7 
3.4 
Immunopathologic Studies…………………………………………………             7 
3.5. 
Baricitinib in Autoimmune Disease…………………………………….          9 
3.6. 
Baricitinib in Giant Cell Arteritis………………………………………… 
9  
4.   OBJECTIVE(S) and ENDPOINT(S)…………………………………………………………… 
9 
5.   STUDY DESIGN……………………………………………………………………………………… 
10 
5.1.1.   Study Definitions …………………………………………………………………… 
 
10 
5.1.2.   Design Overview ……………….……………………………………………………    
10 
5.2.      Study Design and Methods…………………………………………………………            
11 
5.3.  Treatment Arms and Duration…………………………………………………………        
12 
5.4. Type and Number of Subjects…………………………………………………………… 
12 
5.5.      Design Justification………………………………………………………………………… 
12 
5.6.      Dose Justification…………………………………………………………………………  
13 
5.6.1.   Baricitinib……………………………………………………………………… 
13 
5.6.2.   Justification of Trial Dose…………………………………………………….. 
13 
5.6.3 
Glucocorticoids………………………………………………………………………….. 
13 
5.6.4.   Justification of Glucocorticoid Taper…………………………………………. 
13 
6.   BENEFIT:RISK ASSESSMENT………………………………………………………………………………. 
14 
6.1. 
Benefit Assessment……………………………………………………………………………… 
 
14 
6.2.      Risk Assessment………………………………………………………………………………….. 
  14 
6.3.      Overall Benefit:Risk Conclusion…………………………………………………………….      15 
7.   SELECTION OF STUDY POPULATION AND WITHDRAWAL CRITERIA………………... 
 15 
7.1.      Inclusion Criteria……………………………………………………………………………….…        16 
7.2.      Exclusion Criteria………………………………………………………………………………...         17 
7.3.      Excluded Prior/Concomitant Therapy……………………………………………….            19 
8.   STUDY TREATMENT………………………………………………………………………………………… 
 20 
8.1.      Investigational Product………………………………………………………………………..         20 
9.   STUDY PROCEDURES………………………………………………………………………………………. 
 20 
9.1.      Recruitment………………………………………………………………………………………..         20 
9.2.      Screening…………………………………………………………………………………………….         21 
9.3.      Screening Failures……………………………………………………………………………….          21 
9.4.      Retesting…………………………………………………………………………………………….          21 
9.5.      Enrollment…………………………………………………………………………………………..         21 
9.6.      Visit Frequency/Visit Schedule……………………………………………………………..        22 
9.7.      Screening and Critical Baseline Assessments ……………………………………….        23 
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9.8.      Efficacy…………………………………………………………………………………………………     23 
9.9. Patient’s and Physician’s Global Assessment and Disease Activity…………      23 
9.10. Pain Assessment………………………………………………………………………………        23 
9.11. Disease activity/damage………………………………………………………………………        23 
9.12.    Study Completion………………………………………………………………………………..       23 
10. WITHDRAWAL/STOPPING CRITERIA………………………………………………………………..       23 
10.1. Interruption of Investigational Product………………………………………………..       23 
10.2. Permanent Discontinuation of Study Drug………………………………………….. 
24 
11. STUDY ENDPOINTS………………………………………………………………………………………….. 
26 
12. STUDY MONITORING AND ADVERSE EVENT REPORTING…………………………………     26 
12.1.    Study Monitoring, Audits, Inspections ..…………………………………..        26  
      12.1.1 Study Monitoring Plan………………………………………………………………..           26 
    12.1.2 Auditing Inspection……………………………………………………………………..           27 
      12.1.3 Ethical Considerations………………………………………………………………..            27 
12.2.    Safety………………………………………………………………………………………………….      27 
12.3.    Adverse Event……………………………………………………………………………………..      27 
12.4.    Serious Adverse Event…………………………………………………………………………       28 
12.5. Toxicity Grading of Adverse Events………………………………………………………      28 
12.6. Time period and Frequency for Collecting Event Information……………….     28 
12.7. Method of Detecting AEs and SAEs……………………………………………………..      29 
12.8.    Follow-up of AEs and SAEs………………………………………………………………….       29 
12.9. Cardiovascular and Death Events………………………………………………………..       29 
12.10. Regulatory Reporting for SAEs………………………………………………………………   30 
12.11. Pregnancy…………………………………………………………………………………………….   30 
12.12. Physical Exams……………………………………………………………………………………       30 
12.13.  Vital Signs……………………………………………………………………………………………       31 
12.14. Clinical Safety Laboratory Assessments……………………………………………….      31 
13. SAMPLE SIZE AND COMPUTATION RATIONALE……………………………………………… 
31 
14. STATISTICAL ANALYSIS PLAN………………………………………………………………………… 
 31 
15. PUBLICATION STRATEGY……………………………………………………………………………….. 
31 
16. REFERENCES …………………………………………………………………………………………………. 
31 
 

 
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1. PROTOCOL OVERVIEW 
 
Protocol Title: Baricitinib in relapsing giant cell arteritis (GCA): a phase II, 
single-institution, open-label pilot study 
Study Chairs: Kenneth J. Warrington, M.D.  – Principal Investigator 
Matthew J. Koster, M.D.  – Co-Principal Investigator 
Statistician: Cynthia Crowson, M.S. 
Study Coordinator: Jane Jaquith, C.C.R.C. 
Participating Sites: Mayo Clinic, Rochester, MN 
Activation Date: 1/1/2017 
Sample Size: 15 
Target Enrollment 
Period: 
60 weeks 
Study Design: Open-label, Phase II 
Primary objective: To determine the safety and tolerability of baricitinib, 4mg 
oral daily, in GCA 
Secondary objective To gather preliminary data on the efficacy of baricitinib, 4mg 
oral daily, in patients with relapsing GCA 
• 
Relapse-free survival at week 52 
• 
Relapse-free survival at week 24 
• 
Duration of glucocorticoid-free remission 
• 
Number of relapses per subject over time 
• 
Change from baseline erythrocyte sedimentation rate 
(ESR) to end of study 
• 
Change from baseline C-reactive protein to end of 
study 
• 
Glucocorticoid dose (mg) at week 52 compared to 
enrollment 
• 
Change in BVAS from baseline to end of study 
Inclusion criteria 1. Diagnosis of GCA defined by the following Revised GCA 
Diagnosis Criteria: 
• 
Age ≥50 years. 
• 
History of ESR ≥ 50 mm/hour or CRP ≥ 10 mg/L. 
• 
Presence of at least one of the following: 
o Unequivocal cranial symptoms of GCA (new 
onset localized headache, scalp or temporal 
artery tenderness, otherwise unexplained 
mouth or jaw pain upon mastication). 
o Unequivocal symptoms of PMR, defined as 
shoulder and/or hip girdle pain associated 
with inflammatory stiffness. 
o Systemic inflammatory disease in which the 
presence of the fever (>38 degrees Celsius 
for ≥ 7 days), weight loss (> 5 lbs or 10% 
premorbid weight), and/or night sweats were 
attributable to GCA and no other cause was 
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identified. 
• 
Presence of at least one of the following: 
o Temporal artery biopsy revealing features of 
GCA. 
o Evidence of large-vessel vasculitis by 
angiography or cross-sectional imaging, 
including but not limited to magnetic 
resonance angiography (MRA), computed 
tomography angiography (CTA), positron 
emission tomography-computed tomography 
(PET-CT) or evidence of large-vessel or 
temporal artery vasculitis by ultrasound (US). 
 
2. Relapse with active GCA within 6 weeks of study entry 
where active disease is defined by an ESR ≥30 mm/hr or 
CRP ≥10 mg/L AND the presence of at least one 
of the following: 
• 
Unequivocal cranial symptoms of GCA (new onset or 
recurrent localized headache, scalp or temporal 
artery tenderness, otherwise unexplained mouth or 
jaw pain upon mastication [i.e., jaw claudication]). 
• 
Unequivocal symptoms of PMR, defined as shoulder 
and/or hip girdle pain associated with inflammatory 
stiffness. 
• 
Other feature(s) judged by the clinician investigator 
to be consistent with GCA or PMR flares (e.g. fever 
of unknown origin, unexplained weight loss, 
fatigue/malaise, etc.) 
 
3. Clinically stable at baseline visit (study drug initiation) 
such that the subject is able to safely participate in the 
standardized taper regimen in the opinion of the investigator. 
 
. 
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2.  STUDY RATIONALE / SPECIFIC AIMS 
Giant cell arteritis (GCA) is the most common idiopathic systemic vasculitis in Europe and North 
America, with an annual incidence of 11-29/100,000 persons ≥ 50 years of age [1-4]. This chronic 
immune-mediated vasculitis is characterized by inflammation of the medium- and large-sized blood 
vessels resulting in significant morbidity including blindness, stroke, aortic aneurysm with rupture, and 
sudden death. GCA affects patients aged 50 years and older and is considered a medical emergency 
because of the high risk of vision loss, which can occur in up to 15-20% [5, 6]. 
Glucocorticoids (GC) have remained the mainstay for both induction to remission and 
maintenance therapy in GCA. Unfortunately, GC contribute substantial toxicity with up to 90% of 
patients developing significant GC-associated adverse events [7, 8]. Therefore, steroid-sparing agents 
for both induction and maintenance therapy are greatly needed to decrease treatment associated 
morbidity. Despite efforts, a steroid-sparing agent with consistent benefit in GCA has not been identified 
leaving a large unmet need for adjunct immunomodulatory medications in this condition. 
Advances in understanding the pathogenesis of GCA has led to developments in potential 
targeted therapeutics. Recent studies have elucidated the pathogenic role of CD4+ T cells in vasculitic 
lesions of GCA and two distinct lineages have been identified as key regulators; type 17 helper T cells 
(Th17) and type 1 helper T cells (Th1) [9]. While Th17 cells appear to be steroid-responsive, Th1 cells 
appear to be steroid-resistant and likely contribute to ongoing disease activity and late stage 
complications of the disease. Although biologic agents in GCA are currently under investigation, 
therapeutics targeting interleukin-6 (tocilizumab and secukinumab) only further block the Th17 pathway 
with little to no anticipated effect on the pathologic Th1 response. 
Baricitinib, an orally administered, potent, selective and reversible inhibitor of JAK1 and JAK2 
has shown preliminary safety and efficacy in chronic, immune-mediated inflammatory conditions such 
as rheumatoid arthritis [14] and psoriasis [11]. This small molecule is uniquely suited as a potential 
novel therapeutic agent in GCA because of its suppressive effect on both the Th17 (IL-6, IL-23) and 
Th1 (IL-12, IFN-γ) pathways. 
The purpose of this study is to evaluate the safety and tolerability of baricitinib in a population of 
patients with relapsing GCA. To accomplish this we will perform a single-institution, open-label pilot 
study assessing the safety and tolerability of baricitinib (4 mg daily, oral, for 52 weeks) in addition to a 
standardized glucocorticoid taper. It is anticipated that adjunct baricitinib will be safe and well tolerated 
by patients with GCA and demonstrate preliminary efficacy as measured by reducing inflammatory 
markers, decreasing steroid requirements and increasing relapse-free survival. 
The vasculitis group at Mayo Clinic in Rochester, Minnesota is well-suited for this study with 50 
years of GCA research experience accounting for over 200 publications in this condition. In addition, 
this institution has one of the largest referral and population-based GCA cohorts in North America and 
has successfully participated in three recent multicenter, international therapeutic clinical trials 
evaluating biologic agents in patients with GCA. 
 
