Clinical trial NCT01829295
Conditions: Uveitis
Keywords: antimetabolite, noninfectious
Sponsor: University of California, San Francisco
Start date: 2013-08-01; Completion date: 2018-08-09
Enrollment: 216 participants; Allocation: RANDOMIZED; Intervention model: CROSSOVER

Brief summary:
In the First-line Antimetabolites as Steroid-sparing Treatment (FAST) Uveitis Trial, the investigators propose to establish which immunosuppressive therapy, methotrexate or mycophenolate mofetil, is more effective as a first-line, corticosteroid-sparing agent for the treatment of non-infectious uveitis in a block-randomized, observer-masked, comparative effectiveness trial.

Detailed description:
This is a randomized comparative effectiveness trial to determine which treatment, methotrexate or mycophenolate mofetil, is more effective as first-line corticosteroid-sparing treatment for patients with non-infectious intermediate, posterior and panuveitis requiring corticosteroid-sparing therapy. The primary outcome is treatment success assessed at the 6 month visit (Phase 1, 0-6 months). If patients are a treatment success, they continue on the medication for another 6 months (Phase 1, 6-12 months). Patients who are a treatment failure can crossover to the other medication (Phase 2, 0-6 months).

Arms: arm 1: oral methotrexate arm 2: oral mycophenolate mofetil
Interventions: intervention 1: Mycophenolate mofetil intervention 2: Methotrexate intervention 3: Prednisone
Intervention descriptions: intervention 1: For the first two weeks, an introductory dose of 500 mg twice a day (BID) orally. After two weeks, the dose will be increased to 1.5 g BID. intervention 2: For the first two weeks, an introductory dose of 15 mg/week (7.5mg BID once a week) orally. After two weeks, the dose will be increased to 25 mg/week (12.5mg BID once a week) intervention 3: All patients enrolled in the study will be initially taking concomitant oral corticosteroids at 1 mg/kg or 60 mg daily, whichever is less. Initial corticosteroid dose will be continued for 2 to 4 weeks at which point prednisone will be gradually tapered. Prednisone will be tapered to and held at 7.5 mg/day for the first 6 months of the study.

Protocol documents:
Prot_SAP_000.pdf: 
First-line Antimetabolites as Steroid-sparing Treatment (FAST) Uveitis Trial 
 
NCT01829295 
 
UCSF IRB Date of Approval: 12/04/2018 


 
 
 
 
 
NEI U10 EY021125-01 
 
 
 
 
 
First-line Antimetabolites as Steroid-sparing 
Treatment (FAST) Uveitis Trial 
 
 
 
 
 
 
 
Manual of Operations & Procedures 
 (MOP)  
 
 
 
 
 
 
 
January 06, 2017 
Version 4.5


First-line Antimetabolites as Steroid-sparing Treatment (FAST) Uveitis Trial 
Manual of Operation and Procedures 
 
January 6, 2017 - Version 4.5 
 
 
 
TABLE OF CONTENTS 
 
INVESTIGATORS, PERSONNEL AND STUDY SITES .................................................................................... 4 
DATA SAFETY AND MONITORING COMMITTEE (DSMC) MEMBERS ......................................................... 6 
NATIONAL EYE INSTITUTE (NEI) PROGRAM OFFICER ............................................................................... 6 
BACKGROUND ................................................................................................................................................. 7 
1. INTRODUCTION TO TRIAL .......................................................................................................................... 8 
1.1. RESEARCH QUESTION ................................................................................................................................. 8 
1.2. SPECIFIC AIMS ............................................................................................................................................ 8 
2. TRIAL DESIGN .............................................................................................................................................. 9 
2.1. DESIGN SUMMARY ...................................................................................................................................... 9 
2.2. STUDY TIMELINE .......................................................................................................................................10 
2.3. ELIGIBILITY ...............................................................................................................................................11 
2.3.1. Anatomical location of inflammation ................................................................................................11 
2.3.2. Inclusion Criteria ..............................................................................................................................12 
2.3.3. Exclusion criteria .............................................................................................................................13 
2.3.3.a. Screening for Active Tuberculosis ................................................................................................13 
2.4. RANDOMIZATION AND MASKING ..................................................................................................................14 
2.5. DEFINITIONS FOR PRIMARY ENDPOINT ........................................................................................................16 
2.5.1. Determination of Treatment Success/Failure ..................................................................................16 
2.5.2. Treatment failure .............................................................................................................................16 
2.5.3. Dropouts, Non-Compliant Patients and Follow-up ..........................................................................18 
2.5.4 Primary Endpoint Flowchart .............................................................................................................19 
3. TREATMENT PLAN .....................................................................................................................................20 
3.1. STUDY DRUGS ..........................................................................................................................................20 
3.1.1. Methotrexate ...................................................................................................................................21 
3.1.2. Mycophenolate Mofetil ....................................................................................................................22 
3.1.3. Folic acid .........................................................................................................................................23 
3.1.4. Packaging and distribution of study medications ............................................................................23 
3.1.5. Adherence to the treatment plan .....................................................................................................24 
3.2. CORTICOSTEROID THERAPY ......................................................................................................................24 
3.2.1. Oral prednisone ...............................................................................................................................24 
3.2.2. Supplements ...................................................................................................................................27 
3.2.3. Topical corticosteroid ......................................................................................................................27 
3.2.4. Periocular and Intravitreal Injections ...............................................................................................27 
3.2.5 Other adjunctive treatments/procedures ..........................................................................................28 
3.3. STUDY PROCEDURES ................................................................................................................................28 
4. STUDY VISITS .............................................................................................................................................29 
4.1. VISIT SCHEDULES .....................................................................................................................................29 
4.1.1. Phase I: First-line treatment ............................................................................................................29 
4.1.2. Phase II: Rescue treatment .............................................................................................................30 
4.1.3. Non-study visits ...............................................................................................................................31 
4.2. STUDY FORMS COMPLETION SCHEDULE ......................................................................................................32 
4.3. PHASE I ENROLLMENT/BASELINE VISIT .......................................................................................................33 
4.3.1. Consent and eligibility evaluation ....................................................................................................33 
4.3.2. Randomization ................................................................................................................................34 
4.3.3. Procedures for data collection .........................................................................................................34 
4.3.4. Specimens .......................................................................................................................................34 
4.3.5. Forms for data collection .................................................................................................................35 
4.4. FOLLOW-UP VISITS ....................................................................................................................................35 
4.4.1. Procedures for data collection .........................................................................................................35 
4.4.2. Specimens .......................................................................................................................................35 


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4.4.3. Forms for data collection .................................................................................................................36 
4.5. BASELINE PHASE II ...................................................................................................................................36 
4.5.1. Eligibility...........................................................................................................................................36 
4.6. NON-STUDY VISITS....................................................................................................................................37 
4.6.1. Study Procedures ............................................................................................................................37 
4.6.2. Specimens .......................................................................................................................................37 
4.6.3. Forms for data collection .................................................................................................................37 
5. STUDY EXAMINATIONS AND PROCEDURES..........................................................................................38 
5.1. QUALITY OF LIFE QUESTIONNAIRE ADMINISTRATION ....................................................................................38 
5.2.A REFRACTION AND VISUAL ACUITY (PROTOCOL – FOR LETTER VISION CHARTS) .............................38 
5.2.1.A Refraction procedure ....................................................................................................................38 
5.2.2.A Visual acuity procedure.................................................................................................................46 
5.2.3.A Visual acuity training and certification ...........................................................................................49 
5.2.B REFRACTION AND VISUAL ACUITY (PROTOCOL – FOR TUMBLING E CHART) .....................................50 
5.2.1.B Refraction procedure ....................................................................................................................50 
5.2.2.B Visual acuity procedure.................................................................................................................57 
5.2.3.B Visual acuity training and certification ...........................................................................................61 
5.3. OPHTHALMIC PROCEDURES .......................................................................................................................61 
5.3.1. Grading Cataracts ...........................................................................................................................61 
5.3.2. Grading inflammation ......................................................................................................................62 
5.3.3. Inter-observer variation of ocular inflammation ...............................................................................65 
5.3.4. Training and certification of ophthalmologists and study coordinators ...........................................65 
5.4. OPTICAL COHERENCE TOMOGRAPHY .........................................................................................................66 
5.4.1. Required patient assessments—Heidelberg Spectralis ..................................................................66 
5.4.2. Scan procedures—Heidelberg Spectralis .......................................................................................66 
5.4.3. Obtaining retinal thickness data—Heidelberg Spectralis ................................................................67 
5.4.4. Saving/Exporting data—Heidelberg Spectralis ...............................................................................67 
5.4.5. Required patient assessments—Zeiss Cirrus .................................................................................69 
5.4.6. Scan procedures—Zeiss Cirrus ......................................................................................................69 
5.4.7. Obtaining retinal thickness data—Zeiss Cirrus ...............................................................................70 
5.4.8. Saving/Exporting data—Zeiss Cirrus ..............................................................................................70 
5.4.9. OCT operator qualifications .............................................................................................................70 
5.5. FUNDUS PHOTOGRAPHY ...........................................................................................................................71 
5.6. LABORATORY MEASUREMENTS ..................................................................................................................71 
6.  ADVERSE EVENTS ....................................................................................................................................72 
6.1. NON-SERIOUS ADVERSE EVENT (AE) .........................................................................................................72 
6.2. SERIOUS ADVERSE EVENT (SAE) ..............................................................................................................72 
6.3. ADVERSE EVENT REPORTING .....................................................................................................................72 
6.4. PATIENT DEATH ........................................................................................................................................73 
7.  DATA COLLECTION AND MANAGEMENT ..............................................................................................73 
7.1. DATA COLLECTION FORMS ........................................................................................................................73 
7.2. DATA REVIEW ...........................................................................................................................................74 
7.3. DATA ENTRY .............................................................................................................................................74 
7.3.1.   Data entry errors ...........................................................................................................................74 
7.3.2.   Data consistency and validity ........................................................................................................74 
7.3.3.   Data preparation and cleaning ......................................................................................................75 
7.3.4.   Monitoring ......................................................................................................................................75 
7.4. DATA ANALYSIS ........................................................................................................................................75 
7.5. DATA STORAGE AND SECURITY ..................................................................................................................75 
8. QUALITY CONTROL ...................................................................................................................................76 
8.1. MEDICATION STORAGE AND EXPIRY ...........................................................................................................76 
8.2. PERIODIC REPORTS ..................................................................................................................................76 
8.3. DATA MANAGEMENT, SECURITY AND QUALITY ASSURANCE ..........................................................................77 
8.4. MONITORING COMPLIANCE ........................................................................................................................77 
8.5. CERTIFICATION ........................................................................................................................................77 


First-line Antimetabolites as Steroid-sparing Treatment (FAST) Uveitis Trial 
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8.6. DATA AUDITS ............................................................................................................................................77 
9. DUTIES AND RESPONSIBILITIES OF STAFF ...........................................................................................77 
9.1. OPHTHALMOLOGIST ..................................................................................................................................77 
9.2. CLINICAL TRIAL MANAGER ........................................................................................................................77 
9.3. STUDY COORDINATOR ..............................................................................................................................77 
9.4. DATA ANALYST .........................................................................................................................................78 
9.5. DATA ENTRY OPERATOR ..........................................................................................................................78 
9.6. BIOSTATISTICIAN (
 ....................................................................................................................78 
9.7. OPHTHALMIC ASSISTANTS .........................................................................................................................78 
9.8. REFRACTIONISTS ......................................................................................................................................78 
9.9. OCT OPERATORS ....................................................................................................................................78 
9.10. FUNDUS PHOTOGRAPHERS .....................................................................................................................79 
9.11. THE READING CENTER ...........................................................................................................................79 
10. STUDY ORGANIZATION ...........................................................................................................................79 
10.1. EXECUTIVE COMMITTEE ..........................................................................................................................79 
10.2. CLINICAL COORDINATING CENTER (CCC) ................................................................................................79 
10.3. UVEITIS PHOTOGRAPH READING CENTER (UPRC) ..................................................................................79 
10.4. DATA COORDINATING CENTER (DCC) .....................................................................................................80 
10.5. DATA ANALYSIS CENTER (DAC) ..............................................................................................................80 
10.6. DATA SAFETY AND MONITORING COMMITTEE (DSMC) .............................................................................80 
10.7. EDITORIAL COMMITTEE ...........................................................................................................................80 
10.8. STUDY SITES..........................................................................................................................................81 
10.9. PHARMACY .............................................................................................................................................81 
10.10 STUDY COMMUNICATIONS ......................................................................................................................81 
11. BIBLIOGRAPHY .......................................................................................................................................82 
 
APPENDIX A: STUDY FORMS 
APPENDIX B: CERTIFICATION FORMS 
APPENDIX C: QUALITY OF LIFE QUESTIONNAIRES 
APPENDIX D: PATIENT CALENDARS 
APPENDIX E: UPRC MANUAL 
APPENDIX F: TABLE FOR ASSESSING UVEITIS ACTIVITY 
 








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Background 
 
In the First-line Antimetabolites as Steroid-sparing Treatment (FAST) Uveitis Trial, we 
propose to establish which immunosuppressive therapy, methotrexate or mycophenolate 
mofetil, is more effective as a first-line, corticosteroid-sparing agent for the treatment of non-
infectious uveitis. Uveitis, a set of conditions defined by intraocular inflammation, is a 
significant cause of vision loss and morbidity in the United States and the world.1, 2 The 
incidence was recently estimated to be more than 50 cases per 100,000 person-years, with 
a prevalence of approximately 115 per 100,000 persons.3 Additionally, uveitis is believed to 
be the cause of up to 10% of cases of legal blindness in the United States, or approximately 
30,000 new cases of blindness per year.1, 3, 4 In contrast to common age-related eye 
disorders, uveitis may have a stronger socio-economic impact because it disproportionately 
affects younger working-age patients.5 Although the etiology of uveitis is varied, most cases 
are presumed to be immune-mediated and lack a known infectious cause.6-9 Even in 
developing countries such as India that have a larger burden of infection, the vast majority of 
cases are non-infectious.10, 11  
 
The current mainstay of treatment for non-infectious uveitis is corticosteroids (topical, 
systemic, locally injected, or corticosteroid-eluting implants). Due to the well documented 
local 
and 
systemic 
side 
effects 
associated 
with 
corticosteroid 
therapy, 
other 
immunosuppressive therapies are frequently used as corticosteroid-sparing agents in 
patients who need long-term therapy. These include antimetabolites, calcineurin inhibitors, 
alkylating agents, and biologic drugs.12 Cost and morbidity associated with uncontrolled 
inflammation make the selection of an effective initial steroid-sparing agent extremely 
important. 
 
When corticosteroid-sparing therapy is required, the two most commonly used first-line 
immunosuppressive agents are methotrexate and mycophenolate mofetil.13 Because of cost 
and potentially dangerous long-term side effects, other classes of drugs such as biologics 
are typically reserved for refractory cases in which other treatments have failed.12 It is 
common practice for patients requiring a steroid-sparing agent to be treated first with the 
less expensive methotrexate and then switched to mycophenolate mofetil in the event of 
treatment failure. However, results from non-comparative retrospective case series indicate 
that uveitis patients may be much more likely to achieve controlled inflammation and tolerate 
treatment with mycophenolate mofetil. 13-28 Furthermore, approximately half of the patients 
who fail treatment with methotrexate go on to successful treatment with mycophenolate 
mofetil.29 Unlike in rheumatology, where clinical trials have demonstrated differential efficacy 
of antimetabolites for systemic inflammatory diseases, there have been no prospective 
randomized, controlled trials in uveitis to systematically determine which antimetabolite is 
more clinically efficacious as initial corticosteroid-sparing therapy. This makes it difficult for 
clinicians to make informed, evidence-based decisions about first-line immunosuppressive 
treatment. In addition, if patients fail one antimetabolite, there is no evidence basis for 
deciding whether to switch to another antimetabolite, or to move on to another class of 
immunosuppressives, including biologics.   
 
 
 
 
 
 
 








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2.3. Eligibility 
. 
2.3.1. Anatomical location of inflammation 
 
All patients must have met the criteria for intermediate, anterior and intermediate, posterior 
or panuveitis, as defined by the Standardization of Uveitis Nomenclature (SUN) Working 
Group, at any time since their diagnosis of uveitis. 
 
The Standardization of Uveitis Nomenclature 
______________________________________________________________ 
Type  
        Primary Site of Inflammation     Includes 
______________________________________________________________ 
Anterior Uveitis 
    Anterior Chamber  
Iritis 
 
 
 
 
 
 
 
Iridocyclitis 
 
 
 
  
 
 
 
Anterior cyclitis 
Intermediate Uveitis     Vitreous 
 
 
Pars planitis 
 
 
 
 
 
 
 
Posterior cyclitis 
 
 
 
 
 
 
 
Hyalitis 
Posterior Uveitis 
     Retina or Choroid  
Focal, multifocal, or  
 
 
 
 
 
 
 
Diffuse choroiditis 
 
 
 
 
 
 
 
Chorioretinitis 
 
 
 
 
 
 
 
Retinochoroiditis 
 
 
 
 
 
 
 
Retinitis 
 
 
 
 
 
 
 
Neuroretinitis 
Panuveitis 
 
     Anterior Chamber 
 
 
 
     Vitreous 
 
 
 
     Retina or Choroid 
______________________________________________________________  
 
*Adapted from the SUN Working Group Anatomic Classification of Uveitis 
 
According to SUN criteria:  
 
“There was consensus that the term intermediate uveitis should be used for that subset of 
uveitis where the vitreous is the major site of inflammation, and that the presence of 
peripheral vascular sheathing and macular edema should not change the classification. 
The diagnostic term pars planitis should be used only for that subset of intermediate 
uveitis where there is snowbank or snowball formation occurring in the absence of an 
associated infection or systemic disease (that is “idiopathic”). The term panuveitis should 
be reserved for those situations in which there is no predominant site of inflammation, but 
inflammation is observed in the anterior chamber, vitreous, and retina and/or choroid (this 
is, retinitis, choroiditis, or retinal vasculitis). For the definition of panuveitis, structural 
complications such as macular edema or neovascularization should not be considered in 
classifying the anatomic location of uveitis. Inflammation in the anterior chamber and 
vitreous (this is, more vitritis than in an iridocyclitis and more anterior chamber 
inflammation than in intermediate uveitis) should be referred to as anterior and 
intermediate uveitis and not panuveitis.” 30 If vasculitis is present in the setting of 
intermediate uveitis, it should be called intermediate uveitis with vasculiltis, not posterior 
uveitis.  
 
 
 
 


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2.3.2. Inclusion Criteria 
 
All the following criteria must be met at enrollment: 
• 
History of non-infectious intermediate, anterior and intermediate, posterior or 
panuveitis in at least one eye   
• 
Active inflammation within the last 180 days, defined by the presence of any of 
the following (in at least one eye) according to SUN criteria and the NEI vitreous 
haze grading scale: 
≥ 2+ anterior chamber cells  and/or 
≥ 2+ vitreous haze  and/or 
active retinal or choroidal inflammation 
• 
Active inflammation in at least one eye at enrollment, defined by any of the 
following: 
 ≥ 1+ anterior chamber cells and/or  
 ≥ 1+ vitreous haze and/or  
 active retinal/choroidal inflammation (bullous serous retinal   
    detachment qualifies if choroidal thickening)  
• 
At least one of the following criteria must be met before or at enrollment: 
1.) Active inflammation after 4 weeks of high-dose (1mg/kg prednisone 
equivalent) oral corticosteroid treatment 
2.) Treatment with oral corticosteroids resulting in a reduction of inflammation, 
followed by an increase in inflammation (of at least 1 grade in anterior chamber 
cells or vitreous haze or a change of non-active to active retinal/choroidal 
lesions) when corticosteroid is tapered, in the 180 days prior to enrollment 
3.) Treatment with t10mg/day oral prednisone or equivalent over at least the 
past 90 days prior to enrollment 
4.) Active inflammation after long-acting corticosteroid injection 4 weeks to 180 
days prior to enrollment 
5.) One of the following uveitic conditions necessitating corticosteroid-sparing 
immunosuppressive treatment12:  
 
Behcet’s disease with posterior segment involvement 
 
Multifocal choroiditis with panuveitis  
 
Serpiginous choroidopathy  
 
Birdshot retinochoroidopathy 
 
Diffuse retinal vasculitis 
 
Severe Vogt-Koyanagi-Harada syndrome (VKH) (for example: acute 
VKH that has been active for at least 4 weeks, or VKH with bullous 
serous retinal detachments and/or choroidal detachments with other 
signs of ocular inflammation) 
 
Sympathetic ophthalmia 
 
 
6.) If the patient does not fit any of these categories, but the physician believes  
 
corticosteroid-sparing immunosuppressive therapy is indicated, eligibility may  
 
be assessed on a case-by-case basis after discussion with the coordinating  
 
center. Please contact 
 or by email.   
• 
Willingness to start corticosteroid treatment at 1mg/kg or 60mg a day of 
prednisone, whichever is less (starting at a lower dose is acceptable if patient has 
known tolerability issues) 
• 
Willingness to limit alcohol consumption (American College of Rheumatology 
recommendation is 2 drinks per month or less)  
• 
Willingness to use an acceptable method of contraception during the study period 
(i.e. pharmacologics, devices, barrier methods) or abstinence.  


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2.3.3. Exclusion criteria 
 
Any one excludes patient: 
• 
Any infectious cause of uveitis 
• 
Prior immunosuppressive therapy other than corticosteroids in the past 12 months 
• 
Prior intolerability or safety issues with methotrexate or mycophenolate mofetil 
• 
Prior failure to control ocular or other inflammation using methotrexate or 
mycophenolate mofetil 
• 
Prior biologic therapy at any time   
• 
< 16 years of age at enrollment 
• 
Media opacity (such as cataract and/or corneal scar) and/or extensive posterior 
synechiae such that examination of the posterior segment is not possible in both 
eyes 
• 
Chronic hypotony (IOP < 5 mm Hg for > 3 months) in both eyes  
• 
Periocular or intravitreal corticosteroid injection in the past 4 weeks 
• 
Fluocinolone acetonide implant in either eye in < 3 years 
• 
Intraocular surgery in < 30 days, or planned surgery within the next 180 days 
•   Best spectacle-corrected visual acuity of hand motion or worse in better eye 
• 
Planning to conceive during the study period, pregnant or breast-feeding (blood 
or urine pregnancy test for all females, excluding those who are post-menopausal 
is mandatory within 4 weeks prior to enrollment) 
•   History of cancer (If a patient has a history of non-melanoma skin cancer they can   
      still be considered for inclusion in this study, provided it is not currently active).   
• 
Systemic autoimmune disease or ocular condition (besides uveitis) anticipated to 
dictate treatment course 
• 
Abnormal CBC (≤ 2,500 white blood cells and/or ≤ 75,000 platelets and/or ≤9   
     hemoglobin) within 4 weeks prior to enrollment*  
• 
Abnormal alanine aminotransferase (ALT) and/or aspartate aminotransferase 
(AST) ≥ 2 times the upper limit of normal for the lab and/or creatinine ≥ 1.5 
within 4 weeks prior to enrollment 
• 
Evidence of active tuberculosis, HIV infection, syphilis, or hepatitis B or C 
(patients must have a tuberculin skin test, or interferon-gamma release assay, a 
chest radiograph, RPR/VDRL, FTA-ABS, or other treponemal tests, Hepatitis B 
surface antigen and Hepatitis C antibody tests within 90 days prior to enrollment) 
 
Beyond the tests listed above, the remainder of the work-up is at the discretion of the 
investigator and should be tailored to the clinical situation. Distinguishing between infectious 
and non-infectious uveitis is part of standard of care and should be dictated by the patient’s 
clinical exam, but at minimum, all patients must have testing for tuberculosis, syphilis and 
hepatitis within 90 days prior to enrollment. If there is any clinical suspicion of infection, other 
tests should be considered at the investigator’s discretion (i.e. leptospirosis in India). Testing 
is available for this at 
 if indicated.  
 
2.3.3.a. Screening for Active Tuberculosis  
Given that treatment with antimetabolites is not thought to increase the risk of tuberculosis, 
patients with latent (but not active) tuberculosis will be eligible for this study. It is at the study 
doctor’s discretion to determine if the patient has active or latent tuberculosis, based on the 
testing required. There is no specific cut off for the tuberculin skin test for inclusion in the 
trial. Treatment for latent TB should be handled according to the standard of care in the 










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If the investigator thinks the SAE is related to the study drug, he/she can stop the 
study medication anytime (including prior to determination of treatment failure by 
the Medical Monitor). If the investigator thinks treatment failure is likely (prior to 
hearing from the Medical Monitor) they should obtain all study assessments which 
would be collected at a treatment failure visit. However, the investigator will wait to 
complete the Treatment Assessment Form and officially declare treatment failure 
until they are instructed to do so by the Medical Monitor.  
  
 
2.5.3. Dropouts, Non-Compliant Patients and Follow-up   
 
•  Dropout from study: Patients will be considered to have dropped out from 
the study only if they declare they are no longer interested in further 
participation and not willing to return for any study visits, or are 
deceased. If patients are not willing to return for any study visits, no further 
information will be collected on those patients. We anticipate that a few 
patients may drop out due to unwillingness to continue or death. In case of 
patient dropout, the patient dropout form should be filled out.  
 
 
If death is considered to be related to the study drug, the patient will be 
counted as a treatment failure. If death is not related to the study drug, the 
patient will be counted as a dropout. This would be at the discretion of the 
Medical Monitor.  
 
