Conditions: Uveitis
Keywords: Immunosuppression Adalimumab Antimetabolites Calcineurin inhibitors Corticosteroid sparing
Allocation: RANDOMIZED | Intervention model: PARALLEL
Enrollment: 227
Healthy volunteers: no

Brief summary:
Non-infectious intermediate, posterior, and panuveitides are chronic, potentially-blinding diseases. Vision-threatening cases require long-term therapy with oral corticosteroids and immunosuppression. Based upon preliminary data, adalimumab, a fully-human, anti-tumor necrosis(TNF)-α monoclonal antibody, now US FDA-approved for uveitis treatment, may be a superior corticosteroid-sparing agent than conventional immunosuppressive drugs. The ADVISE Trial is multicenter randomized, parallel-treatment, comparative effectiveness trial comparing adalimumab to conventional (small molecule) immunosuppression for corticosteroid spring in the treatment of non-infectious, intermediate, posterior, and panuveitides.

Detailed description:
Abstract from protocol: The uveitides are a collection of diseases characterized by intraocular inflammation. Collectively, they are the 5th leading cause of blindness in the US, and the estimated cost of treating them is similar to that of treating diabetic retinopathy. Non-infectious intermediate, posterior, and panuveitides have the highest rates of visual loss and typically are treated with oral corticosteroids and immunosuppression. The Multicenter Uveitis Steroid Treatment (MUST) Trial (a randomized, comparative effectiveness trial, which compared 2 treatment paradigms for these diseases, systemic therapy with corticosteroids and immunosuppression vs. regional therapy \[the fluocinolone acetonide implant\]), and Follow-up Study demonstrated the superiority of the systemic approach to the regional ocular approach in terms of long-term visual outcomes with essentially no increase in systemic side effects in the systemic group. One key to systemic therapy's success was the use of systemic immunosuppression in 88% of participants, coupled with tapering the prednisone to \<7.5 mg/day, a relatively safe dose. Non-alkylating agents are typically the first choice and the most often used are azathioprine, methotrexate, mycophenolate, cyclosporine, and tacrolimus. The alkylating agents, cyclophosphamide and chlorambucil, are used less often because of concerns about potential increased malignancy risk. Data from the Systemic Immunosuppressive Therapy for Eye Diseases (SITE) Cohort Study suggest that each of the conventional, non-alkylating agent immunosuppressive drugs is effective in controlling the inflammation while permitting tapering prednisone in \~40-55% of patients; hence combination therapy often is needed. Furthermore, minimizing the daily dose of prednisone is important, as the risk of cardiovascular disease and mortality increase with the cumulative dose of oral corticosteroids. In June 2016, the fully-human, anti-TNF-α monoclonal antibody, adalimumab, was approved by the US Food and Drug Administration (FDA) for the treatment of uveitis. Anti-TNF-α monoclonal antibody therapy has revolutionized the management of the rheumatic diseases largely due to its superior efficacy compared to conventional Disease Modifying Anti-Rheumatic Drugs. Data from VISUAL III, the extension of the two phase 3 trials that led to the FDA approval of adalimumab for the treatment of uveitis, suggest that adalimumab may be superior to conventional immunosuppression, as \~75% of participants had controlled inflammation with prednisone doses \<5 mg/day. The ADalimumab Vs. conventional ImmunoSupprEssion for uveitis (ADVISE) Trial is a randomized, comparative effectiveness trial comparing adalimumab to conventional agent immunosuppression for patients with non-infectious, intermediate, posterior, and panuveitides. The primary outcome is the ability to successfully taper prednisone to \<7.5 mg/day by 6 months after randomization while maintaining control of the inflammation. Secondary outcomes include prednisone discontinuation by 1 year, visual acuity, and complications of uveitis and its treatment.

ADVISE is being conducted under investigational new drug (IND) 132532. Adalimumab was FDA approved for the treatment of non-infectious intermediate, posterior, and panuveitides in adult patients in 2016 and in pediatric patients 2 years of age and older in 2018. In 2016, prior to the approval for pediatric patients, the FDA determined that use of adalimumab for the treatment of non-infectious intermediate, posterior, and panuveitides in adolescent patients in the ADVISE Trial does not increase risk for these patients as the drug is approved for treatment of pediatric patients for other indications. Although conventional immunosuppressive drugs are the standard approach and in widespread use, these drugs are not FDA approved for treatment of non-infectious intermediate, posterior, and panuveitides, and therefore an IND has been issued for this trial.

Arms:
arm 1: Adalimumab administered by subcutaneous injection at dosage and frequency specified below; total duration of treatment is 12 months.

Adults (≥ 18 years of age) and adolescents ≥30 kg: 80 mg as initial dose; one week later by 40 mg then 40 mg every two weeks. Adolescents \<30 kg: 40 mg as initial dose; one week later 20 mg then 20 mg every 2 weeks. arm 2: Conventional immunosuppressive agent selected by study ophthalmologist at dose and frequency specified below;12 month treatment duration.

Azathioprine: initially 2 mg/kg/day; max dose 200 mg/day. Methotrexate initially 15mg/wk; max dose 25 mg/wk. Mycophenolate initially 1 gm twice daily (BID); max dose1.5 gm BID. Cyclosporine (Sandimmune - dose 2.5 mg/kg BID and Neoral dose 2 mg/kg BID. Tacrolimus initially 1 mg BID; max dose 3 mg BID.

Interventions: intervention 1: Adalimumab (ADA) intervention 2: Conventional immunosuppression (CON)
Intervention descriptions: intervention 1: Adalimumab is a fully-human monoclonal antibody to TNF-α, which is approved by the U.S. FDA for the treatment of non-infectious intermediate, posterior, and panuveitides in adults and children 2 years of age and older. intervention 2: The study ophthalmologist will select amongst the permissible drugs (methotrexate, mycophenolate mofetil or azathioprine for antimetabolites; cyclosporine or tacrolimus for calcineurin inhibitors) taking into account the side effect profile of each drug with respect to subject's clinical situation.

Protocol document:
ICF_002.pdf: 
 
 
 
 
 
 
 
Adalimumab vs. Conventional Immunosuppression for Corticosteroid-
sparing for Uveitis (ADVISE) Trial 
 
Adult Consent 
Version date  November 8, 2021 
 
 
 ClinicalTrials.gov identifier: NCT03828019 


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JOHNS HOPKINS BLOOMBERG SCHOOL OF PUBLIC HEALTH 
 
INFORMED CONSENT DOCUMENT 
 
Adult consent  
 
Study Title:  Adalimumab vs. Conventional Immunosuppression for 
Corticosteroid-sparing for Uveitis (ADVISE) Trial 
Principal Investigator:  Janet Holbrook, PhD, MPH 
IRB No.:  00009196 
Funded By: National Eye Institute of the National Institutes of Health  
PI Version Date:  November 8, 2021 
 
Key information about this study 
• We are asking you to volunteer for a research study of treatments 
for non-infectious uveitis.  You do not have to join the study; it is 
your choice and there is no penalty for not joining.  Ask as many 
questions as you need to help you make your decision.  Please 
review the details about the study described in the rest of this 
consent document before deciding about joining the study. 
• In the study you will receive standard treatments for uveitis.  You 
and your doctor will not have a choice to which drugs you receive.  
You will receive the same kind of care and monitoring that you 
would get outside the study.  We do not know if being in the study 
will benefit you more than if you received similar care outside of 
the study. 
• The study is being conducted to see whether adalimumab 
(Humira) or conventional immunosuppressive drugs works better 
to control uveitis and allow the dose of prednisone to be reduced 
to 7.5 mg/day or less.  You are being asked to participate because 
you have intermediate, posterior, or panuveitis that requires a 
dose of prednisone that is greater than 7.5 mg/day.   
• If you join, you will be randomly assigned by computer to receive 
either adalimumab or a conventional immunosuppression drug in 
addition to prednisone.   


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• If you are assigned to adalimumab, the study will provide the 
adalimumab.  Adalimumab is given by injection under the skin on 
the thigh or abdomen.  If you are assigned to receive adalimumab, 
we will teach you (or a care-giver) how to give an injection at the 
first study visit.  We will give you the first injection.  After that you 
will give yourself an injection on the same day (in the clinic).  Then 
you will give yourself an injection one week later and then every 
other week at home for the rest of the study.  The most common 
side effects of adalimumab are redness, itching, pain or swelling at 
the injection site, which is reported in 20% of patients.  If you are 
assigned to receive adalimumab, it will be provided free of charge 
because it has been donated by the drug company AbbVie.  
If a second study drug (a conventional immunosuppressive drug) 
needs to be added to adalimumab to treat your uveitis, it will be 
charged to your insurance and you will be responsible for any co-
payments.  The study will reimburse you for co-payments up to 
$1500 for conventional immunosuppressive drugs you were 
prescribed as part of the study. 
• If you are assigned to conventional immunosuppression, your 
doctor will prescribe one of five different conventional 
immunosuppressive drugs.  Conventional immunosuppressive 
drugs are usually given by mouth in the form of a pill.  The side 
effects depend upon the type and dose of the particular drug.  
Your doctor will explain the side effects of these drugs, each has 
different side effects.  You and your doctor will select the best one 
for you.  You should fill the prescription and start taking the drug 
as soon as possible.  The cost of the drug will be charged to your 
insurance and you will be responsible for any co-payments.  The 
study will reimburse you up to $3000 for co-payments for 
immunosuppressive drugs prescribed for you as part of the study. 
• All participants will also take prednisone.  Your doctor may change 
the type and dose of the study drugs prescribed to treat your 
uveitis depending upon how well the study medications work for 
you. 
• The study will include 10 study visits at the clinic and last for one 
year.  At the study visits we will do eye examinations, take pictures 
(digital images) of the insides of your eyes, perform vision tests, 
draw blood, and ask you to answer questions about your health 


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and well-being.  The first study visit will take 4 to 5 hours, later 
visits should be shorter (about 2 to 4 hours).  You will receive $75 
for each study visit.  If you complete all 10 visits you will receive a 
total of $750. 
• The study will only pay for tests and procedures that would not be 
done as part of your usual care for uveitis.  You or your insurance 
company will be charged for your regular medical care for uveitis. 
• The information above is a brief summary of the study.  If you are 
interested in joining the study, it is important to read the entire 
consent statement. 
Purpose of research project 
This study is evaluating treatments for uveitis, which is an inflammation 
inside of the eye.  The types of uveitis being studied can cause vision loss.  
Treatment helps to avoid vision loss.  This study compares two kinds of 
drugs for treatment of non-infectious uveitis that requires more than an oral 
corticosteroid to control.  The two kinds of drugs are adalimumab and 
conventional immunosuppressive drugs.  Both treatment regimens are 
commonly used to treat uveitis.  
The first-line treatment for uveitis is an oral corticosteroid drug like 
prednisone.  Often a high dose of prednisone is needed to control the 
inflammation.  Because high doses of prednisone can lead to side effects 
like weight gain and increased blood pressure, patients who need high 
doses of prednisone are often given immunosuppressive drugs to help 
control inflammation.  Adding immunosuppressive drugs allows the dose of 
prednisone to be reduced over time.  
The immunosuppressive drugs that have been typically used to treat uveitis 
include drugs like methotrexate, mycophenolate, azathioprine, 
cyclosporine, and tacrolimus.  We refer to these drugs as “conventional 
immunosuppressive drugs.”  Conventional immunosuppression drugs are 
not approved by the FDA for treatment of uveitis, however they are 
approved for other conditions involving inflammation and are commonly 
used to treat uveitis.  Adalimumab will be compared to the conventional 
immunosuppressive drugs in this study.  Adalimumab is a newer kind of 
immunosuppressive drug called a biologic.  It was approved by the FDA 
specifically for the treatment of uveitis in 2016.  It is also used to treat other 
inflammatory conditions.   


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Both conventional immunosuppression and adalimumab are used in clinical 
care to allow the dose of prednisone to be reduced or stopped without an 
increase in uveitis inflammation.  We are doing this study to find out which 
is better at keeping uveitis under control on lower doses of prednisone, 
conventional immunosuppressive drugs or adalimumab.  
This study is funded by the National Eye Institute (NEI), a part of the 
National Institutes of Health (NIH).  The NIH is a United States government 
agency.  
The drug company AbbVie is donating adalimumab for this study.  AbbVie 
has no role in the design, decision making, conduct, or interpretation of the 
study results. 
Why we are asking you to participate 
You have non-infectious uveitis that needs treatment with an oral 
corticosteroid drug such as prednisone.  Because of the severity of your 
uveitis, treatment with immunosuppressive drugs also is recommended 
according to standard treatment guidelines.  In this study you will receive 
either adalimumab or conventional immunosuppressive drugs in addition to 
oral corticosteroids to treat your uveitis.   
About 222 patients will participate in this study at clinics in the United 
States, Australia, Canada, and the United Kingdom.  Up to 40 participants 
will participate at this clinic.  
Study procedures 
Screening and baseline phase 
If you agree to take part in this study and sign this consent form, we will 
need to find out if you are eligible and collect baseline information.  The 
procedures for checking eligibility and collecting information about you are 
listed below.  Most are done as part of the usual clinical care for uveitis.  
• 
We will ask you about your medical history, eye problems, and 
treatments you have had for uveitis. 
• 
Your eyes will be examined by the study doctor.  Drops will be 
placed in your eyes before the exam to make the pupils larger.  This 
will make it easier for the doctor to see inside of your eyes.  The 
doctor will use a tool called an ophthalmoscope to see the inside of 
your eyes. 
• 
Your vision will be tested by asking you to read letters on a chart.  


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• 
Your height, weight, and blood pressure will be measured. 
• 
You will have digital images of the back of your eyes taken. 
• 
You will have an optical coherence tomography (OCT) scan to get 
images of your retinas at the back of your eyes. The scan is like an 
ultrasound of your eye, except it uses light instead of sound waves.    
• 
You will have about 18 mL (a little more than a tablespoon) of blood 
taken from your arm.  The blood will be used to test for tuberculosis 
(TB), hepatitis B and C, and for standard blood tests required for 
treatment.  These tests will be done by the laboratory the clinic 
typically uses for blood testing.  
• 
You will fill out questionnaires about your health and vision and how 
they affect your life.  This is done for the study, not as part of usual 
care for uveitis. 
• 
If you are able to become pregnant, you will have a pregnancy test. 
The test will be done on a urine sample.  You may not be in the 
study if you are pregnant or nursing.    
You also may be asked to sign a medical release form that will allow the 
study doctor to get information from your medical records from other 
doctors. 
If you have a certain type of intermediate uveitis, you will need to have 
another test to make sure you don’t have multiple sclerosis (MS) or 
another demyelinating disease and that it is safe for you to enroll in the 
study.  The next three paragraphs describe the test. 
• 
You will have a magnetic resonance imaging (MRI) scan of your 
brain.  The MRI will be done to look for evidence of a demyelinating 
disease, such as MS, in your brain.  Certain types of intermediate 
uveitis are sometimes associated with MS.  If the MRI shows brain 
changes that might be from a demyelinating disease, you cannot be 
in the study.  This is because one of the drugs used in this study 
might make such diseases worse. 
• 
A drug containing a metal called gadolinium will be injected into your 
arm before the MRI.  It makes it easier for the doctor see if there is 
evidence of MS in your brain than an MRI taken without use of the 
drug.  MRI scans create images using a magnet and radio waves.  
There is no radiation involved in this test.   


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• 
The MRI machine is like a large tube.  You will lie flat on a platform 
and then the platform will slide inside of the tube.  You will need to 
stay still.  The machine will make loud banging noises.  The scan will 
take about 20 minutes.  Your total time at the imaging facility will be 
about one hour. 
If you have certain types of uveitis, you will need to have other tests, 
such as a visual field test or additional images of your eyes.  The results 
of the test will be used to monitor your uveitis.  You will only undergo the 
tests below that are relevant to the type of uveitis you have. 
• 
A visual field test that checks your side vision (peripheral visual field) 
is used to evaluate uveitis characterized by small spots on the back 
of the eye (birdshot uveitis).   
• 
A special kind of photograph of your eyes called fundus 
autofluorescence is used to evaluate uveitis that is characterized by 
inflammation throughout the eye (choroiditis).  
• 
A photography test called fluorescein angiography is used to 
evaluate uveitis that involves inflammation of the branches of the 
retinal artery (retinal vasculitis).  For this test a dye is injected into a 
vein in your arm or hand.  The dye will move through your 
bloodstream, including the blood vessels in the back of your eyes.  A 
series of images will be taken.  The doctor evaluates the images to 
see where blood vessels are inflamed and severity of the 
inflammation.  The test takes about 20 minutes.  
Study treatment 
If you are eligible and you complete the baseline procedures described 
above, you will be enrolled in the study.  Everyone in the study will be 
treated with oral corticosteroids.  The most common type of oral 
corticosteroid used is prednisone.  It will be given according to the 
established standards for treating uveitis.  In addition to treatment with oral 
corticosteroids, you will be randomly assigned by a computer program to 
receive either adalimumab or conventional immunosuppression.  You will 
have an equal chance of receiving adalimumab or conventional 
immunosuppression as your study treatment.  Your study doctor will not get 
to choose which of these two study treatments you receive.  
If you are assigned to receive adalimumab, it will be given by subcutaneous 
injection (injection right under the skin).  The first dose will be given in the 


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clinic as described below.  After that you or a care-giver (for example a 
relative or friend) will give the injections at home.  We will teach you (or the 
care-giver) how to give the injection. 
• 
The first dose will be given at the clinic so that we can monitor you 
for any adverse reactions to the drug and teach you (or the person 
you choose) how to give the injection.  The first dose will be higher 
than the dose you will receive for the rest of your time in the study.  
This higher dose, 80 mg, is called a loading dose.  It is given to help 
the treatment work faster.  The first dose will be given in two 
injections at the clinic.  We will administer the first injection and show 
you (or the person you choose) how to do it.  Then you (or the 
person you choose) will give the second injection to yourself (you) in 
the clinic under observation.   
• 
From then on you will give yourself the injection (or the person you 
have chosen and has been trained will give you your injection) at 
home according to the following schedule.  One week after your first 
dose in the clinic, you will give yourself one injection (40 mg) at 
home.  After that you will give yourself an injection of 40 mg every 
other week for the rest of the study.  We will provide you with 
adalimumab to take home with you. 
If you are assigned to receive conventional immunosuppression, your study 
doctor will decide which conventional immunosuppressive drug, or 
combination of drugs, you will receive.  The doctor will use guidelines 
established by uveitis experts to select the drug.  The type of uveitis you 
have and other health conditions will be considered.  Most of these drugs 
are taken by mouth.    
• 
The conventional immunosuppressive drugs that may be used are:  
methotrexate, mycophenolate, azathioprine, cyclosporine, and 
tacrolimus.   
• 
Sometimes two of these drugs are used together so you may be 
asked to take 2 immunosuppressive drugs at the same time.  
Depending on your situation, you may receive one or two of these 
drugs as your study treatment.  
o If you are already taking one of these drugs when you join the 
study, you will continue on that drug during the study and one 
of the other drugs will be added. 


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o If you are not taking any of these drugs when you join the 
study, you will be started on one of them.   
• 
Some of these drugs are taken every day.  Some are only taken 
once a week. 
• 
You will be provided with a prescription for the assigned drug.  You 
will be responsible for any co-pay required.  However, as described 
earlier, we will reimburse you for up to $3000 for out of pocket costs 
for the study-assigned treatments.  
No matter which treatment you are assigned to start with, a second drug 
may be added later if your uveitis is not controlled by the first study drug. 
The second drug will be a conventional immunosuppressive drug.  All of 
these drugs typically are used in the clinical care of patients with your type 
of uveitis.  If you were assigned to adalimumab and require a second drug 
to control your uveitis, the study will reimburse you for up to $1500 for out 
of pocket costs for the second drug.  
Study visit schedule 
You will be in the study for one year and will have 10 study visits at this 
clinic.  The procedures for the first study visit may be spread out over more 
than one day.  For example, if you need to have an MRI before you enroll, 
the MRI may need to be scheduled on a different day.   
For the first 6 months you will come to the clinic for a study visit every 
month.  After your six-month study visit, you will have a study visit every 
two months.  You may need to come into the clinic more often for clinical 
care and those visits will not be part of the study.  The table on the next 
page shows what will be done at each study visit.  At each follow-up visit, 
you will have about 10 mL (less than a tablespoon) of blood taken from 
your arm.  The blood will be used for standard tests to monitor for possible 
side effects of the drugs you are taking. 
Most of the procedures done as part of the study visits are usually done as 
part of standard of care for uveitis.  However, standard of care for uveitis 
may vary by doctor, patient needs, and monitoring requirements for specific 
treatments.  The procedures that are being done that are just for research 
are the quality of life questionnaires, the type of vision test, and in some 
cases pregnancy testing and an MRI. 


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Procedures done at visit are marked with X under visit month 
Visit month 
0 
1 
2 
3 
4 
5 
6 
8 
10 
12 
Visit code 
V01 
V02 
V03 
V04 
V05 
V06 
V07 
V08 
V09 
V10 
Medical, eye, and treatment history 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Vision test  
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Measure weight and blood pressure  
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Height 
X 
 
 
 
 
 
 
 
 
 
Eye exam 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Photographs (digital images) of eyes 
X 
 
 
 
 
 
X 
 
 
X 
OCT  
X 
 
 
X 
 
 
X 
 
 
X 
Quality of life questionnaires 
X 
 
 
X 
 
 
X 
 
 
X 
Blood draw for complete blood count 
and chemistry panel 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Blood test for tuberculosis and 
hepatitis 
X 
 
 
 
 
 
 
 
 
 
Pregnancy test for menstruating 
individuals 
X 
 
 
 
 
 
 
 
 
 
Additional procedures for patients with specific types of uveitis only 
Visit month 
0 
1 
2 
3 
4 
5 
6 
8 
10 
12 
Visit code 
V01 
V02 
V03 
V04 
V05 
V06 
V07 
V08 
V09 
V10 
MRI of brain for patients with 
anterior/intermediate or 
intermediate uveitis without 
systemic disease 
X 
 
 
 
 
 
 
 
 
 
Peripheral field test for patients with 
birdshot chorioretinitis 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
OCT will be done at all visits for 
patients with early stage VKH*  
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Fundus autofluorescence 
photographs for patients with 
choroiditis or late stage VKH* 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Fluorescein angiography for patients 
with retinal vasculitis 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
*Vogt-Koyanagi-Harada disease 


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Risks/discomforts 
If you enroll in the study your treatment will be decided based on 
randomization.  The treatment you are assigned might be different than 
what you would have received if you did not enroll and instead you and 
your doctor decided which treatment you would receive.  Since the risks of 
treatment, which are described below, are different for each treatment, you 
may be exposed to different risks if you enroll than you would be exposed 
to if you received treatment outside of the study.  Based on the results of 
previous studies, we think the overall risk rate will be about the same for 
both treatment groups in this study.  
Risks associated with each of kind of drug used as study treatment are 
listed below.  Usually the risks can be avoided or reversed if the drug dose 
is lowered or you stop taking the drug.  
Risks associated with oral corticosteroids 
All study participants will take oral corticosteroids (for example, 
prednisone).  The most common side effects of oral corticosteroids are: 
• 
Ocular side effects 
o About 6% of patients per year need cataract surgery  
o About 3% of patients per year have increased eye pressure  
o About 1.3% patients per year develop glaucoma 
• 
Water retention, weight gain, headache, muscle weakness, and loss 
of muscle mass 
• 
Face puffiness, growth of facial hair, easy bruising, acne, and 
rounding of the upper back 
• 
Irregular menstrual periods 
• 
Mental changes such as trouble sleeping, mood swings, increased 
energy, and personality changes 
• 
Increased blood pressure, cholesterol, and blood sugar 
• 
Lowered resistance to infections and making infections harder to 
treat, slow wound healing 
• 
Increased risk of osteoporosis (bone thinning) 
• 
Increased risk of congestive heart failure for those already at risk of it 
• 
Aseptic necrosis of bone is a rare and serious side effect    


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Serious side effects are rare especially when treatment is managed 
using the guidelines that will be followed in this study.  Side effects occur 
more often with longer periods of treatment and with higher doses.  Side 
effects usually go away when the dose is lowered or treatment is 
stopped.  An objective of this study is to reduce your dose of oral 
corticosteroids to the lowest possible dose or even stop it as long as your 
uveitis is controlled.  
In addition to oral corticosteroids, your study treatment will include either 
adalimumab or a conventional immunosuppressive drug.  The risks 
associated with these drugs are described below.    
Risks associated with adalimumab   
You may be assigned to receive adalimumab.  The risks of adalimumab are 
listed below. 
 
