The Diabetic Retinopathy Clinical Research Network 11

Background: Persistent DME  Experience from DRCR.net Protocol I 52% of ranibizumab eyes didn’t achieve ≥2 vision-line improvement ≥40% did not have resolution of retinal thickening (<250 µm) at year 2 Eyes that remain edematous at 6 months and 1 year following ranibizumab treatment have been consistently thickened throughout the treatment period. 2

Evidence from Clinical Trials of Beneficial Effects of Intravitreal Corticosteroids for DME  DRCR.net Protocol I pseudophakic subgroup had a visual gain similar to the Ranibizumab groups  FAME study Fluocinolone Acetonide demonstrated benefits over 3 years  MEAD study benefit of dexamethasone intravitreal implant over three year treatment period Cataract and IOP rise are issues

Rationale  There is a need for alternative or additional treatments due to incomplete response to ranibizumab in about ½ the eyes.  Protocol I data showed that the pseudophakic subgroup achieved the same results as ranibizumab at 2 yrs (this was not a prespecified subgroup, however).  As intravitreal steroids have been shown to have a positive effect on DME in some eyes, despite safety issues, and might add benefit in eyes that are already receiving anti-VEGF, where benefits might outweigh risks. 4

Why This Study?  To assess short-term effects of combination corticosteroid+anti-VEGF therapy on OCT retinal thickness and visual acuity in comparison with that of continued anti-VEGF therapy alone in pseudophakic eyes with persistent DME and visual acuity impairment despite previous anti- VEGF treatment.  To provide more information needed for future conduct of a definitive phase III clinical trial. 5

Study Drugs Dexamethasone (OZURDEX®)  Sustained-release polymer that provides 700 μg of dexamethasone  FDA-approved for uveitis and macular edema due to RVO, and for DME that that have had (or will imminently have) cataract surgery  Provided by Allergan Inc. Ranibizumab 0.3mg (LUCENTIS®) 6  Anti-human VEGF monoclonal antibody  FDA-approved for treatment of wet AMD, macular edema following RVO, and DME  Provided by Genentech Inc.

METHODS 7

Study Overview 8 Week 0 Week 4 Week 8 Week 12 Week 16 Week 20 Week 24 Week 0 Week 4 Week 8 Week 12 Week 16 Week 20 Week 24 Week 0 Week 4 Week 8 Week 12 VGF Enrollment SHM VGF Dex VGF SHM Dex Group A: Sham + Ranibizumab Group B: Dexamethasone+ Ranibizumab Run-In Phase (3 months) Randomization Phase (6 months) Assess Eligibility For Randomization

Study Eye  Both eyes can be enrolled if eligible for the run-in phase  Both eyes can be randomized if criteria met for randomization  Two eyes from the same participant will be randomized to different treatment arms 9

Study Sample Size A minimum of 75 study eyes in each group (from approximately 62 participants) 10

Major Eligibility Criteria  Age ≥18 years  Type 1 or type 2 diabetes  At least 1 eye meeting study eye eligibility criteria  No history of chronic renal failure requiring dialysis or kidney transplant  BP <180/110  No history of cardiac event or stroke within 1 month prior to enrollment 11

Major Study Eye Eligibility Criteria  Pseudophakic  At least 3 injections of anti-VEGF drugs (aflibercept, bevacizumab, or ranibizumab) within the prior 20 weeks (5 months)  Visual acuity letter score ≤78 and ≥24 (20/32 to 20/320)  Central-involved DME on clinical exam  OCT CSF thickness within 8 days of enrollment  Zeiss Cirrus: ≥290 in women; ≥305 in men  Heidelberg Spectralis: ≥305 in women; ≥320 in men  No macular laser or PRP within 4 months or anticipated need for PRP in next 6 months  No previous history of glaucoma or steroid intraocular pressure response in either eye 12

Other Important Study Eye Exclusion Criteria  History of cataract extraction within 6 months  IOP ≥25 mmHg or history of open angle glaucoma  Sutured PC-IOL with ruptured post. capsule 13

Non-Study Eye Criteria  In subjects with only one study eye, the following must be met in the fellow non-study eye: IOP <25 mm Hg No history of open-angle glaucoma No history of steroid-induced IOP elevation that required IOP-lowering treatment No exam evidence of pseudoexfoliation 14

Enrollment Testing Procedures  E-ETDRS visual acuity testing at 3 meters in each eye within 8 days prior to enrollment Includes protocol refraction prior to VA testing  OCT on study eye within 8 days prior to enrollment and at least 21 days after any prior intravitreal anti-VEGF treatment  Ocular examination on each eye including slit lamp, measurement of intraocular pressure, lens assessment, and dilated ophthalmoscopy (within 8 days prior to enrollment)  Measurement of blood pressure 15