Primary Objective 
To determine the safety and tolerability of adjunct baricitinib (4mg, oral daily, for 52 weeks) in 
combination with standardized glucocorticoid taper among patients with relapsing GCA. 
 
Secondary Objective 
To assess preliminary efficacy of adjunct baricitinib (4mg, oral daily, for 52 weeks) in combination with 
standardized glucocorticoid taper among patients with relapsing GCA. 
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3. BACKGROUND/SIGNIFICANCE 
 
3.1. Giant Cell Arteritis 
Giant cell arteritis (GCA) is the most common idiopathic systemic vasculitis in persons aged ≥50 
years. There is a predilection for vascular inflammation in medium and large arteries with a 
particular tropism for the proximal aorta and its primary branches. Arterial inflammation leads to 
narrowing or occlusion from intimal hyperplasia and can have dramatic consequences. 
Specifically, ischemic cranial symptoms are considered a medical emergency due to the risk of 
transient or permanent visual loss, which can occur in up to 15-20% of patients with GCA [6, 
12]. In addition, patients with GCA are at elevated risk of developing aortic complications 
(aneurysm, dissection, rupture) which can be associated with significant morbidity and mortality. 
Indeed, in a population-based study, patients with GCA were 17.3 times more likely to develop 
thoracic aortic aneurysm [13]. Furthermore, patients with GCA who develop aortic aneurysm 
and/or dissection have a near 3-fold increased mortality compared to non-GCA patients[14]. 
 
3.2. Glucocorticoids 
Prompt initiation of high-dose glucocorticoids (GC) remains the cornerstone of treatment of GCA 
and delay in treatment initiation can increase the risk of severe ischemic complications [15]. 
Although highly variable, improvement of inflammation can occur within days to weeks, leading 
to dramatic reduction in inflammatory markers and systemic symptoms. After attaining 
remission, the GC dose is gradually decreased over a prolonged course of approximately 18-36 
months. Nevertheless, within the first year of diagnosis approximately 50% of patients will 
experience a clinical relapse of the disease despite GC treatment [16]. Furthermore, GC 
treatment in the affected age-group is associated with a high number of adverse effects (AEs) 
including, but not limited to, infection, hypertension, diabetes, cataracts, glaucoma and 
osteoporosis. Such AEs have been reported in up to 90% of patients receiving GC for the 
treatment of GCA and the risk of AEs increases with the cumulative dose and duration of GC 
exposure [7, 17]. Therefore, glucocorticoid-sparing agents are greatly needed for both induction 
and maintenance therapy to decrease the frequency of GC-associated morbidity. 
 
3.3. Glucocorticoid-sparing Agents 
Many investigations have attempted to find a suitable replacement for GC for the treatment of 
GCA; however, no clear therapeutic agent has shown comparable efficacy or superiority to date. 
Among conventional immunosuppressive agents, methotrexate has been considered a 
reasonable second-line agent after GC in patients with severely active/relapsing disease or in 
patients with high risk for GC-associated adverse events. Nevertheless, small clinical trials 
evaluating methotrexate in GCA have only found a modest benefit in decreasing relapse risk and 
glucocorticoid dose reduction [18]. Limited or no benefit has been observed among other oral 
conventional immunosuppressive agents including leflunomide [19, 20], azathioprine [21]       
and mycophenolate mofetil [22]. Biologic agents, including tumor necrosis factor alpha 
inhibitors, have shown equally disappointing results [23-25]. 
 
3.4. Immunopathologic Studies 
Lymphocytic infiltration in vascular lesions is largely driven by two T cell subsets: T helper type 
17 (Th17) and T helper type 1 (Th1) cells [26, 27] (Figure 1). These T cell lineages appear to be 
stimulated by independent signals from different antigen presenting cells (APC) with Th17 cells 
requiring interleukin (IL)-1β / IL-6 / IL-21 / IL-23, whereas the Th1 pathway is dependent on 
APCs secreting IL-12 / IL-18 and interferon gamma (IFN-γ) [27, 28]. In early untreated GCA, 
both T cell lineages are increased in the peripheral circulation as well as within vascular 
inflammatory infiltrates. The Th17 pathway appears to be very sensitive to treatment and GC 
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rapidly control the Th17 effector cytokine production of IL-1, IL-6, IL-17 and IL-23 with 
concomitant depletion of both circulating and infiltrating Th17 cells [26, 28]. 
 
FIGURE 1: Pathophysiology of giant cell arteritis 
 
 
 
 
Despite the effective reduction of the Th17 pathway, a Th1 cell response persists in both biopsy 
and blood samples of treated patients with GCA [26]. The Th1 cytokine signature (IL-2 and IFN- 
γ) associated with chronic vasculitis in GCA is poorly susceptible to GC-mediated suppression 
[28]. Currently, multiple clinical trials investigating biologic agents targeting extracellular 
proinflammatory cytokines are underway [IL-6, tocilizumab and secukinumab; IL-12/IL-23, 
ustekinumab; IL-1, gevokizumab]. However, with the exception of ustekinumab, these biologic 
agents do not impact the Th1 / IL-12 / IFN-γ pathway and therefore may be less likely to exert a 
greater long-term benefit over GC for suppression of chronic inflammation in GCA mediated by 
the Th1 cell subset. Results from the small open-label study evaluating ustekinumab have 
shown initial promise [29]. These preliminary findings may further underscore the importance of 
blocking aspects of both Th cell lineages involved in the pathogenesis of GCA. To date 
interruption of the intracellular signaling upregulated by proinflammatory extracellular cytokines 
has not been pursued in patients with GCA. 
 
Collaborative efforts between the Mayo Clinic vasculitis group and Drs. Cornelia Weyand and 
Jorg Goronzy have identified the importance of signal transducer and activator of transcription 
(STAT) transcripts in GCA [30].  Human temporal arteries were implanted in immunodeficient 
mice and peripheral blood mononuclear cells from patients with GCA were used to reconstitute 
the murine immune system. In the arterial lesional tissue, STAT-1 transcripts were notably 
abundant. IFN-γ, the major cytokine inducer of STAT-1, was also 10-fold higher than in age- 
matched non-GCA controls. Treatment with high-dose dexamethasone reduced IL-6 and IL-1β 
expression but did not affect Th1 cell accumulation in the vessel wall or decrease IFN-γ 
production. However, treatment with tofacitinib, a Janus kinase (JAK)/STAT inhibitor, effectively 
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prevented Th1 cell accumulation in the vessel wall and decreased circulating levels of IFN-γ by 
65%. This proof-of-concept study demonstrates that JAK/STAT inhibition can lead to 
reprogramming of T cell trafficking and prevent T cells from infiltrating the arterial wall, an effect 
that has not yet been observed with other therapeutic agents in this condition. 
 
 
3.5. Baricitinib in Autoimmune Disease 
Extracellular cytokines bind to cell-surface receptors which then generate downstream signaling 
through the activation of tyrosine kinases, including JAK. Cytokines induce JAK enzymatic 
activity by binding to the extracellular portion of their associated receptors, leading to activation 
of the receptor and initiation of intracellular signaling cascades. STATs, which reside in the 
cytosol, when stimulated by cytokines bind active phosphorylated receptors and are then in turn 
phosphorylated by JAKs. This leads to STATs translocating to the nucleus where they bind DNA 
and activate transcription. Exaggerated, aberrant, or protracted JAK/STAT signaling has been 
implicated in several autoimmune diseases and therefore provides potential targets for disease 
modification [31]. Indeed tofacitinib (JAK3 preferential inhibitor) has already been approved for 
use in rheumatoid arthritis and baricitinib has shown preliminary efficacy in rheumatoid arthritis 
[32-34], psoriasis [35] and alopecia areata [36]. 
 
 
3.6. Baricitinib in Giant Cell Arteritis 
Cytokines and mediators that have been associated with aberrant autoimmunity and increased 
inflammatory responses in GCA include IL-6, IL-12, IL-23, and interferon γ (IFN-γ). These 
cytokines signal through the JAK family (JAK1, JAK2, JAK3 and tyrosine kinase 2 [Tyk2]) [37]. 
Baricitinib is an oral Janus kinase inhibitor with preferential inhibition of JAK1 and JAK2. IL-6 
and IFN-γ primarily signal through JAK1 and IL-12 and IL-23 through JAK2. Therefore an agent 
that preferentially inhibits both JAK1 and JAK2 will provide reduction of intracellular signaling 
through multiple proinflammatory pathways, reducing activity of both pathologic Th17 and Th1 
cell lineages. 
 
Given these findings, an open-label phase II trial of baricitinib in patients with relapsing GCA is 
proposed. The purpose of this study will be to evaluate the safety and preliminary efficacy of 
baricitinib in treatment of patients with relapsing GCA. 
 
4. OBJECTIVE(S) and ENDPOINT(S) 
 
Objectives 
Endpoints/Measures 
Primary 
• 
To investigate the safety of baricitinib, 4 
mg oral daily for duration of 52 weeks, 
administered to patients with relapsing 
GCA in combination with a standardized 
glucocorticoid taper 
• 
Incidence of adverse effects and 
serious adverse effects, changes in 
hematology and clinical chemistry 
patterns 
Secondary 
• 
To evaluate preliminary efficacy of 
baricitinib, 4 mg oral daily for duration of 
52 weeks, administered to patients with 
relapsing GCA in combination with a  
standardized glucocorticoid taper 
• 
Relapse-free survival at week 52 
• 
Relapse-free survival at week 24 
• 
Duration of glucocorticoid-free 
remission 
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5. STUDY DESIGN 
5.1.1. Study Definitions 
• 
Active Disease: ongoing signs or symptoms attributable to GCA accompanied by an 
elevated ESR ≥ 30 mm/hour or CRP 10 mg/L. 
• 
Clinically stable: improvement in or absence of ongoing signs or symptoms 
attributable to GCA as evidenced by reduction in symptoms and/or improvement in 
(or normalization of) inflammatory markers 
• 
Relapse: the recurrence of signs or symptoms (i.e. active disease) attributable to GCA in 
subject previously in remission 
• 
Remission: the absence of signs or symptoms attributable to GCA and normalization of 
erythrocyte sedimentation rate (<30 mm/hour) and C-reactive protein (<10 mg/L). 
• 
Glucocorticoid-free remission: the absence of signs or symptoms attributable to GCA 
following discontinuation of glucocorticoids 
• 
Signs and symptoms of GCA: fronto-temporal headache; scalp tenderness; 
abnormality of temporal artery (tenderness, nodularity, decreased pulse); jaw, arm or 
leg claudication; polymyalgia rheumatica; vision change (blurring, diplopia);  
transient (amaurosis fugax) or permanent vision loss.  
5.1.2. Design Overview 
• 
A screening phase of up to 6 weeks in duration 
• 
52-week open-label study drug treatment phase with standardized prednisone taper 
• 
A 12-week follow-up phase to ensure that all subjects are evaluated for safety at 12 
weeks after receiving the last dose of study drug. 
 
