Tofacitinib for the Treatment of Inflammatory Eye Disease
Phase: PHASE2
Conditions: Uveitis, Scleritis
Sponsor: Washington University School of Medicine

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Tofacitinib for the Treatment of Non-Infectious Inflammatory 
Eye Disease 
 
NCT03580343 
 
 
 
Principal Investigator:   
Lynn Hassman M.D. Ph.D. 
 
Co-Investigator: 
Michael Paley M.D. Ph.D. 
 
 
 
 

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TABLE OF CONTENTS 
 
A 
INTRODUCTION .................................................................................................................4 
A1 
STUDY ABSTRACT ..........................................................................................................4 
A2 
PRIMARY HYPOTHESIS ....................................................................................................4 
A3 
PURPOSE OF THE STUDY PROTOCOL ................................................................................4 
B 
BACKGROUND ..................................................................................................................4 
B1 
PRIOR LITERATURE AND STUDIES .....................................................................................4 
B2 
RATIONALE FOR THIS STUDY ............................................................................................5 
C 
STUDY OBJECTIVES .........................................................................................................5 
C1 
PRIMARY AIM .................................................................................................................5 
C2 
SECONDARY AIM ........................................................... ERROR! BOOKMARK NOT DEFINED. 
C3 
RATIONALE FOR THE SELECTION OF OUTCOME MEASURES .................................................5 
D 
INVESTIGATIONAL AGENT ...............................................................................................6 
D1 
PRECLINICAL DATA .........................................................................................................6 
D2 
CLINICAL DATA TO DATE .................................................................................................6 
D3 
DOSE RATIONALE AND RISK/BENEFITS .............................................................................7 
E 
STUDY DESIGN ..................................................................................................................7 
E1 
OVERVIEW OR DESIGN SUMMARY ....................................................................................7 
E2 
SUBJECT SELECTION AND WITHDRAWAL ...........................................................................8 
2.a 
Inclusion Criteria.......................................................................................................8 
2.a 
Exclusion Criteria .....................................................................................................8 
2.b 
Ethical Considerations ..............................................................................................8 
2.c 
Subject Recruitment Plans and Consent Process .....................................................8 
2.d 
Randomization Method and Blinding .........................................................................9 
2.e 
Risks and Benefits ....................................................................................................9 
2.f 
Early Withdrawal of Subjects ....................................................................................9 
2.g 
When and How to Withdraw Subjects .......................................................................9 
2.h 
Data Collection and Follow-up for Withdrawn Subjects .............................................9 
E3 
STUDY DRUG ............................................................................................................... 10 
3.a 
Description ............................................................................................................. 10 
3.b 
Treatment Regimen ................................................................................................ 11 
3.c 
Method for Assigning Subjects to Treatment Groups .............................................. 11 
3.d 
Preparation and Administration of Study Drug......................................................... 11 
3.e 
Subject Compliance Monitoring .............................................................................. 11 
3.f 
Prior and Concomitant Therapy .............................................................................. 11 
3.g 
Packaging .............................................................................................................. 11 
3.h 
Blinding of Study Drug ............................................................................................ 11 
3.i 
Receiving, Storage, Dispensing and Return ............................................................ 11 
F 
STUDY PROCEDURES..................................................................................................... 12 
F1 
SCREENING FOR ELIGIBILITY .......................................................................................... 12 
F2 
SCHEDULE OF MEASUREMENTS ..................................................................................... 12 
F3 
VISIT 1 ........................................................................................................................ 12 
Deleted: ¶
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¶
Version Date/Number:  3¶
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F4 
VISIT 2 ETC. .................................................................. ERROR! BOOKMARK NOT DEFINED. 
F5 
SAFETY AND ADVERSE EVENTS ..................................................................................... 13 
5.a 
Safety and Compliance Monitoring ......................................................................... 13 
5.b 
Medical Monitoring ................................................................................................. 13 
i 
Investigator only ................................................................................................................. 13 
ii 
Independent expert to monitor ................................................. Error! Bookmark not defined. 
iii 
Institutional Data and Safety Monitoring Board ......................... Error! Bookmark not defined. 
iv 
Independent Data and Safety Monitoring Board ....................... Error! Bookmark not defined. 
5.c 
Definitions of Adverse Events ................................................................................. 13 
5.d 
Classification of Events .......................................................................................... 14 
i 
Relationship ....................................................................................................................... 14 
ii 
Severity .............................................................................................................................. 14 
iii 
Expectedness ..................................................................................................................... 14 
5.e 
Data Collection Procedures for Adverse Events ...................................................... 14 
5.f 
Reporting Procedures ............................................................................................. 14 
5.g 
Adverse Event Reporting Period ............................................................................. 14 
5.h 
Post-study Adverse Event ...................................................................................... 15 
F6 
STUDY OUTCOME MEASUREMENTS AND ASCERTAINMENT ................................................ 15 
G 
STATISTICAL PLAN ......................................................................................................... 15 
G1 
SAMPLE SIZE DETERMINATION AND POWER .................................................................... 15 
G2 
INTERIM MONITORING AND EARLY STOPPING ................................................................... 15 
G3 
ANALYSIS PLAN ............................................................................................................ 15 
G4 
STATISTICAL METHODS ................................................................................................. 16 
G5 
MISSING OUTCOME DATA .............................................................................................. 16 
G6 
UNBLINDING PROCEDURES ............................................................................................ 16 
H 
DATA HANDLING AND RECORD KEEPING .................................................................... 16 
H1 
CONFIDENTIALITY AND SECURITY ................................................................................... 16 
H2 
TRAINING..................................................................................................................... 16 
H3 
CASE REPORT FORMS AND SOURCE DOCUMENTS ............ ERROR! BOOKMARK NOT DEFINED. 
H4 
RECORDS RETENTION .................................................................................................. 16 
H5 
PERFORMANCE MONITORING .......................................... ERROR! BOOKMARK NOT DEFINED. 
I 
STUDY MONITORING, AUDITING, AND INSPECTING .................................................... 16 
I1 
STUDY MONITORING PLAN ................................................................................................ 16 
I2 
AUDITING AND INSPECTING ................................................................................................ 17 
J 
STUDY ADMINISTRATION ............................................................................................... 17 
J1 
ORGANIZATION AND PARTICIPATING CENTERS..................................................................... 17 
J2 
FUNDING SOURCE AND CONFLICTS OF INTEREST ................................................................. 17 
J3 
COMMITTEES .................................................................... ERROR! BOOKMARK NOT DEFINED. 
J4 
SUBJECT STIPENDS OR PAYMENTS .................................................................................... 17 
J5 
STUDY TIMETABLE ........................................................................................................... 17 
K 
PUBLICATION PLAN ........................................................................................................ 18 
L 
ATTACHMENTS ............................................................................................................... 18 
L1 
TABLES ....................................................................................................................... 18 
L2 
INFORMED CONSENT DOCUMENTS .................................................................................. 19 
L3 
PATIENT EDUCATION BROCHURES .................................................................................. 19 
L4 
SPECIAL PROCEDURES PROTOCOLS ................................ ERROR! BOOKMARK NOT DEFINED. 
L5 
QUESTIONNAIRES OR SURVEYS ...................................................................................... 19 
M 
REFERENCES .................................................................................................................. 19 
 

