TABLE OF CONTENTS

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
   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
   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
9. 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
10. 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

Investigators, Personnel and Study Sites

Investigators, Personnel and Study Sites, continued.

Data Safety and Monitoring Committee (DSMC) Members

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Background

1. Introduction to trial

1.1. Research question

1.2. Specific aims

2. Trial design

2.1. Design summary

Study type

• Randomized, observer-masked comparative effectiveness trial
• Block randomization by site:
• Sample size: 216 patients, 108 patients per arm (Table 1)

Treatment arms

• Oral methotrexate
• Oral mycophenolate mofetil

Treatment timeline

• Phase I
• Initial treatment from 0-6 months. If treatment success (i.e. achieving corticosteroid-sparing control of inflammation at 6 months), treatment extended to 12 months.
• Phase II
• Second therapy initiated after failure to achieve corticosteroid-sparing control of inflammation in Phase I (0-6 months).

Outcomes

• Primary outcome (Specific Aim 1):
• Proportion of overall treatment success at 6 months, where treatment success is defined as controlled ocular inflammation (Table 2) with day of oral prednisone and drops/day of topical 1% prednisolone acetate
• Secondary outcomes
• Proportion of corticosteroid-sparing treatment success at 6 months after switching treatments in patients who are a treatment failure in the first 6 months where treatment success is defined as in Aim 1 (Specific Aim 2)
• Time to control of inflammation
• Time to treatment success
• Proportion achieving treatment success at 5 months and sustaining, for at least 28 days, to 6 months
• Proportion achieving treatment success at 12 months in Phase I
• Phase I treatment success ( months) with complete discontinuation of corticosteroid
• Proportion achieving treatment success at 6 months in Phase II
• Change in best spectacle-corrected visual acuity (BSCVA)
• Presence of macular edema
• Change in macular thickness
• Change in vitreous haze as assessed clinically by the Miami (formerly Davis) scale
• Change in vitreous haze as assessed by fundus photography grading by NEI and Miami (formerly Davis) scales
• Efficacy for intermediate, posterior and panuveitis subgroups
• Efficacy for retinal vasculitis
• Proportion discontinuing due to intolerability
• Rate of adverse events
• Proportion discontinuing due to serious adverse events
• Quality of life (Health related and vision related)
• Dose reduction
• Efficacy of treatment in patients with Vogt-Koyanagi-Harada (VKH) disease
• Proportion of patients beginning with at least inflammation in anterior chamber cells who experience a 2 -step reduction (i.e. decreasing from to to ; to ).
• Proportion of patients beginning with at least inflammation in vitreous haze who experience a 2 -step reduction (i.e. decreasing from to to to ).
• Proportion of patients who started with at least 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 inflammation levels in vitreous haze who achieve a decrease to 0 level of inflammation in vitreous haze.
• Proportion of patients achieving controlled inflammation defined by 0 level of inflammation in vitreous haze and 0 level of inflammation in anterior chamber cells
• Proportion of patients requiring injections for severe inflammation during the trial
• Proportion of patients requiring injections for macular edema during the trial

2.2. Study timeline

2.3. Eligibility

2.3.1. Anatomical location of inflammation

2.3.2. Inclusion Criteria

• 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:
  anterior chamber cells and/or
  vitreous haze and/or
  active retinal or choroidal inflammation
• Active inflammation in at least one eye at enrollment, defined by any of the following:
  anterior chamber cells and/or
  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 ( 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 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 treatment :
• 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 or 60 mg 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.

2.3.3. Exclusion criteria

• 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 for months) in both eyes
• Periocular or intravitreal corticosteroid injection in the past 4 weeks
• Fluocinolone acetonide implant in either eye in 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 ( white blood cells and/or platelets and/or hemoglobin) within 4 weeks prior to enrollment*
• Abnormal alanine aminotransferase (ALT) and/or aspartate aminotransferase (AST) times the upper limit of normal for the lab and/or creatinine 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)

2.3.3.a. Screening for Active Tuberculosis

2.4. Randomization and masking

Block randomization of the patients will ensure that an equal number of patients are randomized to each study arm at each site. Randomization lists will be created by the biostatistician () and accessed online via REDCap database. The following people will be able to access to the list of patients who have been randomized through the REDCap database:

*Emergency contacts will log into REDCap to consult the list of randomized patients in case of an emergency in which unmasking is necessary for patient safety and of the DCC cannot be reached.