•
Duration of glucocorticoid-free remission 
•
Number of relapses per subject over 
time 
•
Change from baseline erythrocyte 
sedimentation rate to end of study 
•
Change from baseline C-reactive 
protein to end of study 
•
Glucocorticoid dose (mg) at week 52 
compared to baseline 
•
Change in BVAS from baseline to end of 
study 

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5.2. Study Design and Methods 
 
This open-label, single-center pilot study will enroll and treat 15 subjects with relapsing GCA. All 
subjects will receive oral baricitinib 4 mg daily for a duration of 12 months. All patients with GCA 
enrolled will have undergone a recent relapse within 6 weeks prior to study entry. In response to 
the observed relapse, prednisone will be re-instituted (for patients who have previously tapered off 
glucocorticoids) or increased (for patients currently on glucocorticoids) based on the level of 
glucocorticoid treatment the patient was on when the relapse occurred, as further outlined below. 
 
Subjects with evidence of relapse will be recruited from the clinical practice of Mayo Clinic 
Rheumatology. If initial inclusion criteria are met, the subject will be consented and begin 
screening for study enrollment. The screening period may be as short as 2 weeks or as long as 6 
weeks. During the screening period, treating physicians may increase prednisone in the following 
manner: if relapse occurred with prednisone doses ≥ 20 but <30 mg/day, an increase to at least 
30 mg/day (but not to exceed 40 mg/day) will occur. For those with relapse present with 
prednisone dose ≥10 but <20 mg/day an increase to at least 20 mg/day (but not to exceed 30 
mg/day) will occur. For those with relapse occurring with prednisone from 0 to <10 mg/day, a 
reinstitution or increase to at least 10 mg/day (but not exceeding 20 mg) will occur. This increase 
will occur during the screening phase following informed consent. The prednisone increase is in 
response to the observed relapse, in keeping with standard clinical practice. 
 
To be enrolled, subjects must have clinically stable disease and treated with a prednisone dose of 
either 30 mg, 20 mg, or 10 mg (in accordance with their respective entry tier) for a minimum of 2 
weeks before initiation of study drug and standardized taper. As such, the patient is not, by the 
physician’s clinical assessment, showing signs of worsening disease (new symptoms or 
increasing severity of the symptoms that were observed at time of relapse) attributable to GCA.  
For example, a patient with relapse occurring at 30 mg prednisone may be increased to 40 
mg/day for 2 weeks, 35 mg/day for 2 weeks and then 30 mg/day for two weeks. If deemed 
clinically stable on 30 mg/day prednisone after two weeks, the subject may enroll and begin 
study drug and standardized glucocorticoid taper. Additional examples: 1) if a relapse occurred at 
15 mg/day, a patient may be increased to 20 mg for 2 weeks and if deemed clinically stable may 
undergo initiation of study drug after being on 20 mg for 2 weeks; 2) if a patient has previously 
been able to discontinue prednisone therapy and has a clinical relapse, prednisone can be re-
initiated at 10 mg/day and if clinically stable at 2 weeks may proceed to enrollment  Once 
enrolled, subjects will begin study drug and reduce their prednisone dose on a standardized 
tapering schedule according to their respective entry dose (30 mg, 20 mg, 10 mg), as outlined in 
Table 1. 
 
If a relapse occurs during the standardized taper (without evidence of severe ischemic event: 
defined as stroke, vision loss, critical limb ischemia) the patient will be removed from the 
standardized prednisone taper regimen but continue study drug for the remaining balance of the 
52-week study period, provided no contraindication or criteria for study drug withdrawal is present 
at time of relapse. Once removed from the standardized prednisone taper, subsequent prednisone 
dose and management will be at the discretion of the treating provider. If a second relapse occurs, 
or if a relapse with the accompaniment of an aforementioned severe ischemic event is observed, 
then the study drug will be discontinued and prednisone and/or other alternative treatments will be 
provided as directed and at the discretion of the treating provider. 
 
Safety and efficacy data will be collected at the time of each clinical visit. In the absence of 
disease worsening, relapse, or drug toxicity, subjects will continue baricitinib for 52 weeks. 
Following completion of 52 weeks of treatment, all subjects will discontinue baricitinib. For safety 
purposes a follow-up visit will occur 12 weeks after discontinuation of the study drug for all 

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subjects, including those with earlier study drug withdrawal. 
The maximum duration of subject participation (including screening) is 70 weeks. Completion of 
the study is defined as completion of the 52-week treatment period and 12-week follow-up visit. 
 
TABLE 1: Standardized prednisone taper 
Time (Week) 
Prednisone dose and tapering schedule 
Screening: -6 to -2* 
30 
20 
10 
0 
30 
20 
10 
1 
25 
17.5 
9 
2 
22.5 
15 
8 
3 
20 
12.5 
7 
4 
17.5 
10 
6 
5 
15 
9 
5 
6 
12.5 
8 
5 
7 
10 
7 
4 
8 
9 
6 
4 
9 
8 
5 
3 
10 
7 
5 
3 
11 
6 
4 
2 
12 
5 
4 
2 
13 
5 
3 
1 
14 
4 
3 
1 
15 
4 
2 
0 
16 
3 
2 
17 
3 
1 
18 
2 
1 
19 
2 
0 
20 
1 
21 
1 
22 
0 
*subjects must be on stable dose of either 30 mg, 20 mg, or 10 mg for 2 weeks prior to baseline 
(week 0) 
 
 
5.3. Treatment Arms and Duration 
This is an open-label, single-arm study. All subjects will receive the study drug for a 
maximum of 52 weeks in combination with a standardized prednisone taper. 
 
5.4. Type and Number of Subjects 
The study population will be comprised of 15 subjects with GCA who have experienced a 
relapse, determined by demonstrating active disease, within 6 weeks of baseline. Active 
disease will be defined as showing evidence of signs or symptoms attributable to GCA 
and the  presence of either an ESR ≥ 30 mm/hr or a CRP ≥ 10 mg/L. Subjects 
demonstrating symptoms of visual manifestations (i.e. double vision, transient or 
permanent partial/complete vision loss), cerebrovascular compromise (ischemic stroke 
deemed secondary to GCA), or limb ischemia will be ineligible for enrollment. Patients on 
glucocorticoids for ≥ 4 years consecutively (without interruption of more than 1 month) will 
be excluded to avoid issues with precipitating secondary adrenal insufficiency and/or 
symptoms of steroid withdrawal from an accelerated standardized glucocorticoid taper.  
 

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5.5. Design Justification 
This is a single-center, open-label study to evaluate the safety of baricitinib in GCA and to 
develop preliminary evidence of efficacy to support the potential conduct of a larger 
randomized trial. 
 
The design of this study is similar in to other open-label phase II studies evaluating biologic 
medications in subjects with GCA [29, 38]. 
 
Glucocorticoids represent the only current standard of care treatment for patients with GCA. As 
such, prednisone will be continued during the initiation of the study drug. Subjects will enter the 
study at one of three doses of prednisone (30 mg, 20 mg, or 10 mg). Subjects should be on a 
stable prednisone dose for a minimum of 2 weeks (maximum 6 weeks) prior to initiation of study 
drug. Following study drug initiation prednisone tapering will occur in a standardized manner. 
 
The 52-week study duration was chosen to assess for safety of medication use as well as to 
observe preliminary evidence of efficacy based on duration of glucocorticoid-free remission and 
relapse-free survival. 
 
5.6 Dose Justification 
 
5.6.1. Baricitinib 
  Subjects will receive a fixed dose of baricitinib, 4 mg oral daily, for duration of 52 weeks. The 
dose of baricitinib will remain constant throughout the study. If serious adverse events occur 
related to the study medication, the dose will not be decreased rather the study drug will be 
withdrawn. 
 
5.6.2. Justification of Trial Dose 
  Baricitinib doses of 1 mg, 2mg, 4 mg, and 8 mg have been investigated in subjects with 
rheumatoid arthritis. Doses ≤4 mg have shown efficacy in rheumatoid arthritis with adverse event 
rates similar to placebo. However, adverse event rates have been noticed to be higher in subject 
groups receiving 8 mg [32-34, 39]. 
 
 
5.6.3. Glucocorticoids (prednisone) 
Glucocorticoids are considered by consensus expert opinion to be the only class of medications 
that has shown consistent efficacy in GCA and are considered standard of care. As such all 
subjects will receive background prednisone at time of enrollment and then undergo standardized 
taper. 
 
5.6.4. Justification of Glucocorticoid Taper 
Consensus guidelines recommend an increase in glucocorticoid treatment at the time of relapse 
to a previous higher dose, followed by repeat attempts at tapering once symptoms have 
improved/stabilized [40]. The protocol standardized tapering regimen is expedited compared to 
clinical practice in order to assess preliminary efficacy of the study drug. 
 
Study subjects may enter the standardized taper at one of three levels; 30 mg, 20 mg or 10 mg. 
These strata were specifically designed to allow for appropriate increase of GC in response to the 
relapsing disease in a manner proportional to the dose of GC the subject was on at the time of 
relapse. It is common practice in treating relapses to increase GC to a prior dose in which the 
subject was asymptomatic. As such the three tier strata allows for clinicians to increase GC 
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an increase to a required entry dose regardless of the GC dose at time of relapse. For example, it 
would be considered unnecessary, in the majority of circumstances, to increase a patient from 5 
mg/day of prednisone to 30 mg/day for a moderate relapse of PMR symptoms, however an 
increase to 10 mg/day would be reasonable. 
 
6. BENEFIT:RISK ASSESSMENT 
 
6.1. Benefit Assessment 
The efficacy of baricitinib in subjects with GCA has not yet been established. However, 
available pre-clinical data provide rationale for the use of JAK inhibitors in GCA. Furthermore, 
baricitinib has been shown to be safe and effective in patients with rheumatoid arthritis. 
Glucocorticoids are the current standard of care treatment for GCA. However, prolonged use 
with GCs is associated with significant risk of adverse events. This study, if successful, will 
provide preliminary  evidence that may result in a new therapy for GCA where there remains 
a clear unmet        need. 
 