• 
Non-compliant Patients: Patients who stop the study treatment for 
reasons other than efficacy, tolerability and/or safety (i.e. fear of potential 
side effects) but are willing to return for study visits, are not considered 
dropouts. Also, if patients miss study visits, and do not respond to contact, 
they are not considered dropouts. These patients will be considered non-
compliant patients, and will be encouraged to return for subsequent study 
visits regardless of whether or not they are taking study medication, 
especially the 6 month visit (Phase I and Phase II). 
 
 
 
It should be noted that missing a visit does not mean that a patient has 
dropped out of the study. These patients are considered to be non-
compliant. For example, if they missed the 1 month visit, every attempt will 
be made to bring them back as soon as possible and to continue with 
subsequent visits. Also, a non-serious adverse event or discontinuation of 
study medication does not mean that the patient has dropped out and they 
should continue to be followed according to the protocol, as they may be 
able to resume treatment. Even if the patient is not willing to resume 
treatment, but is willing to return for study visits they are not considered 
dropouts.  
 
•  Following Patients who fail prior to Phase I & Phase II (6 months): If 
patients are declared a treatment failure prior to Phase I or Phase II 6 
Months, every effort should be made to bring the patient back for the 6 
month visit. Note, that patients who are declared treatment failure, and are 
switching from Phase I to Phase II will already be followed.  


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Randomization to 
MTX or MMF 
Monthly: evaluation of efficacy, 
tolerability, and safety; steroid taper 
with adjustments 
At any time: 
serious adverse 
event 
Treatment 
failure 
At any time: 
clinician deems 
treatment futile 
Switch to alternate 
medication, Phase II 
At any time: 
intolerable side 
effects 
Dose reduction 
I 
Intolerable side 
effects persist 
Dose reduction 
II 
Intolerable side 
effects persist 
Switch to alternate 
medication, Phase II 
Side effects 
resolve 
Continue treatment 
per protocol 
Side effects 
resolve 
Continue treatment 
per protocol 
At six months: controlled 
inflammation* with 7.5 mg 
prednisone and ≤2 drops/day**? 
Yes, treatment 
success 
Continue treatment in 
Phase I, months 6-12 
At 12 months: controlled 
inflammation* with ≤7.5 mg 
prednisone and ≤2 
drops/day**? 
Yes: treatment 
success 
No: treatment 
failure 
No: switch to alternate 
medication, Phase II 
6 months later: controlled 
inflammation* with ≤7.5 mg 
prednisone and ≤2 
drops/day**? 
Yes: treatment 
success 
No: treatment 
failure 
*Criteria for controlled inflammation: Anterior chamber cells ≤0.5 +; Vitreous haze ≤ 0.5 +; No active choroid and retina lesions 
** 2 drops/day refers to topical 1% prednisolone acetate or equivalent 
2.5.4 Primary Endpoint Flowchart 




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All individuals handling methotrexate and mycophenolate, including study participants and/or 
family members/others caring for and assisting study participants with their medications outside of 
the hospital/clinic, will be educated on the Safe Handling of Hazardous Medications guidelines 
outlined in the National Institute for Occupational Safety and Health manual, Preventing 
Occupational Exposures to Antineoplastic and Other Hazardous Drugs in Health Care Settings. 
  
The National Institute for Occupational Safety and Health manual can be found at: 
http://www.cdc.gov/niosh/docs/2004-165/pdfs/2004-165.pdf  
 
3.1.1. Methotrexate 
 
All methotrexate doses will be taken once per week in a divided dose, one dose taken in 
the morning and one in the evening. Patients on methotrexate will be instructed to take their 
medication with food. For the first two weeks, an introductory dose of 15 mg/week (7.5mg 
BID once a week) orally will be administered to assess tolerability. This means taking 3 pills 
in the morning and 3 pills in the evening once a week. Patients should be instructed at the 
Enrollment/Baseline visit to begin methotrexate on a day that is convenient for them, within 6 
days of enrollment. After two weeks, the dose will be increased to 25 mg/week (12.5mg BID) 
This means taking 5 pills in the morning and 5 pills in the evening once a week, until the end 
of follow-up or until treatment failure due to intolerability, adverse events, or of lack of 
efficacy. 
 
If there are tolerability issues in the first two weeks such that the patient is not able to 
increase the dose, and unwilling to continue the current dose, treatment failure due to 
intolerability should be declared. The patient would then be eligible to switch treatment in 
Phase II. If this occurs in Phase II, treatment failure would be declared and patient will be 
treated according to best medical judgment. If the dose is increased per protocol at two 
weeks, the study ophthalmologist can decide to reduce the maintenance dose if the patient 
experiences severe side effects.  
 
 
 
3.1.1.a. Dose Reduction MTX 
 
If the patient is experiencing intolerable side effects, the study coordinator and 
patient will speak to the doctor about the possibility of a dose reduction, without 
revealing the name of the medication or the dosing instructions. The study doctor 
will then decide if the dose reduction should be done and inform the study 
coordinator and patient. The study coordinator will then provide the patient with 
new dosing instructions, away from sight of study physician. A dose reduction is 
not mandatory but is encouraged in the setting of intolerability.  
 
For the first dose reduction, methotrexate will be reduced to 20 mg/week (10mg 
BID, once a week). This means taking 4 pills in the morning and 4 pills in the 
evening once a week. If side effects persist and the study ophthalmologist wishes 
to reduce the dose a second time, the dose will be reduced to 15mg/week (7.5mg 
BID, once a week). This means taking 3 pills in the morning and 3 pills in the 
evening, once a week. After the second dose reduction, treatment can be stopped 
if intolerability persists and the patient can switch to Phase II.  
 
Although dose reductions are strongly encouraged, they are not mandatory to 
attempt before determining treatment failure. Treatment failure due to 
intolerability can be declared without trial of a dose reduction.  


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If a dose reduction has been utilized, and the investigator feels that the 
tolerability/safety issues have been resolved, it is at their discretion to return the 
patient to the maintenance dose level of the medication.  
 
3.1.2. Mycophenolate Mofetil 
 
Mycophenolate mofetil will be taken twice daily. Patients on mycophenolate mofetil will be 
instructed to take their medication on an empty stomach with no food one hour before or 
after taking each dose. For the first two weeks, an introductory dose of 500 mg BID orally will 
be administered to assess tolerability. This means taking one pill in the morning and one pill 
in the evening. After two weeks, the dose will be increased to 1.5 g BID. This means taking 3 
pills in the morning and 3 pills in the evening until the end of follow-up or until treatment 
failure due to intolerability, adverse events, or lack of efficacy.  
 
If there are tolerability issues in the first two weeks such that the patient is not able to 
increase the dose, and also is unwilling to continue, treatment failure due to intolerability 
should be declared. The patient would then be eligible to switch treatment in Phase II. If this 
occurs in Phase II, treatment failure would be declared. If the dose is increased per protocol 
at two weeks, the study ophthalmologist can decide to reduce the maintenance dose if the 
patient experiences severe side effects.  
 
At any point if treatment failure is declared due to tolerability, the patient should be treated 
according to best medical judgment and still be followed up to their 6th month assessment 
(Phase I and Phase II).  
 
 
 
3.1.2.a. Dose Reduction Mycophenolate Mofetil 
 
If the patient is experiencing intolerable side effects, the study coordinator and 
patient will speak to the doctor about the possibility of a dose reduction, without 
revealing the name of the medication or the dosing instructions. The study doctor 
will then decide if the dose reduction should be done and inform the study 
coordinator and patient. The study coordinator will then provide the patient with 
new dosing instructions, away from sight of study physician. A dose reduction is 
not mandatory but is encouraged in the setting of intolerability.  
 
For the first dose reduction, mycophenolate will be reduced to 1g BID. This means 
taking 2 pills in the morning and 2 pills in the evening.  If side effects persist and 
the study ophthalmologist wishes to reduce the dose a second time, the dose will 
be reduced to 500 mg BID. This means taking 1 pill in the morning and 1 pill in the 
evening. After the second dose reduction, treatment can be stopped if intolerability 
persists and the patient can switch to Phase II.  
 
Although dose reductions are strongly encouraged, they are not mandatory to 
attempt before determining treatment failure. Treatment failure due to 
intolerability can be declared without trial of a dose reduction.  
 
If a dose reduction has been utilized, and the investigator feels that the 
tolerability/safety issues have been resolved, it is at their discretion to return the 
patient to the maintenance dose level of the medication.  
 
 




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If at any time the patient fails to bring in their used maintenance bottles, the study coordinator 
should refer to the clinic staff member responsible for maintaining the randomization list to verify 
patient assignment. This will ensure that the patient is given the correct maintenance bottle 
corresponding to their assignment.  
 
3.1.5. Adherence to the treatment plan 
 
Patients will be given a treatment diary in the form of a monthly calendar on which they will be 
asked to record the medications they are taking as well as reasons for missed doses. They will be 
asked to bring the calendars with them to each visit. Adherence will be monitored by the study 
coordinator through review of the calendars, and will be recorded on the Medication Log in each 
patient file. Pill counting of pills in bottles remaining from the previous study period will also be 
done for a more objective measure of adherence. If a patient has just started on a new bottle 
shortly before the visit, do not count these pills. For instance, if a patient returns for their two week 
visit two weeks plus two days after the baseline visit, the study coordinator will not count the pills 
remaining in the maintenance dose bottle they have just started on. If the patient fails to bring in 
their calendar, the study coordinator should ask the patient to estimate the number of doses they 
have missed.  
 
3.1.5.a. Missed Doses  
 
The following instructions will be given to the patients if they miss scheduled 
doses of their medication: 
 
Methotrexate: If a patient misses their scheduled dose, they may take it the next 
day. If it is not taken the next day, they should wait until the following week. If  
patients make-up their dose on the next day, they should continue their  
medication weekly from the original day.   
 
Mycophenolate Mofetil: If the patient misses a dose, they should continue with 
the regular dosing schedule. 
 
3.2. Corticosteroid therapy 
 
3.2.1. Oral prednisone 
 
Prednisone vs. alternative oral corticosteroid 
 
Unless contraindicated, oral prednisone should be used. An equivalent dose of an alternative oral 
corticosteroid may be used only if a specific contraindication to oral prednisone is present. All 
references to oral corticosteroid and specific dosing schedules presented in this Manual of 
Procedures are given for oral prednisone. 
 
Initial dose 
 
All patients enrolled in the study will be initially taking concomitant oral corticosteroids at 1 mg/kg 
or 60 mg daily, whichever is less. Treatment success is dependent upon successfully tapering 
concomitant prednisone to 7.5 mg/day. Initial corticosteroid dose will be continued for 2 to 4 
weeks at which point prednisone will be gradually tapered.1 Prednisone will be tapered to and held 
at 7.5 mg/day for the first 6 months of the study. Further reduction of corticosteroids will be 
allowed in Phase I after six months. If patients switch treatments and enter Phase II due to a 
failure of efficacy in Phase I, they will follow the same protocol as the initial Phase I corticosteroid 






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3.2.2. Supplements 
 
All patients will be given recommendations for supplemental treatment. This treatment is 
important for patients receiving oral corticosteroids, in order to minimize the incidence of 
osteoporosis. Recommendations will include:  
• 
Calcium supplement, 500 mg 3 times daily (unless contraindicated)  
• 
Vitamin D, 400-800 IU daily. 
 
3.2.3. Topical corticosteroid 
 
 
In addition to oral prednisone, patients may enter the study on varying doses of topical 
corticosteroid drops. Topical corticosteroids should be tapered according to the suggested 
guidelines (Table 8). Various types of topical corticosteroids are acceptable. The chronic 
use of two times a day prednisolone acetate 1% was considered to be medically acceptable 
in a survey we conducted of the American Uveitis Society members. Thus, a dose of ≤ 2 
drops a day prednisolone acetate 1% or equivalent corticosteroid will be considered 
sufficient in order to declare treatment success. If possible, the goal will be to completely 
taper off topical corticosteroids. In order to determine treatment success or failure, the 
equivalent amount of prednisolone acetate 1% would have to be determined, and if greater 
than 2 times a day treatment failure will be declared. 
         Table 8: Suggested tapering schedule for topical corticosteroid drops 
 
Dose 
            Duration (weeks)  
1 drop, 8-10 times a day                 1-2 
1 drop, 6 times a day  
1 
1 drop, 4 times a day 
1 
1 drop, 3 times a day  
1 
1 drop, 2 times a day 
1 
1 drop, 1 time a day  
1 
None 
 
 
3.2.4. Periocular and Intravitreal Injections 
 
The use of periocular and intravitreal injections during the trial is strongly discouraged, as it 
hinders the ability to assess the study drugs’ effectiveness for controlling inflammation. One 
injection, either periocular triamcinolone 40mg or intravitreal triamcinolone 4mg, may be 
administered to treat persistent macular edema during the first 90 days of follow-up if the 
investigator thinks this is medically necessary. One injection for persistent macular edema 
is permitted in the first 90 days of follow-up of Phase I, and similarly, one injection treating 
persistent macular edema is permitted in the first 90 days of follow-up of Phase II. If an 
injection is given at any time solely for the purpose of treating inflammation, a Protocol 
Deviation Form should be completed and sent to the Medical Monitor 
(
), Principal Investigator (
), and 
Coordinating Center Manager (
).  If an injection is given for any reason 
after the first 90 days of follow-up of either Phase I or Phase II, a Protocol Deviation Form 
should be completed and sent to the Medical Monitor, Principal Investigator, and 


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Coordinating Center Manager.  
 
 
3.2.5 Other adjunctive treatments/procedures 
 
The protocol dictates use of oral prednisone, corticosteroid drops and study medication 
(methotrexate or mycophenolate). The investigator may use other topical adjunctive 
medications such as IOP lowering medications and cycloplegic agents. These should be 
recorded on the Treatment Assessment form at each visit. The protocol does not allow for 
intravenous therapy, additional immunosuppressives or surgery during the study period. If 
such therapies are deemed necessary, the Protocol Deviation form should be completed 
and sent to the Medical Monitor, Principal Investigator, and Coordinating Center Manager.  
3.3. Study procedures  
 
Enrollment/Baseline visit  
 
Study coordinators should adhere to the following protocol for study procedures taking place at the 
enrollment visit.  
 
• 
The patient’s eligibility for participating in the study will be determined by the 
study ophthalmologist, aided by the study coordinator. 
• 
If eligible, the patient will review the consent form with the study coordinator and 
the study physician, and give their consent.  
• 
After consent, the study coordinator will assign the patient a unique Patient ID 
(derived from the list provided to study coordinator by the principal statistician).  
• 
The study coordinator will then contact the designated person on site, holding 
the randomization list, to obtain the patient’s drug assignment. This will be done 
away from sight of the study physician.  
• 
The study coordinator will then label the medication with the assigned Patient 
ID. They should also place the appropriate number for the bottles (i.e. if it is the 
first bottle dispensed, it should have the #1 on the bottle).   
 
Study visits  
 
Study coordinators should adhere to the following protocol for study procedures taking place, after 
the patient is consented, enrolled and randomized. All study procedures should follow the schedule 
listed below:   
 
• 
The patient comes for a study visit and meets with the study coordinator before 
their study doctor.  
• 
The patient’s medication bottle and folic acid bottle (if applicable) is immediately 
placed in a secure, opaque bag and left at the study coordinators desk for the 
remainder of the visit. Patient medication calendars should also be placed in the 
opaque bag.  
• 
The study coordinator will check-in with the patient and complete the following 
in any order:  
o Review of patient medication diaries 
o Review of adverse events since last visit*  
o Dispense new medication bottle (if applicable) 
o Completion of SF-36 questionnaire (All patients) (if applicable) 






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Patients will be given 2 weeks to enter into Phase II after treatment failure in Phase I. If patients 
do not enter within the 2-week window, they should be treated according to best medical judgment 
of their physician. If the physician believes a patient would benefit from treatment in Phase II, but 
there is an exceptional circumstance preventing the patient from entering Phase II within the 2-
week window, contact the Coordinating Center for assistance. 
 
Guidelines for Visit Schedule II 
 
• 
Day 1 corresponds to the Baseline-II visit, which is also the first day the patient 
receives rescue treatment with the medication not initially received. Day 1 may 
be its own visit date (i.e. if within 2 weeks of the end of Phase I). Alternatively 
Day 1 may be the same day as the last day of Phase I. All study forms should 
indicate what visit it is for Phase I and what visit it is for Phase II, if applicable. 
See the following example below.  
 
Phase 
  ☒1          ☒ 2 
 
 
 
Visit 
☒ Baseline 
☐ Two weeks 
☐ Non-study visit (treatment failure only) 
 
 
 
Month:  
☐ 1 
☐ 
2 
☐ 3 
☐ 
4 
☐ 
5 
☒ 
6 
☐ 9 
☐ 12 
 
• 
Visit dates are determined based on the date of the Baseline-II visit (which may 
be the same date as Phase I treatment failure), and may not be changed. 
• 
The Baseline-II visit form should be completed to gather information on any 
changes in health status or medications.  
• 
There should be a minimum of 2 weeks between each study visit. 
• 
Data for the follow-up visits may be collected anytime within the visit window.  
  
4.1.3. Non-study visits 
 
Despite the regular follow-up outlined in the visit schedules above, it is anticipated that some 
patients will have inflammation that is difficult to control or be intolerant to the drug, leading to 
additional visits. These additional visits may not fall within the study visit window. It is possible that 
the circumstances leading to such visits may result in changes to oral or topical corticosteroid 
dose, or a declaration of treatment failure and a need for rescue treatment. If treatment failure is 
declared at a non-study visit, all of the forms required at the time treatment failure is declared 
should be completed.  
 
Guidelines for non-study visits 
 
• 
Any changes to oral or topical corticosteroid dose will be noted on the appropriate form 
during the next scheduled study visit. 
• 
If a treatment failure is declared at a non-study visit during follow-up while being treated 
during…  
• 
Phase I (initial randomized treatment): Record a treatment failure using 
Treatment Assessment Form. Perform Baseline II visit at this time or within 14 
days. Phase II rescue treatment can start immediately.  
• 
Phase II: Record a treatment failure using the Treatment Assessment Form. 
Patient should continue to be followed until 6 months and 6th month data collected.     
• 
If treatment failure is declared at a non-study visit, an attempt should be made to 
collect as much information as possible, including the forms listed in Section 4.2. 




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   4.3. Phase I Enrollment/Baseline visit 
 
The Phase I Enrollment/Baseline visit should occur after the patient has been screened and 
determined to be eligible for the study. Screening is a process that should occur before or on 
the date of the patient’s Enrollment/Baseline visit. The baseline eye exam and other baseline 
assessments may be collected at a separate visit up to 14 days before the patient is enrolled 
and randomized,  with  the  exception  of  laboratory measurements which may be collected 
within 4 weeks or 90 days prior to or on the date of randomization (depending on the test). 
 
Many patients will still have active enough inflammation at the time of enrollment to meet 
criteria (≥1+ AC cells, ≥1+ vitreous haze by NEI scale, or active retinal/choroidal 
inflammation).  However, some patients may have had active inflammation when screened 
(within 14 days prior to enrollment) but at the time of enrollment, the inflammation is 
improved because of steroid treatment. As long as the inflammation met inclusion criteria 
within this 14 day period, those values can be used for the baseline exam (enrollment exam).  
If there is a patient whom you think is very likely to be enrolled in the next 14 days but you 
are still waiting for some screening labs, it is fine to go ahead and consent and obtain the 
baseline study assessments (eye exam with secondary grader using both NEI and Miami 
scales for vitreous haze, fundus photos, OCT, questionnaires, etc.), as long as you do not 
randomize.  Randomization can only occur once all eligibility criteria have been verified. The 
inflammation recorded on the baseline Clinical Eye Exam form needs to meet inflammation 
eligibility criteria. 
 
4.3.1. Consent and eligibility evaluation 
 
 
Procedures for obtaining consent include explaining the patient’s disease, prognosis, and 
treatment options, discussing the risks and benefits of participation, and addressing the 
patient’s questions and concerns. After explaining the nature of the study and the rights 
and responsibilities of the patient, the ophthalmologist and/or the study coordinator will 
obtain written consent from the subject, or written minor assent and parental consent if 
applicable. The subject is assured that participation in this study is voluntary and he/she 
can withdraw at any time if he/she feels uncomfortable. 
 
The eligibility evaluation will be performed using the Eligibility Form, which is to be filled 
out at the Baseline-I visit. For detailed inclusion/exclusion criteria please see Section 2.3.  
 
There is not a mandated separate visit for eligibility screening.  If the patient fulfills all 
eligibility and exclusion criteria on a visit, he/she may sign the consent form and be 
randomized at the beginning of the official Baseline-I visit. Note that this requires that 
the patient have laboratory results that are current according to inclusion criteria 
guidelines. 
 
In some cases, partial eligibility will be confirmed on a screening visit but more 
information may be needed (such as laboratory confirmation of acceptable values of 
the CBC, AST, ALT and creatinine). If and when the laboratory results meet eligibility 
criteria, the patient will then be asked to complete a consent form, followed by 
randomization and the official Baseline-I visit. All other criteria must be met at the time the 
consent form is signed and randomization occurs (except the active inflammation criteria 
which must be met within 14 days prior to randomization). 
  
 
 


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4.3.2.   Randomization 
 
Randomization treatment assignment takes place during the Baseline-I visit after 
eligibility has been determined and the consent forms have been signed by the patient. 
In some cases randomization can occur on the same day that patient is screened for 
enrollment, if the patient signs the consent form on that day. If the patient wishes to 
come back at a later time to sign the consent forms, randomization will occur on the 
date they return. If a patient returns to sign the consent and enroll on a different date 
to his or her screening visit, he or she must have had the relevant laboratory tests 
within 4 weeks prior to enrollment for trial eligibility. 
 
After obtaining the written consent, the study coordinator will assign the next 
identification number from the patient ID list. The coordinator will then log into the 
REDCap database to perform the randomization for the corresponding patient ID. The 
coordinator will take note of the treatment assigned by REDCap, dispense the assigned 
treatment to the patient, and review dosing instructions with the patient.  
 
 
4.3.3. Procedures for data collection 
 
Required study procedures include the following: 
• 
Medical and Treatment History 
• 
Clinical eye exam 
• 
Visual acuity exam 
• 
Optical Coherence Tomography (OCT) 
• 
Fundus photography 
• 
Laboratory measurements 
• 
Health-related quality of life questionnaire 
• 
Vision-related quality of life questionnaire(s) 
 
4.3.4. Specimens 
 
The following specimens will be collected for laboratory measurements within 4 weeks 
prior to enrollment: 
• 
Blood for complete blood count (CBC with differential, limited to percentages of  
 
neutrophils and lymphocytes) 
• 
Blood for CD4 at 
 sites only  
• 
Blood for serum chemistry panel (AST, ALT, creatinine)  
• 
Blood or urine pregnancy test (all female patients, excluding those that 
are post-menopausal) 
 
The following specimens will be collected for laboratory measurements within 90 days prior 
to enrollment: 
 
• 
Hepatitis B surface antigen (HBsAg) 
• 
Hepatitis C antibody 
• 
Tuberculin skin test 
• 
Interferon gamma release assay 
• 
Chest radiograph 
• 
Syphilis (RPR/VDRL/other non-specific) 
• 
Syphilis (FTA-ABS/MHATP/other specific) 


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4.3.5.  Forms for data collection 
 
 
The following forms will be filled out as part of the Baseline-I visit: 
• 
Patient Consent Forms 
• 
Eligibility/Screening Form 
• 
Baseline History Form 
• 
Clinical Eye Exam Form 
• 
Secondary Clinical Eye Exam Form 
• 
Right Eye Visual Acuity Form 
• 
Left Eye Visual Acuity Form 
• 
OCT Form 
• 
Fundus Photography Form 
• 
Laboratory Report Form 
• 
Quality of Life Questionnaire Forms 
• 
Treatment Assessment Form  
• 
Protocol Deviation Form (if applicable)  
 
4.4. Follow-up visits 
 
It is strongly encouraged for all follow up data to be collected within the study visit window, but 
should be collected regardless.  
 
All Phase II procedures and protocol are the same as Phase I. For Phase I patients who 
are continuing on the same medication, physicians can see the patients as often as they 
would like. However, for purposes of this study we will only be recording information at 
Month 9 and Month 12, or a non-study visit that leads to treatment failure.  
 
Laboratory test results will be collected monthly.  
 
4.4.1. Procedures for data collection 
 
 
Required study procedures include the following: 
• 
Clinical eye exam 
• 
Secondary Clinical eye exam* 
• 
Visual acuity exam 
• 
Optical Coherence Tomography 
• 
Fundus Photography* 
• 
Laboratory measurements 
• 
Quality of Life Questionnaire Forms* 
*Phase 1: treatment failure and 6 month visit (whichever is first), 12 month visit; Phase 2: 
treatment failure and 6 month visit.  
 
4.4.2. Specimens 
 
 
The following specimens will be collected for laboratory measurements: 
• 
Blood for complete blood count (CBC with differential, limited to percentages of  
 
neutrophils and lymphocytes) 
• 
Blood for CD4 at 
 sites only at Baseline, Month 3, 6, &12  
• 
Blood for serum chemistry panel (AST, ALT, creatinine) 
• 
Blood or urine pregnancy test (all female patients, excluding those that 
are post- menopausal) 


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4.4.3. Forms for data collection 
 
The following forms will be filled out as part of the follow-up visits: 
• 
Clinical Eye Exam Form 
• 
Secondary Clinical Eye Exam Form* 
• 
Right Eye Visual Acuity Form 
• 
Left Eye Visual Acuity Form 
• 
OCT Form 
• 
Fundus Photography Form* 
• 
Laboratory Report Form 
• 
Adverse Event Checklist 
• 
Medication Log  
• 
Patient Medication Calendar (to be completed by the patient)  
• 
Treatment Assessment Form 
• 
Adverse Event Log (update if necessary) 
• 
Quality of Life Questionnaire Forms * 
• 
Serious Adverse Event Narrative Form (if applicable) 
• 
Patient Dropout Form (if applicable) 
• 
Protocol Deviation Form (if applicable) 
 
*Phase 1: baseline, treatment failure and 6 month visit, 12 month visit; Phase 2: treatment 
failure and 6 month visit; Treatment failure anytime (study or non-study visit)  
 
For follow-up visits, all the above procedures and forms should be completed for all 
patients, regardless of if they are taking the medication or compliant with study visits.  
 
