Conditions: Uveitis
Keywords: Panuveitis Intermediate Uveitis Uveitis
Allocation: NON_RANDOMIZED | Intervention model: SEQUENTIAL
Enrollment: 8
Healthy volunteers: no

Brief summary:
Background:

Uveitis is an inflammation of the eye that can cause vision loss. It is treated with medications and sometimes surgery. However, in many people, treatment does not always prevent loss of vision. A new medication, ustekinumab, reduces inflammation in patients with other inflammatory diseases. Therefore, it might be helpful in treatment of uveitis.

Objective:

To see if ustekinumab is safe and can help people with uveitis.

Eligibility:

People ages 18 and older with uveitis

Design:

Participants will be screened with:

Medical and eye disease history

Physical exam

Eye exam: The pupil is dilated with eye drops. A machine scans the back of the eye. Pictures are taken of the inside of the eye.

Blood and urine tests

Tuberculosis test

Participants will have 6 clinic visits over 28 weeks. Visits lasts 2-3 hours and include:

* Medical and eye disease history
* Physical and eye exams
* Blood and urine tests
* Fluorescein angiography: A needle guides a thin plastic tube into an arm vein. A dye is injected into the tube. The dye travels through the veins up to the blood vessels in the eyes. A camera takes pictures of the dye as it flows through the blood vessels in the eyes.
* Cohort 1 - Ustekinumab injections at Weeks 0, 4, and 8: The injection is under the skin of the upper arm, leg, or abdomen.

Participants will have their uveitis monitored and receive standard uveitis care during the study.

* Cohort 2 - Ustekinumab injections via intravenous (IV) injection at first visit, followed by a single 90 mg injection of ustekinumab under the skin of the upper arm, leg or abdomen. For the IV injection a needle will be used to guide a thin plastic tube (catheter) into one of the arm veins. The needle will be removed, leaving only the catheter in the vein.

Detailed description:
Objective: Uveitis refers to intraocular inflammatory diseases that are an important cause of visual loss. Standard systemic immunosuppressive medications for uveitis can cause significant adverse effects and many patients continue to experience disease flare-ups. Ustekinumab is a human IL-12 and -23 antagonist. The involvement of IL-12 and IL-23 in the pathophysiology of uveitis and other autoimmune diseases known to be associated with uveitis suggests that ustekinumab could be a potential treatment for uveitis. The study objective is to investigate the safety, tolerability and potential efficacy of ustekinumab as a possible treatment for active intermediate uveitis, posterior uveitis or panuveitis.

Study Population: The first cohort will consist of five participants with active intermediate uveitis, posterior uveitis or panuveitis who meet the inclusion criteria. The second cohort will include up to four participants with active intermediate uveitis, posterior uveitis or panuveitis who meet the inclusion criteria. Up to eleven participants may be enrolled, as up to two participants may be accrued in the second cohort to account for participants who withdraw from the study prior to Week 16.

Design: This is a prospective, non-randomized, uncontrolled, two-arm pilot study to evaluate of ustekinumab as a possible treatment for active intermediate uveitis, posterior uveitis or panuveitis. Five participants in the first cohort will receive a 90 mg subcutaneous (SC) injection of ustekinumab at baseline and a second and third injection at Week 4 and 8 for a total of 3 injections. For the second cohort, up to four participants will receive an initial high, weight-based dose of ustekinumab via intravenous (IV) injection (up to 55 kg, 260 mg (2 vials); greater than 55 kg to 85 kg, 390 mg (3 vials); greater than 85 kg, 520 mg (4 vials)), followed by a single 90 mg subcutaneous injection at Week 8. In participants who demonstrate allergic reaction to the first dose, the second dose can also be administered as IV infusion with pre-infusion desensitization instead of a subcutaneous injection as it allows better control on the rate of drug administration. Participants will continue in the study for a total of 28 weeks and will be able to receive standard of care after the first 16 weeks.

Outcome Measures: For each cohort, the primary outcome is the number of participants who experience treatment response by Week 16. Secondary outcomes for each cohort include changes in visual acuity, the number of participants who experience a recurrence, the number of days to recurrence, presence or extent of macular edema, the amount of retino-vascular leakage, changes in retinal thickening, the length of time to quiescence and the ability to taper concomitant immunosuppressive medications. Safety outcomes for each cohort include the number and severity of systemic and ocular toxicities and adverse events, the proportion of participants who experience vision loss of greater than or equal to 15 letters as measured by Electronic Visual Acuity (EVA) and the number of participants who experience a substantial rise in elevated intraocular pressure (IOP).

Arms:
arm 1: Subcutaneous injections of Ustekinumab at baseline. arm 2: Initial IV infusion of ustekinumab at baseline followed by one subcutaneous injection at Week 8. In participants who demonstrate an allergic reaction to the baseline IV infusion, the second dose at Week 8 can also be administered as an IV infusion instead of a subcutaneous injection.

Interventions: intervention 1: Ustekinumab intervention 2: Ustekinumab
Intervention descriptions: intervention 1: Subcutaneous Injection intervention 2: Intravenous Infusion

Protocol document:
Prot_000.pdf: 
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Protocol Title: A Pilot Study to Investigate Ustekinumab (STELARA®) for the Treatment of 
Active Sight-Threatening Uveitis  
NCT Number: NCT02911116 
Date of This Submission/Version: September 18, 2019/v10.0 
Principal Investigator 
H. Nida Sen, MD, 
MHSc 
NIH/NEI 
Building 10, 
Rm. 10D45
301-402-3254 
senh@nei.nih.gov 
 
Coordinating Center : 
 
The Emmes Company, LLC 
401 North Washington St. 
Suite 700 
Rockville, MD 20850 USA 
Phone: (301) 251-1161 
Facsimile: (202) 478-0243 
 
Human Research Protections Program Investigator and Staff Training: 
“Just in time” human subjects protection training courses are required for investigators and staff 
participating on this protocol: None 
 
Total Requested Accrual: 
 
11  Participants – 5 Participants, ages 18 and older, will be initially enrolled and included 
in the first cohort. For the second cohort, up to 4 participants, ages 18 and older will be 
enrolled. Up to an additional 2 participants may be enrolled in the second cohort to 
account for participants who withdraw from the study prior to the Week 16 visit. 
0  Healthy Volunteers 
 
Project Uses Ionizing Radiation:   
 No   
 Yes  
 
IND/IDE: 
 
 
 
 
 No   
 Yes 
  
 
Drug #:  
 
131,716 
 
Sponsor:  
 
National Eye Institute 
 
Durable Power of Attorney: 
 
 No   
 Yes  
 
Multi-Institutional Project:  
 
 No   
 Yes 
 
 
 
Data and Safety Monitoring Board: 
 No   
 Yes  
 
Technology Transfer Agreement:   
 No   
 Yes 
 
Samples are Being Stored:  
 
 No   
 Yes 
 
Flesch-Kincaid Reading Level of Consent:  
 
9.9 


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TABLE OF CONTENTS 
PROTOCOL ABBREVIATION LIST .................................................................................................. IV 
PRÉCIS ............................................................................................................................................ 1 
1.0 
INTRODUCTION/SCIENTIFIC RATIONALE .......................................................................... 3 
1.1 
Uveitis ............................................................................................................................. 3 
1.2 
Ustekinumab ................................................................................................................... 4 
2.0 
STUDY OBJECTIVES ............................................................................................................ 8 
3.0 
PARTICIPANTS .................................................................................................................... 8 
3.1 
Inclusion Criteria ............................................................................................................ 8 
3.2 
Exclusion Criteria ........................................................................................................... 9 
3.3 
Choice of Study Eye ....................................................................................................... 9 
4.0 
STUDY DESIGN AND METHODS ........................................................................................ 10 
4.1 
Recruitment ................................................................................................................... 10 
4.2 
Screening....................................................................................................................... 10 
4.3 
Study Procedures .......................................................................................................... 11 
4.4 
Ocular and Systemic Evaluations ................................................................................. 12 
4.5 
Follow-up/Termination Procedures .............................................................................. 13 
4.6 
Management of Samples and Data ............................................................................... 13 
4.7 
Data and Sample Sharing Plan ...................................................................................... 13 
4.8 
Study and Concomitant Therapies ................................................................................ 14 
4.8.1 
Ustekinumab Formulation ........................................................................................ 14 
4.8.2 
Ustekinumab Storage ................................................................................................ 15 
4.8.3 
Ustekinumab Preparation and Administration .......................................................... 15 
4.8.4 
Concomitant Therapy................................................................................................ 16 
4.8.5 
Investigational Product Accountability ..................................................................... 17 
5.0 
RISKS/DISCOMFORTS ....................................................................................................... 17 
5.1 
Examination Risks ........................................................................................................ 17 
5.2 
Ustekinumab Risks ....................................................................................................... 18 
5.2.1 
Administration-related Risks .................................................................................... 18 
5.2.2 
Ustekinumab-related Risks ....................................................................................... 18 
6.0 
PARTICIPANT MONITORING ............................................................................................. 21 
6.1 
Withdrawal Criteria ...................................................................................................... 21 
6.2 
Pregnancy Monitoring .................................................................................................. 22 
7.0 
OUTCOME MEASURES ...................................................................................................... 22 
7.1 
Primary Outcome .......................................................................................................... 22 
7.2 
Secondary Outcomes .................................................................................................... 23 
7.3 
Safety Outcomes ........................................................................................................... 23 
7.4 
Exploratory Outcomes .................................................................................................. 23 
8.0 
STATISTICAL ANALYSIS ................................................................................................... 23 
8.1 
Study Design and Primary Analysis ............................................................................. 24 
8.2 
Analysis of Secondary Outcomes ................................................................................. 24 
8.3 
Sample Size/Accrual Rate ............................................................................................. 24 


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9.0 
HUMAN SUBJECTS PROTECTION ...................................................................................... 25 
9.1 
Equitability .................................................................................................................... 25 
9.1.1 
Justification for the Exclusion of Children ............................................................... 25 
9.1.2 
Justification for the Exclusion of Pregnant or Lactating Women ............................. 25 
9.1.3 
Justification for Exclusion of Persons Who Cannot Consent ................................... 25 
10.0 
CONSENT DOCUMENTS AND PROCESS ............................................................................. 25 
11.0 
DATA AND SAFETY MONITORING .................................................................................... 26 
11.1 
Coordinating Center ...................................................................................................... 26 
11.2 
NEI Serious Adverse Event Review Committee .......................................................... 26 
12.0 
QUALITY ASSURANCE ...................................................................................................... 27 
13.0 
REPORTABLE EVENTS ...................................................................................................... 28 
14.0 
ALTERNATIVE THERAPIES ............................................................................................... 28 
15.0 
PRIVACY ........................................................................................................................... 28 
16.0 
CONFIDENTIALITY ............................................................................................................ 28 
17.0 
CONFLICT OF INTEREST ................................................................................................... 29 
18.0 
TECHNOLOGY TRANSFER................................................................................................. 29 
19.0 
COMPENSATION ................................................................................................................ 29 
20.0 
REFERENCES ..................................................................................................................... 30 
APPENDIX 1: DEFINITIONS OF DISEASE ACTIVITY ...................................................................... 32 
APPENDIX 2: DETERMINING CHILDBEARING POTENTIAL .......................................................... 33 
APPENDIX 3: STUDY FLOWSHEET ................................................................................................ 34 
APPENDIX 4: SUBCUTANEOUS INJECTION INSTRUCTIONS .......................................................... 36 
 
 
 


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Protocol Abbreviation List 
> 
Greater Than or Equal To 
AC
Anterior chamber
BCVA
Best-corrected visual acuity 
CBC
Complete blood count
CC 
Clinical Center 
CD 
Crohn’s Disease
EAU
Experimental autoimmune uveitis 
ETDRS
Early Treatment Diabetic Retinopathy Study 
EVA
Electronic visual acuity
FA
Fluorescein angiography 
FDA
Food and Drug Administration 
HIV 
Human Immunodeficiency virus
IFN
Interferon gamma 
IL 
Interlukein 
IOP
Intraocular pressure 
IRB
Institutional Review Board 
IV
Intravenous
mL 
Milliliter 
MTX 
Methotrexate
NEI
National Eye Institute 
NIH 
National Institutes of Health
NIMH 
National Institute of Mental Health 
NLM 
National Library of Medicine
NSAIDS
Nonsteroidal anti-inflammatory drugs 
OCT
Optical coherence tomography 
PPD 
Purified protein derivative
PI
Principal Investigator
RCT
Randomized clinical trial
SAE 
Serious Adverse Event 
SC
Subcutaneous
SOP 
Standard operating procedure
SUN
Standard of Uveitis Nomenclature
TB
Tuberculosis 
TNF-alpha
Tumor necrosis factor alpha 
VEGF 
Vascular endothelial growth factor 
 


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Précis 
Objective: Uveitis refers to intraocular inflammatory diseases that are an important cause of visual 
loss. Standard systemic immunosuppressive medications for uveitis can cause significant adverse 
effects and many patients continue to experience disease flare-ups. Ustekinumab is a human IL-
12 and -23 antagonist. The involvement of IL-12 and IL-23 in the pathophysiology of uveitis and 
other autoimmune diseases known to be associated with uveitis suggests that ustekinumab could 
be a potential treatment for uveitis. The study objective is to investigate the safety, tolerability and 
potential efficacy of ustekinumab as a possible treatment for active intermediate uveitis, posterior 
uveitis or panuveitis.  
Study Population: The first cohort will consist of five participants with active intermediate 
uveitis, posterior uveitis or panuveitis who meet the inclusion criteria. The second cohort will 
include up to four participants with active intermediate uveitis, posterior uveitis or panuveitis who 
meet the inclusion criteria. Up to eleven participants may be enrolled, as up to two participants 
may be accrued in the second cohort to account for participants who withdraw from the study prior 
to Week 16. 
Design: This is a prospective, non-randomized, uncontrolled, single-center, two-arm pilot study 
to evaluate ustekinumab as a possible treatment for active intermediate uveitis, posterior uveitis or 
panuveitis. Five participants in the first cohort will receive a 90-mg subcutaneous (SC) injection 
of ustekinumab at baseline and a second and third injection at Week 4 and 8 for a total of three 
injections. For the second cohort, up to four participants will receive an initial high, weight-based 
dose of ustekinumab via intravenous (IV) injection (up to 55 kg, 260 mg (2 vials); greater than 55 
kg to 85 kg, 390 mg (3 vials); greater than 85 kg, 520 mg (4 vials)), followed by a single 90 mg 
subcutaneous injection at Week 8. In participants who demonstrate allergic reaction to the first 
dose, 
the 
second 
dose 
can 
also 
be 
administered 
as 
IV 
infusion 
with  
pre-infusion desensitization instead of a subcutaneous injection as it allows better control on the 
rate of drug administration. Participants will continue in the study for a total of 28 weeks and will 
be able to receive standard of care after the first 16 weeks.  
 
 


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Outcome Measures: For each cohort, the primary outcome is the number of participants who 
experience treatment response (as defined in Appendix 1) by Week 16. Secondary outcomes for 
each cohort include changes in visual acuity, the number of participants who experience a 
recurrence, the number of days to recurrence, presence or extent of macular edema, the amount of 
retino-vascular leakage, changes in retinal thickening, the length of time to quiescence and the 
ability to taper concomitant immunosuppressive medications. Safety outcomes for each cohort 
include the number and severity of systemic and ocular toxicities and adverse events, the 
proportion of participants who experience vision loss of ≥15 letters as measured by Electronic 
Visual Acuity (EVA) and the number of participants who experience a substantial rise in elevated 
intraocular pressure (IOP). 


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1.0 
Introduction/Scientific Rationale 
1.1 
Uveitis 
Uveitis, an inflammatory condition that affects the uvea (iris, ciliary body and choroid) and 
adjacent structures of the eyes, is an important cause of visual loss in both adults and children.  
A recent study in Northern California suggests that the incidence and prevalence of uveitis is three 
times what was previously thought, at 52/100,000 and 115/100,000 respectively.1,2 It is believed 
that approximately 100,000 American citizens currently require the use of systemic corticosteroids 
or other immunosuppressive agents as treatment for ocular inflammation. It is particularly common 
to use immunosuppressive or immunomodulatory therapy for the treatment of posterior segment 
uveitis (intermediate, posterior or panuveitis), which are considered to be more likely to be sight 
threatening.3 Management and prevention of the iatrogenic complications of immunosuppressive 
therapy accounts for most of the medical resources devoted to these individuals.2 
Uveitis is a predominantly T-cell mediated immune disease, and drugs like cyclosporine targeted 
primarily at T-cells have demonstrated efficacy.4 The dominant role of T-cells in the pathogenesis 
of uveitis is also observed in the experimental animal models of uveitis. Both Th1 and Th17 
pathways are believed to drive inflammation in uveitis.4 IL-12 and IL-23 are crucial parts of Th1 
and Th17 pathways which have been implicated in autoimmune disorders including uveitis. IL-
12, a heterodimer of p40 and p35 subunits, induces CD4+ differentiation into Th1 cells which 
produce interferon (IFN)-gamma and mediates cellular immunity. IL-23, also a heterodimer with 
p40 and p19 subunits, induces naïve CD4 cells to differentiate into Th17 cells which produce IL-
17, IL-6 and tumor necrosis factor alpha (TNF-alpha) and similarly mediate cellular immunity. In 
addition, IL-12 and IL-23 each play an important role in the expression of experimental model of 
uveitis (EAU).4,5 Anti-IL-12 administration in experimental uveitis models not only prevented the 
development of disease and pathogenic Th1 cells, but also induced suppressive Th2 cells.6 Keino 
et. 
al. 
showed 
that 
oral 
administration 
of 
a 
potent  
IL-12/IL-23 inhibitor abrogated inflammation in an EAU both in afferent and efferent phases of 
the disease. They also found that IL-12/23 inhibitor administration also reduced the expansion of 
IL-17 producing cells.7 Ustekinumab, by targeting the p40 subunit shared by both IL-12 and  
IL-23, offers a novel mechanism of action; it prevents IL-12/23 interaction with their receptors 
and blocks signaling through the IL-12β1 receptor, cell differentiation and cytokine production. 


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IL-12 is also believed to be responsible for CD4+ cells escaping suppressor effects of regulatory 
T-cells (Tregs).8 It is possible that IL-12/23 blockage may, in addition to inhibiting Th1 and Th17, 
also help expand regulatory T-cells through multiple mechanisms. 
1.2 
Ustekinumab  
Ustekinumab is a human IL-12 and -23 antagonist and is currently approved by the FDA for the 
treatment of adult patients (18 years or older) with moderate to severe plaque psoriasis who are 
candidates for phototherapy or systemic therapy. Ustekinumab is administered by subcutaneous 
(SC) injection. For patients weighing <100 kg (220 lbs), the recommended dose is 45 mg initially 
and four weeks later, followed by 45 mg every 12 weeks. For patients weighing >100 kg (220 lbs), 
the recommended dose is 90 mg initially and four weeks later, followed by 90 mg every 12 weeks. 
In a randomized, controlled trial (RCT) of ustekinumab for moderate-to-severe Crohn’s disease, 
clinical 
response 
was 
most 
notable 
in 
infliximab 
non-responders 
and  
sub-optimal responders indicating a different, perhaps more robust, clinical effect.  
More importantly, adverse events with ustekinumab have been mostly mild and non-serious in 
clinical trials so far. The most common side effects were upper respiratory tract infections, 
nasopharyngitis, headache, fatigue and arthralgia.9 In PHOENIX 1 and 2 randomized,  
double-masked phase III trials, in which a total of 1,996 patients were enrolled, serious adverse 
events occurred in 0.8% of the patients receiving the 45 mg dose of ustekinumab, 1.6% of the 
patients receiving the 90 mg dose of ustekinumab and 0.8% of the patients receiving placebo.10 
Injection site reactions occurred in 1% of patients receiving ustekinumab injections and 0.4% of 
patients receiving placebo injections.11 No episodes of anaphylactic or serum-like sickness 
reactions, lymphoma, tuberculosis or demyelinating diseases were reported.12 
Ustekinumab has also been used in Crohn’s disease (CD) and psoriatic arthritis in large clinical 
trials. A double-blind, cross-over trial of the clinical effects of ustekinumab in 104 patients with 
moderate-to-severe CD used a more frequent dosing of 90 mg SC ustekinumab injections weekly 
for four weeks. In this trial, the investigators allowed concomitant use of prednisolone at a 
maximum daily dose of 20 mg, azathioprine, 6-mercaptopurine or methotrexate.  
Concomitant medication doses remained constant during the study except corticosteroids, which 
could be tapered. Ustekinumab induced a clinical response in patients with CD and helped improve 
disease 
activity 
scores, 
especially 
in 
patients 
previously 
given 
infliximab.  