Run-In Phase  Overview All enrolled eyes are required to complete a 12-week run- in phase, where they receive 3 additional anti-VEGF injections  Objective To ensure that enrolled eyes truly have “persistent DME” despite prior anti-VEGF therapy when given up to 3 injections within the controlled environment of a study  Visit Schedule 4 weeks (±1 week) 8 weeks (±1 week) 12 weeks (±1 week) – Randomization visit  A minimum of 21 days required between visits 16

Treatment During Run-in Phase  All study eyes will receive an injection of ranibizumab 0.3 mg at enrollment, 4 weeks, and 8 weeks.  Injections must be at least 21 days apart.  If each injection is not given within window for any reason (e.g. AE, DME resolution), the eye will not continue in the study 17

Randomization  At end of run-in phase, study eye(s) are randomized if: All 3 run-in visits and injections completed within ±10 days of the target visit date Randomization visit is no more than 5 weeks from 8- week visit Has been ≥21 days since prior study injection VA letter score ≤78 and ≥24 (20/32 to 20/320) Definite central-involved DME on clinical exam Definition of “persistent DME” is met Confirmation that no exclusion criteria for enrollment have developed/occurred during run-in phase  If above are not met, study eyes exit the study 18

Persistent DME at End of Run-in Phase  CSF thickness on OCT meeting either one of the following two gender- and OCT machine-specific criteria: Zeiss Cirrus o≥290 in women o≥305 in men Heidelberg Spectralis o≥305 in women o≥320 in men 19

Randomization Visit Procedures  E-ETDRS visual acuity (including protocol refraction) in each eye on day of randomization  OCT on study eye (on day of randomization)  Ocular examination on each eye including slit lamp, measurement of intraocular pressure, lens assessment, and dilated ophthalmoscopy (on day of randomization)  HbA1c  Measurement of blood pressure 20

Study Treatment Groups  Participants with one study eye Group A: Sham + intravitreal ranibizumab Group B: Intravitreal dexamethasone + intravitreal ranibizumab  Participants with two study eyes ( both eyes are eligible at the time of randomization ): One eye randomly receives Group A, and the other eye receives Group B 21

Treatment On Day of Randomization  The ranibizumab injection must be given on the day of randomization.  The sham or dexamethasone injection will be given within 0-8 days of the ranibizumab injection.  If the injections are given consecutively on the same day, Group A: Give Sham injection first Group B: Give Ranibizumab injection first  Dexamethasone injection is NEVER given first 22

Post-Randomization Treatment 23 Evaluate VA and OCT at each protocol visit VA ≥84 (20/20 or Better) AND OCT CSF thickness < Cirrus: 290 ♀ / 305 ♂ Spectralis: 305 ♀ / 320 ♂ VA <84 (worse than 20/20) OR OCT CSF thickness ≥ Cirrus: 290 ♀ / 305 ♂ Spectralis: 305 ♀ / 320 ♂ NO Protocol Injection(s) Give Protocol Injection(s) * Retreatment at investigator’s discretion if AE occurs from prior injection * Non-protocol treatment for DME should not be given

About Treatment….  If combination injections were not given at the 12-week for any reason, combination injections should be given at the first visit at which retreatment criteria for injections are met (16- or 20-week visits).  Treatment at the 24 week visit is at investigator discretion.  The Protocol Chair’s approval must be obtained before treating the study eye with any DME treatment that is different from the treatment detailed in the protocol. 24

Order of Combination Injections 25 Group A (Ranibizumab alone) SHAM FIRST RANIBIZUMAB Group B (Combination) RANIBIZUMAB DEXAMETHASONE Group A (Ranibizumab alone) Random. day: RANIBIZUMAB Day 1-8: SHAM Group B (Combination) Random. day: RANIBIZUMAB Day 1-8: DEXAMETHASONE If the participant returns after a protocol visit specifically to receive a study injection, testing prior to the injection is at investigator discretion. Must be Given 0 to 8 Days of Each Other

OCT Machines  Only the following spectral domain machines are permitted Zeiss Cirrus Heidelberg Spectralis  Time domain machines are not permitted  Same machine as baseline (randomization) should be used in follow-up visits 26

Efficacy Outcomes at 24 Weeks  Primary: Mean change in visual acuity letter score adjusted for baseline (randomization)  Secondary: Visual Acuity o% of eyes with ≥10 and ≥15 letter increase or decrease oArea under the curve (AUC) from baseline OCT oChange in CSF thickness adjusted for baseline o% ≥2 logOCT step gain or loss in CSF oCSF thickness < spectral-domain value equivalent to 250 microns on Zeiss Stratus oAUC from baseline Diabetic Retinopathy worsening or improvement on clinical exam 27

Safety Outcomes Ocular Drug-Related  Increased IOP  IOP-lowering treatment  Migration of Ozurdex to anterior chamber 28 Injected Related  Increased IOP  Endophthalmitis  Retinal Detachment  Intraocular Hemorrhage  Wound problems Systemic Drug-Related  Cardiovascular  Cerebrovascular

The Diabetic Retinopathy Clinical Research Network Thank you 2929