4.5. Baseline Phase II  
 
This visit may occur on the same day as treatment failure in Phase I, if the patient proceeds 
directly to Phase II. If both visits occur on the same day, study coordinators will mark the 
Phase I visit and Phase II visit at the same time on the case report forms. However, patients 
have up to two weeks to come back to clinic and begin Phase II after treatment failure in Phase 
I. In this case, complete the Baseline Phase II form packet on the date Baseline II starts. 
 
4.5.1. Eligibility 
 
 
In Phase I, if failure is due to efficacy or tolerability or for selected cases for safety (if deemed 
safe by the Medical Monitor), the patient will be considered as eligible for Phase II of the 
study. If there is a serious adverse event in Phase I, deemed to be related to the study drug 
by the Medical Monitor, the patient will be declared a treatment failure. The Medical Monitor 
will determine if it is safe for the patient to enter Phase II. If not, the patient should still be 
followed for 6 months.  
 
As in Phase I, there is no mandated separate visit for eligibility screening in Phase II. If the 
patient is declared a treatment failure in Phase I for any reason other than an SAE deemed 
to be related to the study drug (by the Medical Monitor), he/she may immediately proceed to 
Phase II. Any reason for eligibility failure for Phase II will be captured in the adverse event 
log of the last Phase I visit, thus there is no need to have a separate eligibility screening 
form.  
 
 


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4.6. Non-study visits 
 
Despite frequent study visits, some patients may need additional visits with their 
ophthalmologist according to standard of care that do not fall within study visit windows. 
Required data collection during these non-study visits is limited to adverse event reporting 
and declaration of treatment failure if it occurs. It is preferable that treatment failure is 
declared at a regularly scheduled study visit rather than a non-study visit, however if it is 
necessary the physician can decide to do so. 
 
4.6.1.   Study Procedures  
 
Every attempt should be made to obtain all study procedures at a non-study visit if 
treatment failure is being declared. However, if this is not possible the required study 
procedures include the following: 
• 
Clinical eye exam (if treatment failure is declared) 
 
4.6.2.   Specimens 
 
No specimens are required during non-study visits. 
 
 
4.6.3. Forms for data collection 
 
The following forms will be filled out at non-study visits only if treatment failure is declared. 
Every attempt should be made to acquire information for all other forms. However, if this is not 
possible, at the minimum the following must be completed:  
  
• 
Clinical Eye Exam Form 
• 
Treatment Assessment Form 
• 
Quality of Life  
• 
Medication Log  
• Adverse Event Checklist 
• Adverse Event Log (update if necessary) 
• Serious Adverse Event Narrative Form (if applicable) 
 
 
 


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5. Study examinations and procedures  
 
5.1. Quality of life questionnaire administration 
 
All patients will be asked to complete standard quality of life questionnaires related to 
overall health and visual function at baseline visits as well as at 6 months or treatment 
failure (whichever is first) in order to measure quality of life outcomes. Patients who 
experience treatment success with Phase I treatment and continue into Phase I (6-12 
months) also complete questionnaires at the 12-month visit, or earlier if treatment failure is 
declared. The following questionnaires will be administered: 
 
If treatment failure occurs prior to 6 months (Phase I and Phase II) questionnaires should also 
be collected at the time of treatment failure as well as 6 months.  
Health-related quality of life  
• SF-36 questionnaire (all patients) 
Vision-related quality of life 
•   NEI-VFQ-25 (all patients) 
•   IND-VFQ (Indian patients only) 
 
Given data suggesting that SF-36 scores vary by method of administration such that 
patients overstate their quality of life in clinic interviews, questionnaires will be self-
administered whenever possible at clinic appointments. Additionally the NEI-VFQ should 
be self-administered whenever possible. It is anticipated that some patients will not have 
adequate visual function to complete the questionnaires on their own, and some patients 
may also be illiterate. In such cases, the coordinator will read the questions aloud to the 
patient and record the patient’s answers on the appropriate questionnaire forms (Section 
A.13). It is very important that the questions are answered in their original form, so 
coordinators should never rephrase or interpret questions for the patient. 
 
 
5.2.A Refraction and visual acuity (PRIMARY – FOR LETTER VISION CHARTS) 
 
5.2.1.A   Refraction procedure 
 
Beginning Approximate Refraction 
The beginning approximate refraction should be obtained by performing retinoscopy or 
auto- refraction. One of these measurements is used as the beginning approximate 
refraction at each visit. 
 
Subjects who arrive for examination wearing contact lenses are asked to remove the 
lenses prior to refraction. The subject must wait for 30 minutes after removing the contact 
lenses before refraction can be performed. 
 
Refraction  may  be  initially  performed  at  distances  different  than  four  meters  (i.e. 
using a phoropter in a common refraction lane). However, if this is done, the spherical 
power refinement step must be repeated with lenses in place after the subject has been 
positioned at four meters for visual acuity testing. 
 


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The examiner will use Chart R (Precision Vision Chart Version 2110) for manifest 
refraction. Each eye is refracted at four meters unless the visual acuity measured at this 
distance on chart R is worse than 20/200 (defined as missing 2 or more letters on the top 
line, the 20/200 or 6/60 line).  This subject must then be moved to a distance of one meter 
from the study visual acuity chart, and refraction must be performed and recorded at this 
distance.  
 
 
Manifest Refraction 
In general, instructions are to ‘push plus’ and to add minus diopter corrections only if there 
is a demonstrated increase in visual acuity, i.e., the patient is able to read more letters.   
The steps are as follows: 
• 
Seat the subject 4 meters in front of the refraction chart; 
• 
Place and adjust the trial frame on the subject’s face so that the lens cells are 
parallel to the anterior plane of the orbit; 
• 
Adjust the pupillary distance of the trial frame to make sure that the lenses 
position in front of the centers of the pupils; 
• 
Adjust the lens cells for the proper distance from the cornea; 
• 
Occlude the eye not being refracted; 
• 
Insert spherical lens correction into the compartment closest to the eye; 
• 
Place cylindrical lens correction in the compartment in the front of the frame; 
• 
Set cylindrical lens to appropriate axis setting 
 
 
Please refer to the table below to ensure that proper lenses are used for the appropriate 
visual acuity level: 
 
Vision with  
Best 
Correction 
Sphere 
Cylinder 
Use correct Jackson Cross 
Cylinder as below 
Sphere Refinement 
 
Power 
Increment 
Axis 
Power 
Increment 
Power 
Increment 
20/10-20/80 
6/3-6/24 
 (4 meters) 
   +0.50 
   - 0.37 
   +0.50 
    +0.50 
    - 0.25 
    +0.50 
  0.50 
   0.25 
    +0.25 
     -0.25 
   +0.37 
    -0.37 
   +0.37 
    +0.25 
     -0.25 
    +0.25 
20/100-20/200 
6/30-6/60 
 (4 meters) 
+1.00 
 -1.00 
+1.00 
+1.00 
 -1.00 
+1.00 
1.00 
1.00 
+1.00 
 -1.00 
+0.50 
 -0.50 
+0.50 
+0.50 
 -0.50 
+0.50 
<20/200 
<6/60 
 (1 meter) 
+2.00 
 -2.00 
+2.00 
+2.00 
 -2.00 
+2.00 
1.00 
1.00 
+1.00 
 -1.00 
+1.00 
 -1.00 
+1.00 
+1.00 
 -1.00 
+1.00 
 
Examples for each visual acuity level are detailed below. 
 
 
For Patients with Visual Acuity of 20/10-20/80 (6/3-6/24): 
 
Determine Sphere Power 
 
• 
Ask patient to identify the smallest possible line that he/she can see on the Chart 
R; 
• 
With the subject looking at the smallest line legible on the visual acuity chart, 
place a +0.50 spherical lens in front of the eye being tested. Ask the subject, “Is 


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vision better, worse, or the same?” 
• 
If the subject responds that vision is made better or if there is no change, 
replace the spherical lens with one that is +0.50 more plus; 
• 
Continue to check with the +0.50 lens to see if the subject will accept more 
plus by repeating the step above; 
• 
When an additional +0.50 lens makes the subject’s vision worse, remove the +0.50 
lens  
• 
Then hold a -0.37 spherical lens over the eye; 
• 
If this -0.37 lens improves the subject’s vision, even by one letter, replace the 
spherical lens in the trial frame by one that is -0.25 more minus; 
• 
Remember, if the patient reports that the -0.37 lens makes the vision better but if 
s/he is unable to read more letters, do not change spherical lens by -0.25. 
• 
If the -0.37 spherical lens does not allow the patient to read more letters or if it 
makes the vision worse, recheck using the +0.50 lens 
• 
If the +0.50 lens makes vision better or the same, repeat above sequence 
• 
If the +0.50 lens makes vision worse, move on to cylindrical testing 
 
 
Determine and refine cylinder axis 
 
The following descriptions are for plus cylinders. Adjust accordingly for minus cylinder 
refraction. 
• 
Ask the subject to look at a letter on a line of Chart R which is one line larger 
than the smallest line he/she could read (one above threshold); 
• 
If no cylinder is present in the beginning approximate refraction, place the 
+/- 0.50 diopter cross-cylinder with the positive axis first at 90º and then at 180º, 
asking if either position makes the letter clearer; 
• 
If the patient prefers either one of these positions, place a +0.50 cylindrical lens 
in the trial frame aligned with the preferred axis; 
• 
If the patient did not prefer cylinder at axis 90° or 180°, position the cross 
cylinder with the positive axis first at 45° then 135°; 
• 
Ask if the patient prefers either of these positions; 
• 
If so, place a +0.50 cylinder lens in the trial frame aligned with the preferred axis; 
• 
If the subject prefers none of the four positions, no further cylinder testing is 
required; 
• 
If cylinder is present in the beginning approximate refraction or if you have 
added +0.50 cylinder power in the above step, position the +/- 0.50 diopter 
cross-cylinder first with the positive axis 45º to the right of the cylinder axis 
(position one), and secondly with the positive axis at 45º to the left of the cylinder 
axis (position two). Ask the subject which position improves vision (position one or 
position two?); 
• 
If the subject responds that neither position is better and if this was the first test 
of axis position, move the axis of the cylinder in the trial frame 15º to the right or 
left and repeat; 
• 
If the subject prefers one position to the other, rotate the cylinder toward the 
preferred positive axis of the cross-cylinder in the step sizes recommended (see 
Table below) and repeat. (If the subject states that one position of the cross-
cylinder is no better than the other position, proceed to refining cylinder power). 
 
 
 
 
 
 




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For Patients with Visual Acuity of 20/100-20/200 (6/30-6/60): 
 
 
Determine Sphere Power 
 
• 
Ask patient to identify the smallest possible line that he/she can see on the Chart 
R; 
• 
With the subject looking at the smallest line legible on the visual acuity chart, 
place a +1.00 spherical lens in front of the right eye.  Ask the subject, “Is vision 
better, worse, or no change?” 
• 
If the subject responds that vision is made better or is the same, replace the 
spherical lens with one that is +1.00 more plus; 
• 
Continue to check with the +1.00 lens to see if the subject will accept more 
plus by repeating the step above; 
• 
When an additional +1.00 lens makes the subject’s vision worse, remove the +1.00 
lens 
• 
Then hold a -1.00 spherical lens over the eye; 
• 
If this -1.00 lens improves the subject’s vision, even by one letter, replace the 
spherical lens in the trial frame by one that is -1.00 more minus; 
• 
Remember, if the patient reports that the -1.00 lens makes the vision better but if 
s/he is unable to read more letters, do not change spherical lens by -1.00. 
• 
If the -1.00 spherical lens does not allow the patient to read more letters or if it 
makes the vision worse, recheck using the +1.00 lens; recheck using +1.00 lens 
• 
If the +1.00 lens makes vision better or the same, repeat above sequence 
• 
If the +1.00 lens makes vision worse, move on to cylindrical testing; 
• 
NOTE: if visual acuity improves significantly during manifest refraction, the 
examiner may need to change to trial lenses that are specified for the new level 
of acuity for the remainder of the refraction. Please refer to the Trial Lens Guide 
above. 
 
 
 
Determine and refine cylinder axis 
 
The following descriptions are for plus cylinders. Adjust accordingly for minus cylinder 
refraction. 
• 
Ask the subject to look at a letter on a line of Chart R which is one line larger 
than the smallest line he/she could read (one above threshold); 
• 
If no cylinder is present in the beginning approximate refraction, place the 
+/- 1.00 diopter cross-cylinder with the positive axis first at 90º and then at 180º, 
asking if either position makes the letter clearer; 
• 
If the patient prefers either of these positions, place a +1.00 cylindrical lens in 
the trial frame at the preferred axis; 
• 
If the patient did not prefer cylinder at axis 90° or 180°, position the cross 
cylinder with the positive axis first at 45° then 135°; 
• 
Ask if the patient prefers either of these positions; 
• 
If so, place a +1.00 cylinder lens in the trial frame at the preferred axis; 
• 
If the subject prefers none of the four positions, no further cylinder testing is  
 
required; 
• 
If cylinder is present in the beginning approximate refraction or if you have 
added +1.00 cylinder power in the above step, position the +/- 1.00 diopter 
cross-cylinder first with the positive axis 45º to the right of the cylinder axis 
(position one), and secondly with the positive axis at 45º to the left of the cylinder 
axis (position two). Ask the subject which position improves the vision (position one 
or position two?); 




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same?” 
• 
If patient responds that vision is better or the same, repeat spherical refinement 
testing as detailed above; 
• 
If patient responds that vision is worse, refraction testing is complete. 
• 
Remember to always to end the refraction by checking with plus power. 
 
For Patients with Visual Acuity <20/200 (<6/60): 
 
 
Determine Sphere Power 
 
NOTE: If refraction cannot be performed at 4 meters, defined as missing 2 or more 
letters on the largest line, then the subject should be moved to 1 meter and the above 
refraction sequence followed. At 1 meter, a + 0.75 spherical lens is added to the 
beginning approximate refraction to adjust for the accommodative difference between 4 
and 1 meter. 
• 
Ask patient to identify the smallest possible line that he/she can see on the Chart 
R; 
• 
With the subject looking at the smallest line legible on the visual acuity chart, 
place a +2.00 spherical lens in front of the right eye.  Ask the subject, “Is it better, 
worse, or no change?” 
• 
If the subject responds that vision is made better or is the same, replace the 
spherical lens with one that is +2.00 more plus; 
• 
Continue to check with the +2.00 lens to see if the subject will accept more 
plus by repeating the step above; 
• 
When an additional +2.00 lens makes the subject’s vision worse, remove the +2.00 
lens 
• 
Then hold a -2.00 spherical lens over the eye; 
• 
If this -2.00 lens improves the subject’s vision, even by one letter, replace the 
spherical lens in the trial frame by one that is -2.00 more minus; 
• 
Remember, if the patient reports that the -2.00 lens makes the vision better but if 
s/he is unable to read more letters, do not change spherical lens by -2.00. 
• 
If the -2.00 spherical lens does not allow the patient to read more letters or if it 
makes the vision worse, retest using +2.00 lens;If the +2.00 lens makes vision 
better or the same, repeat above sequence; 
• 
If the +2.00 lens makes vision worse, move onto cylindrical testing; 
• 
NOTE: if visual acuity improves significantly during manifest refraction, the 
examiner may need to change to trial lenses that are specified for the new level 
of acuity for the remainder of the refraction. Please refer to the Trial Lens Guide 
above. 
 
 
 
Determine and refine cylinder axis 
 
The following descriptions are for plus cylinders. Adjust accordingly for minus cylinder 
refraction. 
• 
Ask the subject to look at a letter on a line of Chart R which is one line larger 
than the smallest line he/she could read (one above threshold); 
• 
If no cylinder is present in the beginning approximate refraction, place the 
+/- 1.00 diopter cross-cylinder with the positive axis first at 90º and then at 180º, 
asking if either position makes the letters clearer; 
• 
If the patient prefers either of these positions, place a +1.00 cylindrical lens in 
the trial frame at the preferred axis; 
• 
If the patient did not prefer cylinder at axis 90° or 180°, position the cross 






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Illumination 
 
The overhead room lights should be turned off during the visual acuity test.   The 
box itself provides sufficient illumination for the examiner to record the test results.  
Additional light can have an adverse effect such as glare.  With the box light off, not 
more than 15 foot-candles of light should fall on the center of the chart.  The visual 
acuity light box is equipped with two 20- watt fluorescent tubes. Because the 
illumination of fluorescent tubes diminishes by 5 percent during the first 100 hours and 
by another 5 percent during the next 2,000 hours, new tubes should be kept "on" for 
about 4 days (approximately 96 hours, does not have to be continuous) before use. All 
tubes should be replaced once a year. 
 
Each tube is partially covered by a 14-inch (35.6 cm) fenestrated sleeve, open in the 
back, which serves as a baffle to reduce illumination. Each sleeve should be centered 
on the tube such that an equal length of tube (about 4 and 3/16 inches or 10.6 cm) is left 
uncovered to the right and left of the sleeve. 
 
 
4- and 1-Meter Visual Acuity Lanes 
 
A distance of 4 meters (13 feet and 1.5 inches, or 157.5 inches) is required between the 
subject's eyes and the visual acuity chart for the 4-meter test, and a distance of 1 meter 
(39 and 3/8 inches) is required for the 1-meter test. The room for visual acuity testing 
must have, in addition to the 4- meter lane, space for the visual acuity box (and possibly a 
stand) and space for the subject. 
• 
Wall-mounted box: In addition to the 4-meter lane, 7 inches (17.8 cm) must be 
allowed for the depth of the box plus space for the subject to sit or stand. 
• 
 Stand-mounted box: In addition to the 4-meter lane, 13 inches (33 cm) must be 
allowed for two of the stand's casters to touch the rear wall (or a line marked on 
the floor when there is no wall) plus space for the subject to sit or stand. 
 
Marking the Distance 
 
4 Meters 
 
• 
If the chair and visual acuity box are permanently affixed, distance 
measurements need to be made only once and no floor marks are needed to 
ensure the correct distance. 
• 
If the box is mounted on the wall but the subject's chair is not permanently affixed, 
the 4- meter distance of the subject's eye from the chart must be marked clearly 
and permanently. 
• 
If the box is mounted on a movable stand, the 4-meter distance must be 
marked clearly and permanently. The location and orientation of the box must be 
rechecked each time a new chart is put in place or the box is touched.  When the 
stand touches the rear wall of the room, two of the five casters should touch the 
wall. 
 
 
1 Meter 
 
• 
The 1-meter distance is measured from the eye of the subject, who is seated 
comfortably in a chair with his or her back firmly placed against the chair's back, 
to the center of the second (for testing the left eye) or fourth letter (for testing the 
right eye) of the third line of the chart.  A stick, one meter long, should be used 
to confirm the distance for each subject. 


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Visual Acuity Procedure 
 
• 
Visual acuity will be measured at each study visit. 
• 
Visual acuity should be measured for each eye AFTER refraction.  Visual acuity 
should NOT be recorded during the refraction procedure. 
• 
It is very important that the examiner is not aware of the patient’s clinical 
records, in order to minimize bias.  Therefore, the visual acuity examiner will not 
have access to the patient’s previous clinical examination or treatment results. 
• 
Visual acuity is tested separately for each eye (one eye at a time).  The patient’s 
untested eye will be completely covered with a patch, to block out all light from 
entering this eye. The examiner must constantly ensure that this eye remains 
occluded at all times. 
• 
The patient is instructed to read each letter on the chart starting with the largest 
line, at the 4-meter distance, and is encouraged to read as many letters as 
possible. 
• 
If the patient cannot identify a letter, they are encouraged to guess. Only one 
response is allowed per letter. 
• 
The examiner must ensure that the patient does not squint (creating a pin-hole 
effect) or lean forward (reducing the distance to the chart). 
• 
Once a patient has given a response for a letter and has moved on to provide a 
response for the next letter, any corrections of previous response will not be 
accepted. 
• 
However, if the patient has given a response for a letter and has not yet 
moved on to provide a response for the next letter, a correction of the previous 
response is accepted. 
• 
If the subject gives two possible responses for a letter, tell the patient to commit 
to one answer.  The examiner CANNOT, at any time, give the patient any 
indication as to whether a response is correct or incorrect. 
• 
In the case that the patient reads less than 20 letters at 4 meters, move the 
patient or the chart so that there is a distance between the two of 1 meter. 
• 
Visual acuity will then be retested at this 1 meter distance. 
• 
Only the first 6 rows of letters need to be read at 1 meter. 
• 
If no letters are read at 1 meter, then the examiner must proceed to Low Vision 
Testing (see below), starting with Count Fingers testing.   If the patient does not 
adequately Count Fingers, proceed to  Hand  Motion. If the patient does not 
adequately recognize Hand Motion, then proceed to Light Perception. 
 
Testing of Count Fingers Vision 
 
In testing for count fingers vision, the examiner’s hand presenting 1, 2, or 5 fingers is held 
steady at a distance of 1 meter directly in front of the eye being examined. The fellow 
eye is completely occluded with a patch.   Refractive correction should not be used.   
A light should be shown directly  on  the  hand  from  behind  the  subject  and  room  
lights  should  be  turned  on.    The examiner’s fingers should be presented in random 
order and repeated 5 times.  Eccentric viewing should be encouraged.   If the subject 
correctly identifies three of the five presentations, then count fingers visions is noted. If 
not, then the subject must be tested for hand motion vision. 
 
 
 
Testing of Hand Motion Vision 
 
The examiner’s hand with all fingers spread out should be extended ½ meter directly in 
front of the eye being examined.  The fellow eye should be occluded with a patch.  


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Refractive correction should not be used.  A light should be shone directly on the hand 
from behind the subject and room lights should be turned on.   The examiner’s hand 
should be moved in an up-and-down direction (vertically) or in a side-to-side direction 
(horizontally) at a constant speed of approximately one back and forth presentation per 
second.   The subject is instructed that the examiner’s hand will be presented and 
they will have to respond to the question: “What am I doing with my hand?” This 
should be repeated five times.  Four out of five correct responses indicate that hand 
motions visions is present.  If the subject does not correctly identify four out of five, then 
you must test for light perception. 
 
 
Testing for Light Perception 
 
The indirect ophthalmoscope is used as the light source for testing light perception.  
Room lights should be off.   The opposite eye must be completely patched.  No 
correction should be used. From a distance of ½ meter with the light source turned up 
to maximum intensity, the light from the indirect ophthalmoscope is directed into the 
subject’s eye four times.  The subject is asked to respond when the light is “on”.  Light 
Perception is recorded if the examiner is convinced the subject sees the light. 
Otherwise, the vision should be recorded as “No Light Perception”. 
 
 
Scoring Best Corrected Visual Acuity 
 
On the Visual Acuity Forms, the examiner will circle all letters read correctly.  Letters 
read incorrectly or not read at all will be left unmarked.   At the end of each row of 
letters, the examiner will write down the total number of letters read correctly on the line 
provided. If visual acuity was not tested at 1 meter, the examiner will indicate this on the 
form. 
 
After each measurement of visual acuity, the biostatistician will calculate the score for 
the visit.  
 
The Snellen equivalent, defined as the Snellen ratio corresponding to the most difficult 
line for which the subject read at least 4 of 5 letters correctly, will also be entered by the 
examiner on the 4-meter Visual Acuity Form (Section A.5). 
The data entry staff will enter the number correct on each row at 4 meters, and if 
applicable, 1 meter and low vision testing results (They will not enter which letters the 
examiner circled, i.e., which letters the patient identified correctly.). Coordinating center 
personnel will double check the data entered by the examiner and data entry staff.  
 
5.2.3.A    Visual acuity training and certification  
 
The goal of the certification process is to standardize methodology for refraction and 
visual acuity measurement.  All visual function examinations must be performed by 
study-certified technicians. The principal investigator at each site is responsible for 
ensuring that the appropriate personnel are identified, trained and certified. A qualified 
visual function examiner (SL) from the Clinical Coordinating Center (
) 
will certify the rooms and technicians at each site. 
 
Technicians are expected to perform the refraction and visual acuity tests on at least 
one and possibly more non-study subjects according to protocol requirements. The 
examiner will determine whether or not the candidate executes the study protocol 
accurately for each procedure. A checklist (Visual Acuity/Refraction Certification Form, 
Section B.1) containing required procedures will be used to facilitate this process. 
 


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Room certification will be performed and recorded (Room Certification Form, section 
B.2) to ensure that all study rooms meet illumination, equipment, and distance 
requirements. Logs should be kept to document dates of light box bulb replacement. 
 
Certification is valid for a period 18 months (± 2 months) from the date of 
certification. The process should begin as soon as possible, as technicians must be 
certified before the first study subject is seen. A minimum of two certified technicians 
are required at each site. The visual acuity measurement schedule may be found on 
the Study Forms Completion Schedule. 
 
5.2.B Refraction and visual acuity (PROTOCOL FOR TUMBLING E CHART) 
 
5.2.1.B   Refraction procedure 
 
Beginning Approximate Refraction 
The beginning approximate refraction should be obtained by performing retinoscopy or 
auto- refraction. One of these measurements is used as the beginning approximate 
refraction at each visit. 
Subjects who arrive for examination wearing contact lenses are asked to remove the 
lenses prior to refraction. The subject must wait for 30 minutes after removing the contact 
lenses before refraction can be performed. 
 