Subjects will be receiving standard of care treatment with GC during the study period, albeit 
with a quicker taper than is typically followed in clinical practice. Subjects will receive high 
level of care throughout the study and will benefit from the frequent physical examinations 
and frequent monitoring of vital signs and blood tests. 
 
6.2. Risk Assessment 
 
There are currently no known contraindications or identified risks requiring special warnings or 
special precautions for use of Baricitinib. Potential risks have been identified and are detailed in 
the included accompanying Investigator Brochure for Baricitinib (LY3009104). Potential risks 
are summarized below.  
 
Increased Adverse Events Due to Increased Exposures in Patients with Renal 
Impairment: 
Data from completed studies indicate that subjects with renal impairment have increased 
exposure to baricitinib. Increased exposure could place a person at increased risk for any other 
risk that is related to exposure. Investigators will follow dosing guidelines specified in the 
protocol, and monitor creatinine in study subjects and follow protocol drug interruption and 
discontinuation criteria. 
 
Myelosuppression: Baricitinib is anticipated to down-regulate the JAK pathway and result in 
changes to white blood cell counts. Although dose-related decreases in neutrophils and other 
phagocytic cell lines have been observed, neutropenia and lymphocytopenia have been 
observed infrequently. Investigators will monitor leukocyte parameters in study subjects and 
follow protocol drug interruption and discontinuation criteria. 
 
Increased Infections (including opportunistic infections and herpes zoster): In addition to 
the observed decreases in phagocytic cells, JAK inhibition down-regulates cytokines related to 
the immune system. Although infections and infestations were the most frequently reported 
treatment emergent adverse event (TEAE) occurrence of infections typically considered to be 
opportunistic has not been observed in clinical studies with baricitinib. The incidence rate of 
herpes zoster observed in baricitinib studies is within the range reported in observational 
studies and clinical trials of patients with RA. Investigators will monitor subjects for clinical signs 
and symptoms of infectious events, including herpes zoster. If a subject is clinically diagnosed 
with herpes zoster, the investigator will interrupt investigational product, initiate standard of care 

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(including antiviral therapy and relevant supportive care as appropriate), monitor for multi-
dermatomal involvement or other evidence of dissemination, and follow subjects until clinical 
recovery of skin lesions (vesicles).  
 
Increased Cardiovascular Events Due to Changes in Lipids: Increases in mean total 
cholesterol, LDL, HDL, and triglycerides have been noted in studies with baricitinib. Nuclear 
magnetic resonance data indicate that the changes in cholesterol are due primarily to increases 
in the number of HDL particles without a change in HDL particle size; an increase in the number 
of large LDL particles with no significant increases in small, medium-small or very small LDL 
particles; and an increase in the number of total, as well as medium and small, very low density 
lipoprotein particles. The mean values for the HDL/LDL ratio did not change. These changes in 
lipid particles, particularly in view of the observed increase in large LDL particles, suggest that 
the overall effect on the vasculature may not be atherogenic  Any increase in cholesterol carries 
a potential risk of cardiovascular events. Data from patients with rheumatoid arthritis given 4 to 
15 mg baricitinib QD or 5 mg baricitinib BID have shown no clinically meaningful changes in 
vital signs or ECG parameters for baricitinib versus placebo. Investigators will monitor for 
change in lipid profile from baseline to week 16 to assess for the development of 
hyperlipidemia. If present then institution of hyperlipidemia medications will be suggested if 
clinically recommended.  
 
Fetal Malformations: Reproductive toxicity was observed in rat and rabbit toxicology studies, 
including maternal toxicity and skeletal malformations in the rat fetus. A decrease in mating 
performance (fertility and copulation indices) was observed in the male rat fertility study. This 
change occurred without effects on spermatogenesis as assessed by histopathology and 
semen/sperm endpoints. Pregnant women will not participate in this study. To manage risks, 
women of reproductive potential should avoid becoming pregnant by using 2 forms of highly 
effective contraceptives while participating in clinical studies and for 28 days following exposure 
to baricitinib. Screening for pregnancy will occur during the screening period and at all study 
visits. The population affected by GCA has an average diagnosis age of 72, therefore the 
likelihood of patients being of childbearing age is of low likelihood.  
 
Emergence of Malignancies Previously Contained by the Immune System: Baricitinib has 
immunomodulatory effects on the immune system. Effects on the immune system may permit 
emergence of malignancies previously contained by the immune system. No signals concerning 
effects of baricitinib on malignancy have emerged from clinical studies. Patients should be 
monitored closely for evidence of neoplasia or malignancy, and study drug should be 
discontinued if such events occur. 
 
Accelerated Prednisone Taper: In addition to the information available for Baricitinib, a 
quicker taper of steroids may lead to withdrawal side effects. Subjects may experience GCA 
relapse during steroid taper. Inclusion of subjects with stable disease on study entry who are 
able to safely participate in the steroid taper and have had duration of steroids ≤ 4 years. 
Monitoring of subjects during steroid taper and following discontinuation. Subjects with severe 
ischemic manifestations related to GCA will be excluded from the trial. Disease relapses will be 
treated with increased dose of GCs. 
 
6.3. Overall Benefit:Risk Conclusion 

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While the efficacy of baricitinib in subjects with GCA is unknown, pathophysiologic rationale 
exists to consider use in GCA, given that baricitinib has been shown to be safe and effective in 
rheumatoid arthritis. 
 
Taking into account the measures taken to minimize risk to subjects participating in this study, 
the potential risks identified in association with baricitinib are justified by the anticipated benefits 
that may be afforded to subjects with GCA. If baricitinib is able to sustain a GC-free remission 
this would significantly reduce the burden of GC-related toxicity, which is commonly 
encountered in long term management of subjects with GCA. 
 
 
7.  SELECTION OF STUDY POPULATION AND WITHDRAWAL CRITERIA 
 
7.1 Inclusion Criteria 
 
Subjects are eligible for enrollment in the study if the following inclusion criteria are met: 
 
1. Diagnosis of GCA defined by the following Revised GCA Diagnosis Criteria: 
• 
Age ≥50 years. 
• 
History of ESR ≥ 50 mm/hour or CRP ≥ 10 mg/L. 
• 
Presence of at least one of the following: 
o Unequivocal cranial symptoms of GCA (new onset localized headache, scalp or 
temporal artery tenderness, otherwise unexplained mouth or jaw pain upon mastication). 
o Unequivocal symptoms of PMR, defined as shoulder and/or hip girdle pain associated 
with inflammatory stiffness. 
o Systemic inflammatory disease in which the presence of the fever (>38 degrees Celsius 
for ≥ 7 days), weight loss (> 5 lbs or 10% premorbid weight), and/or night sweats were 
attributable to GCA and no other cause was identified. 
• 
Presence of at least one of the following: 
o Temporal artery biopsy revealing features of GCA. 
o Evidence of large-vessel vasculitis by angiography or cross-sectional imaging, including 
but not limited to magnetic resonance angiography (MRA), computed tomography 
angiography (CTA), positron emission tomography-computed tomography (PET-CT) or 
evidence of large-vessel or temporal artery vasculitis by ultrasound (US). 
 
2. Relapse with active GCA within 6 weeks of study entry where active disease is 
defined by an ESR ≥30 mm/hr or CRP ≥10 mg/L AND the presence of at least one 
of the following: 
• 
Unequivocal cranial symptoms of GCA (new onset or recurrent localized headache, scalp or 
temporal artery tenderness, otherwise unexplained mouth or jaw pain upon mastication [i.e., jaw 
claudication]). 
• 
Unequivocal symptoms of PMR, defined as shoulder and/or hip girdle pain associated with 
inflammatory stiffness. 
• 
Other feature(s) judged by the clinician investigator to be consistent with GCA or PMR flares 
(e.g. fever of unknown origin, weight loss, fatigue/malaise, etc.) 
 
3. Clinically stable at baseline visit (study drug initiation) such that the subject is able to safely 
participate in the standardized taper regimen in the opinion of the investigator. 
 
 
 
 

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7.2. Exclusion Criteria 
  
A subject will not be eligible for inclusion in this study if any of the following criteria 
apply: 
 
 
1. Presence of any other autoimmune disease (such as systemic lupus erythematosus, 
rheumatoid arthritis, inflammatory arthritis, other vasculitides, scleroderma, polymyositis, 
dermatomyositis, or other similar systemic connective tissue diseases). 
2. Subjects demonstrating symptoms of active or newly developing visual loss (transient or 
permanent blindness) or diplopia attributable to GCA at the time of relapse. Patients with 
history of visual ischemia present at the time of original GCA diagnosis will still be 
considered eligible if at the time of the documented pre-study relapse there is no evidence 
of change/progression of their known visual deficit that can be attributed to active GCA.  
3. Subjects with history of aortic dissection, myocardial infarction, or cerebrovascular attack 
attributable to GCA. 
4. Has received, or is expected to receive, any live virus vaccinations (with the exception of herpes 
zoster vaccination) within 3 months before the first dose of study drug, during the study, or within 3 
months after the last administration of the study drug. All patients who have not received the 
herpes zoster vaccine at screening will be encouraged (per local guidelines) to do so prior to 
randomization; vaccination must occur >4 weeks prior to randomization and start of investigational 
product.  Patients will be excluded if they were exposed to herpes zoster (Zostavax) vaccination 
within 4 weeks of planned randomization. Patients may receive the inactivated (non-live) herpes 
zoster vaccine (Shingrix) at any time prior to or after the study start. 
5. Organ transplant recipients. 
6. Have had a major surgery within 8 weeks prior to screening or will require major surgery during the 
study that, in the opinion of the investigator would pose an unacceptable risk to the patient. 
7. Have experienced any of the following within 12 weeks of screening: myocardial infarction (MI), 
unstable ischemic heart disease, stroke, or New York Heart Association Stage IV heart failure 
8. Have a history or presence of cardiovascular (including but not limited to uncontrolled hypertension), 
respiratory, hepatic, gastrointestinal, endocrine, hematological, neurological, or neuropsychiatric 
disorders, or any other serious and/or unstable illness that, in the opinion of the investigator, could 
constitute an unacceptable risk when taking investigational product or interfere with the 
interpretation of data. 
9. Are largely or wholly incapacitated permitting little or no self-care, such as being bedridden or 
confined to a wheelchair. 
10. Have an estimated glomerular filtration rate (eGFR) of <50 mL/min/1.73 m². 
11. Have a known history of chronic liver disease with the most recent available aspartate 
aminotransferase (AST) or alanine aminotransferase (ALT) > 2 times the upper limit of normal (>2 
x ULN) 
12. Known evidence of hyperbilirubinemia with a prior total bilirubin ≥1.5 x ULN. 
13. Have a history of lymphoproliferative disease; or have signs or symptoms suggestive of possible 
lymphoproliferative disease, including lymphadenopathy or splenomegaly; or have active primary or 
recurrent malignant disease; or have been in remission from clinically significant malignancy for < 5 
years. 
a. Subjects with uterine cervical carcinoma in situ that has been resected with no evidence 
of recurrence or metastatic disease for at least 3 years may participate in the study 
b. Subjects with basal cell or squamous epithelial skin cancers which have been 
completely resected with no evidence of recurrence for at least 3 years may participate 
in the study. 
14. Active infections, or history of recurrent infections or have required management of acute or 
chronic infections as evidenced by any of the following: 