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A Introduction 
 
A1 Study Abstract 
Non-infectious inflammatory eye disease, such as uveitis, is a chronic, auto-immune 
process that can occur in isolation or in the context of a systemic auto-immune condition. 
While corticosteroids are effective therapies, the side-effects of chronic steroid use 
require us to develop effective steroid-sparing therapies. There is only one FDA-
approved steroid-sparing therapy for uveitis. 
 
Tofacitinib is a small molecule that inhibits the signaling pathways of multiple 
inflammatory cytokines. It is already FDA-approved for the treatment of rheumatoid 
arthritis, psoriatic arthritis, and ulcerative colitis. It is routinely prescribed by practicing 
rheumatologists at Washington University for diseases that place patients at risk for 
long-term disability.  
 
We have successfully treated a patient with refractory uveitis with off-label use of 
tofacitinib after failure with multiple conventional steroid-sparing therapies (Paley et al. in 
submission). We plan to evaluate whether tofacitinib may have efficacy in a larger series 
of cases. 
A2 Primary Hypothesis 
Treatment with tofacitinib will limit ocular inflammation in the after steroids have been 
tapered off. 
A3 Purpose of the Study Protocol 
To evaluate whether tofacitinib has clinical efficacy as a steroid-sparing agent for 
patients with uveitis.  
B Background 
 
B1 Prior Literature and Studies 
There are several lines of evidence to suggest that tofacitinib would be an effective 
agent in ocular inflammatory disease. For example, inflammatory cytokines that activate 
JAK/STAT signaling have been implicated in the pathogenesis of inflammatory eye 
disease (1-3). Furthermore, inhibitors of IL-2 (4, 5) and IL-6 (6), which activate 
JAK/STAT signaling, have had clinical efficacy in small studies of inflammatory eye 
disease. Tofacitinib has also been used topically to treat a mouse model of ocular 
inflammation (7). Additionally, tofacitinib has demonstrated clinical efficacy in rheumatoid 
arthritis, psoriatic arthritis, and ulcerative colitis (8-11), which are associated with 
inflammatory eye disease. Thus, treatment of these patients with tofacitinib may trigger 
resolution of ocular inflammation by resolving the underlying systemic inflammatory 
disorder. Finally, reduced penetration of the blood-aqueous barrier may limit the efficacy 
of certain targeted therapies, such as etanercept and other biologic DMARDs. In 
contrast, a small molecule such as tofacitinib is likely to more efficiently cross of the 
blood-aqueous barrier. 

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B2 Rationale for this Study 
Non-infectious inflammatory ocular disease is an auto-immune condition of unknown 
etiology. Although uveitis often responds adequately to corticosteroids, there are many 
patients for which this treatment is either inadequate or not tolerated. In addition, chronic 
steroid use leads to significant morbidity. We propose an open-label trial of tofacitinib for 
patients with non-infectious inflammatory eye disease.   
 