Data Coordinating Center (DCC) Personnel

The following study coordinators will have access to REDCap to perform randomizations but will not know the treatment assignments prior to randomizing patients:

D

The

will be responsible for purchasing and distributing bottles of the medications labeled with NDC/lot number and expiration dates to

who will add dosing instructions and distribute medication to
where they will distribute the medication.

2.5. Definitions for primary endpoint

2.5.1. Determination of Treatment Success/Failure

2.5.2. Treatment failure

• Failure due to efficacy: Patients can be declared a treatment failure due to futility and be declared a treatment failure and enter Phase II at any time during follow-up if the following occurs: The treating physician determines that it is futile to continue the current study medication due to persistent, uncontrolled inflammation that appears to be non-responsive to treatment. This option of declaring futility should only be declared if treatment with study medication seems completely unlikely to be able to control inflammation. Since the medications take up to a few months to fully take effect, increase in inflammation early on in the trial is not an indication of treatment failure. Corticosteroids may be increased in the case of increased inflammation.

• Failure due to intolerability: Patients who experience severe symptoms thought to be related to the drug should try a dose reduction if they are willing. If this is not successful and the patient is unable to continue their
  medication due to symptoms and is also not willing to continue, treatment failure can be declared. Please refer to Table 5 for dose reduction guidelines. Trial of a dose reduction is strongly encouraged, however it is not required for a patient to be determined a treatment failure due to intolerability.
• Failure due to safety: Patients who experience abnormal lab results meeting the designated threshold of a non-serious adverse event (e.g. AST or ALT increasing to twice the upper limit of normal) will immediately stop taking their medication. As these abnormalities are often reversible, patients whose abnormalities are classified as nonserious adverse events (see Table 3) will be allowed 28 days to regain eligibility. It is recommended that these patients repeat lab tests within weeks of the initial abnormal result to see if the results return below the designated threshold (e.g. AST or ALT less than twice the upper limit of normal). If the lab results return below the designated threshold of a non-serious adverse event within 28 days, patients may be re-administered the study drug per protocol or at one of the designated dose reduction levels, at the investigator's discretion.

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.

• 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 noncompliant 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).

• 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.
  

  

3. Treatment plan

3.1. Study drugs

3.1.1. Methotrexate

3.1.1.a. Dose Reduction MTX

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

3.1.2.a. Dose Reduction Mycophenolate Mofetil

3.1.2.b. Proton Pump Inhibitors and Mycophenolate Mofetil

3.1.3. Folic acid

3.1.4. Packaging and distribution of study medications

3.1.5. Adherence to the treatment plan

3.1.5.a. Missed Doses

3.2. Corticosteroid therapy

3.2.1. Oral prednisone

Prednisone vs. alternative oral corticosteroid

Initial dose

Tapering schedule

Directions for Rescue Taper

• Increase oral prednisone up to a dose of for severe reactivations, or for mild reactivations, up to double the dose at which the flare occurred, until uveitis is controlled. Then re-taper according to the guidelines.

• Hold the current dose of prednisone for an additional week. If still no improvement, treatment failure due to futility may be declared, and patients may proceed to Phase II. Alternatively, other therapies may be added, but these should be noted as a protocol deviation.
• If treatment failure is declared due to futility in Phase I, before the primary endpoint of 6 months, patients may switch to Phase II. Patients who refuse to switch to Phase II should be encouraged to return for a 6 -month visit. Patients who switch to Phase II will already be followed.
• If treatment failure is declared due to futility in Phase II, before the primary endpoint of 6 months, patients will be treated according to best medical judgment. If treatment failure is declared prior to 6 months, Phase I and Phase II, every attempt must be made to bring patients back for their 6 month assessment.

3.2.2. Supplements

• Calcium supplement, 500 mg 3 times daily (unless contraindicated)
• Vitamin D, 400-800 IU daily.

