Randomized Trial Comparing Immediate vs Deferred Surgery for Symptomatic Epiretinal Membranes - PowerPoint Presentation

1. Randomized Trial Comparing Immediate vs Deferred Surgery for Symptomatic Epiretinal Membranes (Protocol AM)Protocol Chairs: Darrell Baskin & Mathew MacCumber

2. BackgroundAlthough vitrectomy with ERM peeling has a high success rate, some patients experience less than optimal VA improvementPatients with significant macular changes on OCT but relatively good vision are often advised to defer surgery until vision declines to 20/40 or worseIt is unknown whether delaying surgery, which allows the foveal architecture to remain compromised and potentially to deteriorate, results in worse VA outcomes than if surgery is performed earlierThere is a need to better understand predictors of outcomes when surgery is performed and predictors of progression when surgery is deferred2

3. Study ObjectivesPrimaryCompare visual acuity outcomes at 36 months between eyes randomized to immediate versus deferred surgerySecondary - between group comparisonsCompare changes in metamorphopsia, reading speed, and OCT outcomes from randomization to 36 months between eyes randomized to immediate versus deferred surgeryCompare complication rates between eyes randomized to immediate versus deferred surgery 3

4. Study ObjectivesSecondary - within group comparisonsDetermine the rate of and time to progression of ERM to needing vitrectomy in eyes randomized to deferred surgery Determine if there are baseline or later variables (such as performance of cataract surgery or OCT findings) that predict ERM progression to needing vitrectomy in eyes randomized to deferred surgery 4

5. Study ObjectivesOther objectivesExplore associations between participant factors and retinal anatomy with outcomesAssess how often lens removal is needed after phakic vitrectomy (among eyes receiving surgery during study) Collect natural history data for deferred surgery eyesAssess whether fundus autofluorescence (FAF) images are of value in assessing progression of ERM or improvement in macular anatomy after ERM removal (as part of an ancillary study among sites with machine capabilities)5

6. Study DesignAt least 1 eye meeting all the following criteriaE-ETDRS visual acuity 20/25 to 20/40 (69 to 83 letters)ERM must be thought to be the primary cause of vision lossERM meeting the following criteria (no RC confirmation required)Symptoms of visual loss and/or distortion (and in the opinion of the investigator, the ERM is contributing to the participant’s symptoms); either new or worsening in the past 24 monthsEpiretinal membrane involving or altering the central 3 mm of the macula on OCT Distortion of the foveal center by ERM on OCT Multi-Center Randomized Clinical Trial (400 Eyes)Primary Outcome: Mean change in visual acuity letter score from baseline to 36 months6Immediate Surgery (within 4 weeks)Deferred Surgery (vitrectomy only if protocol criteria met)

7. Major Patient Eligibility CriteriaAge ≥50 yearsBlood pressure ≤160 systolic and ≤100 diastolicNo known condition that, in the opinion of the investigator, would preclude participation in the study (e.g. unstable medical status that might preclude completion of follow-up)Immediate vitrectomy not required (investigator and participant are willing to wait at least 4 weeks to see if vision remains stable without having to proceed to vitrectomy) 7

8. Important RemindersThe participant must be willing to accept the randomization assignment. We do not want participants requesting surgery when they find out they are in the deferred group.Participants should be comfortable with their level of visual function at baseline and should be willing to wait for surgery until vision or symptoms worsens8

9. Major Exclusion CriteriaSecondary ERM due to retinal vascular disease, vitreous hemorrhage, retinal detachment, inflammatory disease, or associations other than vitreous syneresis, retinal break, or posterior vitreous detachmentPrior retinal tears treated with laser or cryosurgical retinopexy are permittedPrior intraocular surgery (except uncomplicated cataract extraction) Cataract extraction within prior 3 monthsHistory of diabetic macular edema (DME), retinal vein occlusion (RVO), or uveitis9

10. Major Exclusion CriteriaVMT within 1,500 microns of the foveal centerCentral serous chorioretinopathyNonproliferative diabetic retinopathy or worse (DR severity >20)Macular holeMacular pseudoholeDegenerative lamellar macular holeERM foveoschisis (“tractional” lamellar hole) is permitted10

11. Hubschman et al 2020 DefinitionsMacular pseudoholeMandatory criteriaFoveal center sparing ERMRetinal thickening Verticalized or steepened foveal profileOptional criteriaPresence of microcystoid spaces in the INLNear normal central foveal thickness11

12. Hubschman et al 2020 DefinitionsDegenerative lamellar macular holeIrregular foveal contour Foveal cavity with undermined edgesPresence of at least one other sign evoking a loss of foveal tissuePseudo-operculumThinning of its foveal center or around12

13. Hubschman et al 2020 DefinitionsERM foveoschisis or ‘tractional’ lamellar macular holesMandatory criteriaContractile ERMFoveoschisis at the level of HFLOptional criteriaMicrocystoid spaces in the INLRetinal thickeningRetinal wrinkling13

14. Schematic of Study Design14

15. Criteria for VitrectomyVitrectomy may occur during follow-up for eyes in the deferred surgery group if one of the following criteria is met:Decrease in E-ETDRS VA ≥10 letters from baseline at a single visit presumed to be from ERMDecrease in E-ETDRS VA ≥5 letters from baseline at two consecutive visits (at least 1 month apart)  presumed to be from ERM      Participant actively requests surgery due to worsening symptomsComplication requires prompt surgical intervention (e.g. macular hole, retinal detachment)15