A patient with inadequate response to treatment would manifest with uveitis activity by 
slit lamp examination determination of anterior chamber cellularity, vitreous haze or new 
lesions of the retina / choroid.  Persistent inflammation can manifest as ocular 
hypertension (greater than 21 mmHg measured by tonometry), complicating chronic 
topical corticosteroid administration, leading to glaucoma and permanent visual loss or 
perforation of the eye (which also can lead to permanent visual loss).  Moreover, 
systemic corticosteroids may be required  at a dose unsafe for chronic administration.  In 
these situations, an immunosuppressive medication is often added as a “steroid-sparing” 
agent.  If and when there is clinical response to the added immunosuppressive, the oral 
and/or topical corticosteroid dose can be reduced or eliminated to avoid toxicity.  
 
There is currently only one FDA-approved steroid-sparing therapy (adalimumab) for the 
treatment of uveitis. Furthermore, adalimumab is effective in only 40-60% of cases of 
uveitis (12, 13). As a result, additional steroid-sparing therapies are needed for these 
vision-threatening diseases. 
C Study Objectives 
 
C1 Primary Aim 
The primary endpoint will be treatment failure at week 24: 
 
Treatment failure will be defined as 
• Before or at week 8 (any one of the following criteria) 
o new inflammatory lesions relative to baseline 
o anterior chamber cell or vitreous haze > 0.5+ on SUN scale 
o worsening of visual acuity by two or more rows on ETDRS (Early 
Treatment of Diabetic Retinopathy Study) chart  
• After week 8 (any one of the following criteria) 
o new inflammatory lesions relative to baseline 
o 2-step increase in anterior chamber cell or vitreous haze 
o worsening of visual acuity by two or more rows on ETDRS chart  
 
Grade ‘0’ will denote zero cells present per high power field or no vitreous haze and a 
change of full number grade will represent a “step change” (e.g. a change from grade 1 
to 0 is considered a 1-step change). 
 
C2 Exploratory Analysis 
1. Treatment Failure According to Reason for Failure 

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• 
anterior chamber cell 
• 
vitreous haze 
• 
new retinal lesions 
• 
worsening of best corrected visual acuity 
2. Time to Treatment Failure 
3. Cystoid Macular Edema 
• 
change of cystoid macular edema based on optical coherence tomography 
4. Intraocular Pressure: 
• 
change in intraocular pressure as measured in mmHg during clinical evaluation 
5. Improvement Visual acuity (best-corrected ETDRS chart-measured acuities) 
• 
a clinically significant change in visual acuity will be defined as an improvement 
by 2 lines in the ETDRS chart. 
6. Angiography 
• 
Angiography will be assessed for clinically relavent patients (e.g. posterior or pan 
uveitis) 
7. Cataract 
• 
Patients will be assessed for cataract formation 
C3 Rationale for the Selection of Outcome Measures 
Outcome measures for uveitis are based on previously published phase 3 trials for 
steroid-sparing agents in inflammatory eye-disease (12, 13). Measurement of intraocular 
pressure, cataract formation, cystoid macular edema and visual acuity are important to 
determine the improvement or worsening of secondary effects of active inflammatory 
disease. 
D Investigational Agent  
 
D1 Preclinical Data 
Tofacitinib is a small molecule that reversibly inhibits Janus associated kinases (JAKs) 
with some selectivity for JAK1 and JAK3 (14). JAKs execute cytokine receptor signaling 
by phosphorylation and activation of signal transducers and activator of transcription 
(STAT) proteins, which subsequently dimerize, enter the cell nucleus, and initiate 
transcription of numerous inflammatory genes. Topical administration of tofacitinib has 
demonstrated efficacy in treating ocular inflammation in animal models (7). 
 
D2 Clinical Data to Date  
We successfully treated one patient with off-label use of tofacitinib for refractory uveitis 
(Paley et al. in submission). Tofacitinib is also clinically efficacious and FDA-approved 
for the associated systemic rheumatologic diseases, rheumatoid arthritis and psoriatic 
arthritis, which are associated with inflammatory eye disease (8-10). Treatment with 
tofacitinib leads to a clinical response starting at 4-8 weeks after initiation of therapy (8-
10). Administration of tofacitinib is approved for 5mg twice daily or 11mg extended 
release for rheumatoid arthritis. This dose has been in clinical practice since its FDA 
approval in 2012 with 19,406 patient-years of accumulated safety data. 

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D3 Dose Rationale and Risk/Benefits  
The planned use of this product uses the FDA-approved dose and route of 
administration for rheumatoid arthritis. Tofacitinib has more than 8 years of safety data 
from clinical trials and clinical use (15, 16). The risk of this medication is equivalent to 
the single FDA-approved steroid-sparing agent for uveitis, adalimumab (8, 10, 12, 13, 
15, 17). Notable risks include infection, reactivation of tuberculosis and the development 
of malignancy. Benefits of tofacitinib included the protection of organs and tissues from 
autoimmune or inflammatory disease without the requirement for steroids. 
E Study Design  
 
E1 Overview or Design Summary 
This study is a prospective, single-site, open-label investigation of tofacitinib for 
refractory uveitis. The study will be for 24 weeks, with potential 1-year extension for 
treatment responders. The patients will self-administer the medication. 
 