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Population pharmacokinetic data analyses indicated that the clearance of ustekinumab was not 
impacted by concomitant Methotrexate (MTX), nonsteroidal anti-inflammatory drugs (NSAIDs), 
and oral corticosteroids, or prior exposure to anti-tumor necrosis factor (anti-TNF) agents in 
patients with psoriatic arthritis. Anti-ustekinumab antibodies were negative in 99 patients that were 
tested throughout the study duration of 54 weeks. In the PHOENIX 1 and 2 trials, approximately 
3-5% of patients showed positive anti-ustekinumab antibodies. For the most part, adverse event 
rates in the treatment groups (IV or SC ustekinumab) were comparable to placebo groups. The 
most common adverse events in either group were nausea, headache, abdominal pain, worsening 
CD and fatigue, some of which were related to underlying disease. Administration-site reactions, 
interestingly, 
were 
more 
common 
in 
the 
placebo 
group.  
Serious adverse event (SAE) rates occurred in 6% of the placebo-treated patients and 4% of the 
ustekinumab-treated patients. Infections were observed in 23% of the placebo vs. 15% of the 
ustekinumab-treated patients.13 Similarly, in a large multi-center, international, double-blind, 
randomized, 
placebo-controlled 
crossover 
study 
of 
psoriatic 
arthritis 
patients,  
weekly-administered ustekinumab significantly reduced signs and symptoms of psoriatic arthritis 
and skin lesions within 12 weeks.14 Of note, single doses up to 6 mg/kg intravenously have been 
administered in clinical studies without dose-limiting toxicity.9 Ustekinumab also improved the 
quality of life in this patient population. It is important to note that in this frequent dosing study, 
the drug was well-tolerated.14 More recently, ustekinumab (90 mg SC) was evaluated for the 
treatment of Ankylosing spondylitis in a proof of concept open-label trial (N=20, TOPAS study) 
and was shown to be effective in improving the signs and symptoms of active spondyloarthritis 
when administered at 0, 4, and 16 weeks.15 In this study too, ustekinumab was well tolerated with 
no adverse events requiring discontinuation of the study drug.15 While ustekinumab has not been 
effective in treating multiple sclerosis it did not cause worsening of the disease -unlike  
anti-TNF agents- and remains one of the two safe biologics available to patients that have both 
psoriasis and MS.16  
More recently, STELARA® is approved for moderate to severely active CD. STELARA® is used 
for induction in IV infusion form at doses up to 520 mg/infusion (4 vials) for one infusion (at 6 
mg/kg/infusion), followed by a single, SC 90 mg dose eight weeks after, and, for maintenance, a 
SC 90 mg dose every eight weeks thereafter. Mean ±SD peak serum ustekinumab concentration 
was 125.2 ± 33.6 mcg/mL following an IV infusion and steady state steady-state trough 


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concentration was 2.51 ± 2.06 mcg/mL for 90 mg ustekinumab administered every eight weeks 
following IV infusion. This was higher than steady-state trough serum ustekinumab concentrations 
observed with SC administration alone (0.69 ± 0.69 mcg/mL to 0.74 ± 0.78 mcg/mL). In these 
induction studies, a greater proportion of patients treated with STELARA® achieved clinical 
response at Week 6 and clinical remission at Week 8 compared to placebo. Clinical response and 
remission were significant as early as Week 3 in STELARA®-treated patients and continued to 
improve through Week 8. This is in keeping with the finding that, in general, higher rates of clinical 
response and remission are observed in IV ustekinumab groups compared to SC ustekinumab 
groups in CD patients.17 
The safety of STELARA® was assessed in 1407 patients that participated in three randomized 
clinical trials. Overall, the safety profile of STELARA® was consistent with the safety profile seen 
in the adult psoriasis and psoriatic arthritis clinical studies. Most common adverse reactions with 
IV dosing in CD trials was vomiting (4% among CD patients vs. 3% in Placebo) and most common 
adverse reactions during SC maintenance therapy among CD patients observed at a rate >=3% 
were: nasopharyngitis, injection site erythema, vulvovaginal candidiasis/mycotic infection, 
bronchitis, pruritus, urinary tract infection, and sinusitis. Hypersensitivity reactions with 
STELARA® has been rare. In CD trials the incidence of hypersensitivity reaction was encountered 
in two patients, one following SC administration and one following IV administration (0.1% 
among SC dosing group and 0.08% among IV dosing group). Immunogenicity to ustekinumab 
(antibodies against ustekinumab) was less common in CD Trials (<3%) than was observed in 
psoriasis trials (6-12%) (see section 6.2.2 for more information on adverse events in clinical trials 
using high dose IV administration). 
The rate of adverse events and serious adverse events was not significantly different between trials 
using different dose regimens. During the placebo-controlled PHOENIX trials (0, 4 weeks and 
every 12-week dose regimen), adverse events occurred in 47.9%-54.5% of the patients receiving 
ustekinumab and 48.2%-49.8% of the patients receiving placebo. Serious adverse events occurred 
in 1.2%-2% in the treatment group vs. 0.8%-2% in the placebo groups in PHOENIX 1 and 2 trials. 
In comparison, during the placebo-controlled psoriatic arthritis trial, where a weekly dose regimen 
was used, adverse events occurred in 61% of patients in the treatment group and in 63% of patients 


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receiving placebo, and serious adverse events occurred in 0% in the treatment group vs. 4% in the 
placebo group.10,11,14  
Overall, while there appears to be a dose-response relationship in terms of effectiveness, the rate 
of adverse events has not been found to be significantly different between different dosing groups 
across multiple large RCTs using ustekinumab.18  
Thousands of patients world-wide are treated for autoimmune disorders with various types of 
immunosuppressive and cytotoxic agents. 
Less toxic, more 
specific, or targeted 
immunosuppressive modalities are constantly being sought. Attempts to decrease morbidity, or 
reduce the dose of more toxic immunosuppressive drugs, or reduce the frequency or severity of 
episodes of recurrence are clearly all important goals. Although previous clinical trials have not 
generated specific evidence, the involvement of IL-23 and IL-12 in the pathophysiology of uveitis 
and other autoimmune diseases known to be associated with uveitis and the clinical evidence from 
autoimmune diseases where ustekinumab has been used successfully suggests that ustekinumab 
could be a potential treatment for uveitis (as shown below).19  
 


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2.0 
Study Objectives 
The study objective is to investigate the safety, tolerability and potential efficacy of ustekinumab 
as a possible treatment for active intermediate uveitis, posterior uveitis or panuveitis.  
3.0 
Participants 
For the first cohort, five participants with active intermediate, posterior or panuveitis will be 
initially accrued. For the second cohort, up to four participants with active intermediate uveitis, 
posterior uveitis or panuveitis who meet the eligibility criteria may be enrolled in this protocol. In 
the event that a participant in the second cohort withdraws from the study prior to Week 16, a 
maximum of two additional participants will be accrued in order to obtain the four participants in 
each cohort completing the primary outcome visit.  
3.1 
Inclusion Criteria 
1. Participant has the ability to understand and sign the informed consent document. 
2. Participant is 18 years of age or older. 
3. Participant has negative purified protein derivative (PPD) or quantiferon testing done 
within three months prior to enrollment or had latent tuberculosis (TB) but has completed 
prophylactic anti-TB treatment. 
4. Participant has active intermediate uveitis, posterior uveitis or panuveitis in at least one eye 
requiring systemic therapy. Active disease is defined as (also listed in Appendix 1): 
 +1 or more vitreous haze (according to Standardization of Uveitis Nomenclature 
(SUN) criteria20) AND/OR  
 Active chorioretinitis or leakage on Fluorescein angiography (FA) (that is in more 
than one quadrant) that requires treatment. 
5. Participant has visual acuity in at least one eye of 20/400 or better. 
6. Participant is willing and able to comply with the study procedures. 
7. Female participants of childbearing potential must not be pregnant or breast-feeding, have 
a negative pregnancy test at screening and must be willing to undergo pregnancy testing 
throughout the study.  
8. Both female participants of childbearing potential (see Appendix 2 for definition) and male 
participants able to father a child must have (or have a partner who has) had a hysterectomy 


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or vasectomy, be completely abstinent from intercourse or must agree to practice two 
effective methods of contraception throughout the course of the study and for six weeks 
after the last investigational product injection. Acceptable methods of contraception for 
this study include:  
 hormonal contraception (i.e., birth control pills, injected hormones, dermal patch 
or vaginal ring),  
 intrauterine device,  
 barrier methods (diaphragm, condom) with spermicide, or  
 surgical sterilization (tubal ligation). 
3.2 
Exclusion Criteria 
1. Participant has a significant active infection (an infection requiring treatment as 
determined by the medical team), including active tuberculosis or human 
immunodeficiency virus (HIV). 
2. Participant received a live vaccination within the past six weeks. 
3. Participant is expected to receive a live vaccination at any time during the study. 
4. Participant received the Bacillus Calmette-Guérin (BCG) vaccine within the past year.  
5. Participant is expected to receive the BCG vaccine at any time during the study or up 
to one year after discontinuing ustekinumab. 
6. Participant has a history of cancer (other than a non-melanoma skin cancer) diagnosed 
within the past five years. 
7. Participant has received intraocular (or periocular) steroid or anti-vascular endothelial 
growth factor (VEGF) injections within the last six weeks. 
8. Participant received rituximab within the last six months or another biologic agent (e.g., 
infliximab, daclizumab, adalimumab) within the last two months.  
9. Participant has received alkylating agents (e.g., cyclophosphamide, chlorambucil) 
within the last nine months. 
10. Participant has a known hypersensitivity to ustekinumab or any of its components. 
3.3 
Choice of Study Eye 
Since this is a systemic treatment, a study eye selection does not apply. Any eye meeting the 
eligibility criteria will be considered in the outcomes.  


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4.0 
Study Design and Methods 
This is a prospective, non-randomized, uncontrolled, single-center, two-arm pilot study to evaluate 
ustekinumab as a possible treatment for active intermediate uveitis, posterior uveitis or panuveitis. 
The first cohort will receive a 90 mg subcutaneous injection of ustekinumab at Weeks 0, 4 and 8. 
The second cohort will receive an initial high, weight-based dose of ustekinumab via intravenous 
infusion, followed by a single, 90 mg subcutaneous injection of ustekinumab at Week 8. In 
participants who demonstrate allergic reaction to the first dose, the second dose can also be 
administered as IV infusion with pre-infusion desensitization instead of a subcutaneous injection 
as it allows better control on the rate of drug administration. 
4.1 
Recruitment 
Participants will be recruited from the NEI uveitis clinic. In addition, the study will be posted on 
the National Library of Medicine (NLM) and the NEI and the Clinical Center (CC) web sites. Self-
referral and referral from outside physicians will be permitted. The projected recruitment time is 
approximately 12 months. 
4.2 
Screening 
Participants will be screened under one of the following protocols: NEI Screening protocol (NIH 
Protocol 08-EI-0102), NEI Ocular Natural History protocol (NIH Protocol 16-EI-0134) or NEI 
iBank protocol (NIH protocol 16-EI-0046) to establish eligibility. Baseline examinations include 
a medical/ophthalmic history, a vaccination history, physical examination, vital signs and a 
concomitant medication assessment. Ophthalmic assessments include best-corrected visual acuity 
(BCVA) with manifest refraction, slit lamp examination, intraocular pressure (IOP) measurement, 
dilated fundus examination, color fundus photography, fluorescein angiogram (FA) and optical 
coherence tomography (OCT). The procedures must be performed on both eyes, where 
appropriate. Laboratory assessments include a complete blood count (CBC) with differential, acute 
care, mineral and hepatic laboratory panels, urinalysis, TB screening, HIV screening and 
pregnancy testing. These are outlined in Appendix 3. Some of the baseline examinations may be 
performed under the NEI screening, ocular natural history or iBank protocols (see Appendix 3). If 
determined eligible, the participant will enroll by signing this protocol’s consent form and 
complete any remaining baseline procedures at the first study visit.  


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4.3 
Study Procedures 
Following completion of screening procedures and enrollment, eligible participants in the first 
cohort will receive an initial subcutaneous injection of ustekinumab. Second and third 
subcutaneous injections of ustekinumab will be given at Weeks 4 and 8. Following protocol 
Amendment G, eligible participants in the second cohort will receive an initial weight-based 
intravenous infusion of ustekinumab, followed by a single subcutaneous injection at Week 8.  
In participants who demonstrate allergic reaction to the first dose, the second dose can be 
administered as IV infusion with pre-infusion desensitization instead of a subcutaneous injection 
as it allows better control on the rate of drug administration.  
For both cohorts, participants that experience recurrence (or those that are nonresponders)  
(see Appendix 1 for definition) by Week 16 can receive standard of care. Participants may continue 
to receive ustekinumab through Week 8 unless there is a medical contraindication  
(e.g., severe infection or severe allergic reaction). The last injection will occur at the Week 8 visit 
followed by monthly visits until Week 16 and a final safety visit at Week 28. 
The Week 4 and 8 visits must be conducted within a window of 5 days from the target day and 
the remaining visits must be conducted within a window of 14 days. The examinations scheduled 
at each visit can be completed over 1-3 days (though we expect that they will be completed in one 
day).  
Each participant will be instructed to contact the study investigators upon experiencing any 
symptoms of flare-up. Such symptoms include: blurred vision, decreased visual acuity, floaters, 
pain, redness, irritation or photophobia. Participants experiencing flare-up symptoms during the 
study duration will return to the clinic as soon as possible for evaluation.  
A physical examination will be performed at Baseline, Weeks 4, 8 and 28. Vital signs, a live 
vaccination history query, concomitant medications assessment and an adverse event assessment 
will be completed at every visit. 
BCVA, manifest refraction, a slit lamp examination, IOP, dilated fundus examination and OCT 
will be assessed at every visit. The imaging (color fundus photography and fluorescein angiogram) 
will be collected at Baseline, Weeks 8, 12, 16 and 28. 


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The laboratory assessments (CBC with differential, acute care, mineral and hepatic panels and 
urinalysis) will be monitored throughout the study at Baseline, Weeks 4, 8 and 28. Women of 
childbearing potential (see Appendix 2 for definition) will undergo pregnancy testing at every visit.  
Research blood (up to 60 mL per study visit) will be collected at Baseline, Weeks 4, 8, 16 and 28. 
The total amount of blood collected for research purposes will not exceed 360 mL.  
The research blood will be used for studying soluble and intracellular cytokine expression, 
proliferative or antibody responses, exosomes and epigenetic changes. 
4.4 
Ocular and Systemic Evaluations 
In this study, examinations will be performed both as clinical care and for research purposes.  
The following examinations will be performed at the study visits as indicated in the study 
flowsheet (Appendix 3):  
1. Medical/Ophthalmic History 
2. Vaccination History 
3. Physical Examination 
4. Vital Signs 
5. Concomitant Medications Assessment 
6. Adverse Event Assessment 
7. Best-Corrected Visual Acuity (BCVA) using EVA   
8. Manifest Refraction  
9. Slit Lamp Examination 
10. Intraocular Pressure (IOP) 
11. Dilated Fundus Examination 
12. Color Fundus Photography 
13. Fluorescein Angiography (FA)1 
14. Optical Coherence Tomography (OCT) 
15. Complete Blood Count (CBC) with Differential 
16. Acute Care Panel 
17. Mineral Panel 
18. Hepatic Panel 
19. Urinalysis 
20. Tuberculosis (TB) test (PPD or Quantiferon testing) 
21. HIV Test 
22. Pregnancy Test for Women of Childbearing Potential (serum) (see Appendix 2) 
23. Research Blood Collection  


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1Participants who are allergic to fluorescein dye are exempt from this procedure. 
4.5 
Follow-up/Termination Procedures 
After Week 8, participants will no longer be able to receive investigational product under this 
protocol. Participants will be followed through Week 28. If the participant withdraws or terminates 
prior to Week 28, follow-up care will be arranged with an outside ophthalmologist or the 
participant may continue to be seen at the NIH under another protocol, if available and if the 
participant is eligible. The participants and their physicians, with written consent, will be informed 
of the participant’s disease status during this study. Clinical data obtained during participation will 
be shared with the participant and their private physicians (with written permission from the 
participant). Results from the overall study will be shared once the study team has analyzed the 
data from all participants. 
4.6 
Management of Samples and Data 
Research blood samples will be stored for this study. The samples will be coded and stored in 
secured freezers on the NIH campus. The clinical data will be stored in the NEI’s research database 
and The Emmes Company’s secured database. All individual data will remain confidential. 
Research blood samples may be stored for future use at the NEI as specified in the informed 
consent document. The participant has a choice to limit sample usage by selecting one of the 
following consent options: 
Your samples may be used for other research projects, including those not related to uveitis if 
you agree. Please initial on the line below that reflects your choice: 
______YES My samples and data may be used for other research projects including those not 
related to uveitis.    
______NO I do not want my samples and data used for other research projects.  
Please destroy my samples once this project is complete. 
4.7 
Data and Sample Sharing Plan 
If the participant is enrolled in other NEI protocols, identifiable data and samples may be shared 
with investigators across these studies to help minimize the need to repeat procedures if data and 
samples are already collected.  


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Samples and data, including genomic data, will be shared with other sites only after all 
requirements are met.  
Data and samples may also be shared with collaborating laboratories at NIH or outside of NIH 
and/or submitted to NIH-designated repositories and databases if consent for sharing was obtained. 
Repositories receiving data and/or samples from this protocol may be open-access or restricted 
access.  
Samples and data will be stripped of identifiers and may be coded (“de-identified”) or unlinked 
from an identifying code (“anonymized”). When coded data is shared, the key to the code will not 
be provided to collaborators, but will remain at NIH. Data and samples may be shared with 
investigators and institutions with an FWA or operating under the Declaration of Helsinki (DoH) 
and reported at the time of continuing review. Sharing with investigators without an FWA or not 
operating under the DoH will be submitted for prospective IRB approval. Submissions to  
NIH-sponsored or supported databases and repositories will be reported at the time of Continuing 
Review. Submission to non-NIH sponsored or supported databases and repositories will be 
submitted for prospective IRB approval. 
Required approvals from the collaborating institution will be obtained and materials will be 
shipped in accordance with NIH and federal regulations. 
4.8 
Study and Concomitant Therapies 
4.8.1 Ustekinumab Formulation 
Ustekinumab (STELARA®) for subcutaneous injection is supplied as a sterile solution in a single-
use, pre-filled syringe with a 27-gauge fixed ½-inch needle, or a single-use 2 mL Type I glass vial 
with a coated stopper. The pre-filled syringe formulation will be used for this study. The syringe 
is fitted with a passive needle guard and a needle cover that is manufactured using a dry natural 
rubber (a derivative of latex). 
Each pre-filled syringe contains 90 mg ustekinumab along with: L-histidine and L-histidine 
monohydrochloride monohydrate (1 mg), polysorbate 80 (0.04 mg) and sucrose (76 mg) to fill to 
a final volume of 1.0 mL. 


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Ustekinumab (STELARA®) for intravenous infusion is supplied as a single-dose 26 mL Type 1 
glass vial with a coated stopper. Each 26 mL vial contains 130 mg ustekinumab, ethylene diamine 
tetraacetic acid disodium salt dihydrate (0.52 mg), L-histidine (20 mg), L-histidine hydrochloride 
monohydrate (27 mg), L-methionine (10.4 mg), Polysorbate 80 (10.4 mg) and sucrose (2210 mg). 
The ustekinumab solution ranges from colorless to slightly yellow in appearance and has a pH of 
5.7 – 6.3. Ustekinumab does not contain preservatives. 
4.8.2 Ustekinumab Storage  
Ustekinumab pre-filled syringes and vials will be refrigerated at 2ºC to 8ºC (36ºF to 46ºF).  
The investigational product will remain in the original carton to protect it from light until the time 
of use and will not be frozen or shaken before use. Ustekinumab does not contain a preservative; 
therefore, any unused portions will be discarded following administration. 
4.8.3 Ustekinumab Preparation and Administration 
4.8.3.1 Subcutaneous Administration 
Prior to administration, the syringe must be visually inspected for particulate matter and 
discoloration. Ustekinumab ranges from colorless to light yellow and may contain a few small 
translucent or white particles. The investigational product must not be used if it is discolored or 
cloudy, or if other particulate matter is present (see Appendix 4 for administration instructions).  
The needle cover on the pre-filled syringe contains dry natural rubber (a derivative of latex).  
The needle cover must not be handled by study personnel sensitive to latex. Each injection will be 
administered at a different anatomic location than the previous injection (e.g., upper arms, thighs, 
or any quadrant of abdomen) and not into areas where the skin is tender, bruised, erythematous or 
indurated. 
4.8.3.2 Intravenous Administration 
The intravenous solution must be diluted and prepared prior to administration. The dose will be 
calculated based on the participant’s weight as described below. IV administration will be 
performed in the day hospital of the Clinical Center.  


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Body Weight of Patient at the time of 
dosing 
Dose 
Number of 130 mg/26 mL  
(5 mg/mL) STELARA® vials 
55 kg or less 
260 mg 
2 
More than 55 kg to 85 kg 
390 mg 
3 
More than 85 kg 
520 mg 
4 
Prior to preparing the dose, 20 mL of 0.9% Sodium Chloride, USP from a 250 mL bag will be 
drawn up and discarded. This is the estimated bag overfill volume. To prepare the dose, a volume 
of the 0.9% Sodium Chloride Injection, USP from the 250 mL infusion bag equal to the volume 
of investigational product to be added will be withdrawn and discarded (discard 26 mL sodium 
chloride for each vial of investigational product needed, for two vials, discard 52 mL, for three 
vials- discard 78 mL, four vials- discard 104 mL). Twenty-six (26) mL of the investigational 
product will be withdrawn from each vial needed and added to the 250 mL infusion bag. The final 
volume in the infusion bag should be 250 mL. 
The diluted solution must be visually inspected before infusion. The investigational product must 
not be used if visibly opaque particles, discoloration or foreign particles are observed.  
The diluted solution should be infused over a period of at least one hour. Once diluted, the infusion 
solution may be stored for up to four hours prior to infusion. Only an infusion set with an in-line, 
sterile, non-pyrogenic, low protein binding filter (pore size 0.2 micrometer) will be used. 
STELARA® will not be infused concomitantly in the same intravenous line with other agents. 
Any remaining solution will be discarded. 
4.8.4 Concomitant Therapy 
Participants will be allowed to remain on Prednisone at a maximum dose of 20 mg (if this was 
their existing regimen) and another nonbiologic immunomodulatory agent (e.g., MTX, 
azathioprine, 
cyclosporine, 
etc.). 
Tapering 
of 
topical 
treatments 
and 
systemic 
immunosuppressives, including steroids, if needed, may start after Week 16 if the disease is quiet 
(or anytime if medically indicated such as due to an intolerable side effect). An increase in 
immunosuppressive therapy in the first 16 weeks will only be done if there is significant vision 
loss (≥15 letters) from baseline due to worsening inflammation. Treatment for 
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4.8.5 Investigational Product Accountability 
The NIH Pharmacy is responsible for the accountability of all unused investigational product. 
Adequate investigational product accountability records include documentation of all 
investigational product shipped, received, stored and dispensed by the NIH Pharmacy.  
The investigator is responsible for the accountability of all used investigational product. Adequate 
investigational product accountability records include documentation of all investigational product 
administered by and disposed by the investigator. Used investigational product will be disposed in 
the hazardous waste disposal bins.  
5.0 
Risks/Discomforts 
5.1 
Examination Risks 
There are risks associated with the procedures required for participants in this study.  
However, these are all standard procedures that are performed as part of a normal eye and medical 
examination, except for the ustekinumab injections and the research blood collection. Some of the 
discomforts associated with the ocular examination include the following: 
1. Dilating drops or anesthetic drops may sting. They can cause an allergic reaction, or if 
contaminated, can cause an infection, but neither of these problems is very likely to occur. 
Dilating drops can also cause a sudden increase of pressure (acute glaucoma) in eyes that 
are already predisposed to develop this condition. There is little risk of glaucoma being 
triggered in this way, but if it is, treatment is available. The participant’s IOP will be 
obtained at each ophthalmic examination to determine whether there is an increased risk 
of developing glaucoma. 
2. Color fundus photographs involve a bright flash to take pictures of the retina. This brief 
flash may cause temporary discomfort but does not damage the eye. 
3. In rare instances, the cornea may be scratched during measurement of IOP or use of a 
funduscopic contact lens. A corneal abrasion of this sort may be painful, but it heals quickly 
with no lasting effects. 
4. The fluorescein dye used in fluorescein angiography can make a participant’s skin turn 
yellow for several hours. This yellow color is transient and usually disappears in one day. 
Because the dye undergoes renal excretion, the participant’s urine will turn dark orange for 


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up to 24 hours after the examination. The study team will educate the participant regarding 
this urine color change. Some participants may be slightly nauseated during the 
examination, but their nausea usually lasts only a few seconds. If the dye extravasates 
during the injection, the skin around the injection site may feel mildly uncomfortable or 
become yellow. The discomfort usually lasts only a few minutes, and the yellow color fades 
in a few days. There is a chance of ecchymosis at the site of injection and a remote 
possibility of cellulitis from the needle track. In rare cases, participants may have an 
allergic reaction to the dye. Treatment typically consists of an oral antihistamine 
medication, but may require intravenous antihistamine administration if the symptoms are 
severe. Very rarely a participant experiences anaphylaxis. This would be treated 
immediately by trained personnel with medications or, if necessary, intubation. 
Possible discomforts associated with non-ocular examinations include: 
1. Blood draws can cause discomfort and bleeding/bruising at the site of venous puncture. 
There is a remote risk of fainting or local infection. If any of these discomforts arise, they 
will be treated. 
5.2 
Ustekinumab Risks 
5.2.1 Administration-related Risks 
There is minimal risk associated with subcutaneous injections. Common risks include bruising, 
itching, swelling, irritation, transient pain or injection site redness and, very rarely, injection site 
infection. In trials with ustekinumab, injection site reactions occurred in approximately 1% of 
patients receiving ustekinumab injections and 0.4% of patients receiving placebo injections. 
There is minimal medical risk associated with intravenous infusions. Common risks include 
discomfort and bruising from the needle insertion. The risks of an intravenous catheter include 
bleeding, infection, or inflammation of the skin and/or vein.  
5.2.2 Ustekinumab-related Risks 
Ustekinumab may increase the risk of infections and reactivation of latent infections, including 
serious bacterial, fungal and viral infections. Serious infections include cellulitis, diverticulitis, 
osteomyelitis, viral infections, gastroenteritis, pneumonia and urinary tract infections.  
Serious infections from mycobacteria, Salmonella and BCG vaccinations have been reported in 