• 
The most common side effects are redness, itching, pain, or swelling 
at the injection site, reported in 20% of patients. 
• 
Less common side effects include an increased risk of infections, 
particularly tuberculosis, fungal infections, and herpes zoster 
(shingles).   
o About 7% of patients get an infection that requires treatment 
with antibiotics in a year.   
o There also may be a small increased risk (less than 1%) of 
opportunistic infections.   
o Rarely, some of these infections, including an infection of the 
brain called progressive multifocal leukoencephalopathy 
(PML), can be life-threatening. 
You should not receive any live vaccines while using adalimumab. 
• 
Uncommon side effects include 
o Nausea, vomiting, abdominal pain, or diarrhea 
o Reversible bone marrow suppression 
o Reversible liver damage 
• 
Rare side effects include 
o Development of anti-adalimumab antibodies and a lupus-like 
syndrome 
o Worsening of demyelinating disease, such as multiple sclerosis   


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• 
Cancers, including lymphoma, have been reported in some patients 
using these types of drug.  Cancers occur commonly in the general 
population.  Published reports analyzing information from eye 
patients suggest the risk may not be increased by use of this kind of 
drug.  However, some studies suggest that use of these drugs may 
increase the risk of non-melanoma skin cancer. 
Risks associated with conventional immunosuppressive drugs 
If you are assigned to conventional immunosuppression, your study 
treatment will be one or two conventional immunosuppressive drugs.  Your 
initial study treatment will be one drug; a second could be added later in the 
study if it is needed to control your uveitis.  If you are assigned to 
adalimumab as your study treatment, a conventional immunosuppressive 
drug may be added later in the study if needed to control your uveitis.  
Different drugs are used for conventional immunosuppression, you and 
your doctor will decide which of these is the best drug (or drugs) for you. 
These drugs will be given according to established standards.  Some of 
these drugs require routine testing of blood to be given safely.  Your doctor 
will talk to you about the specific side effects of the drugs you receive.  The 
risks associated with conventional immunosuppressive drugs are described 
below.    
• 
In general, side effects can affect the kidney, liver, GI tract, and bone 
marrow.  
• 
These drugs may lower your resistance to infections.  
o About 7% of patients get an infection that requires treatment 
with antibiotics in a year.  
o There also may be a small increased risk (less than 1%) of 
opportunistic infections.   
o Rarely, some of these infections, including an infection of the 
brain called progressive multifocal leukoencephalopathy 
(PML), can be life-threatening. 
• 
Most side effects are reversible if the dose of the drug is lowered or if 
the drug is stopped.  In general, these drugs have to be stopped due 
to side effects 10-20% of the time.  If a drug needs to be stopped 
due to side effects, your doctor may start another 
immunosuppressive drug as a replacement treatment.  Your doctor 
will discuss with you the best treatment for you. 


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• 
Cancers, including lymphoma, have been reported in some patients 
using these types of drug.  Cancers occur commonly in the general 
population.  Published reports analyzing information from eye 
patients suggest the risk may not be increased by use of this kind of 
drug.  However, some studies suggest that use of these drugs may 
increase the risk of non-melanoma skin cancer.  
• 
Pregnancy risks for both genders – Some of these drugs are 
associated with an increased risk of first trimester pregnancy loss 
and birth defects.  These risks apply to men as well as women 
because the drugs may affect sperm cells.  Problems can result if 
you are using one of the drugs before you become or while you are 
pregnant or if you are using one of the drugs before or at the time 
you impregnate someone.  You may not join this study if you plan to 
become a biological parent (get pregnant or impregnate someone) in 
the next 18 months.  If you are a person who can become pregnant, 
you will have a pregnancy test at your first study visit.  
If you are pregnant or breastfeeding, you cannot join this study.   
If you are able to become pregnant or impregnate someone, you 
must agree to practice birth control while you are in the study and for 
6 months after you complete the study.  The acceptable forms of 
birth control are abstinence, combination barrier and spermicide, 
hormonal or intrauterine device.  Your doctor will talk to you about 
risks if you are taking specific drugs that are known to cause 
problems in pregnancy.  If you or your partner become pregnant 
during the study, you must agree to let the study doctor know 
immediately.  You must agree to report any problems during the 
pregnancy and the outcome of the pregnancy.   
Your doctor will talk to you about the specific side effects for the drugs you 
are taking. 
Other risks 
As with all research studies, this study may involve unknown risks.  Any 
unknown risks you are exposed to in the study are likely to be the same 
risks you would have if you were being treated for uveitis outside of the 
study.  You will be told of any findings that might change your decision 
about continuing in the study. 


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Your uveitis may not get better or could get worse.  Uveitis getting worse or 
failing to improve is unlikely because oral corticosteroids and 
immunosuppression is the standard treatment and known to be effective for 
most cases.  If the study treatments do not work, your doctor may change 
your treatment according to best medical judgment. 
If you have any questions or concerns regarding any of these risks, please 
talk to your study doctor.  If you experience any illness or discomfort during 
the study, you should notify your study doctor.  
The risks associated with study procedures are minimal.  Most of the study 
procedures are part of standard care for patients with the type of uveitis 
you have.  The risks include:  
• Discomfort, bruising, or swelling at the site of your blood draw.  
• Discomfort from bright lights used while taking images of your 
eyes. 
If you have a certain type of intermediate uveitis you will need to have an 
MRI of your brain before you can join the study.  The MRI will be conducted 
at an imaging center.  A drug containing gadolinium will be injected into a 
vein in your arm before the MRI to improve the MRI's ability to detect 
disease.  The doctor or staff at the imaging center will discuss the risks of 
the MRI and the drug with you.  The main risk of the MRI is feeling 
uncomfortable and closed in while you are in the MRI machine.  Risks 
associated with the injection of the drug include: 
• You may experience headache, nausea, and dizziness for a short 
time.  
• You may get an unpleasant taste in your mouth. 
• You may feel hot, numbness, or tingling, have itching or a rash. 
• You may have a feeling of cold, warmth, pain, or burning at the 
injection site. 
• Some people can have an allergic reaction to the drug.  Sometimes 
the reaction can be serious. 
• For people with kidney problems there is a risk of developing a 
condition called scleroderma.  This is very uncommon.  Scleroderma 
involves thickening of the skin, muscles, and organs. You should let 
the radiologist know if you have kidney disease. 


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Some types of uveitis need to be monitored by fluorescein angiography.  If 
you have one of these types of uveitis, you will have this procedure at 
every study visit.  
• You may experience pain or bruising where the dye is injected into 
your hand or arm.   
• You may have nausea or vomiting from the injection, however, this 
usually lasts only a short time.  
• The dye used in this procedure may make your skin look darker for 
one or two days after the test.  Your urine may be orange after the 
test.   
• Some people can have an allergic reaction to the fluorescein dye.  
Rarely the allergic reaction is severe enough to cause the person to 
go to the hospital.  This happens in less than 1 in 10,000 tests.  
Benefits 
You will receive standard treatments for uveitis; all of these treatments 
have been shown in research studies to be effective for the treatment of 
non-infectious uveitis.  There are no experimental treatments in this study.  
The benefits of taking part in this study for you are unknown because it is 
not clear which treatment will work best for which patients.  Information 
from this study may be helpful in the future to other people with uveitis.  
The information also may help you because you may need treatment for 
uveitis in the future. 
Payment 
You will receive $75 for each study visit.  If you complete all 10 visits you 
will receive a total of $750.  If you leave the study before finishing all visits, 
you will be paid for the visits you have completed.  If you receive $600 or 
more in one year from this study or combined with payments from other 
studies you participated in at this institution, these payments will be 
reported to you and the IRS on a 1099-MISC Form.  You will be required to 
list the amount reported on the 1099-MISC Form as income on your 
Federal and State tax returns.  We will send you the 1099-MISC Form in 
January or February of the next year.  The amount reported on the 1099-
MISC Form will NOT include monies you received as a reimbursement for 
costs you incurred related to participating in this study.  For example, 
reimbursements for parking or for drug co-pays will not be reported to the 
IRS or listed on the 1099-MISC Form. 


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Protecting data confidentiality 
All research projects carry some risk that information about you may 
become known to people outside of the study.  In order to minimize this 
risk, your name and other identifying information will be kept private.  Your 
information used for the study will be labeled with a unique number and 
special code to keep them private.  The unique number and code cannot 
be linked to your name except at the clinical center where you complete 
visits.  Data from study visits labeled with the study ID will be sent to the 
Coordinating Center located at The Johns Hopkins University in Baltimore, 
Maryland.  Some or all of the images taken of your eyes will be sent to the 
Photograph Reading Center located at the University of Wisconsin in 
Madison, Wisconsin.  These images also will be identified only by your 
study ID.  People at Johns Hopkins University, the National Eye Institute, 
the Food and Drug Administration (FDA), and the Institutional Review 
Board at this clinic may see the data collected about you during the study 
and review your records.  These people work on the study and/or need to 
make sure the study is being done correctly.  They may see your name and 
other identifying information as part of their review.  However, they also 
must keep this information private.  
People at AbbVie may see data collected from you that has to do with 
reports of possible side-effects of the drugs.  AbbVie is the company 
donating adalimumab for the study.  
Study data may be made available to other researchers.  Results from this 
study may be published in medical journals.  In both cases, your name or 
other identifying information will not be released to other researchers or 
medical journals.   
By joining this study, you give permission for the study doctor or staff to 
contact you in the future about how you are doing or about other research 
studies.  You do not have to join any other studies unless you want to. 
Let us know if you have another doctor with whom you would like us to 
share the results of your study tests.  We will share the test results with 
your other doctor if you give us your permission. 


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Certificate of Confidentiality protections 
Your study information is covered by Certificate of Confidentiality 
protections.  This allows us, in some cases, to refuse to give out your 
information without your permission even if requested using legal means.  It 
does not protect information that we have to report by law, such as child 
abuse or some infectious diseases.  It does not prevent us from disclosing 
your information if we learn of possible harm to yourself or others, or if you 
need medical help.  
Disclosures that you consent to in this document are not protected. This 
includes putting research data in the medical record or sharing research 
data for this study or future research.  Disclosures that you make yourself 
are also not protected. 
Alternatives to procedures or treatments 
All of the study treatments are standard treatments for uveitis.  They are all 
available outside of the study.  Also, there are other treatments for uveitis 
that you could receive outside of this study.    
Cost of participation in the study 
Medical Care 
You and/or your insurance will be charged for the regular medical care you 
need, in the same manner as if you were not part of this study.  You will be 
responsible for costs not covered by insurance (for example, co-payments) 
for regular medical procedures and non-study treatments for uveitis just as 
you would be if you were not in the study.  
Drugs that are prescribed to you as your assigned study treatment  
Adalimumab 
If you are assigned to receive adalimumab, the study will provide 
adalimumab to you at no cost for the time you are in the study.  The maker 
of adalimumab, AbbVie, is donating the drug to the study.  If a conventional 
immunosuppressive drug is added as part of your study treatment you will 
need to use your insurance coverage to cover the cost of the drug.  The 
study will reimburse you up to $1500 for your out of pocket expenses for 
the drug. 
  


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Conventional immunosuppressive drugs 
If you are assigned to conventional immunosuppression, you will need to 
use your insurance coverage to cover the cost of the drug or drugs.  The 
study will reimburse you up to $3000 for your out of pocket expenses for 
these drugs.  
You may need to provide receipts or other proof of your out-of-pocket cost 
to receive reimbursement.  [Clinic provide details if required.] 
Study procedures 
Most of the procedures done in this study are standard procedures done as 
part of usual care for uveitis.  Costs of standard procedures that are part of 
usual care will be billed to your health insurance and you may be 
responsible for co-pays depending on your insurance.  This is done 
according to the policy of the National Institutes of Health, the government 
agency paying for this study. 
Costs of procedures done only for the study are paid for by the study.  For 
example, the study will pay for an MRI for patients with certain types of 
intermediate uveitis.  This study is being conducted at many different clinics 
and includes patients with different kinds of uveitis.  This will result in some 
differences in what procedures are done as usual care for a particular 
participant.  If some procedures are required for the study more often than 
would be done for your usual clinical care, these extra procedures may be 
charged to the study. 
What happens if you leave the study early?   
You can agree to be in the study now and change your mind later.  If you 
wish to stop participating in the study, please tell us right away.  Leaving 
this study early will not stop you from getting regular medical care from this 
doctor and at this center.  
If you leave the study early we will: 
• Use and share the information and images of your eyes collected up 
to that time unless you contact [insert name of the site’s Principal 
Investigator] to cancel or change your permission.  Instructions to 
cancel or change your permission for use and sharing of your 
information and images are included in the Authorization for 
Disclosure of Protected Health Information for Research section of 
this consent form. 


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• Ask you if we can contact you to find out about your health and give 
you new information that we learn during the study, including the 
results of the study.   
• Ask you for permission to collect information about your eye condition 
and health from your clinic visits for the study.  We would get the 
information from your electronic medical record until the time that you 
would have completed the study, which is one year after you enrolled 
in the study. 
Your study doctor may take you out of this study if staying in the study 
would be harmful to you or if you fail to follow instructions.  The sponsor or 
regulatory agencies may stop this study at any time without your consent.  
If this happens, you will be notified and your study doctor will discuss other 
options with you. 
How will I get my treatment after the study is over? 
If you are doing well on your study treatment, you may want to continue it 
after you have completed the study.  All of the study treatments are 
available outside of the study.  If you are assigned to adalimumab, we will 
provide it to you for free during the study.  If you want to continue 
adalimumab after you complete the study, you should check with your 
insurance to see if it covers this drug.  AbbVie, the company that makes 
adalimumab, has a patient assistance program that might help you get the 
drug if you cannot otherwise afford it. 
Conflict of Interest 
A conflict of interest occurs when a researcher or the University has a 
financial or other interest that might affect the researcher’s judgment when 
conducting a research study.  In some situations, the results of a study 
might lead to a financial gain for the investigator(s) and/or [Johns Hopkins].  
All such conflicts must be disclosed to the Conflict of Interest Committee.  
At this time, [Johns Hopkins University] is unaware of any potential conflicts 
of interest with regard to this research study. 


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Payment of treatment costs for injury or illness from study 
participation 
If you are hurt or become ill as a result of being in this study, contact your 
study doctor immediately.  Your study doctor will arrange for short-term 
emergency care or referral if it is needed.  However, neither [Johns 
Hopkins University] nor the NIH have insurance plans that will pay you if 
you are hurt or have other bad results.  Costs of such treatment may be 
billed to you or your insurance.  Your health insurance may or may not pay 
for treatment of injuries as a result of your participation in this study.  You 
do not waive any of your legal rights or release anyone from liability for 
negligence by signing this document. 
Study Results 
The purpose of this study is to determine which treatment is better for 
treating uveitis.  Once the study is over, we will try to contact you to let you 
know the major conclusion(s) of this study.  If your contact information has 
changed, this information may not reach you.  However, according to 
National Institutes of Health policy, study results must be published on 
ClinicalTrials.gov.   
Clinical Trial Registration 
A description of this clinical trial is available on 
http://www.ClinicalTrials.gov, as required by the National Institutes of 
Health policy.  The study registration number is NCT03828019.  This web 
site will not include information that can identify you.  At most, the web site 
will include a summary of the results.  You can search this web site at any 
time. 
Authorization for Disclosure of Protected Health Information for 
Research 
The Health Care Providers listed above are required by the Federal Privacy 
Rule to protect your private health information.  By signing this 
Authorization, you permit them to release your information to the 
researchers for use in this research study.  The researchers will try to make 
sure that everyone who needs to see your private information for this 
research keeps it confidential, but we cannot guarantee this.  Although the 
researchers may not be covered by the Federal Privacy Rule, they will 
make an effort to protect your information using the same standards.   


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Your private health information that will be used for this research includes 
things learned by the procedures described in this consent form.  The 
research team at your clinic also will collect your name, address, phone 
number, and other information that can identify you and link you to the 
health information collected in the study.  Your date of birth and other dates 
(for example dates of study visits and procedures) will be included in the 
information sent to the Coordinating Center but other identifiers such as 
your name or address will not.  Some or all of the images of your eyes 
taken during the study will be sent to the Reading Center.  These images 
will be labeled only with your study ID and the dates the images were 
taken.   
After this study ends, the Coordinating Center and Reading Center will 
continue to store the data and images of your eyes collected from you and 
other participants during the study.  These data and images may be used 
for future research in uveitis and other health topics.  
Some other people may see your private health information outside of the 
research team.  They may include the sponsor of the study, study safety 
monitors, government regulators, and legal compliance staff.  All these 
people must also keep your information confidential. 
You do not have to sign this Authorization, but if you do not you may not 
join the study.  It is your choice.  Your Authorization does not have an 
expiration date; it will continue as long as the research continues.  You may 
change your mind and take back this Authorization at any time.  You may 
revoke (cancel) your permission to use or disclose all or part of your 
information and/or images of your eyes by contacting [the site Principal 
Investigator] by phone or in writing.  [The Principle Investigator’s] 
information is listed in the next section of the consent form.  If you contact 
[the Principal Investigator] by phone, you must follow-up with a written 
request that includes: 
• The name of the study:  Adalimumab vs. Conventional 
Immunosuppression for Corticosteroid-sparing for Uveitis (ADVISE) 
Trial 
• Your contact information 
•  What type(s) of information you no longer wish to share: (1) 
information from study visits; (2) images of your eyes (3) both 
information and images  


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• For which purpose do you no longer wish to share: (1) for use in 
future research; (2) for use in the study; (3) for use in either future 
research or the study 
• The date and your signature 
Who do I call if I have questions or problems? 
• Call the principal investigator, [Janet Holbrook at 443-287-5791], if 
you have questions, complaints, or get sick or injured as a result of 
being in this study, or want to cancel your permission to use and 
share your information and images for the study or for future 
research.  
• Call or contact [the Johns Hopkins Bloomberg School of Public 
Health IRB Office] if you have questions about your rights as a study 
participant.  Contact the IRB if you feel you have not been treated 
fairly or if you have other concerns.  The IRB contact information is:   
 
Address: 
Johns Hopkins Bloomberg School of Public Health 
 
 
 
615 N. Wolfe Street, Suite E1100 
 
 
 
Baltimore, MD   21205 
 
Telephone: 410-955-3193 
 
Toll Free: 1-888-262-3242 
 
E-mail: 
JHSPH.irboffice@jhu.edu 
 


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What does your signature on this consent form mean? 
Your signature (or thumbprint/mark) on this form means: 
• You have been informed about this study’s purpose, procedures, 
possible benefits and risks. 
• You have been given the chance to ask questions before you sign. 
• You have voluntarily agreed to be in this study.  
 
___________________________________                      
Print name of Adult Participant                    
 
___________________________________             __________________ 
Signature of Adult Participant                                     Date 
 
 
 
 
___________________________________                      
Print name of Person Obtaining Consent                    
 
___________________________________             __________________ 
Signature of Person Obtaining Consent                     Date 
 
 
 
 
 
 
Give one copy to the participant and keep one copy in study records 

Prot_000.pdf: 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
ADalimumab Vs. conventional 
ImmunoSupprEssion for uveitis 
(ADVISE) 
Trial 
 
 
 
 
 
 
 
 
 
 
 Protocol version 1.3 
12 October 2020 
 
 
 
ClinicalTrials.gov identifier:  NCT03828019 
 
 


ADVISE PROTOCOL 1.3 (12 OCT 2020) 
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ADVISE Protocol 1.3 (12 Oct 2020) 
Contents 
Contents ............................................................................................................................... 2 
Document revision history .................................................................................................... 5 
Document distribution ..........................................................................................................10 
Abstract ...............................................................................................................................11 
1. Introduction ...................................................................................................................12 
1.1 
Title ......................................................................................................................12 
1.2 
IND .......................................................................................................................12 
1.3 
Financial sponsor .................................................................................................12 
1.4 
Resource centers .................................................................................................12 
1.5 
Clinical centers .....................................................................................................13 
1.6 
Additional Support ................................................................................................13 
1.7 
Background and significance ................................................................................14 
1.8 
Preliminary studies ...............................................................................................17 
Table 1.  Distribution of uveitic diseases in the MUST Trial .................................................18 
1.9 
Rationale for trial ..................................................................................................18 
2. Objective and study hypothesis .....................................................................................19 
2.1 
Objective and specific aims ..................................................................................19 
2.2 
Hypotheses ..........................................................................................................19 
3. Design ...........................................................................................................................20 
3.1 
Design elements ...................................................................................................20 
3.2 
Randomized treatment arms ................................................................................20 
3.3 
Trial schematic .....................................................................................................21 
3.4 
Outcomes .............................................................................................................22 
3.4.1 
Primary outcome .........................................................................................22 
3.4.2 
Secondary outcomes ...................................................................................22 
3.4.3 
Disease-specific assessment to permit ascertainment of outcomes pertaining 
to activity of uveitis .......................................................................................23 
3.5 
Eligibility criteria ....................................................................................................25 
3.6 
Stratification and randomization............................................................................26 
3.7 
Data collection schedule .......................................................................................27 
Table 2.  Visit and examination schedule ............................................................................28 
4. Treatment ......................................................................................................................29 
4.1 
Overview ..............................................................................................................29 


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4.2 
Systemic corticosteroids .......................................................................................29 
4.2.1 
Initial prednisone dose .................................................................................30 
Table 3.  Initial prednisone dosing summary .......................................................................31 
4.2.2 
Prednisone tapering schedule and goals .....................................................31 
Table 4.  Prednisone tapering schedule ..............................................................................32 
4.3 
Corticosteroid-sparing drugs .................................................................................33 
4.3.1 
Adalimumab treatment group .......................................................................33 
4.3.2 
Conventional immunosuppression treatment group .....................................33 
Table 5.  Conventional immunosuppressive drugs in the ADVISE Trial ...............................34 
4.4 
Advancement of immunosuppressive treatment ...................................................35 
4.5 
Management of uveitis reactivation ......................................................................35 
Table 6.  Reactivation management guidelines ...................................................................37 
4.6 
Monitoring for toxicity of immunosuppressive drugs..............................................38 
4.7 
Discontinuation of treatment within the assigned treatment arm ...........................38 
4.7.1 
Discontinuation for toxicity ...........................................................................38 
4.7.2 
Discontinuation for pregnancy .....................................................................39 
4.8 
Ancillary therapy ...................................................................................................39 
4.8.1 
Regional corticosteroid Injections ................................................................39 
4.8.2 
Topical corticosteroids .................................................................................39 
4.8.3 
Non-corticosteroid ophthalmic medications ..................................................39 
4.8.4 
Systemic medications other than corticosteroids and immunosuppressive 
drugs ...........................................................................................................39 
4.8.5 
Treatment monitoring ...................................................................................40 
5. Study treatment procurement ........................................................................................41 
6. Possible side effects and complications of study treatments .........................................42 
Table 7.  Potential risks of therapy ......................................................................................45 
7. Safety reporting of adverse events ................................................................................47 
7.1 
Adverse events .....................................................................................................47 
7.2 
Serious adverse events ........................................................................................47 
8. Sample size and statistical methods ..............................................................................48 
8.1 
Hypotheses ..........................................................................................................48 
8.2 
Sample size and power calculations .....................................................................48 
8.3 
Statistical analysis plan ........................................................................................49 
9. Regulatory and ethical issues ........................................................................................50 
9.1 
Recruitment and informed consent procedures ....................................................50 


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9.2 
IRB/Protection of human subjects .........................................................................51 
9.3 
Data and Safety Monitoring Committee ................................................................51 
10. Study implementation ....................................................................................................52 
10.1 Study organization ................................................................................................52 
10.1.1 Characteristics of target population and recruitment strategies ....................52 
10.2 Quality assurance .................................................................................................52 
10.2.1 Medical Therapy Quality Assurance Committee ..........................................52 
10.2.2 Visual Function Quality Assurance Committee ............................................53 
References ..........................................................................................................................54 
 
Table of Tables 
Table 1.  Distribution of uveitic diseases in the MUST Trial .......................................................18 
Table 2.  Visit and examination schedule ..................................................................................28 
Table 3.  Initial prednisone dosing summary .............................................................................31 
Table 4.  Prednisone tapering schedule ....................................................................................32 
Table 5.  Conventional immunosuppressive drugs in the ADVISE Trial 14,21 ..............................34 
Table 6.  Reactivation management guidelines .........................................................................37 
Table 7.  Potential risks of therapy ............................................................................................45 
 
 


ADVISE PROTOCOL 1.3 (12 OCT 2020) 
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Document revision history 
 
Version 1.0 (6 Feb 2019)  
• 
Cover:  added ClinicalTrials.gov identifier 
 
• 
Table 2:  Visit and Examination Schedule: Added height at month zero (baseline) 
 
• 
Table 4:  Prednisone tapering schedule: 7.5 mg/day hold period modified from “Hold for 
4 weeks” to “Hold until two study visits ≥4 weeks (28 days) apart have occurred* 
*Note: This may involve maintaining the dose for more than two consecutive study visits if they 
occur <28 days apart. 
 