Eligible patients would be those patients with a diagnosis of uveitis who meet the 
following criteria: 
 
1) Disease sufficiently severe to require treatment with systemic corticosteroids, and  
2) Referred from Ophthalmology to Rheumatology or Uveitis specialist for a steroid-
sparing agent  
 
For patients naive to oral steroid-sparing therapy (e.g., methotrexate, azathioprine, or 
mycophenolate), tofacitinib will be initiated as monotherapy. For patients who have failed 
or had only a partial response to oral steroid-sparing therapy, tofacitinib will be initiated 
as an add-on therapy. For patients intolerant to a conventional agent, tofacitinib will be 
initiated as replacement monotherapy. For patients who have failed biologic therapy 
(e.g. adalimumab), biologic therapy will be discontinued and tofacitinib will be initiated as 
replacement therapy without change to concurrent conventional steroid-sparing agents. 
Study visits will occur at baseline/enrollment, and weeks 4, 8, 12, 16, & 24 (+/- 2 weeks). 
Clinic visits may occur more frequently as determined by the treating physician. 
Laboratory monitoring (Table 1) will be obtained according to standard of care for drug 
toxicity monitoring. Clinical responses will be evaluated at 24 weeks, with the primary 
outcome defined as treatment failure. 
 
All patients will undergo a predetermined oral steroid taper starting at 60mg of 
prednisone (or equivalent) and tapering over 14 weeks (Table 2). All patients will 
undergo a predetermined topical steroid drop taper starting at their current dose (Table 
3). 
 
Patients will have an ophthalmological evaluation by their treating ophthalmologist at 
Washington University. Steroid sparing therapy will be managed by rheumatologists or 
uveitis specialists at Washington University. All patients will be evaluated for an 
associated systemic rheumatologic condition. 

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E2 Subject Selection and Withdrawal  
 
2.a 
Inclusion Criteria  
• 18 years of age or older 
• diagnosis of uveitis 
• for patients with uveitis (documented in medical record): 
o prior treatment failure with adalimumab 
o medical contraindication to adalimumab 
o patient unable or unwilling to perform self-injections 
o patient unable to obtain adalimumab due to cost or insurance 
• a clinical response to steroids 
• active disease requiring at least 10mg of prednisone (or steroid 
equivalent) for 2 or more weeks 
o active disease is defined as any of the following  
§ at least one active inflammatory chorioretinal or retinal 
vascular lesion 
§ anterior chamber cell grade of 2+ or higher (according to 
Standardization of Uveitis Nomenclature Working Group 
criteria) 
§ vitreous haze grade of 2+ or higher (according to National 
Eye Institute [NEI] criteria adapted by the Standardization of 
Uveitis Nomenclature Working Group) 
• practice of preventative contraception for women of childbearing age 
2.a 
Exclusion Criteria  
• presence of an active or uncontrolled systemic rheumatologic disorder  
• suspected or confirmed ocular infection 
• chronic or recurring infections, such as HIV 
• renal insufficiency, which would preclude safe administration of tofacitinib 
 
2.b 
Ethical Considerations  
There is one FDA-approved steroid-sparing therapy for uveitis (adalimumab). Tofacitinib 
and adalimumab are equally effective in treating the associated systemic disorder, 
psoriatic arthritis. For patients who have failed adalimumab, tofacitinib offers a 
reasonable alternative therapy.  
 
Patients will have regular follow-up with both Ophthalmology and Rheumatology to 
monitor disease activity. Treatment with corticosteroids will be available for rescue 
therapy for all patients with uncontrolled disease. 
 
Patients may be influenced to participate because an authority figure (their physician) 
may propose the study, however, steps that will be taken by the research team to 
minimize the possibility of coercion or undue influence during the consent process. The 
consent process will include full study disclosure, giving the patient a reasonable amount 

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of time to decide regarding participation and the opportunity to discuss with family and 
friends, and assuring the patient that they will receive the same quality of care 
regardless of study participation. 
2.c 
Subject Recruitment Plans and Consent Process 
Patients seen in the clinical offices of the Department of Ophthalmology & Visual 
Sciences and the Division of Rheumatology at Washington University will be consented 
in a private room within the clinical office.  
2.d 
Randomization Method and Blinding 
There is no randomization or blinding in this study. 
2.e 
Risks and Benefits 
As with other immunosuppressive treatments to control autoimmune diseases, the 
patients will be at increased risk of infection (20%). Other risks include nasopharyngitis 
(3% to 14%), hypertension (2%), headache (4% to 9%), rash (6%), acne vulgaris (≥2%), 
increased serum cholesterol (5% to 9%), diarrhea (4% to 5%), gastroenteritis (4%), 
nausea (4%), urinary tract infection (2%), anemia (4%), herpes zoster infection (5%; 
including disseminated cutaneous, meningoencephalitis, ophthalmologic), increased 
creatine phosphokinase (3% to 7%), increased serum creatinine (<2%), upper 
respiratory tract infection (4% to 6%), and fever (≥2%).  
 