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patients genetically deficient in IL-12/IL-23. Because of a risk of worsening a latent infection such 
as TB, all participants will be monitored for TB prior to enrollment.  
Participants being treated with ustekinumab should not receive live vaccines. BCG vaccines should 
not be given during treatment with ustekinumab or for one year prior to initiating treatment or one 
year following discontinuation of treatment. Caution is advised when administering live vaccines 
to household contacts of participants receiving ustekinumab because of the potential risk for 
shedding from the household contact and transmission to participant. Non-live vaccinations 
received during a course of ustekinumab may not elicit an immune response sufficient to prevent 
disease. 
Because ustekinumab is an immunosuppressant it may increase the risk of malignancy.  
Although rare, anaphylaxis or serious allergic reactions may occur. The infusion can be preceded 
by pretreatment with Benadryl, Tylenol and IV solumedrol to minimize infusion reactions.  
In participants who demonstrate allergic reaction to the first dose, the second dose may be 
administered as IV infusion with pre-infusion desensitization instead of subcutaneous injection as 
it allows better control on the rate of drug administration. Although extremely rare, there is a risk 
of reversible posterior leukoencephalopathy syndrome (RPLS), as one case was reported. RPLS 
can present with headache, seizures, confusion and visual disturbances. Other risks include upper 
respiratory infections, headache and tiredness. 
In the placebo-controlled clinical studies of psoriasis patients, subject-reported infection rate was 
1.39 per subject-year of follow-up in the ustekinumab-treated group, compared with 1.21 per 
subject-year of follow-up in the placebo-treated group. Serious infections occurred in 0.3% of 
ustekinumab-treated patients (0.01 per subject-year of follow-up) and in 0.4% of placebo-treated 
patients (0.02 per subject-year of follow-up). Serious infections were reported in 0.9% of patients 
(0.01 per subject-year of follow-up).9 
More than 3,000 psoriasis patients have used ustekinumab, including 2,414 exposed for at least 
six months, 1,855 exposed for at least one year, 1,653 exposed for at least two years,  
1,569 exposed for at least three years, 1,482 exposed for at least four years and 838 exposed for at 
least five years.9 Safety data available from these patients are illustrated below.  
Adverse reactions that occurred at a rate of at least 1% and at a higher rate in the ustekinumab-


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treated groups than the placebo-treated groups during the placebo-controlled studies (PHOENIX 
1 and 2) are shown below: 
 
The most common adverse events were nasopharyngitis, upper respiratory tract infection, 
headache and fatigue. Adverse drug reactions that occurred at rates less than 1% included: 
cellulitis, and certain injection site reactions (pain, swelling, pruritus, induration, hemorrhage, 
bruising and irritation). 
Adverse reactions occurring in ≥3% of STELARA®-treated patients and higher than placebo 
during the placebo-controlled CD studies (CD-1 and CD-2) are shown below. Overall, the safety 
profile of STELARA® was consistent with the safety profile seen in the adult psoriasis and 
psoriatic arthritis clinical studies.  
Common adverse reactions through Week 8 in Studies CD-1 and CD-2occurring in ≥3% of 
STELARA®-treated patients and higher than placebo: 
 


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Other less common adverse reactions reported in patients in Studies CD-1 and CD-2 included 
asthenia (1% vs 0.4%), acne (1% vs 0.4%), and pruritus (2% vs 0.4%). 
Common adverse reactions through Week 44 in Study CD-3 occurring in ≥3% of STELARA®-
treated patients and higher than placebo: 
 
In CD trials the incidence of hypersensitivity reaction was encountered in two patients, one 
following SC administration and one following IV administration (0.1% among SC dosing and 
0.08% among IV dosing). Immunogenicity to ustekinumab (antibodies against ustekinumab) was 
less common in CD Trials (<3%) than was observed in Psoriasis trials (6-12%). Rate of incident 
non-melanoma skin cancers were similar between placebo and STELARA® treated CD patients 
(0.2%). All other malignancies occurred in 0.2% of STELARA® treated patients (0.27 events per 
100 patient years). In CD studies, immunomodulators (6-mercaptopurine, azathioprine, 
methotrexate) were used concomitantly in approximately 30% of patients and corticosteroids were 
used concomitantly in approximately 40% of patients. Use of these concomitant therapies did not 
appear to influence the overall safety or efficacy of STELARA®.9 
6.0 
Participant Monitoring 
Participants will be monitored during all study visits for adverse events by the study investigators.  
6.1 
Withdrawal Criteria 
Participants may choose to withdraw from this study for any reason at any time without penalty, 
without loss of benefits or prohibition from enrolling in other clinical protocols. Reasons for 
participant discontinuation may include, but are not limited to, the following: 


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 Investigator determination that study continuation is not in the best medical interest of the 
participant; 
 Findings in the course of the trial that may affect willingness to participate; 
 Participant requires additional medicines or intravitreal injections that will interfere with 
the investigational product; 
 Serious suspected adverse reaction; 
 Participant requires ocular surgery which cannot safely be postponed until the end of the 
study; 
 Any other safety concerns; 
 Inability to keep study visits or to comply with study requirements. 
Study staff will request participants complete the study even if they are discontinued from the 
investigational product. Otherwise, the participant will exit the study and continue his/her 
ophthalmic care either with an outside ophthalmologist or at the NEI. The participant will be 
monitored by study investigators and clinical staff at each visit to the clinic. 
6.2 
Pregnancy Monitoring 
If the staff becomes aware that a female study participant became pregnant during the study, the 
investigator will advise the participant that they will no longer receive the investigational product. 
The investigator and participant will determine whether to continue any remaining study visits or 
to exit the study.  
If the staff becomes aware that a male study participant impregnates his partner during the study, 
the investigator will remind the participant of the potential risks to the unborn fetus.  
In either case of reported pregnancy, participant will be referred to the NIH OB/GYN consultation 
service for evaluation and counseling. The investigator must follow the participant (or partner) 
until the pregnancy outcome. 
7.0 
Outcome Measures 
7.1 
Primary Outcome 
The primary outcome for each cohort is the number of participants who experience a treatment 
response (as defined in Appendix 1) by Week 16. 


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7.2 
Secondary Outcomes 
The secondary outcomes include the following, as relevant to baseline: 
 Mean and median change in visual acuity via EVA at all follow-up visits; 
 Number of participants who experience a recurrence (as defined in Appendix 1);  
 Mean and median number of days following the baseline injection until first recurrence (of 
the participants who recur); 
 Presence or extent of macular edema as determined by OCT and FA at all follow-up visits; 
 Amount of retino-vascular leakage as measured by FA at all follow-up visits; 
 Changes in retinal thickening as measured by OCT at all follow-up visits; 
 Length of time to quiescence; 
 Ability to taper concomitant immunosuppressive medications. 
7.3 
Safety Outcomes 
Safety outcomes include: 
 Number and severity of systemic and ocular toxicities and adverse events; 
 Proportion of participants with loss of ≥15 letters at any follow-up visit; 
 Number of participants experiencing a clinically significant increase in elevated IOP at any 
follow-up visit. A change ≥10 mmHg as compared with baseline is considered a clinically 
significant increase. 
7.4 
Exploratory Outcomes 
Participant serum and lymphocytes will be analyzed for soluble cytokines, exosomes and 
intracellular immune markers as well as RNA-Seq before and after therapy at regular time points. 
Lymphocyte proliferation prior to and following treatment will be assessed. The changes in 
epigenetic modification following treatment will also be assessed. 
8.0 
Statistical Analysis 
The primary efficacy analyses will include all participants who receive ustekinumab and complete 
the Week 16 visit. The secondary and safety analyses will include all participants who receive 
ustekinumab and complete the Week 16 visit. 


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8.1 
Study Design and Primary Analysis 
In this prospective, non-randomized, uncontrolled, single-center, two-arm pilot study, analyses 
will be primarily descriptive and by participant. As the small sample size does not lend itself to 
formal statistical analyses, no formal statistical hypothesis tests will be performed. Slit lamp 
examination will be evaluated at each scheduled visit, with the primary outcome defined as the 
number of participants who experience a treatment response by Week 16. Treatment response is 
defined as (all of the below for both/eligible eyes): 
 No active inflammatory chorioretinal lesion and/or absent or decreased retinal vascular 
leakage  
 ≤ 0.5+ anterior chamber (AC) cells (SUN criteria)  
 ≤ 0.5+ vitreous haze (VH; National Eye Institute [NEI]/SUN criteria) 
8.2 
Analysis of Secondary Outcomes 
In general, secondary outcomes will be monitored throughout the study period in both the study 
and non-study eyes. The mean and median change in visual acuity via EVA and number of days 
until first recurrence will be calculated at all follow-up visits. The number of participants who 
experience a recurrence (as defined in Appendix 1), the presence or extent of macular edema as 
determined by OCT and FA, the amount of retino-vascular leakage as measured by FA, changes 
in retinal thickening as measured by OCT, length of time to quiescence and ability to taper 
concomitant immunosuppressive medications will be tabulated by participant at all follow-up 
visits. 
Safety outcomes, including the number and severity of systemic and ocular toxicities and adverse 
events, will be tabulated by severity, type and assessed relatedness to the study therapy throughout 
the study period. 
8.3 
Sample Size/Accrual Rate 
For the first cohort, the accrual goal is to have four participants receive three ustekinumab 
injections and complete at least 12 weeks of follow-up. For the second cohort, the accrual goal is 
to have four participants receive the high induction dose via IV, followed by one subcutaneous 
injection and complete at least 12 weeks of follow-up. These are appropriate sample sizes for the 


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study objectives, since this preliminary investigation will not attempt to definitively determine the 
safety or efficacy of this treatment.   
9.0 
Human Subjects Protection 
9.1 
Equitability 
Accrual for this study will be equitable among patients with uveitis meeting the enrollment criteria.  
9.1.1 Justification for the Exclusion of Children 
Children are not eligible for this study due to the lack of safety information for ustekinumab 
injection in children. 
9.1.2 Justification for the Exclusion of Pregnant or Lactating Women 
Pregnant or lactating women are excluded because of the unknown effects of ustekinumab 
injection on the fetus or nursing baby.  
9.1.3 Justification for Exclusion of Persons Who Cannot Consent 
Adults unable to understand and sign an informed consent are excluded from this study because 
they are frequently unable to cooperate with evaluation and testing in the manner standardized for 
other adult participants. The research question can be answered by enrolling only adults who can 
provide their own consent and there is no direct clinical benefit for the participant. Thus, the risks 
will outweigh the benefit for this population. 
10.0 
Consent Documents and Process 
Study investigators with consenting privileges will obtain informed consent. All participants will 
receive a verbal explanation in terms suited to their comprehension of the purposes, procedures 
and potential risks of the study. Participants must have the ability to understand and sign an 
informed consent form, which must be signed prior to enrollment. Participants will have the 
opportunity to carefully review the consent and ask questions regarding this study prior to signing, 
and they will be informed that they may withdraw from the study at any time without prejudice to 
themselves or benefits lost. 
If a participant requires the consent to be in larger font in order to read it well, this will be provided. 
If a participant is visually impaired to the point of being unable to read the consent, s/he can take 


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the consent home to read it over with a family member or with the use of magnifying devices. If a 
participant chooses, the investigator can also read the consent verbatim to the participant and 
answer any questions that may arise.  
Because ustekinumab is commercially-available, participants must be given a current copy of the 
STELARA® Medication Guide, which describes both subcutaneous and intravenous medication 
and associated risks in further detail. The Medication Guide will be reviewed with the participant 
along with the informed consent for this study. 
An investigator present during the consent process will document the consent process in the 
participant’s medical record. A copy of the signed informed consent form will be provided to the 
participant to take home. 
11.0 
Data and Safety Monitoring 
The NEI Serious Adverse Event (SAE) Review Committee is responsible for monitoring data and 
safety and will exercise oversight of the clinical investigation independently from the study 
investigators. 
11.1 
Coordinating Center 
The Emmes Company, LLC (Emmes) has been assigned as the coordinating center for this trial to 
conduct data collection, protocol monitoring, data analysis and reporting. The coordinating center 
provides routine monitoring of study participants’ data. Monitoring visits will occur on a schedule 
depending on the status of the study. More frequent monitoring visits will be performed at the 
beginning of the study when enrollment is open. Monitoring will decrease as enrollment closes 
and as participant follow-up continues.  
Although Emmes advises the NEI Clinical Director and Principal Investigator (PI) on data and 
statistical activities, the coordinating center staff does not have direct access to or interaction with 
participants.  
11.2 
NEI Serious Adverse Event Review Committee 
The NEI SAE Review Committee, which consists of the NEI Clinical Director and three other NEI 
physicians, will be responsible for reviewing any reported serious safety events, if they occur under 


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this protocol. The Committee will review accumulating data on a semiannual basis to determine 
whether the study should continue. If changes to the protocol are indicated, recommendations will 
be made to the NEI Director and IRB who will consider and act on such recommendations in a 
timely manner. Should any serious suspected adverse reactions occur, the NEI Clinical Director 
may, at his discretion, assemble the Review Committee before the scheduled date to consider 
whether the study should move forward. The Committee or Principal Investigator can stop the 
study at any time if it appears there are any unexpected serious suspected adverse reactions that 
would 
outweigh 
any 
potential 
benefits 
of 
treatment.  
In addition, if three or more participants experience non-serious suspected adverse reactions that 
require temporary or permanent cessation of the investigational product, the Principal Investigator 
shall report this to the NEI Clinical Director. The NEI Clinical Director may convene the Review 
Committee before the scheduled time to consider the cessation of the study as a whole. The NEI 
SAE Review Committee or IRB may recommend temporarily suspending, closing enrollment or 
stopping the study at any time due to safety concerns, demonstration of efficacy or lack of efficacy 
or slow recruitment. 
12.0 
Quality Assurance 
The NEI and Emmes maintain quality control by adhering to standard operating procedures  
(NEI QA program and NEIS standard operating procedures). These procedures cover the full 
protocol cycle beginning with staff credentialing and training, and protocol development and 
approval, through database development, data collection, monitoring and analysis, and finally 
manuscript preparation at the conclusion of the study. Data quality assurance is of the utmost 
importance to the NEI and Emmes. The two groups use a quality assurance system that relies on 
real-time data checks and reports throughout the course of a study to ensure the accuracy of 
information. This system is a secure and confidential data management system that stores data and 
provides quality assurance and reporting. Emmes has developed a number of routine reports 
specifically designed for monitors (e.g., listings of serious adverse events, etc.). 
Additionally, Emmes has developed summary reports of discrepancies, as well as reports of the 
exceptions databases, which include requests and reasons for exceptions. The results of the reports 
are communicated back to site staff, and, along with protocol compliance issues, to the NEI Serious 
Adverse Event Review Committee (if applicable).  


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Following the monitoring plan for this study, Emmes will perform monitoring activities, including 
on-site audits, review of database entries and the resolution of study issues. In addition to 
monitoring, Emmes performs various detailed automated and manual data quality checks.  
The results from these checks and any protocol compliance issues are communicated back to site 
staff and to the NEI Project Officer, NEI Clinical Director and applicable regulatory bodies. 
13.0 
Reportable Events 
Reportable events will be tracked and submitted to the IRB as outlined in Policy 801.  
14.0 
Alternative Therapies 
Alternatives to participation include continuation with the current standard-of-care, which includes 
the use of systemic steroids, periocular steroids and systemic immunosuppressive agents.  
As ustekinumab is commercially available, participants may be able to receive this drug from their 
physician for “off-label” use. 
15.0 
Privacy 
All research activities will be conducted in as private a setting as possible. 
16.0 
Confidentiality 
Blood samples will be stored for the purposes of this study. The samples will be coded and stored 
in secured freezers on the NIH campus. All medical records will be kept confidential and will only 
be reviewed by the participating investigators. Data will be kept in password-protected computers 
held at the NEI and the coordinating center. Only study investigators and authorized coordinating 
center staff will have access to the study data. The participants’ names will not appear on any of 
the data forms reported to the coordinating center. A unique identifier, without personally 
identifying information but linked to a code retained by the investigators, will be assigned to data 
if participant information is shared with the coordinating center for research purposes. The 
participants’ names will not appear in any publication of the study results. Participants’ personal 
information will be kept as private as possible. However, records can be inspected by organizations 
for quality assurance and data analysis. These include the members of the IRB, coordinating center 
and NEI Serious Adverse Event Review Committee. 


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17.0 
Conflict of Interest 
The NIH guidelines were distributed to all the investigators and none of the investigators had any 
conflicts of interest. 
18.0 
Technology Transfer 
There are no technology transfer agreements for this study. 
19.0 
Compensation 
For this study, there is no compensation for participation. This protocol does not include 
reimbursement for travel and subsistence. Participants needing financial assistance will be able to 
receive supplemental reimbursement based upon need. Requests for supplemental reimbursement 
will be evaluated on a case-by-case basis for valid financial and/or medical need through a 
standardized process. 


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20.0 
References 
1. Gritz DC, Wong IG. Incidence and prevalence of uveitis in Northern California; the 
Northern California Epidemiology of Uveitis Study. Ophthalmology. 2004 
Mar;111(3):491-500. 
2. Djalilian AR, Nussenblatt RB. Immunosuppression in uveitis. Ophthalmol Clin North 
Am. 2002 Sep;15(3):395-404, viii. 
3. Ref: Dick AD, Tundia N, Sorg R, Zhao C, Chao J, Joshi A, Skup M. Risk of Ocular 
Complications in Patients with Noninfectious Intermediate Uveitis, Posterior Uveitis, 
or 
Panuveitis. 
Ophthalmology. 
2016 
Mar;123(3):655-62. 
doi: 
10.1016/j.ophtha.2015.10.028. Epub 2015 Dec 19. PubMed PMID: 26712559. 
4. Luger D, Silver PB, Tang J, Cua D, Chen Z, Iwakura Y, Bowman EP, Sgambellone 
NM, Chan CC, Caspi RR. Either a Th17 or a Th1 effector response can drive 
autoimmunity: conditions of disease induction affect dominant effector category.  
J Exp Med. 2008 Apr 14;205(4):799-810. Epub 2008 Apr 7. PubMed PMID: 
18391061; PubMed Central PMCID: PMC2292220. 
5. Tarrant TK, Silver PB, Chan CC, Wiggert B, Caspi RR. Endogenous IL-12 is required 
for 
induction 
and 
expression 
of 
experimental 
autoimmune 
uveitis.  
J Immunol. 1998 Jul 1;161(1):122-7. PubMed PMID: 9647215. 
6. Yokoi H, Kato K, Kezuka T, Sakai J, Usui M, Yagita H, Okumura K. Prevention of 
experimental autoimmune uveoretinitis by monoclonal antibody to interleukin-12. Eur 
J Immunol. 1997 Mar;27(3):641-6. PubMed PMID: 9079803. 
7. Keino H, Watanabe T, Sato Y, Niikura M, Wada Y, Okada AA. Therapeutic effect of 
the potent IL-12/IL-23 inhibitor STA-5326 on experimental autoimmune uveoretinitis. 
Arthritis Res Ther. 2008;10(5):R122. Epub 2008 Oct 13. PubMed PMID: 18847496; 
PubMed Central PMCID: PMC2592812. 
8. King IL, Segal BM. Cutting edge: IL-12 induces CD4+CD25- T cell activation in the 
presence of T regulatory cells. J Immunol. 2005 Jul 15;175(2):641-5. PubMed PMID: 
16002658. 
9. Stelara™ Prescribing Information. ©Janssen Biotech, Inc., 2011. Horsham, PA 
10. Leonardi, C.L., Kimball, A.B., Papp, K.A., Yeilding, N., Guzzo, C., Wang, Y. et al. 
(2008) Efficacy and safety of ustekinumab, a human interleukin-12/23 monoclonal 
antibody, in patients with psoriasis: 76-week results from a randomized, double-blind, 
placebo-controlled trial (PHOENIX 1). Lancet 371: 1665_1674. 
11. Papp, K.A., Langley, R.G., Lebwohl, M., Krueger, G.G., Szapary, P., Yeilding, N. et 
al. (2008) Efficacy and safety of ustekinumab, a human interleukin-12/23 monoclonal 
antibody, in patients with psoriasis: 52-week results from a randomized, double-blind, 
placebo-controlled trial (PHOENIX 2). Lancet 371: 1675_1684. 
12. Scherl EJ, Kumar S, Warren RU. Review of the safety and efficacy of ustekinumab. 
Therap Adv Gastroenterol. 2010 Sep;3(5):321-8. PubMed PMID: 21180612; PubMed 
Central PMCID: PMC3002587. 


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13. Sandborn WJ, Feagan BG, Fedorak RN, Scherl E, Fleisher MR, Katz S, Johanns J, 
Blank M, Rutgeerts P; Ustekinumab Crohn’s Disease Study Group. A randomized trial 
of ustekinumab, a human interleukin-12/23 monoclonal antibody, in patients with 
moderate-to-severe Crohn’s disease. Gastroenterology. 2008 Oct;135(4):1130-41. 
Epub 2008 Jul 17. PubMed PMID: 18706417. 
14. Gottlieb A, Menter A, Mendelsohn A, Shen YK, Li S, Guzzo C, Fretzin S, Kunynetz 
R, Kavanaugh A. Ustekinumab, a human interleukin 12/23 monoclonal antibody, for 
psoriatic arthritis: randomized, double-blind, placebo-controlled, crossover trial. 
Lancet. 2009 Feb 21;373(9664):633-40. Epub 2009 Feb 11. Erratum in: Lancet. 2010 
Nov 6;376(9752):1542. Lancet. 2009 Apr 18;373(9672):1340. PubMed PMID: 
19217154. 
15. Poddubnyy D, Hermann KG, Callhoff J, Listing J, Sieper J. Ustekinumab for the 
treatment of patients with active ankylosing spondylitis: results of a 28-week, 
prospective, open-label, proof-of-concept study (TOPAS). Ann Rheum Dis. 2014 
May;73(5):817-23 doi: 10.1136/annrheumdis-2013-204248. Epub 2014 Jan 3. PubMed 
PMID: 24389297. 
16. Chang S, Chambers CJ, Liu FT, Armstrong AW. Successful treatment of psoriasis with 
ustekinumab in patients with multiple sclerosis. Dermatol Online J. 2105 Jul 15;21(7). 
Pii: 13030/qt3bs971cr. PMID: 26436967. 
17. Sandborn WJ, Feagan BG, Fedorak RN, Scherl E, Fleisher MR, Katz S, Johanns J, 
Blank M, Rutgeerts P; Ustekinumab Crohn's Disease Study Group. A randomized trial 
of Ustekinumab, a human interleukin-12/23 monoclonal antibody, in patients with 
moderate-to-severe Crohn's disease. Gastroenterology. 2008 Oct;135(4):1130-41doi: 
10.1053/j.gastro.2008.07.014. Epub 2008 Jul 17. PubMed PMID: 18706417. 
18. Donald JK, Nguyen TM, Khanna R, Timmer A. Anti-IL-12/23p40 antibodies for 
induction of remission in Crohn's disease. Cochrane Database Syst Rev. 2016 Nov 
25;11:CD007572. Review. PubMed PMID: 27885650. 
19. Teng MW, Bowman EP, McElwee JJ, Smyth MJ, Casanova JL, Cooper AM, Cua DJ. 
IL-12 and IL-23 cytokines: from discovery to targeted therapies for immune-mediated 
inflammatory diseases. Nat Med. 2015 Jul;21(7):719-29. 
20. Jabs DA, Nussenblatt RB, Rosenbaum JT; Standardization of Uveitis Nomenclature 
(SUN) Working Group. Standardization of uveitis nomenclature for reporting clinical 
data. Results of the First International Workshop. Am J of Ophthalmol 2005 
Sep;140(3):509-16. 
 
 


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Appendix 1: Definitions of Disease Activity 
 
Active disease is defined as: 
 +1 or more vitreous haze (according to SUN criteria18); and/or  
 Active chorioretinitis or leakage on FA (that is in more than one quadrant) that requires 
treatment. 
 
Recurrence is defined as presence of one of the following four parameters in at least one eye: 
1. New active inflammatory chorioretinal lesion and/or retinal vascular leakage.  
2. A 2+ increase in AC cells relative to Baseline (SUN criteria). This is represented by a 
change of Grade 0 to Grade 2+; or Grade 0.5+ to Grade 3+.  
3. A 2-step increase in vitreous haze relative to Baseline (NEI/SUN criteria). This is 
represented by a change of Grade 0 to Grade 2+; or Grade 0.5+ to Grade 3+.  
4. Worsening of BCVA by ≥ 15 letters (ETDRS) relative to Baseline. 
 