Refraction  may  be  initially  performed  at  distances  different  than  four  meters  (i.e. 
using a phoropter in a common refraction lane). However, if this is done, the spherical 
power refinement step must be repeated with lenses in place after the subject has been 
positioned at four meters for visual acuity testing. 
 
The examiner will use Chart R (Precision Vision Chart Version 2305b) for manifest 
refraction. Each eye is refracted at four meters unless the visual acuity measured at this 
distance on chart R is worse than 20/200 (defined as missing 2 or more letters on the top 
line, the 20/200 or 6/60 line).  This subject must then be moved to a distance of one meter 
from the study visual acuity chart, and refraction must be performed and recorded at this 
distance. Use of Visual Acuity Form R is optional but may be helpful in keeping track of 
patient’s acuity level. 
 
 
Manifest Refraction 
In general, instructions are to ‘push plus’ and to add minus diopter corrections only if there 
is a demonstrated increase in visual acuity, i.e., the patient is able to read more letters.   
The steps are as follows: 
• 
Seat the subject 4 meters in front of the refraction chart; 
• 
Place and adjust the trial frame on the subject’s face so that the lens cells are 
parallel to the anterior plane of the orbit; 
• 
Adjust the pupillary distance of the trial frame to make sure that the lenses 
position in front of the centers of the pupils; 
• 
Adjust the lens cells for the proper distance from the cornea; 
• 
Occlude the eye not being refracted; 
• 
Insert spherical lens correction into the compartment closest to the eye; 
• 
Place cylindrical lens correction in the compartment in the front of the frame; 
• 
Set cylindrical lens to appropriate axis setting 
 


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Please refer to the table below to ensure that proper lenses are used for the appropriate 
visual acuity level: 
Vision with  
Best 
Correction 
Sphere 
Cylinder 
Use correct Jackson Cross 
Cylinder as below 
Sphere Refinement 
 
Power 
Increment 
Axis 
Power 
Increment 
Power 
Increment 
6/3-6/24 
20/10-20/80 
(4 meters) 
+0.50 
-0.37 
+0.50 
+0.50 
-0.25 
+0.50 
0.50 
0.25 
+0.25 
-0.25 
+0.37 
-0.37 
+0.37 
+0.25 
-0.25 
+0.25 
6/30-6/60 
20/100-20/200 
(4 meters) 
+1.00 
-1.00 
+1.00 
+1.00 
-1.00 
+1.00 
1.00 
1.00 
+1.00 
-1.00 
+0.50 
-0.50 
+0.50 
+0.50 
-0.50 
+0.50 
<6/60 
<20/200 
(1 meter) 
+2.00 
-2.00 
+2.00 
+2.00 
-2.00 
+2.00 
1.00 
1.00 
+1.00 
-1.00 
+1.00 
-1.00 
+1.00 
+1.00 
-1.00 
+1.00 
 
 
Examples for each visual acuity level are detailed below. 
 
 
For Patients with Visual Acuity of 6/3-6/24 (20/10-20/80): 
 
Determine Sphere Power 
 
• 
Ask patient to identify the orientation of the tumbling “E”s on the smallest 
possible line that he/she can see on the Chart R; 
• 
With the subject looking at the smallest line legible on the visual acuity chart, 
place a +0.50 spherical lens in front of the eye being tested. Ask the subject, “Is 
vision better, worse, or the same?” 
• 
If the subject responds that vision is made better or if there is no change, 
replace the spherical lens with one that is +0.50 more plus; 
• 
Continue to check with the +0.50 lens to see if the subject will accept more 
plus by repeating the step above; 
• 
When an additional +0.50 lens makes the subject’s vision worse, remove the +0.50 
lens  
• 
Then hold a -0.37 spherical lens over the eye; 
• 
If this -0.37 lens improves the subject’s vision, even by one letter, replace the 
spherical lens in the trial frame by one that is -0.25 more minus;  
• 
Remember, if the patient reports that the -0.37 lens makes the vision better but if 
s/he is unable to read more letters, do not change spherical lens by -0.25. 
• 
If the -0.37 spherical lens does not allow the patient to read more letters or if it 
makes the vision worse, retest using the +0.50 lens; 
• 
If the +0.50 lens makes vision better or the same, repeat above sequence 
• 
If the +0.50 lens makes vision worse, move on to cylindrical testing 
 
 
Determine and refine cylinder axis 
 
The following descriptions are for plus cylinders. Adjust accordingly for minus cylinder 
refraction. 
• 
Ask the subject to look at a letter on a line of Chart R which is one line larger 
than the smallest line he/she could read (one above threshold); 
• 
If no cylinder is present in the beginning approximate refraction, place the 
+/- 0.50 diopter cross-cylinder with the positive axis first at 90º and then at 180º, 




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• 
With the subject looking at the smallest line legible on the visual acuity chart, 
place a +0.37 spherical lens in front of the eye being tested. Ask the subject, “Is 
vision better, worse, or the same?” 
• 
If the subject responds that vision is made better or if there is no change, 
replace the spherical lens with one that is +0.25 more plus; 
• 
Continue to check with the +0.37 lens to see if the subject will accept more 
plus by repeating the step above; 
• 
When an additional +0.37 lens makes the subject’s vision worse, remove the +0.37 
lens; 
• 
Then hold a -0.37 spherical lens over the eye; 
• 
If this -0.37 lens improves the subject’s vision, even by one letter, replace the 
spherical lens in the trial frame by one that is -0.25 more minus; 
• 
Continue presenting the -0.37 lens to see if there is any further improvement in 
vision; 
• 
When an additional -0.37 lens does not improve vision; 
• 
Present the +0.37 lens, again asking “if vision is better, worse or the same?” 
• 
If patient responds that vision is better or the same, repeat spherical refinement 
testing as detailed above; 
• 
If patient responds that vision is worse, testing is complete. 
• 
Remember to always to end the refraction by checking with plus lenses. 
 
For Patients with Visual Acuity of 6/30-6/60 (20/100-20/200): 
 
 
Determine Sphere Power 
 
• 
Ask patient to identify the orientation of the tumbling “E”s on the smallest 
possible line that he/she can see on the Chart R; 
• 
With the subject looking at the smallest line legible on the visual acuity chart, 
place a +1.00 spherical lens in front of the right eye.  Ask the subject, “Is vision 
better, worse, or no change?” 
• 
If the subject responds that vision is made better or is the same, replace the 
spherical lens with one that is +1.00 more plus; 
• 
Continue to check with the +1.00 lens to see if the subject will accept more 
plus by repeating the step above; 
• 
If an additional +1.00 lens makes the subject’s vision worse, remove the +1.00 lens 
• 
Then hold a -1.00 spherical lens over the eye; 
• 
If this -1.00 lens improves the subject’s vision, even by one letter, replace the 
spherical lens in the trial frame by one that is -1.00 more minus; 
• 
Remember, if the patient reports that the -1.00 lens makes the vision better but if 
s/he is unable to read more letters, do not change spherical lens by -1.00. 
• 
If the -1.00 spherical lens does not allow the patient to read more letters or if it 
makes the vision worse, retest using the +0.50 lens; 
• 
If the +1.00 lens makes vision better or the same, repeat above sequence; 
• 
If the +1.00 lens makes vision worse, move on to cylindrical testing; 
• 
NOTE: if visual acuity improves significantly during manifest refraction, the 
examiner may need to change to trial lenses that are specified for the new level 
of acuity for the remainder of the refraction. Please refer to the Trial Lens Guide 
above. 
 
Determine and refine cylinder axis 
 
The following descriptions are for plus cylinders. Adjust accordingly for minus cylinder 
refraction. 
• 
Ask the subject to look at a letter on a line of Chart R which is one line larger 




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Spherical refinement 
 
End the refraction by performing the spherical refinement step. 
• With the subject looking at the smallest line legible on the visual acuity chart, 
place a +0.50 spherical lens in front of the eye being tested. Ask the subject, “Is 
vision better, worse, or the same?” 
• 
If the subject responds that vision is made better or if there is no change, 
replace the spherical lens with one that is +0.50 more plus; 
• 
Continue to check with the +0.50 lens to see if the subject will accept more 
plus by repeating the step above; 
• 
When an additional +0.50 lens makes the subject’s vision worse, remove the +0.50 
lens 
• 
Then hold a -0.50 spherical lens over the eye; 
• 
If this -0.50 lens improves the subject’s vision, even by one letter, replace the 
spherical lens in the trial frame by one that is -0.50 more minus; 
• 
Continue presenting the -0.50 lens to see if there is further improvement in vision; 
• 
When an additional -0.50 lens does not improve vision; 
• 
Show the patient the +0.50 lens, again asking “if vision is better, worse or the 
same?” 
• 
If patient responds that vision is better or the same, repeat spherical refinement 
testing as detailed above; 
• 
If patient responds that vision is worse, refraction testing is complete. 
• 
Remember to always to end the refraction by checking with plus power. 
 
For Patients with Visual Acuity < 6/60 (<20/200): 
 
Determine Sphere Power 
  
NOTE: If refraction cannot be performed at 4 meters, defined as missing 2 or more 
letters on the largest line, then the subject should be moved to 1 meter and the above 
refraction sequence followed. At 1 meter, a + 0.75 spherical lens is added to the 
beginning approximate refraction to adjust for the accommodative difference between 4 
and 1 meter. 
• 
Ask patient to identify the orientation of the tumbling “E”s on the smallest 
possible line that he/she can see on the Chart R; 
• 
With the subject looking at the smallest line legible on the visual acuity chart, 
place a +2.00 spherical lens in front of the right eye.  Ask the subject, “Is it better, 
worse, or no change?” 
• 
If the subject responds that vision is made better or is the same, replace the 
spherical lens with one that is +2.00 more plus; 
• 
Continue to check with the +2.00 lens to see if the subject will accept more 
plus by repeating the step above; 
• 
If an additional +2.00 lens makes the subject’s vision worse, remove the +2.00 lens 
• 
Then hold a -2.00 spherical lens over the eye; 
• 
If this -2.00 lens improves the subject’s vision, even by one letter, replace the 
spherical lens in the trial frame by one that is -2.00 more minus; 
• 
Remember, if the patient reports that the -2.00 lens makes the vision better but if 
s/he is unable to read more letters, do not change spherical lens by -2.00. 
• 
If the -2.00 spherical lens does not allow the patient to read more letters or if it 
makes the vision worse, retest using the +2.00 lens; 
• 
If the +2.00 lens makes vision better or the same, repeat above sequence; 
• 
If the +2.00 lens makes vision worse, move on to cylindrical testing; 






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measuring aided visual acuity of the left eye at all visits. Chart R will be used for 
obtaining all manifest subjective refractions. 
 
 
Visual Acuity Boxes 
 
The dimensions of the light box are 24 and 3/4 inches (62.9 cm) by 25 and 3/4 inches 
(65.4 cm) by 7 inches (17.8 cm).  The box can be mounted on a wall or on a cylindrical 
stand.  The stand is mounted on a five-pronged wheelbase, with each prong about 14 
inches (35.6 cm) long; two of the five wheels are lockable.  When the box is mounted 
on the stand, its height can be varied. The light box should be mounted at a height 
such that the top of the third row of letters (0.8 logMAR, 45 letters, 20/125 Snellen) is 
49 +/- 2 inches (124.5 +/-5.1 cm) from the floor.  The rear of the box provides storage 
space for the two charts not being used. 
 
 
Illumination 
 
The overhead room lights should be turned off during the visual acuity test.   The 
box itself provides sufficient illumination for the examiner to record the test results.  
Additional light can have an adverse effect such as glare.  With the box light off, not 
more than 15 foot-candles of light should fall on the center of the chart.  The visual 
acuity light box is equipped with two 20- watt fluorescent tubes. Because the 
illumination of fluorescent tubes diminishes by 5 percent during the first 100 hours and 
by another 5 percent during the next 2,000 hours, new tubes should be kept "on" for 
about 4 days (approximately 96 hours, does not have to be continuous) before use. All 
tubes should be replaced once a year. 
 
Each tube is partially covered by a 14-inch (35.6 cm) fenestrated sleeve, open in the 
back, which serves as a baffle to reduce illumination. Each sleeve should be centered 
on the tube such that an equal length of tube (about 4 and 3/16 inches or 10.6 cm) is left 
uncovered to the right and left of the sleeve. 
 
 
4- and 1-Meter Visual Acuity Lanes 
 
A distance of 4 meters (13 feet and 1.5 inches, or 157.5 inches) is required between the 
subject's eyes and the visual acuity chart for the 4-meter test, and a distance of 1 meter 
(39 and 3/8 inches) is required for the 1-meter test. The room for visual acuity testing 
must have, in addition to the 4- meter lane, space for the visual acuity box (and possibly a 
stand) and space for the subject. 
• 
Wall-mounted box: In addition to the 4-meter lane, 7 inches (17.8 cm) must be 
allowed for the depth of the box plus space for the subject to sit or stand. 
• 
 Stand-mounted box: In addition to the 4-meter lane, 13 inches (33 cm) must be 
allowed for two of the stand's casters to touch the rear wall (or a line marked on 
the floor when there is no wall) plus space for the subject to sit or stand. 
 
Marking the Distance 
 
4 Meters 
 
• 
If the chair and visual acuity box are permanently affixed, distance 
measurements need to be made only once and no floor marks are needed to 
ensure the correct distance. 
• 
If the box is mounted on the wall but the subject's chair is not permanently affixed, 
the 4- meter distance of the subject's eye from the chart must be marked clearly 
and permanently. 


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• 
If the box is mounted on a movable stand, the 4-meter distance must be 
marked clearly and permanently. The location and orientation of the box must be 
rechecked each time a new chart is put in place or the box is touched.  When the 
stand touches the rear wall of the room, two of the five casters should touch the 
wall. 
 
1 Meter 
 
• 
The 1-meter distance is measured from the eye of the subject, who is seated 
comfortably in a chair with his or her back firmly placed against the chair's back, 
to the center of the second (for testing the left eye) or fourth letter (for testing the 
right eye) of the third line of the chart.  A stick, one meter long, should be used 
to confirm the distance for each subject. 
 
 
Visual Acuity Procedure 
 
• 
Visual acuity will be measured at each study visit. 
• 
Visual acuity should be measured for each eye AFTER refraction.  Visual acuity 
should NOT be recorded during the refraction procedure. 
• 
It is very important that the examiner is not aware of the patient’s clinical 
records, in order to minimize bias.  Therefore, the visual acuity examiner will not 
have access to the patient’s previous clinical examination or treatment results. 
• 
Visual acuity is tested separately for each eye (one eye at a time).  The patient’s 
untested eye will be completely covered with a patch, to block out all light from 
entering this eye. The examiner must constantly ensure that this eye remains 
occluded at all times. 
• 
The patient is instructed to read each letter on the chart starting with the largest 
line, at the 4-meter distance. 
• 
The patient will show the orientation of the tumbling “E” with the hand that they 
are not using to occlude the untested eye.  If the patient cannot identify the 
orientation of a letter, they are encouraged to guess. Only one response is 
allowed per letter. 
• 
The examiner must ensure that the patient does not squint (creating a pin-hole 
effect) or lean forward (reducing the distance to the chart). 
• 
Once a patient has given a response for a letter and has moved on to provide a 
response for the next letter, any corrections of previous response will not be 
accepted. 
• 
However, if the patient has given a response for a letter and has not yet 
moved on to provide a response for the next letter, a correction of the previous 
response is accepted. 
• 
If the subject gives two possible responses for a letter, tell the patient to commit 
to one answer.  The examiner CANNOT, at any time, give the patient any 
indication as to whether a response is correct or incorrect. 
• 
If 3 or fewer letters are identified correctly on any row from Row 3 or below, 
STOP testing on that row. 
• 
In the case that the patient reads less than 10 letters at 4 meters, move the 
patient or the chart so that there is a distance between the two of 1 meter. 
• 
Visual acuity will then be retested at this 1 meter distance. 
• 
Only the first 6 rows of letters need to be read at 1 meter. 
• 
If less than 10 letters are read at 1 meter, then the examiner must proceed to 
Low Vision Testing, starting with Count Fingers testing.   If the patient does not 
adequately Count Fingers (see  below),  proceed  to  Hand  Motion. If the patient  
does  not  adequately recognize Hand Motion (see below), then proceed to Light 


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Perception. 
 
Testing of Count Fingers Vision 
 
In testing for count fingers vision, the examiner’s hand presenting 1, 2, or 5 fingers is held 
steady at a distance of 1 meter directly in front of the eye being examined. The fellow 
eye is completely occluded with a patch.   Refractive correction should not be used.   
A light should be shown directly  on  the  hand  from  behind  the  subject  and  room  
lights  should  be  turned  on.    The examiner’s fingers should be presented in random 
order and repeated 5 times.  Eccentric viewing should be encouraged.   If the subject 
correctly identifies three of the five presentations, then count fingers visions is noted. If 
not, then the subject must be tested for hand motion vision. 
 
 
Testing of Hand Motion Vision 
 
The examiner’s hand with all fingers spread out should be extended ½ meter directly in 
front of the eye being examined.  The fellow eye should be occluded with a patch.  
Refractive correction should not be used.  A light should be shone directly on the hand 
from behind the subject and room lights should be turned on.   The examiner’s hand 
should be moved in an up-and-down direction (vertically) or in a side-to-side direction 
(horizontally) at a constant speed of approximately one back and forth presentation per 
second.   The subject is instructed that the examiner’s hand will be presented and 
they will have to respond to the question: “What am I doing with my hand?” This 
should be repeated five times.  Four out of five correct responses indicate that hand 
motions visions is present.  If the subject does not correctly identify four out of five, then 
you must test for light perception. 
 
 
Testing for Light Perception 
 
The indirect ophthalmoscope is used as the light source for testing light perception.  
Room lights should be off.   The opposite eye must be completely patched.  No 
correction should be used. From a distance of ½ meter with the light source turned up 
to maximum intensity, the light from the indirect ophthalmoscope is directed into the 
subject’s eye four times.  The subject is asked to respond when the light is “on”.  Light 
Perception is recorded if the examiner is convinced the subject sees the light. 
Otherwise, the vision should be recorded as “No Light Perception”. 
 
 
 
Scoring Best Corrected Visual Acuity 
 
On the Visual Acuity Forms, the examiner will circle all letters read correctly.  Letters 
read incorrectly or not read at all will be left unmarked.   At the end of each row of 
letters, the examiner will write down the total number of letters read correctly on the line 
provided. If visual acuity was not tested at 1 meter, the examiner will indicate this on the 
form. 
 
After each measurement of visual acuity, the biostatistician will calculate the score for 
the visit. The visual acuity score is defined as follows: 
• 
If 10 or more letters of the first line are read correctly at 4 meters, the 4 meter 
visual acuity score is equal to the number of letters read correctly at 4 meters plus 
30. 
• 
If 3 or fewer letters of the largest line are read correctly at 4 meters, the visual 
acuity score is equal to the number of letters read correctly at 1 meter. 
• 
If 3 or fewer letters are read at 1 meter, then low vision testing must be 


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performed. (This result, count fingers, hand motion, light perception, or no light 
perception, will be used for  the  analysis  by  converting  into  a  logMAR  score  
according  to  Visual  Acuity Calculation Table). 
 
The highest attainable 4-meter visual acuity score is 100. 
The Snellen equivalent, defined as the Snellen ratio corresponding to the most difficult 
line for which the subject read at least 4 of 5 letters correctly, will also be entered by the 
examiner on the 4-meter Visual Acuity Form (Section A.5). 
The data entry staff will enter the number correct on each row at 4 meters, and if 
applicable, 1 meter and low vision testing results (They will not enter which letters the 
examiner circled, i.e., which letters the patient identified correctly.). Coordinating center 
personnel will double check the data entered by the examiner and data entry staff.  
 
5.2.3.B    Visual acuity training and certification  
 
The goal of the certification process is to standardize methodology for refraction and 
visual acuity measurement.  All visual function examinations must be performed by 
study-certified technicians. The principal investigator at each site is responsible for 
ensuring that the appropriate personnel are identified, trained and certified. A qualified 
visual function examiner (SL) from the Clinical Coordinating Center 
 
will certify the rooms and technicians at each site. 
 
Technicians are expected to perform the refraction and visual acuity tests on at least 
one and possibly more non-study subjects according to protocol requirements. The 
examiner will determine whether or not the candidate executes the study protocol 
accurately for each procedure. A checklist (Visual Acuity/Refraction Certification Form, 
Section B.1) containing required procedures will be used to facilitate this process. 
 
Room certification will be performed and recorded (Room Certification Form, section 
B.2) to ensure that all study rooms meet illumination, equipment, and distance 
requirements. Logs should be kept to document dates of light box bulb replacement. 
 
Certification is valid for a period 18 months (± 2 months) from the date of 
certification. The process should begin as soon as possible, as technicians must be 
certified before the first study subject is seen. A minimum of two certified technicians 
are required at each site. The visual acuity measurement schedule may be found on 
the Study Forms Completion Schedule. 
 
5.3. Ophthalmic procedures 
 
5.3.1. Grading Cataracts 
 
The study ophthalmologist will grade cataracts at every clinical exam based on the Age-
Related Eye Disease Study (AREDS) clinical lens grading system (Chew et al., 2010). 
Pupils must be dilated maximally and lenses should be examined at the slit lamp for the 
presence and severity of three types of opacity: nuclear, cortical and posterior 
subcapsular. For each type of opacity, the examiner should compare the lens being 
examined with the AREDS 2008 Clinical lens opacity standard photographs, of increasing 
severity. In each series, “1” indicates clinical presence, “2” indicates clinical significance, 
and “3” indicates severe occurrence. Half grades may be given, for example if a nuclear 
opacity was thought to be half way between the first and second standard photographs, a 
decimalized grade of “1.5” could be assigned.  


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The study ophthalmologists will refer to laminated photos of the scale in real time when 
making the clinical assessment. If no cataract is present, he/she will indicate this on the 
clinical exam form.  
 
The following categories of severity are present for all types of opacity (nuclear, cortical 
and posterior subcapsular): <1, 1, 1.5, 2, 2.5, >3.  
 
 
 
*Clinical grading adapted from: Chew EY, KIM J, Sperduto RD et al. Evaluation of the Age-Related Eye Disease 
Study Clinical Lens Grading System AREDS Report No. 31. Ophthalmology 2010: 11; 2112-2119.   
 
5.3.2.   Grading inflammation 
 
Slit lamp examination and dilated funduscopic exam are important parts of our study:  
assessments of anterior chamber cells and vitreous haze will determine the patient’s course 
of treatment. All of our study physicians are fellowship-trained uveitis specialists who have 
participated in prior uveitis studies. 
 
The study ophthalmologist at each site will be required to perform an eye examination at 
each study visit. This examination should be similar to that performed in the routine care of 
uveitis patients. Several components will be assessed in detail per study protocol. The 
grading schemes to be used for these assessments are adapted from the Standardization of 
Uveitis Nomenclature (SUN) Working Group.2 
 
Anterior Chamber Cells 
SUN Working Group Grading Scheme for Anterior Chamber Cells 
Grade 
Cells in Field* 
0 
<1 
0.5+ 
1-5 
1+ 
6-15 
2+ 
16-25 
3+ 
26-50 
4+ 
>50 
*Field size is a 1mm by 1mm slit lamp beam. Grading should be done with the highest magnification and 
illumination and conducted in a completely dark room, prior to dilation. 


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Anterior Chamber Flare 
 
Anterior Chamber Flare will be assessed by slit lamp exam but will not be part of our study 
criteria for controlled inflammation. 
 
SUN Working Group Grading Scheme for Anterior Chamber Flare 
Grade 
Description 
0 
None 
1+ 
Faint 
2+ 
Moderate (iris and lens details clear) 
3+ 
Marked (iris and lens details hazy) 
4+ 
Intense (fibrin or plastic aqueous) 
        *Adapted from: Hogan MJ, Kimura SJ, Thygeson P. Signs and symptoms of uveitis: I. Anterior 
Uveitis. AM J Ophthal 1964;47:155-170; Grading should be conducted in a completely dark room  
 
Vitreous Cells 
 
There is currently no accepted standard for grading vitreous cells, which will not be part of 
our study criteria for controlled inflammation. However, we will collect this information using 
the grading scheme below, which is adapted from the 
: 
 
Grade 
Cells in Field* 
0 
No cells 
0.5+ 
0 to 5 cells 
1+ 
6-10 cells 
2+ 
11-20 cells 
3+ 
21-50 cells 
4+ 
>50 
*Field size is a 1mm by 0.5mm beam; Grading should be conducted in a completely dark room; These cells are 
graded by slit lamp exam after dilation.  
 
Vitreous Haze 
 
Vitreous haze will be assessed using an indirect ophthalmoscope set at mid-power and a 
20D lens. Fundus examination will be done with the last view being the area around the 
optic disc. The examiner should then compare this view to the photograph (Figure 1) and 
determine the level of vitreous haze. The National Eye Institute System for grading 
vitreous haze will be used for all primary and secondary outcome measures. Additionally, 
vitreous haze will be assessed separately on the 9-point grading scale recently published 
by Davis et al., known as the Miami scale. The examiner should compare the vitreous 
haze view with the Miami photograph. An exploratory analysis will correlate 
measurements from the NEI and Miami scales. Clinical measurements of vitreous haze 
will also be compared to objective assessments done by grading of fundus photos by the 
reading center.  
 
If the physician thinks that the grading of vitreous haze is affected by a significant media 
opacity (i.e. a dense/mature cataract) they should indicate on the Clinical Exam Form that 
they cannot make a reliable judgment of vitreous haze due to the opacity. 
 