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a. Currently on any suppressive therapy for a chronic infection (such as tuberculosis, 
cytomegalovirus, herpes simplex, herpes zoster, or atypical mycobacteria). 
b. History or suspicion of chronic infection (e.g. prosthetic joint infection) 
c. Hospitalization for treatment of infection within 60 days of baseline visit 
d. Use of parenteral (IV or IM) antimicrobials (antibacterial, antifungals, antivirals, or 
antiparasitic agents) within 60 days of baseline or oral antimicrobials within 30 days of 
baseline visit for treatment of an active infection. This does not include the use of antibiotics 
for prophylaxis against pneumocystis pneumonia since this is considered standard of care 
for patients on prednisone ≥ 20 mg/day for longer than 3 consecutive months.  
15. Have had symptomatic herpes zoster infection within 12 weeks prior to screening. 
16. Have a history of disseminated/complicated herpes zoster (for example, multidermatomal 
involvement, ophthalmic zoster or CNS involvement) 
17. In the opinion of the investigator, are at an unacceptable risk for participating in the study. 
18. Have known or documented diagnosis of human immunodeficiency virus (HIV). 
19. Have known or documented primary immunodeficiency. 
20. Have had household contact with a person with active tuberculosis (TB) and did not receive 
appropriate and documented prophylaxis for TB. 
21. Have had evidence of active TB or have previously had evidence of active TB and did not 
receive appropriate and documented treatment. 
22. Have evidence of latent TB as documented by a local lab positive QuantiFERON®-TB Gold test 
and a normal chest x-ray, unless a patient completes at least 4 weeks of appropriate treatment 
prior to study entry and agrees to complete the remainder of treatment while in the trial. 
a. If the QuantiFERON®-TB Gold test results are positive, the patient will be considered to 
have latent TB and will be excluded, unless treatment is initiated as outlined above. If the 
test is indeterminate, the test may be repeated once within 2 weeks of the initial value with 
either a second QuantiFERON®-TB Gold Test or with a different interferon gamma release 
assay (i.e. T-Spot tuberculosis test).. If the second test result is again not negative (i.e. 
positive or indeterminate), the subject will be considered to have latent TB (for purposes of 
this study) and will be excluded, unless treatment is initiated as outlined above. 
b. Exceptions include subjects with a history of active or latent TB who have documented 
evidence of appropriate treatment and with no history of re-exposure since their treatment 
was completed. (Such subjects would not be required to undergo the protocol specific TB 
testing, but would require a baseline chest x-ray). 
23. Have a positive test for HBV defined as: 
a. Positive for hepatitis B surface antigen (HBsAg), or 
b. Positive for anti-hepatitis B core antibody (HBcAb)  
If any of the HB tests have an indeterminate result, confirmatory testing will be performed by an 
alternate method. 
 
24. Have HCV (positive for anti-hepatitis C antibody with confirmed presence of HCV). 
25. Have any of the following specific abnormalities at time of relapse or during screening: 
a. ALT or AST > 2 x ULN 
b. Hemoglobin < 10 g/dL 
c. Total white blood cell count (WBC) < 2500 cells/μL) 
d. Neutropenia (absolute neutrophil count [ANC] < 1200 cells/μL 
e. Lymphopenia (lymphocyte count < 750 cells/μL) 
f. 
Thrombocytopenia (platelets < 100,000 cells/μL) 
g. eGFR < 50 mL/min/1.73m² 
 
In the case of any of the aforementioned laboratory abnormalities, the tests may be 
repeated once within approximately 2 weeks from the initial values, and values resulting 
from repeat testing may be accepted for enrollment eligibility if they meet the eligibility 

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criterion. 
26. Are pregnant or breast feeding at the time of screening or enrollment. 
27. Are females of childbearing potential who do not agree to use 2 forms of highly effective birth 
control when engaging in sexual intercourse with a male partner while enrolled in the study and for 
at least 4 weeks following the last dose of the study drug 
a. Females of non-childbearing potential are defined as women ≥60 years of age, women 
≥40 but <60 years of age what had had cessation of menses for at least 12 months, or 
whom who are congenitally or surgically sterile (that is have had a hysterectomy, or 
bilateral oophorectomy or tubal ligation) 
b. The following birth control methods are considered highly effective (the subject should 
choose 2 to be used with their male partner 
i. Oral, injectable, or implanted hormonal contraceptives 
ii. Condom with spermicidal foam, gel film, cream or suppository 
iii. Occlusive cap (diaphragm or cervical/vault caps) with a spermicidal foam, gel, 
film, cream or suppository 
iv. .  Intrauterine device 
v. Intrauterine system (for example progestin-releasing coil) 
vi. Vasectomies male (with appropriate post-vasectomy documentation of the 
absence of sperm in the ejaculate) 
28. Are males who do not agree to use 2 forms of highly effective birth control (see above) while 
engaging in sexual intercourse with females partners of childbearing potential while enrolled in the 
study and for 4 weeks after the last dose of the study drug. 
29. 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. 
30. Have a history of chronic alcohol abuse, IV drug abuse, or other illicit drug above within the 2 
years prior to screening. 
31. Have previously received baricitinib for other investigational study. 
32. Are unable or unwilling to make themselves available for the duration of the study and/or are 
unwilling to follow study restrictions/procedures 
33. Are currently enrolled in, or discontinued within 4 weeks prior to screening from any other 
clinical trial involving an investigational product or nonapproved use of a drug or device or 
concurrently enrolled in any other type of medical research judged not to be scientifically or 
medically compatible with this study. 
34. Are investigator site personnel directly affiliated with this study and/or their immediate families. 
Immediate family is defined as a spouse, parent, child, or sibling whether biological or legally 
adopted. 
35. Have a chronic medical illness requiring the use of oral of IV glucocorticoid treatment (e.g. asthma 
or emphysema) during the trial or requiring long term glucocorticoid treatment such that they would 
not be able to safely undergone a standardized glucocorticoid taper. 
 
 
7.3. Excluded Prior/Concomitant Therapy 
 
Had prior treatment with any of the following: 
• 
Systemic immunosuppressives, including azathioprine, oral cyclosporine A, tacrolimus, 
mycophenolate mofetil and IL-1ra (anakinra) within 4 weeks of baseline. 
• 
Leflunomide within 12 weeks of baseline 
• 
Methotrexate within 2 weeks of baseline 
• 
Etanercept within 4 weeks or within 8 weeks of baseline with adalimumab, certolizumab, 
golimumab, infliximab 
• 
Cyclophosphamide within 8 weeks of baseline 

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• 
Received any anti-IL6 agent (tocilizumab, sirukumab, sarilumab) and had failure to control GCA 
symptoms (i.e. primary therapeutic failure) at any point prior to study screening/entry.  
• 
Patients having received an anti-IL6 agent that were intolerant to the medication (e.g. 
injection site or infusion reaction) may still be considered eligible for study enrollment.  
• 
Patients for which an IL-6 agent is being stopped for reason other than therapeutic 
failure are also considered eligible for study enrollment.  
• 
Prior to baseline visit/study drug initiation, the patient must be off of the anti-IL6 agent for 
4 weeks prior to baseline for infusible (intravenous) formulations and 2 weeks prior for 
subcutaneously administered formulations.   
• 
Rituximab within 12 months of baseline or longer if B cell counts have not returned to normal 
range or baseline levels 
• 
Abatacept within 8 weeks of baseline 
• 
Tofacitinib  at any point prior to study screening/entry 
• 
Intravenous (pulse) doses of glucocorticoid defined as methylprednisolone > 100 mg/day within 
8 weeks of baseline 
• 
Probenecid within 2 weeks of baseline visit 
 
8.  STUDY TREATMENT 
 
8.1 Investigational Product 
 
Study Treatment 
Product name 
Baricitinib 
Dosage form 
Tablet 
Unit dose 
4 mg 
Route of administration 
Oral 
Dosing instruction 
Daily 
 
The term “study drug” and “study treatment” are used throughout the protocol to describe the 
investigational product received by the subject per protocol design (i.e. barcitinib 4 mg oral tablet). 
 
Baricitinib will be supplied by Eli Lilly [investigational product (IP) manufacturer]. The tablets are 
composed of baricitinib free base and the inactive ingredients microcrystalline cellulose, mannitol, 
croscarmellose sodium and magnesium stearate. Each tablet contains baricitinib equivalent to 4 mg of 
the free base compound. The supplied tablets will be held at the Mayo Clinic Outpatient Research 
Pharmacy during the duration of the study and dispensed to the patient at each scheduled visit with 
sufficient doses until the subsequent scheduled visit. The maximum amount of supply provided will be 2 
months. The medication will be stored according to specification on the label. Patients will keep a diary 
of all days on which baricitinib is taken to assess compliance at each study visit. 
 
 
9. STUDY PROCEDURES 
 
9.1. Recruitment 
Recruitment will occur through the clinical practices of the investigators at the study site. Subject 
enrollment at the study site will not occur until Institutional Review Board (IRB) approval of this protocol 
and the informed consent form (ICF) has been obtained. Details of the goals of the research and the 
risk and benefits of the protocol will be reviewed with each potential study subject. Recruitment will 
occur by physicians or study coordinators. 
 

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Subjects who decline participation will continue to be followed by their current physician as deemed 
appropriate. 
9.2. Screening 
This research study will be explained in lay language to each potential research subject. The subject  
will sign an informed consent form before undergoing any screening investigations (including labs). The 
screening period will last for a minimum of two weeks and a maximum of six weeks. 
 
9.3. Screening Failures 
Screen failures are defined as subjects who consent to participate in the trial but are not enrolled or do 
not receive study drug. In order to ensure transparent reporting of screen failure subjects, to meet the 
Consolidated Standards of Reporting Trials (CONSORT) publishing requirements and to respond to 
queries from regulatory authorities, a minimal set of screen failure information will be collected and 
retained including demographics, screen failure details and eligibility criteria. 
 
Subjects who are not able to achieve a clinically stable dose (as outlined in the tiered entry description), 
for a minimum of two weeks during the screening period will be considered screen failures.It is anticipated 
that for each patient enrolled, 2-3 subjects will need to be screened. Therefore, it is expected that 30-45 
patients will be screened in order to enroll 15 patients. 
 