• 
Corrected typographical errors, e.g., <7.5 mg/day prednisone to ≤ 7.5 mg/day in section 
2.2 (secondary hypotheses #1 and 4.2.2 in description of primary outcome) 
 
Version 1.1 (31 Oct 2019) 
• 
Section 1.2 IND 
- 
 Added clarification that the IND covers the conventional immunosuppressive 
drugs used in the trial 
 
• 
Section 1.4 Resource centers 
- 
Updated the location of Study Chairman’s Office (as of 1 Aug 2019) 
 
• 
Section 3.1 Design elements 
- 
Corrected time points for masked assessment of photographic images and OCT 
by the RC (graders masked) 
 
All patients 
∙ 
OCT at baseline, 3, 6, and 12 months 
∙ 
Retinal color photographs at baseline, 6 and 12 months  
 
Disease-specific image or OCT, as applicable, at baseline, 1, 3, 6, and 12 
months 
 
• 
Section 3.2.1 Randomized treatment arms (Adalimumab) 
- 
Removed adalimumab dosing schedule for adolescents <30 kg (they are now 
excluded from the study) 
 
• 
Section 3.4.3 Disease-specific assessment to permit ascertainment of outcomes 
pertaining to activity of uveitis 
- 
For birdshot chorioretinitis - corrected Humphrey 24-2 to 30-2 
- 
Removed “other conditions with exudative detachment(s)” from list of conditions 
for which OCT will be used to determine resolution of exudative detachments.   
Vogt-Koyanagi-Harada early disease is the only condition that will be monitored 
in that manner. 
 


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• 
Section 3.5 eligibility criteria 
- 
Added inclusion criterion: Weight 30 kg (66 lbs) or greater 
- 
Added exclusion criterion: Any of the following baseline lab values  
a. White blood count <3500 cells per microliter 
b. Platelets <100,000 per microliter 
c. Hematocrit <30% 
d. AST or ALT >1.5X upper limit normal value 
e. Serum creatinine >1.1X upper limit normal value 
- 
Expanded exclusion criterion “Multiple sclerosis’ to “Multiple sclerosis or other 
demyelinating disease” 
- 
Added clarification regarding MRI screening as italicized: For patients with 
anterior/intermediate or intermediate uveitis without systemic disease, abnormal 
magnetic resonance imaging (MRI) of the brain consistent with demyelinating 
disease  
- 
Added exclusion criterion:  Severe uncontrolled infection 
- 
Added exclusion criterion:  Moderate to severe heart failure (NYHA class III/IV 
- 
Added exclusion criterion:  Active malignancy 
- 
Expanded pregnancy exclusion and length of time birth control use required: 
For persons of child-bearing potential or impregnating potential, unwillingness to 
use appropriate birth control (abstinence, combination barrier and spermicide, 
hormonal, or intrauterine device) for the next 15 months or plans to become a 
biological parent within the next 15 months 
 
• 
Section 3.7 Data collection table 
- 
Added note for disease specific test early-stage VKH, – OCT:   Ʌ OCT centered 
on fovea and additionally, as needed, OCT centered to capture the area with 
greatest subretinal thickness 
- 
Removed other conditions with exudative detachment(s) from conditions for 
which OCT will be used to determine resolution of exudative detachments for 
determination of uveitis activity.   
- 
Added italicized clarification: Gadolinium enhanced MRI for patients with 
anterior/intermediate or intermediate uveitis without systemic disease only 
- 
Corrected parameter for automated perimetry with Humphrey SITA-fast 30-2 
(previously 24-2 in error) and P60. 
 
• 
Section 4. Treatment 
General modifications to section 4 and subparts: 
- 
Renamed section from Treatment schedule to Treatment 
- 
No essential changes made; generally reworked of sections for clarification 
including 
 
Clarification that study treatments should adhere to guidelines.  For 
situations not covered by guidelines, follow general study treatment 
principles and use best medical judgment 
 
Specified  basic principles for study treatment 
 
Clarified that time points in treatment guidelines (e.g., 4 weeks) are 
targets and that variations due to scheduling of study visits is permitted 
and expected 
 
• 
Section 4.2.1  Initial prednisone dose 
- 
Revised Table 3:  Initial prednisone dosing summary to include more detail 


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• 
Section 4.3.1 Adalimumab treatment group 
- 
Removed dosing protocol for adolescent patients based on body weight (i.e., 
different dosing protocols for adolescents < 30 kg vs those ≥30 kg for which 
dosing protocol is same as for adults). Only patients ≥30 kg will be enrolled in 
trial, thus the same dosing protocol will be used for all patients. 
- 
Changed reference for adolescent dosing (previously referenced Sycamore 
study)  
 
• 
Section 4.3.2 Conventional immunosuppression treatment group 
- 
Table 5:  Conventional immunosuppressive drugs in the ADVISE Trial - revised 
footnote re: timing of dose escalation for tracrolimus  from monthly to every 2 to 4 
weeks 
 
• 
Section 4.4 Advancement of immunosuppression – entire section was added 
 
• 
Section 4.5 Management of uveitis reactivation 
- 
Section reworked for reactivation for clarity with the addition of some details 
including specification of prednisone dose to be reinstated if uveitis reactivates 
after achieving cessation 
- 
Table 6.  Reactivation management guidelines was revised to two tables, 6a and 
6b, for prednisone and immunosuppression, respectively 
 
• 
Section 9.1 Recruitment and informed consent 
- 
Added clarification that adolescent participants and parent or guardian will give 
written assent/consent according to the guidelines of the clinic’s governing IRB. 
- 
Changed reading level of consent from 8th grade level to 9th grade level 
 
• 
Section 10.2.2 Visual Function Quality Assurance Committee 
- 
Corrected Humphrey 24-2 to 30-2 
 
• 
References 
- 
Removed: Ramanan AV, Dick AD, Jones AP, McKay A, Williamson P, 
Compeyrot-Lacassagne S, Hardwick B, Hickey H, Hughes D, Woo P, Benton D, 
Edelsten C, Beresford M for the SYCAMORE Study Group.  Adalimumab plus 
methotrexate for uveitis in juvenile idiopathic arthritis.  N Engl J Med 
2017;376:1637-46.  PMID:  28445959 
 
• 
Corrected typographical and spelling errors throughout 
 
Version 1.2 (13 Dec 2019) 
• 
Section 3.1 Design elements, added: First patient enrolled in September 2019; the end 
of the trial (completion of follow-up of last patient enrolled) is expected to be February 
2023. 
 
• 
Section 3.5 Eligibility criteria  
− 
Added the following clarification to exclusion criterion Untreated active hepatits B 
or C infection: Active hepatitis B is defined as positive surface antigen; active 


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hepatitis C is defined as positive antibody and positive polymerase chain reaction 
(PCR) 
− 
Added exclusion:   Receipt of a live vaccine within past 30 days 
− 
Added exclusion:  Hypersensitivity to any of the study treatments or their 
excipients 
− 
For exclusion re: unwillingness to use birth control for persons of child-bearing or 
impregnating potential: 
 
Changed time for use of birth control from 15 to 18 months 
 
Added note  that combination barrier and spermicide should not be used 
by UK patients 
 
• 
Section 6. Possible side effects and complications of study treatments 
Added medications that are prohibited during the trial for safety reasons:  
− 
Live vaccines  
− 
Substrates for the multidrug efflux transporter P-glycoprotein or the organic anion 
transporter proteins (OATP), e.g., bosentan, dabigatran etexilate and aliskiren. 
− 
Products containing Hypericum perforatum (St John´s Wort) to avoid risk of 
interaction with tacrolimus (also added to tacrolimus entry in Table 7, Potential 
risks of therapy 
 
• 
Section 7.2 Serious adverse events:  Specified that UK clinics are required to report 
SAEs to the CC within 24 hours as to be compliant with EU/UK requirements.  Non-UK 
clinics have 72 hours to report SAEs to the CC. 
 
 
Version 1.3 (9 Oct 2020) 
• 
Section 3.7 Data collection schedule, Table 1 Visit and examination schedule 
− 
Added clarification to footnote:  chemistry panel including serum glucose 
− 
Added clarification: Screening P-60 test  
 
• 
Section 3.4.3 Disease-specific assessment to permit ascertainment of outcomes 
pertaining to activity of uveitis: Birdshot chorioretinitis – Corrected Humphry settings by 
changing 24-2 to 30-2 in two places as missed during  
 
• 
Section 4.2 Systemic corticosteroids:  Corrected typo in first paragraph, maximum dose 
of prednisone; changed 60 mg/kg/day to 60 mg/day 
 
• 
Section 4.2.1 Initial prednisone dose, Table 3. Initial prednisone dosing summary:   
Added text (as italicized) to scenarios “substantively improved “and “not controlled” in 
last column: Taper but not below 7.5 mg/day until inactive 
 
• 
Section 4.5 Management of uveitis reactivation, Table 6a, Reactivation guidelines – 
Prednisone:  Added italicized text for clarification for scenario, Reactivation during 
prednisone taper -Not controlled, 4 weeks after prednisone increase: Taper but not 
below 7.5 mg/day until inactive 


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• 
Section 4.8.1 Regional corticosteroid Injections:  Revised to make the intravitreal 
dexamethasone pellet an acceptable ancillary treatments for macular edema.  
Previously treatment with the dexamethasone pellet was excluded because, at the time 
the protocol was written, the expected duration of the treatment effect was about 5 
months based on data from the HURON Trial.  However, in the POINT Trial we found 
the treatment effect to be shorter, about the same as Triesence, approximately 3 
months.  
 
• 
Section 4.8.2 Topical corticosteroids 
− 
Corrected typo in the concentration of difluprednate from 0.005 to 0.05 
− 
In 3rd bullet, clarified the maintenance dose permitted for each of three drugs 
 
• 
References:  Added reference 74 (results of POINT Trial)  
 
 
 


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Document distribution 
 
Version 
Version date 
Distribution 
Distribution date 
1.0 
26 Oct 2018 
Abbvie   
29 Oct 2018 
 
 
JHSPH IRB 
06 Nov 2018 
 
 
 
 
 
19 Dec 2018 
JHSPH IRB 
28 Dec 2018 
 
 
Clinical Centers 
24 Jan 2019 (PPM 1) 
 
 
FDA 
06 Feb 2019 
 
 
 
 
 
06 Feb 2019* 
JHSPH IRB 
8 Feb 2019 
 
 
 
 
1.0 Canada† 
 
30 Oct 2019 
 
Health Canada 
MUHC clinical center 
30 Oct 2019 
04 Nov 2019 
 
 
 
 
1.0 UK‡ 
 
 
 
22 Nov 2019 
 
 
 
UK Medicines and 
Healthcare products 
Regulatory Agency 
(MHRA) 
28 Nov 2019 
 
 
 
 
 
 
 
1.1 
31 Oct 2019* 
JHSPH IRB 
5 Nov 2019 
 
 
 
 
 
 
 
 
1.2 
13 Dec 2019 
JHSPH IRB 
16 Dec2019 
 
 
Clinical Centers 
31 Jan 2020 (PPM 21)\ 
 
 
FDA 
05 Jun 2020 
 
 
Health Canada 
12 Mar 2020 
 
 
 
 
1.3 
12 Oct 2020 
 
 
 
* Interim versions, not distributed to clinical centers 
 
† Interim Canadian version only (19 Dec 2018 to 30 Oct 2019):  Revisions requested by Health Canada 
were made to this Canadian-only version. The following exclusion criteria were added: severe 
uncontrolled infection; moderate to severe heart failure (NYHA class III/IV); active malignancy. 
Subsequently these revisions were incorporated into protocol version 1.2 (13 Dec 2019. 
 
‡ Interim UK only version (19 Dec 2019 to 22 Nov):  Revisions requested by the UK Medicines and 
Healthcare products Regulatory Agency (MHRA) were made to this UK version.  These are the 
substantive changes made to exclusion criteria:  clarification of lab results for active hepatitis B and C 
infections; added exclusion for specificed baseline lab values; added exclusions for severe uncontrolled 
infection, live vaccine within past 30 days,hypersensitivity to and study treatments or excipients; revision 
of pregnancy criteria to include persons of child-bearing or impregnating potential.  Added medications 
not to be used during the trial (end of section 6.).  Subsequently these revisions were incorporated into 
protocol version 1.2 (13 Dec 2019). 
 


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Abstract 
 
 
The uveitides are a collection of diseases characterized by intraocular inflammation.  
Collectively, they are the 5th leading cause of blindness in the US, and the estimated cost of 
treating them is similar to that of treating diabetic retinopathy.  Non-infectious intermediate, 
posterior, and panuveitides have the highest rates of visual loss and typically are treated with 
oral corticosteroids and immunosuppression.  The Multicenter Uveitis Steroid Treatment 
(MUST) Trial (a randomized, comparative effectiveness trial, which compared 2 treatment 
paradigms for these diseases, systemic therapy with corticosteroids and immunosuppression 
vs. regional therapy [the fluocinolone acetonide implant]), and Follow-up Study demonstrated 
the superiority of the systemic approach to the regional ocular approach in terms of long-term 
visual outcomes with essentially no increase in systemic side effects in the systemic group.  
One key to systemic therapy’s success was the use of systemic immunosuppression in 88% of 
participants, coupled with tapering the prednisone to <7.5 mg/day, a relatively safe dose.  Non-
alklyating agents are typically the first choice and the most often used are azathioprine, 
methotrexate, mycophenolate, cyclosporine, and tacrolimus.  The alkylating agents, 
cyclophosphamide and chlorambucil, are used less often because of concerns about potential 
increased malignancy risk. Data from the Systemic Immunosuppressive Therapy for Eye 
Diseases (SITE) Cohort Study suggest that each of the conventional, non-alkylating agent 
immunosuppressive drugs is effective in controlling the inflammation while permitting tapering 
prednisone in ~40-55% of patients; hence combination therapy often is needed.  Furthermore, 
minimizing the daily dose of prednisone is important, as the risk of cardiovascular disease and 
mortality increase with the cumulative dose of oral corticosteroids. In June 2016, the fully-
human, anti-TNF-α monoclonal antibody, adalimumab, was approved by the US Food and Drug 
Administration (FDA) for the treatment of uveitis.  Anti-TNF-α monoclonal antibody therapy has 
revolutionized the management of the rheumatic diseases largely due to its superior efficacy 
compared to conventional Disease Modifying Anti-Rheumatic Drugs.  Data from VISUAL III, the 
extension of the two phase 3 trials that led to the FDA approval of adalimumab for the treatment 
of uveitis, suggest that adalimumab may be superior to conventional immunosuppression, as 
~75% of participants had controlled inflammation with prednisone doses <5 mg/day.  The 
ADalimumab Vs. conventional ImmunoSupprEssion for uveitis (ADVISE) Trial is a randomized, 
comparative effectiveness trial comparing adalimumab to conventional agent 
immunosuppression for patients with non-infectious, intermediate, posterior, and panuveitides.  
The primary outcome is the ability to successfully taper prednisone to <7.5 mg/day by 6 months 
after randomization while maintaining control of the inflammation.  Secondary outcomes include 
prednisone discontinuation by 1 year, visual acuity, and complications of uveitis and its 
treatment. 
 
 


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1. 
Introduction 
 
1.1 
Title 
ADalimumab Vs. conventional ImmunoSupprEssion for corticosteroid-sparing for uveitis 
(ADVISE) Trial  
 
 
1.2 
IND  
ADVISE is being conducted under IND 132532 held by Jennifer E. Thorne, MD, PhD, the Study 
Medical Safety Officer, for the Coordinating Center.  The product named in the IND is Humira 
(adalimumab); the IND covers the conventional immunosuppressive drugs used in ADVISE (i.e., 
azathioprine, methotrexate, mycophenolate, cyclosporine, tacrolimus). 
Adalimumab was FDA approved for the treatment of non-infectious intermediate, posterior, and 
panuveitides in adult patients in 2016 and in pediatric patients 2 years of age and older in 2018.  
In 2016, prior to FDA approval of adalimumab for treatment of uveitis in pediatric patients, the 
Coordinating Center submitted an IND exemption request to the FDA for use of adalimumab in 
adolescent patients (13 to <18 years of age) for the ADVISE Trial.  In response, the FDA 
determined that use of adalimumab for the treatment of non-infectious intermediate, posterior, 
and panuveitides in adolescent patients in ADVISE does not increase risk for these patients as 
the drug was approved for treatment of pediatric patients for other indications.  However, 
although conventional immunosuppressive drugs are the standard approach and in widespread 
use, these drugs are not FDA approved for treatment of non-infectious intermediate, posterior, 
and panuveitides, and therefore an IND is required.    
   
1.3 
Financial sponsor  
ADVISE is funded by the National Eye Institute through linked UG1 grants to the Study 
Chairman’s Office (CO), the Coordinating Center (CC), and the Reading Center (RC).  Clinical 
centers are funded through sub-agreements with the CC.  
 
 
1.4 
Resource centers 
 
Center 
 
Director/Co-Directors 
 
 
Study Chairman’s Office 
Johns Hopkins Bloomberg School of Public Health, Baltimore 
 
Coordinating Center  
 
Douglas Jabs, MD, MBA 
 
Johns Hopkins Bloomberg School of Public Health, Baltimore, MD 
 
Janet Holbrook, PhD, MPH 
Elizabeth Sugar, PhD  
Reading Center 
 
University of Wisconsin at Madison, Madison, WI 
Michael Altaweel, MD 
 
 


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1.5 
Clinical centers 
Clinical centers will be located in the United States, the United Kingdom, Australia, and Canada. 
A list of participating clinical centers is included in the ADVISE Manual of Procedures.    
 
1.6 
Additional Support 
AbbVie (Chicago, IL) will donate adalimumab for the trial. 
 
 


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1.7 
Background and significance 
The uveitides are a collection of diseases characterized by intraocular inflammation.1  In the 
United States (US), the uveitides collectively are the 5th leading cause of blindness and are 
responsible for an estimated 30,000 new cases of blindness annually.2  They cause an 
estimated 2.8% to 10% of blindness in the working age population.2,3,4,5,6 The cost of treating 
the uveitides is comparable to that of treating diabetic retinopathy.7  In addition to the estimated 
direct cost of treatment, there are substantial indirect costs, as treatment of the more severe 
uveitides is labor intensive, typically requiring patient visits every 4-6 weeks for at least several 
years. The estimated incidence of uveitis is 17-54/100,000/year, and the estimated prevalence 
of active uveitis is 115-204/100,000.3,5 In 1993, Research to Prevent Blindness estimated the 
prevalence as 1% of the US population.8 Because the uveitides affect all ages, including 
children and working-age adults, the potential years of vision lost and economic impact per case 
exceed that of age-related diseases, such as cataract and age-related macular degeneration.  
Hence research into improving the outcomes of management of these diseases is critical for 
lessening their burden of visual impairment and blindness. For these reasons, improving 
methods for the treatment of the uveitides is one of the strategic goals of the National Plan for 
Eye and Vision Research (htpps://nei.nih.gov/strategicplanning/np_retinal, accessed 30 August 
2016).   
 
The uveitides typically are classified by the primary site of inflammation as anterior, 
intermediate, posterior, or panuveitis.1,9  Although anterior uveitides are somewhat more 
common than intermediate, posterior, or panuveitides, the incidences of visual impairment 
(worse than 20/40) and blindness (20/200 or worse) are far greater among intermediate, 
posterior and panuveitides.  For posterior and panuveitides, the rates of visual impairment and 
blindness are nearly 3-fold greater than those seen with anterior uveitides.10 Hence 
intermediate, posterior, and panuveitides cause a disproportionately large share of visual 
impairment and blindness from uveitis.  Uveitides may be infectious or non-infectious; the 
majority of cases in the US are non-infectious.1,9 Uveitides also may be monophasic and 
spontaneously-remitting, recurrent acute (episodic with periods of inactive disease off treatment 
between attacks), or chronic (with prompt relapse upon discontinuation of treatment and the 
need for chronic suppression).  The large majority of cases of intermediate, posterior, and 
panuveitides are chronic and require long-term, possibly life-long, therapy.1,9  Although some 
cases of intermediate uveitis may be observed or treated intermittently,11,12 many cases of 
intermediate uveitis and nearly all posterior and panuveitides require treatment with oral 
corticosteroids and immunosuppression.13,14,15,16 Immunosuppressive drug treatment provides 
superior outcomes to corticosteroids alone for several specific uveitic diseases.15,17,18,19,20  In the 
MUST Trial and Follow-up Study, systemic therapy with oral corticosteroids and 
immunosuppression produced superior visual acuity outcomes at 7 years of follow-up compared 
to regional therapy with the fluocinolone acetonide intraocular implant, in part due to the variable 
duration of effect of regional therapies and the uveitis reactivation that occurs prior to re-
implantation.15  Furthermore, the systemic approach had a significantly lower risk of ocular 
adverse effects (primarily cataract and ocular hypertension/glaucoma) with no significantly 
increased risk of systemic side effects, except for a greater use of antibiotics for 
infections.15,21,22,23,24   Sustained, drug-free, remissions (defined as inactive disease off all 
treatment) occasionally are possible for some chronic uveitides managed with 
immunosuppression, but they are infrequent.15,25,26,27  The Systemic Immunosuppressive 
Therapy for Eye Disease (SITE) Cohort Study estimated the drug-free remission rate in 
intermediate uveitis at 8.6%/person-year (PY).25  In juvenile idiopathic arthritis (JIA)-associated 
chronic uveitis, the median time to a drug-free remission for mild disease is ~10 years, and only 


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~25% of those with severe disease ever achieve a remission.26,27  The Mount Sinai Multifocal 
Choroidopathy Study reported that no patients with these posterior uveitides were in drug-free 
remissions at 2 years of follow-up, and only 11% were able to discontinue prednisone 
successfully, despite the use of immunosuppression in all patients.16 The SITE Cohort Study 
estimated the rate of drug-free remissions for each non-alkylating agent immunosuppressive 
drug at 5 to 9%/PY.28,29,30,31  In the MUST Trial and Follow-up Study, only ~25% of participants 
treated with systemic therapy were in drug-free remissions at 7 years of follow-up.15  Hence 
long-term, chronic therapy with oral corticosteroids and/or immunosuppression typically is 
needed to control these diseases and preserve vision. 
   
Oral corticosteroids and immunosuppression have the potential for systemic side effects, but 
most are reversible with dose reduction or discontinuation of the appropriate agent.13,14  In the 
MUST Trial and Follow-up Study, there was no significant increase in systemic adverse effects 
through 7 years of follow-up among those assigned to systemic therapy versus those assigned 
to treatment with a regional, intraocular therapy (the fluocinolone acetonide implant) with the 
one exception.  Those assigned to systemic therapy were more likely to be given antibiotics for 
infections.15,21,22,24  A key to the successful management of this systemic approach is tapering 
prednisone to relatively safe doses.  Meta-analyses of trials in rheumatoid arthritis have shown 
that prednisone at a dose of <7.5 mg/day appears safe for the intermediate-term (~ 2 years),32 
and in the MUST Trial and Follow-up Study (in which minimal systemic side effects occurred), 
the median dose of prednisone among those still on prednisone at 7 years of follow-up was 6.25 
mg/day.15  However, long-term studies of patients with rheumatoid arthritis demonstrate that the 
risks of overall and cardiovascular mortality both increase with the cumulative dose of 
prednisone,33 suggesting that efforts must be made to discontinue or at least minimize the daily 
dose of oral corticosteroids.  Although doses of prednisone of 5 to 7.5 mg/day might be 
tolerated for years, they cannot be used indefinitely, due to the increased risk of cardiovascular 
disease.33  Improved corticosteroid-sparing immunosuppression among uveitis patients is critical 
to minimizing the use of systemic corticosteroids and improving patients’ long-term outcomes 
given that long-term, potentially life-long, treatment may be required and the relatively low rate 
of remission.14  
  
Immunosuppressive drugs include small molecules (conventional agents) and biologic agents.  
The principal small molecule immunosuppressive drugs include the antimetabolites, 
azathioprine, methotrexate, and mycophenolate; the calcineurin inhibitors, cyclosporine and 
tacrolimus; and the alkylating agents, cyclophosphamide and chlorambucil.14,28,29,30,31,34,35,36  The 
biologic agents most often used for treatment of the uveitides are anti-tumor necrosis factor 
(TNF)-α monoclonal antibodies (e.g., infliximab, adalimumab), although there are case reports 
and small case series with other agents.37,38,39,40,41,42  In the MUST Trial and Follow-up Study, 
88% of participants assigned to systemic therapy received immunosuppression; all of these 
patients received conventional immunosuppression as the initial agent. Currently, the majority of 
patients with uveitis receiving immunosuppression are treated with antimetabolites or 
calcineurin inhibitors.  Alkylating agents may be more effective,34 but their use has been 
curtailed due to their increased cancer risk.43,44,45,46,47 Biologic agents also have been used less 
often in the past, in part due to restricted access in the US prior to US FDA approval for uveitis.  
Data from the SITE Cohort Study suggest that antimetabolites and calcineurin inhibitors, when 
used as the only immunosuppression agent, are effective in controlling the inflammation and 
allowing tapering of prednisone to <10 mg/day in ~40-55% of patients by 6 months of 
treatment.28,29,30,31  As such, dose escalation of immunosuppressive agents, switching agents, 
and combination therapies (e.g., an antimetabolite with a calcineurin inhibitor) commonly are 
needed.14,16  When uveitis reactivation occurs, the dose of prednisone is increased until the 


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uveitis is inactive again and the prednisone taper resumed, sometimes more slowly, increasing 
the cumulative exposure to oral corticosteroids and the potential for side effects. 
   