Treatment response is defined as (all of the below for both/eligible eyes):  
 No active inflammatory chorioretinal lesion and/or absent or decreased retinal vascular 
leakage  
 ≤ 0.5+ anterior chamber (AC) cells (SUN criteria)  
 ≤ 0.5+ vitreous haze (VH; National Eye Institute [NEI]/SUN criteria) 
 


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Appendix 2: Determining Childbearing Potential 
A female participant who is considered non-childbearing due to a medical condition  
(i.e., participant has previously undergone a hysterectomy) does not need a pregnancy test, 
Follicle-stimulating Hormone (FSH) test or contraception. 
If a female participant is considered non-childbearing due to menopause, it must be in accordance 
with 
the 
IRB/NIH 
Ob-Gyn 
guidance 
on 
the 
definition 
of 
menopause.  
This guidance defines menopause as: 
Women over age 55 who have not had a period for one year will be considered menopausal 
and do not need a pregnancy test, FSH test or contraception. 
Women between 50 and 55, who have not had a period for one year, should have an FSH test. 
If their FSH level is ≥ 20 mIU/mL, they will be considered menopausal and do not need 
pregnancy testing or contraception. If their FSH level is < 20 mIU/mL, they will need 
pregnancy testing and contraception as required by the protocol. 
Women between 45 and 50 who have not had a period for one year will need both an FSH test 
and a pregnancy test. If they are not pregnant and their FSH level is ≥ 20 mIU/mL, they will 
be considered menopausal and will not require contraception or additional pregnancy testing. 
If their FSH test is < 20 mIU/mL, they will need pregnancy testing and contraception as 
required by the protocol. 


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Appendix 3: Study Flowsheet 
Visit Schedule (Weeks)  
01 
4 
8 
12 
16 
282
Visit Number
000
004
008
012
016
028
Target Day from Baseline
0
28
56
84 
112
196
Visit Window (days) 
N/A  
5
5
14
14
14
Investigational Product 
 
 
 
 
 
Intravenous  
Ustekinumab*
X 
 
 
 
Primary 
outcome 
assessment
Safety 
visit 
Subcutaneous 
Ustekinumab** 
 
 
X 
 
General Assessments
Medical/Ophthalmic 
History
X 
 
 
 
 
 
Vaccination History3
X
X
X
X
X
X
Physical Examination 
X 
X 
X 
 
 
X 
Vital Signs
X
X
X
X
X
X
Concomitant Medications 
Assessment 
X 
X 
X 
X 
X 
X 
Adverse Event 
Assessment
X 
X 
X 
X 
X 
X 
Ophthalmic Assessments
BCVA (EVA)
X
X
X
X
X
X
Manifest Refraction4 
(MRx)
X 
X 
X 
X 
X 
X 
Slit Lamp Examination
X
X
X
X
X
X
Intraocular Pressure (IOP)
X 
X 
X 
X 
X 
X 
Dilated Fundus 
Examination
X 
X 
X 
X 
X 
X 
Color Fundus 
Photography
X6 
 
X 
X 
X 
X 
Fluorescein Angiogram5 
(FA)
X6 
 
X 
X 
X 
X 
Optical Coherence 
Tomography (OCT)
X6 
X 
X 
X 
X 
X 
Laboratory Assessments 
 
 
 
 
 
CBC with Differential
X7
X
X
X
Acute Care, Mineral and 
Hepatic Panels 
X7 
X 
X 
 
 
X 
Urinalysis
X7
X
X
X
TB Test (PPD or 
quantiferon testing)8
X 
 
 
 
 
 
HIV Testing7 
X
 
Pregnancy Testing 
(serum)9
X 
X 
X 
X 
X 
X 
Research Blood Collection
X
X
X
 
X
X
 
* Participants who enroll in the second cohort (subsequent to Amendment G) will receive one intravenous 
infusion at Week 0, followed by one subcutaneous injection at Week 8. In participants who demonstrate 


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allergic reaction to the first dose, the second dose may be administered as IV infusion with pre-infusion 
desensitization instead of subcutaneous injection as it allows better control on the rate of drug 
administration. 
** Participants who enrolled prior to Amendment G received subcutaneous injections at Weeks 0, 4  
and 8.  
1 All visits can be completed over one to three days. 
2 This visit represents the final safety visit. 
3 At each study visit, the participant will be asked whether they have received a live vaccine.  
The participant will be reminded to avoid live vaccines while on ustekinumab, including a reminder of 
the risks of infection from exposure to household members who receive a live vaccine. 
4 BCVA with manifest refraction must be performed when scheduled and when there is a change in visual 
acuity of  10 ETDRS letters ( 0.20 logMAR) from relevant baseline.  
5 Participants who are allergic to fluorescein dye are exempt from this procedure. 
6 These examinations can be performed within 7 days prior to enrollment under NIH protocols  
08-EI-0102, 16-EI-0134 or 16-EI-0046. 
7 These laboratory assessments can be performed within 14 days prior to enrollment under NIH protocols 
08-EI-0102, 16-EI-0134 or 16-EI-0046. 
8 Testing performed within three months prior to enrollment can be used to determine TB status. 
9 For women of childbearing potential only. 
 
 
 


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Appendix 4: Subcutaneous Injection Instructions 
 
Refer to the diagram below for the provided instructions.  
To prevent premature activation of the needle safety guard, do not touch the NEEDLE GUARD 
ACTIVATION CLIPS at any time during use.  
 
 
 
1. 
Hold the BODY and remove the NEEDLE COVER. Do not hold the PLUNGER 
or PLUNGER HEAD while removing the NEEDLE COVER or the 
PLUNGER may move. Do not use the prefilled syringe if it is dropped without 
the NEEDLE COVER in place.  
2. 
Inject ustekinumab subcutaneously.  
3. 
Inject all of the medication by pushing in the PLUNGER until the PLUNGER 
HEAD is completely between the needle guard wings. Injection of the entire 
prefilled syringe contents is necessary to activate the needle guard.  
 
 
 
 
4. 
After injection, maintain the pressure on the PLUNGER HEAD and remove the 
needle from the skin. Slowly take your thumb off the PLUNGER HEAD to allow 
the empty syringe to move up until the entire needle is covered by the needle guard, 
as shown by the illustration below:  


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5. 
Used syringes should be disposed of in the hazardous waste bin.  
 

SAP_001.pdf: 
Statistical Analysis Plan 
for 
A Pilot Study to Investigate Ustekinumab (STELARA®) for the Treatment of  
Active Sight-Threatening Uveitis 
 
NCT Number: NCT02911116 
 
Version 2.0 
November 20, 2020 
 
Prepared by  
Christiana Hawn 
 
 
 
Original Author Signature: 
 
__________________________________________ 
 
 
 
 
 
Christiana Hawn, MS, MPH 
 
Reviewer Signature:  
 
__________________________________________ 
 
 
 
 
 
Maria Abraham, ScM 
 
Principal Investigator Signature: 
__________________________________________ 
 
 
 
 
 
H. Nida Sen, MD, MHSc 
 
 
 


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LIST OF ABBREVIATIONS ............................................................................................................................ V 
1.0 
INTRODUCTION ............................................................................................................................. 1 
1.1 
Uveitis ............................................................................................................................................ 1 
1.2 
Ustekinumab ................................................................................................................................... 2 
2.0 
DATA SOURCE ............................................................................................................................... 3 
3.0 
GENERAL REVIEW OF STUDY DESIGN. ........................................................................................ 3 
3.1 
Study Design .................................................................................................................................. 3 
3.2 
Study Objective .............................................................................................................................. 4 
3.3 
Study Population ............................................................................................................................ 4 
3.3.1 
Participant Eligibility Criteria ................................................................................................. 4 
3.4 
Outcomes ........................................................................................................................................ 6 
3.4.1 
Primary Study Outcome .......................................................................................................... 6 
3.4.2 
Secondary Study Outcomes .................................................................................................... 6 
3.4.3 
Safety Outcomes ..................................................................................................................... 6 
3.4.4 
Exploratory Outcomes............................................................................................................. 7 
4.0 
STATISTICAL CONSIDERATIONS .................................................................................................. 7 
4.1 
Sample Size Calculation ................................................................................................................. 7 
4.2 
Analysis Population ........................................................................................................................ 7 
4.3 
Descriptive Statistics ...................................................................................................................... 8 
4.4 
Handling Duplicate Assessments ................................................................................................... 8 
4.5 
Handling of Missing Values ........................................................................................................... 8 
4.6 
Software for Analyses .................................................................................................................... 8 
5.0 
PARTICIPANT DISPOSITION .......................................................................................................... 8 
6.0 
PARTICIPANT CHARACTERISTICS ................................................................................................ 8 
6.1 
Participant Demographics .............................................................................................................. 9 
6.2 
Determination of Eligible Eyes ...................................................................................................... 9 
6.3 
Medical, Medication, and Ocular History ...................................................................................... 9 
7.0 
PARTICIPANT COMPLIANCE ......................................................................................................... 9 
7.1 
Protocol Deviations and Unanticipated Problems .......................................................................... 9 
7.1.1 
Study Procedure Deviations .................................................................................................. 10 
7.1.2 
Visit Schedule Deviations ..................................................................................................... 10 
7.2 
Premature Treatment and Study Withdrawals .............................................................................. 10 
8.0 
IP ADMINISTRATION ................................................................................................................... 11 
9.0 
PRIMARY OUTCOME ANALYSIS ................................................................................................. 11 
10.0 
SECONDARY OUTCOMES ANALYSIS ........................................................................................... 12 
10.1 Best-Corrected Visual Acuity (BCVA) ........................................................................................ 12 
10.2 Recurrence of Uveitis ................................................................................................................... 12 
10.3 Macular Edema ............................................................................................................................. 13 
10.4 Retino-vascular leakage ................................................................................................................ 13 
10.5 Changes in Retinal Thickening .................................................................................................... 13 
10.6 Length of Time to Quiescence ..................................................................................................... 13 
10.7 Ability to Taper Concomitant Immunosuppressive Medications ................................................. 14 
11.0 
SAFETY OUTCOMES .................................................................................................................... 14 
11.1 Adverse Events (AEs) .................................................................................................................. 14 
11.2 Loss of  ≥ 15 Letters ..................................................................................................................... 14 
11.3 Intraocular Pressure (IOP) ............................................................................................................ 15 


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12.0 
EXPLORATORY OUTCOMES ........................................................................................................ 15 
13.0 
ADDITIONAL OPHTHALMIC ASSESSMENTS ............................................................................... 15 
14.0 
OTHER SAFETY ASSESSMENTS ................................................................................................... 15 
14.1 Withdrawal from IP due to Vision Loss, Adverse Events, and Treatment Failure ...................... 15 
14.2 Laboratory Assessments ............................................................................................................... 16 
14.3 Physical Examination ................................................................................................................... 16 
14.4 Vital Signs .................................................................................................................................... 16 
14.5 Vaccine Reminders ....................................................................................................................... 16 
14.6 Additional Safety Presentations ................................................................................................... 16 
15.0 
RATIONALE FOR ANY DEVIATIONS FROM PRE-SPECIFIED ANALYSIS PLAN .......................... 17 
16.0 
QUALITY ASSURANCE PLANS ..................................................................................................... 17 
17.0 
REFERENCES ............................................................................................................................... 18 
18.0 MOCK SHELLS .................................................................................................................................... 19 
 
 


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LIST OF TABLES 
Table 1. Participant Disposition .................................................................................................... 19 
Table 2. Summary of Participant Demographics .......................................................................... 20 
Table 3. Medical and Medication History .................................................................................... 21 
Table 4. Ocular History................................................................................................................. 22 
Table 5. Protocol Deviations and Unanticipated Problems .......................................................... 24 
Table 6. Study Procedure Deviations ............................................................................................ 25 
Table 7. Visit Schedule Deviations ............................................................................................... 26 
Table 8. Number of Participants Who Experienced Treatment Response .................................... 27 
Table 9. BCVA Total Letters Read over Time ............................................................................. 28 
Table 10. Number of Participants Who Experienced Recurrence of Uveitis ............................... 29 
Table 11. Days Until First Recurrence of Uveitis ......................................................................... 29 
Table 12. Summary of Retino-Vascular Leakage Over Time ...................................................... 30 
Table 13. Central Retinal Thickness over Time ........................................................................... 31 
Table 14. Length of Time to Quiescence (Days) .......................................................................... 31 
Table 15. Summary of Quiescence ............................................................................................... 32 
Table 16. Summary of Adverse Events ........................................................................................ 33 
Table 17. AEs by System Organ Class (SOC) and Preferred Term (PT) ..................................... 34 
Table 18. IOP over Time .............................................................................................................. 35 
Table 19. Summary of Anterior Chamber Cells ........................................................................... 36 
Table 20. Summary of Anterior Chamber Flare ........................................................................... 37 
Table 21. Summary of Vitreous Cells........................................................................................... 38 
Table 22. Summary of Vitreous Haze........................................................................................... 39 
Table 23. Summary of Chorioretinal Assessments and FA Leakage ........................................... 40 
Table 24. Summary of Laboratory Assessments .......................................................................... 41 
Table 25. Summary of Physical Exam Findings ........................................................................... 41 
Table 26. Blood Pressure Summary.............................................................................................. 42 
Table 27. Temperature Summary ................................................................................................. 43 
 
LIST OF LISTINGS 
Listing 1. Treatment Response Criteria ........................................................................................ 44 
Listing 2. BCVA Total Letters Read Over Time .......................................................................... 45 
Listing 3. Recurrence of Uveitis ................................................................................................... 46 
Listing 4. Retino-Vascular Leakage ............................................................................................. 47 
Listing 5. Central Retinal Thickness on OCT Over Time ............................................................ 48 
Listing 6. Quiescence .................................................................................................................... 49 
Listing 7. Steroid Tapering ........................................................................................................... 50 
 
LIST OF FIGURES 
Figure 1. Study Disposition .......................................................................................................... 51 
Figure 2. BCVA Total Letters Read Over Time ........................................................................... 52 
Figure 3. Central Retinal Thickness Over Time ........................................................................... 52 
 
 


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VERSION HISTORY 
Version/Date 
Changes 
1.0/30JAN2020
Initial Document  
2.0/10NOV2020 
Sections 3.4.3: Updated other safety outcomes to clarify that laboratory assessments 
will include clinically significant changes from baseline and physical exams will 
include significant findings as well as vital signs; 
Section 4.2: Specified that additional ophthalmic assessments will be presented for the 
safety population; 
Section 6.2: Indicated that eligible eyes will be determined based on eye-specific 
inclusion criteria and presented by participant in a listing. 
Section 7.1:  Updated per NIH Intramural Research Program Policy 801 and indicated 
that protocol deviations and unanticipated problems will be summarized by cohort and 
overall;  
Section 7.1.1, 7.1.2, 10.4: Indicated that information will be presented by cohort and 
overall; 
Section 9.0: Clarified that participants will be considered treatment responders if all 
eligible eyes met the definition for treatment response.   
Section 9.0, 10.0, and 11.0: Clarified that listings will include data from all enrolled 
participants. 
Section 9.0 and 10.2: Indicated that information will be presented for each eye. 
Section 10.1: Added boxplots presenting distribution of best-corrected visual acuity in 
each cohort at each visit  
Section 10.5: Added boxplots presenting distribution of central retinal thickness in 
each cohort at each visit 
Section 10.6: Added table summarizing number of participants experiencing 
quiescence  
Section 13.0: Indicated that additional ophthalmic assessments will be summarized by 
cohort and overall and based on the safety population  
Section 14.3: Specified that reported medications will be included in listing of 
physical examination findings  
Section 14.4: Added summaries for blood pressure and temperature and indicated that 
height and weight will also be included in vital signs listing  
Section 14.5: Indicated that responses to the vaccine reminder question from each visit 
will be presented by participant in a listing.  
Section 14.6: Indicated that additional safety presentations will include presentations 
for primary, secondary, and safety outcomes for all participants who received at least 
one dose of ustekinumab. 
Section 18.0: Made applicable corresponding updates described above to mock shells. 
 
 
 
 
 


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LIST OF ABBREVIATIONS 
> 
Greater Than or Equal To 
AC
Anterior chamber
BCVA 
Best-corrected visual acuity 
CBC 
Complete blood count 
CC 
Clinical Center 
CD 
Crohn’s Disease 
EAU 
Experimental autoimmune uveitis 
ETDRS 
Early Treatment Diabetic Retinopathy Study 
EVA 
Electronic visual acuity 
FA 
Fluorescein angiography 
FDA 
Food and Drug Administration 
HIV 
Human Immunodeficiency virus 
IFN 
Interferon gamma 
IL 
Interlukein 
IOP 
Intraocular pressure 
IRB 
Institutional Review Board 
IV
Intravenous
mL 
Milliliter 
MTX 
Methotrexate 
NEI 
National Eye Institute 
NIH 
National Institutes of Health 
NIMH 
National Institute of Mental Health 
NLM 
National Library of Medicine 
NSAIDS 
Nonsteroidal anti-inflammatory drugs 
OCT 
Optical coherence tomography 
PPD 
Purified protein derivative 
PI 
Principal Investigator 
RCT
Randomized clinical trial
SAE 
Serious Adverse Event 
SC
Subcutaneous
SOP 
Standard operating procedure 
SUN 
Standard of Uveitis Nomenclature 
TB 
Tuberculosis 
TNF-alpha 
Tumor necrosis factor alpha 
VEGF 
Vascular endothelial growth factor 
 
 


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1.0 
INTRODUCTION 
This statistical analysis plan (SAP) provides the proposed analyses for the protocol “A Pilot Study 
to Investigate Ustekinumab (STELARA®) for the Treatment of Active Sight-Threatening Uveitis” 
(STAR). This document has 18 sections: (1) background of the study, (2) data sources for analyses, 
(3) an overview of the study design, (4) statistical considerations, (5) participant disposition,  
(6) participant characteristics, (7) participant compliance, (8) treatment administration,  
(9) statistical analysis for primary outcome, (10) statistical analyses for secondary outcomes,  
(11) analysis of safety outcomes, (12) exploratory analyses, (13) additional ophthalmic 
assessments, (14) other safety assessments, (15) rationale for any deviations from this SAP, (16) 
quality assurance plans, (17) references, and (18) mock shells for proposed tables, figures, and 
listings. This document is based on version 10.0 of this protocol dated September 18, 2019. Any 
deviation from this SAP, not outlined in Section 15.0, will be described and justified in protocol 
amendments and/or in the final study report, as appropriate. 
1.1 
Uveitis 
Uveitis, an inflammatory condition that affects the uvea (iris, ciliary body and choroid) and 
adjacent structures of the eyes, is an important cause of visual loss in both adults and children.  
A recent study in Northern California suggests that the incidence and prevalence of uveitis is three 
times what was previously thought, at 52/100,000 and 115/100,000 respectively.1,2 It is believed 
that approximately 100,000 American citizens currently require the use of systemic corticosteroids 
or other immunosuppressive agents as treatment for ocular inflammation. It is particularly common 
to use immunosuppressive or immunomodulatory therapy for the treatment of posterior segment 
uveitis (intermediate, posterior or panuveitis), which are considered to be more likely to be sight 
threatening.3 Management and prevention of the iatrogenic complications of immunosuppressive 
therapy accounts for most of the medical resources devoted to these individuals.2 
Uveitis is a predominantly T-cell mediated immune disease, and drugs like cyclosporine targeted 
primarily at T-cells have demonstrated efficacy.4 The dominant role of T-cells in the pathogenesis 
of uveitis is also observed in the experimental animal models of uveitis. Both Th1 and Th17 
pathways are believed to drive inflammation in uveitis.4 IL-12 and IL-23 are crucial parts of Th1 
and Th17 pathways which have been implicated in autoimmune disorders including uveitis.  
IL-12, a heterodimer of p40 and p35 subunits, induces CD4+ differentiation into Th1 cells which 


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produce interferon (IFN)-gamma and mediates cellular immunity. IL-23, also a heterodimer with 
p40 and p19 subunits, induces naïve CD4 cells to differentiate into Th17 cells which produce  
IL-17, IL-6 and tumor necrosis factor alpha (TNF-alpha) and similarly mediate cellular immunity. 
In addition, IL-12 and IL-23 each play an important role in the expression of experimental model 
of uveitis (EAU).4,5 Anti-IL-12 administration in experimental uveitis models not only prevented 
the development of disease and pathogenic Th1 cells, but also induced suppressive Th2 cells.6 
Keino et. al. showed that oral administration of a potent IL-12/IL-23 inhibitor abrogated 
inflammation in an EAU both in afferent and efferent phases of the disease. They also found that 
IL-12/23 inhibitor administration also reduced the expansion of IL-17 producing cells.7 
Ustekinumab, by targeting the p40 subunit shared by both IL-12 and IL-23, offers a novel 
mechanism of action; it prevents IL-12/23 interaction with their receptors and blocks signaling 
through the IL-12β1 receptor, cell differentiation and cytokine production. IL-12 is also believed 
to be responsible for CD4+ cells escaping suppressor effects of regulatory T-cells (Tregs).8 It is 
possible that IL-12/23 blockage may, in addition to inhibiting Th1 and Th17, also help expand 
regulatory T-cells through multiple mechanisms. 
1.2 
Ustekinumab 
Ustekinumab is a human IL-12 and -23 antagonist and is currently approved by the FDA for the 
treatment of adult patients (18 years or older) with moderate to severe plaque psoriasis who are 
candidates for phototherapy or systemic therapy. Ustekinumab is administered by subcutaneous 
(SC) injection. For patients weighing <100 kg (220 lbs), the recommended dose is 45 mg initially 
and four weeks later, followed by 45 mg every 12 weeks. For patients weighing >100 kg (220 lbs), 
the recommended dose is 90 mg initially and four weeks later, followed by 90 mg every 12 weeks.  
More recently, STELARA® is approved for moderate to severely active Crohn’s disease. 
STELARA® is used for induction in intravenous (IV) infusion form at doses up to 520 mg/infusion 
(4 vials) for one infusion (at 6 mg/kg/infusion), followed by a single, SC 90 mg dose eight weeks 
after, and, for maintenance, a SC 90 mg dose every eight weeks thereafter. 
Thousands of patients world-wide are treated for autoimmune disorders with various types of 
immunosuppressive and cytotoxic agents. 
Less toxic, more 
specific, or targeted 
immunosuppressive modalities are constantly being sought. Attempts to decrease morbidity, or 
reduce the dose of more toxic immunosuppressive drugs, or reduce the frequency or severity of 


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episodes of recurrence are clearly all important goals. Although previous clinical trials have not 
generated specific evidence, the involvement of IL-23 and IL-12 in the pathophysiology of uveitis 
and other autoimmune diseases known to be associated with uveitis and the clinical evidence from 
autoimmune diseases where ustekinumab has been used successfully suggests that ustekinumab 
could be a potential treatment for uveitis.9  
2.0 
DATA SOURCE 
Data will be received from the National Eye Institute (NEI) via their electronic data capture system 
(EMR), which will then be uploaded on a daily basis to the Coordinating Center’s database. 
3.0 
GENERAL REVIEW OF STUDY DESIGN 
3.1 
Study Design 
The STAR study is a prospective, non-randomized, uncontrolled, single-center, two-arm pilot 
study to evaluate ustekinumab as a possible treatment for active intermediate uveitis, posterior 
uveitis or panuveitis. The first cohort will receive a 90 mg SC injection of ustekinumab at Baseline, 
Week 4 and Week 8. The second cohort will receive an initial high, weight-based dose of 
ustekinumab via IV infusion at the baseline visit, followed by a single, 90 mg SC injection of 
ustekinumab at Week 8. In second cohort participants who demonstrate allergic reaction to the 
first IV dose, the second dose can also be administered as IV infusion with pre-infusion 
desensitization instead of an SC injection as it allows better control on the rate of drug 
administration.  
In both cohorts, participants will continue in the study for a total of 28 weeks, with follow-up visits 
monthly until Week 16 and a final safety visit at Week 28. Participants who experience recurrence 
(or those that are non-responders) by Week 16 can receive standard of care. Participants may 
continue to receive ustekinumab through Week 8 unless there is a medical contraindication 
(e.g., severe infection or severe allergic reaction). Participants will be instructed to contact the 
study investigators and return to the clinic as soon as possible for evaluation upon experiencing 
any symptoms of flare-up. Such symptoms include blurred vision, decreased visual acuity, floaters, 
pain, redness, irritation or photophobia.  