 
 
 
 


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Figure 1: National Eye Institute system for grading vitreous haze 
 
Grade 
Description 
0 
Clear 
0.5+ 
Slight blurring of optic disc margin 
Normal striations and reflex of nerve fiber 
layer cannot be visualized 
1+ 
Opacities without obscuration of retinal details 
2+ 
Few opacities resulting in mild blurring of 
details of optic nerve and retinal vessels 
3+ 
Optic nerve head and retinal vessels 
significantly blurred but still visible 
4+ 
Dense opacity obscuring optic nerve head 
*Grading should be conducted in a completely dark room; From Nussenblatt et al.Standardization of vitreal 
inflammatory activity in intermediate and posterior uveitis.Ophthalmology1985;92:467-471. 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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Figure 2: Miami 9-point system for grading vitreous haze 
 
 
 
               
 
Miami Scale for photographic grading of vitreous haze in uveitis. Am J    
                
 
Ophth;150:637-641 e1. 
 
Grading Retinal/Choroidal Inflammation  
 
Assessment of active inflammation of the retina and choroid should be based on the 
clinical exam and ancillary testing if needed for certain diseases (i.e. fluorescein 
angiogram, fundus photography, B-scan ultrasound). Please refer to the table in 
Appendix F for imaging required for assessing uveitis activity by disease. 
Active vasculitis posterior to the equator qualifies as active inflammation, but according to 
SUN criteria should be confirmed with a fluorescein angiogram. Macular edema in 
isolation is not sufficient to qualify as active inflammation, but a bullous serous retinal 
detachment, with any amount of accompanying vitreous, retinal or choroidal inflammation 
would qualify as an active inflammation. In addition, per protocol, if patients have ≥1+ 
anterior chamber inflammation, vitreous haze and/or other retinal/choroidal lesions aside 
from macular edema, that would qualify as active as well.  
 
5.3.3.   Inter-observer variation of ocular inflammation 
 
At Baseline (Phase I and Phase II) the 6th month study visit (Phase I and Phase II), the 12th 
month study visit (Phase I), or at treatment failure (whichever is earlier), inter-observer 
agreement on slit lamp observations and funduscopic exam will be assessed.  Coordinators 
will arrange for two certified study physicians to measure anterior chamber cells, anterior 
chamber flare, vitreous cells, vitreous haze, and retinal/choroidal lesions at the Month 6 and 
12 visit or at declaration of treatment failure. The inter- observer variation will be reported. 
The primary study ophthalmologist’s measurements will be used for primary analysis. 
 
5.3.4. Training and certification of ophthalmologists and study coordinators 
All exams must be performed by uveitis specialists. The study protocol and classification 
system for grading inflammation will be reviewed by 
 (or another study 
ophthalmologist from 
) with the investigators at all sites.  An open-book 
exam on the study protocol will be administered, and a score of 80% is needed for 


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certification to participate in the trial. For investigators with scores less than 80%, additional 
instruction and a re-test will be done. Prior to study start, each site investigator will grade 
inflammation on 5 uveitis patients and scores will be compared to the 
 investigator’s 
scores. If a discrepancy of greater than 1 grade in any of the measurements occurs, then 
additional patients will be graded until there are 5 consecutive patients where the grade is 
within 1 level for each of the measurements (i.e. anterior chamber cells, vitreous haze, and 
retinal/choroidal lesions). If both graders assess each area to have 0 inflammation in a 
particular patient, that patient would not count towards the 5 patients needed to complete 
the training. This grading assessment will be done prior to initiation of the trial and yearly 
thereafter. Duplicate measurements of inflammation will also be collected at the 6 and/or 12-
month study visits. Inter-observer agreement will be reported.  
 
The study protocol will be reviewed with all study coordinators by coordinating center 
personnel. An open-book exam on the study protocol will be administered, and a score of 
80% is needed for certification to participate in the trial. For coordinators with scores less 
than 80%, additional instruction and a re-test will be done. 
 
5.4. Optical coherence tomography 
 
We will be using spectral-domain optical coherence tomography (SD-OCT) in this study to 
monitor the effects of treatment by measuring macular thickness and changes in macular 
thickness. We will be utilizing the Heidelberg Spectralis SD-OCT unit for all study 
assessments. Each site must have access to the Heidelberg Spectralis unit at the time of 
study initiation and must continue to use that same scanner for all patients for the duration of 
the study. If Heidelberg Spectralis is not available, the Zeiss Cirrus SD-OCT may be used.  
 
 
5.4.1. Required patient assessments—Heidelberg Spectralis 
 
For our study, one of each of the following scans is required for each eye: 
 
• 
20° x 20° High Speed Volume scan centered on the macula 
 
o 20° x 20° 
o 49 sections 
o 16 frames (ART) 
 
• 
7-Lines  scan centered on the macula 
o 30° x 5° 
o 7 sections 
o 25 frames (ART) 
 
5.4.2. Scan procedures—Heidelberg Spectralis 
 
Procedures for Obtaining Scans 
General Guidelines 
• 
Scans may be obtained if the patient’s pupils are not dilated. However, pupil 
dilation prior to obtaining scans is encouraged 
• 
Clean chin rest and forehead rests 
• 
Adjust table and chin rest height to ensure patient comfort 
• 
Make sure that patient is aligned straight; slight face turns to the left or 
right may decrease scan quality 
 


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Click on the Preset “Dense” scan icon on the screen to obtain the 20° x 20° volume 
scan. Please make sure that the scan will have the following parameters: 
o 20° x 20° 
o 49 sections 
o 16 frames (ART) 
 
• 
Pull the camera all the way back 
• 
Move the instrument toward the patient slowly, taking care not to alarm patient 
and to not touch the patient’s eyes or eyelashes with the instrument 
• 
Ask patient to fixate on the blue light on the inside of the machine 
• 
Remind patient not to follow the movement of the red scan lines 
• 
If patient is having trouble focusing on fixation light, you may need to help the 
patient direct his/her gaze by using external fixation targets 
• 
Focus in on the circular black and white retinal reflex 
• 
Move the camera forward so that the fundus image comes into view and fills the 
screen 
• 
Use the focusing knob to obtain maximum brightness and clarity of the image 
• 
Ensure that the image is maintained in the upper third of the screen 
• 
Click “Acquire” 
• 
Repeat for next eye 
 
Click on the “7 Lines” Preset Scan icon 
This scan will have the following parameters: 
o 30° x 5° 
o 7 sections 
o 25 frames (ART) 
 
• Focus image as described above 
• 
Click “Acquire” 
• 
Repeat for next eye 
• 
Please review scans for completeness and quality. A good quality scan 
should have a score of at least 20. Please repeat any scans that are not 
complete or of poor quality. 
 
 
5.4.3. Obtaining retinal thickness data—Heidelberg Spectralis 
 
 
• 
After closing the acquisition window, double click on the volume scan. 
• 
Select “Thickness Map” tab 
• 
Record central subfield thickness of each eye on data sheet 
• 
Print out copy of scan for patient file  
 
Be sure to complete analysis of data and record information on data collection form as 
soon as possible. This will ensure that the treating physician will be able to use the 
SD-OCT results in real time to determine if macular edema is present or not. 
 
5.4.4. Saving/Exporting data—Heidelberg Spectralis 
 
 
Saving Data 
• 
All scans should be saved and archived at each study site on the Heidleberg SD-
OCT unit. 
• 
Even if your clinic saves all scans onto a server, please follow the instructions 


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below to save all scans for FAST study patients onto an external hard drive. 
o After obtaining scans, highlight all study scans together, right click and 
choose “Export as E2E” 
o Click on the “Anonymize data” box in order to ensure patient confidentiality 
o In the “Export File” filed: Name the E2E file as “Patient Study ID-Visit 
Number-Date of visit”, example “2H003-M6-17NOV2014” 
o In the “Last Name” field: Type in the Patient’s Study ID and Visit, example 
“2H003 M6” 
 
 
o Save the “E2E” data onto a removable hard drive separate from the main 
unit; this raw data may be requested from each site at a later date.  
o Please ensure that your removable storage drive(s) is/are HIPAA compliant 
as defined by your institution 
 
Exporting E2E Data to Reading Center 
• 
  Create a folder on the desktop and/or on a removable drive for each patient visit: 
Label this new folder with “Study-SiteID-Patient Study ID-Visit Number- Date 
of visit”, example: “FAST-
-2Q001-M1-10AUG2012” 
• 
Place the E2E file into the folder 
• 
Complete a “FAST Study Transmittal Form” (electronic copy or scan completed 
paper form) and add into the created folder 
o In the “Clinic ID” field of the Transmittal Form, please enter the 4-letter 
code for your clinic.  Contact coordinating center if you have any questions 
regarding your Clinic ID code. 






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site before that start of the trial to meet with these technicians to review all required OCT 
procedures specified in our protocol. OCT operators must be able to demonstrate ability to 
obtain quality scans as well as knowledge of the study protocol. 
 
5.5. Fundus Photography 
 
Color fundus photography will be performed at baseline, 6 months, 12 months or treatment 
failure. Photos will include fundus reflex images and non-stereoscopic fundus images. Images 
should be uploaded to: http://eyehealthusf.org/uploadi/index.php according to instructions in 
UPRC manual.  
Vitreous haze will be graded according to the NEI and Miami scales by masked graders. 
Photographers will need to be certified by the Uveitis Photograph Reading Center prior to 
obtaining photos for our study. Please see UPRC manual (Appendix E) for instructions on 
certification and obtaining study photos. 
 
5.6. Laboratory measurements 
 
Hematology and serum chemistry will be monitored in all patients prior to enrollment and 
throughout participation in the study. Each of the participating sites has an accredited onsite 
laboratory where all blood draws and laboratory measurements will be performed. The 
following will be measured and recorded on the Laboratory Report Form (Section A.8) for 
each: 
 
Hematology 
•   Hemoglobin and/or hematocrit 
•  Platelet count 
•  White blood cell count (WBC) 
• % neutrophils; % lymphocytes 
• CD4 lymphocyte count (
 sites only, at Baseline, Month 3, 6, & 12)  
 
Serum Chemistry 
•   SGOT (AST) 
•   SGPT (ALT) 
•   Creatinine 
•   Serum or urine pregnancy test  
 
Laboratory measurements used for baseline visits should be collected 4 weeks prior to 
enrollment. Those used for follow-up visits may be collected at any time within the study visit 
window. Laboratory measurements must be collected at each study visit.  
 
All abnormal values will be reported on the Adverse Event Checklist (Section A.10) and 
monitored for resolution on the Adverse Event Log. Abnormalities which result in a non-
serious adverse event (i.e. AST or ALT increasing to twice the upper limit of normal) will 
result in immediate stopping of study medications. As these abnormalities are often 
reversible, patients will be allowed one month to regain eligibility. If the lab results have 
returned to normal within one month, patients may be re-administered the study drug 
according to protocol. Labs can be checked prior to one month, and if normal, treatment 
can resume. Otherwise, treatment failure will be declared and patients may be treated 
according to best medical judgment of physician. They should still be followed for their 6th 
months visit and be treated according to the best medical judgment of their physician.  
 






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assessed. Teleconferences and site visits will be held periodically for all users of the forms to 
review procedures and address questions. 
 
 
7.2. Data review 
 
Data will be reviewed in real time, as the patient is being assessed. The study coordinator 
will verify with the personnel filling out the forms that they are complete. Before scanning to 
be sent to 
 for data entry, the forms will be reviewed and cross-checked for 
consistency and completeness by the study coordinator within 24 hours of completing the 
form. If the forms are not filled out completely, the study coordinator will contact the person 
responsible for completing the form to provide the missing data, or clarify any inconsistent 
data.  The study coordinator or investigators who filled out the form are the only people who 
are authorized to add missing data or make any changes to the study forms.  All changes 
should be made with a red ink pen, and then signed and dated. Further investigation may 
be conducted if certain fields or personnel are associated with a higher rate of paper form 
errors. 
  
7.3. Data entry 
 
Once the completed study forms have been reviewed and approved by the study 
coordinator, the study coordinator will scan and email the forms to the study email 
address (
) within 10 days of the patient visit.  All data will be 
entered into the official electronic research data capture service at 
: REDCap. 
Each study form will be double entered by two independent data entry operators at 
 The data entry manager will merge the entries, checking for any 
inconsistencies or errors. The goal is for both data entries and data merging to occur 
within 10 days of receiving the completed forms in order to prevent the accumulation of 
un-entered forms. The database program contains an entry module for each form, 
prompting the user to enter the data in the same order as the form and clearly 
indicating each question.  
 
7.3.1.   Data entry errors 
 
The data entry manager will compare double-entered study data using the automated feature 
in REDCap. Wherever there is a mismatch, an error file will be generated with relevant data 
such as the form, field name, visit name, and data for which discrepancy is found. The data 
entry manager will then contact the data entry operators to verify the forms and re-enter the 
data. Discrepancies and missing values will be assessed by the data entry manager, and 
resolved by queries sent to the study coordinator and appropriate observers (clinician, 
refractionist, etc). A logfile will preserve the date and time of any changes, together with who 
entered the changes. 
 
7.3.2.   Data consistency and validity 
 
A database data quality assessment program will be created in R programming software to 
help prevent inconsistencies or invalid data. The database program will check for the 
following errors: (1) improper entry of the patient ID based on the checksum, (2) data fields 
that are out of range, (3) inconsistent or illogical entries, (4) incompleteness, and (5) 
numerical values that are far outside the range of those previously entered. The software will 
create an error file with relevant data such as the form identification, field names and the 
data. Automated checks will be made to ensure consistency and that each variable in the 
analysis set has in-range values (protecting against negative ages, spelling errors in 


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categorical factors, and similar errors). The DCC will conduct regular checks of the data at 
each site and will contact the study coordinator about any errors in order to resolve the 
inconsistencies and have the data entry operators enter the correct data. 
 
7.3.3.   Data preparation and cleaning 
 
 
Data sets for analysis will be produced in Microsoft Excel® worksheets (downloaded from 
the REDCap system) containing a single header line whose variable names match the 
REDCap database. Each analysis set will be in the form of a rectangular table in which each 
column corresponds to a single variable and each row to an observation.  All missing values 
will be coded explicitly using the string “NA” (as used in the R software). Codes for 
categorical variables (such as 1 for male, and 2 for female) will be avoided in favor of self-
documenting character strings (such as Male, Female) whenever possible. 
 
A detailed codebook will be prepared, containing for each variable, (a) the form from which 
the variable derived, (b) the text of the question, (c) all possible values for the variable, and 
(d) summary statistics for the variable. Note that all codes and character strings that 
represent categorical factors will be clearly defined in the codebook. Units for each 
continuous variable (e.g. logMAR) will be unambiguously indicated for each variable. Each 
release of the analysis set will be accompanied by the corresponding version of the 
codebook. Version numbering with dates will be strictly observed. 
 
7.3.4.   Monitoring 
 
We will maintain a record of (1) changes to the initial entries on database forms, and (2) 
changes made to all entered data. Database errors include (a) missing information, (b) 
erroneous information that was initially entered, and (c) errors arising from difficulties with the 
forms themselves. Quality assurance reports will summarize the number of each of these. 
Most importantly, we will closely monitor the waiting time between the collection of the initial 
form and the entry of the data. If entry times exceed 30 days, then this will trigger a 
response, which may include investigation, retraining, and even reassignment. 
 
7.4. Data analysis 
 
Following data checks by the data analyst, the Data Analysis Committee will be responsible 
for analyzing the data. At designated time points, it will be merged the unmasked data 
with the randomization list, perform statistical analyses and prepare reports. 
 
Standard report-generation software included with the R statistical and data analysis 
package will be used to ensure consistency of the codebook and analysis set at all times. 
 
Data monitoring reports will be prepared based on analysis data sets.  These will be 
prepared using report-generation software.  Monitoring reports will include (a) recruitment 
reports for each center, (b) compliance reports, (c) retention reports, and (d) data quality 
reports.  These will be reviewed by the DCC on a monthly basis, and communicated to the 
study sites on a monthly basis. 
 
 
7.5. Data storage and security 
 
Paper forms will be maintained in locked file cabinets in locked rooms only accessible to 
research staff at each study site. All PDFs of forms will be sent to the study coordinator at 


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 They should be sent through a secure email and saved on a secure server.  
 
All electronic storage will be subject to standard security procedures in compliance with 
established enterprise information security standards. Each computer will be hardware-
firewalled and will not be accessible outside the Local Area Network. Hard-disk encryption 
will be used for each machine, and the machine will not be accessible without a network 
account and password. Only one individual at each site will have password access to the 
machine; new accounts may be provided by the local network administrator only with the 
approval of the DCC. Accounts will be immediately deactivated for data entry or other 
personnel who leave the study. The computer used for data entry and storage will be kept 
in a physically locked room, and only authorized study personnel will be able to access this 
machine. All individuals who access the server room will be logged as to time and date.  At 
each center, the complete database (including all data tables as well as change logs) will be 
backed up weekly on the server and weekly on a CD/DVD, which will be kept at a safe, 
locked cabinet. Temperature logs will be maintained for the server room and reported. 
 
 
The database at the DCC will be stored on a SQL server located at 
 
 and three sets of backup copies on CD/DVD will be kept. The server is 
hardware-firewalled and also uses hard-disk encryption; it is inaccessible outside the 
 
network and cannot be physically accessed by anyone other than the network administrator.  
Other visitors must be accompanied by an information security professional and the visit will 
be logged. All data will be protected with passwords and the computer/server on which the 
data is stored and the backup copies on CD/DVD will be located in a lock-secured facility.   
Each back-up file will be archived offsite.  In the event of disruption due to unforeseen 
circumstances, all materials needed to continue will be available from the offsite archive. 
 
8. Quality control 
 
With the help of the Data Coordinating Center and the Data Analysis Committee, the 
Clinical Coordinating Center will evaluate the quality of study activities (clinical examination, 
treatment compliance, refraction, etc.). 
 
 
8.1. Medication storage and expiry 
 
Study medications will be stored at room temperature. The expiration dates of the treatment 
kits will be regularly monitored and all expired study medicine will be discarded appropriately. 
 
 
 
8.2. Periodic reports 
 
The Study Coordinators will send weekly reports to the clinical coordinating center, on the 
number of eligible patients screened, the number of patients enrolled, reasons for 
ineligibility, and the number of patients who have come back for follow-up visits. This will be 
used to monitor the enrollment/follow-up progress and any protocol violation in 
enrollment. The CCC will send monthly  reports  to  all  investigators  with  a  summary  of  
overall  enrollment  and  breakdown  of enrollment at each site. 
 
When a site visit or training/certification is conducted at a study site, a report will be 
prepared and sent to the Executive Committee. 
 
The minutes of the DSMC meeting will be circulated electronically among the investigators 
and the members of the DSMC after each meeting. 


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8.3. Data management, security and quality assurance 
See Section 7. 
 
8.4. Monitoring compliance 
 
Patients will be asked to record missed doses in individual treatment calendars and to bring 
them with their medication to each follow-up visit. The study coordinator will collect details of 
the number of doses missed by the patient and record these in the medication log. In 
addition study coordinators will conduct pill counts at each visit.  
 
8.5. Certification 
 
For training and certification process, see Sections 5.2.3. 
 
 
8.6. Data audits 
 
Samples  of  data  forms  will  be  audited  at  each  site  to  ensure  consistency between  
the  source documents and data entry. Patient charts will also be reviewed two times a year 
to confirm adherence to the protocol.  
 
9. Duties and responsibilities of staff 
 
9.1. Ophthalmologist 
 
• 
Note: whenever possible, the primary study ophthalmologist should be the same 
person across all a patient’s study visits, for consistency of measurements 
• 
Responsible for enrolling study subjects 
• 
Provide information for completing the clinical examination forms 
• 
Obtain written consent from the subjects with the help of study coordinator 
• 
Initiate study medication as per the randomization 
• 
Responsible for the care of the patient throughout the course of the study 
• 
Manage adverse events 
 
9.2. Clinical Trial Manager 
 
• 
Ensure the execution of the study as per the protocol 
• 
Arrange training of the ophthalmic assistants, and refractionists 
• 
Coordinate with the collaborating centers 
• 
Prepare monthly reports regarding recruitment and follow-up progress 
• 
Handle correspondence between centers 
• 
Maintain IRB approval and renewals 
• 
Communicate with central pharmacy regarding drug orders and distribution to sites  
 
9.3. Study Coordinator  
 
• Make sure that appropriate patients are screened and enrolled in to the study 
(including obtaining appropriate assent/consent) 
• 
Prepare weekly reports regarding recruitment and follow-up progress  
• 
Send reminders to study patients for follow-up visits 
• 
Meet with the patient at each study visit, prior to the study ophthalmologist to help 
maintain masking  


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• 
Assist ophthalmologist, ophthalmic assistants, and refractionists with conforming 
to study procedures 
• 
Verify data forms for completion and collect missing information 
• 
Send study forms for prompt data entry 
• 
Maintain stock of and dispense study medications 
 
9.4. Data Analyst 
 
• 
Develop data entry programs specific to the study forms under the supervision of 
DCC 
• 
Monitor the flow of forms from the coordinator 
• 
Supervise data entry operators for any errors or omissions 
• 
Develop consistency checks 
• 
Communicate with study coordinators and data entry operators to correct any 
mistakes in study forms and data entry 
• 
Transfer data as and when requested by the DCC 
• 
Back up all data appropriately 
 
9.5. Data Entry Operator 
 
• 
Enter all data from study forms when submitted by the study coordinator 
• 
Verify inconsistencies in the forms and send them for correction to the study 
coordinator 
• 
Perform double entry to ensure accurate recording 
 
9.6. Biostatistician 
 
 
• 
Review data for quality control purposes 
• 
Prepare reports for DSMC 
• 
Lock database at completion of study after database is cleaned 
• 
Conduct analyses at the conclusion of the study 
• 
Prepare randomization list and distribute the list to a pharmacist and non-
masked, senior physicians at the study sites in case of emergency. 
 
9.7. Ophthalmic Assistants 
 
• 
Obtain patient information 
• 
Measure preliminary vision 
• 
Assist ophthalmologist in the clinical examination/enrollment of the subject 
• 
Counsel and motivate patients to return for scheduled follow-up visits 
 
9.8. Refractionists 
 
• 
Perform manifest refraction as specified by protocol of both eyes at each visit 
• 
Measure and record best spectacle-corrected visual acuity at each visit 
• 
Enter visual acuity (number of letters read and Snellen equivalent) on the form 
 
9.9. OCT Operators  
 
• 
Perform OCT photography as specified by protocol of both eyes at all visits 
 
 








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11. Bibliography 
 
1. Nussenblatt RB. The natural history of uveitis. Int Ophthalmol 1990;14:303-8. 
2. Rothova A, Suttorp-van Schulten MS, Frits Treffers W, Kijlstra A. Causes and frequency of blindness 
in patients with intraocular inflammatory disease. Br J Ophthalmol 1996;80:332-6. 
3. Gritz DC, Wong IG. Incidence and prevalence of uveitis in Northern California; the Northern California 
Epidemiology of Uveitis Study. Ophthalmology 2004;111:491-500; discussion 500. 
4. Suttorp-Schulten MS, Rothova A. The possible impact of uveitis in blindness: a literature survey. Br J 
Ophthalmol 1996;80:844-8. 
5. Durrani OM, Meads CA, Murray PI. Uveitis: a potentially blinding disease. Ophthalmologica 
2004;218:223-36. 
6. Rothova A, Buitenhuis HJ, Meenken C, et al. Uveitis and systemic disease. Br J Ophthalmol 
1992;76:137-41. 
7. Smit RL, Baarsma GS, de Vries J. Classification of 750 consecutive uveitis patients in the Rotterdam 
Eye Hospital. Int Ophthalmol 1993;17:71-6. 
8. McCannel CA, Holland GN, Helm CJ, Cornell PJ, Winston JV, Rimmer TG. Causes of uveitis in the 
general practice of ophthalmology. UCLA Community-Based Uveitis Study Group. Am J Ophthalmol 
1996;121:35-46. 
9. Mercanti A, Parolini B, Bonora A, Lequaglie Q, Tomazzoli L. Epidemiology of endogenous uveitis in 
north-eastern Italy. Analysis of 655 new cases. Acta Ophthalmol Scand 2001;79:64-8. 
10. Das D, Bhattacharjee H, Bhattacharyya PK, et al. Pattern of uveitis in North East India: a tertiary eye 
care center study. Indian J Ophthalmol 2009;57:144-6. 
11. Rathinam SR, Namperumalsamy P. Global variation and pattern changes in epidemiology of uveitis. 
Indian J Ophthalmol 2007;55:173-83. 
12. Jabs DA, Rosenbaum JT, Foster CS, et al. Guidelines for the use of immunosuppressive drugs in 
patients with ocular inflammatory disorders: recommendations of an expert panel. Am J Ophthalmol 
2000;130:492-513. 
13. Galor A, Jabs DA, Leder HA, et al. Comparison of antimetabolite drugs as corticosteroid-sparing 
therapy for noninfectious ocular inflammation. Ophthalmology 2008;115:1826-32. 
14. Siepmann K, Huber M, Stubiger N, Deuter C, Zierhut M. Mycophenolate mofetil is a highly effective 
and safe immunosuppressive agent for the treatment of uveitis : a retrospective analysis of 106 patients. 
Graefes Arch Clin Exp Ophthalmol 2006;244:788-94. 
15. Teoh SC, Hogan AC, Dick AD, Lee RW. Mycophenolate mofetil for the treatment of uveitis. Am J 
Ophthalmol 2008;146:752-60, 760 e1-3. 
16. Thorne JE, Jabs DA, Qazi FA, Nguyen QD, Kempen JH, Dunn JP. Mycophenolate mofetil therapy for 
inflammatory eye disease. Ophthalmology 2005;112:1472-7. 
17. Larkin G, Lightman S. Mycophenolate mofetil. A useful immunosuppressive in inflammatory eye 
disease. Ophthalmology 1999;106:370-4. 
18. Kilmartin DJ, Forrester JV, Dick AD. Rescue therapy with mycophenolate mofetil in refractory uveitis. 
Lancet 1998;352:35-6. 
19. Baltatzis S, Tufail F, Yu EN, Vredeveld CM, Foster CS. Mycophenolate mofetil as an 
immunomodulatory agent in the treatment of chronic ocular inflammatory disorders. Ophthalmology 
2003;110:1061-5. 
20. Choudhary A, Harding SP, Bucknall RC, Pearce IA. Mycophenolate mofetil as an 
immunosuppressive agent in refractory inflammatory eye disease. J Ocul Pharmacol Ther 2006;22:168-
75. 
21. Bom S, Zamiri P, Lightman S. Use of methotrexate in the management of sight-threatening uveitis. 
Ocul Immunol Inflamm 2001;9:35-40. 
22. Dev S, McCallum RM, Jaffe GJ. Methotrexate treatment for sarcoid-associated panuveitis. 
Ophthalmology 1999;106:111-8. 
23. Foeldvari I, Wierk A. Methotrexate is an effective treatment for chronic uveitis associated with 


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juvenile idiopathic arthritis. J Rheumatol 2005;32:362-5. 
24. Gangaputra S, Newcomb CW, Liesegang TL, et al. Methotrexate for Ocular Inflammatory Diseases. 
Ophthalmology 2009. 
25. Holz FG, Krastel H, Breitbart A, Schwarz-Eywill M, Pezzutto A, Volcker HE. Low-dose methotrexate 
treatment in noninfectious uveitis resistant to corticosteroids. Ger J Ophthalmol 1992;1:142-4. 
26. Shah SS, Lowder CY, Schmitt MA, Wilke WS, Kosmorsky GS, Meisler DM. Low-dose methotrexate 
therapy for ocular inflammatory disease. Ophthalmology 1992;99:1419-23. 
27. Taylor SR, Habot-Wilner Z, Pacheco P, Lightman SL. Intraocular methotrexate in the treatment of 
uveitis and uveitic cystoid macular edema. Ophthalmology 2009;116:797-801. 
28. Daniel E, Thorne JE, Newcomb CW, et al. Mycophenolate Mofetil for Ocular Inflammation. Am J 
Ophthalmol 2009. 
29. Sobrin L, Christen W, Foster CS. Mycophenolate mofetil after methotrexate failure or intolerance in 
the treatment of scleritis and uveitis. Ophthalmology 2008;115:1416-21, 1421 e1. 
30. Jabs DA, Nussenblatt RB, Rosenbaum JT. Standardization of uveitis nomenclature for reporting 
clinical data. Results of the First International Workshop. Am J Ophthalmol 2005; 140: 509-16. 
31. Nussenblatt RB, Palestine AG, Chan CC, Roberge F. Standardization of vitreal inflammatory activity 
in intermediate and posterior uveitis. Ophthalmology 1985;92:467-71. 
32. Manual of Operations: Age Related Eye Disease Study, 2000. 
33. Sherring AK. A Practical Guide on Refraction, 1999. 
 