In June 2016, adalimumab (Humira®, AbbVie, Chicago, IL), a fully human monoclonal antibody 
to TNF-α, administered subcutaneously, was approved by both the US FDA and by the 
European Commission for the treatment of noninfectious, intermediate, posterior, and 
panuveitides.  These approvals were based on two industry-sponsored, randomized, placebo-
controlled, double masked, drug-licensing trials comparing adalimumab versus placebo for 
patients with active and inactive uveitis (VISUAL I and II, respectively).  These trials 
demonstrated the superiority of adalimumab over placebo by prolonging the time to treatment 
failure (uveitis relapse) among participants on a rapid corticosteroid taper to discontinuation.37,38  
In the VISUAL III treatment extension study participants were permitted to use low-dose oral 
corticosteroids.  In VISUAL III, ~75% of patients had inactive uveitis with a prednisone dose 
<5mg/day, beginning at 11 weeks after entry and continued through at least 1 year of follow-up.  
Furthermore, in VISUAL III, the mean dose of prednisone over time was 2 mg/day. (Douglas, 
Kevin, AbbVie, personal communication, 2017).  These data suggest that adalimumab may be 
superior to conventional immunosuppression as corticosteroid-sparing therapy (success rates of 
~40 to 55% in the SITE Cohort Study28,29,30,31 and long-term mean doses of prednisone of 5-6 
mg/day in the both Mount Sinai Multifocal Choroidopathy Study and the MUST Trial Follow-up 
Study15,16).  A recently-published, randomized, placebo-controlled clinical trial of adalimumab 
added to methotrexate demonstrated its efficacy in managing JIA-associated uveitis in children.  
Furthermore, aside from an increased risk of infection (also seen with conventional 
immunosuppression in the MUST Trial and Follow-up Study) and injection site reactions, 
adalimumab appears relatively safe for long-term use.48,49,50 Although the initial SITE Cohort 
Study publication suggested a possible increased risk of malignancy with anti-TNF biologic 
agents,45 these data were from a very small sample size, and sensitivity analyses of the 
estimates were unstable.  Large observational databases48,49 and meta-analyses50 have 
demonstrated no increased risk of malignancies with anti-TNF treatment, except possibly non-
melanoma skin cancer, a risk also sometimes reported with conventional, small molecule 
immunosuppression.46 The potential superiority as a corticosteroid-sparing agent and apparently 
similar safety of adalimumab to conventional immunosuppressive agents suggest the need for a 
randomized, comparative effectiveness trial comparing adalimumab to conventional 
immunosuppression for the treatment of non-infectious, intermediate, posterior, and 
panuveitides.   
 
A key feature in the management of the uveitides is successful control of the 
inflammation.51,52,53  When evaluated using time-updated methodology, the presence of any 
inflammation increases the risks of visual impairment and blindness by 2- and 3-fold, 
respectively, and there appears to be a dose-response effect with greater inflammation resulting 
in higher risks of visual impairment and blindness.51,52,53  Therefore, the definition of treatment 
success for corticosteroid-sparing includes tapering prednisone to <7.5 gm/day while 
maintaining inactive disease.9,16,32 Measurement of uveitis control varies by specific disease.  
For example, for intermediate uveitis, vitreous haze is a good measure of activity (and has been 
used for US FDA drug approval of Ozurdex®),9,54 but for serpiginous choroiditis it is not, as there 
is no vitritis with serpiginous.  For serpiginous choroiditis, multimodal imaging has demonstrated 
that fundus autofluorescence (FAF) correlates well with disease activity, and it has become the 
standard method for following such patients.55  Similarly, for birdshot chorioretinitis (BSCR), 
vitreous haze typically is mild, and FAF is not helpful, but prevention of loss of peripheral visual 
field (and sometimes reversal of loss) from active disease is an important measure.17,18,55  To 
address this heterogeneity, the ADVISE Trial will use disease-specific assessments for 


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determining active vs. inactive disease in each participant (see Table 2. Visit and Examination 
Schedule in section 3.7 below and the Guidelines for Determining Inactive Disease in the 
ADVISE Manual of Procedures). 
 
1.8 
Preliminary studies  
The MUST Trial and Follow-up Study compared the fluocinolone acetonide intraocular implant 
(a strictly regional corticosteroid approach, designed to last 3 years, with re-implantation as 
needed) to systemic therapy with oral corticosteroids and immunosuppression for the treatment 
of non-infectious, intermediate, posterior, and panuveitides.15,21,22,23,24 The MUST Trial enrolled 
255 participants (Table 1), and the primary outcome was change in visual acuity from baseline.  
At 2 and 4.5 years of follow-up, the implant and systemic therapy had similar visual acuity 
outcomes; both treatments controlled the inflammation in the large majority of participants; the 
implant had better control of the inflammation but at a cost of higher rates of ocular hypertension 
(OHT), glaucoma, and cataracts; and both groups had similar rates of systemic side effects, 
except for a greater use of antibiotics for infections in the systemic group.21,22,23,24  However, at 7 
years of follow-up visual acuity outcomes significantly favored systemic therapy, with greater 
rates of ocular adverse events in the implant group, but generally similar rates of systemic 
adverse events in both groups.15 Furthermore, throughout the 7 years of follow-up, participants 
on systemic therapy maintained good visual acuity (mean ~20/40).   
 
Clinician-reported causes of visual impairment suggested that patients in the implant group 
more often had retinal lesions/scars as the cause.  These data suggest that systemic therapy 
has advantages over strictly regional therapies for the long-term management of these more 
severe, vision-threatening uveitides.  In the systemic group, 88% of participants received 
immunosuppression in addition to oral corticosteroids.  Of the 88% of participants using 
immunosuppression, 85% (75% of the entire cohort) initiated immunosuppression with a single 
immunosuppressive agent, and 15% (13% of the entire cohort) with a combination of immuno-
suppressive agents.  The most commonly used single-agent immunosuppressive drugs were 
mycophenolate 41%, methotrexate 29%, azathioprine 7%, and cyclosporine 6%.  The most 
commonly used combination regimens were mycophenolate and cyclosporine 5%, azathioprine 
and cyclosporine 3%, and methotrexate and cyclosporine 2%.  For each participant the choice 
of immunosuppressive drug was made by the investigator at the clinical center, based on the 
patient’s needs and the drug’s side effect profiles (e.g., methotrexate is avoided in patients with 
liver disease), but the drugs were used in a standardized fashion following MUST Trial 
guidelines.14,21  Adherence to protocol for the use of immunosuppressive drugs was monitored 
regularly by a Medical Therapy Quality Assurance Committee (MTQAC), thereby assuring their 
proper and consistent use.  
 
 


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Table 2.  Distribution of uveitic diseases in the MUST Trial 
Disease 
               % Participants 
Intermediate uveitis (including pars planitis) 
27 
Undifferentiated anterior and intermediate uveitis 
19 
Undifferentiated or sarcoid-related panuveitis 
17 
Multifocal choroiditis with panuveitis 
10 
Birdshot chorioretinitis 
9 
Vogt-Koyanagi-Harada disease 
6 
Undifferentiated retinal vasculitis 
5 
Behçet disease 
3 
Multiple sclerosis associated uveitis 
1 
Other*  
3 
*Sympathetic ophthalmia, serpiginous choroiditis, and punctate inner choroiditis each 1%  
 
 
1.9 
Rationale for trial 
Available data suggest that each of the conventional, non-alkylating-agent, immuno-suppressive 
drugs is effective in successful corticosteroid-sparing with inflammation control in ~40-55% of 
patients when used as a single immunosuppressive agent in conjunction with 
corticosteroids.28,29,30,31,34 hence, combination therapy often is needed.16  In June 2016, the 
United States (US) Food and Drug Administration (FDA) approved adalimumab, a fully-human 
monoclonal antibody to TNF-α, for the treatment of non-infectious intermediate, posterior, and 
panuveitides.37,38  Monoclonal antibody therapies, particularly those against TNF-α, have 
transformed the management of rheumatic diseases, such as rheumatoid arthritis and 
ankylosing spondylitis, and largely have supplanted older Disease Modifying Anti-Rheumatic 
Drugs (DMARDs).  Although the relative effectiveness of adalimumab vs. conventional 
immunosuppression for the treatment of non-infectious intermediate, posterior, and panuveitides 
is unknown, data from the VISUAL III study suggest that adalimumab may be superior to 
conventional immunosuppression for corticosteroid sparing while maintaining uveitis control.  In 
VISUAL III uveitis control was maintained in ~75% of participants with prednisone doses <5 
mg/day (Tari S, AbbVie, personal communication, 2016).  Minimizing the daily dose of 
prednisone is important, as there is a cumulative effect of oral corticosteroids on the risk of 
cardiovascular disease and mortality.33 Therefore, the ADVISE Research Group proposes to 
perform a randomized, comparative effectiveness trial of adalimumab vs. immunosuppression 
with conventional agents for the treatment of non-infectious intermediate, posterior, and 
panuveitides, the ADlamimumab Vs. conventional ImmunoSupprEssion for uveitis (ADVISE) 
Trial.   
 


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2. 
Objective and study hypothesis 
 
2.1 
Objective and specific aims 
The ADVISE Trial is a randomized, parallel-treatment, comparative effectiveness trial, 
comparing adalimumab to conventional (small molecule) immunosuppression for the treatment 
of non-infectious, intermediate, posterior, and panuveitides.    
 
The specific aims of the ADVISE Trial are to: 
 1. Compare the relative effectiveness of adalimumab vs. conventional 
immunosuppression at controlling ocular inflammation while permitting tapering of 
prednisone to <7.5 mg/day.  
  
 2. Compare the relative effectiveness of adalimumab vs. conventional 
immunosuppression at controlling ocular inflammation while permitting tapering and 
discontinuation of prednisone.  
 
 3. Compare the visual acuity outcomes, rates of ocular complications of uveitis (e.g., 
macular edema), and drug-related adverse event profiles between the two treatment 
groups.  
  
 4. Compare the quality of life profiles between the two treatment approaches.   
 
2.2 
Hypotheses 
Based on the preliminary data we hypothesize that adalimumab will be superior to conventional 
immunosuppression for successful corticosteroid-sparing with no clinically important increase in 
systemic adverse events.   
 
Primary Hypothesis 
Adalimumab will be superior to conventional immunosuppression for corticosteroid sparing, as 
determined by the proportion achieving the primary outcome, namely inactive uveitis and 
prednisone <7.5 mg/day for 2 visits >28 days apart by 6 months of follow-up.  
 
Secondary hypotheses are: 
 1. Adalimumab will be superior to conventional immunosuppression for corticosteroid-
sparing by one year of follow-up as determined by the proportion achieving inactive 
uveitis at prednisone ≤7.5 mg/day for 2 visits >28 days apart within one year of 
follow-up; 
 
 2.  Adalimumab will be superior to conventional immunosuppression for maintaining 
control of inflammation after discontinuation of prednisone for 2 visits >28 days apart 
by one year of follow-up. 
 
 


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3. 
Design 
 
The ADVISE Trial is a randomized, parallel-treatment, comparative effectiveness trial, 
comparing adalimumab to conventional (small molecule) immunosuppression for corticosteroid 
sparing in the treatment of non-infectious, intermediate, posterior, and panuveitides. 
 
3.1 
Design elements 
• 
Randomized, parallel-treatment, controlled comparative effectiveness clinical trial 
• 
Randomization stratified by: 
- 
Whether patient is receiving zero or one immunosuppressive agent at enrollment 
- 
Whether the initial dose of prednisone in the trial will be <30 mg/day or ≥ 30 
mg/day 
• 
The unit of randomization is the patient 
• 
The unit of analysis for the primary outcome is the patient 
• 
Allocation ratio 1:1 
• 
Multicenter, international 
• 
Fixed sample size = 222 (111 per treatment group) 
• 
Unmasked treatment administration and outcome assessments (participants, study 
ophthalmologists, visual function examiners, and study coordinators are all unmasked).   
• 
Masked assessment of photographic images and OCT by the RC (graders masked) 
- 
All patients 
 
OCT at baseline, 3, 6, and 12 months 
 
Retinal color photographs at baseline, 6 and 12 months  
• 
Disease-specific image or OCT, as applicable, at baseline, 1, 3, 6, and 12 
monthsAnniversary close-out at the 12-month visit 
• 
First patient enrolled in September 2019; the end of the trial (completion of follow-up of 
last patient enrolled) is expected to be February 2023. 
• 
Conducted under IND 132532  
 
 
3.2 
Randomized treatment arms 
• 
Adalimumab 
- 
80 mg subcutaneously once as the initial dose 
- 
40 mg subcutaneously a week later, then 40 mg subcutaneously every other 
week thereafter 
 
• 
Conventional immunosuppression 
The treatment of participants randomized to conventional immunosuppression will 
depend on whether or not patient is using an immunosuppressive agent at enrollment 
and, if one is being used, the type of immunosuppressive agent in use.  
- 
For patients receiving no immunosuppressive agents at the time of enrollment 
the initial immunosuppressive drug will be an antimetabolite (azathioprine, 
mycophenolate, or methotrexate) 
 
- 
For patients already on one immunosuppressive drug at enrollment, the original 
drug will be continued at the dose at baseline.  Additional treatment will be based 
on the drug already being received at baseline:  
 
Those on an antimetabolite will receive a calcineurin inhibitor 
 
Those on a calcineurin inhibitor will receive an antimetabolite 
 


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3.3 
Trial schematic 
 
 
 
 


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3.4 
Outcomes 
3.4.1 Primary outcome 
The primary outcome of the ADVISE Trial will be a corticosteroid-sparing treatment success, 
defined as inactive uveitis, on prednisone <7.5 mg/day for 2 consecutive visits >28 days apart 
within the first 6 months after randomization.9,16,28,29,30,31,34  The SITE Cohort Study required 2 
consecutive visits >28 days apart to avoid overestimation of benefits among patients who 
transiently achieve corticosteroid-sparing, but promptly relapse at the next visit.28,29,30,31,34 We 
will use a similar methodology for the same reasons.  The prednisone taper schedule used in 
the ADVISE Trial (see Table 4 in section 4.2.2) is designed to permit clear evaluation of this 
outcome.   
 
3.4.2 Secondary outcomes 
  
Secondary corticosteroid sparing outcomes 
 
 1. The ability to achieve inactive uveitis and prednisone <7.5 mg/day for 2 consecutive 
visits >28 days apart within one year of randomization. 
 
 2. The ability to achieve inactive uveitis and completely discontinue prednisone for 2 
consecutive visits >28 days apart within  6 months and one year of randomization. 
 
 3. Prednisone exposure (e.g., cumulative prednisone dose and/or mean prednisone dose) 
in the 2 groups over 1 year with emphasis on the 6-month (primary outcome) and 1-year 
(end of follow-up) visits. 
    
    Other secondary outcomes (assessed at every visit unless otherwise indicated)  
 
 4. Best corrected visual acuity measured after a standardized refraction using logarithmic 
visual acuity charts21,56,57 over 1 year with emphasis on the 6-month (primary outcome) 
and 1-year (end of follow-up) visits. 
 
 5. Incidence of the following infections over 1 year with emphasis on the 6-month (primary 
outcome) and 1-year (end of follow-up) visits: 
a. Infections requiring antimicrobial therapy 
b. Tuberculosis (clinical diagnosis of tuberculosis)  
c. Invasive fungal infections  
d. Dermatomal or disseminated herpes zoster  
 
Diagnosis of these entities will rely on medical record confirmation thereof, but specific 
testing will not be performed prospectively to ascertain the individual infections, which 
likely will be unusual.   
 
 6. Systemic adverse events, e.g., cytopenias, elevated creatinine, elevated liver 
enzymes15,21,22,23,24 over 1 year with emphasis on the 6-month (primary outcome) 
and 1- year (end of follow-up) visits. 
 
 7. Macular edema58,59,60,73 over 1 year with emphasis on the 6-month (primary outcome) 
and 1-year (end of follow-up) visits. 
 
 8. Quality of life (QoL) data as assessed using the following patient reported outcomes that 
have been used in prior MUST 61,62,63,64,65,66,67  over 1 year with emphasis on the 6-month 
(primary outcome) and 1- year (end of follow-up) visits 
a. Health Utility (EuroQoL 5-dimension and visual analog scales) 
b. Generic Health-related Quality of life (SF-36) 
c. Vision-related QoL (the 25-item NEI Visual Function Questionnaire [VFQ]) 
 


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3.4.3 Disease-specific assessment to permit ascertainment of outcomes 
pertaining to activity of uveitis 
As there is no one uveitis activity measure or simple combination of measures appropriate for all 
intermediate, posterior, and panuveitides, disease-specific testing/assessment will be used to 
determine whether the uveitis is active. The specific uveitic diagnosis documented at enrollment 
(including undifferentiated uveitides by anatomic class) will dictate the disease-specific tests 
required (Table 2) and the criteria for determining inactive uveitis for that participant (Guidelines 
for Determining Inactive Uveitis in the ADVISE Manual of Procedures).  If the unlikely situation 
is encountered in which different eyes have different diagnoses, each eye will be assessed 
using the disease-specific tests indicated for each eye’s diagnosis and both eyes must have 
inactive uveitis for the patient to be counted as inactive for corticosteroid-sparing outcomes. 
These tests will be performed according to the schedule outlined in Table 2.  Some of the 
assessments are part of the eye examination (e.g., grading of anterior chamber cells and of 
vitreous haze), but other assessments involving ancillary testing will be done only for selected 
diseases (e.g., FAF, visual fields, fluorescein angiography) for which the results are relevant to 
the determination of activity.  However, for each participant, the test(s) and methods of 
assessment will be the same from baseline throughout the duration of the trial, so that a 
longitudinal assessment of active vs. inactive can be made consistently on an individual 
participant basis. 
 
Uveitides included in the ADVISE Trial which require specific testing in addition to clinical 
examination to determine activity/quiescence include: 
  
• 
Multifocal choroidal/retinal pigment epithelium inflammation including undifferentiated 
panuveitides (except birdshot chorioretinitis):  For most such cases, fundus 
autofluorescence shows hyper-autofluorescent spots or borders with active disease and 
hypo-autofluorescent spots with inactive scarring.55,68,69 Fundus autofluorescence is non-
invasive, easily performed, and will be done at each follow-up visit during the trial in 
patients for which it is indicated.  
 
• 
Birdshot chorioretinitis:  An exception to the utility of autofluorescence for multifocal 
choroidopathies is birdshot chorioretinitis, where fundus autofluorescence does not 
correlate with active disease.55 However, patients with active birdshot choroiditis suffer a 
progressive loss of visual field.  The earliest changes are a loss of peripheral field, not 
adequately captured on automated perimetry of the central field (e.g., the Humphrey 30-
2), but well captured with quantitative Goldmann perimetry18 or alternative evaluations of 
the peripheral field (e.g., automated perimetry using both the SITA-fast 30-2 and the 
peripheral 60 [P60], a suprathreshold screening test of the peripheral field).  Therefore, 
patients with birdshot will undergo one of these two forms of visual field testing at each 
visit throughout the trial.  Quantitative Goldmann visual fields (QGVFs) are performed in 
a standard fashion and produce visual field scores for I/4 and IV/4 isopters (normal 
values >560˚ of total field and >700˚ of total field, respectively).  The inter-test variation 
in the field is estimated at 16%, so scores within 16% of the previous field will be 
considered stable.18 Published data have demonstrated improving QGVF scores with 
immunosuppression, vs. declining ones without treatment.16,18  Goldmann perimetry is 
not universally available; therefore clinical centers without it will use automated perimetry 
with both evaluation of the central and peripheral field (e.g., Humphrey 30-2 SITA-fast 
and P60 screening test), in order to address the limitations of Humphrey 30-2 testing 
alone.  As with QGVFs, automated perimetry results within the variability of the test will 


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be considered “stable” (e.g., <3 dB mean deviation for the 30-2 and a change of <8 
spots missed for the P60, a supra-threshold screening test [Ramulu P, unpublished data, 
personal communication, 2017]). 
 
• 
Early stage Vogt-Koyanagi-Harada disease:  OCT will be used to determine the 
resolution of exudative retinal detachments. 
 
• 
Late stage Vogt-Koyanagi-Harada disease:  Fundus autofluorescence will be used to 
evaluate chorioretinal lesions 
 
• 
Retinal vasculitis and panuveitis with retinal vasculitis (including undifferentiated 
panuveitis with retinal vasculitis and panuveitis with retinal vasculitis with systemic 
disease):  Fluorescein angiography will be used to evaluate patients with these 
conditions.  Because resolution of intraretinal hemorrhages can take 3 months after 
vascular occlusion, the absence of new areas of intraretinal hemorrhage or retinal 
infarction or non-perfusion in conjunction with no new or increase in areas of retinal 
vascular staining and leakage will be used as evidence of uveitis control on fluorescein 
angiography.    
 
Structural complications, such as macular edema, epiretinal membrane formation, and choroidal 
neovascularization, will be scored separately, as they do not necessarily indicate active 
inflammation.   
 
In order to obtain consistency of evaluation, the RC will conduct a training session for the study 
ophthalmologists, emphasizing interpretation of the various modes of imaging and the 
determination of active vs. inactive disease.  In addition, the RC will provide a guidebook with 
examples of active and inactive disease based on the disease-specific imaging by disease.  
Real-time central determination of activity by the RC is not feasible logistically, as treatment 
decisions must be made at the time of the participant’s visit, and determination of activity 
requires examination of the patient as well as the images.  However, images taken at the 
baseline, 1-, 3-, 6-, and 12-month visits, including disease-specific images, will be sent to the 
RC for interpretation and will be used in quality control evaluations. 
 
The MTQAC will monitor activity assessment with support from the CC from regular screen as 
well as ad hoc assessments (e.g., site visits).  At month, the CC will screen the data stream for 
discrepancies between the site determination of activity and the corresponding disease-specific 
criteria for each eye with uveitis.  In addition, the CC will compare the RC and clinical evaluation 
of disease-specific images collected at baseline, 1-, 3-, 6-, and 12-month visits.  Discrepancies 
will be flagged and forwarded to the MTQAC, which will recommend corrective action as 
needed.     
 