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3.2 
Study Objective 
The study objective is to investigate the safety, tolerability and potential efficacy of ustekinumab 
as a possible treatment for active intermediate uveitis, posterior uveitis or panuveitis.  
3.3 
Study Population 
The first cohort will consist of five participants with active intermediate uveitis, posterior uveitis 
or panuveitis who meet the eligibility criteria. The second cohort will include up to four 
participants with active intermediate uveitis, posterior uveitis or panuveitis who meet the eligibility 
criteria. Up to eleven participants may be enrolled, as up to two additional participants may be 
accrued in the second cohort to account for participants who withdraw from the study prior to 
Week 16. 
3.3.1 Participant Eligibility Criteria  
To be eligible, participants must meet all the inclusion criteria, when applicable, and none of the 
exclusion criteria.  
3.3.1.1 
Inclusion Criteria 
1. Participant has the ability to understand and sign the informed consent document. 
2. Participant is 18 years of age or older. 
3. Participant has negative purified protein derivative (PPD) or quantiferon testing done 
within three months prior to enrollment or had latent tuberculosis (TB) but has completed 
prophylactic anti-TB treatment. 
4. Participant has active intermediate uveitis, posterior uveitis or panuveitis in at least one eye 
requiring systemic therapy. Active disease is defined as: 
 +1 or more vitreous haze (according to Standardization of Uveitis Nomenclature 
(SUN) criteria10) AND/OR  
 Active chorioretinitis or leakage on fluorescein angiography (FA) (that is in more 
than one quadrant) that requires treatment. 
5. Participant has visual acuity in at least one eye of 20/400 or better. 
6. Participant is willing and able to comply with the study procedures. 


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7. Female participants of childbearing potential must not be pregnant or breast-feeding, have 
a negative pregnancy test at screening and must be willing to undergo pregnancy testing 
throughout the study.  
8. Both female participants of childbearing potential and male participants able to father a 
child must have (or have a partner who has) had a hysterectomy or vasectomy, be 
completely abstinent from intercourse or must agree to practice two effective methods of 
contraception throughout the course of the study and for six weeks after the last 
investigational product injection. Acceptable methods of contraception for this study 
include:  
 hormonal contraception (i.e., birth control pills, injected hormones, dermal patch 
or vaginal ring),  
 intrauterine device,  
 barrier methods (diaphragm, condom) with spermicide, or  
 surgical sterilization (tubal ligation). 
3.3.1.2 
Exclusion Criteria 
1. Participant has a significant active infection (an infection requiring treatment as determined 
by the medical team), including active TB or human immunodeficiency virus (HIV). 
2. Participant received a live vaccination within the past six weeks. 
3. Participant is expected to receive a live vaccination at any time during the study. 
4. Participant received the Bacillus Calmette-Guérin (BCG) vaccine within the past year.  
5. Participant is expected to receive the BCG vaccine at any time during the study or up to 
one year after discontinuing ustekinumab. 
6. Participant has a history of cancer (other than a non-melanoma skin cancer) diagnosed 
within the past five years. 
7. Participant has received intraocular (or periocular) steroid or anti-vascular endothelial 
growth factor (VEGF) injections within the last six weeks. 
8. Participant received rituximab within the last six months or another biologic agent (e.g., 
infliximab, daclizumab, adalimumab) within the last two months.  
9. Participant has received alkylating agents (e.g., cyclophosphamide, chlorambucil) within 
the last nine months. 
10. Participant has a known hypersensitivity to ustekinumab or any of its components. 


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3.3.1.3 
Choice of Study Eye  
Since this is a systemic treatment, a study eye selection does not apply. Any eye meeting the 
eligibility criteria will be considered in the primary outcome. All eyes will be considered in the 
remaining outcomes.   
3.4 
Outcomes 
3.4.1 Primary Study Outcome 
The primary outcome for each cohort is the number of participants who experience a treatment 
response by Week 16.  
3.4.2 Secondary Study Outcomes 
The secondary outcomes include the following, as relevant to baseline: 
 Mean and median change in visual acuity via electronic visual acuity (EVA) at all follow-
up visits; 
 Number of participants who experience a recurrence; 
 Mean and median number of days following the baseline injection until first recurrence (of 
the participants who recur); 
 Presence or extent of macular edema as determined by optical coherence tomography 
(OCT) and FA at all follow-up visits; 
 Amount of retino-vascular leakage as measured by FA at all follow-up visits; 
 Changes in retinal thickening as measured by OCT at all follow-up visits; 
 Length of time to quiescence; 
 Ability to taper concomitant immunosuppressive medications. 
3.4.3 Safety Outcomes 
Protocol-specified safety outcomes include: 
 Number and severity of systemic and ocular toxicities and adverse events (AEs); 
 Proportion of participants with loss of ≥15 letters at any follow-up visit; 
 Number of participants experiencing a clinically significant increase in elevated intraocular 
pressure (IOP) at any follow-up visit. A change ≥10 mmHg as compared with baseline is 
considered a clinically significant increase. 


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3.4.4 Exploratory Outcomes 
Participant serum and lymphocytes will be analyzed for soluble cytokines, exosomes, and 
intracellular immune markers as well as RNA-Seq before and after therapy at regular time points. 
Lymphocyte proliferation prior to and following treatment will be assessed. The changes in 
epigenetic modification following treatment will be addressed.  
4.0 
STATISTICAL CONSIDERATIONS 
4.1 
Sample Size Calculation  
The accrual goal is five participants in the first cohort and four participants in the second cohort, 
for a total of nine participants. Up to two additional participants may be accrued in the second 
cohort to account for participants who withdraw from the study prior to Week 16. No formal 
sample size calculation was conducted, since this pilot study will not attempt to definitively 
determine the safety or efficacy of this treatment. 
4.2 
Analysis Population 
The following analysis populations will be considered for this study: 
Enrolled population: Includes all participants enrolled in the study, regardless of compliance, 
follow-up, or treatment received. Participant disposition, characteristics, and compliance will be 
based on this population. 
Primary Analysis population: Includes all enrolled participants who received at least one dose of 
ustekinumab and completed the Week 16 visit. The primary, secondary, and safety analyses will 
be based on this population. 
Safety population: Includes all enrolled participants who receive at least one dose of ustekinumab. 
The additional ophthalmic assessments and safety parameters described in Sections 13.0 and 14.0 
will be based on this population. 


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4.3 
Descriptive Statistics 
For continuous parameters, descriptive statistics will include number of observations, mean, 
standard deviation, median, and range (minimum, maximum). For categorical parameters, 
frequency and percentage of participants will be summarized. 
4.4 
Handling Duplicate Assessments  
The assessments at each visit may be completed over multiple days. If participants completed 
assessments at both scheduled and supplementary visits, the assessments from the scheduled visit 
will be considered in the analysis and tabular summaries. However, if an assessment is completed 
only at supplementary visits, then the assessment from the most recent supplementary visit will be 
included in the analysis and tabular summaries. Results of all assessments, including those 
performed during supplementary visits, will be included in the listings.  
4.5 
Handling of Missing Values  
In general, missing observations will be excluded from analyses.  
4.6 
Software for Analyses 
Statistical analyses will be performed using SAS v9.4 or higher or R v3.6.1 or higher.  
All tables, listings and figures presented in the analysis will be created using either SAS v9.4 or 
Rv3.6.1 or higher. 
5.0 
PARTICIPANT DISPOSITION 
Participant disposition including the number of participants enrolled, received treatment at each 
visit, discontinued treatment early, terminated the study early, and completed the study will be 
summarized for each cohort and overall as in Table 1. A consort diagram showing participant flow 
will be included as in Figure 1. Reasons for treatment and study discontinuation will also be 
summarized in Table 1 and listed by participant (see Section 7.2). These presentations will be 
based on the enrolled population. 
6.0 
PARTICIPANT CHARACTERISTICS 
These presentations will be based on the enrolled population.  


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6.1 
Participant Demographics 
Demographic data including baseline age, gender, race and ethnicity will be summarized by cohort 
and overall (Table 2) and presented by participant.  
6.2 
Determination of Eligible Eyes 
Since this is a systemic treatment, a study eye selection does not apply. Any eye meeting the 
eligibility criteria will be considered in the outcomes. Eye eligibility will be determined based on 
the eye-specific items in the inclusion criteria. An eye must meet the criteria defined below to be 
eligible. 
o The eligible eye has active intermediate uveitis, posterior uveitis or panuveitis in at least 
one eye requiring systemic therapy. Active disease is defined as: 
 +1 or more vitreous haze (according to Standardization of Uveitis Nomenclature 
(SUN) criteria10) AND/OR  
 Active chorioretinitis or leakage on fluorescein angiography (FA) (that is in more 
than one quadrant) that requires treatment. 
o The eligible eye has visual acuity of 20/400 or better.  
Eligible eyes will be presented by participant in a listing.  
Only eligible eyes will be considered in the primary outcome analysis. All eyes, regardless of 
eligibility, will be considered in the remaining presentations. 
6.3 
Medical, Medication, and Ocular History 
History of medical and ophthalmic conditions and procedures and medication history will be 
summarized by cohort and overall (Tables 3 and 4) and presented by participant.  
7.0 
PARTICIPANT COMPLIANCE 
These presentations will be based on the enrolled population. 
7.1 
Protocol Deviations and Unanticipated Problems 
The total number of protocol deviations and unanticipated problems and the number and 
percentage of participants with deviations and unanticipated problems, will be summarized by 
cohort and overall as in Table 5.  


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Effective July 1, 2019, with the implementation of NIH Intramural Research Program Policy 801, 
protocol deviations and unanticipated problems are classified by the Investigator as major or minor 
at the time of data entry (as opposed to serious or not serious), and seriousness of major deviations 
and unanticipated problems is determined after review by the NIH Institutional Review Board 
(IRB). The type (minor, serious, not serious, or pending determination by IRB) and outcome of 
events will also be summarized (Table 5). Listings of participant-specific and non-participant-
specific protocol deviations and unanticipated problems will be presented. 
7.1.1 Study Procedure Deviations 
Table 6 presents the expected number of procedures, and number and percentage of procedures 
missed by participant, cohort, procedure, and cumulatively across all participants. Number of 
procedures missed is defined when a site reports a missed procedure or when the protocol monitors 
note missed procedures at a site and will be presented as a sum. Expected number of procedures 
is defined based on the study flowsheet and will also be presented as a sum. Percentage of 
procedures missed will be calculated as follows:  
%procedures missed = (Nprocedures missed / Nexpected procedures) * 100 
 
7.1.2 Visit Schedule Deviations 
The number of expected visits, number and percentage of missed visits, and number and 
percentage of out-of-window visits will be summarized by participant, cohort, and cumulatively 
across all participants as in Table 7. The percentage of missed and out of window study visits will 
be calculated as follows:  
%missed visits = (Nmissed visits / Nexpected visits) * 100 
 
%out of window visits = (Nout of window visits / Nexpected visits) * 100 
 
7.2 
Premature Treatment and Study Withdrawals 
Participants who withdrew from treatment and study early will be summarized as in Table 1 and 
listed separately along with reasons(s) for withdrawal.  


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8.0 
INVESTIGATIONAL PRODUCT (IP) ADMINISTRATION 
Details of ustekinumab administration will be presented by participant. The listings will include 
date of visit and associated visit number, location of injection or start/end time of infusion  
(as applicable), whether treatment was not administered or stopped before completion for any 
reason, and any complications experienced.  
9.0 
PRIMARY OUTCOME ANALYSIS 
The analysis of primary outcome will be exploratory and descriptive; no formal hypothesis testing 
will be performed. These presentations will be based on the primary analysis population; data from 
all enrolled participants will be included in the corresponding listings. 
Treatment response is defined in the protocol as (all of the below for both/eligible eyes):  
 No active inflammatory chorioretinal lesion and/or absent or decreased retinal vascular 
leakage  
 ≤ 0.5+ anterior chamber (AC) cells (SUN criteria)  
 ≤ 0.5+ vitreous haze (VH; NEI/SUN criteria) 
A participant is considered a treatment responder if all eligible eyes met the definition for treatment 
response.   
The definition of treatment response referencing the variables as specified in the case report forms 
will be as follows:  
At least one of the following criteria in each eligible eye: 
 No active inflammatory chorioretinal lesions    
 Absent retinal vascular lesion      
 Decreased retinal vascular lesions  
AND all of the following criteria in each eligible eye:  
 AC cells graded as 0, 0.5, or Trace 
 VH graded as Clear or Trace 


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Table 8 summarizes the number and percentage of participants who achieved the treatment 
response criteria in each all eligible eyes at each visit and cumulatively by Week 16, by cohort and 
overall.  
Treatment response by specific criteria and overall will be presented by participant as in Listing 1. 
10.0 SECONDARY OUTCOMES ANALYSIS 
These presentations will be based on the primary analysis population; data from all enrolled 
participants will be included in the corresponding listings. 
10.1 
Best-Corrected Visual Acuity (BCVA) 
BCVA with manifest refraction is assessed at baseline and all follow-up visits in both/eligible 
eyes. Total letters read and change from baseline in total letters read will be summarized by cohort 
and overall as in Table 9 and presented by participant as in Listing 2. Boxplots showing distribution 
of change from baseline in BCVA at each visit will be presented as in Figure 2. Frequency and 
percentage of participants presenting with a loss of  ≥ 15 letters from baseline at each follow-up 
visit will be included in Table 9. 
10.2 
Recurrence of Uveitis 
The criteria for recurrence of uveitis will be evaluated at all follow-up visits.  
Recurrence is defined in the protocol as presence of one of the following four parameters in at 
least one eye: 
1. New active inflammatory chorioretinal lesion and/or retinal vascular leakage.  
2. A 2+ increase in AC cells relative to baseline (SUN criteria). This is represented by a 
change of Grade 0 to Grade 2+; or Grade 0.5+ to Grade 3+.  
3. A 2-step increase in vitreous haze relative to baseline (NEI/SUN criteria). This is 
represented by a change of Grade 0 to Grade 2+; or Grade 0.5+ to Grade 3+.  
4. Worsening of BCVA by ≥ 15 letters (ETDRS) relative to baseline. 
The definition of recurrence referencing the variables in the case report forms will be as follows:  
At least one of the following criteria in at least one eye:  
 New/increased active inflammatory chorioretinal lesion  


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 New/increased retinal vascular lesion  
 One of the following changes in AC cell grading compared to baseline: 0 to 2+, 0.5 to 3+, 
1 to 3+, 2 to 4  
 One of the following changes in VH grading compared to baseline: 0 to 2+, T to 3+, 1 to 
3+, 2 to 4. 
 Worsening of BCVA by ≥ 15 letters relative to baseline  
Table 10 will summarize the number of participants who experience recurrence of uveitis in each 
eye at each visit by cohort and overall. Number of days until first recurrence will be summarized 
for each eye and cumulatively by cohort and overall as in Table 11 and specific recurrence criteria 
and days until first recurrence will be presented by participant (Listing 3). 
10.3 
Macular Edema 
Presence or extent of macular edema will be analyzed by researchers at the NEI.  
10.4 
Retino-vascular leakage  
Number and percentage of participants experiencing presence and increase of active inflammatory 
retinal vascular lesions will be summarized by cohort and overall as in Table 12 and presented by 
participant as in Listing 4. 
10.5 
Changes in Retinal Thickening 
Central retinal thickness at each visit and changes from baseline in central retinal thickness will be 
summarized by cohort and overall as in Table 13 and presented by participant as in Listing 5. 
Boxplots showing distribution of change from baseline in central retinal thickness at each visit will 
be presented as in Figure 3. 
10.6 
Length of Time to Quiescence  
Quiescence will be defined as the absence of active disease.  
Active disease is defined in the protocol as:  
 +1 or more VH (according to SUN criteria10); and/or  
 Active chorioretinitis or leakage on FA (that is in more than one quadrant) that requires 
treatment.  


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The definition of quiescence, referencing the variables in the case report forms, will be as follows:  
All of the following in the specified eye:  
 VH grading of 0 (Clear) or T (Trace) 
 Absence of active chorioretinitis  
 Absence of leakage on FA (that is more than one quadrant) that requires treatment 
Length of time to quiescence in each eye will be summarized by cohort and overall as in Table 14. 
Number of participants experiencing quiescence in each eye will be summarized by cohort and 
overall as in Table 15. Quiescence criteria in each eye and time until quiescence will be presented 
by participant as in Listing 6. 
10.7 
Ability to Taper Concomitant Immunosuppressive Medications 
Tapering of concomitant immunosuppressive medications, including medication name, starting 
dose, steroid indication, and the target and actual dates and doses of the tapering will be presented 
by participant as in Listing 7.  
11.0 SAFETY OUTCOMES 
These presentations will be based on the primary analysis population; data from all enrolled 
participants will be included in the corresponding listings. 
11.1 
Adverse Events (AEs) 
Table 16 will summarize total number and percentage of participants with AEs by severity of the 
AE, ocular specification (ocular vs. systemic) and relation to IP. A summary of AEs by Medical 
Dictionary for Regulatory Activities (MedDRA) system organ class (SOC) and preferred term 
(PT) will be presented as in Table 17. Additional details for all reported AEs will be presented by 
participant, with serious adverse events (SAEs) highlighted in red. If sufficient data are present, 
summaries similar to Table 16 and 17 will be generated for SAEs. Events corresponding to natural 
progression of the disease will be listed by participant. If sufficient data are present, summaries 
similar to Tables 16 and 17 will be presented for these events. 
11.2 
Loss of  ≥ 15 Letters  
The proportion of participants with loss of ≥ 15 total letters read will be included in the BCVA 
summary in Table 9 and the individual occurrences will be highlighted in the listing. 


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11.3 
Intraocular Pressure (IOP) 
IOP is assessed at baseline and all follow-up visits in both eyes. IOP will be summarized for each 
eye by cohort and overall as in Table 18 and presented by participant in a listing. A change 
≥ 10 mmHg relative to baseline is considered a clinically significant increase in IOP. Number of 
participants experiencing this change will be included in the summary in Table 18 and the 
individual occurrences will be highlighted in the listing.  
12.0 EXPLORATORY OUTCOMES 
Exploratory outcomes will be analyzed by researchers at the NEI.  
13.0 ADDITIONAL OPHTHALMIC ASSESSMENTS 
The following additional ophthalmic assessments are conducted at each visit and will be presented 
by participant and summarized by cohort and overall as in Tables 19-23. These presentations will 
be based on the safety population. 
 Anterior Chamber Cells 
 Anterior Chamber Flare 
 Vitreous Cells 
 Vitreous Haze 
 Active Chorioretinitis and Chorioretinal Lesions 
 FA Leakage in More Than One Quadrant (requiring treatment) 
14.0 OTHER SAFETY ASSESSMENTS 
These presentations will be based on the safety population. 
14.1 
Withdrawal from IP due to Vision Loss, Adverse Events, and Treatment Failure 
Participants who discontinue IP due to vision loss (manually identified based on investigator’s 
comments for those participants with reason for withdrawal from IP indicated as “safety 
withdrawal”), AEs (reason for withdrawal from IP indicated as “safety withdrawal” for the 
occurrence of AEs assessed as being related to study IP that preclude further administration of IP) 


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and treatment failure (reason for withdrawal from IP indicated as “lack of efficacy”) will be 
summarized in Table 1 and will be listed as outlined in Section 7.2. 
14.2 
Laboratory Assessments  
Laboratory assessments including complete blood count (CBC) with differential, acute care, 
mineral and hepatic panels, and urinalysis are collected at baseline, Week 4, Week 8, and Week 28.  
Abnormal lab results, as well as clinically significant changes from baseline, will be presented by 
participant for each visit. Frequency and percentage of participants reporting laboratory 
abnormalities at baseline and changes from baseline will be summarized at each follow-up visit in 
Table 24.  
14.3 
Physical Examination 
Physical examinations are conducted at baseline, Week 4, Week 8, and Week 28. Notable physical 
exam findings, as well as clinically significant changes from baseline and reported medications, 
will be presented by participant for each visit. Frequency and percentage of participants reporting 
significant physical exam findings at each visit will be summarized as in Table 25. 
14.4 
Vital Signs 
Vital signs are recorded at baseline and all follow-up visits. Blood pressure and temperature at 
each visit and change from baseline at each follow-up visit will be summarized by cohort and 
overall (Tables 26 and 27) and presented by participant. Height and weight at each visit will also 
be included in the listing. 
14.5 
Vaccine Reminders  
At each visit, the site staff filling out the case report form will be asked if the participant was 
reminded to avoid live vaccines while on ustekinumab and reminded about the risks of exposure 
to household members who receive a live vaccine. Responses to this question will be presented by 
participant in a listing.  
14.6 
Additional Safety Presentations 
In the event that one or more participants discontinue therapy prior to reaching Week 16, the 
presentations for primary, secondary, and safety outcomes will be repeated for the safety 


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population, in a similar manner as described in Sections 9.0-11.0. These presentations will be 
similar to Tables 8-18.  
15.0 RATIONALE FOR ANY DEVIATIONS FROM PRE-SPECIFIED ANALYSIS PLAN  
Depending on the nature of the data, certain outcomes may be presented differently than outlined 
in this analysis plan. Tables and figures will be presented only when an adequate amount of data 
is available. Data for some outcomes may not be available to the Coordinating Center at every 
visit. Because of this, some outcomes may not be presented until after study closure. 
16.0 QUALITY ASSURANCE PLANS 
To ensure accurate, reliable study results, all SAS code used to generate primary and secondary 
outcomes will undergo a code audit by an independent project statistician. All protocol tables, 
figures, listings, and reports will also undergo review by a secondary statistician. Documentation 
of these audits will be kept on file at the Coordinating Center.  


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17.0 REFERENCES 
1. Gritz DC, Wong IG. Incidence and prevalence of uveitis in Northern California; the 
Northern California Epidemiology of Uveitis Study. Ophthalmology. 2004 
Mar;111(3):491-500. 
2. Djalilian AR, Nussenblatt RB. Immunosuppression in uveitis. Ophthalmol Clin North 
Am. 2002 Sep;15(3):395-404, viii. 
3. Ref: Dick AD, Tundia N, Sorg R, Zhao C, Chao J, Joshi A, Skup M. Risk of Ocular 
Complications in Patients with Noninfectious Intermediate Uveitis, Posterior Uveitis, 
or 
Panuveitis. 
Ophthalmology. 
2016 
Mar;123(3):655-62. 
doi: 
10.1016/j.ophtha.2015.10.028. Epub 2015 Dec 19. PubMed PMID: 26712559. 
4. Luger D, Silver PB, Tang J, Cua D, Chen Z, Iwakura Y, Bowman EP, Sgambellone 
NM, Chan CC, Caspi RR. Either a Th17 or a Th1 effector response can drive 
autoimmunity: conditions of disease induction affect dominant effector category.  
J Exp Med. 2008 Apr 14;205(4):799-810. Epub 2008 Apr 7. PubMed PMID: 
18391061; PubMed Central PMCID: PMC2292220. 
5. Tarrant TK, Silver PB, Chan CC, Wiggert B, Caspi RR. Endogenous IL-12 is required 
for 
induction 
and 
expression 
of 
experimental 
autoimmune 
uveitis.  
J Immunol. 1998 Jul 1;161(1):122-7. PubMed PMID: 9647215. 
6. Yokoi H, Kato K, Kezuka T, Sakai J, Usui M, Yagita H, Okumura K. Prevention of 
experimental autoimmune uveoretinitis by monoclonal antibody to interleukin-12. Eur 
J Immunol. 1997 Mar;27(3):641-6. PubMed PMID: 9079803. 
7. Keino H, Watanabe T, Sato Y, Niikura M, Wada Y, Okada AA. Therapeutic effect of 
the potent IL-12/IL-23 inhibitor STA-5326 on experimental autoimmune uveoretinitis. 
Arthritis Res Ther. 2008;10(5):R122. Epub 2008 Oct 13. PubMed PMID: 18847496; 
PubMed Central PMCID: PMC2592812. 
8. King IL, Segal BM. Cutting edge: IL-12 induces CD4+CD25- T cell activation in the 
presence of T regulatory cells. J Immunol. 2005 Jul 15;175(2):641-5. PubMed PMID: 
16002658. 
9. Teng MW, Bowman EP, McElwee JJ, Smyth MJ, Casanova JL, Cooper AM, Cua DJ. 
IL-12 and IL-23 cytokines: from discovery to targeted therapies for immune-mediated 
inflammatory diseases. Nat Med. 2015 Jul;21(7):719-29. 
10. Jabs DA, Nussenblatt RB, Rosenbaum JT; Standardization of Uveitis Nomenclature 
(SUN) Working Group. Standardization of uveitis nomenclature for reporting clinical 
data. Results of the First International Workshop. Am J of Ophthalmol 2005 
Sep;140(3):509-16. 
 