9.4. Retesting 
If the subject has signed the Informed Consent Form (ICF) and failed to meet at least one entry criterion, 
the site may retest laboratory values once during the screening period. Laboratory parameters can only 
be re-tested once. If a different laboratory parameter is found to be out of range in the re-test, no further 
testing is allowed and the patient will be ineligible. Re-testing may be performed to determine eligibility 
within the screening window. Subjects that have laboratory values that do not meet the entry criteria 
following the re-test are deemed a screen failure. A Quantiferon-TB® test can only be repeated once if 
initial is indeterminate. If second test is indeterminate or positive then the subject is considered a screen 
failure. 
 
9.5. Enrollment 
Women: GCA occurs more commonly in women than men (approximate 2:1 ratio) and as such it is 
anticipated that more women will be enrolled than men. 
Pregnant women: Pregnant women are excluded from this study. 
Pediatric Subjects: GCA, by classification, occurs in subjects aged ≥ 50 years of age. As such pediatric 
subjects are not included in this study. 
Underrepresented Ethnic/Racial Minorities:GCA has been reported to occur in most ethnicities; however, it 
is most common in Caucasians. There will be no exclusion of any subject based on sex, ethnicity, race, or 
socioeconomic status. 
 
9.6. Visit Frequency/Visit Schedule 
 
Subjects will be evaluated for potential eligibility. Once eligibility is deemed likely, they will be 
consented and undergo screening. Labs pertaining to determination of eligibility will be obtained 
during the screening period [ QuantiFERON-TB, Hepatitis panel, pregnancy test (if applicable)]. If 
standard of care labs (complete blood count, inflammatory markers, creatinine, transaminases ) 
were performed at time of observed relapse these will be used for assessment of their respective 
eligibility laboratory parameters. If they were not drawn at time of observed relapse they will be 
drawn during the screening period. Standard of care labs will be obtained at each follow up visit, 
including the 12-week post treatment visit (W64).Lipid profiles will be obtained at week 0 and 
week 16.   
 
Imaging can be performed in the study period with non-invasive angiography if clinically indicated and is 

23 
 
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not considered a requirement for screening or necessary for study enrollment. Computed tomography 
angiography (CTA) and magnetic resonance angiography (MRA) is recommended at time of diagnosis 
for patients with GCA (level of evidence Class I, Level C) [41]. If large vessel involvement is observed on 
advanced imaging, follow up scan at 12-15 months is recommended. 
 
Upon enrollment (Week 0), the study drug will be initiated and standardized GC taper begun. A follow-
up visit will occur at week 4 (W4), week 8 (W8), then every 8 weeks until week 52 (W52) when study 
drug will be discontinued. After study drug is completed a 12-week follow up visit will occur (W64).  
Visit dates can by ±4 days from the assigned week to allow for subject travel and investigator availability. 
A summary of the visit schedule can be seen in the Table 2.  
 
Table 2:  Visit Schedule 
 
Study Date W=Week (±4 days) 
Observed 
Relapse 
Screening 
(up to 42 
days) 
W0 
W4 
W8 
W16 
W24 
W32 
W40 
W52 
W64 
Study drug initiation 
 
 
X 
 
 
 
 
 
 
 
 
Prednisone taper initiation 
 
 
X 
 
 
 
 
 
 
 
 
Office visit 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Data Forms 
 
 
 
 
 
 
 
 
 
 
 
Informed consent 
X 
 
 
 
 
 
 
 
 
 
 
Eligibility review 
X 
   X 
X 
 
 
 
 
 
 
 
 
Demographics 
 
X 
 
 
 
 
 
 
 
 
 
Baseline medical history 
 
X 
 
 
 
 
 
 
 
 
 
Medications 
 
X 
 
 
 
 
 
 
 
 
 
Tobacco use 
 
X 
 
 
 
 
 
 
 
 
 
Patient Global Assessment 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Physician Global Assessment 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Vascular Damage Index 
 
 
X 
 
 
 
 
 
 
X 
 
Birmingham Vasculitis Activity Score 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Imaging 
 
 
 
 
 
 
 
 
 
 
 
CTA or MRA Chesta 
 
X 
 
 
 
 
 
 
 
 
 
Labs 
 
 
 
 
 
 
 
 
 
 
 
Hepatitis panelb 
 
X* 
 
 
 
 
 
 
 
 
 
Tuberculosis test (Quantiferon-TB or T-
spot TB) 
 
X* 
 
 
 
 
 
 
 
 
 
Lipid profile 
 
 
X 
 
 
X 
 
 
 
 
 
Pregnancy testc 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
CBC w/diff 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
ESR 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
CRP 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
ALT 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Creatinine w/EGFR 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
As necessary 
 
 
 
 
 
 
 
 
 
 
 
Hospitalization 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Adverse event report 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Death 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Protocol deviation 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Study therapy discontinuation 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 

24 
 
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 aComputed tomography angiography (CTA) and magnetic resonance angiography (MRA) at physician discretion if has not had previously or at baseline of 
diagnosis. If large vessel involvement observed on advanced imaging, follow up scan at 12-15 months is recommended. These imaging studies are not part of 
protocol screening requirements and are considered standard of care (Class I, Level C) [41]. 
 bHepatitis panel consists of the following: Hepatitis B surface antigen (HBsAg), anti-hepatitis B surface antibody (anti-HBs), anti-hepatitis B core antibody 
(anti-HBc) total, and anti- hepatitis C (anti-HCV). 
 cFor women of child bearing potential. Subjects of non-child bearing potential as defined in exclusion criteria are exempt from pregnancy screening. 
*For patients with hepatitis panel and/or tuberculosis testing (Quantiferon-TB or T-Spot TB test) performed within 6 months prior to study entry screening for 
other clinical purpose, if these tests were confirmed negative and the patient has had no known exposure to either hepatitis or tuberculosis and the patient 
demonstrates no clinical symptomatology suggestive of these conditions then the prior negative result (within the aforementioned time frame) will be 
considered as their baseline negative evaluation and repeat testing for these conditions during the screening period is not required.  

 
Version: 7.0 
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25 
 
 
9.7. Screening and Critical Baseline Assessments 
Cardiovascular medical history/risk factors (as detailed in the case report form) will 
be assessed at screening. 
 
The following demographic parameters will be captured: year of birth, sex, and 
ethnicity. 
 
Medical/medication/family history will be assessed as related to the inclusion/exclusion criteria. 
 
9.8. Efficacy 
Efficacy of baricitinib in GCA will be assessed from the presence of GCA activity including 
investigator assessment of signs and symptoms of GCA (new onset localized headache, scalp or 
temporal artery tenderness, ischemia-related vision loss [permanent vision loss due to AION, 
amaurosis fugax, episodic blurry vision], diplopia, or otherwise unexplained mouth or jaw pain upon 
mastication [i.e., jaw claudication], PMR symptoms [shoulder and/or hip girdle pain associated with 
inflammatory stiffness], and other features such as new or worsened extremity claudication, and 
fever of unknown origin), and laboratory results for serum ESR and CRP levels. 
 
9.9.  Patient’s and Physician’s Global Assessment of Disease Activity  
The Patient’s and Physician’s Global Assessments of Disease Activity will be recorded on a visual 
analog scale (VAS). The scale for each ranges from 0 to 100 with the subject’s disease activity 
assessment ranging from “very well” (0) to “very poor” (100). The scale for the physician’s 
assessment ranges from “no GCA activity” (0) to “extremely active GCA” (100). The evaluating 
physician and subject must complete the global assessment independently of each other. The 
physician should preferably be the same person at every study visit for a given subject. 
 
9.10. Pain Assessment 
Subjects will be asked to assess their average pain now on a VAS ranging from “no pain” (0) to “the 
worst possible pain” (100). 
 
9.11. Disease activity/damage 
The Vasculitis Damage Index (VDI) will be assessed at baseline (M0) and the visit following 
completion of study drug (M12). The Birmingham Vasculitis Activity Score (BVAS) will be recorded at 
all visits including the 12-week follow up visit (M15). 
 
9.12. Study Completion 
A completed subject is one that has completed the screening period, been enrolled in the 52-week 
open-label enrollment period and has attended the 12-week post-treatment follow up visit. The end of 
the study is defined as the last subject’s last visit. 
 
 
10. WITHDRAWAL/STOPPING CRITERIA 
 
10.1. Interruption of Investigational Product 
In some circumstances, it may be necessary to temporarily interrupt treatment as a result of an adverse 
event (AEs) or abnormal laboratory values that may have an unclear relationship to investigational 
product. Retest timing and frequency is at the investigator’s discretion. 
 
Investigational product must be held in the following situations and may be resumed as noted in the 
TABLE 3. 

 
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26 
 
 
Table 3. 
Criteria for Temporary Interruption of Investigational Product 
 
Hold investigational product if the 
following laboratory test results occur: 
Investigational product may be resumed 
when: 
WBC count <2000 cells/µL 
WBC count ≥2500 cells/µL 
ANC <1000 cells/µL 
ANC ≥1200 cells/µL 
Lymphocyte count <500 cells/µL 
Lymphocyte count ≥750 cells/µL 
Platelet count <75,000/µL 
Platelet count ≥100,000/µL 
eGFR <40 mL/min/1.73 m2 (from serum 
creatinine) 
eGFR ≥50 mL/min/1.73 m2 
ALT* or AST >5 x ULN 
ALT and AST return to <2 x ULN, and 
investigational product is not considered to be 
the cause of enzyme elevation 
Hemoglobin <8 g/dL 
Hemoglobin ≥10 g/dL 
Symptomatic herpes zoster 
All skin lesions have crusted and are resolving 
Severe infection that, in the opinion of the 
investigator, merits the IP being discontinued 
Resolution of infection 
Abbreviations:  ALT = alanine aminotransferase; ANC = absolute neutrophil count; AST = 
aspartate aminotransferase; eGFR = estimated glomerular filtration rate; IP = investigational 
product; ULN = upper limit of normal; WBC = white blood cell. 
*ALT will be used for monitoring purposes. If abnormal then AST will be checked for further 
assessment of abnormalities. Alkaline phosphatase and total bilirubin will be obtained if 
evidence of liver disease present on ALT and/or AST to assess for need of drug interruption 
10.2. Permanent Discontinuation of Study Drug 
Any subject who is permanently discontinued from investigational product for an AE or abnormal 
laboratory result should have the reason for investigational product discontinuation reported as the AE 
or abnormal laboratory value. 
 
Patients will discontinue study drug if the following disease related clinical events occur during the 
study period: 
 
• 
Unprovoked venous thromboembolism (deep vein thrombosis, pulmonary embolism) 
 
• 
GCA relapse occurs with objective evidence of severe ischemic event (vision loss, stroke, 
critical limb ischemia) 
 
• 
Second GCA relapse occurs during study period 
 
Patients will discontinue study drug following temporary interruption of the study drug if either of the 
following occurs.  
 