3.2.3. Topical corticosteroid

3.2.4. Periocular and Intravitreal Injections

3.2.5 Other adjunctive treatments/procedures

3.3. Study procedures

Enrollment/Baseline 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

• 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:
• Review of patient medication diaries
• Review of adverse events since last visit*
• Dispense new medication bottle (if applicable)
• Completion of SF-36 questionnaire (All patients) (if applicable)
• Completion of NEI-VFQ-25 (all patients) and IND-VFQ (Indian patients only)
• Remind the patient that they should not speak to their study doctor about their dosing schedule, or the name of the medication that they are currently taking.
  *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.
• The patient will then complete the study assessments, in the following order:
• Visual Acuity Assessment
• Slit lamp front of the eye exam and intra-ocular pressure
• The patient's eyes will then be dilated and the following assessments will be completed, in any order**:
• Posterior segment exam
• OCT imaging
• Fundus photography
• Fluorescein angiogram (not a study assessment, but if performed results should be recorded)
• Laboratory measurements
• After completion of the study visit, the patient will meet with the coordinator, review scheduling for the next study visit, and retrieve their medication.
  **It is essential that visual acuity measurements, front of the eye exams and intra-ocular pressure are completed before dilation of the eyes.

Data handling and data entry

4. Study visits

4.1. Visit schedules

4.1.1. Phase I: First-line treatment

Guidelines for Visit Schedule I

• Day 1 corresponds to the Baseline-I visit, which is also the first day the patient receives treatment.
• Visit windows are determined based on the date of randomization.
• 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. Laboratory measurements may be collected within either 4 weeks or 90 days prior to the date of randomization, depending on the laboratory test.
• There should be a minimum of 2 weeks between each study visit.
• Data for the baseline and follow-up visits may be collected anytime within the visit window.

• Since baseline/treatment administration (Phase 1)

4.1.2. Phase II: Rescue treatment

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.
  

  

• 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

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 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.

4.2. Study form completion schedule

4.3. Phase I Enrollment/Baseline visit

4.3.1. Consent and eligibility evaluation

4.3.2 Randomization

4.3.3. Procedures for data collection

• 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

• 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)

• 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)

4.3.5. Forms for data collection

• 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

4.4.1. Procedures for data collection

• 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

• 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)

4.4.3. Forms for data collection

• 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)

4.5. Baseline Phase II

4.5.1. Eligibility

4.6. Non-study visits

4.6.1. Study Procedures

• Clinical eye exam (if treatment failure is declared)

4.6.2. Specimens

4.6.3. Forms for data collection

• 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)

5. Study examinations and procedures

5.1. Quality of life questionnaire administration

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)

5.2.A Refraction and visual acuity (PRIMARY - FOR LETTER VISION CHARTS)

5.2.1.A Refraction procedure

Beginning Approximate Refraction

Manifest Refraction

• 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

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
  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

• 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 and then at , 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 or , position the cross cylinder with the positive axis first at then ;
• 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 cylinder power in the above step, position the +/- 0.50 diopter cross-cylinder first with the positive axis to the right of the cylinder axis (position one), and secondly with the positive axis at 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 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 crosscylinder is no better than the other position, proceed to refining cylinder power).

Refine cylinder power

• Ask the subject to look at the lowest line on the visual acuity chart which can be read;
• Switch to diopter cross-cylinder;
• Align the diopter cross-cylinder first with the positive axis and then with the negative axis coincident with the cylinder axis. Ask the subject which is better;
• If the subject prefers the negative axis coincident with the cylinder axis, decrease the power of the cylinder in the trial frame by +0.25 diopter;
• If a subject indicates a change that would introduce negative cylinder power, remove all cylinder power and continue testing for positive cylinder power at an axis away from the previous axis;
• If the subject prefers the positive axis coincident with the cylinder axis, increase the power of the trial frame by +0.25 diopter and retest;
• Beginning with cylinder powers of diopter or more, for each diopter change in cylinder power, adjust the sphere power by 0.25 diopter of the opposite sign; this is done to maintain the spherical equivalent.