 


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18.0 MOCK SHELLS 
 
TABLES 
 
Table 1. Participant Disposition 
Disposition 
Cohort 1 
N (%)1 
Cohort 2 
N (%)1 
Overall 
N (%)1 
Enrolled 
x 
x 
x 
Received at least one dose of IP 
(Safety Population) 
x (x) 
x (x) 
x (x) 
     Received IP at Week 0
x (x) 
x (x) 
x (x) 
        Received IP at Week 4
x (x) 
N/A 
x (x) 
        Received IP at Week 8
x (x) 
x (x) 
x (x) 
     Discontinued IP Early  
x (x) 
x (x) 
x (x) 
    Reason for Discontinuation2
     Participant non-
compliance 
x (x) 
x (x) 
x (x) 
    Therapy unavailable
x (x)
x (x)
x (x)
    Safety withdrawal
x (x)
x (x)
x (x)
    Lack of efficacy
x (x)
x (x)
x (x)
    Other 
x (x)
x (x)
x (x)
Terminated Early from the 
Study 
       Reason for Termination3 
x (x) 
x (x) 
x (x) 
AE/intercurrent illness
x (x)
x (x)
x (x)
Death
x (x)
x (x)
x (x)
Insufficient therapeutic 
response
x (x) 
x (x) 
x (x) 
Lost to follow-up
x (x)
x (x)
x (x)
Participant request/refusal
x (x)
x (x)
x (x)
Early study closure
x (x)
x (x)
x (x)
Protocol deviation/violation
x (x)
x (x)
x (x)
Other
x (x)
x (x)
x (x)
Completed Study through 
Week 16 (Primary Analysis 
Population) 
x (x) 
x (x) 
x (x) 
Completed Study through Week 
28 
x (x) 
x (x) 
x (x) 
1Denominators are the number of participants in the enrolled population in the respective cohort 
or overall, unless otherwise specified. Percentages are rounded to the nearest whole number. 
2Denominators are the number of participants who discontinued IP early. 
3Denominators are the number of participants who terminated early from the study.
 
 
 


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Table 2. Summary of Participant Demographics  
 
 
 
Demographic Characteristics 
Cohort 1 
(N=X)1 
Cohort 2 
(N=X)1 
Overall 
(N=X)1 
Gender, N (%) 
    Male
x (x)
x (x)
x (x)
    Female
x (x)
x (x)
x (x)
Age Category (years) at Baseline, N (%) 
    18-25
x (x)
x (x)
x (x)
    26-30
x (x)
x (x)
x (x)
    31-35
x (x)
x (x)
x (x)
    36-40
x (x)
x (x)
x (x)
    41-45
x (x)
x (x)
x (x)
    46-50
x (x)
x (x)
x (x)
    51-55
x (x)
x (x)
x (x)
    56-60
x (x)
x (x)
x (x)
    61-65
x (x)
x (x)
x (x)
    66-70
x (x)
x (x)
x (x)
    71-75
x (x)
x (x)
x (x)
    76-80
x (x)
x (x)
x (x)
    > 80
x (x)
x (x)
x (x)
Age (years) at Baseline 
    N
x
x
x
    Mean (SD)
x (x)
x (x)
x (x)
    Median 
x
x
x
    Range (min, max) 
(x, x)
(x, x)
(x, x)
Ethnicity, N (%) 
    Hispanic or Latino
x (x)
x (x)
x (x)
    Not Hispanic or Latino
x (x)
x (x)
x (x)
    Unknown 
x (x)
x (x)
x (x)
Race, N (%) 
    American Indian or Alaskan Native
x (x)
x (x)
x (x)
    Asian
x (x)
x (x)
x (x)
    Black
x (x)
x (x)
x (x)
    Hawaiian or Pacific Islander
x (x)
x (x)
x (x)
    White 
x (x)
x (x)
x (x)
    Multiple Race
x (x)
x (x)
x (x)
    Unknown 
x (x)
x (x)
x (x)
1Column header counts and denominators are the number of participants in the enrolled population 
in the respective cohort or overall. Percentages are rounded to the nearest whole number. 


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Table 3. Medical and Medication History 
Conditions 
Cohort 1 
(N=X) 
N (%)1 
Cohort 2 
(N=X) 
N (%)1 
Overall 
(N=X) 
N (%)1 
Any Medical Condition 
x (x) 
x (x) 
x (x) 
    CVA/TIA 
 
 
 
      Yes 
x (x) 
x (x) 
x (x) 
      No  
x (x) 
x (x) 
x (x) 
    MI 
 
 
 
      Yes 
x (x) 
x (x) 
x (x) 
      No  
x (x) 
x (x) 
x (x) 
    Hypertension 
 
 
 
      Yes 
x (x) 
x (x) 
x (x) 
      No  
x (x) 
x (x) 
x (x) 
    Hypercholesterolemia 
 
 
 
      Yes 
x (x) 
x (x) 
x (x) 
      No  
x (x) 
x (x) 
x (x) 
    Renal failure 
 
 
 
      Yes 
x (x) 
x (x) 
x (x) 
      No  
x (x) 
x (x) 
x (x) 
    Diabetes 
 
 
 
      Yes 
x (x) 
x (x) 
x (x) 
      No  
x (x) 
x (x) 
x (x) 
    Autoimmune disease 
 
 
 
      Yes 
x (x) 
x (x) 
x (x) 
      No  
x (x) 
x (x) 
x (x) 
    Cancer 
 
 
 
      Yes 
x (x) 
x (x) 
x (x) 
      No  
x (x) 
x (x) 
x (x) 
    Active infection  
 
 
 
      Yes 
x (x) 
x (x) 
x (x) 
      No  
x (x) 
x (x) 
x (x) 
    PPD 
 
 
 
      Yes 
x (x) 
x (x) 
x (x) 
      No  
x (x) 
x (x) 
x (x) 
    Live vaccine within the last three months 
 
 
 
      Yes 
x (x) 
x (x) 
x (x) 
      No  
x (x) 
x (x) 
x (x) 
    BCG vaccine within the last year 
 
 
 
      Yes 
x (x) 
x (x) 
x (x) 
      No  
x (x) 
x (x) 
x (x) 
    Expected to receive BCG vaccine 
 
 
 
      Yes 
x (x) 
x (x) 
x (x) 
      No  
x (x) 
x (x) 
x (x) 
Any Medication History 
x (x) 
x (x) 
x (x) 
     Rituximab within the last year 
 
 
 
      Yes 
x (x) 
x (x) 
x (x) 
      No  
x (x) 
x (x) 
x (x) 
     Other biologic (infliximab, daclizumab,   
    adalimumab) within past six months 
 
 
 
      Yes 
x (x) 
x (x) 
x (x) 
      No  
x (x) 
x (x) 
x (x) 
     Alkylating agent (cyclophosphamide,  
    chlorambucil) within the last year 
 
 
 
      Yes 
x (x) 
x (x) 
x (x) 
      No  
x (x) 
x (x) 
x (x) 
1Column header count and denominators are the number of participants in the enrolled population in the respective cohort or 
overall. Percentages are rounded to the nearest whole number. 
 
 
 


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Table 4. Ocular History 
 
Cohort 1 
Cohort 2 
Overall 
Conditions/Procedures 
OD 
(N=X) 
N (%)1 
OS 
(N=X) 
N (%)1 
Total  
(N=X) 
N (%)1.2 
OD 
(N=X) 
N (%)1 
OS 
(N=X) 
N (%)1 
Total 
(N=X) 
N (%)1,2 
OD 
(N=X) 
N (%)1 
OS 
(N=X) 
N (%)1 
Total 
(N=X) 
N (%)1,2 
Any Ocular Disease 
x (x) 
x (x) 
x (x) 
x (x) 
x (x) 
x (x) 
x (x) 
x (x) 
x (x) 
    Uveitis
 
 
 
 
 
 
 
 
 
      Yes 
x (x) 
x (x) 
x (x) 
x (x) 
x (x) 
x (x) 
x (x) 
x (x) 
x (x) 
      No 
x (x) 
x (x) 
x (x) 
x (x) 
x (x) 
x (x) 
x (x) 
x (x) 
x (x) 
    Other 
 
 
 
 
 
 
 
 
 
      Yes 
x (x) 
x (x) 
x (x) 
x (x) 
x (x) 
x (x) 
x (x) 
x (x) 
x (x) 
       No 
x (x) 
x (x) 
x (x) 
x (x) 
x (x) 
x (x) 
x (x) 
x (x) 
x (x) 
Any Ocular Procedure 
x (x) 
x (x) 
x (x) 
x (x) 
x (x) 
x (x) 
x (x) 
x (x) 
x (x) 
   Intraocular steroid injection3 
 
 
 
 
 
 
 
 
 
      Yes 
x (x) 
x (x) 
x (x) 
x (x) 
x (x) 
x (x) 
x (x) 
x (x) 
x (x) 
       No 
x (x) 
x (x) 
x (x) 
x (x) 
x (x) 
x (x) 
x (x) 
x (x) 
x (x) 
   Periocular steroid injection3 
 
 
 
 
 
 
 
 
 
      Yes 
x (x) 
x (x) 
x (x) 
x (x) 
x (x) 
x (x) 
x (x) 
x (x) 
x (x) 
       No 
x (x) 
x (x) 
x (x) 
x (x) 
x (x) 
x (x) 
x (x) 
x (x) 
x (x) 
   Intravitreal anti-VEGF3 
 
 
 
 
 
 
 
 
 
      Yes 
x (x) 
x (x) 
x (x) 
x (x) 
x (x) 
x (x) 
x (x) 
x (x) 
x (x) 
       No 
x (x) 
x (x) 
x (x) 
x (x) 
x (x) 
x (x) 
x (x) 
x (x) 
x (x) 
   Cataract surgery
 
 
 
 
 
 
 
 
 
      Yes 
x (x) 
x (x) 
x (x) 
x (x) 
x (x) 
x (x) 
x (x) 
x (x) 
x (x) 
       No 
x (x) 
x (x) 
x (x) 
x (x) 
x (x) 
x (x) 
x (x) 
x (x) 
x (x) 
   Glaucoma surgery
 
 
 
 
 
 
 
 
 
      Yes 
x (x) 
x (x) 
x (x) 
x (x) 
x (x) 
x (x) 
x (x) 
x (x) 
x (x) 
       No 
x (x) 
x (x) 
x (x) 
x (x) 
x (x) 
x (x) 
x (x) 
x (x) 
x (x) 
  Vitrectomy 
 
 
 
 
 
 
 
 
 
      Yes 
x (x) 
x (x) 
x (x) 
x (x) 
x (x) 
x (x) 
x (x) 
x (x) 
x (x) 
       No 
x (x) 
x (x) 
x (x) 
x (x) 
x (x) 
x (x) 
x (x) 
x (x) 
x (x) 


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Cohort 1 
Cohort 2 
Overall 
Conditions/Procedures 
OD 
(N=X) 
N (%)1 
OS 
(N=X) 
N (%)1 
Total  
(N=X) 
N (%)1.2 
OD 
(N=X) 
N (%)1 
OS 
(N=X) 
N (%)1 
Total 
(N=X) 
N (%)1,2 
OD 
(N=X) 
N (%)1 
OS 
(N=X) 
N (%)1 
Total 
(N=X) 
N (%)1,2 
   Other Procedure
 
 
 
 
 
 
 
 
 
      Yes 
x (x) 
x (x) 
x (x) 
x (x) 
x (x) 
x (x) 
x (x) 
x (x) 
x (x) 
       No 
x (x) 
x (x) 
x (x) 
x (x) 
x (x) 
x (x) 
x (x) 
x (x) 
x (x) 
1Column header counts and denominators are the number of participants in the enrolled population, in the respective cohort or overall. Percentages are rounded to 
the nearest whole number. 
2Participants who reported an ocular condition or procedure in both eyes are counted only once in this column. 
3Within the last three months.
 
 


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Table 5. Protocol Deviations and Unanticipated Problems 
 
 
Participant-Specific 
Non-Participant 
Specific 
Total 
Number of Events 
Number of Participants with Events
N (%)1 
 
Number of 
Events 
Number of 
Events 
 
Cohort1 Cohort 2 Overall 
Cohort 1 
(N=X) 
Cohort 2 
(N=X) 
Overall 
(N=X) 
 
 
All events2
x 
x 
x 
x (x) 
x (x) 
x (x) 
x 
x 
Protocol deviations 
x 
x 
x 
x (x) 
x (x) 
x (x) 
x 
x 
Unanticipated problems 
x 
x 
x 
x (x) 
x (x) 
x (x) 
x 
x 
 
 
 
 
 
 
Type3  
 
 
 
 
 
 
    Minor 
x 
x 
x 
x (x) 
x (x) 
x (x) 
x 
x 
Serious 
x 
x 
x 
x (x) 
x (x) 
x (x) 
x 
x 
Not serious 
x 
x 
x 
x (x) 
x (x) 
x (x) 
x 
x 
    Determination Pending 
x 
x 
x 
x (x) 
x (x) 
x (x) 
x 
x 
 
 
 
 
 
 
 
 
Outcome 
 
 
 
 
 
 
Participant follow-up continues 
x 
x 
x 
x (x) 
x (x) 
x (x) 
x 
x 
Participant follow-up terminated 
x 
x 
x 
x (x) 
x (x) 
x (x) 
x 
x 
     Investigational product remains  
    stable
x 
x 
x 
x (x) 
x (x) 
x (x) 
x 
x 
 
Investigational product returned or 
discarded 
x 
x 
x 
x (x) 
x (x) 
x (x) 
x 
x 
Other
x 
x 
x 
x (x) 
x (x) 
x (x) 
x 
x 
1Column header count and denominators are the total number of participants in the enrolled population, in the respective cohort or overall. Percentages are 
rounded to the nearest whole number.  
2Events that are both protocol deviations and unanticipated problems are included in both rows. 
3Prior to July 1, 2019, Investigators classified deviations and unanticipated problems as serious or not serious. Effective July 1, 2019, Investigators classify 
deviations and unanticipated problems as minor or major and the IRB classifies the major deviations and unanticipated problems as serious or not serious. 
Determination pending category corresponds to those major deviations or unanticipated problems that the IRB is yet to classify as serious or not serious. 


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Table 6. Study Procedure Deviations 
 
Cohort 
Participant ID 
Number of 
Expected 
Procedures1 
Number of Missed
Procedures2 
Percentage (%) of
Missed 
Procedures3 
1 
By participant 
 
NEI001
x
x
xx.x
 
NEI002
x
x
xx.x
 
… 
x
x
xx.x
 
   Overall  
x 
x 
xx.x 
      2 
NEI006
x
x
xx.x
 
NEI007
x
x
xx.x
 
… 
x
x
xx.x
 
   Overall 
x 
x 
xx.x 
NA 
By procedure 
 
Adverse Event 
Assessment
x 
x 
xx.x 
 
BCVA (EVA)
x
x
xx.x
 
… 
x
x
xx.x
NA 
Overall Total 
x 
x 
xx.x 
1The number of expected procedures is defined based on the study flowsheet included in the protocol.
2Missed procedures are defined when the site reports a missed procedure or when the protocol monitors note missed 
procedures at a site visit.
3Percentages are rounded to the nearest tenth. 
 
 


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Table 7. Visit Schedule Deviations 
 
 
Cohort 
Participant 
ID 
Number of 
Expected Visits  
Number of Missed 
Visits 
Percentage of 
Missed Visits1 
Number of Out of 
Window Visits 
 Percentage of 
Out of Window 
Visits1 
Visits Missed or 
Out of Window 
1 
NEI001
x 
x 
xx.x 
x 
xx.x 
xxx, xxx 
NEI002
x 
x 
xx.x 
x 
xx.x 
xxx, xxx 
…
x 
x 
xx.x 
x 
xx.x 
xxx, xxx 
Overall 
x 
x 
xx.x 
x 
xx.x 
 
2 
NEI006
x 
x 
xx.x 
x 
xx.x 
xxx, xxx 
…
x 
x 
xx.x 
x 
xx.x 
xxx, xxx 
Overall 
x 
x 
xx.x 
x 
xx.x 
 
NA 
Total 
x 
x 
xx.x 
x 
xx.x 
 
1Percentages are rounded to the nearest tenth. 
 
 
 


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Table 8. Primary Outcome Analysis of Treatment Response 
 
Cohort 1 
n/N (%)1 
Cohort 2 
n/N (%)1 
Overall 
n/N (%)1 
Visit 
OD 
OS 
Total2 
OD 
OS 
Total2 
OD 
OS 
Total2 
Week 4 
x/x (x) 
x/x (x) 
x/x (x) 
x/x (x) 
x/x (x) 
x/x (x) 
x/x (x) 
x/x (x) 
x/x (x) 
Week 8 
x/x (x) 
x/x (x) 
x/x (x) 
x/x (x) 
x/x (x) 
x/x (x) 
x/x (x) 
x/x (x) 
x/x (x) 
Week 12
x/x (x) 
x/x (x) 
x/x (x) 
x/x (x) 
x/x (x) 
x/x (x) 
x/x (x) 
x/x (x) 
x/x (x) 
Week 16
x/x (x) 
x/x (x) 
x/x (x) 
x/x (x) 
x/x (x) 
x/x (x) 
x/x (x) 
x/x (x) 
x/x (x) 
Total by Week 16
x/x (x) 
x/x (x) 
x/x (x) 
x/x (x) 
x/x (x) 
x/x (x) 
x/x (x) 
x/x (x) 
x/x (x) 
1Denominators are the number of participants in the primary analysis population who completed the indicated visit, in the respective cohort or overall, 
considering only eligible eyes. Percentages are rounded to the nearest whole number.  
2Only participants meeting treatment response criteria in all eligible eyes are counted as a treatment responder in this column. Highlighted cells 
correspond to primary outcome analysis. 


STAR SAP 
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Version 2.0 
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Table 9. BCVA Total Letters Read over Time 
 
 Cohort 1 
 Cohort 2 
 Overall 
 
 BCVA Total 
Letters Read 
 Change from 
Baseline 
 BCVA Total 
Letters Read 
 Change from 
Baseline 
 BCVA Total 
Letters Read 
 Change from 
Baseline 
Visit 
 
OD 
OS 
OD 
OS 
OD 
OS 
OD 
OS 
OD 
OS 
OD 
OS 
Baseline 
 
 
 
 
 
 
 
 
 
 
 
 
N 
x 
x 
 
 
x 
x 
 
 
x 
x 
 
 
Mean (SD)
x (x) 
x (x) 
 
 
x (x) 
x (x) 
 
 
x (x) 
x (x) 
 
 
Median 
x 
x 
 
 
x 
x 
 
 
x 
x 
 
 
Range (min , max) 
(x, x) 
(x, x) 
 
 
(x, x) 
(x, x) 
 
 
(x, x) 
(x, x) 
 
 
… 
 
 
 
 
 
 
 
 
 
 
 
 
Week 28 
 
 
 
 
 
 
 
 
 
 
 
 
N 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
Mean (SD)
x (x) 
x (x) 
x (x) 
x (x) 
x (x) 
x (x) 
x (x) 
x (x) 
x (x) 
x (x) 
x (x) 
x (x) 
Median 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
Range (min, max) 
(x, x) 
(x, x) 
(x, x) 
(x, x) 
(x, x) 
(x, x) 
(x, x) 
(x, x) 
(x, x) 
(x, x) 
(x, x) 
(x, x) 
>=15 letter loss, N 
(%)1 
 
 
x (x) 
x (x) 
 
 
x (x) 
x (x) 
 
 
x (x) 
x (x) 
1Denominators are the number of participants in the primary analysis population who completed the indicated visit, in the respective cohort or overall. Percentages are 
rounded to the nearest whole number. 


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Version 2.0 
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Table 10. Recurrence of Uveitis 
 
Cohort 1 
n/N (%)1 
Cohort 2 
n/N (%)1 
Overall 
n/N (%)1 
Visit  
OD 
OS 
Total2 
OD 
OS 
Total2 
OD 
OS 
Total2 
Week 4 
x/x (x) 
x/x (x) 
x/x (x) 
x/x (x) 
x/x (x) 
x/x (x) 
x/x (x) 
x/x (x) 
x/x (x) 
Week 8 
x/x (x) 
x/x (x) 
x/x (x) 
x/x (x) 
x/x (x) 
x/x (x) 
x/x (x) 
x/x (x) 
x/x (x) 
Week 12 
x/x (x) 
x/x (x) 
x/x (x) 
x/x (x) 
x/x (x) 
x/x (x) 
x/x (x) 
x/x (x) 
x/x (x) 
Week 16 
x/x (x) 
x/x (x) 
x/x (x) 
x/x (x) 
x/x (x) 
x/x (x) 
x/x (x) 
x/x (x) 
x/x (x) 
Total by Week 16 
x/x (x) 
x/x (x) 
x/x (x) 
x/x (x) 
x/x (x) 
x/x (x) 
x/x (x) 
x/x (x) 
x/x (x) 
1Denominators are the number of participants in the primary analysis population who completed the indicated visit, in the respective cohort or overall. 
Percentages are rounded to the nearest whole number.  
2Participants who experienced recurrence in both eyes are counted only once in this column. 
 
 
 
Table 11. Length of Time Until First Recurrence of Uveitis (Days) 
 
 
Cohort 1 
Cohort 2 
Overall 
 
 
OD 
 
OS 
 
Total 
 
OD 
 
OS 
 
Total 
 
OD 
 
OS 
 
Total 
N1 
x 
x 
x 
x 
x 
x 
x 
x 
x 
Mean (SD) 
x (x)  
x (x)  
x (x)  
x (x)  
x (x)  
x (x)  
x (x)  
x (x)  
x (x)  
Median 
x 
x 
x 
x 
x 
x 
x 
x 
x 
Range (min, max) 
(x, x) 
(x, x) 
(x, x) 
(x, x) 
(x, x) 
(x, x) 
(x, x) 
(x, x) 
(x, x) 
1Number of participants in the primary analysis population who experienced recurrence of uveitis following the baseline injection or infusion, in the respective cohort or overall. 
 
. 