Lymphoma and other malignancies have been reported in patients receiving tofacitinib 
 
Tuberculosis (pulmonary or extrapulmonary) has been reported in patients receiving 
tofacitinib. Standard laboratory screening is performed in all patients to assess for latent 
/ chronic infection, such as TB.  
 
There is a risk associated with lack of efficacy. In the case of a treatment failure based 
on the primary outcome criteria, tofacitinib will be discontinued and the patient will be 
switched to an alternative steroid-sparing therapy at the discretion of the patient’s 
treating physician. 
 
Potential benefits include improved control of the ocular inflammatory disease, reduced 
corticosteroid usage, reduced intraocular pressure, improved visual acuity, and 
prevention of permanent vision loss. The participants may also derive benefit from 
contributing to medical research. 
2.f 
Early Withdrawal of Subjects  
Participants may withdraw at any time from the study. They will be asked to undergo an 
Early Exit Visit. 
2.g 
When and How to Withdraw Subjects  
Participants will contact the researcher if they wish to withdraw. 
2.h 
Data Collection and Follow-up for Withdrawn Subjects  
Participants who withdraw will no longer be followed in the study. 

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2.i 
Cessation of tofacitinib therapy 
i 
Indications for cessation of tofacitinib therapy 
• 
Laboratory abnormalities:  
o New elevation of ALT or AST > 3x upper limit of normal 
o New leukopenia with ANC < 1.5 
o New anemia with hemoglobin <7 g/dl or a decrease of > 3g/dl 
o New renal failure that would preclude the safe administration of tofacitinib 
§ 
Patients may restart tofacitinib after recovery of renal function 
• 
Clinical events: 
o Shingles or opportunistic infection:  
§ 
Patients that develop an opportunistic infection or shingles may 
opt to (1) withdraw from the study or (2) hold tofacitinib while 
undergoing treatment with antivirals or antibiotics 
o Hospitalization due to tofacitinib 
§ 
Any patient hospitalized secondary to treatment with tofacitinib as 
determined by a rheumatology research clinician.  
o Infection with tuberculosis: 
§ 
Patients that develop active mycobacterium tuberculosis. All 
patients will have undergone screening with a PPD or interferon 
gamma release assay to rule out TB at the beginning of the study. 
o Treatment failure after week 8 
 
ii 
Monitoring after tofacitinib cessation 
• 
If a patient is not a treatment failure as defined by the primary outcome measure 
at the time of tofacitinib cessation, they will be monitored for disease relapse 
• 
If a patient is a treatment failure at the time of tofacitinib cessation, they will be 
switched to another steroid sparing agent at the discretion of their treating 
physician 
• 
Patients who discontinue tofacitinib treatment will remain in the study and be 
followed to obtain safety data. 
 
2.j 
Adjustment of tofacitinib therapy 
i 
Indications for dose reduction of tofacitinib therapy to 5mg daily 
• 
moderate to severe renal impairment 
• 
ESRD requiring hemodialysis 
• 
moderate hepatic impairment  
 
E3 Study Drug  
3.a 
Description  
Tofacitinib is a small molecule that inhibits Janus kinase (JAK). Specifically, it inhibits 
JAK1 and JAK3 and to a lesser extent JAK2. This inhibition occurs downstream of 
multiple pro-inflammatory cytokines, such as IL-2, IL-6, & IFN, and explains the anti-

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inflammatory effects of tofacitinib. It has demonstrated clinical efficacy in multiple 
inflammatory disorders: rheumatoid arthritis, psoriatic arthritis, and ulcerative colitis. 
3.b 
Treatment Regimen  
Tofacitinib will be taken as extended release, 11mg, once daily. 
3.c 
Method for Assigning Subjects to Treatment Groups  
All subjects will be in the same treatment group. 
3.d 
Preparation and Administration of Study Drug  
Preparation is not required. Study Drug will be provided by Pfizer, the manufacturer of 
the drug. The research team will provide pre-packaged bottles to the patients. Patients 
will self-administer the study drug. 
3.e 
Subject Compliance Monitoring  
Patients will be asked about medication adherence during regular clinical follow-up. 
3.f 
Prior and Concomitant Therapy  
All patients will be prescribed steroids with a uniform and pre-determined taper starting 
at prednisone 60mg daily (or equivalent) and tapering over 14 weeks to off. 
 
Patients intolerant to an initial steroid-sparing therapy (e.g. methotrexate, azathioprine, 
or mycophenolate) will be started on tofacitinib and their prior steroid-sparing therapy will 
be discontinued. No other steroid sparing therapy will be initiated during the study period 
to avoid confounding of clinical efficacy. 
 
Patients tolerant to prior steroid sparing therapy but with an incomplete control of their 
disease will have tofacitinib added to their steroid-sparing therapy. No other steroid 
sparing therapy will be initiated during the study period to avoid confounding of clinical 
efficacy. 
 
Concomitant therapy with biologic steroid-sparing therapy such as adalimumab is 
prohibited due to the risk of infection.  
3.g 
Packaging  
Packaging will be provided by Pfizer, the manufacturer of the drug. 
3.h 
Blinding of Study Drug  
There is no blinding. 
3.i 
Receiving, Storage, Dispensing and Return  
The study drug will be shipped to the PI who will store the drug in a locked room at room 
temperature. An established and validated local temperature management system with 
temperature logs will be used to record the storage temperature. The research team will 
dispense the drug to the patients during their clinical visit. 
 