Spherical refinement

• 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 end the refraction by checking with plus lenses.

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 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 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

• 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 diopter cross-cylinder with the positive axis first at and then at , 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 or , position the cross cylinder with the positive axis first at then ;
• 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 cylinder power in the above step, position the diopter cross-cylinder first with the positive axis to the right of the cylinder axis (position one), and secondly with the positive axis at to the left of the cylinder axis (position two). Ask the subject which position improves the 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 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 crosscylinder is no better than the other position, proceed to refining cylinder power).

Refine cylinder power

• Ask the subject to look at the lowest line on the visual acuity chart which can be read;
• Align the diopter cross-cylinder first with the positive axis and then with the negative axis coincident with the cylinder axis. Ask the subject which is better;
• If the subject prefers the negative axis coincident with the cylinder axis, decrease the power of the cylinder in the trial frame by +1.00 diopter;
• If a subject indicates a change that would introduce negative cylinder power, remove all cylinder power and continue testing for positive cylinder power at an axis away from the previous axis;
• If the subject prefers the positive axis coincident with the cylinder axis, increase the power of the trial frame by +1.00 diopter and retest;
• Beginning with cylinders of 1.00 diopter or more, for each 0.5 diopter change in cylinder power, adjust the sphere by 0.25 diopter of the opposite sign; this is done to maintain the spherical equivalent.

Spherical refinement

• 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 <20/200 (<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 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;lf 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

• 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 and then at , 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 or , position the cross
  cylinder with the positive axis first at then ;
• 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 cylinder power in the above step, position the diopter cross-cylinder first with the positive axis to the right of the cylinder axis (position one), and secondly with the positive axis at to the left of the cylinder axis (position two). Ask the subject which position improves the 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 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 crosscylinder is no better than the other position, proceed to refining cylinder power).

Refine cylinder power

• Ask the subject to look at the lowest line on the visual acuity chart which can be read;
• Align the diopter cross-cylinder first with the positive axis and then with the negative axis coincident with the cylinder axis. Ask the subject which is better;
• If the subject prefers the negative axis coincident with the cylinder axis, decrease the power of the cylinder in the trial frame by 1.00 diopter;
• If a subject indicates a change that would introduce negative cylinder power, remove all cylinder power and continue testing for positive cylinder power at an axis away from the previous axis;
• If the subject prefers the positive axis coincident with the cylinder axis, increase the power of the trial frame by +1.00 diopter and retest;
• Beginning with cylinders of 1.00 diopter or more, for each 0.5 diopter change in cylinder power, adjust the sphere by 0.25 diopter of the opposite sign, this is done to maintain the spherical equivalent.

Spherical refinement

• With the subject looking at the smallest line legible on the visual acuity chart, place a +1.00 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 +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;
• Continue presenting the -1.00 lens to see if there is further improvement in vision;
• When an additional -1.00 lens does not improve vision;
• Present the +1.00 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 power.

5.2.2.A Visual acuity procedure

Visual Acuity Charts

Visual Acuity Boxes

Illumination

4- and 1-Meter Visual Acuity Lanes

• Wall-mounted box: In addition to the 4 -meter lane, 7 inches 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 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.

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

Testing of Hand Motion Vision

Testing for Light Perception

Scoring Best Corrected Visual Acuity

5.2.3.A Visual acuity training and certification

5.2.B Refraction and visual acuity (PROTOCOL FOR TUMBLING E CHART)

5.2.1.B Refraction procedure

Beginning Approximate Refraction

Manifest Refraction

• 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

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

• 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 diopter cross-cylinder with the positive axis first at and then at ,
  asking if either position makes the letters 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 or , position the cross cylinder with the positive axis first at then ;
• 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 cylinder power in the above step, position the diopter cross-cylinder first with the positive axis to the right of the cylinder axis (position one), and secondly with the positive axis at 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 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 crosscylinder is no better than the other position, proceed to refining cylinder power).