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November 20, 2020 
Version 2.0 
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Table 12. Retino-Vascular Leakage Over Time 
 
 
 
Retinovascular Lesions Present 
n/N (%)1 
New /Increased Lesions 
n/N (%)1 
Decreased Lesions 
n/N (%)1 
 
 
Visit  
 
Cohort 1 
 
Cohort 2  
Overall 
 
Cohort 1  
Cohort 2  
Overall 
 
Cohort 1 
 
Cohort 2  
Overall 
 
OD 
OS 
OD 
OS 
OD 
OS 
OD 
OS 
OD 
OS 
OD 
OS 
OD 
OS 
OD 
OS 
OD 
OS 
Week 4
x/ x (x) x/x (x)x/x (x)x/x (x) x/x (x) x/x (x) x/x (x)x/x (x)x/x (x)x/x (x) x/x (x) x/x (x) x/x (x) x/x (x)x/x (x)x/x (x) x/x (x) x/x (x) 
Week 8
x/x (x) x/x (x)x/x (x)x/x (x) x/x (x) x/x (x) x/x (x)x/x (x)x/x (x)x/x (x) x/x (x) x/x (x) x/x (x) x/x (x)x/x (x)x/x (x) x/x (x) x/x (x) 
Week 12 
x/x (x) x/x (x)x/x (x)x/x (x) x/x (x) x/x (x) x/x (x)x/x (x)x/x (x)x/x (x) x/x (x) x/x (x) x/x (x) x/x (x)x/x (x)x/x (x) x/x (x) x/x (x) 
Week 16 
/xx (x) x/x (x)x/x (x)x/x (x) x/x (x) x/x (x) x/x (x)x/x (x)x/x (x)x/x (x) x/x (x) x/x (x) x/x (x) x/x (x)x/x (x)x/x (x) x/x (x) x/x (x) 
Week 28 
x/x (x) x/x (x)x/x (x)x/x (x) x/x (x) x/x (x) x/x (x)x/x (x)x/x (x)x/x (x) x/x (x) x/x (x) x/x (x) x/x (x)x/x (x)x/x (x) x/x (x) x/x (x) 
1Denominators are the number of participants in the primary analysis population who completed the indicated visit, in the respective cohort or overall. Percentages 
are rounded to the nearest whole number. 


STAR SAP 
November 20, 2020 
Version 2.0 
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Page 31 
Table 13. Central Retinal Thickness over Time 
 
 Cohort 1 
 Cohort 2 
Overall 
 
Central Retinal 
Thickness (μm) 
 Change from 
Baseline (μm) 
Central Retinal 
Thickness (μm) 
 Change from 
Baseline (μm) 
Central Retinal 
Thickness (μm) 
 Change from 
Baseline (μm) 
Visit 
 
OD 
OS 
OD 
OS 
OD 
OS 
OD 
OS 
OD 
OS 
OD 
OS 
Baseline 
 
 
 
 
 
 
 
 
 
 
 
 
N
x 
x 
 
 
x 
x 
 
 
x 
x 
 
 
Mean (SD) 
x (x) 
x (x) 
 
 
x (x) 
x (x) 
 
 
x (x) 
x (x) 
 
 
Median 
x 
x 
 
 
x 
x 
 
 
x 
x 
 
 
Range (min, max) 
(x, x) 
(x, x) 
 
 
(x, x) 
(x, x) 
 
 
(x, x) 
(x, x) 
 
 
… 
 
 
 
 
 
 
 
 
 
 
 
 
 
Week 28 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
N
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
Mean (SD) 
x (x) 
x (x) 
x (x) 
x (x) 
x (x) 
x (x) 
x (x) 
x (x) 
x (x) 
x (x) 
x (x) 
x (x) 
Median 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
Range (min, max) 
(x, x) 
(x, x) 
(x, x) 
(x, x) 
(x, x) 
(x, x) 
(x, x) 
(x, x) 
(x, x) 
(x, x) 
(x, x) 
(x, x) 
 
Table 14. Length of Time to Quiescence (Days) 
 
 
 
Cohort 1  
 
Cohort 2 
 
Overall 
OD 
OS 
 
Total 
 
OD 
 
OS 
 
Total 
 
OD 
 
OS 
 
Total 
N1 
Mean (SD) 
Median 
Range (min, max) 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x (x)  
x (x)  
x (x)  
x (x)  
x (x)  
x (x)  
x (x)  
x (x)  
x (x)  
x  
x  
x  
x  
x 
x  
x  
x  
x  
(x, x) 
(x, x) 
(x, x) 
(x, x) 
(x, x) 
(x, x) 
(x, x) 
(x, x) 
(x, x) 
1Number of participants in the primary analysis population who experienced quiescence following the baseline injection or infusion, in the respective cohort or overall. 
 


STAR SAP 
November 20, 2020 
Version 2.0 
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Page 32 
Table 15. Quiescence 
 
Cohort 1 
n/N (%)1 
Cohort 2 
n/N (%)1 
Overall 
n/N (%)1 
Visit  
OD 
OS 
Total2 
OD 
OS 
Total2 
OD 
OS 
Total2 
Week 4 
x/x (x) 
x/x (x) 
x/x (x) 
x/x (x) 
x/x (x) 
x/x (x) 
x/x (x) 
x/x (x) 
x/x (x) 
Week 8 
x/x (x) 
x/x (x) 
x/x (x) 
x/x (x) 
x/x (x) 
x/x (x) 
x/x (x) 
x/x (x) 
x/x (x) 
Week 12 
x/x (x) 
x/x (x) 
x/x (x) 
x/x (x) 
x/x (x) 
x/x (x) 
x/x (x) 
x/x (x) 
x/x (x) 
Week 16 
x/x (x) 
x/x (x) 
x/x (x) 
x/x (x) 
x/x (x) 
x/x (x) 
x/x (x) 
x/x (x) 
x/x (x) 
1Denominators are the number of participants in the primary analysis population who completed the indicated visit, in the respective cohort or overall. Percentages are rounded to 
the nearest whole number.  
2Participants experiencing quiescence in both eyes are counted only once in this column. 
 


STAR SAP 
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Version 2.0 
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Page 33 
Table 16. Summary of Adverse Events 
 
Participants with Events  
N (%)1 
Number of Events  
N 
 
Cohort 1  
Cohort 2 
Overall 
Cohort 1 
Cohort 2 
Overall 
All AEs 
x (x)  
x (x)  
x (x)  
x 
x 
x 
Serious Adverse Events 
x (x)  
x (x)  
x (x)  
x 
x 
x 
Severity2 
 
 
 
 
 
 
   Mild
x (x)  
x (x)  
x (x)  
x 
x 
x 
  Moderate 
x (x)  
x (x)  
x (x)  
x 
x 
x 
  Severe 
x (x)  
x (x)  
x (x)  
x 
x 
x 
  Life-threatening 
x (x)  
x (x)  
x (x)  
x 
x 
x 
  Death 
x (x)  
x (x)  
x (x)  
x 
x 
x 
Ocular Specification2 
 
 
 
 
 
 
   Non-ocular 
x (x)  
x (x)  
x (x)  
x 
x 
x 
   OD 
x (x)  
x (x)  
x (x)  
x 
x 
x 
   OS  
x (x)  
x (x)  
x (x)  
x 
x 
x 
Relation to IP2 
 
 
 
 
 
 
  Related 
x (x)  
x (x)  
x (x)  
x 
x 
x 
  Not Related 
x (x)  
x (x)  
x (x)  
x 
x 
x 
Outcome2 
 
 
 
 
 
 
   Resolved 
x (x)  
x (x)  
x (x)  
x 
x 
x 
   Resolved with sequelae 
x (x)  
x (x)  
x (x)  
x 
x 
x 
   Ongoing 
x (x)  
x (x)  
x (x)  
x 
x 
x 
   Death 
x (x)  
x (x)  
x (x)  
x 
x 
x 
   Resolved by convention 
x (x)  
x (x)  
x (x)  
x 
x 
x 
1Denominators are the number of participants in the primary analysis population in the respective cohort or overall. Percentages are rounded to the nearest whole number. 
2Participants may be counted in more than one category.  
 


STAR SAP 
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Version 2.0 
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Table 17. AEs by System Organ Class (SOC) and Preferred Term (PT) 
System Organ Class/ 
Preferred Term 
Participants with Events 
N (%)1 
Number of  
Events  
N  
Cohort 1 
Cohort 2 
Overall 
Cohort 1  
Cohort 2 
Overall 
SOC1 
x (x) 
x (x) 
x (x) 
x 
x 
x 
 
PT1 
x (x) 
x (x) 
x (x) 
x 
x 
x 
 
PT2 
x (x) 
x (x) 
x (x) 
x 
x 
x 
SOC2 
x (x) 
x (x) 
x (x) 
x 
x 
x 
 
PT1 
x (x) 
x (x) 
x (x) 
x 
x 
x 
 
PT2 
x (x) 
x (x) 
x (x) 
x 
x 
x 
… 
x (x) 
x (x) 
x (x) 
x 
x 
x 
… 
x (x) 
x (x) 
x (x) 
x 
x 
x 
1Denominators are the number of participants in the primary analysis population in the respective cohort or overall. Percentages are rounded to the nearest whole number. 
 


STAR SAP 
November 20, 2020 
Version 2.0 
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Page 35 
Table 18. IOP over Time 
 
 Cohort 1 
 Cohort 2 
Overall 
 
 IOP (mmHg) 
 Change from 
Baseline 
(mmHg) 
 IOP (mmHg) 
 Change from 
Baseline 
(mmHg) 
 IOP (mmHg) 
 Change from 
Baseline 
(mmHg) 
Visit 
 
OD 
OS 
OD 
OS 
OD 
OS 
OD 
OS 
OD 
OS 
OD 
OS 
Baseline 
 
 
 
 
 
 
 
 
 
 
 
 
 
N 
 
x 
x 
 
 
x 
x 
 
 
x 
x 
 
 
Mean (SD) 
 
x (x) 
x (x) 
 
 
x (x) 
x (x) 
 
 
x (x) 
x (x) 
 
 
Median 
 
x 
x 
 
 
x 
x 
 
 
x 
x 
 
 
Range (min, max) 
 
(x, x) 
(x, x) 
 
 
(x, x) 
(x, x) 
 
 
(x, x) 
(x, x) 
 
 
… 
 
 
 
 
 
 
 
 
 
 
 
 
 
Week 28 
 
 
 
 
 
 
 
 
 
 
 
 
N 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
Mean (SD) 
x (x) 
x (x) 
x (x) 
x (x) 
x (x) 
x (x) 
x (x) 
x (x) 
x (x) 
x (x) 
x (x) 
x (x) 
Median 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
Range (min, max) 
(x, x) 
(x, x) 
(x, x) 
(x, x) 
(x, x) 
(x, x) 
(x, x) 
(x, x) 
(x, x) 
(x, x) 
(x, x) 
(x, x) 
≥10 mmHg increase, N (%)1 
 
 
x (x) 
x (x) 
 
 
x (x) 
x (x) 
 
 
x (x) 
x (x) 
1Denominators are the number of participants in the primary analysis population who completed the indicated visit, in the respective cohort or overall. Percentages are 
rounded to the nearest whole number.  
 


STAR SAP 
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Version 2.0 
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Page 36 
Table 19. Anterior Chamber Cells  
 
 
 
 
Cohort 1 
n/N (%)1 
Cohort 2 
n/N (%)1 
Overall 
n/N (%)1 
Grade 
OD 
OS 
 
OD 
 
OS 
 
OD 
 
OS 
Grade 0 (no cells seen) 
 
 
 
 
 
     Baseline 
x/x (x) 
x/x (x) 
x/x (x) 
x/x (x) 
x/x (x) 
x/x (x) 
     Week 4 
x/x (x) 
x/x (x) 
 
x/x (x) 
x/x(x) 
x/x (x) 
x/x (x) 
     … 
x/x (x) 
x/x (x) 
x/x (x) 
x/x (x) 
x/x (x) 
x/x (x) 
     Week 28 
x/x (x) 
x/x (x) 
x/x (x) 
x/x(x) 
x/x (x) 
x/x (x) 
0.5 or Trace (1-5 cells) 
 
 
 
 
 
 
     Baseline 
x/x (x) 
x/x (x) 
x/x (x) 
x/x (x) 
x/x (x) 
x/x (x) 
     Week 4 
x/x (x) 
x/x (x) 
x/x (x) 
x/x (x) 
x/x (x) 
x/x (x) 
     … 
x/x (x) 
x/x (x) 
x/x (x) 
x/x (x) 
x/x (x) 
x/x (x) 
     Week 28 
x/x (x) 
x/x (x) 
x/x (x) 
x/x (x) 
x/x (x) 
x/x (x) 
Grade 1 (6-15 cells) 
 
 
 
 
 
 
     Baseline 
x/x (x) 
x/x (x) 
x/x (x) 
x/x (x) 
x/x (x) 
x/x (x) 
     Week 4 
x/x (x) 
x/x (x) 
x/x (x) 
x/x (x) 
x/x (x) 
x/x (x) 
     … 
x/x (x) 
x/x (x) 
x/x (x) 
x/x (x) 
x/x (x) 
x/x (x) 
     Week 28 
x/x (x) 
x/x (x) 
x/x (x) 
x/x (x) 
x/x (x) 
x/x (x) 
Grade 2 (16-25 cells) 
 
 
 
 
 
 
     Baseline 
x/x (x) 
x/x (x) 
x/x (x) 
x/x (x) 
x/x (x) 
x/x (x) 
     Week 4 
x/x (x) 
x/x (x) 
x/x (x) 
x/x (x) 
x/x (x) 
x/x (x) 
     … 
x/x (x) 
x/x (x) 
x/x (x) 
x/x (x) 
x/x (x) 
x/x (x) 
     Week 28 
x/x (x) 
x/x (x) 
x/x (x) 
x/x (x) 
x/x (x) 
x/x (x) 
Grade 3 (26-50 cells) 
 
 
 
 
 
 
     Baseline 
x/x (x) 
x/x (x) 
x/x (x) 
x/x (x) 
x/x (x) 
x/x (x) 
     Week 4 
x/x (x) 
x/x (x) 
x/x (x) 
x/x (x) 
x/x (x) 
x/x (x) 
     … 
x/x (x) 
x/x (x) 
x/x (x) 
x/x (x) 
x/x (x) 
x/x (x) 
     Week 28 
x/x (x) 
x/x (x) 
x/x (x) 
x/x (x) 
x/x (x) 
x/x (x) 
Grade 4 (>50 cells) 
 
 
 
 
 
 
     Baseline 
x/x (x) 
x/x (x) 
x/x (x) 
x/x (x) 
x/x (x) 
x/x (x) 
     Week 4 
x/x (x) 
x/x (x) 
x/x (x) 
x/x (x) 
x/x (x) 
x/x (x) 
     … 
x/x (x) 
x/x (x) 
x/x (x) 
x/x (x) 
x/x (x) 
x/x (x) 
     Week 28 
x/x (x) 
x/x (x) 
x/x (x) 
x/x (x) 
x/x (x) 
x/x (x) 
Cannot grade or 
 Not Done 
 
 
 
 
 
 
     Baseline 
x/x (x) 
x/x (x) 
x/x (x) 
x/x (x) 
x/x (x) 
x/x (x) 
     Week 4 
x/x (x) 
x/x (x) 
x/x (x) 
x/x (x) 
x/x (x) 
x/x (x) 
     … 
x/x (x) 
x/x (x) 
x/x (x) 
x/x (x) 
x/x (x) 
x/x (x) 
     Week 28 
x/x (x) 
x/x (x) 
x/x (x) 
x/x (x) 
x/x (x) 
x/x (x) 
1Denominators are the number of participants in the safety population who completed the indicated visit, in the respective cohort 
or overall. Percentages are rounded to the nearest whole number.  


STAR SAP 
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Version 2.0 
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Page 37 
Table 20. Anterior Chamber Flare 
 
 
 
 
Cohort 1 
n/N (%)1 
Cohort 2 
n/N (%)1 
Overall 
n/N (%)1 
Grade 
OD 
OS 
 
OD 
 
OS 
 
OD 
 
OS 
Absent 
 
 
 
 
 
    Baseline 
x/x (x) 
x/x (x) 
x/x (x) 
x/x (x) 
x/x (x) 
x/x (x) 
    Week 4 
x/x (x) 
x/x (x)  
x/x (x) 
x/x (x) 
x/x (x) 
x/x (x) 
     … 
x/x (x) 
x/x (x) 
x/x (x) 
x/x (x) 
x/x (x) 
x/x (x) 
    Week 28 
x/x (x) 
x/x (x) 
x/x (x) 
x/x (x) 
x/x (x) 
x/x (x) 
Faint, barely detectable 
 
 
 
 
 
 
    Baseline 
x/x (x) 
x/x (x) 
x/x (x) 
x/x (x) 
x/x (x) 
x/x (x) 
    Week 4 
x/x (x) 
x/x (x) 
x/x (x) 
x/x (x) 
x/x (x) 
x/x (x) 
     … 
x/x (x) 
x/x (x) 
x/x (x) 
x/x (x) 
x/x (x) 
x/x (x) 
    Week 28 
x/x (x) 
x/x (x) 
x/x (x) 
x/x (x) 
x/x (x) 
x/x (x) 
Moderate, iris/lens details clear  
 
 
 
 
 
 
    Baseline 
x/x (x) 
x/x (x) 
x/x (x) 
x/x (x) 
x/x (x) 
x/x (x) 
    Week 4 
x/x (x) 
x/x (x) 
x/x (x) 
x/x (x) 
x/x (x) 
x/x (x) 
     … 
x/x (x) 
x/x (x) 
x/x(x) 
x/x (x) 
x/x (x) 
x/x (x) 
    Week 28 
x/x (x) 
x/x (x) 
x/x (x) 
x/x (x) 
x/x (x) 
x/x (x) 
Marked, iris/lens details hazy 
 
 
 
 
 
 
    Baseline 
x/x (x) 
x/x (x) 
x/x (x) 
x/x (x) 
x/x (x) 
x/x (x) 
    Week 4 
x/x (x) 
x/x (x) 
x/x (x) 
x/x (x) 
x/x (x) 
x/x (x) 
     … 
x/x (x) 
x/x (x) 
x/x (x) 
x/x (x) 
x/x (x) 
x/x (x) 
    Week 28 
x/x (x) 
x/x (x) 
x/x (x) 
x/x (x) 
x/x (x) 
x/x (x) 
Intense, fixed coagulated aqueuous  
humour, fibrin present 
 
 
 
 
 
 
    Baseline 
x/x (x) 
x/x (x) 
x/x (x) 
x/x (x) 
x/x (x) 
x/x (x) 
    Week 4 
x/x (x) 
x/x (x) 
x/x (x) 
x/x (x) 
x/x (x) 
x/x (x) 
     … 
x/x (x) 
x/x (x) 
x/x (x) 
x/x (x) 
x/x (x) 
x/x (x) 
    Week 28 
x/x (x) 
x/x (x) 
x/x (x) 
x/x (x) 
x/x (x) 
x/x (x) 
Cannot grade or 
 Not Done 
 
 
 
 
 
 
    Baseline 
x/x (x) 
x/x (x) 
x/x (x) 
x/x (x) 
x/x (x) 
x/x (x) 
    Week 4 
x/x (x) 
x/x (x) 
x/x (x) 
x/x (x) 
x/x (x) 
x/x (x) 
     … 
x/x (x) 
x/x (x) 
x/x (x) 
x/x (x) 
x/x (x) 
x/x (x) 
    Week 28 
x/x (x) 
x/x (x) 
x/x (x) 
x/x (x) 
x/x (x) 
x/x (x) 
1Denominators are the number of participants in the safety population who completed the indicated visit, in the respective 
cohort or overall. Percentages are rounded to the nearest whole number.  


STAR SAP 
November 20, 2020 
Version 2.0 
Confidential 
Page 38 
Table 21. Vitreous Cells 
 
 
 
Cohort 1 
n/N (%)1 
Cohort 2 
n/N (%)1 
Overall 
n/N (%)1 
Grade 
OD 
OS 
 
OD 
 
OS 
 
OD 
 
OS 
Grade 0 (0-1 cell) 
 
 
 
 
 
     Baseline 
x/x (x) 
x/x (x) 
x/x (x) 
x/x (x) 
x/x (x) 
x/x (x) 
     Week 4 
x/x (x) 
x/x (x) 
 
x/x (x) 
x/x (x) 
x/x (x) 
x/x (x) 
     … 
x/x (x) 
x/x (x) 
x/x (x) 
x/x (x) 
x/x (x) 
x/x (x) 
     Week 28 
x (x) 
x/x (x) 
x/x (x) 
x/x (x) 
x/x (x) 
x/x (x) 
Trace (2-20 cells) 
 
 
 
 
 
 
     Baseline 
x/x (x) 
x/x (x) 
x/x (x) 
x/x (x) 
x/x (x) 
x/x (x) 
     Week 4 
x/x (x) 
x/x (x) 
x/x (x) 
x/x (x) 
x/x (x) 
x/x (x) 
     … 
x/x (x) 
x/x (x) 
x/x (x) 
x/x (x) 
x/x (x) 
x/x (x) 
     Week 28 
x/x (x) 
x/x (x) 
x/x (x) 
x/x (x) 
x/x (x) 
x/x (x) 
Grade 1 (21-50 cells) 
 
 
 
 
 
 
     Baseline 
x/x (x) 
x/x (x) 
x/x (x) 
x/x (x) 
x/x (x) 
x/x (x) 
     Week 4 
x/x (x) 
x/x (x) 
x/x (x) 
x/x (x) 
x/x (x) 
x/x (x) 
     … 
x/x (x) 
x/x (x) 
x/x (x) 
x/x (x) 
x/x (x) 
x/x (x) 
     Week 28 
x/x (x) 
x/x (x) 
x/x (x) 
x/x (x) 
x/x (x) 
x/x (x) 
Grade 2 (51-100 cells) 
 
 
 
 
 
 
     Baseline 
x/x (x) 
x/x (x) 
x/x (x) 
x/x (x) 
x/x (x) 
x/x (x) 
     Week 4 
x/x (x) 
x/x (x) 
x/x (x) 
x/x (x) 
x/x (x) 
x/x (x) 
     … 
x/x (x) 
x/x (x) 
x/x (x) 
x/x (x) 
x/x (x) 
x/x (x) 
     Week 28 
x/x (x) 
x/x (x) 
x/x (x) 
x/x (x) 
x/x (x) 
x/x (x) 
Grade 3 (101-250 cells) 
 
 
 
 
 
 
     Baseline 
x/x (x) 
x/x (x) 
x/x (x) 
x/x (x) 
x/x (x) 
x/x (x) 
     Week 4 
x/x (x) 
x/x (x) 
x/x (x) 
x/x (x) 
x/x (x) 
x/x (x) 
     … 
x/x (x) 
x/x (x) 
x/x (x) 
x/x (x) 
x/x (x) 
x/x (x) 
     Week 28 
x/x (x) 
x/x (x) 
x/x (x) 
x/x (x) 
x/x (x) 
x/x (x) 
Grade 4 (>250 cells) 
 
 
 
 
 
 
     Baseline 
x/x (x) 
x/x (x) 
x/x (x) 
x/x (x) 
x/x (x) 
x/x (x) 
     Week 4 
x/x (x) 
x/x (x) 
x/x (x) 
x/x (x) 
x/x (x) 
x/x (x) 
     … 
x/x (x) 
x/x (x) 
x/x (x) 
x/x (x) 
x/x (x) 
x/x (x) 
     Week 28 
x/x (x) 
x/x (x) 
x/x (x) 
x/x (x) 
x/x (x) 
x/x (x) 
Cannot grade or 
 Not Done 
 
 
 
 
 
 
     Baseline 
x/x (x) 
x/x (x) 
x/x (x) 
x/x (x) 
x/x (x) 
x/x (x) 
     Week 4 
x/x (x) 
x/x (x) 
x/x (x) 
x/x (x) 
x/x (x) 
x/x (x) 
     … 
x/x (x) 
x/x (x) 
x/x (x) 
x/x (x) 
x/x (x) 
x/x (x) 
     Week 28 
x/x (x) 
x/x (x) 
x/x (x) 
x/x (x) 
x/x (x) 
x/x (x) 
1Denominators are the number of participants in the safety population who completed the indicated visit, in the respective cohort 
or overall. Percentages are rounded to the nearest whole number.  