9 March 2017 
1 
FAST Uveitis Trial 
Statistical Analysis Plan 
Confidential 
Version 1.5, 0arFK 9, 2017 
Prepared by:  
FI Proctor Foundation Data 
Coordinating Center Box 0412 


9 March 2017 
2 
TABLE OF CONTENTS 
1  Introduction .................................................................................................................................. 4 
2  Investigational Plan ...................................................................................................................... 5 
2.1  Study Design ......................................................................................................................... 5 
2.2  Study Population ................................................................................................................... 5 
2.3  Specific Aims ........................................................................................................................ 5 
2.3.1  Specific Aim 1 ............................................................................................................... 5 
2.3.2  Specific Aim 2 ............................................................................................................... 7 
2.4  Randomization ...................................................................................................................... 8 
2.4.1  Stratification between sites ............................................................................................ 8 
2.4.2  Randomization list ......................................................................................................... 8 
2.4.3  Block randomization ...................................................................................................... 9 
2.4.4  Unique patient identifiers ............................................................................................... 9 
2.4.5  Random number generation ........................................................................................... 9 
2.4.6  Provision of randomization list ...................................................................................... 9 
2.4.7  Quality assurance ......................................................................................................... 10 
2.4.8  Summary of disposition of randomization list ............................................................. 10 
2.5  Masking............................................................................................................................... 11 
3  Statistical Considerations ........................................................................................................... 11 
3.1  Baseline characteristics ....................................................................................................... 11 
3.1.1  Demographics and Patient History .............................................................................. 14 
3.1.2  Prior and concurrent medication .................................................................................. 14 
3.1.3  Baseline comorbidities and history .............................................................................. 14 
3.1.4  Compliance .................................................................................................................. 14 
3.2  Analysis............................................................................................................................... 14 
3.2.1  Summary of Principal Outcome Variables and Regression Variables ........................ 14 
3.2.2  Specific Aim 1 ............................................................................................................. 16 
3.2.3 Specific Aim 2 .............................................................................................................. 20 
3.3  Transformations and model adequacy ................................................................................ 21 
3.3.1  Primary Analysis .......................................................................................................... 21 
3.3.2  Unspecified secondary analyses .................................................................................. 21 
3.3.3  Model validation and sensitivity .................................................................................. 22 
3.4  Sample Size Evaluation ...................................................................................................... 22 
3.4.1  Primary Calculation ..................................................................................................... 22 
3.4.2  Power for Subgroup Analyses and Other Analyses ..................................................... 23 
3.5  Missing data and loss to follow-up ..................................................................................... 27 
3.5.1 Injections ....................................................................................................................... 29 
3.6  Pooling across sites ............................................................................................................. 29 
3.7  Multiple comparisons.......................................................................................................... 29 
3.8  Interim Monitoring.............................................................................................................. 29 
3.9  Accrual Rate........................................................................................................................ 29 
3.10  Interim Analysis ................................................................................................................ 30 


9 March 2017 
3 
3.10.1  Stopping rules ............................................................................................................ 30 
3.10.2  Execution of interim analysis..................................................................................... 30 
3.11  Final Analyses ................................................................................................................... 30 
3.12  Software ............................................................................................................................ 30 
4  Analysis Populations .................................................................................................................. 30 
4.1  Summary ............................................................................................................................. 30 
4.2  Major protocol deviations ................................................................................................... 31 
5  Data Collection and Quality Assurance ..................................................................................... 31 
5.1  Quality assurance and security............................................................................................ 31 
5.2  Analysis sets........................................................................................................................ 31 
5.3  Data monitoring reports ...................................................................................................... 32 
6  Human Subjects ......................................................................................................................... 32 
6.1  Summary of final dispositions ............................................................................................ 32 
6.2  Data and Safety Monitoring Committee ............................................................................. 32 
6.2.1  Scope ............................................................................................................................ 32 
6.2.2  Meetings ....................................................................................................................... 33 
6.2.3  Decisions ...................................................................................................................... 34 
7  Safety and tolerability ................................................................................................................ 35 
7.1  Exposure ............................................................................................................................. 35 
7.2  Adverse Events ................................................................................................................... 35 
7.2.1  Individual events .......................................................................................................... 35 
7.2.2  Pooled adverse events .................................................................................................. 36 
8  Reporting conventions ............................................................................................................... 36 
9  Abbreviations and acronyms...................................................................................................... 38 
10 Appendix ................................................................................................................................... 39 
11 Document Revision History ...................................................................................................... 39 
13 January 2015 ................................................................................................................. 39 
9 March 2017 ..................................................................................................................... 40 
12 Bibliography ............................................................................................................................. 41 




9 March 2017 
5 
2  Investigational Plan 
2.1  Study Design 
The proposed study is an international, multicenter, block randomized, observer-masked, 
comparative effectiveness clinical trial to determine which treatment, methotrexate or 
mycophenolate mofetil, is more effective as first-line corticosteroid-sparing treatment for 
patients with non-infectious intermediate, posterior and panuveitis requiring corticosteroid-
sparing therapy. 
Full details which specify the definition of treatment success are given in the FAST Manual of 
Operations. 
2.2  Study Population 
Eligible volunteers diagnosed with non-infectious uveitis who have given informed consent will 
be enrolled in this trial. Specific eligibility and exclusion criteria are given in the FAST Manual 
of Operations.  The proposed study schedule is listed in the FAST Manual of Operations. 
2.3  Specific Aims 
2.3.1  Specific Aim 1 
Primary Objective.  The primary objective of the study is to establish which 
immunosuppressive treatment, methotrexate or mycophenolate mofetil, results in a 
higher rate of corticosteroid-sparing treatment success, on an intent to treat basis. 
Specifically, we will compare the fraction of subjects who achieve treatment success at 
six months (as defined in the Manual of Operations Section 2.5.1) between the two 
groups.  
Primary Outcome.   The primary outcome for Specific Aim 1 will be the difference in the 
proportion of patients assigned to mycophenolate mofetil vs. methotrexate who achieve 
treatment success (as defined in the Manual of Operations Section 2.5.1). 
Patients who experience success at 6 months with the drug to which they were originally 
randomized (in Specific Aim 1) will continue on the same drug for an additional 6 months. This 
will be called Phase I (6-12 months). Patients will then be seen every 3 months (and will be 
examined at 9 months and at 12 months), until success at 12 months or treatment failure at any 
time. Patients who fail treatment before 12 months with the initial drug will be removed from the 
study and treated according to best medical judgment. 


9 March 2017 
6 
Secondary Objectives  
•
To determine whether patients exhibit a difference in time to control of inflammation
within the first six months.
•
To determine whether patients exhibit a difference in time to corticosteroid sparing control
of inflammation within the first six months.
•
To evaluate the proportion of patients achieving treatment success at 5 months and
sustaining, for at least 28 days, to 6 months.
•
To evaluate a difference in control of inflammation in the posterior/pan anatomic locations
only, assessed at by six months.
•
To evaluate a difference in control of inflammation in the interior and anterior/intermediate
anatomic locations only, assessed at by six months.
• To determine whether there is a change in best spectacle-corrected visual acuity at six
months.
•
To determine whether patients treated exhibit a difference in health related quality of life at
six months.
•
To determine if there are differences in discontinuing treatment due to each of the
following reasons: safety, intolerability or lack of efficacy at six months.
•
To determine whether patients exhibit a difference in the proportion of patients having
macular edema at 6 months
•
To determine whether patients exhibit a difference in macular thickness at 6 months
•
To determine whether patients exhibit a change in vitreous haze, assessed clinically by the
NEI and Davis scales at 6 months
•
To determine whether patients exhibit a change in vitreous haze, assessed by the
photographic grading of haze by the NEI and Davis scales at 6 months.
•
To determine the proportion of patients discontinuing due to intolerability at six months.
•
To determine the rate of adverse events experienced at six months.
•
To determine the proportion of patients discontinuing due to serious adverse events at six
months.
•
To determine whether patients exhibit a change in quality of life at six months.
•
Tabulate the occurrence of dose reduction used in immunosuppressive treatment (see
Manual of Operations Section 3.1 for dose reduction guidelines).
•
To determine efficacy of treatment in Vogt-Koyanagi-Harada (VKH) patients at six
months.
•
To determine the proportion of patients beginning with at least 2+ inflammation in anterior
chamber cells and experience at least a  2-step reduction (i.e. decreasing from 2+ to 0.5+;
3+ to 1+; 4+ to 2+).
•
To determine the proportion of patients beginning with at least 2+ inflammation in vitreous
haze and experience at least a 2-step reduction (i.e. decreasing from 2+ to 0.5+; 3+ to 1+;
4+ to 2+0.


9 March 2017 
7 
•
To evaluate a difference in treatment success controlling for vasculitis at baseline, assessed
at six months.
•
To explore the use of a dynamic process model (such as a Hidden Markov model) to assess
differences in control of inflammation.
•
VKH) patients at six months.
•
Proportion of patients who started with at least 1+ inflammation levels in anterior
chamber cells who achieve a decrease to 0 level of inflammation in anterior chamber
cells.
•
Proportion of patients who started with at least 1+ inflammation levels in vitreous
haze who achieve a decrease to 0 level of inflammation in vitreous haze.
All the above analyses will be examined at the end of Phase I (6-12 months), in addition to the 
following: 
• To determine whether patients exhibit a difference in the probability of controlling
inflammation with complete discontinuation of steroids at twelve months in Phase I.
2.3.2  Specific Aim 2 
Primary Objective.   The primary objective of this aim is to evaluate the clinical efficacy of 
switching agents as rescue therapy after initial treatment failure. 
Patients who experience treatment failure (as defined in the Manual of Operations) with the drug 
to which they were originally randomized in Specific Aim 1 will discontinue the current 
treatment and be administered rescue therapy with the second drug (in a masked fashion). This 
will be called Phase II. Treatment failure with the first drug is defined as the inability to continue 
taking the drug to which the patient has been randomized, either due to intolerability, safety 
concerns, or lack of efficacy.  
Upon declaration of treatment failure, the patient will be automatically screened for Aim 2. If 
eligibility criteria are met, the second treatment will be administered and data will be collected 
for the Phase II baseline visit. Patients will then be seen every 4 weeks until 6 months or until 
treatment failure with the second drug. Treatment failure and success will be defined as in Aim 1. 
Patients who fail treatment before 6 months with the second drug will be removed from the study 
and treated according to best medical judgement. 
Primary Outcome.  The primary outcome is the fraction achieving treatment success at 6 
months after starting Phase II. Treatment success is defined as in Aim 1 and described in the 
Manual of Operations Section 2.5.1. 








9 March 2017 
11 
*
 will act as study coordinator to 
 patients, as well as Coordinating Center 
Manager overseeing all other sites. 
 will have access to the randomization lists for other sites, in 
order to check patient treatment assignment as a quality assessment and manage distribution of 
medications to all sites. 
2.5  Masking 
The clinical examiners, refractionists, OCT technicians, fundus photographers and fundus graders 
will be masked to the treatment assignment. Note that only the individuals listed in Section 2.4.8 
will have copies of the randomization list. Full details of procedures to maintain masking as well 
as for potential unmasking in the event it becomes necessary for safety reasons are provided in 
the Manual of Operations.  Principal Investigator 
 is masked. 
3  Statistical Considerations 
3.1  Baseline characteristics 
 At baseline, each eye (1) may be fully able to be assessed, (2) it may be possible assess part of 
the eye, but not be possible to assess the entire eye, or (3) it may not be possible to assess any of 
the eye.  For each eye for which some assessment is possible, either (1) the eye showns no signs 
of uveitis, or the eye may show some signs of uveitis, but fail to meet the severity criteria (1+ 
anterior chamber cells, vitreous haze or no active retinal/choroidal lesions, as defined in the 
Manual of Operations), or (2) the eye meets the severity criteria as defined in the manual of 
operations.  Some patients are monocular at baseline, one eye being either absent, or exhibiting 
such disease as to preclude the possibility of ever assessing the eye (i.e. phthisis). 
For this trial, we summarize the above possibilities as follows.  Each eye (OD or OS) may be 
classified into one of the following types at baseline: 
A. Eye fully assessible, does not meet the severity criteria as defined in the MOP
B. Eye partially assessible, does not meet the severity uveitis criteria in the assessible region
C. Eye fully assessible, meets severity criteria
D. Eye partially assessible, meets severity criteria in assessible region
E. Eye absent or too diseased to ever assess


9 March 2017 
12 
Patients, not eyes, are the unit of assignment and of randomization.  Thus, there are twenty-five 
possible types of patients.  A patient is required to have at least one eye which meets severity 
criteria for uveitis, and which can be completely assessed.  Eligibility is summarized in the 
following table; cells indicate the possibility of enrollment for a patient whose right eye 
classification corresponds to the row and whose left eye classification corresponds to the column 
(A-E being defined in the previous paragraph).  
 
OS: A 
OS: B 
OS: C 
OS: D 
OS: E 
OD: A 
Not eligible 
Not eligible 
Eligible 
 Not eligible Not eligible 
OD: B 
Not eligible 
Not eligible 
Eligible 
 Not eligible Not eligible 
OD: C 
Eligible 
Eligible 
Eligible 
 Eligible 
Eligible 
OD: D 
Not eligible 
Not eligible 
Eligible 
 Not eligible Not eligible 
OD: E 
Not eligible 
Not eligible 
Eligible 
 Not eligible Not eligible 
 
Assessment and follow-up depends on the status of the eye.  Eyes classified as type E above are 
recorded as such at baseline, and never provide eye outcome related data.  Because (a) inability 
to assess parts of the eye could be related to the progression of disease, but (b) inability to assess 
in the absence of signs of disease cannot be considered evidence of treatment failure, we use the 
following table to summarize how success at six months will be scored.  In this table, the row 
corresponds to the status of an eye at baseline, and the column to the  status of the eye 
considering the primary outcome of success at six months. 
 
Month 6: A 
Month 6: B 
Month 6: C 
Month 6: D 
Month 6: E 
Baseline: A 
Success 
See below**  
Fail 
Fail 
Fail* 
Baseline: B 
Success 
See below** 
Fail 
Fail 
Fail* 
Baseline: C 
Success 
See below** 
Fail 
Fail 
Fail* 
Baseline: D 
Success 
See below** 
Fail 
Fail 
Fail* 
Baseline: E 
NA 
NA 
NA 
NA 
NA 
Specifically, note that an eye which is fully assessible at six months and which does not meet the 
specific criteria for failure of control is always considered a success.  Eyes which are fully or 
partially assessible and which meet any of the criteria for failure are always considered to have 
failed.  However, eyes which are only partially assessible but which meet no criteria in the 
assessible region may be scored successes or failures depending on their baseline status (see next 
paragraphs below). Eyes which were present at baseline but which are missing at the end of the 
study are listed as Fail* in the table; we propose to consider such eyes to have failed unless a 
specific reason demonstrates that the loss of the eye was completely unrelated to the presence or 
progression of disease.  
 
The primary analysis is at the patient level.  Both eyes must meet the success criteria for the 
patient to be considered a success. 
 
**Incompletely assessible eyes. Uveitis assessment for this purpose is based on (i) assessment 
of anterior cells, (ii) vitreous haze, and (iii) retinal or choroidal lesions.  In the pilot study, (iv) 
assessment of vitreous cells was also used.  We will have longitudinal measurements of 
inflammation according to the following schedule: anterior chamber cells, vitreous haze and 


9 March 2017 
13 
active retinal/choroial lesions will be measured at Baseline, Week 2, Month 1 and every 
subsequent 4 weeks until the 6 month assessment (Phase I or Phase II)  or 9 and 12 month 
assessment (Phase I 6-12 months).  
Each of these (including the binary assessment of the presence of retinal or choroidal lesions) 
may be considered an ordinal variable, with relevant threshold values for each (used in 
determining eligibility for enrollment, or success in therapy). 
     Scoring of incompletely assessible eyes is governed by the following guiding principles: 
1. In some patients, the front of the eye may be assessible, but the back of the eye cannot be
examined and assessed clinically (even though the patient can still see out of the eye).
2. Worsening of uveitis may render it harder to assess the back of the eye, so that
information cannot be considered missing at random in general.
3. Many uveitis patients have at least one eye which cannot be fully assessed, because of the
progression of the disease itself.  Excluding such patients or eyes completely is
undesirable.
4. Treatment of uveitis will not reverse the damage which makes it difficult to assess all
parts of the eye.
5. Worsening of cataracts may also cause an eye to become incompletely assessible, so that
a change in assessibility status does not always indicate a worsening of uveitis or a failure
of uveitis treatment.
We chose the following simple, but conservative, approach to scoring such eyes.  For an 
incompletely assessible field (anterior cells, vitreous haze, or presence of retinal or choroidal 
lesions) at any time, the worst value seen until that time will be assigned for the unavailable 
measurement.  Thus, a decreasing ability to assess regions of the eye—in the absence of evidence 
of inflammation or uveitis criteria—does not imply failure of therapy.  Decreasing ability to 
assess eyes which had signs of uveitis will imply failure of therapy.  It is understood that this 
procedure will misclassify some events such as: (i) an eye which had vitreous haze or a retinal or 
choroidal lesion at baseline, which resolved over the course of the six months, and for which a 
progressing cataract rendered the posterior of the eye impossible to assess, will be scored as a 
failure, or (ii) an eye for which the posterior region had no inflammation at baseline, which then 
became impossible to assess, and then which develops posterior inflammation which cannot be 
seen, will be scored as a success. We believe such misclassifications will be infrequent.   
     Selected secondary outcomes, including vision, macular edema, time to control of 
inflammation, will be analyzed at the eye level. All eyes that meet inclusion criteria of 
inflammation at baseline will be included in this analysis.  Linear or generalized linear mixed 
modeling will be conducted (see below for details). 
The following is a brief summary of general guiding principles. 
•
For the primary outcome, if any portion of the eye cannot be assessed at baseline, and it
still cannot be assessed at Visit 6 or Visit 12, if all other markers of success are met, this
portion of the eye would be considered to have had successful therapy.
•
For the primary outcome, if any portion of the cannot be assessed by Visit 6 or 12 and this


9 March 2017 
14 
same portion of the  eye was completely assessable at baseline, if all other markers of 
success are met, then the last worst observation for this eye would be carried forward and 
used at the assessment of this eye portion.  
•
For the primary outcome, if an eye becomes missing by Visit 6 or 12, and it is related to
uveitis (regardless of its disease status at baseline) if all other markers of success are met,
this patient should be considered a failure.
3.1.1  Demographics and Patient History 
All demographic and history variables (in particular, age, gender, occupation, and 
ethnicity/national origin) determined at enrollment will be summarized by counts and 
percentages tabulated by treatment assignment. 
3.1.2  Prior and concurrent medication 
We will present the oral and topical corticosteroid doses at presentation (specifically, the current 
daily dose at baseline) and other medications by randomization arm and study site. 
3.1.3  Baseline comorbidities and history 
Clinical variables at baseline (in particular, anatomical site and vasculitis) will be presented by 
gender, age, and study site. We will also tabulate the presence of associated systemic disease at 
baseline. Anatomical site will be classified at the patient level as site of most serious 
involvement. For example, if a patient has anterior inflammation in the right eye and panuveitis 
in the left, they would be classified as a panuveitis patient.  
3.1.4  Compliance 
Compliance is assessed through patient self-report and regular pill counts by study coordinators 
at each visit when patients bring in their medications.  
3.2  Analysis 
3.2.1  Summary of Principal Outcome Variables and Regression Variables 
Variables 
•
Primary outcome: Patient treatment success by six months (see MOP, Section 2.6)
•
Patient treatment success at twelve months (Phase I)
•
Successful control of inflammation in both eyes by twelve  months, with complete
discontinuation of corticosteroids
•
Best spectacle-corrected visual acuity, at baseline and at the time of failure or six
months (two observations per patient)
•
Time to corticosteroid sparing control of inflammation (6 months and 12 months)
•
Change in health related quality of life subscores (PCS and MCS) from SF-36 and
Vision Related Quality of Life from NEI-VFQ-25 and IND-VFQ at six months and
twelve months


9 March 2017 
15 
•
Reason for discontinuation of therapy (if applicable) at six months and twelve months
•
Macular thickness at baseline, and at six months and twelve months
•
Presence of macular edema at six months and twelve months
•
Vitreous haze assessed clinically by the NEI and Davis scales at baseline, six months,
and twelve months
•
Vitreous haze as assessed by the photographic grading of haze by the NEI and Davis
scales at baseline six months and twelve months
•
The proportion of patients discontinuing due to serious adverse events at six months
and twelve months
•
Tabulate the occurrence of dose redution used in immunosuppressive treatment.
•
Treatment efficacy of VKH patients at six months and twelve months
•
Treatment efficacy of patients with vasculitis at enrollment
Note that the presence of cataracts renders assessment of vitreous haze more difficult. Vitreous 
haze measurements in the presence of certain cataracts will be considered less reliable, and this 
will be considered in statistical modeling. Analyses will be repeated for differing assumptions 
about this bias. A maximum likelihood latent variable model will be considered, in which a true 
underlying vitreous haze level predicts an observed value. The observation model will include a 
higher probability of yielding a large observed value in the presence of a cataract. 
Major independent variable of interest 
•
Treatment assignment (methotrexate or mycophenolate mofetil)
Additional regression variables used in selected analyses 
•
Anatomic location (coded dichotomously as either intermediate (code 0) or  as being
either posterior uveitis or panuveitis (code 1))
•
Country
•
Study site
•
Gender
•
Age
•
Baseline quality of life (health and vision related)
•
Baseline best spectacle-corrected visual acuity, vitreous haze, macular thickness
•
Vasculitis
Inclusion of Data 
•
Data will be included for all outcomes within the window peroid of -2 weeks to +4
weeks around the 6 Month Visit date for Phase I (0-6 months).
•
Data will be inlcuded for all outcomes within the window peroid of -2 weks to +4
weeks around the 12 Month Visit date for Phase I (6-12 months).
•
Data will be included for all outcomes within the window period of -2 weeks to +4
weeks around the 6 Month Visit for Phase II (0-6 months).