 
 
 


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3.5 
Eligibility criteria 
Inclusion criteria 
 
 1. Age 13 years or older 
 
 2. Weight 30 kg (66 lbs) or greater 
 
 3. Active or recently active (≤ 60 days) non-infectious intermediate, posterior, or panuveitis  
 
 4. Prednisone indication meets one of the following:   
a. Active uveitis requiring one of the following 
i. Initiation of prednisone at dose greater than 7.5 mg/day  
ii. Increasing prednisone dose to greater than 7.5 mg/day 
iii. Currently receiving dose greater than 7.5 mg/day 
b. Inactive uveitis on current dose greater 7.5 mg/day 
 
 5. Initiation or addition of an immunosuppressive drug (i.e., a conventional 
immunosuppressive drug or adalimumab) is indicated  
 
 6. If currently receiving a conventional immunosuppressive drug, the drug and dose have 
been stable for at least 30 days 
 
 7. Patient able and willing to self-administer subcutaneous injections or have a qualified 
person available to administer subcutaneous injections 
 
 8. If posterior segment disease is present, ability to assess activity in at least one eye with 
uveitis 
 
 9. Visual acuity of light perception or better in at least one eye with uveitis 
Exclusion criteria 
 
 1. Active tuberculosis or untreated latent tuberculosis (e.g., positive interferon-γ release 
assay [IGRA] test, such as Quantiferon-gold)  
 
 2. Untreated active hepatitis B or C infection 
 Active hepatitis B is defined as positive surface antigen; active hepatitis C is 
defined as positive antibody and positive polymerase chain reaction (PCR)    
 
 
 3. Any of the following baseline lab values  
a. White blood count <3500 cells per microliter 
b. Platelets <100,000 per microliter 
c. Hematocrit <30% 
d. AST or ALT >1.5X upper limit normal value 
e. Serum creatinine >1.1X upper limit normal value 
 
 4. Behçet disease 
 
 5. Multiple sclerosis or other demyelinating disease 
 
 6. For patients with anterior/intermediate or intermediate uveitis without systemic disease, 
abnormal magnetic resonance imaging (MRI) of the brain consistent with demyelinating 
disease  
 
 7. Severe uncontrolled infection 
 
 8. Receipt of a live vaccine within past 30 days 
 


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 9. Moderate to severe heart failure (NYHA class III/IV) 
 
 10. Active malignancy 
 
 11. Use of anti-TNF monoclonal antibody therapy within past 60 days 
 
 12. History of adalimumab intolerance or ineffectiveness 
 
 13. Hypersensitivity to any of the study treatments or their excipients 
 
 14. Current treatment with an alkylating agent 
 
 15. Current treatment with more than one immunosuppressive drug, not including oral 
corticosteroids 
 
 16. Shorter-acting regional corticosteroids administered within the past 30 days in any 
eye(s) with uveitis  
 
 17. Long-acting ocular corticosteroid implants, i.e., fluocinolone acetonide implant (e.g., 
Retisert®, YutiqTM, Iluvien®) placed within past 3 years unless uveitis is active in all eye(s) 
with an implant  
 
 18. Systemic disease that is sufficiently active such that it dictates therapy with systemic 
corticosteroids or immunosuppressive agents at the time of enrollment  
 
 19. Immunodeficiency disease for which immunosuppressive therapy would be 
contraindicated according to best medical judgment 
 
 20. Pregnancy or lactation  
 
 21. For persons of child-bearing potential or impregnating potential, unwillingness to use 
appropriate birth control (abstinence, combination barrier and spermicide, hormonal, or 
intrauterine device) for the next 18 months or plans to become a biological parent within 
the next 18 months. 
 
* In the UK, use of combination barrier and spermicide alone does not meet birth control 
requirements. 
 
† UK female study participants must use highly effective methods of contraception. 
UK male study participants must use condoms for at least 6 months after the end of 
study treatment and their female partners of child-bearing potential are recommended 
to use highly effective contraception for the same duration. In addition, male 
participants should not donate semen during therapy or for 6 months following 
discontinuation of study treatment. 
 
 22. Medical problems or drug or alcohol dependence problems sufficient to prevent 
adherence to treatment and study procedures. 
 
 
3.6 
Stratification and randomization 
After informed consent is obtained, eligible participants will be stratified based on: 1) whether 
they are receiving no or one immunosuppressive agents and (2) whether their initial dose of 
prednisone in the trial will be <30 mg/day or > 30 mg/day.  Participants will be randomized 1:1 to 
adalimumab or conventional immunosuppression by variable-length permuted blocks within 
these 4 strata.  The randomization schedule will be produced in advance by the CC, and the 
randomization revealed via the ADVISE website after eligibility and stratum are confirmed. 
 
 
 


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3.7 
Data collection schedule 
Participants will be followed monthly for 6 months, and every two months thereafter until 
anniversary study closeout 1 year after randomization.  The visit and examination schedule is 
given in Table 2. 
 
 


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Table 3.  Visit and examination schedule 
Month 
BL* 1 
2 
3 
4 
5 
6 
8 
10 
12 
Visit ID 
V01 
V02 
V03 
V04 
V05 
V06 
V07 
V08 
V09 
V10 
 
All patients 
 
 
 
 
 
 
 
 
 
 
Visual acuity† 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Medical, ophthalmic, and treatment history 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Weight and blood pressure 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Height 
X 
 
 
 
 
 
 
 
 
 
Eye examination 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Optical coherence tomography (OCT)+ 
X 
 
 
X 
 
 
X 
 
 
X 
Retinal color photographs‡ 
X 
 
 
 
 
 
X 
 
 
X 
Complete blood count & chemistry panel§ 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Quality of life (EuroQoL, SF-36, NEI-VFQ) 
X 
 
 
X 
 
 
X 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
Disease-specific tests 
 
 
 
 
 
 
 
 
 
 
  Disease                                        Test(s) 
 
 
 
 
 
 
 
 
 
 
   Birdshot chorioretinitis             Visual field¶ 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
   Choroiditis (all except birdshot)       FAF║ 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
    VKH, early disease                     OCTɅ 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
    VKH, late disease                        FAF 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
    Retinal vasculitis and                   FA#     
      panuveitis with retinal vasculitis 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Tests to identify exclusion characteristics 
prior to enrollment 
 
 
 
 
 
 
 
 
 
 
Interferon-γ release assay for tuberculosis 
(all patients)** 
X 
 
 
 
 
 
 
 
 
 
Hepatitis B panel%;hepatitis C antibody (all) 
X 
 
 
 
 
 
 
 
 
 
Gadolinium enhanced MRI for patients with 
anterior/intermediate or intermediate uveitis 
without systemic disease only†† 
X 
 
 
 
 
 
 
 
 
 
Pregnancy test for women of child bearing 
potential 
X 
 
 
 
 
 
 
 
 
 
 
 
 * BL = baseline 
 † Evaluation of best corrected visual acuity after standard refraction  
 + OCT centered on fovea 
  ‡ 9-field 50 or 60˚ photographs or wide-field photograph (e.g., Optos) 
  § Including creatinine, liver enzymes and serum glucose 
   ¶ Either quantitative Goldmann perimetry or automated perimetry with Humphrey SITA-fast 30-2 and Screening P60    
may be used, but once chosen, the visual field testing should be the same for all visit for each individual patient 
 ║ FAF= fundus autofluorescence 
 Ʌ OCT centered on fovea & additionally, as needed, OCT centered to capture area with greatest subretinal thickness 
  Δ VKH = Vogt-Koyangi-Harada 
 # FA = fluorescein angiography 
** E.g., Quantiferon Gold   
% Including hepatitis B surface antigen, hepatitis B core antibody, and hepatitis B surface antibody 
††  Gadolinium enhanced MRI = magnetic resonance imaging of the brain with a gadolinium based contrast agent  
    (GBCA) 
 


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4. 
Treatment  
4.1 
Overview 
All patients enrolled in the study will be treated with prednisone, along with randomization to one 
of the two corticosteroid-sparing treatment strategies being studied.  Approaches for 
administration of ancillary treatments that might be required are specified by the protocol. 
 
The decision to taper, escalate, or change therapy will be dictated by the protocol and the study 
ophthalmologist’s evaluation of activity.  The study ophthalmologist will manage the medications 
according to the treatment guidelines described in the protocol and further detailed in the 
ADVISE Manual of Procedures, accounting for any side effects encountered.  The unit of 
analysis will be the patient, so that active disease in either eye will cause the patient to be 
classified as having active disease and managed accordingly.  In the unlikely event that a 
patient has different diagnoses in the two eyes, each eye will be assessed as indicated in the 
ADVISE disease-specific guidelines for determining inactive disease (Manual of Procedures, 
section 4.2) for the eye’s diagnosis, and both eyes must have inactive uveitis for the patient to 
be counted as inactive for the corticosteroid-sparing outcomes.  The presence of complications 
of the uveitis (e.g., macular edema, epiretinal membranes) will be scored separately and will not 
be used to determine uveitis activity, following consensus recommendations..9  
  
This section provides study treatment guidelines which cover many but not all situations.  The 
guidelines are based on the following basic principles. 
1) Initial therapy involves initiating study-specified immunosuppression with initiation of or 
an increase in prednisone dose if uveitis is active  
2) Initiate prednisone taper once activity has been quieted or maximum duration of high-
dose prednisone has been reached  
3) If uveitis is not controlled after maximum duration of high dose prednisone and maximum 
advancement of immunosuppression per guidelines, treatment is per best medical 
judgment. 
4) Reactivation during follow-up is treated by  
a.  Increasing the dose of prednisone  
b. Advancing immunosuppression if indicated  
 
For situations that are either not covered by these guidelines or are nuanced so that guidelines 
may not be followed exactly, study ophthalmologists should follow best medical judgement.   
Additionally, study ophthalmologists may consult members of the Medical Quality Assurance 
Committee (MTQAC) for guidance. 
 
The time points (e.g., 4 weeks) in the treatment guidelines are targets; variations due to 
scheduling of study visits are both permitted and expected.  
 
 
4.2 
Systemic corticosteroids 
All participants will be treated with prednisone (or an equipotent dose of an alternative 
corticosteroid if prednisone is clinically inappropriate or unavailable). The maximum allowed 
prednisone dose is 1 mg/kg/day up to a maximum of 60 mg/day (i.e., 1 mg/kg/day for patients 


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under 60kg and 60 mg/day for patients at or above 60kg).  Table 3 summarizes the initial 
prednisone dosing for the scenarios described below. 
4.2.1 Initial prednisone dose 
• 
Patients with active uveitis not on prednisone:  
The initial dose of prednisone is the maximum allowed dose (i.e., 1 mg/kg/day up to a 
maximum of 60 mg/day) for 2 weeks. Prednisone tapering will be initiated at 2 weeks per 
section 4.2.2 if the uveitis is controlled.  If the study ophthalmologist expects the uveitis 
to be controlled within 2 weeks, the prednisone tapering may be initiated automatically at 
2 weeks without a clinic visit.  Should uveitis fail to be controlled after 2 weeks or if the 
study ophthalmologist did not expect it to be controlled within 2 weeks, the maximum 
allowed dose will be continued for 2 additional weeks (total of 4 weeks).  To avoid 
complications of systemic corticosteroid therapy, after 4 weeks of prednisone at the 
maximum allowed dose, prednisone tapering will be initiated per section 4.2.2.  If the 
uveitis is neither controlled nor substantially improved such that it is expected to be 
inactive by next visit (V03 in 4 weeks), then, immunosuppression will be advanced per 
section 4.4.  Additional advancement of the immunosuppressive treatment will be 
implemented according to guidelines in section 4.4 until inflammation is controlled or 
else the best medical judgment point of guidelines is reached. 
 
• 
Patients already on prednisone with a reactivation of uveitis:  
The initial dose of prednisone will be increased according to the current dose and the 
severity of the reactivation. For patients on more than half of the maximum allowed dose 
(i.e., maximum dose is 1 mg/kg/day up a maximum of 60 mg/day), the dose will be 
increased to the maximum allowed dose.  For patients on less than half of the maximum 
allowed dose, the dose will be at least doubled but may be increased to any dose 
between double the current dose and the maximum allowed dose depending upon the 
severity of the disease.  Should uveitis fail to be controlled after 2 weeks of this 
increased prednisone dose, then an additional 2 weeks of prednisone at the maximum 
dose, regardless of the initial dose, will be given. If the study ophthalmologist did not 
expect the uveitis to be controlled within 2 weeks, then the initial prednisone period may 
be 4 weeks. To avoid complications of systemic corticosteroid therapy, prednisone 
tapering will be initiated at week 4 per section 4.2.2.  At V02 if the uveitis is neither 
controlled nor substantially improved such that it is expected to be inactive at the next 
visit (V03 in 4 weeks), then, immunosuppression will be advanced per section 4.4.  
Additional advancement of the immunosuppressive treatment will be implemented 
according to the guidelines in section 4.4. until inflammation is controlled or else the best 
medical judgment point on the immunosuppression guidelines is reached. 
  
• 
Patients with recently active but inactive uveitis by enrollment on prednisone >7.5 
mg/day:   
The dose will be held at that level (i.e., the >7.5 mg/day dose patient was on at 
enrollment) for 4 weeks after initiating the new immunosuppressive agent to enable that 
agent to have an effect.  Prednisone tapering will be initiated at week 4. Should the 
patient’s uveitis become active within those four weeks, they will be managed as 
described in the preceding bullet. 
 
 
 
 


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Table 4.  Initial prednisone dosing summary 
Status at 
enrollment 
Initial dose 
(Week 0) 
First opportunity to 
taper*† 
(Week 2) 
Second opportunity to taper 
(Week 4) 
Active, not on 
prednisone 
Maximum allowed dose  
(1 mg/kg/day if < 60 kg  
 OR 60 mg/day if ≥ 60 kg) 
Controlled: Taper 
 
Not controlled: Hold at 
current dose 
Controlled: Taper 
 
Substantially improved‡: Taper, 
but not below 7.5 mg/day until 
inactive.Only advance 
immuno.suppression if control is 
not achieved after 4 more weeks. 
 
Not controlled: Taper but not 
below 7.5 mg/day and advance 
immunosuppression 
Reactivated, 
on prednisone 
Current dose ≥ ½ maximum 
allowed dose§: Increase to 
maximum allowed dose 
  
Current dose < ½ maximum 
allowed dose:  Increase to 
between double current 
dose and maximum allowed 
dose depending on severity 
Controlled: Taper 
 
Not controlled at maximum 
dose: Hold at maximum dose 
for 2 more weeks 
 
Not controlled while below 
maximum dose:  Increase to 
maximum dose for 2 weeks 
Controlled: Taper 
 
Substantially improved‡: Taper.but 
not below 7.5 mg/day until 
inactive. Only advance 
immunosuppression if control is 
not achieved after 4 more weeks. 
 
Not controlled: Taper,but not 
below 7.5 mg/day until inactive 
and advance immunosuppression 
Inactive, on 
prednisone 
 > 7.5 mg/day 
Hold at dose at enrollment 
Controlled: Continue on same 
dose 
 
Not controlled (i.e. 
reactivates): Follow 
instructions for ‘Reactivated, 
on prednisone’ 
Controlled: Taper 
 
Not controlled (i.e. reactivates): 
Follow instructions for 
‘Reactivated, on prednisone’ 
* If the study ophthalmologist does not expect the uveitis to be controlled at 2 weeks, then an initial course of 4 weeks 
of prednisone can be prescribed.  The first assessment of activity would occur at the next scheduled visit (i.e. in 4 
weeks).    
 If the study ophthalmologist expects the uveitis to be controlled at 2 weeks, then the corticosteroid taper can be 
automatically initiated at 2 weeks without a clinic visit.  The first assessment of activity would occur at the next 
scheduled visit (i.e. in 4 weeks)  
‡ Substantially improved such that uveitis is expected to be controlled by the next visit  
§ The maximum allowed dose is 1 mg/kg/day for participants < 60 kg and 60 mg/day for participants ≥ 60 kg 
 
 
 
4.2.2 Prednisone tapering schedule and goals 
After initially obtaining (or maintaining) quiescence of uveitis with treatment(s) or when the 
prednisone dose has been used for the maximum duration described in section 4.2.1, 


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prednisone will be tapered as described in Table 4 below, starting from the dose of 
corticosteroids they begin tapering from. 
• 
The primary outcome of the trial is a prednisone dose of ≤7.5 mg/day for 2 visits ≥ 28 
days apart with inactive uveitis. If a patient is begun on prednisone 60 mg/day, the 
primary outcome should be reached by 15 weeks of follow-up.   
• 
If a patient achieves the primary outcome, an attempt should be made to taper further 
and discontinue prednisone.  A range of tapering decrements for prednisone doses 
below 7.5 mg/day is necessary due to the need to taper prednisone more slowly among 
those already on long-term oral corticosteroid therapy to minimize corticosteroid-
withdrawal symptoms but still permit discontinuation by 1 year of follow-up. 
• 
The prednisone dose should not be tapered below 7.5 mg/day if the patient has active 
uveitis unless required according to best medical judgement. 
• 
If uveitis reactivates during tapering, follow the guidelines for prednisone dosing in the 
reactivation management guidelines in section 4.5.  
 
 
 
 
 
 
 
Table 5.  Prednisone tapering schedule 
Dose 
(mg/day) 
Decrement 
(mg/day) 
Interval 
(decrease every) 
60 to 30 
10 
1 week 
30 to 15 
5 
1 week 
15 to 7.5 
2.5 
1 week 
7.5† 
Hold at 7.5 mg/day until two study visits ≥ 
4 weeks (28 days) apart have occurred* 
           <7.5† 
1-2.5 
2 weeks 
*Note: This may involve maintaining the dose for more than two consecutive 
study visits if they occur <28 days apart. 
† Do not taper below 7.5 mg/day until uveitis is inactive 


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4.3 
Corticosteroid-sparing drugs 
Corticosteroid-sparing therapy will be implemented according to strategies assigned by 
randomization. Patients initially on one immunosuppressive drug will continue it in addition to 
the randomized treatment.  Because of the differences in treatment administration and the use 
of conventional agents with different treatment administration schedules, treatment 
administration will not be masked. 
 
4.3.1 Adalimumab treatment group 
Adalimumab dosing regimen 
• 
80 mg subcutaneously once as an initial dose administered as soon as possible after 
randomization 
• 
40 mg subcutaneously one week after initial dose and then 40 mg every two weeks until 
the end of follow-up unless some contraindication to continuation arises 
 
The adalimumab dosing protocol in ADVISE is the FDA approved regimen for treatment of 
uveitis in adults, i.e., an initial dose of 80 mg followed by 40 mg given every other week starting 
one week after the initial dose.  The FDA approved regimen for treatment of uveitis in pediatric 
patients (2 years of age or older) ≥30 kg is 40 mg every other week but does not include an 
initial dose of 80 mg.  In ADVISE adolescent patients (13 to <18 year olds) will receive an initial 
dose of 80 mg.  While an initial dose of 80 mg is not FDA approved for treatment of uveitis in 
adolescents, an initial dose of 80 mg for adolescent/pediatric patients is FDA approved for other 
conditions, e.g., for adolescent patients ≥30 kg for treatment of hidradenitis suppurativa and for 
pediatric patients ≥ 40 kg for the treatment of pediatric Crohn’s disease. 
 
Management of conventional immunosuppressive agents for patients who are on one at 
baseline 
Patients in the adalimumab treatment group who already are taking a conventional 
immunosuppressive drug will continue that drug throughout the study (in addition to the 
adalimumab) unless some contraindication to continuation arises.  Those for whom existing 
immunosuppressive therapy is deemed non-useful should discontinue it before entering the 
study. 
 
4.3.2 Conventional immunosuppression treatment group 
Patients randomized to conventional immunosuppression will be started as soon as possible on 
a conventional immunosuppressive drug, according to published guidelines,14 using one of the 
drugs in Table 5.  The study ophthalmologist will select amongst the permissible drugs 
(methotrexate, mycophenolate or azathioprine for antimetabolites; cyclosporine or tacrolimus for 
calcineurin inhibitors) taking into account the side effect profile of each drug with respect to the 
patient’s clinical situation. Initial and maximum dosing for antimetabolites and dosing for 
calcineurin inhibitors will be as outlined in Table 5.  Because alkylating agents typically are not 
used in combination with another immunosuppressive drug, they will not be used in ADVISE, 
except possibly among those progressing to treatment according to best medical judgment.   
 
Patients receiving no immunosuppressive agents at the time of enrollment 
• 
The initial immunosuppressive drug will be an antimetabolite (azathioprine, 
mycophenolate, or methotrexate) given at initial dose in Table 5 unless contraindicated 
 
 In the MUST Trial antimetabolites were overwhelmingly the initial choice for 
immunosuppression, and available data suggest similar efficacy (including a randomized trial 
comparing methotrexate to mycophenolate70). Because of the differing side effect profiles, 


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allowing any of the three drugs will allow more patients to participate than choosing one drug 
alone but will not compromise the efficacy estimate of conventional immunosuppression, as all 
3 drugs have similar corticosteroid-sparing efficacy.   
 
Patients already on one immunosuppressive drug at enrollment will be treated based on 
the drug being received.   
• 
Patients on an antimetabolite will receive a calcineurin inhibitor as directed in Table 5 
unless contraindicated 
• 
Patients on a calcineurin inhibitor will receive an antimetabolite at initial dose in Table 5 
unless contraindicated.   
 
Because most patients treated with immunosuppression receive an antimetabolite first, this 
subgroup largely will consist of the addition of a calcineurin inhibitor.  A randomized trial of 
tacrolimus vs cyclosporine suggested similar efficacy for the two drugs,35 so either drug can be 
chosen.  This approach mimics conventional clinical care.   
 
Selection of antimetabolite or calcineurin inhibitor 
As in the MUST Trial, the choice of antimetabolite and the choice of calcineurin inhibitor in the 
conventional arm will be made based on the patient’s clinical history by the clinician at the 
clinical center but used in a standard fashion.21 Initial and maximum dosing for antimetabolites 
and dosing for calcineurin inhibitors will be as outlined in Table 5 below.  
Note:  Systemic immunosuppressive drugs other than those mentioned in this section are not 
permitted as study medications. 
 
 
 
 
 
 
 
Table 6.  Conventional immunosuppressive drugs in the ADVISE Trial 14,21 
Class 
Generic name 
Trade name 
Initial dose 
Max dose 
Antimetabolite 
Azathioprine 
Imuran 
2 mg/kg/day 
200 mg/day 
 
Methotrexate* 
Rheumatrex 
15 mg/week 
25 mg/week 
 
Mycophenolate 
CellCept 
1 gm BID 
1.5 gm BID 
 
 
 
 
 
Calcineurin inhibitor 
Cyclosporine  
Sandimmune 
2.5 mg/kg BID 
2.5 mg/kg BID 
 
 
Neoral 
2 mg/kg BID 
2 mg/kg BID 
 
Tacrolimus† 
Prograf 
1 mg BID 
3 mg BID 
 
 
 
 
 
* Orally or subcutaneously; with folate 
† Escalate every 2 to 4 weeks to therapeutic blood level or maximum dose 


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4.4 
Advancement of immunosuppressive treatment 
For patients who come in to the study with active uveitis, advancement of immunosuppression 
is required if uveitis is neither not controlled or substantially improved such that it is expected to 
be inactive at the next visit four weeks after initiating study-specified medications.  
 
Advancement of immunosuppression is also required if uveitis reactivates during prednisone 
tapering.  See section 4.5 for guidelines for managing uveitis reactivation during prednisone 
tapering, which requires prednisone increase in addition to advancement of 
immunosuppression. As noted in section 4.5, if uveitis reactivates after achieving prednisone 
cessation, the decision of whether to advance immunosuppression should be made according 
to best medical judgment. 
 
The general hierarchy for advancement of immunosuppression is to (1) maximize the dose of 
current immunosuppressive drug(s) as applicable; (2) add a new conventional 
immunosuppressive drug at initial dose and maximize dose as applicable. Patients assigned to 
conventional immunosuppression may receive two conventional immunosuppressive drugs, an 
antimetabolite and a calcineurin inhibitor. Patients assigned to adalimumab may receive one 
conventional immunosuppressive drug.  If uveitis cannot be controlled at maximum permitted 
immunosuppression, patient will be treated per best medical judgment. Additional details are 
included in the ADVISE Manual of Procedures section 8.4.  
 
   
4.5 
Management of uveitis reactivation 
The guidelines for managing uveitis reactivation are summarized in tables 6a. Reactivation 
management guidelines:  Prednisone and 6b. Reactivation management guidelines:  
Immunosuppression. 
 
The prednisone dose to be used for uveitis reactivation will depend upon whether the 
reactivation occurs during the prednisone taper or after prednisone cessation.  If the uveitis 
reactivates during the prednisone taper, the dose of prednisone will be at least doubled, up to 
the maximum allowed dose (1mg/kg/day up to 60 mg/day), depending on the severity of the 
reactivation per table 6a.  If uveitis reactivates after achieving prednisone cessation, 
prednisone will be reinstated at a dose of at least 10 mg/day up to the maximum allowed dose 
(i.e., 1 mg/kg/day if < 60 kg or 60 mg/day if ≥ 60 kg), depending on the severity of the 
reactivation.  The study physician will determine whether to advance immunosuppression per 
best medical judgment.  
 
 As adalimumab is FDA-approved at only a single dose, advancement of immunosuppressive 
therapy will focus on the addition or increase in dose of conventional immunosuppressive 
agents for both treatment arms.  The advancement of conventional immunosuppressive 
agents will depend upon number and dose(s) of the current medications being used.   
 