STAR SAP 
November 20, 2020 
Version 2.0 
Confidential 
Page 39 
Table 22. Summary of Vitreous Haze 
 
 
 
Cohort 1 
n/N (%)1 
Cohort 2 
n/N (%)1 
Overall 
n/N (%)1 
Grade 
OD 
OS 
 
OD 
 
OS 
 
OD 
 
OS 
Clear 
 
 
 
 
 
     Baseline 
x/x (x) 
x/x (x) 
x/x (x) 
x/x (x) 
x/x (x) 
x/x (x) 
     Week 4 
x/x (x) 
x/x (x) 
x/x (x) 
x/x (x) 
x/x (x) 
x/x (x) 
     … 
x/x (x) 
x/x (x) 
 
x/x (x) 
x/x (x) 
x/x (x) 
x/x (x) 
     Week 28 
x/x (x) 
x/x (x) 
x/x (x) 
x/x (x) 
x/x (x) 
x/x (x) 
Trace 
 
 
 
 
 
 
     Baseline 
x/x (x) 
x/x (x) 
x/x (x) 
x/x (x) 
x/x (x) 
x/x (x) 
     Week 4 
x/x (x) 
x/x (x) 
x/x (x) 
x/x (x) 
x/x (x) 
x/x (x) 
     … 
x/x (x) 
x/x (x) 
x/x (x) 
x/x (x) 
x/x (x) 
x/x (x) 
     Week 28 
x/x (x) 
x/x (x) 
x/x (x) 
x/x (x) 
x/x (x) 
x/x (x) 
Few opacities, mild 
blurring 
 
 
 
 
 
 
     Baseline 
x/x (x) 
x/x (x) 
x/x (x) 
x/x (x) 
x/x (x) 
x/x (x) 
     Week 4 
x/x (x) 
x/x (x) 
x/x (x) 
x/x (x) 
x/x (x) 
x/x (x) 
     … 
x/x (x) 
x/x (x) 
x/x (x) 
x/x (x) 
x/x (x) 
x/x (x) 
     Week 28 
x/x (x) 
x/x (x) 
x/x (x) 
x/x (x) 
x/x (x) 
x/x (x) 
Significant blurring, 
but still visible 
 
 
 
 
 
 
     Baseline 
x/x (x) 
x/x (x) 
x/x (x) 
x/x (x) 
x/x (x) 
x/x (x) 
     Week 4 
x/x (x) 
x/x (x) 
x/x (x) 
x/x (x) 
x/x (x) 
x/x (x) 
     … 
x/x (x) 
x/x (x) 
x/x (x) 
x/x (x) 
x/x (x) 
x/x (x) 
     Week 28 
x/x (x) 
x/x (x) 
x/x (x) 
x/x (x) 
x/x (x) 
x/x (x) 
Optic nerve visible, no 
vessels seen 
 
 
 
 
 
 
     Baseline 
x/x (x) 
x/x (x) 
x/x (x) 
x/x (x) 
x/x (x) 
x/x (x) 
     Week 4 
x/x (x) 
x/x (x) 
x/x (x) 
x/x (x) 
x/x (x) 
x/x (x) 
     … 
x/x (x) 
x/x (x) 
x/x (x) 
x/x (x) 
x/x (x) 
x/x (x) 
     Week 28 
x/x (x) 
x/x (x) 
x/x (x) 
x/x (x) 
x/x (x) 
x/x (x) 
Dense opacity obscures 
optic nerve head 
 
 
 
 
 
 
     Baseline 
x/x (x) 
x/x (x) 
x/x (x) 
x/x (x) 
x/x (x) 
x/x (x) 
     Week 4 
x/x (x) 
x/x (x) 
x/x (x) 
x/x (x) 
x/x (x) 
x/x (x) 
     … 
x/x (x) 
x/x (x) 
x/x (x) 
x/x (x) 
x/x (x) 
x/x (x) 
     Week 28 
x/x (x) 
x/x (x) 
x/x (x) 
x/x (x) 
x/x (x) 
x/x (x) 
Cannot grade or 
 Not Done 
 
 
 
 
 
 
     Baseline 
x/x (x) 
x/x (x) 
x/x (x) 
x/x (x) 
x/x (x) 
x/x (x) 
     Week 4 
x/x (x) 
x/x (x) 
x/x (x) 
x/x (x) 
x/x (x) 
x/x (x) 
     … 
x/x (x) 
x/x (x) 
x/x (x) 
x/x (x) 
x/x (x) 
x/x (x) 
     Week 28 
x/x (x) 
x/x (x) 
x/x (x) 
x/x (x) 
x/x (x) 
x/x (x) 
1Denominators are the number of participants in the safety population who completed the indicated visit, in the respective cohort 
or overall. Percentages are rounded to the nearest whole number.  


STAR SAP 
November 20, 2020 
Version 2.0 
Confidential 
Page 40 
Table 23. Chorioretinal Assessments and FA Leakage 
 
 
Cohort 1 
n/N (%)1 
Cohort 2 
n/N (%)1 
Overall 
n/N (%)1 
Grade 
OD 
OS 
 
OD 
 
OS 
 
OD 
 
OS 
Presence of Active Chorioretinitis 
 
 
 
 
 
    Baseline 
x/x (x) 
x/x (x) 
x/x (x) 
x/x (x) 
x/x (x) 
x/x (x) 
    Week 4 
x/x (x) 
x/x (x) 
x/x (x) 
x/x (x) 
x/x (x) 
x/x (x) 
    … 
x/x (x) 
x/x (x)  x/x (x) 
x/x (x) 
x/x (x) 
x/x (x) 
    Week 28 
x/x (x) 
x/x (x) 
x/x (x) 
x/x (x) 
x/x (x) 
x/x (x) 
FA Leakage In More than One Quadrant  
(Needs Treatment) 
 
 
 
 
 
 
    Baseline 
x/x (x) 
x/x (x) 
x/x (x) 
x/x (x) 
x/x (x) 
x/x (x) 
    Week 4 
x/x (x) 
x/x (x) 
x/x (x) 
x/x (x) 
x/x (x) 
x/x (x) 
     … 
x/x (x) 
x/x (x) 
x/x (x) 
x/x (x) 
x/x (x) 
x/x (x) 
    Week 28 
x/x (x) 
x/x (x) 
x/x (x) 
x/x (x) 
x/x (x) 
x/x (x) 
Active Inflammatory Chorioretinal Lesions 
 
 
 
 
 
 
    Week 4 
x/x (x) 
x/x (x) 
x/x (x) 
x/x (x) 
x/x (x) 
x/x (x) 
    … 
x/x (x) 
x/x (x) 
x/x (x) 
x/x (x) 
x/x (x) 
x/x (x) 
    Week 28 
x/x (x) 
x/x (x) 
x/x (x) 
x/x (x) 
x/x (x) 
x/x (x) 
New/Increased Chorioretinal Lesions 
 
 
 
 
 
 
    Week 4 
x/x (x) 
x/x (x) 
x/x (x) 
x/x (x) 
x/x (x) 
x/x (x) 
     … 
x/x (x) 
x/x (x) 
x/x (x) 
x/x (x) 
x/x (x) 
x/x (x) 
    Week 28 
x/x (x) 
x/x (x) 
x/x (x) 
x/x (x) 
x/x (x) 
x/x (x) 
1Denominators are the number of participants in the safety population who completed the indicated visit, in the respective 
cohort or overall. Percentages are rounded to the nearest whole number.  


STAR SAP 
November 20, 2020 
Version 2.0 
Confidential 
Page 41 
Table 24. Laboratory Assessments  
 
 
Abnormal Findings 
n/N (%)1 
Any Change from Baseline 
n/N (%)1 
Clinically Significant  
Change from Baseline 
n/N (%)1 
Visit 
Cohort 1 
Cohort 2 
 Overall 
Cohort 1 
Cohort 2 
Overall 
Cohort 1 
Cohort 2 
Overall 
Baseline 
x/x (x) 
x/x (x) 
x/x (x) 
 
 
 
 
 
 
Week 4 
 
 
x/x (x) 
x/x (x) 
x/x (x) 
x/x (x) 
x/x (x) 
x/x (x) 
… 
 
 
x/x (x) 
x/x (x) 
x/x (x) 
x/x (x) 
x/x (x) 
x/x (x) 
Week 28
 
 
x/x (x) 
x/x (x) 
x/x (x) 
x/x (x) 
x/x (x) 
x/x (x) 
1Denominators are the number of participants in the safety population who completed the indicated visit, in the respective cohort or overall. Percentages are rounded to the 
nearest whole number. 
 
 
Table 25. Significant Physical Exam Findings 
Visit 
Cohort 1 
n/N (%)1 
Cohort 2 
n/N (%)1 
 Overall 
n/N (%)1 
Baseline 
x/x (x) 
x/x (x) 
x/x (x) 
Week 4 
x/x (x) 
x/x (x) 
x/x (x) 
…
x/x (x) 
x/x (x) 
x/x (x) 
Week 28
x/x (x) 
x/x (x) 
x/x (x) 
1Denominators are the number of participants in the safety population who completed the indicated visit, in the respective cohort or overall. Percentages are rounded to the 
nearest whole number. 


STAR SAP 
November 20, 2020 
Version 2.0 
Confidential 
Page 42 
Table 26. Blood Pressure  
 
 
 Cohort 1 
 Cohort 2 
Overall 
 
 Systolic 
 Diastolic 
 Systolic 
 Diastolic 
 Systolic 
 Diastolic 
Visit  
Value 
(mmHg) 
Δ 
(mmHg) 
Value 
(mmHg) 
Δ 
(mmHg) 
Value 
(mmHg) 
Δ 
(mmHg) 
Value 
(mmHg) 
Δ(mmHg) 
Value 
(mmHg) 
Δ 
(mmHg) 
Value 
(mmHg) 
Δ 
(mmHg) 
Baseline 
 
 
 
 
 
 
 
 
 
 
 
 
   N 
x 
 
x 
 
x 
 
x 
 
x 
 
x 
 
   Mean (SD) 
x (x) 
 
x (x) 
 
x (x) 
 
x (x) 
 
x (x) 
 
x (x) 
 
   Median 
x 
 
x 
 
x 
 
x 
 
x 
 
x 
 
   Range (Min, Max)
(x, x) 
 
(x, x) 
 
(x, x) 
 
(x, x) 
 
(x, x) 
 
(x, x) 
 
… 
 
 
 
 
 
 
 
 
 
 
 
 
Week 28 
 
 
 
 
 
 
 
 
 
 
 
 
   N 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
   Mean (SD) 
x (x) 
x (x) 
x (x) 
x (x) 
x (x) 
x (x) 
x (x) 
x (x) 
x (x) 
x (x) 
x (x) 
x (x) 
   Median 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
x 
   Range (Min, Max)
(x, x) 
(x, x) 
(x, x) 
(x, x) 
(x, x) 
(x, x) 
(x, x) 
(x, x) 
(x, x) 
(x, x) 
(x, x) 
(x, x) 
Δ indicates change from baseline. 
 
 
 
 


STAR SAP 
November 20, 2020 
Version 2.0 
Confidential 
Page 43 
Table 27. Temperature 
 
 
 Cohort 1 
 Cohort 2 
Overall 
Visit  
Value (°C) 
Δ (°C) 
Value (°C) 
Δ (°C) 
Value (°C) 
Δ (°C) 
Baseline 
 
 
 
 
 
 
  N
x 
 
x 
 
x 
 
  Mean (SD) 
x (x) 
 
x (x) 
 
x (x) 
 
  Median 
x 
 
x 
 
x 
 
  Range (Min, Max) 
(x, x) 
 
(x, x) 
 
(x, x) 
 
… 
 
 
 
 
 
 
Week 28 
 
 
 
 
 
 
  N
x 
x 
x 
x 
x 
x 
  Mean (SD) 
x (x) 
x (x) 
x (x) 
x (x) 
x (x) 
x (x) 
  Median 
x 
x 
x 
x 
x 
x 
  Range (Min, Max) 
(x, x) 
(x, x) 
(x, x) 
(x, x) 
(x, x) 
(x, x) 
Δ indicates change from baseline. 
 


STAR SAP 
November 20, 2020 
Version 2.0 
Confidential 
Page 44 
LISTINGS 
 
Listing 1. Treatment Response Criteria 
 
No 
Lesion1 
Absent/Decreased 
Leakage2 
AC 
Cells3 
Vitreous 
Haze4 
Cohort 
Participant 
ID 
Visit 
OD 
OS 
OD 
OS 
OD 
OS 
OD 
OS 
1 
NEI001 
Week 4 
Yes / No 
Yes / No 
Yes / No 
Yes / No 
Yes / No 
Yes / No 
Yes / No 
Yes / No 
 
 
Week 8 
Yes / No 
Yes / No 
Yes / No 
Yes / No 
Yes / No 
Yes / No 
Yes / No 
Yes / No 
 
 
Week 12 
Yes / No 
Yes / No 
Yes / No 
Yes / No 
Yes / No 
Yes / No 
Yes / No 
Yes / No 
 
 
Week 16 
Yes / No 
Yes / No 
Yes / No 
Yes / No 
Yes / No 
Yes / No 
Yes / No 
Yes / No 
 
 
Week 28 
Yes / No 
Yes / No 
Yes / No 
Yes / No 
Yes / No 
Yes / No 
Yes / No 
Yes / No 
 
… 
Week 4 
Yes / No 
Yes / No 
Yes / No 
Yes / No 
Yes / No 
Yes / No 
Yes / No 
Yes / No 
 
 
… 
Yes / No 
Yes / No 
Yes / No 
Yes / No 
Yes / No 
Yes / No 
Yes / No 
Yes / No 
2 
NEIxxx 
Week 4 
Yes / No 
Yes / No 
Yes / No 
Yes / No 
Yes / No 
Yes / No 
Yes / No 
Yes / No 
 
 
… 
Yes / No 
Yes / No 
Yes / No 
Yes / No 
Yes / No 
Yes / No 
Yes / No 
Yes / No 
1No active inflammatory chorioretinal lesion. 
2Absent or decreased retinal vascular leakage. 
3Less than or equal to 0.5+ anterior chamber (AC) cells. 
4 Less than or equal to 0.5+ vitreous haze. 
Treatment responses are highlighted in green if occurring only in OD, blue if occurring only in OS, and yellow if in both eyes. 
 
 
 
 
 


STAR SAP 
November 20, 2020 
Version 2.0 
Confidential 
Page 45 
Listing 2. BCVA Total Letters Read Over Time 
 
 
 BCVA Total Letters 
Read 
 Change from Baseline1 
Cohort 
Participant ID 
Visit  
OD 
OS 
OD 
OS 
1 
NEI001 
Baseline
x
x
 
 
Week 4
x
x
x
x
 
 
Week 8
x
x
x
x
 
 
Week 12
x
x
x
x
 
 
Week 16
x
x
x
x
 
 
Week 28
x
x
x
x
 
… 
Baseline
x
x
 
 
…
x
x
x
x
2 
NEIxxx 
Baseline
x
x
 
 
… 
x 
x 
x 
x 
1Yellow highlight indicates loss of ≥ 15 letters from baseline. 
 


STAR SAP 
November 20, 2020 
Version 2.0 
Confidential 
Page 46 
Listing 3. Recurrence of Uveitis 
 
 
Recurrence Criteria 
 
 
 
New 
Lesion1 
New 
Leakage2 
AC 
Cells3 
Vitreous 
Haze4 
BCVA 
Change5 
 
 
Cohort 
Participant
ID 
Visit 
OD 
OS 
OD 
OS 
OD 
OS 
OD 
OS 
OD 
OS 
 
Time (Days)6 
1 
NEI001 
Week 4 Yes /No Yes /No Yes /No Yes /No Yes /No Yes /No Yes /No Yes /No Yes /No 
Yes /No 
xxx 
 
 
Week 8 Yes /No Yes /No Yes /No Yes /No Yes /No Yes /No Yes /No Yes /No Yes /No 
Yes /No 
xxx 
 
 
Week 12 Yes /No Yes /No Yes /No Yes /No Yes /No Yes /No Yes /No Yes /No Yes /No 
Yes /No 
xxx 
 
 
Week 16 Yes /No Yes /No Yes /No Yes /No Yes /No Yes /No Yes /No Yes /No Yes /No 
Yes /No 
xxx 
 
 
Week 28 Yes /No Yes /No Yes /No Yes /No Yes /No Yes /No Yes /No Yes /No Yes /No 
Yes /No 
xxx 
 
… 
 
Yes /No Yes /No Yes /No Yes /No Yes /No Yes /No Yes /No Yes /No Yes /No 
Yes /No 
xxx 
 
 
… 
Yes /No Yes /No Yes /No Yes /No Yes /No Yes /No Yes /No Yes /No Yes /No 
Yes /No 
xxx 
2 
NEIxxx 
Week 4 Yes /No Yes /No Yes /No Yes /No Yes /No Yes /No Yes /No Yes /No Yes /No 
Yes /No 
xxx 
 
 
… 
Yes /No Yes /No Yes /No Yes /No Yes /No Yes /No Yes /No Yes /No Yes /No 
Yes /No 
xxx 
1New active inflammatory chorioretinal lesion. 
2New retinal vascular leakage. 
3A 2+ increase in AC cells relative to baseline. 
4A 2-step increase in vitreous haze relative to baseline. 
5Worsening of BCVA by greater than or equal to 15 letters relative to baseline. 
6Length of time until recurrence of uveitis  relative to baseline. 
Recurrences are highlighted in green if occurring only in OD, blue if occurring only in OS, and yellow if in both eyes. 
 
 
 
 
 
 
 


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November 20, 2020 
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Page 47 
Listing 4. Retino-Vascular Leakage  
 
 
Retinovascular Lesions 
Present 
New/Increased Lesions 
Decreased Lesions 
Cohort 
Participant 
ID 
Visit 
Number 
OD 
OS 
OD 
OS 
OD 
OS 
1 
NEI001 
Week 4 
Yes/No 
Yes/No 
Yes/No 
Yes/No 
Yes/No 
Yes/No 
 
 
Week 8 
Yes/No 
Yes/No 
Yes/No 
Yes/No 
Yes/No 
Yes/No 
 
 
Week 12 
Yes/No 
Yes/No 
Yes/No 
Yes/No 
Yes/No 
Yes/No 
 
 
Week 16 
Yes/No 
Yes/No 
Yes/No 
Yes/No 
Yes/No 
Yes/No 
 
 
Week 28 
Yes/No 
Yes/No 
Yes/No 
Yes/No 
Yes/No 
Yes/No 
 
NEI002 
Week 4 
Yes/No 
Yes/No 
Yes/No 
Yes/No 
Yes/No 
Yes/No 
 
 
… 
Yes/No 
Yes/No 
Yes/No 
Yes/No 
Yes/No 
Yes/No 
2 
NEIxxx 
Week 4 
Yes/No 
Yes/No 
Yes/No 
Yes/No 
Yes/No 
Yes/No 
 
 
… 
Yes/No 
Yes/No 
Yes/No 
Yes/No 
Yes/No 
Yes/No 
 


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November 20, 2020 
Version 2.0 
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Page 48 
Listing 5. Central Retinal Thickness on OCT Over Time  
 
 
 
 
 Central Retinal 
Thickness (μm) 
 Change from Baseline 
(μm) 
Cohort 
Participant ID 
Visit 
OD 
OS 
OD 
OS 
1 
NEI001 
Baseline
x
x
 
 
Week 4
x
x
x
x
 
 
Week 8
x
x
x
x
 
 
Week 12
x
x
x
x
 
 
Week 16
x
x
x
x
 
 
Week 28
x
x
x
x
 
NEI002 
Baseline
x
x
 
 
…
x
x
x
x
2 
NEIxxx 
Baseline
x
x
 
 
…
x
x
x
x


STAR SAP 
November 20, 2020 
Version 2.0 
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Page 49 
Listing 6. Quiescence 
 
Quiescence Criteria 
 
Vitreous 
Haze1 
No 
Chorioretinitis2 
No 
Leakage3 
 
Cohort 
Participant 
ID 
Visit 
Number 
OD 
OS 
OD 
OS 
OD 
OS 
Time 
(Days)4 
1 
NEI001 
Week 4 
Yes/No 
Yes/No 
Yes/No 
Yes/No 
Yes/No 
Yes/No 
xxx 
 
 
Week 8 
Yes/No 
Yes/No 
Yes/No 
Yes/No 
Yes/No 
Yes/No 
xxx 
 
 
Week 12 
Yes/No 
Yes/No 
Yes/No 
Yes/No 
Yes/No 
Yes/No 
xxx 
 
 
Week 16 
Yes/No 
Yes/No 
Yes/No 
Yes/No 
Yes/No 
Yes/No 
xxx 
 
 
Week 28 
Yes/No 
Yes/No 
Yes/No 
Yes/No 
Yes/No 
Yes/No 
xxx 
 
… 
… 
Yes/No 
Yes/No 
Yes/No 
Yes/No 
Yes/No 
Yes/No 
xxx 
2 
NEIxxx 
Week 4 
Yes/No 
Yes/No 
Yes/No 
Yes/No 
Yes/No 
Yes/No 
xxx 
 
 
… 
Yes/No 
Yes/No 
Yes/No 
Yes/No 
Yes/No 
Yes/No 
xxx 
1Less than 1 vitreous haze. 
2Absence of active chorioretinitis. 
3Absence of leakage on FA. 
4Length of time until quiescence relative to baseline. 
Quiescence events are highlighted in green if occurring only in OD, blue if occurring only in OS, and yellow if in both eyes.  
 


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November 20, 2020 
Version 2.0 
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Page 50 
Listing 7. Steroid Tapering 
Cohort 
Participant 
ID 
Medication 
Name 
Starting 
Dose 
Steroid 
Indication 
Target 
Date 
Target 
Dose 
Actual 
Date1 
Actual 
Dose2 
1 
NEIxxx 
xxxxxxxx 
xx mg 
xxxxxxxxxx 
xx/xx/xx 
xx mg 
xx/xx/xx 
xx mg 
 
 
 
 
 
xx/xx/xx 
xx mg 
xx/xx/xx 
xx mg 
 
 
 
 
 
xx/xx/xx 
xx mg 
xx/xx/xx 
xx mg 
 
 
 
 
 
… 
… 
… 
… 
2 
NEIxxx 
 
 
 
xx/xx/xx 
xx mg 
xx/xx/xx 
xx mg 
 
 
 
 
 
… 
… 
… 
… 
2 Actual date only shown if different from target date. 
2 Actual dose only shown if different from target dose. 
 
 
 


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November 20, 2020 
Version 2.0 
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Page 51 
FIGURES 
 
Figure 1. Study Disposition 
 
 
 
 
 
 
 
 
 
 
Enrolled in 
Cohort 1 
 
N=X 
Received at least one 
dose of IP 
 
N=X 
Completed Study 
 
N=X 
Discontinued IP 
 
N=X 
Discontinued Study 
 
N=X 
Enrolled in 
Cohort 2 
 
N=X 
Received at least one 
dose of IP 
 
N=X 
Discontinued IP 
 
N=X 
Discontinued Study 
 
N=X 
Completed Study 
 
N=X 


STAR SAP 
November 20, 2020 
Version 2.0 
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Page 52 
Figure 2. BCVA Total Letters Read Over Time  
 
 
Reference line corresponds to loss of 15 letters compared to baseline. 
OS
OD
Change from Baseline in BCVA Total Letters Read
Cohort 2
Cohort 1
004
008
012
016
028
Visit
-20
-16
-12
-8
-4
0
4
8
12
16
20
-20
-16
-12
-8
-4
0
4
8
12
16
20


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November 20, 2020 
Version 2.0 
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Page 53 
Figure 3. Central Retinal Thickness Over Time  
 
Figure 3 will be similar to Figure 2 and will present boxplots of central retinal thickness at each visit for each cohort.