 

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F Study Procedures  
 
F1 Screening for Eligibility 
Clinicians on the research team will identify potential participants via a computerized 
search for relevant diagnoses and via clinical identification of uveitis during patient 
encounters. The clinician and/or research coordinator will discuss the study with 
potential participants either during the patient encounter. Consent will be signed prior to 
drug administration.  
 
F2 Schedule of Measurements 
Patients will have scheduled visits with a research clinician on weeks 0 (baseline), 4, 8, 
12, 16, & 24 (+/- 2 weeks) as described in Table 1. These visits are standard of care for 
the treatment of uveitis. Measurements taken during these visits are part of standard of 
care. 
 
Laboratory measurements for steroid-sparing therapy will be obtained according to 
Table 1. 
F3 Initial Visit (week 0; baseline) 
• 
Informed consent 
• 
Inclusion/Exclusion criteria verification 
• 
Medical history and Demographics 
• 
Concomitant Medication collection 
o Dose of medications used to treat increased intraocular pressure 
o Dose of topical and/or systemic corticosteroids 
• 
Ophthalmology data 
o Anterior chamber cell 
o Vitreous haze 
o Retinal lesions 
o Visual Acuity 
o Cystoid macular edema 
o Intraocular pressure 
• 
Provide Subject Study Handout 
• 
Provide Drug Package Insert 
• 
Dispense Study Drug 
F4 Subsequent visits (weeks 4, 8, 12, 16, 24 or Early Exit Visit) 
• 
Concomitant Medication collection 
o Dose of medications used to treat increased intraocular pressure 
o Dose of topical and/or systemic corticosteroids 
• 
Ophthalmology data 
o Anterior chamber cell 
o Vitreous haze 
o Retinal lesions 
o Visual Acuity 

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o Cystoid macular edema 
o Intraocular pressure 
• 
Adverse event collection  
• 
Collection of used drug bottle and dispense of new drug bottle for use (drug 
accountability) 
F5 Safety and Adverse Events  
5.a 
Safety and Compliance Monitoring 
Safety and compliance monitoring will be performed at each visit by research clinician in 
Rheumatology, e.g. Drs. Miner, Paley, Lee, & Brasington or Dr. Hassman in 
Ophthalmology. 
 
Patients will return empty bottles of tofacitinib to demonstrate compliance. 
5.b 
Medical Monitoring  
i 
Investigator only 
The principle investigator will review the study data every 6 months until study 
completion.  
 
5.c 
Definitions of Adverse Events 
Any unfavorable medical occurrence in a human subject including any abnormal sign, 
symptom, or disease. 
 
Some possible adverse event include: 
 
1. Drug Reaction 
• 
This includes a rash, drug hypersensitivity or allergic reaction. 
2. Laboratory abnormality 
• 
Elevation of ALT, AST, or creatinine on complete metabolic panel above baseline 
and three times above the upper limit of normal 
• 
Decrease of white blood cell count, absolute neutrophil count, hemoglobin, 
platelet count below baseline and below the normal range 
• 
Increase of blood lipid and cholesterol levels above baseline and above the 
normal range 
3. Infection 
• 
This includes bronchitis, influenza, nasopharyngitis, pharyngitis, rash, upper 
respiratory tract infection, and urinary tract infection. 
4. Malignancy 
• 
Any new diagnosis of malignancy during the study period will be recorded. 
5. Hospitalization 
• 
Any hospitalizations during the study period and the primary diagnosis for 
hospitalization will be recorded. 

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5.d 
Classification of Events 
i 
Relationship 
The definitions for the terms listed that should be used are those provided by the 
Department of Health and Human Services’ Office for Human Research Protections 
(OHRP). A copy of this guidance can be found on OHRP’s website: 
http://www.hhs.gov/ohrp/policy/advevntguid.html 
ii 
Severity 
The descriptions and grading scales found in the revised NCI Common Terminology 
Criteria for Adverse Events (CTCAE) version 4.0 will be utilized for all toxicity reporting. 
A copy of the CTCAE version 4.0 can be downloaded from the CTEP website: 
http://evs.nci.nih.gov/ftp1/CTCAE/About.html 
iii 
Expectedness 
Unanticipated problems are defined as: 
• 
Unexpected (in terms of nature, severity, or frequency) given (a) the research 
procedures that are described in the protocol-related documents, such as the 
IRB-approved research protocol and informed consent document; and (b) the 
characteristics of the subject population being studied. 
• 
Related or possibly related to participation in the research (“possibly related” 
means there is a reasonable possibility that the incident, experience, or outcome 
may have been caused by the procedures involved in the research). 
• 
Suggests that the research places subjects or others at a greater risk of harm 
(including physical, psychological, economic, or social harm) than was previously 
known or recognized. 
5.e 
Data Collection Procedures for Adverse Events 
Patients will be interviewed about adverse events during scheduled follow-up. 
Laboratory studies will be reviewed at each visit. 
5.f 
Reporting Procedures 
The PI is required to promptly notify the IRB of the following events: 
 
• 
Any unanticipated problems involving risks to participants or others which occur 
at any WU, BJH or SLCH institution, or that impacts participants or the conduct of 
the study. 
• 
Noncompliance with federal regulations or the requirements or determinations of 
the IRB. 
• 
Receipt of new information that may impact the willingness of participants to 
participate or continue participation in the research study. 
 