For patients on less than the maximum dose of a conventional immunosuppressive agent, it 
should be increased to the maximum dose in Table 5, as applicable and tolerated.  For 
patients on the maximum dose of a single immunosuppressive drug, a second agent from the 
other class should be added.  For patients on an antimetabolite, a calcineurin inhibitor will be 
added and vice versa.  For patients already on 2 immunosuppressive drugs at maximum 
doses, best medical judgment will be used, including changing one or both of the currently 
used immunosuppressive agents.   
 


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Although it might be argued that conventional immunosuppressive agents might be used 
initially at the maximum dose to avoid the dose escalation step, this alternative approach does 
not mimic clinical practice, whereas the use as outlined in Table 5 does.14  Furthermore, this 
approach minimizes the possibility of drug-related side effects, and many patients respond to 
the initial dose without need for dose escalation.16,71  For example, among patients who 
respond to treatment with methotrexate, the majority do so at a dose of 15 mg/week.71  For 
patients assigned to conventional immunosuppression requiring changes in the 
immunosuppressive agent for side effects, an attempt will be made (if possible) to change 
within class (e.g., a different antimetabolite); if not possible, the alternative class may be used, 
or if necessary best medical judgment.  These guidelines are presented in more detailed 
outline format in the Manual of Procedures section 8.5. 
 
If uveitis reactivates after achieving prednisone cessation, prednisone will be reinstated at a 
dose of at least 10 mg/day up to the maximum allowed dose (i.e., 1 mg/kg/day if < 60 kg or 60 
mg/day if ≥ 60 kg), depending on the severity of the reactivation.  The study physician will 
determine whether to advance immunosuppression per best medical judgment.  
 
 
 


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Table 7.  Reactivation management guidelines 
Table 6a.  Reactivation management guidelines:  Prednisone 
Scenario 
Action for prednisone dose 
First opportunity to 
taper  
(2 weeks after prednisone 
increase)* 
Second opportunity 
to taper  
(4 weeks after 
prednisone increase) 
Reactivation 
during 
prednisone taper 
If current dose ≥ ½ maximum allowed 
dose, increase to maximum allowed 
dose 
If current dose < ½ maximum allowed 
dose, increase to between double 
current dose and maximum allowed 
dose depending on severity 
Controlled: Taper 
Not controlled:  
If increased dose is not 
maximum allowed dose, 
increase to maximum 
allowed dose 
Controlled: Taper 
Not controlled:  Taper 
but not below 7.5 
mg/day until uveitis is 
inactive 
Reactivation after 
tapered off 
prednisone 
Reinitiate prednisone at dose of at 
least 10 mg/day up to the maximum 
allowed dose (i.e., 1 mg/kg/day if < 60 
kg or 60 mg/day if ≥ 60 kg), depending 
on the severity of the reactivation 
Controlled:  Taper 
Not controlled: Treat per 
best medical judgment 
Controlled:  Taper 
Not controlled:  Treat 
per best medical 
judgment 
* If the study ophthalmologist does not expect the uveitis to be controlled within 2 weeks of the prednisone increase, 
then an initial course of 4 weeks of prednisone can be prescribed. The first assessment of activity would occur at 
the next scheduled visit (i.e. in 4 weeks).    
 If the study ophthalmologist expects the uveitis to be controlled within 2 weeks of the prednisone increase, then 
the corticosteroid taper can be automatically initiated at 2 weeks without a clinic visit.  The first assessment of 
activity would occur at the next scheduled visit (i.e. in 4 weeks)  
 
 


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Table 6b.  Reactivation management guidelines:  Immunosuppression  
Treatment 
assignment 
Scenario 
Immunosuppression 
management 
Conventional 
immunosuppression 
1 conventional IMT† at initial dose 
Increase to maximum dose‡ 
 
1 conventional IMT at maximum dose‡ 
Add 2nd  conventional IMT from 
alternative class†† at initial dose 
 
1 conventional IMT at maximum dose‡, 
2nd conventional IMT at initial dose 
Increase 2nd conventional IMT to 
maximum dose‡ 
 
2 conventional IMTs at maximum 
doses‡ 
Treat per best medical judgment 
 
 
 
Adalimumab 
Adalimumab only 
Add conventional IMT¶ 
 
Adalimumab & conventional IMT initial 
dose 
Increase conventional IMT to 
maximum dose‡ 
 
Adalimumab & conventional IMT at 
maximum dose‡ 
Treat per best medical judgment 
† Conventional immunomodulatory therapy (immunosuppressive therapy) drug 
‡ Maximum dose = maximum dose of antimetabolite or dose resulting in therapeutic blood level for tacrolimus, up 
to maximum dose per table in section 8.3.2.1. Note: Cyclosporine has only one dose. 
†† If on an antimetabolite, add a calcineurin inhibitor; if on a calcineurin inhibitor, add an antimetabolite. 
¶Antimetabolite preferred; either class acceptable 
 
 
 
4.6 
Monitoring for toxicity of immunosuppressive drugs   
Patients will be monitored for potential toxicities of adalimumab or conventional 
immunosuppressive therapy/therapies using the schedule described in the Trial’s follow-up 
schedule (Table 2), i.e., complete blood count and chemistry panel including creatinine and 
liver enzymes will be conducted at every study visit and monitoring and prevention strategies 
will be implemented as detailed in Table 7. Potential Risks of Therapy.  As applicable, 
additional monitoring studies should be carried out per routine care.14 When potential toxicities 
are encountered, modification of therapy, including dose reduction or discontinuation as 
clinically appropriate, should be done along the lines indicated in published guidelines.14 
 
4.7 
Discontinuation of treatment within the assigned treatment arm  
4.7.1 Discontinuation for toxicity 
As applicable, when toxicity cannot be managed through modification of treatment regimen, 
assigned treatment may be discontinued and participant managed according to best medical 
judgment. 
 


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4.7.2 Discontinuation for pregnancy 
If a participant becomes pregnant, methotrexate and mycophenolate must be discontinued as 
methotrexate is known to increase the risk of spontaneous abortion and malformations and 
mycophenolate is known to increase the risk of malformations.   Consideration should be given 
to discontinuation of azathioprine, cyclosporine, tacrolimus, and adalimumab. Participants 
should be managed according to best medical judgment.72  
 
4.8 
Ancillary therapy   
4.8.1 Regional corticosteroid Injections 
The MUST Trial demonstrated that the majority of patients with uveitic macular edema require 
supplemental regional corticosteroid injections (either periocular or intravitreal) to improve the 
macular edema, but that they typically need only one or two injections.73  Therefore, participants 
in the ADVISE Trial with uveitic macular edema will be permitted a regional corticosteroid 
injection within the first 2 months, if needed, and a second injection during months 6 to 8 (if 
needed) for persistent macular edema (to meet patients’ clinical needs without contaminating 
key outcomes).  Acceptable regional injections are: 1) periocular triamcinolone acetonide 40 
mg, 2) intravitreal triamcinolone acetonide 4 mg (Triesence® [Alcon Laboratories, Inc., Fort 
Worth, TX] preferred if available due to its being preservative free for intravitreal use).or 3) the 
dexamethasone intravitreal pellet (Ozurdex ®, Allergan, Inc., Irvine, CA).5474   If a participant is 
given an injection during the first 2 months of the trial, the dose of prednisone should 
not go below 7.5 mg/day (or if already <7.5 mg/day, should not be tapered further) until 3 
months after the injection, as the primary outcome only can be ascertained 3 months 
after an injection. Allowing the limited use of regional corticosteroid injections for uveitic 
macular edema is necessary for proper clinical care, and the restrictions on their use will permit 
evaluation of the trial’s outcomes. 
 
4.8.2 Topical corticosteroids 
• 
Adjunctive use of high doses of topical corticosteroids (up to one drop hourly of 
prednisolone acetate 1%, prednisolone sodium phosphate 1% or loteprednol 
etabonate 0.5%, or one drop six times daily of difluprednate 0.05%) is permitted for 
up to two weeks after anterior chamber uveitic activity is first observed. 
• 
Upon quiescence of the anterior chamber inflammation, topical corticosteroids 
should be tapered 
• 
Maintenance therapy of not more than prednisolone acetate 1% or loteprednol 
0.5% three times daily or difluprednate 0.05% one drop daily is permitted. 
• 
Failure to control anterior chamber inflammation using this approach should be 
addressed with systemic corticosteroids and immunosuppression. 
• 
Discontinuation of such therapy, when feasible, is encouraged 
 
4.8.3 Non-corticosteroid ophthalmic medications 
These may be used according to best medical judgment. 
 
4.8.4 Systemic medications other than corticosteroids and immunosuppressive 
drugs  
These may be used according to best medical judgment. 
 


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4.8.5 Treatment monitoring 
Treatment will be monitored for consistency with the treatment guideline by a member of the 
MTQAC,21 MTQAC will monitor treatment patterns as revealed in the data stream, site visits, 
etc., and investigate inconsistencies with treatment guidelines, providing remediation as 
appropriate.   


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5. 
Study treatment procurement 
 
Adalimumab will be donated by AbbVie (Chicago, IL); distribution to clinical centers is described 
in the manual of procedures.  Prednisone and conventional immunosuppressive study 
treatments are not provided by the study and will be obtained per standard care.   
 
 


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6. 
Possible side effects and complications of study treatments 
Although there are potential risks associated with systemic corticosteroids and 
immunosuppression, they typically are reversible with dose reduction or discontinuation of the 
drug.  The MUST Trial and Follow-up Study demonstrated that there was essentially no 
increased risk of these events compared to treatment with a strictly regional therapy, the 
fluocinolone acetonide implant, with the one exception of a greater use of antibiotics among 
participants receiving systemic therapy.15,22,23,24 Hence, with appropriate use, these risks can be 
minimized.  Thus, the risks associated with participation in the ADVISE Trial are expected not to 
be greater than those associated with clinical care for patients with these uveitides. Possible 
side effects of the randomly assigned study treatments and of corticosteroids are summarized in 
Table 7. 
Patients in ADVISE Trial will receive oral corticosteroids for treatment of uveitis, as they would 
in clinical care.  The potential side effects of oral corticosteroids include water retention, weight 
gain, headache, muscle weakness, loss of muscle mass, face puffiness, growth of facial hair, 
easy bruising, acne, rounding of the upper back, irregular menstrual periods, insomnia, mood 
swings, increased energy, personality change, hypertension, hyperglycemia, and 
hypercholesterolemia.  Oral corticosteroid therapy may lower resistance to infections, make 
infections harder to treat, slow wound healing, and increase the risk of osteoporosis.  Aseptic 
necrosis of bone is a rare but serious complication.  For persons already at risk of congestive 
heart failure, corticosteroids can increase the risk. Side effects occur more often with longer 
treatment and with higher doses, and typically resolve when dosage is lowered or treatment is 
discontinued.  As noted previously, serious complications such as these are very rare, 
particularly when appropriate management is used, as was done in the MUST Trial, including 
aggressive tapering of prednisone to a dose <7.5 mg/day15,22,23,24  In the MUST Trial and Follow-
up Study, there generally was no significant increase is systemic side effects with systemic 
therapy through 7 years of follow-up.15,22,23,24  Ocular side effects seen in the eyes of patients 
with uveitis treated with systemic corticosteroids include the need for cataract surgery at 
~6%/year, ocular hypertension at 3%/year, and glaucoma at 1.3%/year.15   Typically, these side 
effects are lower than with alternatively local therapies, as was demonstrated in the MUST 
Trial.15,22,23,24   
In addition to corticosteroids, patients in the ADVISE Trial will receive immunosuppressive 
agents, either conventional (small molecule) drugs or the biologic adalimumab.  For many of 
these diseases, immunosuppression has been shown to produce superior outcomes.15,17,18,19,20 
The eligibility criteria select patients for whom immunosuppression is indicated, so that 
patientsare not expected to experience any greater risk than would be seen with clinical care.  
Conventional immunosuppressive agents with activity against uveitis that will be used in 
ADVISE are the antimetabolites, azathioprine (AZA), methotrexate (MTX), and mycophenolate 
mofetil (MMF); and the calcineurin (or T cell) inhibitors, cyclosporine (CSA) and tacrolimus 
(TAC).14  Because of the potential increased risk of cancer associated with alkylating agent use, 
and because they are not used in conjunction with other immunosuppressive drugs, 
cyclophosphamide and chlorambucil will not be used in the trial,43,44,45,46,47 unless the patient 
suffers sufficient relapses that (s)he is treated with best medical judgment.  Each of these 
agents is associated with its own spectrum of potential systemic side effects.  Side effects 
associated with these medications that are medically important and expected to occur with 
detectable frequency during the trial are described below.14 The ADVISE Trial will conduct 
surveillance for these potential risks in a protocol-directed manner that approximates medical 
care (see Table 7).  However, the side effects mentioned below did not occur with higher 
frequency in the systemic therapy group of the MUST Trial than in the strictly local therapy 
implant group.15,22,24 


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Bone marrow suppression:  a) Reversible neutropenia – which may occur with AZA, MTX, MMF, 
TAC – will be evaluated over time as the cumulative proportion having a total white blood cell 
(WBC) count 2500 cells/μL or fewer, which still is above the level for an increased risk of 
infection, and is a common indication for interruption of therapy.  Change in WBC count from 
baseline and use of granulocyte stimulatory factors also will be noted; b) Reversible 
thrombocytopenia – which may occur with AZA, MTX, MMF, TAC – will be evaluated over time 
as the cumulative proportion having a platelet count 100,000/μL or fewer, which is a common 
indication for suspension of therapy.  Hemorrhagic events and requirement for platelet 
transfusion or other treatments for thrombocytopenia also will be noted; c) Reversible anemia – 
which may occur with AZA, MTX, MMF, CSA, TAC – will be evaluated over time as the 
cumulative proportion having a hemoglobin level <10 g/dL, a level often considered clinically 
meaningful.  Use of transfusions and of erythropoietin also will be noted; and the occurrence of 
myelodysplasia will be noted if confirmed in medical records.  
Reversible hepatotoxicity -- which may occur with AZA, MTX, MMF, CSA, and TAC -- will be 
evaluated over time as the cumulative proportion with any of the following, verified in medical 
records: aspartate aminotransferase (AST) or alanine aminotransferase (ALT) levels greater 
than two times the upper range of normal confirmed by repeat testing; OR discontinuation of an 
immunosuppressive agent due to hepatotoxicity.  Cases of persistent elevation of AST and/or 
ALT after discontinuation of the offending agent will be noted.   
Reversible nephrotoxicity -- which may occur with CSA and TAC -- will be evaluated over time 
as the cumulative proportion with:  serum creatinine level elevated 30% above baseline or to a 
level of 1.5 mg/dL or higher OR discontinuation of an immunosuppressive drug for renal toxicity.  
Persistent renal insufficiency will be noted. 
Pregnancy risks:  MTX and MMF are associated with increased risk of first trimester pregnancy 
loss and congenital malformations; women of child bearing potential and men taking MTX are 
advised to use adequate birth control during the trial, and especially if taking these medications.  
Infection: even without an increased risk of leukopenia among patients in the (unmasked) MUST 
Trial on systemic therapy, there was an increased use of antibiotics for infection.15,22,23,24 
However, there were no long-term sequelae from these infections, and no increase in the risk of 
hospitalization for infection.15 Patients will be queried about infections at every visit, and medical 
records reviewed as necessary, to monitor for infections.  Hospitalization data also will be 
collected.  In non-uveitis use (e.g., transplants) some immunosuppressive regimens may 
increase the risk of severe opportunistic infections (e.g., progressive multifocal 
leukoencephalopathy), which can have serious consequences, including death.  Although there 
were no such events in the MUST Trial, because of their rare nature, their possible occurrence 
in the ADVISE Trial or routine clinical practice using these drugs cannot be excluded.   
Additional recognized potential complications of potent immunosuppressive therapy will be 
deemed to be present when diagnosis is confirmed by medical records.  These conditions 
specifically will include a diagnosis of any of the following conditions (if not present at baseline):  
a) liver cirrhosis; b) interstitial pneumonitis; c) possibly malignancy (drug-specific); d) end-stage 
renal insufficiency.   
In addition to these small molecule immunosuppressive agents, the anti-TNF-α biologic agent 
adalimumab will be used.33 The most common adverse reaction of adalimumab is redness, 
itching, pain, or swelling at the injection site, reported in 20% of patients.  Other less common 
adverse events include: increased risk of infections, particularly tuberculosis, fungal infections, 
and herpes zoster. Patents randomized to adalimumab will be instructed not to get any live 


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vaccines.  Other uncommon potential adverse effects include gastrointestinal symptoms such 
as nausea, vomiting, abdominal pain, or diarrhea; reversible bone marrow suppression; and 
reversible hepatotoxicity.  Other rare adverse events include: development of anti-adalimumab 
antibodies and a lupus erythematosus-like syndrome, and a worsening of demyelinating 
disease, such as multiple sclerosis. All patients enrolled in the ADVISE Trial will have 
tuberculosis testing with either an interferon-γ release assay test, such as the Quantiferon-gold 
test and testing for active hepatitis B or C infection75,76 prior to enrollment.  Active tuberculosis 
and untreated latent tuberculosis and untreated active hepatitis B or C infection are exclusions 
to participation.  Because of the increased risk of multiple sclerosis in patients with pars planitis 
and undifferentiated intermediate uveitis,11,12 all potential participants with these two diseases 
will undergo neuro-imaging with a gadolinium enhanced MRI scan and patients with evidence of 
possible demyelination are excluded from the trial.   
Use of the following medications are prohibited during the trial for safety reasons 
• 
Live vaccines  
• 
Substrates for the multidrug efflux transporter P-glycoprotein or the organic anion 
transporter proteins (OATP) and for which elevated plasma concentrations are 
associated with serious and/or life threatening events, e.g. bosentan, dabigatran 
etexilate and aliskiren. 
• 
Products containing Hypericum perforatum (St John´s Wort) to avoid risk of interaction 
with tacrolimus that lead to either a decrease in blood concentrations of tacrolimus and 
reduced clinical effect of tacrolimus, or an increase in blood concentrations of tacrolimus 
and risk of tacrolimus 
 


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Table 8.  Potential risks of therapy 
Treatment 
Group affected 
Systemic  
Monitoring & Prevention Strategy 
Corticosteroids 
Both groups 
Hyperglycemia 
History; CMP testing 
 
 
Hypertension 
History; BP measurement 
 
 
Osteoporosis 
Routine monitoring/ data collection 
 
 
Hyperlipidemia 
Routine monitoring/ data collection 
 
 
Infection 
Routine monitoring/ data collection 
 
 
Cardiovascular Disease 
Routine monitoring/ data collection; 
Monitor risk factors (per above) 
 
 
 
 
 
 
Cataract 
Slit lamp examination/Eye Exam 
 
 
 
 
 
Intraocular Pressure 
Elevation and Glaucoma 
Eye Examination 
Adalimumab 
Adalimumab 
Infection 
Pre-randomization tuberculosis and 
hepatitis B and C testing; Routine 
monitoring/ data collection. Live vaccines 
should not be given.  
 
 
Worsening of multiple 
sclerosis 
MRI of patients with intermediate uveitis 
at BL; Routine monitoring/ data 
collection 
 
 
Injection Site Reaction* 
Routine monitoring/ data collection 
 
 
Bone marrow toxicity*  
CBC testing 
 
 
Hepatotoxicity* 
CMP testing, pre-treatment Hepatitis 
panel 
Methotrexate 
Conventional 
Bone marrow toxicity* 
CBC testing 
 
 
Hepatotoxicity* 
CMP testing, pre-treatment Hepatitis 
panel 
 
 
GI intolerance* 
History/Routine monitoring 
 
 
Teratogenicity/ 
Miscarriage 
Birth control use for women and men  
 
 
Alopecia* 
Routine monitoring/ data collection 
 
 
 
 
Mycophenolate  
Conventional 
Bone marrow toxicity* 
CBC testing 
 
 
Hepatotoxicity* 
CMP testing, pre-treatment Hepatitis 
panel 
 
 
GI intolerance* 
History/Routine monitoring 
 
 
Teratogenicity 
Birth control use 
 
 
Possibly PML (disputed) 
History/Routine monitoring 


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Treatment 
Group affected 
Systemic  
Monitoring & Prevention Strategy 
 
Azathioprine 
Conventional 
Bone marrow toxicity* 
CBC testing 
 
 
Hepatotoxicity* 
CMP testing, pre-treatment Hepatitis 
panel 
 
 
GI intolerance* 
History/Routine monitoring 
 
 
 
 
Cyclosporine 
Conventional 
Hypertension* 
History; BP measurement 
 
 
Renal insufficiency* 
CMP testing 
 
 
Tremor/paresthesia* 
History/Routine monitoring 
 
 
Hirsutism* 
History/Routine monitoring 
 
 
Gingival hyperplasia* 
History/Routine monitoring 
 
 
 
 
Tacrolimus 
Conventional 
Hypertension* 
History; BP measurement 
 
 
Renal insufficiency* 
CMP testing 
 
 
Tremor/paresthesia* 
History/Routine monitoring 
 
 
Hyperglycemia* 
History; CMP testing 
 
 
Interactions with products 
containing Hypericum 
perforatum 
Products containing Hypericum 
perforatum (St John´s Wort).may not 
used during the study 
 
 
 
 
 
 
*Usually reversible with dose adjustment or cessation of therapy 
 
CMP=complete metabolic panel; BP=blood pressure; CBC=complete blood count 
 
 


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7. 
Safety reporting of adverse events  
7.1 
Adverse events   
Adverse events (AEs) and complications of study treatment will be submitted to the CC.  As 
described in section 7.2, all serious adverse events (SAEs) will require expedited reporting to 
the CC for immediate review by the CC Safety Officer who will determine any further actions 
required including whether the event requires expedited review by the Data and Safety 
Monitoring Committee (DSMC) Safety Officer.  The CC and DSMC Safety Officers will make 
recommendations to the DSMC as to any actions that may be needed.   
 
7.2 
Serious adverse events 
An SAE is an adverse event that results in one of the following outcomes: death, a life-
threatening adverse drug experience, inpatient hospitalization or prolongation of existing 
hospitalization, a persistent or significant disability/incapacity, or congenital anomaly/birth 
defect. Also, important medical events that may not result in death, be life-threatening, or 
require hospitalization may be considered a serious adverse event when, based upon 
appropriate medical judgment, they may jeopardize the patient or subject and may require 
medical or surgical intervention (treatment) to prevent any of the outcomes previously listed in 
this definition.  
 
Clinical centers will report all SAEs to the CC expeditiously regardless of the relationship to 
study treatment.  When an investigator or clinical center staff member becomes aware of an 
SAE, it will be reported to the CC within 72 hours (within 24 hours for UK clinics only*) with 
follow up reporting until the event is terminated.  The SAE report will include an assessment 
by the clinical investigator at the managing clinical center as to the likelihood whether the 
event is related to treatment.  Upon receipt at the CC, the SAE report will be sent to the CC 
Safety Officer for immediate review and determination as to whether the event meets the 
criteria for a safety report and whether expedited review by the DSMC Safety Officer is 
warranted.  
 
All serious and unexpected events possibly related to study treatment will be reported as safety 
reports to the NEI project officer, the pharmaceutical supplier (where appropriate), applicable 
regulatory agencies (.e.g., FDA and Health Canada), and all clinical centers in accordance with 
applicable regulations. The CC and clinical centers will submit all safety reports as expedited 
reports to their Institutional Review Boards (IRBs).  Reports of SAEs not deemed to be 
unexpected will be submitted to the CC’s IRB, to the IRB of the clinical center in which the 
event was reported, as well as to any other study center IRBs which require such reports. 
 
*For compliance with the CT3 directive (2011/C 172/01) (Section 4.3.1): “Communication from the 
European Commission — Detailed guidance on the collection, verification and presentation of adverse 
event/reaction reports arising from clinicaltrials on medicinal products for human use  
 


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8. 
Sample size and statistical methods 
 
8.1 
Hypotheses 
The primary hypothesis is that adalimumab will be superior to conventional immunosuppression 
for corticosteroid sparing, as determined by the proportion of participants that achieve the 
primary outcome, namely inactive uveitis and prednisone <7.5 mg/day for 2 visits >28 days 
apart by 6 months of follow-up.  The 6-month time frame was chosen to allow sufficient time to 
observe the primary outcome regardless of the patient’s prednisone dose at randomization and 
is likely to be more robust to imbalances. 
 
Secondary hypothesis are that adalimumab will be superior to conventional immunosuppression 
for: 
• 
Corticosteroid sparing (inactive uveitis and prednisone <7.5 mg/day for 2 visits >28 
days) apart by one year of follow-up  
• 
Prednisone discontinuation (inactive uveitis for 2 visits >28 days after discontinuation of 
prednisone) by one year.   
 