9 March 2017 
16 
3.2.2  Specific Aim 1 
Primary Analysis.  
The primary analysis will be a logistic regression model, predicting treatment success at 6 
months based on treatment arm.  We wish to aggregate sites within countries, and countries 
within treatments provided we find no evidence of heterogeneity of sites or countries. 
     Specifically, the pre-specified primary analysis will be performed as follows. We denote the 
assignment group of patient i, i=1,...,N (where N is the number of subjects) by 
, which equals 0 
when the patient is in the methotrexate group and 1 when the patient is in the mycophenolate 
mofetil group. The outcome variable is 
, which is 1 if treatment success of patient i is achieved 
by six months, and 0 otherwise. The variable is missing if the patient is lost to follow-up or drops 
out of the study for reasons other than discontinuation due to intolerance or adverse events; if the 
patient discontinues the medication due to intolerance or adverse events such as abnormal 
laboratory findings, the value is 0.  
     The primary analysis is a logistic regression with treatment arm as a predictor. For the primary 
analysis, we propose to use study site as a random effect (random intercept model). The null 
hypothesis is that the regression coefficient for treatment arm equals zero, which will be tested 
using a likelihood ratio test with one degree of freedom. We will also fit the following models: 
(a) a model including drug, site, and drug × site interaction, (b) a model including only drug and
site, (c) a model including only drug and country, and (d) a model with drug, country, drug-
country interaction, and site within country.  Countries or sites with fewer than three observations
will be pooled together. Provided there is no evidence of treatment × site interaction or treatment
× country interaction, we will report pooled treatment effects and confidence intervals.  In the
event evidence suggests a difference between treatment sites, we will report treatment effects by
site, and repeat the analysis excluding particular sites.  Similarly, evidence of a treatment ×
country interaction will lead us to report treatment effects and confidence intervals by country.
     Simulations suggest that use of a model containing interaction terms between site or country 
and treatment for the primary analysis is undesirable.  Such a procedure results in modest loss of 
power unless the treatment effect is of opposite sign in different sites or countries. 
     The hypothesis test is to be two-sided with alpha of 0.05.  We propose to compute the P-value 
by permutation testing, based on the block randomization scheme. 
Prespecified Subgroup Analysis. 
The prespecified subgroup analysis will test the hypothesis that there is a treatment effect 
separately in each anatomic group, using a logistic regression model. 
We denote the two anatomic groups by 
3
i
X , which equals 0 when the patient is in the 
intermediate group and 1 when the patient is in the posterior/pan group.  In the intermediate 
subgroup, we plan to determine whether there is evidence of a treatment effect (regardless of the 
effect in the posterior/pan group). Specifically, we will conduct this analysis in two ways: 
anatomical site at enrollment (split into three categories: anterior, anterior/intermediate or 
intermediate only, and posterior/panuveitis), and anatomical location by history (split into two 


9 March 2017 
17 
categories: anterior/intermediate or intermediate only, and posterior/panuveitis). Anatomical 
location by history is considered the prespecified analysis; anatomical location at enrollment will 
supplement this finding. 
     We propose to proceed as follows.  We propose to begin with Equation (1), adding terms 
3
1
13
3
3
i
i
i
X
X
X
β
β
+
 for anatomic location and for treatment-location interaction. We wish to test the 
hypothesis that 
0
13 =
β
, i.e. that there is a difference in treatment efficacy between the anatomic 
locations, controlling for country. Alternative models will be fit in which the country, site, and 
treatment x country terms are omitted. 
We will also report relative risks in each substratum, using relative risk regression. 
Additional analyses will add gender and age to the predictors. The entire analysis will be 
repeated for each gender, and separately for each country (US and India) and anatomic location. 
Planned Secondary Analyses. 
Each of the following secondary analyses is designed to test the hypothesis that treatment 
assignment affects a given outcome, after controlling for selected covariates.  All analyses will be 
repeated without controlling for covariates (i.e., using treatment assignment as the only 
predictor). In all cases, appropriate regression diagnostics and/or goodness of fit tests will be 
performed (further details are given below).  In addition, we will compute jackknife influence 
statistics in each analysis, to determine whether or not any single observation (eyes or patients, as 
appropriate) have an undue effect on the final conclusion. All models with site effects will be 
repeated omitting this effect, and again repeated including a treatment-site effect, and with 
country and/or treatment by country interactions (i.e., pooling within countries when 
appropriate). When reporting findings, care will be taken to distinguish the single prespecified 
test from supplemental tests (whether prespecified or unprespecified); exploratory analyses will 
always be labeled as such. All alpha levels are to be two-sided. 
1. Twelve-month endpoint for successes. We propose to compare the proportion who maintain
successful control for twelve months (i.e. the outcome is the proportion who have achieved 
control in all study eyes both at the six month visit and at the 12 month visit) between the two 
study arms.  Per protocol, patients with successful control of their inflammation at 6 months 
remain on the same treatment until 12 months. We will use the same statistical model (and Wald 
procedure) as for the primary analysis.  We test the hypothesis that the coefficients for treatment 
assignment and treatment assignment/anatomic location interaction both equal zero. 
2. Time to corticosteroid sparing control of inflammation.  We propose to use a Cox
proportional hazard model with the outcome being the time to (1) first steroid-sparing control, 
and separately (2) first control of inflammation, with treatment assignment (and interaction) as 
the predictors.  Time to first steroid-sparing control is the principal prespecified analysis here; 
alternative approaches will be conducted for additional insight and as sensitivity analyses. We 
will supplement this analysis with a parametric survival analysis using the Weibull distribution 
and also with a gamma distribution (note that individuals may drop out at any time, not just at the 
monthly visits), and with a method treating the time to success as interval censored. The outcome 
for this analysis is a single number for each patient (not for each eye).  The primary statistical 


9 March 2017 
18 
result will be the Wald test for the treatment assignment coefficient. We will repeat the analysis 
using study site as a fixed effect in this model (and as a sensitivity analysis, will explore random-
effects survival analytic methods which are becoming available, see Pankratz et al.).6 In 
supplementary analyses we will include age and anatomic location as additional covariates.  
3. Country and site within country.  We denote the country by 
, which will be 0 for US
locations and 1 for Indian locations; 
 is 1 only for patients in the second Indian site and 0 
otherwise, while 
 is 1 only for patients in the second US site and 0 otherwise. As mentioned 
under the Primary analysis, we propose to fit  models with country only, drug by country 
interaction, and with a drug by country interaction, including site within country as well. 
Analysis will be conducted within each site, then pooling the sites within country together. 
Further details regarding pooling across centers are provided above under the main prespecified 
analysis. 
4. Best spectacle-corrected visual acuity (BSCVA). The primary outcome variable for this
secondary outcome will be the change in best spectacle-corrected visual acuity from baseline to 
final (as defined in the FAST MOP, i.e. for those who successfully control inflammation as 
defined in the MOP, or at the time of failure for those who fail; MOP, Section 2.6).  Visual acuity 
change scores are available for both eyes for each patient.  
The primary analysis will use a linear mixed-effects regression, where the outcome variable is 
the change in BSCVA in each eye, using treatment assignment as a statistical predictor 
(regressor, independent variable); a random effect will be used at the individual level, because of 
the possibility that changes in the two eyes from a given patient are correlated.  In a 
supplementary analysis, we will include as predictors (independent variables) anatomic location 
of uveitis, interaction between anatomic location and treatment assignment, and the study site, 
together with a random effects for patient. We will fit these models using maximum likelihood 
(R procedure lmer) and use likelihood-ratio tests to test the hypothesis that treatment assignment 
affects BSCVA change. Only eyes that are eligible and meet inflammation criteria at baseline 
will be included in this analysis. If at a given visit, vision cannot be assessed, we will carry the 
last observation forward. Additional sensitivity analyses for missing data will be used (including 
mixed effects models controlling for time, including all data from an individual). 
Also, if there is no eye at Month 6 to assess, the patient will be given a logMAR value of 2.0. 
Because of the possibility that the outcome variable (BSCVA change score) will exhibit non-
normality, we will repeat the analyses using transformations of the outcome data (including 
power and log transformations, or more general monotone transformations).  
Additional analyses will be performed using age, gender, ethnicity, and the steroid dose at 
each month as predictors. 
An additional supplemental analysis will be conducted using final BSCVA (instead of the 
change score) as the outcome, and including baseline BSCVA in each eye as a predictor, using 
methods otherwise identical to those above. 
5. Quality of life.  We will also use a linear mixed model to assess health-related quality of
life, measured by the SF-36 questionnaire (PCS and MCS scores) and vision related quality of 
life NEI-VFQ-25 and IND-VFQ at 6 months or at the time of failure, as described in the Manual 


9 March 2017 
19 
of Operations.  Predictors will be baseline quality of life, age, gender, ethnicity, study site (as a 
random effect), and treatment assignment, and we will test the hypothesis that the regression 
coefficient corresponding to treatment assignment equals zero using the Wald t-test.  Similar 
assessments will be performed for vision-related quality of life questionnaires.  
6. Reason for discontinuation.  Individuals who discontinue study medication may do so due
to inability to tolerate side effects, due to lack of efficacy, or for safety reasons.  The outcome 
variable is whether the person discontinued due to intolerance, discontinued due to lack of 
efficacy, discontinued due to safety, or did not discontinue the medication. Because study site 
may be an important factor, we will use polytomous regression to model the discontinuation 
result as a function of treatment assignment (using a fixed effect for study site).7  If evidence is 
found that treatment assignment influences discontinuation result, further analyses may be 
conducted to determine whether or not treatment assignment is associated with discontinuation 
due to intolerance, lack of efficacy, or to safety, or some combination of these. We propose to 
classify all individuals in a two by four table according to treatment assignment and 
discontinuation (not discontinued, discontinued due to intolerance, discontinued due to lack of 
efficacy, discontinued due to safety) and conduct the Fisher’s exact test (in its r×c form). The use 
of an overall test prior to further analysis is designed to protect the overall error rate. 
7. Successful control of inflammation with complete discontinuation of steroids (Phase I 6-12
months).  Some individuals may be able to taper completely off of steroids while maintaining 
control of inflammation.  The outcome variable is the fraction of individuals achieving such 
control in both eyes (out of the number of individuals starting therapy).  We propose to compare 
this fraction between the two treatment groups using logistic regression. The statistical analysis 
will otherwise be identical to the primary analysis. 
8. Macular edema.  We wish to compare the fraction of patients with macular edema at 6
months, between the two treatment arms.  This will be conducted using the Fisher exact test, with 
a two-sided test at alpha of 0.05.  Supplementary analyses will be based on logistic regression 
using the presence of macular edema as a binary outcome variable, with regressors (“independent 
variables”) of treatment arm and anatomic location.  Further analyses (including other baseline 
covariates or other subsets) will be labeled as exploratory. 
9. Change in Macular thickness.  We propose to test the hypothesis that macular thickness is
different in the two treatment arms, at 6 months.  We propose to model the macular thickness at 6 
months using two regressors: treatment arm and baseline thickness.  We will test the hypothesis 
that treatment arm is associated with final macular thickness, using the T-test of the regression 
coefficient for treatment arm in the model including baseline thickness as a second covariate (two 
sided using α=0.05).  We will examine residuals for normality and homoskedasticity, and prepare 
residual vs fitted value plots.  Standard transformations will be used in case of evidence that the 
assumptions have been violated. 
We will also look at change in macular thickness in only patients who had macular edema at 
Baseline.  
10. Bayesian analysis.  Prior to data collection, we will elicit a Bayesian prior for the effect
size (difference between the two treatment arms) from a group of uveitis experts, using methods 
our group has previously applied to the 
.  The likelihood 


 
9 March 2017 
20 
function corresponding to Equation (1) will be used to yield a posterior distribution for the effect 
size. Quantiles of this distribution will be reported, together with sensitivity analyses (with 
respect to model choice, influential observations, and prior distribution).  
11. Alternative definitions for success.  Other definitions will be examined: (i) changing the 
algorithm for assigning values for unobservable uveitis examination fields (anterior cells, 
vitreous haze, retinal/choroidal lesions) so that any worsening of ability to assess the eye for any 
reason is scored a failure, or (ii) use of vitreous cells in the definition of uveitis. 
12. Change in vitreous haze will be assessed using clustered polytomous logistic regression, 
using baseline vitreous haze as a covariate and follow-up time.  Vitreous haze is an ordinal 
outcome variable.  A random effect is needed because the two eyes of a given patient cannot be 
treated as statistically independent.  Both the NEI and Davis scales will be analyzed, for both 
direct observations and photographic grading.  Treatment assignment will be a covariate.  
Alternative methods will be examined, including a simple McNemar test in which we 
dichotomize vitreous haze assessments at baseline and at the final observation. 
13. Rate of adverse events and the proportion of patients discontinuing due to adverse events 
will be tabulated by treatment assignment, age, and gender; confidence intervals will be reported.   
14. Treatment efficacy in VKH patients will be assessed as a planned subgroup analysis.  Note 
that anatomic location is also a planned subgroup analysis, as well as study site and study country 
(aggregating all sites within each country). 
15. Dose reduction will be compared by arm using logistic regression based on treatment, and 
other covariates as needed. 
     16. If no difference is found for the primary outcome comparing treatment success between 
arms, we will assess whether methotrexate is non-inferior to mycophenolate mofetil, assuming a 
10% non-inferiority margin. The non-inferiority margin of 10% is clinically meaningful and was 
based on investigator consensus. Methotrexate will be considered non-inferior to mycophenolate 
if the lower limit of the 95% CI for treatment success at 6 months is less than 10%.  This analysis 
will be conducted because mycophenolate mofetil is much more expensive than methotrexate, so 
a determination that methotrexate is not inferior has clinical implications. We are interested in a 
one-sided comparison given the cost differential between methotrexate and mycophenolate 
mofetil.  
 
17.  Additional exploratory modeling will be conducted using clustered multinomial logistic 
regression using all time points and all observations of anterior chamber cells, vitreous haze, and 
retinal/choroidal lesions.   
3.2.3 Specific Aim 2   
Primary Analysis.    
The primary analysis will compare the proportion of successes between (a) patients treated 
with mycophenolate mofetil following failure on methotrexate and (b) patients treated with 
methotrexate following failure on mycophenolate mofetil.   


 
9 March 2017 
21 
Specifically, we will conduct a logistic regression in which success or failure will be the 
outcome, and the predictors (regressors, independent variables) will be treatment group and 
reason for failure of the first drug (lack of efficacy vs any other reason).  Supplementary analyses 
will include anatomic location (intermediate vs posterior/pan) and country. We will test the 
hypothesis that the coefficient for treatment group equals zero (i.e., that mycophenolate mofetil 
rescue after methotrexate failure has the same result as methotrexate rescue after mycophenolate 
mofetil failure). All alpha levels will be two-sided. 
 
It is important to emphasize that estimation of the success rate of the second drug following the 
failure of the first is a central goal of the trial, arguably as or more important than the hypothesis 
test itself.  The success rates and confidence intervals will be presented regardless of the results 
of the hypothesis test. 
 
Secondary Analyses. 
The following secondary analyses are planned.  
We will also present the estimated success proportion in both treatment groups, together with the 
95% confidence intervals.  The two groups are the individuals who were undergoing 
methotrexate rescue therapy after mycophenolate mofetil, and those who were undergoing 
mycophenolate mofetil rescue therapy after methotrexate.  Logistic regression will also be used 
to adjust for study site. 
 
The second prespecified analysis will compare the rate of success between rescue patients and 
first-line patients, using logistic regression; we will test the hypothesis that the coefficient for 
rescue/initial equals zero. A supplemental variation of this analysis will include an additional 
predictor for whether the patient was on rescue therapy due to lack of efficacy, lack of safety or 
intolerance, or anatomic location.  Two separate analyses are planned, each with an alpha of 0.05. 
 
Exploratory and descriptive analyses of covariates such as reason for failure of the initial regime, 
age, disease (e.g., VKH), and affected region of the eye, will be presented. 
3.3  Transformations and model adequacy 
3.3.1  Primary Analysis 
Sensitivity analyses based on modeling the individuals lost to follow-up will be conducted, 
however; we will determine how much of a treatment effect there would have had to have been in 
the patients lost to follow-up, for the results of the main hypothesis test to change. 
3.3.2  Unspecified secondary analyses 
Unprespecified analyses may be conducted following the primary analysis and will always be 
reported as such.  Analyses will always be repeated including age and gender, in particular.   


9 March 2017 
22 
3.3.3  Model validation and sensitivity 
In all cases, standard statistical procedures will always be followed to ensure that no evidence 
indicates a violation of the assumptions underlying the statistical models used. Specifically, we 
note the following: secondary analyses based on the use of age as a continuous predictor in 
logistic regression models with treatment success as an outcome will be assessed using the 
Hosmer-Lemeshow goodness-of-fit test. Linear models will always be assessed using residual 
plots (residuals vs. predicted values, and QQ plots), together with tests for normality (Anderson-
Darling and Shapiro-Wilk procedures). For mixed models, we will examine marginal residuals, 
conditional residuals, and EBLUPs.8 When modeling binary outcomes (using clustered logistic 
regressions), we will repeat analyses using a probit link as a check on robustness; we will also 
examine the Pearson goodness of fit statistic.9 Jackknife influence estimates will be used in all 
analyses; single observations that could change the conclusions will always be reported. Analyses 
in which time to response is used as the outcome variable (in which Cox regression is conducted) 
will be supplemented with the Gill-Schumacher procedure for assessing the adequacy of the 
proportional hazards assumption for Cox regression.10  Analyses in which our primary interest in 
in final outcomes will still be repeated using all available data (at all time points). 
Failure of the modeling assumptions (such as normality) will result in conducting additional 
analyses. First, for continuous outcome variables, we will undertake normalizing or variance-
stabilizing transformations of the outcome variable (such as power transformations). Second, 
robust procedures will be used to estimate the standard errors whenever possible. Third, the use 
of bootstrap procedures, when applicable, will be considered in estimation of standard errors.11  
3.4  Sample Size Evaluation 
3.4.1  Primary Calculation 
The sample size for the trial will be 216 subjects, which we anticipate will provide 
approximately 80% power to detect a difference of 20% in the proportion of patients 
achieving control of inflammation at six months between the methotrexate and 
mycophenolate mofetil groups. 
This sample size was determined based on the primary objective (superiority comparison of 
mycophenolate mofetil to methotrexate) and primary endpoint (treatment success). We assumed 
an effect size of 20%, as this was deemed to be clinically meaningful, and well within the 
distribution of the investigators’ prior beliefs from published retrospective studies.  
An approximate sample size is provided by the formula 
2N= 
4(Zα+Zβ)2p¯ (1-p¯ )
(pc-pi)2
(5)


9 March 2017 
23 
(see Friedman et al. 2010), where α is the significance level (0.05, two sided), β is one minus 
the power (the desired power is 80%), pc is in this case the probability of success in the
methotrexate group (we estimate this at 0.4), pi is the probability of success in the mycophenolate
mofetil group (we estimate this at 0.6), and p¯  is 1
2(pi+pc). We assume 10% will be lost to follow-
up in the first six months; details are given in the full proposal. This yields approximately 108 
patients in each of the two groups, for a total of 2×108=216 subjects.  
A power table is provided below as a sensitivity analysis (to show how the detectable effect 
size changes with varying success rates.  
Simulation confirms that this method yields adequate sample sizes for the logistic regression 
(results not shown). 
Note that for the final analysis, the critical value will be adjusted slightly because of the 
interim analysis. 
Sample size readjustment 
     Simulation suggests that a baseline covariate which is associated with the outcome variable 
could modestly reduce the sample size needed for 80% power (simulation results are available 
upon request). Sample size readjustment based on baseline predictors will be considered, subject 
to approval by the DSMB.   The guiding principle is (CHMP, Reflection Paper on 
methodological issues in confirmatory clinical trials planned with an adaptive design, 2007): 
Analysis methods that control the type I error must be pre-specified.  Whenever possible, 
methods for blinded sample size reassessment that properly control the type I error should be 
used, especially if the sole aim of the interim analysis is the re-calculation of sample size.  
3.4.2  Power for Subgroup Analyses and Other Analyses 
Subgroups in Specific Aim 1.  
The prespecified subgroup analysis for specific aim 1 is to examine the difference between 
the methotrexate and mycophenolate mofetil groups within each anatomic location. Using 
Equation (5), we anticipate having in excess of 80% power to detect a difference of 25% in 
success rates.  
80% Power 
90% Power 
Success rate with 
Drug A 
Detectable 
effect size 
Success rate 
with Drug B 
Detectable effect 
size 
Success rate 
with Drug B 
20% 
18% 
 38% 
21% 
41% 
30% 
20% 
 50% 
23% 
53% 
40% 
20% 
 60% 
23% 
63% 
50% 
20% 
 70% 
22% 
72% 
60% 
19% 
 79% 
21% 
81% 


9 March 2017 
24 
The power for selected secondary outcomes is provided here. 
Secondary Outcomes in Specific Aim 1. 
1. Twelve-month endpoint for success. We assume an additional loss of 5% between 6 and 12
months (that is, in addition to the 10% already lost to follow-up in the first six months). We
expect approximately 78% power to detect a 20% difference in success rates at the 12-
month endpoint.
2. Time to corticosteroid sparing control of inflammation.  For sample size planning, we use the
approximate formula given in Friedman et al (2010) for the number in each group:
(
)
(
)
(
)
(
)
(
)
2
2
C
I
I
C
Z
Z
N
λ
λ
λ
φ
λ
φ
β
α
−
+
+
=
where λC is the hazard in the methotrexate group, λI is the hazard in the mycophenolate mofetil 
group, and 
uT
e
u
u
−
−
= 1
)
(
2
φ
where T is the censoring time (6 months).  Previous studies suggest a median success time of 
approximately 3.5 months for mycophenolate mofetil.12 Assuming a 10% loss to follow-up, 108 
subjects in each group provides 80% power to detect a difference of 2.47 months in the 
expected difference.  (Note: λC is log(2)/3.5 mo. for this calculation.)  We assume an alpha of 
0.05 (two sided). 
3. Change in BSCVA.  For sample size planning, we assume a T-test comparing change scores
between the two drugs, assuming a standard deviation of the change in visual acuity of 6.5
letters.13, 14 The sample size of 108 will provide approximately 80% power to detect 2.63 letters
of difference in the change score.  In other words, we expect to have 80% power to detect
whether mycophenolate mofetil yields 2.63 letters more of improvement than methotrexate,
and we will have greater power to detect greater differences.  The power formula is provided
in Chow et al and is computationally implemented in R in the function power.t.test (which we
used).15
4. Quality of life.  For a power calculation, we consider the SF-36 questionnaire, which has two
scales, the MCS and the PCS.  The raw score standard deviation will be assumed to be 8.4 points;
we assume a correlation between baseline and six months of 0.6.16, 17  Assuming that the baseline
score will “explain” roughly 36% of the variance allows us to assume a corrected raw score
standard deviation of 6.72 in a simplified calculation in which we treat the analysis as a T-test.
The same power calculation formula used in (3) above reveals that our sample size provides
approximately 80% power to detect a raw score difference of roughly 2.57 between the two
treatment groups.  This difference is roughly comparable to the small difference in scores found
between intermediate uveitis patients and the general population16, a difference we believe to be
more than sufficient to detect clinically significant results.  Note that the population mean of this
score is standardized to 50 on 0 to 100 scale. Similar analyses will be conducted for the vision
related quality of life (i.e. NEI-VFQ-25 and the IND-VFQ).


9 March 2017 
25 
5. Rate of discontinuation.  Based on retrospective studies, we expect approximately 13% to
discontinue methotrexate due to tolerability and 5% to discontinue due to safety (laboratory
abnormalities or other serious adverse events).  We expect approximately 4% to discontinue
mycophenolate mofetil due to tolerability and 5% to discontinue due to safety.12, 18-20  For the
purpose of the power calculation, we assume 10% loss to follow-up and consider only the
comparison of discontinuation due to tolerability.  We use the power formula given in
Freedman et al (p. 104) to calculate a power of 61% for this comparison.3
6. Macular edema.  Previous studies suggest approximately 38% of individuals with uveitis will
manifest macular edema.21  We have approximately 80% power to detect a difference of a
factor of two in the final proportion of macular edema (19% vs 38%).
7. Macular thickness.  A sample size of 108 (before loss to follow-up) provides approximately
80% power to detect a 65 micron difference between the two treatment groups, assuming a
standard deviation of 160 microns in the final macular thickness.22  This analysis is quite
conservative, since a difference of 100 microns between these two groups is consistent with
previous studies.  Moreover, adjustment for variance explained by the baseline thickness (i.e. the
use of a smaller effective standard deviation) would yield a still higher effective power.22, 23
Specific Aim 2.  
In the primary comparison of Specific Aim 2, we will estimate the effectiveness of rescue 
therapy, controlling for treatment group and reason for failure.   
The primary analysis is (a) to estimate the probability of success on mycophenolate mofetil 
following failure of methotrexate, with 95% confidence intervals, and (b) to estimate the 
probability of success on methotrexate following failure of mycophenolate mofetil, with 95% 
confidence intervals.   
These results will also be reported by reason for failure of the first drug, by categories of (i) 
failure because of inability to tolerate the first drug, (ii) failure of the first drug to achieve control 
(efficacy), or (iii) failure due to safety.   
One analysis of interest is to compare the success rates in these two groups, and we include 
the sample size considerations for this analysis below.  For two drugs (mycophenolate mofetil 
and methotrexate), we conduct the sample size planning as follows (denoting two drugs simply as 
A and B).  For treatment group j=0,1 (0 coding drug B rescue in patients failing drug A therapy, 
1 coding drug A rescue in patients failing drug B therapy), we expect 
 subjects 
to be available for Specific Aim 2 (where N0 is the number of subjects randomized to each 
treatment, r1 is the retention fraction in Specific Aim 1 (not lost to follow-up in Specific Aim 1), 
sj is the expected success fraction for patients for initial treatment j, and r2 is the retention 
fraction in Specific Aim 2.  
Thus, the number of available patients for Specific Aim 2 are highly dependent on the results 
from Specific Aim 1.  Scientifically, the result of rescue therapy is important regardless of the 
result in Aim 1.  More power will be available for the primary comparison in Specific Aim 2 if 
treatment in Specific Aim 1 yielded relatively high and similar failure rates for both drugs.  
However, even if success rates are very different in Aim 1, the descriptive analyses will still 
provide important information to guide decision-making on second-line treatment. 