• 
Study drug has been held due to a study drug-related laboratory abnormality necessitating 
temporary interruption (Table 3) and the laboratory abnormality that led to the investigational hold 
has not returned to a level at which the investigational product can be resumed (Table 3) by 4 
weeks (28 days) for renal function (as determined by eGFR) or  6 weeks  for the remaining 
laboratory parameters (42 days) from the date investigational hold commenced. For example: 
Example 1: a patient would be withdrawn from the study if the renal function declined due to 
study drug (i.e. not intercurrent illness) and the eGFR decreased to 30 mL/min/1.73m2 and hold 

 
Version: 7.0 
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27 
 
commenced on January 1st.but the eGFR had not returned to ≥50 mL/min/1.73 m2 by January 
29th. Example 2: a patient would be withdrawn from the study if the WBC count decreased below 
<2000 cells/µL on  January 1st and did not return to a value of >2500 cells/µL by February 11th.   
  
• 
If following a study drug interruption for an identified laboratory abnormality (Table 3) the same 
laboratory parameter that led to study drug interruption is again affected by reinitiation of study 
drug. For example, platelet count prior to study drug was 150,000/uL but decreases to 50,000/uL 
while on the study drug. Study drug is held and the platelet count improves to 125,000/uL 
allowing reinitiation of study drug. Following reinitiation the platelet count decrease again to 
50,000/uL.  
• 
 
 
In addition discontinuation of the study drug will occur if any one of the following laboratory 
abnormalities occur: 
 
• 
ALT or AST >8 x ULN 
• 
ALT or AST >5 x ULN for more than 2 weeks after temporary interruption of 
investigational product 
• 
ALT or AST >3 x ULN and either total bilirubin level (TBL) >2 x ULN or INR >1.5 x ULN 
• 
ALT or AST >3 x ULN with the appearance of fatigue, nausea, vomiting, right upper- 
quadrant pain or tenderness, fever, rash, and/or eosinophilia (>5%) 
• 
Alkaline phosphatase (ALP) >3 x ULN 
• 
ALP >2.5 x ULN and TBL >2 x ULN 
• 
ALP >2.5 x ULN with the appearance of fatigue, nausea, vomiting, right upper quadrant 
pain or tenderness, fever, rash, and/or eosinophilia (>5%). 
Subjects should be discontinued from the investigational product in the following circumstances: 
• 
WBC count <1000 cells/µL 
• 
ANC <500 cells/µL 
• 
Lymphocyte count <200 cells/µL 
• 
Hemoglobin <6.5 g/dL 
For lab values that meet permanent discontinuation thresholds, the study drug will be discontinued 
unless, in the opinion of the investigator, the lab abnormality is due to intercurrent illness or another 
identified factor.  Lab tests may be repeated within 1 week to confirm whether discontinuation criteria 
have been met.  Furthermore, if investigational product is not discontinued due to intercurrent illness, 
the investigator must confirm the lab value no longer meets discontinuation thresholds following the 
resolution of the intercurrent illness or other identified factor. 
 
In addition, subjects will be discontinued from investigational product in the following circumstances: 
• 
Pregnancy 
• 
Malignancy (except for successfully treated basal cell or squamous epithelial skin 
cancers) 
Some possible reasons that may lead to permanent discontinuation include: 

 
Version: 7.0 
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28 
 
• 
Enrollment in any other clinical trial involving an investigational product or enrollment in any 
other type of medical research judged not to be scientifically or medically compatible with this 
study 
• 
Participation in the study needs to be stopped for medical, safety, regulatory, or other reasons 
consistent with applicable laws, regulations, and good clinical practice (GCP) 
• 
Investigator Decision 
o the investigator decides that the patient should be discontinued from the study 
• 
Subject Decision 
o the subject requests to be withdrawn from the study. 
 
The following actions must be taken in relation to a subject that fails to attend the clinic for a required 
study visit. 
o Site must attempt to contact the subject and re-schedule the missed visit as soon as 
possible 
o The site must counsel the subject on the importance of maintaining the assigned visit 
schedule and ascertain whether or not the subject wishes to and/or should continue in 
the study 
o In cases deemed “lost to follow-up”, the investigator must make every effort to regain 
contact with the subject (up to 3 phone calls to listed number and if necessary a certified 
letter to last known mailing address or local equivalent methods). These contact 
attempts will be documented in the medical record. 
o Should the subject be unreachable, only then will the subject be considered to have 
withdrawn from the study with a primary reason of “lost to follow-up”. 
 
Subjects who have withdrawn prematurely from the study should attend an early withdrawal visit and 
undergo the 12 week post-study drug follow-up period for evaluation of safety. 
 
Subjects withdrawn prematurely from the study can be replaced by a new study entry if the study is still 
openly enrolling (that is has not reached enrollment of 15 subjects). 
 
 
11. STUDY ENDPOINTS 
 
Primary endpoint: The primary endpoint is safety. 
The measure by which this will be determined is the following: 
• 
Incidence of adverse events (AEs) and serious adverse 
events (SAEs) related to the study drug 
Secondary endpoint The secondary endpoint preliminary efficacy of baricitinib (4mg, 
oral, daily) in patients with relapsing GCA. 
The measures by which this will determined are the following: 
 

 
Version: 7.0 
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29 
 
 
 
 
 
12. STUDY MONITORING AND ADVERSE EVENT REPORTING 
 
12.1 Study Monitoring, Auditing and Inspecting 
 
12.1.1 Study Monitoring Plan 
As a service to the sponsor-investigator and to assist with the sponsor regulatory obligation to monitor 
study progress, this study will be periodically monitored during the conduct of the trial by staff from the 
Mayo Clinic Office of Research Regulatory Support (ORRS).  Clinical trial monitoring may include but 
will not necessarily be limited to review of the study regulatory documents, source data and database 
entries throughout the duration of the study to help ensure the validity and integrity of the 
data.  Original informed consent forms will be reviewed. Written monitoring reports with findings and 
recommended and suggested corrective actions will be provided to the sponsor. 
 
 
12.1.2 Auditing and Inspecting 
The investigator will permit study-related monitoring by ORRS and audits by the IRB Compliance Unit, if 
indicated, as well as inspections by authorized representative of government regulatory agencies such as 
FDA of all study related documents (e.g. source documents, regulatory documents, data collection 
instruments, drug accountability records and study data etc.).  The investigator will ensure access is 
granted for inspection of applicable study-related facilities (e.g. pharmacy, diagnostic laboratories, etc.). 
 
Participation as an investigator in this study implies acceptance of potential inspection by government 
regulatory authorities and applicable compliance offices. 
 
12.1.3 Ethical Considerations 
This study is to be conducted according to applicable United States government regulations and 
Institutional research policies and procedures. 
 
This protocol and any amendments as well as subject materials such as the informed consent/assent 
forms will be submitted to a properly constituted Mayo Clinic Institutional Review Board (IRB for review 
and formal approval.  The decision(s) 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 (or assent) form describing this study and providing 
sufficient information for subjects to make an informed decision about their participation in this study.  The 
•
Relapse-free survival at week 52 
•
Relapse-free survival at week 24 
•
Duration of glucocorticoid-free remission 
•
Number of relapses per subject over time 
•
Change from baseline erythrocyte sedimentation rate 
(ESR) to end of study 
•
Change from baseline C-reactive protein to end of study 
•
Glucocorticoid dose (mg) at week 52 compared to 
enrollment 
•
Change in BVAS from baseline to end of study 

 
Version: 7.0 
Revised 12/30/19 
 
30 
 
formal consent of a subject, using the IRB approved consent or assent form, must be obtained before 
subject undergoes any study procedure.  The consent form must be signed and dated by the subject or 
the subject’s legally authorized representative, as well as the individual obtaining the informed consent 
 
12.2. Safety 
The Study Principal Investigator has primary oversight responsibility for the clinical trial. All co- 
investigators will report AEs and SAEs to the principal investigator upon alert of occurrence. Safety 
will be assessed from the documentation of adverse events and review of vital signs and laboratory 
assessments including complete blood counts, serum chemistry profiles, fasting serum lipids, and 
hepatitis B and C serologies. Adverse events (including serious and opportunistic infections, 
cardiovascular events, gastrointestinal perforations, hepatic laboratory abnormalities, and cytopenia) 
will be monitored on a regular and/or event-driven basis throughout the study. 
 
The definitions of an adverse event (AE) or serious adverse event (SAE) in the following section will 
comply with the International Council for Harmonisation of Technical Requirements for Pharmaceuticals 
for Human Use (ICH) guidelines for good clinical practice and applies the standards set forth in the 
National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events version 4.0. 
 
12.3. Adverse Events 
An adverse event (AE) will be defined as any unfavorable and unintended sign (including abnormal 
laboratory finding), symptom, or disease temporally associated with the use of a medical treatment or 
procedure that may or may not be considered related to the medical treatment or procedure. 
 
Events meeting AE definition include: 
 
Any abnormal laboratory test results (hematology, clinical chemistry, or urinalysis) or other safety 
assessments (e.g., ECGs, radiological scans, vital signs measurements), including those that worsen 
from baseline, and felt to be clinically significant in the medical and scientific judgment of the 
investigator. 
• 
Exacerbation of a chronic or intermittent pre-existing condition including either an 
increase in frequency and/or intensity of the condition. 
• 
Signs, symptoms, or the clinical sequelae of a suspected interaction. 
• 
Signs, symptoms, or the clinical sequelae of a suspected overdose of either study 
treatment or a concomitant medication (overdose per se will not be reported as an 
AE/SAE unless this is an intentional overdose taken with possible suicidal/self-harming intent. 
This should be reported regardless of sequelae). 
• 
"Lack of efficacy" or "failure of expected pharmacological action" per se will not be reported as 
an AE or SAE. However, the signs and symptoms and/or clinical sequelae resulting from lack of 
efficacy will be reported if they fulfil the definition of an AE or SAE. 
 
Events that do not meet AE definition include: 
 
Any clinically significant abnormal laboratory findings or other abnormal safety assessments which are 
associated with the underlying disease, unless judged by the investigator to be more severe than 
expected for the subject’s condition. 
• 
The disease/disorder being studied or expected progression, signs, or symptoms of the 
disease/disorder being studied, unless more severe than expected for the subject’s condition. 
• 
Medical or surgical procedure (e.g., endoscopy, appendectomy): the condition that leads to the 
procedure is an AE. 
• 
Situations where an untoward medical occurrence did not occur (social and/or convenience 
admission to a hospital). 

 
Version: 7.0 
Revised 12/30/19 
 
31 
 
• 
Anticipated day-to-day fluctuations of pre-existing disease(s) or condition(s) present or detected 
at the start of the study that do not worsen. 
 