Furthermore, we hypothesize that these benefits will be accomplished with no increase in ocular 
or systemic adverse events (other than injection site reactions) with adalimumab, and that both 
approaches will produce similarly visual acuity and incidences of uveitic complications.     
 
8.2 
Sample size and power calculations 
Sample size is calculated for the primary comparison of corticosteroid-sparing treatment 
success (inactive uveitis and prednisone <7.5 mg/day for 2 consecutive visits >28 days apart) at 
6 months. Based on the preliminary data from the VISUAL III Study, we estimate that 
adalimumab will be successful in achieving the primary outcome in 75% of patients across all 
strata.  The success of conventional small molecule immunosuppression varies according to the 
type and number of treatments.  Based upon the Mount Sinai and MUST Trial data, we estimate 
that 75% of the participants will be in the stratum of no prior immunosuppression and 25% will 
be on one immunosuppressive agent at enrollment.16  Based on the SITE data, the estimated 
success rate for antimetabolites is 55% and for calcineurin inhibitors 40%.28,29,30,31  Patients in 
the no immunosuppression stratum will receive antimetabolites, whereas those in the one 
immunosuppression stratum will largely receive calcineurin inhibitors.  Therefore, success rates 
of 55% and 40% are estimated for the no and one immunosuppressive agent strata, 
respectively.  Based on the estimated stratum proportions and corresponding success rates, the 
overall conventional immunosuppression success rate is estimated to be 51%. In the MUST 
Trial, the loss to follow-up was 6% at 2 years.  In order to be conservative, we will assume a 
10% loss to follow-up in each group and that all individuals were lost prior to observing a result. 
Under these assumptions, a sample size of 222 (111 participants per treatment group) provides 
90% power to detect significant differences between the 2 groups if the underlying true 
proportions are 51% vs. 75% (46.1% vs. 67.5%, respectively, after adjusting for the loss to 
follow-up), assuming a two-sided type I error of 0.05. VISUAL I and II, while not appropriate for 
estimation of corticosteroid-sparing due to a rapid taper, do provide some estimates of the 
ability to discontinue prednisone, which can be estimated as 50%.  Based upon data from 
Mount Sinai and the MUST Trial, estimates of the discontinuation rates for standard 
immunotherapy range between 11%-35%. A sample size of 222 provides 80% power to detect 
an increase in the secondary outcome of discontinuing prednisone while controlling the uveitis 


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by 1 year from 30% to 50% (estimated from VISUAL I and II data), assuming a two-sided type I 
error of 0.05. 
 
 
8.3 
Statistical analysis plan 
A detailed description of the statistical principles and analyses is provided in the Statistical 
Analysis Plan.  The primary analyses will be based upon assigned treatment and will include all 
available data, following the principles of intention to treat, with additional sensitivity analyses 
based upon treatment received. The primary analyses will include adjustment for randomization 
strata (immunotherapy use and prednisone dose).  Additional analyses that are unadjusted or 
are adjusted for potential confounders including but not limited to age, gender, race, and uveitis 
class (e.g., intermediate, posterior, panuveitis) will also be performed as secondary analyses  
Robust standard errors will be computed using statistical program-based approaches when 
available and a bootstrap with the individual as the sampling unit when a pre-programmed 
approach is not available. 
 
The primary goal of the trial is to establish whether adalimumab is superior to conventional 
immunosuppression for corticosteroid-sparing in the treatment of individuals with intermediate, 
posterior, or pannuveitis. The analysis will focus on the cumulative proportion with a 
corticosteroid sparing success. Once a success has been achieved, then it will remain fixed for 
that individual thereafter.  A more standard time to event analysis, which allows for censoring 
due to loss to follow-up, was considered.  However, because the time required to taper 
prednisone to < 7.5 mg/day depends substantially on the initial/enrollment dose, small 
imbalances at baseline could influence greatly such analyses despite stratification. Therefore, 
time to event analyses will be used as sensitivity analyses.  The 6-month time frame was 
chosen to allow sufficient time to observe the primary outcome regardless of the participant’s 
prednisone dose at randomization and is likely to be more robust to imbalances.   Multiple 
imputation will be used to address missing data due to missed interim visits and loss to follow-
up. 
 
Since a minimum of two follow-up visits must occur prior to achieving a corticosteroid success 
and prednisone must be tapered, the first outcome evaluation will occur at 2 months (V03) and 
will continue for every visit thereafter.  Modeling will focus upon the period between 6 months 
and 1 year due to the potential for imbalances in the tapering patterns described above.  
Generalized estimating equations (GEE) will be used to fit logistic regression models comparing 
the two treatment groups over time while accounting for the correlation between replicate 
measurements.  A saturated mean structure including visits starting at 6 months (V07-V10), 
treatment, and visit by treatment interaction terms plus the two stratification variables (baseline 
immunotherapy and initial prednisone dose) will be used.  The 6-month visit by treatment 
interaction will be used to assess the primary outcome.  An unstructured correlation matrix will 
be used to model the within-individual repeated measurements.  Alternate correlation structures 
(e.g., exchangeable) will be explored if the unstructured covariance matrix is unstable. This 
model estimates the relative odds of corticosteroid-sparing for adalimumab vs conventional 
immunosuppression. A standardized estimator, which allows for covariate adjustment, will be 
used to compare the absolute (as opposed to relative) difference in proportions at each 
timepoint based upon the logistic model described above and a bootstrap estimate of the 95% 
confidence intervals.  This estimator has the advantage of providing a consistent estimate even 
if the means model is mis-specified.77,78 Analyses of the secondary hypotheses will follow the 
same data management and analysis structure. 
 


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9. 
Regulatory and ethical issues 
 
9.1 
Recruitment and informed consent procedures 
Patients will be recruited at each clinical center by clinicians who will present the opportunity to 
participate in the trial, discussing the potential risks and benefits in the patient’s particular 
circumstances.  Patients choosing to participate will give written consent.  Adolescents and their 
parent or legal guardian will give written assent or consent according to the guidelines of the 
clinic’s governing IRB.     
 
A detailed, IRB-approved, informed consent document will be provided, and the patient will be 
provided ample opportunity to review it.  Study staff will make themselves available to answer 
any questions potential participants will have.  Anonymous data will be collected regarding non-
participants in compliance with CONSORT guidelines, so as to permit those reviewing the 
results of the study to know how many people did not enroll, and why they did not enroll. 
Clinical center consent forms are based on prototypes prepared by the CC and approved by the 
CC’s IRB, the Johns Hopkins University Bloomberg School of Public Health IRB Office.  The 
prototype consent, written at an approximately 9th grade reading level as rated by word 
processing software, is distributed to the clinical centers.  Although clinics may rearrange 
information and modify language of the prototype to conform to local IRB templates and 
guidelines, deletion of information considered by study leadership to be essential to an informed 
consent process is not permitted.   For the ADVISE Trial, as in the MUST Trial, consents will be 
approved by all governing IRBs and will be required to include these key elements:  1) the 
purpose of the study; 2) selection of participants; 3) study visit schedule and study procedures; 
4) involved treatments; 5) risks associated with study procedures, uveitis, and uveitis 
treatments; 6) potential benefits of participation; 7) the voluntary nature of participation; 8) 
assurances that the patient’s treatment will not suffer if he or she declines enrollment or enrolls, 
but subsequently withdraws consent; 9) the names and whereabouts of contact persons; 10) 
explanation of costs for which the patient or patient’s insurer will be responsible and costs which 
will be paid for by the study (i.e., procedures and treatments that are required for the patient’s 
clinical care will be charged to patient’s insurance and patient is responsible for any co-pays; 
procedures done for study purposes only will be paid for by the study)  11) steps taken to 
protect patient confidentiality; 12) payments to assist with the costs of participation (e.g., 
parking, transportation); 13) that short-term care will be arranged if the patient is injured as a 
result of participation in the study but that there is no plan for NIH or the institution to pay for 
such care; and 14) all other elements required by applicable government regulations.  At the 
beginning of each study, as part of clinic certification, the CC reviews each clinic’s IRB approved 
consent to assure that each local consent statement retained the required information.   
 
Over the course of the study as modifications to the consent are required, the CC revises the 
prototype consent and, after Johns Hopkins University Bloomberg School of Public Health IRB 
Office approval has been obtained, distributes the revised prototype to clinics with instructions 
for revising their local consents.  The CC tracks clinics’ IRB approvals for consent revisions, 
maintains an archive of clinics’ IRB-approved consents, and monitors IRB approvals to ensure 
approvals remain current.  Enrollment or conduct of study follow-up, absent the necessary IRB 
approvals, is not permitted. Site visits to clinics include a review of IRB approvals, of 
correspondence with the local IRB, and of consent documents signed and dated by individual 
patients and witnessed by clinic personnel. 
 


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9.2 
IRB/Protection of human subjects 
This protocol will be submitted to the IRB of participating centers for review and approval.  
Clinics may not recruit patients into the ADVISE Trial prior to approval of this protocol by their 
governing IRB.  All ADVISE Trial patients must sign a consent statement and medical record 
release form as well as HIPAA – complaint privacy practices acknowledgment prior to 
participation in the study. 
Surveillance of uveitis and treatment complications is conducted throughout the study; any such 
complications encountered are managed by the best medical judgment of the treating 
ophthalmologist.  These events are recorded on study data forms and are submitted to the CC. 
Summaries of these data are reviewed by the DSMC at each meeting.  Important, serious, or 
unusual adverse events require expedited reporting to the CC and are reviewed by the CC 
Safety Officer, who makes the determination as to whether the event meets the criteria for a 
safety report and whether expedited review by DSMC Safety Officer is warranted.  The CC 
Safety Officer follows all serious adverse events through resolution.  All serious and unexpected 
events possibly related to uveitis treatment will be reported as safety reports to the NEI project 
officer, the FDA, the pharmaceutical supplier (where appropriate), and all clinical centers in 
accordance with FDA regulations.  The CC and clinical centers will submit all safety reports as 
expedited reports to their IRBs.  Reports of serious events not deemed to be unexpected will be 
submitted to the CC IRB, to the IRB of the clinical center in which the event was reported, as 
well as to any other study center IRBs, which require such reports. 
 
Confidentiality of patient data will be maintained in accordance with legal regulations.  Protected 
health information (PHI) not be transmitted to the CO, CC, RC, or to other ADVISE sites.  PHI 
collected for study purposes, possibly including name, social security number, address, and 
other such personal data will be kept solely at the clinical center where the patient receives 
her/his clinical care and will be kept in a secure location.  A dataset limited so as to contain a 
minimal amount of protected health information–that required to make the data useful for 
accomplishing the purposes of the ADVISE Trial–may be disclosed, as needed, to collaborating 
ADVISE sites and the NEI, as will be stated on a study privacy acknowledgment form signed by 
the participant at the time of enrollment.  Also included in the privacy acknowledgment is the 
statement that representatives of NEI, the Institutional Review Boards, and CC may see 
identifying information while reviewing study records.  This privacy acknowledgment will be 
designed to conform with specifications of HIPAA regulations, and any other relevant 
regulations, as approved by the local governing authorities invested with oversight of HIPAA 
regulations at each participating site.  Clinically relevant information from the study may be 
placed in the patient's medical record.  Release of protected health information to any other 
persons or organizations will require additional written consent of the patient affected, except as 
required by law. 
 
9.3 
Data and Safety Monitoring Committee 
Trial monitoring will be conducted by an independent DSMC, appointed as advisory to the 
Executive Committee (EC) and the NEI.  The DSMC is responsible for review of efficacy and 
safety data, policy and ethical issues, and study performance.  The DSMC is composed of two 
ophthalmologists, one rheumatologist, two biostatisticians, and an ethicist; other members may 
be added as deemed appropriate by the ADVISE Executive Committee (EC) and the NEI.  One 
of the physician members of the DSMC, will serve as the DSMC Medical Safety Officer to 
review individual events or summary safety data between DSMC meetings, as deemed 
necessary by the CC Medical Safety Officer.  Treatment effects monitoring, including formal 
interim analyses, will be performed by the CC and presented to the DSMC.  The frequency and 


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type of analyses and evaluation is determined by the ADVISE Trial EC, NEI, and DSMC, with a 
minimum of at least two meets, typically one face-to-face and one conference phone call 
meeting, of the DSMC per year.  The policies and procedures for the DSMC analyses and 
deliberations are modeled on those we have used for other NEI-sponsored trials.  The primary 
focus of the DSMC analyses will be on the comparison of the treatment groups with respect to 
safety and efficacy measures, which will include, but not be limited to, successful corticosteroid 
sparing, measures of visual acuity, quality of life, uveitis activity, uveitis complications, ocular 
and systemic adverse events, etc.  Presentation of the statistical methods that are used will be 
made by selected members of the Statistical Advisory Committee to the DSMC.  The DSMC will 
not be masked.  The DSMC may make recommendations to modify the protocol or to terminate 
the trial if there is early evidence of benefit or harm associated with one of the treatments.  
Summaries of DSMC reviews and recommendations are submitted to the CC and to each 
clinical center’s IRB for review. 
 
Performance monitoring will include comparisons of enrollment, baseline variables, protocol 
deviations, and missing data between clinics. Clinic performance data will be presented at  
DSMC, Steering Committee, and Research Group meetings. 
 
 
10. Study implementation  
 
10.1 
Study organization  
The ADVISE Research Group (RG) consists of participating clinical centers and three resource 
centers:  the CO, the CC, and the RC).  The resource centers are funded via U10 cooperative 
agreements and the clinical centers via subcontracts with the CC.  The responsibilities of the 
clinical and resource centers and the committee structure for the ADVISE Research Group are 
detailed in the ADVISE Manual of Procedures. 
 
10.1.1 Characteristics of target population and recruitment strategies 
The population of interest is that to which results of the trial will be generalized.  Recognizing 
that ethical considerations limit participation to those who agree to become clinical trial subjects, 
we aim to recruit a study population reasonably similar to the population of interest, which is the 
group of patients for whom immunosuppressive drugs would be prescribed as a treatment for 
intermediate, posterior and panuveitis.  This objective will be accomplished by recruiting 
subjects from clinical practices that administer immunosuppressive therapy for eye diseases on 
a frequent basis.  The distribution of uveitis disease types in the recruited study population for 
ADVISE is likely to resemble the distribution of uveitis disease types for the population recruited 
for the MUST Trial which is provided in Table 1. 
 
10.2 
Quality assurance  
10.2.1 Medical Therapy Quality Assurance Committee  
The MTQAC is a committee of 3 experienced uveitis experts, involved in management of the 
ADVISE Trial, but not in managing patients enrolled in the trial. The primary role of the MTQAC 
is to ensure adherence to the assessment of activity and treatment guidelines. Additional details 
of each type of monitoring are provided below.  During the design phase, members of the 
MTQAC will work with the CC to design forms to capture the details required to assess 
adherence, to develop rules to flag potential non-adherence, and to determine the format and 
data to be included in the reports that will be transmitted from the CC to the MTQAC for review.  


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In addition, they will lead the training of study ophthalmologists on the treatment protocol and 
serve as a resource for treatment-related questions throughout the trial.  
At the start of the trial, there will be intensive scrutiny.  Once a site has been certified and is 
open for enrollment, all available data on activity and treatment from the first two participants 
enrolled at that site will be reviewed by a member of the MTQAC.  The evaluations described 
below will be included as part of the intensive monitoring plan.  Thereafter, a combination of 
regularly scheduled and ad hoc reviews (e.g., triggered by issues identified during site visits, 
monthly review of the study data, or other mechanisms) will be performed throughout the course 
of the study.   
 
A member of the MTQAC will review each report provided by the CC and determine whether 
corrective action (e.g., retraining, site visit) is required. The entire MTQAC will hold quarterly 
conference calls to discuss patterns of deviations and to formulate recommendations regarding 
the need for additional training, monitoring or changes to the protocol.  Additional ad hoc 
meetings will be scheduled as necessary. MTQAC members will be included in site visits to 
clinics of concern, and the Study Chair will engage centers resistant or repeatedly inconsistent 
with activity assessment accuracy and/or protocol treatment implementation. 
 
10.2.2 Visual Function Quality Assurance Committee 
The Visual Function Quality Assurance Committee (VFQAC) monitors and certifies visual acuity 
and visual field examiners.  It is regularly present at site visits to the individual clinical centers 
and conducts training and certification of coordinators and other appropriate personnel at RG 
meetings.  In the ADVISE Trial, the visual function protocol and the VFQAC activities will 
conducted in the same manner we have used for other NEI-sponsored clinical trials.21,22,23 Best-
corrected visual acuity score will be measured at every study visit under standardized lighting 
conditions by certified study examiners using logarithmic (ETDRS) visual acuity charts, 
according to the method described by Ferris, et al.56 Peripheral visual fields in patients with 
birdshot chorioretinitis will be assessed by quantitative Goldmann perimetry18 or alternative 
evaluations of the peripheral field (e.g., automated perimetry using both the SITA-fast 30-2 and 
the P60, a suprathreshold screening test of the peripheral field). 
 


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75. Weinbaum CM, Williams I, Mast EE, Wang SA, Finelli L, Wasley, A, Neitzel SM, and 
Ward JW.  Recommendations for identification and public health management of 
persons with chronic hepatitis B virus infection. MMWR 2008;57:RR-8:1-20. 
 
76. Testing for HCV infection: an update of guidance for clinicians and labortorians. MMWR 
2013;62:362-5. 
 
 

SAP_001.pdf: 
 
 
 
 
The Adalimumab Vs. conventional ImmunoSupprEssion 
for uveitis (ADVISE) Trial 
 
Statistical Analysis Plan (SAP) 
 
 
NCT03828019 
 
 
 
 
 
Version 1.0 
10/08/2018 
 
 
 


ADVISE Trial Statistical Analysis Plan (Version 1.0: 8 October 2018) 
 
 
2 
2 
Contents 
 
1.0 Glossary of Abbreviations ...................................................................................................................... 3 
2.0 Introduction ............................................................................................................................................ 4 
3.0 Study Overview...................................................................................................................................... 4 
3.1 
Study Design Synopsis ................................................................................................................. 4 
3.2 
Randomization and Stratification ................................................................................................... 5 
3.3 
Masking ........................................................................................................................................ 6 
4.0 Outcomes .............................................................................................................................................. 6 
4.1 
Primary Outcome .......................................................................................................................... 6 
4.2 
Secondary Outcomes.................................................................................................................... 6 
4.3 
Safety Outcomes ........................................................................... Error! Bookmark not defined. 
5.0 Analysis Sets ......................................................................................................................................... 7 
6.0 Statistical Analysis Methods................................................................................................................... 7 
6.1 
General principles ......................................................................................................................... 7 
6.2 
Sample Size .................................................................................................................................. 7 
6.3 
Primary outcome analysis ............................................................................................................. 8 
6.4 
Analysis of additional outcomes .................................................................................................... 9 
6.5 
Subgroup analyses ..................................................................................................................... 10 
6.6 
Multiplicity ................................................................................................................................... 11 
6.7 
Missing data ................................................................................................................................ 11 
7.0 Trial Monitoring .................................................................................................................................... 11 
7.1 
Interim Efficacy Analysis ............................................................................................................. 11 
7.2 
Safety Monitoring ........................................................................................................................ 12 
References ................................................................................................................................................ 13 
 
 
 
 


ADVISE Trial Statistical Analysis Plan (Version 1.0: 8 October 2018) 
 
 
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1.0 Glossary of Abbreviations 
ADVISE 
ADalimumab Vs. conventional ImmunoSupprEssion for uveitis 
AE 
Adverse Event 
CC 
Coordinating Center 
CI 
Confidence interval 
DSMC 
Data Safety and Monitoring Committee 
EDTRS 
Early Treatment Diabetic Retinopathy Study 
EC 
Executive Committee 
EDA 
Exploratory Data Analysis 
EuroQual 
Euro-Qual Questionnaire 
FA 
Fluorescein Angiography 
GEE 
Generalized Estimating Equations 
HR 
Hazard Ratio 
LTFU 
Lost to Follow-up 
MTQAC 
Medical Therapy Quality Assurance Committee 
MUST 
Multicenter Uveitis Steroid Treatment 
NEI 
National Eye Institute 
OCT 
Optical Coherence Tomography 
OR 
Odds Ratio 
PHM 
Proportional Hazards Model 
RC 
Reading Center 
RG 
Research Group 
SAC 
Statistical Analysis Committee 
SAE 
Serious Adverse Event 
SAP 
Statistical Analysis Plan 
SD 
Standard Deviation 
SF-36 
Short-Form Survey 
SITE 
Systemic Immunosuppressive Therapy for Eye Diseases 
VF 
Visual Field 
VFQ 
Visual Function Questionnaire 
 
 
 


ADVISE Trial Statistical Analysis Plan (Version 1.0: 8 October 2018) 
 
 
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4 
2.0 Introduction 
The goal of the Statistical Analysis Plan (SAP) is to describe the statistical plans for the statistical analyses of 
data collected in the ADalimumab Vs. conventional ImmunoSupprEssion for uveitis (ADVISE) Trial and 
comment on considerations that were incorporated into the plan.  Areas covered include sample size 
estimates, exploratory data analysis (EDA), regression modeling, interim analyses, safety analyses, 
multiplicity, and missing data.  
 
3.0 Study Overview 
 
3.1 Study Design Synopsis 
The proposed ADVISE Trial is a randomized, parallel-treatment, comparative effectiveness, clinical trial 
comparing adalimumab to conventional (small molecule) immunosuppression for the treatment of non-
infectious, intermediate, posterior, or panuveitides (Figure 1).  The primary hypothesis is that adalimumab will 
be superior to conventional immunosuppression for corticosteroid sparing, as determined by the proportion 
achieving inactive uveitis and prednisone <7.5 mg/day for 2 visits >28 days apart by 6 months of follow-up. 
 
Figure 1.  Trial Schema. 
 
 
 
Eligible participants will be age 13 years or greater and have active or recently active (<60 days) non-
infectious, intermediate, posterior, or panuveitis for which immunosuppression is indicated.  Participants should 
have either active uveitis requiring initiation of prednisone or an increase in dose to >7.5 mg/day or, if the 
uveitis is inactive, participants should be on a dose of prednisone >7.5 mg/day.  Exclusion criteria include:  1) 
active tuberculosis; 2) untreated latent tuberculosis (e.g. positive interferon-γ release assay [IGRA] test, such 
as Quantiferon-gold; 3) Behçet disease (data suggest the Behçet disease does better with TNF-α blocking 
drugs1,2); 4) multiple sclerosis (TNF-α blockade may worsen multiple sclerosis); 5) brain magnetic resonance 
imaging (MRI) consistent with demyelinating disease (because individuals with intermediate uveitis are at an 
increased risk of multiple sclerosis3,4, they will have an MRI imaged prior to enrollment); 6) a fluocinolone 
acetonide implant in either eye placed within 3 years of randomization; 7) use of anti-TNF monoclonal antibody 
therapy within 60 days prior to enrollment; 8) history of adalimumab intolerance or ineffectiveness;  9) current 
treatment with 2 immunosuppressive drugs, not including oral corticosteroids (most immunosuppressive drug 
regimens use a maximum of prednisone and 2 immunosuppressive drugs); and 10) pregnancy, lactation, or for 
women of child-bearing age, unwillingness to use appropriate contraception.  Note that the Behçet disease and 
multiple sclerosis exclusions would have made only 4% of the participants in the Multicenter Uveitis Steroid 
Treatment (MUST) Trial ineligible for the ADVISE Trial.  Hence the ADVISE Trial will enroll a population similar 
to that in the MUST Trial.   
 
Participants will be followed every month for the first six months and then every two months thereafter.  Table 1 
shows the data collection schedule at each visit. 