5.g 
Adverse Event Reporting Period 
These events must be reported to the IRB within 10 working days of the occurrence of 
the event or notification to the PI of the event. The death of a research participant that 
qualifies as a reportable event should be reported within 1 working day of the occurrence 
of the event or notification to the PI of the event. 

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15 
 
5.h 
Post-study Adverse Event 
Post-study adverse events will be identified through routine follow-up of these patients 
with chronic diseases by their treating physicians. 
F6 Study Outcome Measurements and Ascertainment 
 
1. Inflammatory lesions will be based on optical coherence tomography (OCT) and 
slit lamp exam by the treating ophthalmologist 
2. Anterior chamber cell will be measured according to Standardization of Uveitis 
Nomenclature (SUN) Working Group criteria; scores range from 0 to 4+, with 
higher scores indicating more cells visible in the anterior chamber and greater 
severity of uveitis (18) 
3. Vitreous haze will be measured according to National Eye Institute [NEI] criteria 
adapted by the SUN Working Group; scores range from 0 to 4+, with higher 
scores indicating greater severity of uveitis (19) 
4. Visual acuity will be measured by Early Treatment Diabetic Retinopathy Study 
chart 
5. Cystoid Macular Edema will be measured by Optovue OCT 
6. Angiography will be performed with the Optovue OCT 
7. Intraocular Pressure will be measured with a Goldmann applanation tonometer 
by the treating ophthalmologist 
8. Cataract formation will be assessed on physical exam by the treating 
ophthalmologist 
 
 
G Statistical Plan  
 
G1  Sample Size Determination and Power 
This is a pilot study evaluating the off-label use of tofacitinib for the treatment of non-
infectious inflammatory eye disease. A maximum of 5 patients with uveitis will be 
enrolled. All analyses will be descriptive in nature. 
G2  Interim Monitoring and Early Stopping 
The study Principal Investigator will monitor for serious toxicities on an ongoing basis. 
Once the Principal Investigator becomes aware of an adverse event, he will report the 
adverse event to the HRPO according to institutional guidelines. The trial will be stopped 
early if the number of serious toxicities exceed the expected rate (15). For example, the 
trial will be stopped if there are 3 or more cases of shingles while on tofacitinib therapy.  
G3  Analysis Plan 
All analysis will be descriptive. We expect 40-60% of patients to meet the primary 
endpoint in each arm similar to adalimumab in the treatment of noninfectious uveitis. 
This is in contrast to the placebo arm, which had a treatment failure rate of 80% at 24 
weeks (12). 

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16 
 
Patients will by analyzed by intent to treat when all 5 patients in a treatment arm have 
either completed 6 months of therapy or discontinued therapy due to study withdrawal or 
indications for treatment cessation. 
G4 Statistical Methods  
All analysis will be descriptive. This study is not powered to draw statistical conclusions. 
G5  Missing Outcome Data 
Patients with missing outcome data in the primary endpoints will be censored for the 
initial analysis for efficacy. 
G6  Unblinding Procedures  
There is no blinding in this study. 
 
H Data Handling and Record Keeping  
 
H1 Confidentiality and Security 
Consents will be scanned into the medical record. Original hard copies of consents will 
be secured under two keys and two locks in a locked file-cabinet within a locked office. 
Prospective clinical data will be collected during the study and entered into RedCap (a 
HIPAA compliant and password-protected database.) All aspects of the medical record 
will be analyzed including age, sex, office visit data, phone number, MRN, chief 
complaint, history of present illness, past medical and surgical history, past ocular 
history, medications, allergies, exam findings, studies including images, ultrasound, and 
radiographic studies, laboratory data, diagnosis, assessment and plan as well as clinical 
outcomes. 
H2 Training  
All researchers have undergone confidentiality and ethical training through Washington 
University. 
H3 Records Retention 
Electronic records of patient treatment will be stored in the electronic medical record 
(EMR) and in RedCap. Consents will be scanned into the EMR. This will be saved for 
the lifespan of the EMR and RedCap. Hard copies of records (e.g. consents) will be kept 
for 3 years after completion of the trial. 
I Study Monitoring, Auditing, and Inspecting  
 
I1 
Study Monitoring Plan  
The investigators will meet weekly to review study data to detect early evidence of 
unanticipated harm to subjects. The review will focus on safety data including but not 

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17 
limited to serious adverse drug events, drug exposure, laboratory test results, and vital 
signs measurements asa well as the rate of treatment failure. 
I2 
Auditing and Inspecting  
2.a 
Audits 
In order to guarantee that the conduct of the study is in accordance good clinical practice 
and the national laws, audits may be performed at the study sites to be carried out by an 
independent auditor. In addition, for-cause audits may be scheduled. The investigator 
agrees to give the auditor access to all relevant documents for review.  
2.b 
Inspections 
Inspections of the study sites may be performed by the local or regulatory authorities at 
any time during or after completion of the study. The investigator agrees to give the 
inspectors access to all relevant documents for review.  
 