9 March 2017 
26 
Here, N0=108, and r1 is assumed to be 0.9 (10% loss to follow-up). For planning Specific 
Aim 2, we assume a success rate of 60% for patients treated with drug A Specific Aim 1, and a 
success rate of 40% for those treated with drug B. This is a conservative estimate of the 
difference expected based on retrospective studies12, 18-20 and consistent with the pilot study. 
Finally, we are assuming an additional 5% loss to follow-up during Specific Aim 2 (in addition to 
the 10% already lost), so that r2=0.95.  The results are summarized in the following table, where 
the number enrolling does not include loss to follow-up, and the “expected complete” column has 
taken loss to follow-up into account (njk). 
We anticipate the following: 
Initial/Second Treatment 
Expected 
Enrollment SA/2 
Expected to 
Complete SA/2 
B/A 
58.3 
55.4 
A/B 
38.9 
36.9 
Thus, we expect a total of n1=58 patients (rounding down) to have failed one first-line 
therapy to be enrolled in rescue therapy.  Similarly, we expect n0=38 patients to be enrolled in the 
other rescue regimen. 
Previous observational studies suggest a 42% success rate of mycophenolate mofetil in 
methotrexate-failing patients,.24  A simple power analysis for comparing these proportions may 
be found from the formula (see Chao et al, p. 87):15 
(
)
(
)
¸¸
¸
¸
¸
¹
·
¨¨
¨
¨
¨
©
§
−
−
+
−
−
Φ
=
−
2
/
1
1
1
0
0
0
0
1
1
1
1
α
β
z
n
p
p
n
p
p
p
p
where p0 is the probability of success with methotrexate rescue following mycophenolate mofetil 
failure, p1 the probability of success with mycophenolate mofetil rescue following methotrexate 
failure, and Φ is the cumulative distribution function of the standard normal distribution.  These 
assumptions yield a power of 0.87 if the rate of success with methotrexate rescue is 0.15.  We 
have approximately 80% power to detect a difference of 17% if the probability of success with 
mycophenolate mofetil is 0.42. 
A power table for sensitivity analysis is provided.  We chose selected scenarios of potential 
interest to show the wide range of scenarios for which we have sufficient power.  The main 
scenario is the first row of the table; in other rows, we varied the number of patients or the 
success fractions for the first drug used.  In particular, the results are not sensitive to the efficacy 
difference found in Specific Aim 1. 
Power Table for Specific Aim 2 


9 March 2017 
27 
Drug A, then 
Drug B 
(number) 
Drug B, then 
Drug A 
(number) 
Success 
probability of 
Drug B in 
patients failing 
Drug A 
Success 
probability of 
Drug A in 
patients failing 
Drug B 
Approximate 
Power 
58 
38 
0.42 
0.15 
87% 
58 
38 
0.42 
0.17 
80% 
58 
38 
0.15 
0.42 
83% 
58 
76 
0.42 
0.15 
94% 
116 
38 
0.42 
0.15 
96% 
40 
40 
0.42 
0.15 
80% 
58 
38 
0.40 
0.15 
80% 
To summarize, the anticipated number of patients from Specific Aim 1 (58 enrolled in in 
Drug A, and 38 in Drug B) should provide approximately 80% power to detect a difference 
of 25% between the two groups, assuming a success probability of 42% and a two-tailed 
alpha of 0.05. 
Secondary Outcomes in Specific Aim 2. 
1. Confidence intervals for the probability of success will be reported for each rescue group
and anatomic location (i.e. Patients receiving methotrexate or mycophenolate mofetil as
first treatment versus receiving it as their second, rescue treatment). Note that in the event
that there are insufficient numbers of patients available in one arm of Specific Aim 2 (for
instance, far fewer patients available for methotrexate rescue than we anticipate),
confidence intervals for estimating the proportion of success can still be computed for the
anatomic locations in the other arm.
2. We propose, for each rescue group, to conduct logistic regression using success as an
outcome, and reason for failure of the first drug as a categorical covariate (safety,
efficacy, tolerability).  An overall likelihood ratio test for each will be conducted, with an
alpha of 0.05/2=0.025.
3. An additional comparison will be undertaken between first-line and rescue patients with
both methotrexate and mycophenolate mofetil.
4. Additionally, the same secondary outcomes assessed in Aim 1 will be analyzed using
similar methods.
3.5  Missing data and loss to follow-up 
     Values of the primary study endpoint (treatment success at six months) cannot be analyzed 
when the individual is lost to follow-up.  We distinguish information which is missing because of 
possible progression of the underlying condition we wish to treat from information which is lost 
for some other reason.  Earlier, we discussed methods for handling missing values for specific 


9 March 2017 
28 
uveitis fields in individuals.  The discussion in this section applies only to loss to follow-up or to 
dropping out of the study. As emphasized in Carpenter & Kenward (2007), “there can be no 
universal analysis when data are missing”.  Our purpose is to vary the assumptions as well as the 
methods, to establish that the estimates of the treatment effect are robust as such assumptions are 
varied. 
     Our priority is the preservation of the intent to treat principle.  We propose to report the results 
from all of the following methods: 
1. The use of regression-based multiple imputation, based on all observed data for the
patient.
2. Use of longitudinal generalized linear mixed effects regression, with visit as a covariate,
and including a random effect for each person and for each eye within each person, using
all the available measurements on each individual
3. Sensitivity analysis in which missing final outcome values are assigned success or failure,
and the analysis conducted conditional on these assignments.
4. Analysis of complete cases only (individuals for which the six month follow-up is
available)
However, we are proposing that method 4 (complete case analysis) be considered the primary 
outcome, based on recommendation by the DSMB.  All other analyses are to be considered 
supplementary. 
     Multiple imputation will be conducted as follows.  The following information will be used as 
regression covariates: (i) age, (ii) gender, (iii) inflammation assessments at all prior time points 
(anterior cells, vitreous haze, and retinal/choroidal lesions), (iv) steroid dose, (v) anatomic 
location (by patient, classified as anterior/intermediate or posterior/panuveitis), (vi) anatomic 
location by history, (vii) maximum steroid dose within the 90 days prior to enrollment, (vii) 
steroid dose at enrollment prior to randomization or study-related intervention, (ix) country, and 
(x) site within country.  Any additional covariates must be prespecified.  A regression model for
the missing outcome information will be derived; specifically, a cross-validated procedure to
yield the best prediction based on complete subjects will be derived, and ten multiple imputations
will be derived from it.  The formula in Little and Rubin25 will be used to derive the overall test
statistic.  All replications will be recorded and reported.
An alternative method (which we propose to used for sensitivity analysis) is hot deck multiple 
imputation (with ten replications).25 Note that treatment assignment would never be missing.  For 
definiteness, we choose the recursive random partitioning hot deck method used in the R package 
rrp with the default settings (command rrp.impute). 
     The possibility of data-driven modeling may render multiple imputation of an outcome 
variable undesirable to many reviewers as a primary outcome.  An alternative method is to model 
the treatment success of person i at visit j, Yij, using generalized linear mixed models, with 
covariates being site, country, treatment assignment, country-assignment interaction, visit (1:6), 
and visit-drug interaction (method 2 above).  Note that additional statistical modeling will be 
reported, in which we (a) omit visit-drug interaction, and/or country assignment interaction, (b) 
add visit-country interaction, or (c) add age or gender as covariates.   


9 March 2017 
29 
     We believe carrying forward last observations to be particularly unhelpful in this study, 
because all patients are on a prescribed steroid taper.  We also believe that differential loss to 
follow-up of well performing patients on one drug or the other could falsely make the poorer 
drug appear to give more favorable results, so that the complete case analysis must be interpreted 
with caution. 
3.5.1 Injections 
If a patient receives a corticosteroid injection 90 days after enrollment, it is not possible to truly 
assess the study drug’s ability to manage inflammation at the Month 6 visit. Therefore, as a 
senstivity analysis, the primary outcome for these patients will be considered by the 
inflammation levels at the time of the injection. If the patient received the injection because of 
uncontrolled inflammation, the patient will be considered a treatment failure. If the patient met 
the definition of treatment success at the time of the injection, the patient will be considered a 
treatment success.  
3.6  Pooling across sites 
Approximately three-fourths of patients are expected to come from the 
 sites, which are 
in the same hospital network in the geographic region serving the same patient population. 
 serve slightly different populations, although we expect fewer 
cases overall in the U.S. sites. 
3.7  Multiple comparisons 
An alpha of 0.05 will be used for the primary analysis of Specific Aims 1 and the primary 
analysis of Specific Aim 2. The prespecified subgroup analyses of Specific Aim 1 will be 
conducted at an alpha level of 0.05 (as stated above) as well.  However, the use of an overall test 
prior to subgroup analysis protects the overall type I error rate for the primary outcome, a 
procedure we apply within the analysis of each secondary outcome as well.   
3.8  Interim Monitoring 
The study will be monitored by a Data Safety Monitoring Committee (DSMC) appointed by the 
National Eye Institute.  There will be one in-person meeting a year and additional phone calls as 
deemed necessary. The DSMC will be unmasked and received reports with information by 
treatment arm from the principal statistician.  
3.9  Accrual Rate 
Based on enrollment rates in previous trials and preliminary data (see proposal for details) we 
anticipate enrolling 7-8 subjects per month at all sites, for a total enrollment period of 2.5 years. 
If we conservatively assume we may only accrue 25% fewer subjects per month, then completion 
of enrollment would occur 3 years and 3 months after the start of the trial. 
We will establish monthly recruitment goals for each of the sites, taking into careful 
consideration local holidays which may cause recruitment rates to drop at certain times of the 


9 March 2017 
30 
year. Careful monitoring of the recruitment process will enable us to determine whether one of 
our sites may be falling behind in recruitment, precursory to further investigation and 
intervention. Standard graphs of realized cumulative recruitment together with cumulative 
recruitment goals for (a) the study as a whole, and (b) for each of the four sites will be prepared, 
and provided to the Data and Safety Monitoring Committee at each meeting (or more frequently, 
if requested).  
3.10  Interim Analysis 
We propose to conduct two interim analyses, at approximately one-third and at approximately 
two-thirds of the way through the study.  The exact fractions will be determined by availability of 
data and timing of DSMB meetings. We plan to examine the primary outcome variable using the 
same statistical model we plan for the final analysis.  A flexible alpha spending function is 
specified in Section 6. 
3.10.1  Stopping rules 
Stopping rules for benefit, harm, and futility are discussed in Section 6.2. These rules or 
guidelines would be determined at the first meeting of the DSMC (see Section 6.2). 
3.10.2  Execution of interim analysis 
The principal statistician 
 will conduct the interim analysis in an unmasked manner, subject 
to independent statistical review by the DSMC. Quality assurance will be conducted by database 
manager 
. 
3.11  Final Analyses 
The Primary Aim 1 analysis (and secondary objectives), identified in this Statistical Analysis 
Plan will be performed when all patients complete their 6 month assessment and the window 
period is completed. All other analyses will be completed after the 12 month visit for Phase I or 6 
month visit for Phase II and window periods are complete.  
3.12  Software 
The standard software program R version 2.12 or higher (http://www.r-project.org) for the 
MacIntosh OS X will be used for all descriptive and inferential analyses.  
4  Analysis Populations 
4.1  Summary 
The following analysis populations are planned for this study: 
•
The screening population, which is to include all patients who are screened for
participation in the trial.


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31 
•
The safety population, which is to include all patients who receive any amount of planned
study medication (mycophenolate mofetil or methotrexate).
•
The intent-to-treat efficacy population, which is to include all patients who are
randomized. This is the primary population for the efficacy analyses.
•
The per-protocol efficacy population, which is to include all patients in the intent-to-treat
efficacy population, excluding patients with any of the following: (a) major protocol
deviations, or (b) noncompliance with study medications (less than 50% of the study drug
received by self report or pill counts at study visits).
4.2  Major protocol deviations 
The incidence of deviations from the inclusion and exclusion criteria will be summarized using 
counts and percentages, and the treatment groups compared for the overall frequency of 
deviations using a 2×N Fisher’s exact test. Similar deviations will be grouped into general 
categories of deviations for a more condensed summary. A listing of deviations by participant 
will also be produced. Any major deviations from the protocol will be listed and/or summarized, 
including, but not limited to, participants who:  
•
never received study drug
•
were subsequently found to be ineligible for the study
•
never returned for a follow-up visit
•
have follow-up visits outside the prescribed visit window
•
received a corticosteroid injection >90 days after enrollment for macular edema or at any
time for inflammation
The number and percentage of randomized participants actually receiving study medication, 
permanently discontinuing study drug (subdivided by reason), and receiving injections >90 days 
past enrollment will be summarized. A summary of study participants randomized by site will 
also be provided. Treatment groups will be compared for the proportion and reason for study 
drug discontinuation using the chi-square test. A summary of participant status at the end of the 
study period will also be generated with categories including lost to follow-up.  
5  Data Collection and Quality Assurance 
5.1  Quality assurance and security 
Data collection forms, training, security, and quality assurance are discussed in the Manual of 
Operations for the FAST Treatment Trial. 
5.2  Analysis sets 
Data sets for analysis will be produced at the 
 central site by database manager 
 Each 
will be a Microsoft Excel® worksheet containing a single header line whose variable names 
match the Access database. Each analysis set will be in the form of a rectangular table in which 


9 March 2017 
32 
each column corresponds to a single variable and each row to an observation. All missing values 
will be coded explicitly using the string NA (as used in the R software). Codes for categorical 
variables (such as 1 for male, and 2 for female) will be avoided in favor of self-documenting 
character strings (such as Male, Female) whenever possible. Automated checks will be made to 
ensure consistency and that each variable in the analysis set has in-range values (protecting 
against negative ages, spelling errors in categorical factors, and similar errors). 
A detailed codebook will be prepared, containing for each variable, (a) the form from which 
the variable derived, (b) the text of the question, (c) all possible values for the variable, and (d) 
summary statistics for the variable. Note that all codes and character strings that represent 
categorical factors will be clearly defined in the codebook. Units for each continuous variable 
(e.g. central subfield thickness, logMAR) will be unambiguously indicated for each variable. 
Each release of the analysis set will be accompanied by the corresponding version of the 
codebook. Version numbering with dates will be strictly observed. Standard report-generation 
software included with the R statistical and data analysis package will be used to ensure 
consistency of the codebook and analysis set at all times. 
5.3  Data monitoring reports 
Data monitoring reports will be prepared based on analysis data sets. These will be prepared 
using report-generation software. Monitoring reports will include (a) recruitment reports for each 
site, (b) compliance reports, (c) retention reports, and (d) data quality reports. These will be 
reviewed at the central site on a monthly basis, and communicated to the study sites on a monthly 
basis. 
6  Human Subjects 
6.1  Summary of final dispositions 
All subjects who provide informed consent will be accounted for in this study. The frequency of 
subjects in each population will be presented. We will also present the frequency of subjects in 
each subgroup, the frequency of withdrawal and loss to follow-up, and any major protocol 
violations. 
6.2  Data and Safety Monitoring Committee 
6.2.1  Scope 
A Data and Safety Monitoring Committee (DSMC) will be empaneled by the NEI. We propose 
that this committee consist of 5-7 individuals, and should include (a) uveitis specialists, (b) an 
independent biostatistician, (c) a bioethicist, and (d) a member to protect the interest of the Indian 
population. The committee will meet in person at least once per year. Ad hoc meetings as needed 
may also be convened. All study protocols will be subject to review and approval by Institutional 
Review Boards at 
, and by the DSMC. 




9 March 2017 
34 
6.2.3  Decisions 
The DSMC will make decisions with the benefit of prespecified decision guidelines. These 
guidelines will be agreed upon at the initial meeting, and are expected to include (a) safety, (b) 
efficacy, (c) clinical importance, (d) effect of baseline covariates, or (e) validity. 
Benefits.  Unmasked interim analyses (See Section 3.10) will be conducted to determine 
whether or not sufficient evidence has accumulated to justify stopping the trial because one 
treatment is clearly superior (and therefore should be extended to all future cases). The guidelines 
for efficacy will use group sequential boundaries for judging the statistical significance of the 
primary outcome measure. The Lan and DeMets flexible alpha spending approach will be used.   
Early discontinuation in this trial has the following disadvantages.  First, early discontinuation 
will make it more difficult to assess homogeneity of study sites.  In this trial, where the majority 
of planned enrollment is not from the US, discontinuation at time t=1/3 for instance would occur 
when only 15 American patients had been enrolled (under our enrollment projections), and at 
t=2/3, only 30 American patients.  Reflection on these small numbers of American patients may 
limit the adoption of the results of the trial.  Second, early discontinuation reduces the power to 
assess the secondary aims of Specific Aim 1, and for Specific Aim 2.  For these reasons, we 
propose to use conservative stopping rules.   
We propose to use a Hwang-Shih-deCani alpha spending function of the form 
with γ chosen to be equal to -5.623626 exactly.  This value was chosen to make the alpha at t=1/3 
approximately equal to 0.001.  The resulting alpha at t=2/3 is approximately 0.0075.  The R 
package gsDesign (v. 2.7-04 or higher) will be used for selected analyses. 
      The proposed plan is to have two interim looks, at approximately t=1/3 and t=2/3 (one third 
and two-thirds through the study), with the specific fractions to depend on the total available data 
at face to face DSMB meetings. 
The use of a flexible alpha-spending function protects the 0.05 alpha level of the overall trial 
while allowing for additional interim analyses for efficacy (if needed), without specifying the 
number and timing of the analyses at the start of the study. We note that the alpha spending 
function, including the value of γ, cannot be changed once the trial has begun. 
Harm.  Stopping for harm will be done at the judgment of the DSMC. Several endpoints will 
be examined, including serious adverse events such as significant and sustained laboratory 
abnormalities as described in the protocol, or mortality. While the analysis would consider 
maldistribution of predictive factors such as age, it is recognized that ethical considerations 
require careful considerations of statistical tests as well as qualitative judgments in the light of 
experience. Any additional analyses required by the DSMC will be conducted by 
, as 
needed. 
Note that serious adverse events (SAE) are reported directly to the medical monitor 
within 24 hours of the time the study site learns of them, and the medical monitor will 
subsequently pass this information on to the DSMC Chair. The medical monitor will receive 


9 March 2017 
35 
notification of the event, the timing of the event, a medical narrative from the study site, the site 
location, and the patient identification number. The statistician will report the study treatment 
assignment to the DSMC Chair if deemed necessary by the DSMC.  If use of either drug use 
clearly results in an unacceptable increase in the risk of treatment failures, then the study will be 
stopped. It is difficult to fully prescribe boundaries for monitoring safety because there need not 
be strong evidence to discontinue the study if it appears that the treatment is harmful. 
Futility.  Early discontinuation due to the unlikeliness of significant findings conditional on 
interim results would prevent the analysis of Specific Aim 2 and of the secondary aims of 
Specific Aim 1.  No stopping rules based on futility or conditional power calculations are 
included in the trial plan. 
7  Safety and tolerability 
The analysis of safety in this study will include summaries of the following: 
•
Exposure
•
Adverse events
•
Adverse events and serious adverse events (including deaths)
•
Adverse events leading to withdrawal
•
Any deaths
7.1  Exposure 
Individuals are assumed to have exposure to the drug corresponding to the arm to which they 
were randomized. 
7.2  Adverse Events 
7.2.1  Individual events 
Adverse event reporting procedures are described fully in the MOP. Non-serious adverse events 
(not requiring narrative form) are described in the MOP (Section 6.1). Serious non-ocular or 
ocular adverse events (which must be reported within 24 hours and which require a narrative 
form) are described in the MOP (Section 6.2). Adverse events will be reported in all 
presentations and publications according to Consort guidelines. 
The proportion of subjects with safety-related events will be compared using logistic regression, 
using treatment assignment and age as predictors, and including enrollment site as a random 
effect. Descriptive tables of the number and frequency of adverse events will be broken down by 
treatment arm, age, gender, and known comorbidities.  We will report total adverse events and 
serious adverse events, cross-tabulated by whether the adverse events were anticipated or 
unanticipated and by whether or not the adverse event led to discontinuation of medication. 
In addition, we will compare the rate of each of the adverse events during the follow-up period 
using Poisson regression, which can take into account multiple instances of adverse events within 


9 March 2017 
36 
a single subject. Age will be included as a predictor as well as treatment group, and enrollment 
site will be included as a random effect. 
The additional statistical analysis of adverse events we describe here is undertaken strictly to 
provide additional insight which may be useful to the DSMC and investigators.  Interpretation of 
such findings must reflect the fact that unanticipated adverse events may occur and that we may 
have insufficient power to make inferences between the arms when considering rare events.  Note 
that adverse events contribute to the outcome of the trial and specific analyses have been defined 
earlier. 
7.2.2  Pooled adverse events 
Adverse events will be analyzed according to four main categories: 
•
Proportion of subjects with any ocular adverse event
•
Proportion of subjects with any serious ocular adverse event
•
Proportion of subjects with any systemic adverse event
•
Proportion of subjects with any systemic serious adverse event
The proportion of subjects with these events will be compared between the arms using Fisher’s 
Exact Test. Poisson or negative binomial regression will be applied to compare the rates of 
overall adverse events, including recurrent events. 
8  Reporting conventions 
•
All tables and data listings will be presented in landscape orientation, unless presented as
part of the text of the final report.
•
Figures will be presented in landscape orientation, unless the information is substantially
easier to interpret in portrait orientation.
•
Direct annotation of figures will be preferred to legends. All figures with more than one
variable or item will contain either direct annotation or legends. All annotation will be
unambiguously identifiable as such.
•
Color will be used in figures only when needed to enhance clarity of communication. All
color schemes will be evaluated for visual clarity for individuals with diminished color
vision. All color encodings will be identified. Redundant encodings (such as the use of
different plot symbols or line dash patterns) will be used in addition to color, so that all
figures are interpretable after monochrome reproduction at 100 dots per inch. All dash
patterns and line widths will be adequate to be distinguishable after monochrome
reproduction at 100 dots per inch. Any distinction between plot symbols (circles, filled
circles, diamonds, etc.) will remain clear after monochrome reproduction at 100 dots per
inch.
•
Fixed width sans serif fonts will be used for all labeling (Helvetica, Arial, or Futura).
•
Boldface and italics will not be used unless substantial value is added.


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37 
•
Decorative fonts and enhancements, including borders and shading, will not be used.
Decorative presentation methods, such as ribbon graphs, will never be used.
•
All information given in figures will also be presented in summary tables (perhaps only
included in an Appendix or in supplementary materials).
•
Only standard characters will be used in tables and data listings.
•
All titles will be centered. The first title line will be the number of the table, figure, or
listing. The second and possibly third lines will be the description of the table, figure, or
data listing. The ICH numbering convention will be used for all.
•
All footnotes will be left justified and at the page bottom. Footnotes will be used sparingly.
Reference footnotes will be complete enough to locate any reference based on the
information provided (Author, Journal, Pages, Date, or PubMed accession number).
•
Missing values for numeric or character variables will be unambiguously identified as such
using the special string NA (not available) in all settings; NA is the standard missing value
code for our software. Each figure or table caption in which NA is used will indicate the
meaning of NA in that figure or table. The abbreviation NA will never be used for any
other purpose.
•
All date values will presented in the form DDmmmYYYY format (e.g. 01jan2008), using
four digit years. June will be encoded as jne (otherwise jan and jun would differ by only a
single character), and July as jly (so that the lowercase letter l, easily confused with the
digit 1, will not be adjacent to any numerals).
•
All tables, figures, and data listings will have the name of the program and a date/time
stamp on the bottom of the output.


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38 
9  Abbreviations and acronyms 
AES Advanced Encryption Standard  
CAS Chemical Abstracts Service  
DSMC Data and Safety Monitoring Committee  
FAST First-line Antimetabolites as Steroid-sparing Treatment 
FIPS Federal Information Processing Standard  
ICH International Conference on Harmonization 
logMAR log of minimum angle of resolution 
MOP Manual of Operations and Procedures 
NIST National Institute of Standards and Technology 
SAP Statistical Analysis Plan  




 
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40 
3.2.2 Planned Analysis of Primary Outcome 
• Added non-inferiority analysis with a prespecified non-inferiority limit if the primary 
outcome is no statistically significant. 
 
3.5.1 Injections (New Section) 
• Added section: If a patient receives a corticosteroid injection 90 days after enrollment, it 
is not possible to truly assess the study drug’s ability to manage inflammation at the 
Month 6 visit. Therefore, as a senstivity analysis, the primary outcome for these patients 
will be considered by the inflammation levels at the time of the injection. If the patient 
received the injection because of uncontrolled inflammation, the patient will be 
considered a treatment failure. If the patient met the definition of treatment success at the 
time of the injection, the patient will be considered a treatment success.  
 
4.2  Major protocol deviations 
• Added: received a corticosteroid injection >90 days after enrollment for macular edema or 
at any time for inflammation  
 
 
9 March 2017  
2.4.2 Randomization List 
• Updated: Starting 18 January 2017, all patients will be randomized using the REDCap 
database. Coordinators can access only the randomization lists for their site. When 
patients are enrolled, the ID is logged in REDCap and the system provides the medication 
assignment. All emergency contacts have access to the REDCap database for their site in 
case of an emergency when unmasking is needed for patient safety.  The REDCap 
database contains assignments for all previously enrolled patients. All previous 
randomization lists were deemed void and were destroyed. Each site submitted a 
certification of destruction form.  
 
2.4.6  Provision of randomization list 
• Updated: As of 17 January 2017, all randomization lists are electronic on REDCap. Once 
a patient is enrolled, the study coordinator logs the patient in the database and the system 
reveals the drug assignment, written out in full.  
 


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41 
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