12.4. Serious Adverse Event 
Defined according to 21CFR 312.32. A serious adverse event (SAE) is any untoward medical 
occurrence that at any dose 
• 
Results in death 
• 
Is life-threatening 
• 
Requires hospitalization or prolongs existing hospitalization 
• 
Is a congenital anomaly/birth defect 
• 
An important medical event may be considered an SAE when, based upon appropriate medical 
judgment, it may jeopardize the subject and may require medical or surgical intervention to 
prevent one of the outcomes listed above 
 
12.5. Toxicity Grading of Adverse Events 
Toxicity grades for AE will be assessed using the National Cancer Institute (NCI) Common Terminology 
Criteria for Adverse Events (CTCAE). AEs will be recorded and graded 1 to 5 according to the CTCAE 
grade outlined below: 
• 
Grade 1 = mild adverse event 
• 
Grade 2 = moderate adverse event 
• 
Grade 3 = severe and undesirable adverse event 
• 
Grade 4 = life-threatening or disabling adverse event 
• 
Grade 5 = death 
 
12.6. Time Period and Frequency for Collecting Event Information 
• 
AEs and SAEs will be collected from the start of Study Treatment until the 12 week follow-up 
visit and documented at time of occurrence and each study visit. 
 
• 
Medical occurrences that begin prior to the start of study treatment but after obtaining informed 
consent may be recorded on the Medical History/Current Medical Conditions section and will not 
be considered treatment related side effects. 
 
 
• 
Any SAEs assessed as related to study participation or related to the investigational product 
will be recorded from the time a subject consents to participate in the study up to and 
including any follow-up contact. 
 
• 
All SAEs will be recorded and reported to the Sponsor (Mayo Clinic) and Eli Lilly [Investigational 
Product (IP) Manufacturer] within 24 hours. 
 
• 
Investigators are not obligated to actively seek AEs or SAEs in former study subjects (those 
whom have completed the study including the 12 weeks post-study drug visit). However, if the 
investigator learns of any SAE, including a death, at any time after a subject has been 
discharged from the study, and he/she considers the event reasonably related to the study 
treatment or study participation, the investigator must promptly notify Mayo Clinic  (Sponsor) 
and the IP manufacturer. 
 
12.7 Method of Detecting AEs and SAEs 
Open-ended and non-leading verbal questioning of the subject will be used to inquire about AE 
occurrence. Such questions include: 
• 
“How are you feeling?” 

 
Version: 7.0 
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32 
 
• 
“Have you had any (other) medical problems since your last visit/contact?” 
• 
“Have you taken any new medicines, other than those provided in this study, since your last 
visit/contact?” 
 
 
12.8. Follow-up of AEs and SAEs 
After the initial AE/SAE report, the investigator is required to proactively follow each subject at 
subsequent visits/contacts. All SAEs, and non-serious AEs of special interest will be followed until 
resolution, until the condition stabilizes, until the event is otherwise explained, or until the subject is lost 
to follow-up. All SAEs and their outcomes will be reported to the Food and Drug Administration (FDA).  
 
AEs of special interest include total or partial blindness, limb claudication, and scalp or tongue necrosis. 
In addition, severe disease flares, including hospitalizations will be monitored. 
 
Other AEs of special interest for baricitinib are hematologic laboratory abnormalities, hepatobiliary 
laboratory abnormalities and lipid parameter abnormalities. Changes in these values leading to 
temporary or permanent discontinuation of the study drug will be reported as an AE. Additional events 
of interest include serious CV events, infections and malignancies. 
 
All initial reports of cardiovascular AEs (myocardial infarction, stroke, death, hospitalization for angina, 
hospitalization for TIA), newly identified malignancies and active TB will be recorded by the 
investigational staff within 24 hours of their knowledge of the event even if these events do not meet 
the definition of a SAE. 
 
Glucocorticoid-related AEs such as diabetes mellitus, osteoporosis, fractures, infection, glaucoma, and 
cataracts among others will be evaluated in relation to steroid exposure and baseline risk. 
  
12.9. Cardiovascular and Death Events 
All cardiovascular events and all deaths, whether or not they are considered SAEs, will be documented. 
Major Adverse Cardiovascular Events (MACE), defined as myocardial infarction, stroke, death, 
hospitalization for unstable angina, and hospitalization for TIA, will be collected. 
 
Definition of Cardiovascular Events: 
Investigators will be required to fill out an adverse event form for the following cardiovascular events if 
they occur in the subject following the initiation of study drug. 
• 
Myocardial infarction/unstable angina 
• 
Congestive heart failure 
• 
Arrhythmias 
• 
Valvulopathy 
• 
Pulmonary hypertension 
• 
Cerebrovascular events/stroke and transient ischemic attack 
• 
Peripheral arterial thromboembolism 
• 
Deep vein thrombosis/pulmonary embolism 
• 
Revascularization 
 
12.10. Regulatory Reporting Requirements for SAEs 
Prompt notification by the investigator to the Sponsor and the FDA of all SAEs related to study 
treatment is essential so that legal obligations and ethical responsibilities towards the safety of subjects 
and the safety of a product under clinical investigation are met. Upon identification or knowledge of a 
SAE, investigators will alert the Sponsor and the IP manufacturer within 24-hours through MedWatch 
reporting form.  

 
Version: 7.0 
Revised 12/30/19 
 
33 
 
 
The Sponsor has a legal responsibility to notify both the local regulatory authority and other regulatory 
agencies about the safety of a product under clinical investigation. The Sponsor will comply with 
regulatory requirements relating to safety reporting to the regulatory authority, Institutional Review 
Board (IRB)/Independent Ethics Committee (IEC) and investigators. 
 
Investigator safety reports are prepared for suspected unexpected serious adverse reactions according 
to local regulatory requirements and Eli Lilly policy and are forwarded to investigators as necessary. 
 
An investigator who receives an investigator safety report describing a SAE(s) or other specific safety 
information (e.g., summary or listing of SAEs) from the IP manufacturer will notify the IRB/IEC, if 
appropriate according to local requirements. 
 
Expedited Adverse Event Reporting Criteria to the IP Manufacturer (Eli Lilly) 
The PI or designee will report all Serious Adverse Events to the IP Manufacturer within 24 hours of the 
Investigator(s) becoming aware of them. 
Fax all SAE forms to: Lilly Global Patient Safety at 866-644-1697 
Additionally, the IP manufacturer will be provided with copies of all investigational product-related 
reports submitted to regulatory authorities. 
 
12.11. Pregnancy 
Given the age group under investigation, pregnancy during the course of the study is unlikely. 
Nevertheless, if a pregnancy is reported then the investigator will inform the IP manufacturer, Eli Lilly, 
within 24 hours of learning of the pregnancy. 
 
Female subjects who become pregnant during the study must have study drug withdrawn immediately 
and be withdrawn from the study. An early withdrawal visit and 12-week follow-up will still occur. 
Information regarding the patient and fetal outcome for patients that become pregnant during the study 
will continue until the end of the pregnancy and result of the final outcome will be reported to the IP 
manufacturer for monitoring purposes.  
 
12.12. Physical Exams 
A complete physical examination will be conducted during screening and will include, at a minimum, 
assessment of the Cardiovascular, Respiratory, Gastrointestinal, Vascular and Neurological systems. 
Height and weight will also be measured and recorded. 
 
A brief physical examination will be conducted at all other time points and include, at a minimum 
assessments of the skin, lungs, CV system, and abdomen (liver and spleen). Investigators will pay 
special attention to clinical signs related to previous serious illnesses. 
 
12.13. Vital Signs 
Vital signs will be measured in seated position and will include temperature, systolic and diastolic blood 
pressure and pulse rate. 
 
12.14. Clinical Safety Laboratory Assessments 
All laboratory tests with values that are considered clinically significantly abnormal during participation 
in the study or within 12 weeks after the last dose of study treatment will be repeated until the values 
return to normal or baseline. 
 
13. SAMPLE SIZE AND COMPUTATION RATIONALE 
The study is intended to examine safety and to explore preliminary signal of efficacy. The sample size 
of 15 was based upon a sufficient number of subjects to begin such explorations prior to pursuit of a 

 
Version: 7.0 
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34 
 
randomized controlled trial. With an accrual of 15 evaluable subjects, there is a 95% confidence that 
any AE (or SAE) with an incidence of at least 18% will be reported. The standard error of the estimate 
of the incidence of reported AEs will not exceed 13%. 
 
A historical cohort of patients with biopsy-proven GCA from the Mayo Clinic has recently been reported 
[16]. In this large single-institution cohort, we found the rate of second relapse in the subset of patients 
with at least one relapse was 50% at one year (or 50% relapse-free survival at one year). These relapses 
occurred during GC treatment performed at the discretion of the treating provider and patients were not 
subject to an accelerated taper, thus likely overestimating relapse-free survival at one year after initial 
relapse. A recent completed clinical trial evaluating the use of abatacept in GCA with standardized taper 
has been completed and preliminary results are available [42]. Relapse-free survival at one year in the 
placebo group was 31% and 48% in the treatment group. The relapse-free survival in Langford et al. 
study may also be slightly overestimated because all patients received three months of study drug prior to 
undergoing a standardized GC taper. Prior clinical trials in GCA have observed one year relapse-free 
survival among placebo groups to range from 10-29% [23,24,43]. With a sample size of 15 patients, an 
exact binomial test will have 80% power to detect an additional 37% above the expected relapse-free rate 
with a 0.05 one sided-significance level. Based on available clinical trial data and the preliminary results 
from Langford et al. [42] a conservative expected relapse-free survival in patients with relapsing GCA 
receiving only GC and undergoing an accelerated taper would be a 30% relapse-free survival at one year. 
As such, evidence of efficacy can be identified if 10 of 15 (67%) patients receiving study drug remain 
relapse-free during the study period.  
 
14. STATISTICAL ANALYSIS PLAN 
The primary purpose of this pilot study is to evaluate the safety of baricitinib in subjects with GCA. No 
specific statistical hypothesis tests are planned. Safety data will be summarized for all treated subjects 
using appropriate tabulations, descriptive statistics, and graphical presentations. The incidence rate of 
each AE will be estimated and reported as number (n) and percentage (%). 
 
Descriptive statistics will be provided for all secondary outcome measures. Differences between 
glucocorticoid dose (mg), C-reactive protein (mg/L), erythrocyte sedimentation rate (mm/hr) and BVAS 
score from baseline to end of study will be calculated and reported with means and standard 
deviations. The proportion of subjects in sustained remission will be reported with exact 95% 
confidence intervals. Kaplan-Meier methods will be used to evaluate relapse-free survival and the 
duration of glucocorticoid-free remission. Number of relapses per subject over time will be reported as 
relapses/year. 
 
 
15. PUBLICATION STRATEGY 
This study will be registered with ClinicalTrials.gov prior to enrolling the first subject and the 
ClinicalTrials.gov Identifier (NCT#) will be included in manuscripts pertaining to this study. Results will 
be reported according to the requirements for applicable clinical trials.  
 
Data generated from this study will be presented at national and international meetings pertaining to 
rheumatology (e.g. American College of Rheumatology and European League Against Rheumatism). 
Manuscript publication will target a high impact journal (Arthritis & Rheumatology). 
 
 
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