Refine cylinder power

• Ask the subject to look at the lowest line on the visual acuity chart which can be read;
• Switch to +/- 0.25 diopter cross-cylinder;
• Align the diopter cross-cylinder first with the positive axis and then with the negative axis coincident with the cylinder axis. Ask the subject which is better;
• If the subject prefers the negative axis coincident with the cylinder axis, decrease the power of the cylinder in the trial frame by +0.25 diopter;
• If a subject indicates a change that would introduce negative cylinder power, remove all cylinder power and continue testing for positive cylinder power at an axis away from the previous axis;
• If the subject prefers the positive axis coincident with the cylinder axis, increase the power of the trial frame by +0.25 diopter and retest;
• Beginning with cylinder powers of diopter or more, for each diopter change in cylinder power, adjust the sphere power by 0.25 diopter of the opposite sign; this is done to maintain the spherical equivalent.

Spherical refinement

• 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 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 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

• 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 and then at , 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 or , position the cross cylinder with the positive axis first at then ;
• 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 cylinder power in the above step, position the diopter cross-cylinder first with the positive axis to the right of the cylinder axis (position one), and secondly with the positive axis at to the left of the cylinder axis (position two). Ask the subject which position improves the 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 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 crosscylinder is no better than the other position, proceed to refining cylinder power).

Refine cylinder power

• Ask the subject to look at the lowest line on the visual acuity chart which can be read;
• Align the diopter cross-cylinder first with the positive axis and then with the negative axis coincident with the cylinder axis. Ask the subject which is better;
• If the subject prefers the negative axis coincident with the cylinder axis, decrease the power of the cylinder in the trial frame by +1.00 diopter;
• If a subject indicates a change that would introduce negative cylinder power, remove all cylinder power and continue testing for positive cylinder power at an axis away from the previous axis;
• If the subject prefers the positive axis coincident with the cylinder axis, increase the power of the trial frame by +1.00 diopter and retest;
• Beginning with cylinders of 1.00 diopter or more, for each 0.5 diopter change in cylinder power, adjust the sphere by 0.25 diopter of the opposite sign; this is done to maintain the spherical equivalent.

Spherical refinement

• 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

• 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;
• 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

• 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 and then at , 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 or , position the cross cylinder with the positive axis first at then ;
• 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 cylinder power in the above step, position the +/- 1.00 diopter cross-cylinder first with the positive axis to the right of the cylinder axis (position one), and secondly with the positive axis at to the left of the cylinder axis (position two). Ask the subject which position improves the 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 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 crosscylinder is no better than the other position, proceed to refining cylinder power).

Refine cylinder power

• Ask the subject to look at the lowest line on the visual acuity chart which can be read;
• Align the diopter cross-cylinder first with the positive axis and then with the negative axis coincident with the cylinder axis. Ask the subject which is better;
• If the subject prefers the negative axis coincident with the cylinder axis, decrease the power of the cylinder in the trial frame by 1.00 diopter;
• If a subject indicates a change that would introduce negative cylinder power,
  remove all cylinder power and continue testing for positive cylinder power at an axis away from the previous axis;
• If the subject prefers the positive axis coincident with the cylinder axis, increase the power of the trial frame by +1.00 diopter and retest;
• Beginning with cylinders of 1.00 diopter or more, for each 0.5 diopter change in cylinder power, adjust the sphere by 0.25 diopter of the opposite sign, this is done to maintain the spherical equivalent.

Spherical refinement

• With the subject looking at the smallest line legible on the visual acuity chart, place 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 +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;
• Continue presenting the -1.00 lens to see if there is further improvement in vision;
• When an additional -1.00 lens does not improve vision;
• Present the +1.00 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 power.

5.2.2.B Visual acuity procedure

Visual Acuity Charts

Visual Acuity Boxes

Illumination

4- and 1-Meter Visual Acuity Lanes

• Wall-mounted box: In addition to the 4 -meter lane, 7 inches 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 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.

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

Perception.

Testing of Count Fingers Vision

Testing of Hand Motion Vision

Testing for Light Perception

Scoring Best Corrected Visual Acuity

• 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
  performed. (This result, count fingers, hand motion, light perception, or no light perception, will be used for the analysis by converting into a score according to Visual Acuity Calculation Table).