J Study Administration 
 
J1 Organization and Participating Centers 
Principle Investigator: Lynn Hassman, MD, PhD 
Co-Investigator: Michael Paley, MD, PhD 
 
See IRB submission for complete list of participating clinicians. 
 
This is a single-site study at Washington University. 
J2 Funding Source and Conflicts of Interest 
The funding source is departmental for the physicians. Dr Brasington receives speaking 
fees for Pfizer. Dr Brasington will be a treating physician. He will identify and consent 
patients for study enrollment and manage their steroid-sparing therapy. However, Dr 
Brasington will not be scoring the amount of inflammatory eye disease or be involved in 
primary analysis of the study data. He will not be in a position to influence the outcome 
of the trial. 
J3 Subject Stipends or Payments  
Subjects will not receive Stipends or Payments. 
J4  Study Timetable 
Planned Start Date: November 1st, 2018 
Planned Completion Date: May 31st, 2020 
 

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18 
K Publication Plan  
The results of this study will be submitted for publication to a peer-reviewed journal. 
L  Attachments  
 
L1  Tables  
Table 1. Schedule of Laboratory measurements 
 
 
Week 
 
0 
4 
8 
12 
16 
24 
Clinic visit 
X 
X 
X 
X 
X 
X 
CMP & CBC 
X 
X 
 
X 
 
X 
Lipid Panel 
X 
 
 
 
 
X 
Hepatitis B 
X 
 
 
 
 
 
Hepatitis C 
X 
 
 
 
 
 
PPD / IGRA* 
X 
 
 
 
 
 
 
*IGRA: Interferon-gamma release assay a.k.a. T spot for TB 
 
Patients with Hepatitis B & C serologies within the past 5 years will not need repeat labs. 
 
Patients with a PPD / IGRA in the past 12 months will not need repeat labs. 
 
Table 2. Oral steroid (prednisone or equivalent) taper 
 
Week 
Prednisone dose (mg/day) 
0 
60 
1 
60 
2 
50 
3 
40 
4 
30 
5 
20 
6 
15 
7 
12.5 
8 
10 
9 
7.5 
10 
5 
11 
4 
12 
3 
13 
2 
14 
1 
15 
0 
 
Table 3. Prednisone Drop Taper Schedule – patient-specific wherever they start 
 
Dose (# of drops/day) per Week 

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19 
12 
10 
8 
6 
5 
4 
3 
2 
1 
 
L2 Informed consent documents 
See separate informed consent document. 
L3  Patient education brochures 
See separate informed consent document. 
L4  Questionnaires or surveys 
Patients will not be required to complete questionnaires or surveys. 
 
M References 
 
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chemokines in uveitis: is there a correlation with clinical phenotype? Clin Med 
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2. 
W. Chen et al., Cytokine Expression Profile in Aqueous Humor and Sera of 
Patients with Acute Anterior Uveitis. Curr Mol Med 15, 543-549 (2015). 
3. 
G. Velez et al., Precision Medicine: Personalized Proteomics for the Diagnosis 
and Treatment of Idiopathic Inflammatory Disease. JAMA Ophthalmol 134, 444-
448 (2016). 
4. 
H. N. Sen et al., High-dose Daclizumab for the Treatment of Juvenile Idiopathic 
Arthritis-Associated Active Anterior Uveitis. American Journal of Ophthalmology 
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K. Wroblewski et al., Long-term daclizumab therapy for the treatment of 
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10. 
P. Mease et al., Tofacitinib or Adalimumab versus Placebo for Psoriatic Arthritis. 
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Engl J Med 375, 932-943 (2016). 
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Q. D. Nguyen et al., Adalimumab for prevention of uveitic flare in patients with 
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the Management of Rheumatoid Arthritis. Clinical Therapeutics 36, 1074-1086 
(2014). 
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S. B. Cohen et al., Long-term safety of tofacitinib for the treatment of rheumatoid 
arthritis up to 8.5 years: integrated analysis of data from the global clinical trials. 
Ann Rheum Dis 76, 1253-1262 (2017). 
16. 
C. Charles-Schoeman et al., Effects of tofacitinib and other DMARDs on lipid 
profiles in rheumatoid arthritis: implications for the rheumatologist. Semin Arthritis 
Rheum 46, 71-80 (2016). 
17. 
R. Fleischmann et al., Efficacy and safety of tofacitinib monotherapy, tofacitinib 
with methotrexate, and adalimumab with methotrexate in patients with 
rheumatoid arthritis (ORAL Strategy): a phase 3b/4, double-blind, head-to-head, 
randomised controlled trial. Lancet 390, 457-468 (2017). 
18. 
D. A. Jabs, R. B. Nussenblatt, J. T. Rosenbaum, G. Standardization of Uveitis 
Nomenclature Working, Standardization of uveitis nomenclature for reporting 
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509-516 (2005). 
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R. B. Nussenblatt, A. G. Palestine, C. C. Chan, F. Roberge, Standardization of 
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