16. Baseline Testing ProceduresThe following must be performed within 21 days of randomization unless otherwise specifiedMedical historyOnly key pre-existing conditions and medications will be collected (no separate PEC or Medications form to complete)Blood pressure – on day of randomizationE-ETDRS visual acuity in each eyeOCT in study eye onlyFAF in study eye only (if site has Spectralis and is participating in ancillary study)16

17. Baseline Testing ProceduresEye exam on study eyeA scleral depression is required at baseline to carefully assess the peripheral retina and identify retinal breaks Visual function testing with M-CHARTS on study eyeCompleted twice at baselineReading Speed using MNREAD on study eye17

18. M-CHARTSPaper binder M-CHARTIncludes a straight line and 19 kinds of dotted lines with dot intervals ranging from 0.2 ̊ to 2.0 ̊ of visual angleMetamorphopsia is assessed by the degree of visual angle at which the participant perceives that all the dots are in a straight line18

19. MNREADiPad application to measure reading speedParticipant will read 14 sentences, each with decreasing font size, and the number of incorrect words will be recordedThe app generates statistics such as the reading acuity, maximum reading speed, critical print size, and a reading accessibility index19

20. Follow-Up Testing ProceduresE-ETDRS visual acuity in each eyeOCT in study eye onlyFAF in study eye only (if site has Heidelberg Spectralis machine and is participating in ancillary study) – 36 months onlyEye exam on study eyeScleral depression can be performed as needed; not required during follow-upVisual function testing (except 1 month post vitrectomy visit)M-CHARTS – study eye onlyReading Speed using MNREAD – annual visits only20

21. 30-month Phone Call The purpose of the 30-month phone call will be to solicit vision changes and safety events & remind the participant of the 36-month visit21

22. Pre-Vitrectomy VisitAdditional visits may occur as required for usual care of the study participant. Testing procedures at unscheduled visits are at investigator discretion. However, it is recommended that procedures that are performed should follow the standard DRCR Retina Network protocol for each procedure.If the decision to proceed to surgery is made during an unscheduled visit for a participant in the deferred surgery group, this visit is considered a Pre-Vitrectomy visit and all study procedures (including reading speed and FAF) must be repeated prior to surgery. 22

23. MaskingInvestigators, coordinators, and participant will be unmasked to the treatment group assignmentImaging technicians, VA testers, and refractionists must be masked to the participant’s treatment groupIt is recommended the reading speed and visual function testers are also maskedThe 1-month post-vitrectomy visit has the potential to unmask study personnelPlease try to prevent this from happening by not sharing information on the timing of the visit to the masked study personnel23

24. Vitrectomy ProceduresVitrectomy will be performed according to the investigator’s standard practiceInvestigators may use staining agents and peel the ILM if they typically do as part of their standard vitrectomy practiceCombined cataract surgery is also permittedDetails on the vitrectomy procedure will be collected on the Vitrectomy Form24

25. Vitrectomy TimingEyes randomized to immediate surgery must receive surgery within 4 weeksEyes in the deferred surgery group can only receive vitrectomy if the protocol criteria is metA Vitrectomy Form must be completed for the initial vitrectomy performed during the study (subsequent vitrectomy procedures can be reported on a Study Eye Procedure Form)A paper print-out of the Vitrectomy Form may be brought to the surgical center and later entered on the electronic CRF if direct data entry is not possibleThe 1-month post-vitrectomy visit only needs to be completed once (after the initial vitrectomy)25

26. Cataract SurgeryInvestigators should evaluate lens changes throughout the course of follow-up and consider cataract surgery (or referral for possible cataract surgery) when a lens change is thought to be visually significant based on the investigator’s judgment. If the visual potential of the study eye is unknown, the investigator should assume that there is potential for clinically relevant improvement in vision. Cataract surgery may be performed as part of the surgeon’s usual routine. Limited data will be collected for the study. 26

27. Reporting of Adverse EventsUnlike prior DRCR studies, not all adverse events will be collectedReportable Adverse Events include:An ocular adverse event in the study eyeA serious adverse eventAn adverse event occurring in association with a study procedure27

28. DRCR.net WebsiteLike all DRCR trials, the website will help guide you though each visit, including:Assessing eligibility Vitrectomy criteria for the deferred groupVisit schedule and required testing at each visit28

29. Keys to a Successful TrialEnrollmentIdentify eligible participants with ERM according to protocol criteria – this is based on investigator assessment aloneInterventionEnsure participants randomized to immediate vitrectomy have surgery scheduled within 4 weeksEnsure participants randomized to deferred surgery meet criteria prior to proceeding with vitrectomyRetentionMissing follow-up data is detrimental to primary analysisThe key to retention is enrolling participants likely to return29

30. CertificationRecruitment is planned to start in January 2022It is expected about 50 sites will participateSites should be able to enroll at least 3 participants All US sites must use the Jaeb IRBPlease contact Jaeb IRB to begin reliance agreement if needed 30

31. Certification RequirementsProtocol training callProtocol acknowledgement formProtocol Q&ADelegation logiPad for MNREAD (otherwise JCHR will supply)Must have IOS 13 or above M-CHART type 1 (version with single dotted line) (otherwise JCHR will supply)Visual function and reading speed training for delegated staff31

32. Thank You32