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Table 1.  Visit and Examination Schedule for the ADVISE Trial 
Month 
BL* 
1 
2 
3 
4 
5 
6 
8 
10 
12 
Visit ID 
V01 
V02 
V03 V04 V05 V06 V07 V08 V09 V10 
All patients 
 
 
 
 
 
 
 
 
 
 
Visual acuity† 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Medical, ophthalmic, and treatment history 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Weight and blood pressure 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Eye examination 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Optical coherence tomography 
X 
 
 
X 
 
 
X 
 
 
X 
Retinal color photos‡ 
X 
 
 
 
 
 
X 
 
 
X 
Complete blood count & chemistry panel§ 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Quality of life (EuroQoL, SF-36, NEI-VFQ) 
X 
 
 
X 
 
 
X 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
Disease-specific tests 
 
 
 
 
 
 
 
 
 
 
  Disease:  Test(s) 
 
 
 
 
 
 
 
 
 
 
   Birdshot chorioretinitis:  Visual field¶ 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
   Choroiditis (all types):  FAF║ 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
   Vogt-Koyangi-Harada:  FAF and OCT 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
   Retinal vasculitis and panuveitis with 
retinal vasculitis:  FA#  
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
    
Tests to identify exclusion 
characteristics prior to enrollment 
 
 
 
 
 
 
 
 
 
 
Interferon-γ release assay for tuberculosis 
(all patients)** 
X 
 
 
 
 
 
 
 
 
 
MRI for patients with intermediate uveitis 
only†† 
X 
 
 
 
 
 
 
 
 
 
Pregnancy test for women of child bearing 
age 
X 
 
 
 
 
 
 
 
 
 
 
 
 * BL = baseline 
 † Evaluation of best corrected visual acuity after standard refraction  
  ‡ 50 or 60˚ stereo photos of field 1-2 (disc and macula).   
  § Including creatinine and liver enzymes 
   ¶ Either Goldmann perimetry or automated perimetry with Humphrey SITA-fast 24-2 and  
    P60 may be used, but once chosen, the visual field testing should be the same for all visit for each    
    individual patient 
 ║ FAF= fundus autofluorescence. 
 # FA = fluorescein angiography 
** E.g. Quantiferon Gold   
††  MRI = magnetic resonance imaging of the brain 
 
 
3.2 Randomization and Stratification 
Eligible participants will be randomized to receive adalimumab or conventional immunosuppression with a 1:1 
allocation ratio. Randomization will be stratified by current immunosuppressive treatment for uveitis (1 or none) 


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and prednisone dose at randomization (< 30 vs ≥ 30 mg/day), i.e. a total of 4 strata, and implemented with a 
permuted block design with multiple block sizes. The randomization schedule will be produced in advance by 
the Coordinating Center (CC), and the randomization revealed via the ADVISE website after eligibility and 
stratum are confirmed. 
 
3.3 Masking 
Treatment administration will not be masked. Trial images will be uploaded to the Reading Center (RC) and 
evaluated there by graders masked as to treatment assignment.  All other assessments will be made using 
unmasked examiners. 
 
 
4.0 Outcomes 
 
4.1 Primary Outcome 
The primary outcome of the ADVISE Trial will be a corticosteroid-sparing treatment success, defined as 
inactive uveitis, on prednisone <7.5 mg/day for 2 consecutive visits >28 days apart within the first 6 months 
after randomization with individuals as the unit of analysis. The 2 consecutive visits >28 days apart was used 
in the SITE Cohort Study to avoid overestimation of benefits among participants who transiently achieve 
corticosteroid-sparing, but promptly relapse at the next visit. Since a minimum of two follow-up visits must 
occur prior to achieving a corticosteroid sparing success and prednisone must be tapered, the first outcome 
evaluation will occur at 2 months (V03) and will continue at every visit until the final study visit at 12 months 
(V10).   
4.2 Secondary Outcomes 
Secondary outcomes will include data collected at all follow-up visits, i.e. V02-V10, according to the collection 
schedule presented in Table 1.  
• 
Secondary corticosteroid sparing outcomes: 
o Corticosteroid-sparing success: The ability to achieve inactive uveitis and prednisone <7.5 
mg/day for 2 consecutive visits >28 days apart within one year of randomization 
o Prednisone discontinuation success: The ability to achieve inactive uveitis and discontinue 
prednisone for 2 consecutive visits >28 days apart within one year of randomization 
o Prednisone exposure (e.g. cumulative prednisone dose and/or mean prednisone dose) in the 
two groups through 1 year of follow-up. 
• 
Best corrected visual acuity measured after a standardized refraction using logarithmic visual acuity 
charts 
• 
Incidence of infections 
o Any infections requiring antimicrobial therapy 
o Tuberculosis (clinical diagnosis of tuberculosis) 
o Invasive fungal infections 
o Dermatomal or disseminated herpes zoster 
• 
Macular edema measured using Optical Coherence Tomography (OCT) 
• 
Quality of life (QoL) data collected at baseline, 3, 6, and 12 months 
o Health utility (EuroQoL 5-dimension [5D] and visual analog scales) 
o General health assessment (SF-36) 
o Vision related QoL (the 25-item National Eye Institute Visual Function Questionnaire [NEI-VFQ-
25]) 
• 
Safety outcomes: 
o Systemic adverse events (e.g. cytopenias, elevated creatininte, elevated liver enzymes) 
o Serious adverse events (e.g. death, life-threatening adverse drug experience, inpatient 
hospitalization or prolongation of existing hospitalization) 


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5.0 Analysis Populations 
The primary analyses will be based upon the ‘as randomized’ population, i.e. individuals will be included in the 
analysis according to their assigned treatment regardless of the actual treatment received, which follows the 
principle of intention to treat (ITT).  A number of sensitivity analyses based upon the treatment received will be 
explored including but not limited to the following two examples.  First, an ‘as treated’ analysis will incorporate 
individuals according to the current treatment received, which may change over time.  Second, a ‘per protocol’ 
analysis will limit the analysis to the subset that received the assigned treatment according to the guidelines of 
the protocol throughout follow-up. Additional sensitivity analyses using causal inference techniques will be 
considered to address the issues of confounding and treatment by indication that arise from analyses based 
upon treatment received. 
 
6.0 Statistical Analysis Methods 
 
6.1 General principles 
The primary analyses will include adjustment for randomization strata (immunotherapy use and prednisone 
dose).  Additional analyses that are unadjusted or are adjusted for potential confounders will also be performed 
as secondary analyses.   Robust standard errors will be computed using statistical program-based approaches 
when available and a bootstrap with the individual as the sampling unit when a pre-programmed approach is 
not available.  All statements of statistical significance and confidence intervals will be based upon a 2-tailed 
test with a 0.05 level of significance, unless stated otherwise.  Key analyses will be duplicated by a second 
statistician.  All analyses will be performed using SAS version 9 or higher, STATA or R. 
 
Prior to formal testing, exploratory data analyses including graphical techniques (e.g. histograms, scatter-plots, 
boxplots, spaghetti and lasagna plots) and summary statistics (e.g. median, IQR, proportion) will be used to 
examine cross-sectional and longitudinal patterns in the data as well as identifying potential violations of the 
assumptions underpinning formal testing, which can help guide decisions to apply transformations or 
alternative methods.  In some cases, transformations of raw data have already been identified (e.g. log-
transformation for retinal thickness and IOP) and will be implemented. Summaries will be made overall and by 
treatment group. During model selection and formal testing, graphical (e.g. residual plots) and analytic (e.g. 
tests of normality, proportional hazards assumptions) methods will be used to detect violations of modeling 
assumptions. 
 
6.2 Sample Size 
Sample size is calculated for the primary comparison of corticosteroid-sparing treatment success (inactive 
uveitis and prednisone <7.5 mg/day for 2 consecutive visits >28 days apart) at 6 months. Based on the 
preliminary data from the VISUAL III Study, we estimate that adalimumab will be successful in achieving the 
primary outcome in 75% of participants across all strata.  The success of conventional small molecule 
immunosuppression varies according to the type and number of treatments.  Based upon the Mount Sinai and 
MUST Trial data, we estimate that 75% of the participants will be in the stratum of no prior immunosuppression 
and 25% will be on one immunosuppressive agent at enrollment.5  Based on the SITE data, the estimated 
success rate for antimetabolites is 55% and for calcineurin inhibitors 40%.6-9  Participants in the no 
immunosuppression stratum will receive antimetabolites, whereas those in the one immunosuppression 
stratum will largely receive calcineurin inhibitors.  Therefore, success rates of 55% and 40% are estimated for 
the no and one immunosuppressive agent strata, respectively.  Based on the estimated stratum proportions 
and corresponding success rates, the overall conventional immunosuppression success rate is estimated to be 
51%. In order to be conservative, we will assume a 10% loss to follow-up in each group and that all individuals 
were lost prior to observing a result. This is a conservative estimate since the loss to follow-up was 6% at 2 
years in the MUST Trial.   
 


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Under these assumptions, a sample size of 222 (111 participants per treatment group) provides 90% power to 
detect significant differences between the 2 groups at 6 months if the underlying true proportions are 51% vs. 
75% (46.1% vs. 67.5%, respectively, after adjusting for the loss to follow-up by assuming all of those lost did 
not achieve the corticosparing), assuming a two-sided type I error of 0.05. Prednisone discontinuation rates in 
VISUAL I and II were estimated to be 50%.  Based upon data from Mount Sinai and the MUST Trial, estimates 
of prednisone discontinuation rates for standard immunotherapy range between 11%-35%. A sample size of 
222 provides 80% power to detect an increase in the secondary outcome of discontinuing prednisone with 
inactive uveitis by 1 year from 30% to 50% (estimated from VISUAL I and II data), assuming a two-sided type I 
error of 0.05. 
6.3 Primary outcome analysis 
The primary goal of the trial is to establish whether adalimumab is superior to conventional 
immunosuppression for corticosteroid-sparing in the treatment of individuals with intermediate, posterior, or 
pannuveitis. The analysis will focus on the cumulative proportion with a success. Once a success has been 
achieved, then it will remain fixed for that individual thereafter.  A more standard time to event analysis, which 
allows for censoring due to loss to follow-up, was considered.  However, because the time required to taper 
prednisone to ≤ 7.5 mg/day depends substantially on the initial prednisone dose, small imbalances at baseline 
could influence greatly such analyses despite stratification. Therefore, time to event analyses will be used as 
sensitivity analyses.  The 6-month time frame was chosen to allow sufficient time to observe the primary 
outcome regardless of the participant’s prednisone dose at randomization and is likely to be more robust to 
imbalances.   Multiple imputation will be used to address missing data due to missed interim visits and loss to 
follow-up. 
 
Since a minimum of two follow-up visits must occur prior to achieving a corticosteroid success and prednisone 
must be tapered, the first outcome evaluation will occur at 2 months (V03) and will continue for every visit 
thereafter.  Modeling will focus upon the period between 6 months and 1 year due to the potential for 
imbalances in the tapering patterns described above.  Generalized estimating equations (GEE) will be used to 
fit logistic regression models comparing the two treatment groups over time while accounting for the correlation 
between replicate measurements.  A saturated mean structure including visits starting at 6 months (V07-V10), 
treatment, and visit by treatment interaction terms plus the two stratification variables (baseline immunotherapy 
and initial prednisone dose) will be used. The mean model structure is: 
logit(Y) =  β0 +  β1A + β2P + β3S +  β4V7 + β5V8 +  β6V9 +  β7V10 + β8I7 +  β9I8+ β10I9 + β11I10 
where Y indicates the outcome (0: no corticosteroid sparing success, 1: corticosteroid sparing success), A 
indicates treatment (0: conventional immunosuppression, 1: adalimumab), P is an indicator of prednisone dose 
stratum (0: < 30mg/day, 1: ≥ 30 mg/day),  S is an indicator of baseline immunotherapy stratum (0: none; 1: 
one), Vj  is an indicator for visit j (j ∈ 7, …10), and Ij is an indicator for the visit by treatment interaction term for 
the jth visit.    An unstructured correlation matrix will be used to model the within-individual repeated 
measurements.  Alternate correlation structures (e.g. exchangeable) will be explored if the unstructured 
covariance matrix is unstable. This model estimates the relative odds of corticosteroid-sparing for adalimumab 
vs conventional immunosuppression. The primary outcome will be represented by exp(β1A + β8I7), i.e. the odds 
ratio of the cumulative proportion for adalimumab vs conventional immunosuppression at six months (i.e. V07). 
 
A standardized estimator, which allows for covariate adjustment, will be used to compare the absolute (as 
opposed to relative) difference in proportions at each time-point based upon the logistic model described 
above.  This estimator has the advantage of providing a consistent estimate even if the means model is mis-
specified.10, 11  For each participant, the probability of a corticosteroid-sparing success at each time point is 
computed under two scenarios to create the counter-factual probabilities: (a) as if the participant had been 
assigned to adalimumab and (b) as if the participant had been assigned to conventional immunosuppression.   
Next, the average probabilities are computed for each group and the absolute treatment effect is calculated by 
taking the difference.  The bootstrap will be used to calculate 95% confidence intervals and p-values.  The 
equivalence margin is defined to be 5%.  


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Sensitivity analyses will be used to explore the alternate quantifications and robustness of the comparisons 
between the two groups. Longitudinal assessments of the components of corticosteroid sparing (activity and 
prednisone dose ≤ 7.5 mg/day) will be performed.  In addition, time to event analyses will be used to assess 
the duration of success.  Details of these modeling techniques are described in section 6.4.  In addition, a 
variety of missing data techniques (Section 6.7) will be used to assess the potential impact of both interim 
missed visits and loss to follow-up. 
 
 
6.4 Analysis of additional outcomes 
The analyses of prednisone sparing success, an important secondary outcome, will be analyzed using the 
methods described for the primary outcome in Section 6.3 with the focus on the cumulative proportion at 1 
year.   Most of the remaining outcomes will be analyzed using longitudinal analysis techniques or event 
analysis techniques.   Table 2 summarizes the outcome type and corresponding analysis technique for these 
outcomes with safety outcomes highlighted in italics.  Additional details of safety monitoring are provided in 
Section 7.2. 
 
Table 2.  Summary of the type, modeling and frequency of secondary and safety outcomes for the ADVISE trial.   
Safety outcomes are highlighted in italics. RZ = randomization; CI = confience interval; NLP = no light perception; LP = light perception. 
Outcome Type 
Modeling Techniques 
Visit Intervals 
ADVISE Outcomes 
Continuous 
 
 
 
    Person-level 
GEE with a linear link  
Linear mixed effects models  
V01-V10 
V01, V04, V07, V12 
Prednisone dose 
QoL outcomes (EQ-5D, SF-36, NEI-VFQ) 
    Eye-level 
GEE with a linear link and 
bootstrap CIs 
Linear mixed effects models with 
a person-specific random 
intercept 
V01-V10 
 
V01, V04, V07, V12 
Visual acuity 
 
Retinal thickness (log-scale) 
Binary 
 
 
 
     Person-level 
GEE with a logistic link 
 
V01-V10 
 
V02-V10 
Individual level activity (no activity in either 
eye) 
Prednisone dose ≤ 7.5 mg 
Prednisone halted 
     Eye-level 
GEE with a logistic link and 
bootstrap CIs 
V01-V10 
 
 
V01, V04, V07, V12 
V02-V10 
 
V04, V07, V12 
VA 20/40 or better 
VA worse than 20/200 
Uveitis activity 
Macular edema (≥ 260µm) 
Improvement in macular edema  
Resolution of macular edema 
Worsening of macular edema 
Event rates 
 
 
 
      Person-level 
Negative binomial regression 
 
Real time post randomization 
 
Hospitalization 
Infections requiring antimicrobial therapy 
Type-specific infections 
SAEs 
Time to first event 
 
 
 
      Person-level 
Kaplan-Meier estimates 
Cox proportional hazards models  
 
 
Real time post randomization 
 
 
 
 
V02-V10 
Death 
Hospitalization 
Infections requiring antimicrobial therapy 
Type-specific infections  
SAEs 
Other Systemic Events 
      Eye-level 
Frailty models 
 
V02-V10 
V04, V07, V12 
Decline in VA ≥ 6 lines or to NLP or LP 
New onset macular edema 
 
Evaluations of repeated binary outcomes (e.g activity, macular edema) and continuous outcomes (e.g. visual 
acuity) over time will be analyzed using generalized estimating equations (GEE) with Gaussian or logit links 


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that account for the nested correlations between observations over time and, for eye-specific outcomes, 
between eyes of the same participant.12  A saturated mean structure including visit, treatment and visit by 
treatment interaction terms will be used.  The visits that are included in the model depend upon the outcome 
(e.g. visual acuity V01-V10, corticosteroid sparing V07-V10) and are denoted in Table 2.  An unstructured 
covariance matrix will be used to model the within-individual (or within-eye) repeated measurements.  For eye-
specific outcomes, the bootstrap will be used to compute standard errors, confidence intervals and p-values to 
adjust for between-eye correlation.   Alternative correlation structures (e.g. exchangeable, AR(1)) will be 
explored if the unstructured covariance model is unstable 
  
Events will be evaluated in two ways.  Time to first event will be graphically explored using Kaplan-Meier 
curves and comparisons will be made using Cox proportional hazards models for individual outcomes (e.g. 
prednisone cessation) and frailty models for eye level outcomes (e.g. decline in VA ≥ 6 lines).  Event rates and 
comparisons for repeated events (e.g. ocular corticosteroid injections) will be modeled using Negative binomial 
regression to account for over-dispersion and the model will include a random effect to account for between-
eye correlation for eye-specific outcomes.13 
 
An important safety consideration is cumulative prednisone exposure, which has been shown to be related to 
increased risks of cardiovascular disease and mortality.  A variety of techniques will be used to monitor 
cumulative exposure.  First, the longitudinal pattern of prednisone dose will be modeled using the techniques 
described above.  Using these models, the population estimates of the cumulative dose over the lifetime of the 
trial will be computed by adding the dose estimates for each treatment group.  Model-based estimates of 95% 
confidence intervals and treatment comparisons will be calculated.  This method uses model-based 
approaches to adjust for missed visits and loss to follow-up.  Alternately, multiple imputation will be used to ‘fill 
in’ the doses as the missed visits.  Important factors in the imputation include, but are not limited to, prednisone 
dose at adjacent visits (given the rigorous nature of tapering regimes) and activity.  Once the missing doses 
have been ‘filled in’ the cumulative usage can be calculated directly for each participant and standard analytic 
techniques can be used to compare the two treatment arms.  Multiple iterations ensure that the analysis takes 
into account the uncertainty in the imputed values. 
 
6.5 Subgroup analyses 
In addition to gender, race, and ethnicity subgroup analyses, a number of planned subgroup analyses will be 
performed to assess the heterogeneity of the treatment effect.  Of particular interest are the effects of the 
stratification factors: immunotherapy use at randomization (none vs one) and prednisone dose (< 30 vs ≥ 30).  
Other planned subgroup analyses include age (< 18 vs ≥ 18), clinic and baseline clinical characteristics 
including visual acuity (20/40 or better vs worse than 20/40) and macular edema (present vs absent).  
Depending upon recruitment, the assessment of clinic variability may be limited to regional and/or country level 
clustering; especially since treatment allocation is not stratified by clinic.  Additional subgroups of interest that 
were not pre-planned may be identified during the course of the study.  Such subgroups will be explored but 
the findings will be clearly labeled as unplanned explorations that are hypothesis generating in nature.  
For exploratory purposes, the summary statistics and graphical techniques described above will be repeated 
within each subgroup to identify potential sources of heterogeneity.  Tests of interaction (treatment effect x 
subgroup) will be used to evaluate whether or not there is significant heterogeneity between the groups defined 
by each subgroup.   Subgroup analyses of clinical interest or with large differences in effect size that do not 
meet the strict criteria for significance (p < 0.05) may still be reported; however, they will clearly be labeled as 
not having met the criteria for establishing heterogeneity. 
 


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6.6 Multiplicity 
When performing multiple hypothesis tests (as is the case here with the large number secondary outcomes), 
caution is needed when interpreting the results. Our primary focus for analyses of these outcomes will be on 
the parameter estimates and confidence intervals and overall consistency and interpretation of trial results as 
opposed to p-values as recommended by Wang et al.14 Several methods of adjusting p-values for multiple 
comparisons exist; however, there is no clear consensus as to the most appropriate method available and it is 
difficult if not impossible to quantify the number of comparisons that will be performed ahead of time. In 
general, issuing cautions is sufficient along with calculating the expected number of false positives given the 
number of comparisons that were performed.   For identifiable and related sets of outcomes (e.g. multiple 
assessments of macular edema or IOP), we will consider formal adjustments.  Bonferroni adjustments assume 
that the tests are independent and therefore would be extremely conservative for outcomes that we would 
expect to be related. Therefore, we will estimate the covariance matrix for these related sets using a bootstrap 
approach and also estimate the null distribution of the minimum p-values for the multivariate distribution of z-
scores using a global null hypothesis permutation distribution. 
 
6.7 Missing data 
For the primary outcome, multiple imputation will be used to address missing data due missed interim visits 
and loss to follow-up.15 A variety of sensitivity analyses will be performed to determine the potential impact of 
missing data on our conclusions for the primary outcome as well as secondary outcomes.  ‘Best’ and ‘worst’ 
case single imputation techniques will be implemented to define the range of impact.  In addition, the effect 
size that would need to be observed in the missing data in order to change inference will be computed.  For a 
more sophisticated approach, a variety of tools including but not limited to inverse probability weighting will be 
used.16 
 
 
7.0 Trial Monitoring 
An independent Data and Safety Monitoring Committee (DSMC) will be responsible for ongoing review of 
efficacy and safety data, policy and ethical issues, and study performance.  The DSMC is composed of two 
ophthalmologists, one rheumatologist, two biostatisticians, and an ethicist.  The current DSMC membership is 
listed in the DSMC Charter. Safety and efficacy monitoring, including formal interim analyses, will be performed 
by the CC and presented to the DSMC at regular DSMC meetings every 6 months with additional meetings as 
needed 
 
7.1 Interim Efficacy Analysis 
A single, formal, interim efficacy analysis will be performed once 40% of the participants have achieved 6 
months of follow-up (i.e. evaluated for the primary outcome if not lost to follow-up or missing the visit), which is 
expected to occur when 67% of the participants have been recruited (estimated to be in the fourth quarter of 
year 3).    We will employ an O’Brien-Flemming α-spending function in order to control the cumulative type I 
error rate for the primary outcome.  The trial will be stopped for efficacy at the interim analysis if the p-value is 
<0.0008.  The nominal type I error for the final analysis will be 0.0492.  After adjusting for the interim analysis, 
we have 90% power (a loss of <1% from that described in Section 6.2) to detect an increase in the proportion 
of participants with treatment success from 51% to 75% (i.e. 46.1% vs. 67.5% after adjusting for 10% loss to 
follow-up) for conventional immunosuppression vs. adalimumab, assuming a 2-sided type I error of 0.0492.  
Additional efficacy analyses may be requested by the DSMC as needed during the course of the trial. 
 
No stopping rules for futility will be implemented.  However, if there is no significant difference between 
treatments at the end of the study, then we will assess whether adalimumab meets the criteria for non-
inferiority as compared to standard immunotherapy using the pre-specified boundary of 5%, i.e. the lower 
boundary for the difference between the proportion with corticosteroid sparing at 6 months (adalimumab minus 
conventional) is greater than -5%. 


ADVISE Trial Statistical Analysis Plan (Version 1.0: 8 October 2018) 
 
 
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7.2 Treatment and Assessment Monitoring 
The CC will work with members of the MTQAC to ensure that the image evaluation and treatment guidelines 
are being followed at each clinic.  Each month, the CC will identify discrepancies between the RC and clinic 
evaluation of disease-specific images as well as discrepancies between retreatment criteria and actual 
treatment received.   For each individual with a discrepancy, a report including the images, treatment, and any 
additional data required by MTQAC to determine whether or not corrective action is required will be prepared 
by the CC and then forwarded to a representative of the MTQAC for review.  
 
7.3 Safety Monitoring 
Complications of uveitis and its treatment will be recorded on study data forms and submitted to the CC. 
Important serious or unusual medical events are reported to the CC within 7 days after clinical center 
personnel become aware of the event (see also Protocol section 7).  An assessment will be made by the 
clinical investigator at the managing clinical center as to whether the event is related to treatment.  These 
reports will be sent to the CC Safety Officer for immediate review and determination as to whether the event 
meets the criteria for a safety report and recommend whether expedited reporting to the DSMC, IRBs, or the 
FDA is needed.  In addition, all events judged to be suspected unexpected serious adverse reactions will be 
reported as IND safety reports to the NEI project officer, the FDA, the pharmaceutical supplier (where 
appropriate), and all clinical centers in accordance with FDA regulations.  The CC and clinical centers will 
submit all IND safety reports as expedited reports to their IRBs.  Reports of important, serious or unusual 
medical events not deemed to be unexpected will be submitted as ad hoc, interim reports to the CC IRB, to the 
IRB of the clinical center in which the event was reported, as well as to any other study center IRBs which 
require such reports.  Annual reports listing all reported adverse events will be submitted to the FDA as part of 
the annual IND report and to local IRBs as required. 
Safety monitoring will be performed at every DSMC meeting.  The DSMC will be provided with graphical and 
numeric summaries of the safety data (See Section 6), as well as formal statistical comparisons between the 
two treatment groups.  Graphical and numeric summaries of efficacy outcomes without formal statistical testing 
will be provided to the DSMC at all meetings to allow sufficient information to adequately evaluate the risk 
benefit profile of the trial. 
 
 
 
 
 
 


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