5.2.3.B Visual acuity training and certification

5.3. Ophthalmic procedures

5.3.1. Grading Cataracts

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

Anterior Chamber Cells

Anterior Chamber Flare

SUN Working Group Grading Scheme for Anterior Chamber Flare

Vitreous Cells

Vitreous Haze

*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.

Figure 2: Miami 9-point system for grading vitreous haze

Grading Retinal/Choroidal Inflammation

5.3.3. Inter-observer variation of ocular inflammation

5.3.4. Training and certification of ophthalmologists and study coordinators

5.4. Optical coherence tomography

5.4.1. Required patient assessments-Heidelberg Spectralis

• High Speed Volume scan centered on the macula
• 49 sections
• 16 frames (ART)
• 7-Lines scan centered on the macula
• 7 sections
• 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

• 49 sections
• 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

• 7 sections
• 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

5.4.4. Saving/Exporting data-Heidelberg Spectralis

Saving Data

• All scans should be saved and archived at each study site on the Heidleberg SDOCT unit.
• Even if your clinic saves all scans onto a server, please follow the instructions
  below to save all scans for FAST study patients onto an external hard drive.
• After obtaining scans, highlight all study scans together, right click and choose "Export as E2E"
• Click on the "Anonymize data" box in order to ensure patient confidentiality
• In the "Export File" filed: Name the E2E file as "Patient Study ID-Visit Number-Date of visit", example "2H003-M6-17NOV2014"
• In the "Last Name" field: Type in the Patient's Study ID and Visit, example "2H003 M6"
  

  

• 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.
• 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
• 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.
• If images cannot be obtained or are of poor quality, please provide comments on the Transmittal Form
• Compress the folder into "ZIP" format.
• Upload the ZIP folder to the Uveitis Reading Center server:

5.4.5. Required patient assessments-Zeiss Cirrus

• Macular Cube Scan
• 5 Line Raster scan centered on the macula

5.4.6. Scan procedures-Zeiss Cirrus

Creating Patient Files

• In the Last Name field, enter study name: FAST
• In the First Name field, enter patient's unique study number
• For Date of Birth, always use 1/1/2000
• Click proper field in gender section
• In Patient ID field enter patient's unique study ID number, example: "1Q001"

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
• Ensure that the camera is pulled 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

• In the Iris Viewport, center the scan beam through the pupil by clicking on the pupil center or using the X-Y controls
• Focus the iris image using the chinrest arrows
• Center the fundus image in the Fundus Viewport
• Click on "Auto Focus"
• Use small arrows to focus manually
• Click "Optimize"
• Ask patient to blink right before image capture
• Click "Capture"
• Review scan; if acceptable, click "Save"
• If not acceptable, click "Try Again"

• 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
• Ensure that the scan image is maintained in the upper half of the screen
• Please review scans for completeness and quality. Signal strength should be at least 5 or higher. Please repeat any scans that are not complete or of poor quality.

5.4.7. Obtaining retinal thickness data-Zeiss Cirrus

• Obtain Macular Thickness analysis
• Obtain 5 Line Raster analysis
• Record central subfield thickness on data sheet

5.4.8. Saving/Exporting data-Zeiss Cirrus

• All scans should be saved and archived at each study site on the Zeiss Cirrus SDOCT unit. This raw data should also be saved onto a separate removable hard drive so that it is available for export and review at a later date.
• The following images should be uploaded to the server of the Uveitis Reading Center for review.
• Under Records select Export Exams
• Browse to folder where to save files
• Search for the subject to export
• Under Exam Export select the Eye(s) and Exam Type for the visit you want to export
• Select Export
• Label the file with patient's unique study ID, visit number, and date of visit, example: "FAST_1Q001_BL_10AUG2012_IB"
• Fill out transmittal form
• Compress the folder containing the image files for both eyes and the Transmittal form in ZIP format
• Upload the ZIP folder to the Uveitis Reading Center server:
  

  

5.4.9. OCT operator qualifications

5.5. Fundus Photography

5.6. Laboratory measurements

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

6. Adverse events

6.1. Non-serious adverse event (AE) *see the adverse event checklist (Section A.10)

• Increased intraocular pressure ( )
• Abnormal lab findings ( times but times the upper limit of normal AST or ALT, rise in creatinine to to , reduction of white blood cell count to below 2.5)
• Concurrent accident or illness
• Increase in the frequency and severity of symptoms of a pre-existing condition
• Side effects such as gastrointestinal upset, nausea, vomiting, fatigue

6.2. Serious adverse event (SAE) *see the adverse event checklist (Section A.10)

• times the upper limit of normal AST or ALT
• Death
• Non-elective surgery or hospitalization for any reason
• Myocardial infarction or stroke
• Life-threatening adverse drug experience or any life threatening event
• Persistent or significant disability or incapacity
• Cancer
• Seizure
• Congenital anomaly/birth defect
• Disability or permanent damage
• Required intervention to prevent permanent impairment/damage

6.3. Adverse event reporting

6.4. Patient death

7. Data collection and management

7.1. Data collection forms

7.2. Data review

7.3. Data entry

7.3.1. Data entry errors

7.3.2 Data consistency and validity

7.3.3. Data preparation and cleaning

7.3.4. Monitoring

7.4. Data analysis

7.5. Data storage and security

8. Quality control

8.1. Medication storage and expiry

8.2 Periodic reports

8.3. Data management, security and quality assurance

8.4. Monitoring compliance

8.5. Certification

8.6. Data audits

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
• 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 nonmasked, 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

9.10. Fundus Photographers

• Perform fundus photography as specified by protocol of both eyes at the baseline, 6 months, 12 months or treatment failure visits

9.11. The Reading Center

• Complete grading of vitreous haze from images of fundus photography
• Process OCT images

10. Study Organization

10.1. Executive Committee

10.2. Clinical Coordinating Center (CCC)

10.3. Uveitis Photograph Reading Center (UPRC)

10.4. Data Coordinating Center (DCC)

10.5. Data Analysis Center (DAC)

10.6. Data Safety and Monitoring Committee (DSMC)

10.7. Editorial Committee

The Editorial investigators

10.8. Study Sites

10.9. Pharmacy

10.10 Study Communications

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. BrJ 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;22:16875.
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
    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.

FAST Uveitis Trial

Statistical Analysis Plan

Confidential

TABLE OF CONTENTS

1 Introduction

• FAST Uveitis Trial Manual of Operations
• ICH Guidance on Statistical Principles for Clinical Trials
• Statistical Analysis Plan
• Statistical Analysis Plan

2 Investigational Plan

2.1 Study Design

2.2 Study Population

2.3 Specific Aims

2.3.1 Specific Aim 1

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 inflammation in anterior chamber cells and experience at least a 2 -step reduction (i.e. decreasing from to ; to to ).
• To determine the proportion of patients beginning with at least inflammation in vitreous haze and experience at least a 2 -step reduction (i.e. decreasing from to to ; to .
• 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 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 inflammation levels in vitreous haze who achieve a decrease to 0 level of inflammation in vitreous haze.

• 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

2.4 Randomization

2.4.1 Stratification between sites

2.4.2 Randomization list

Distribution of the randomization list to will be accomplished using the
encrypted email provision. Email is encrypted using the Advanced Encryption Standard (NIST FIPS 197) whenever the first four characters of the subject line are PHI: The sender is notified when the recipient receives a secure email; the recipient receives a notification of a secure email and can view it using the

Secure Messenger website. We have successfully used this method in previous clinical trials
□ . The randomization lists will each contain more randomization assignments than needed. Successively recruited patients will receive sequential
assignments from the list. The long list provides a measure of added safety in case one of these sites recruits far more patients than expected relative to the other site.

2.4.3 Block randomization

2.4.4 Unique patient identifiers

2.4.5 Random number generation

2.4.6 Provision of randomization list

2.4.7 Quality assurance

2.4.8 Summary of disposition of randomization list

*Emergency contact persons who will consult the list only in case of an emergency in which unmasking is necessary for patient safety and on the DCC cannot be reached.

Data Coordinating Center (DCC) Personnel

2.5 Masking

3 Statistical Considerations

3.1 Baseline characteristics