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Randomized Trial of Intravitreous Aflibercept Versus Intravitreous Bevacizumab + Deferred Aflibercept for Treatment of Central-Involved Diabetic Macular Edema

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Randomized Trial of Intravitreous Aflibercept Versus Intravitreous Bevacizumab + Deferred Aflibercept for Treatment of Central-Involved Diabetic Macular Edema Diabetic Retinopathy Clinical Research Network Randomized Trial of Intravitreous Aflibercept versus Intravitreous Bevacizumab + Deferred Aflibercept for Treatment of Central-Involved Diabetic Macular Edema Version 3.0 December 6, 2019 Aflibercept Switch Protocol 3.0 12-6-19 Contact Information Coordinating Center Director: Adam R. Glassman, M.S. Jaeb Center for Health Research 15310 Amberly Drive, Suite 350 Tampa, FL 33647 Phone: 813-975-8690 Fax: 800-816-7601 Email: [email protected] Protocol Co-Chairs Chirag Jhaveri, MD Retina Research Center 3705 Medical Parkway Suite 420 Austin, TX 78705 Phone: 512-454-5851 Email: [email protected] Frederick L. Ferris III, MD National Eye Institute BG 10-CRC RM 3-2531 10 CENTER DR BETHESDA MD 20814 Phone: 301-496-5248 Email: [email protected] Aflibercept Switch Protocol 3.0 12-6-19 1 Table of Contents 2 3 Chapter 1 Background Information and Study Synopsis ...................................................... 1-1 4 1.1 Background Information ............................................................................................... 1-1 5 1.1.1 Diabetic Retinopathy Complications and Public Health Impact ........................... 1-1 6 1.1.2 DME and Its Treatment ......................................................................................... 1-1 7 1.1.3 Rationale for Comparing Aflibercept to Bevacizumab + Deferred Aflibercept .... 1-1 8 1.1.4 Summary of Previous Research of Switching Anti-VEGF Agents ....................... 1-2 9 1.2 Study Objectives ........................................................................................................... 1-2 10 1.3 Study Design and Synopsis of Protocol ........................................................................ 1-2 11 1.4 General Considerations ................................................................................................. 1-5 12 Chapter 2 Study Participant eligibility and enrollment ......................................................... 2-1 13 2.1 Identifying Eligible Subjects and Obtaining Informed Consent ................................... 2-1 14 2.2 Study Participant Eligibility Criteria ............................................................................. 2-1 15 2.2.1 Participant-level Criteria ........................................................................................ 2-1 16 2.2.2 Study Eye Criteria .................................................................................................. 2-2 17 2.3 Screening Evaluation and Baseline Testing .................................................................. 2-4 18 2.3.1 Historical Information ............................................................................................ 2-4 19 2.3.2 Baseline Testing Procedures .................................................................................. 2-4 20 2.4 Enrollment/Randomization of Eligible Study Participants ........................................... 2-5 21 Chapter 3 Treatment Regimens ............................................................................................... 3-1 22 3.1 Introduction ................................................................................................................... 3-1 23 3.2 Intravitreous Injections .................................................................................................. 3-1 24 3.2.1 Intravitreous Aflibercept Injection (Eylea) ............................................................ 3-1 25 3.2.2 Bevacizumab (Avastin) .......................................................................................... 3-1 26 3.2.3 Intravitreous Injection Technique .......................................................................... 3-1 27 3.2.4 Deferral of Injections Due to Pregnancy ............................................................... 3-2 28 3.2.5 Delay in Giving Injections ..................................................................................... 3-2 29 Chapter 4 Follow-up visits and treatment ............................................................................... 4-1 30 4.1 Visit Schedule ............................................................................................................... 4-1 31 4.2 Testing Procedures ........................................................................................................ 4-1 32 4.3 Treatment During Follow Up ........................................................................................ 4-2 33 4.3.1 Intravitreous Injection Re-Treatment ..................................................................... 4-2 34 4.3.2 Switch Criteria (Bevacizumab + Deferred Aflibercept group) .............................. 4-2 35 4.3.3 Failure Criteria ....................................................................................................... 4-3 36 4.3.4 Laser for DME ....................................................................................................... 4-4 37 Chapter 5 Miscellaneous Considerations in Follow-up .......................................................... 5-1 38 5.1 Endophthalmitis ............................................................................................................ 5-1 39 5.2 Use of Intravitreous Anti-VEGF for Conditions Other than DME in the Study Eye ... 5-1 40 5.3 Treatment in Non-study Eye ......................................................................................... 5-1 41 5.4 Diabetes Management ................................................................................................... 5-1 42 5.5 Study Participant Withdrawal and Losses to Follow-up ............................................... 5-1 43 5.6 Discontinuation of Study ............................................................................................... 5-1 Aflibercept Switch Protocol 3.0 12-6-19 44 5.7 Contact Information Provided to the Coordinating Center ........................................... 5-1 45 5.8 Study Participant Reimbursement ................................................................................. 5-2 46 Chapter 6 Adverse Events ......................................................................................................... 6-1 47 6.1 Definition ...................................................................................................................... 6-1 48 6.2 Recording of Adverse Events ........................................................................................ 6-1 49 6.3 Reporting Serious or Unexpected Adverse Events ....................................................... 6-2 50 6.4 Data and Safety Monitoring Committee Review of Adverse Events ............................ 6-2 51 6.5 Risks .............................................................................................................................. 6-3 52 6.5.1 Potential Adverse Effects of Study Drugs ............................................................. 6-3 53 6.5.2 Potential Adverse Effects of Intravitreous Injection .............................................. 6-5 54 6.5.3 Risks of Eye Examination and Tests ..................................................................... 6-6 55 Chapter 7 Statistical Methods................................................................................................... 7-1 56 7.1 Primary Outcome .......................................................................................................... 7-1 57 7.2 Sample Size ................................................................................................................... 7-1 58 7.2.1 Outcome Projections .............................................................................................. 7-1 59 7.2.2 Sample Size Estimates ........................................................................................... 7-2 60 7.3 Primary Analysis Plan ................................................................................................... 7-2 61 7.3.1 Principles for Analysis ........................................................................................... 7-2 62 7.3.2 Sensitivity Analyses ............................................................................................... 7-3 63 7.3.3 Subgroup Analyses ................................................................................................ 7-3 64 7.3.4 Interim Analysis Plan ............................................................................................. 7-3 65 7.4 Secondary Outcomes for Treatment Group Comparison .............................................. 7-4 66 7.5 Economic Analysis ........................................................................................................ 7-4 67 7.6 Safety Analysis Plan...................................................................................................... 7-4 68 7.7 Additional Tabulations and Analyses ........................................................................... 7-6 69 Chapter 8 References ................................................................................................................. 8-1 70 Aflibercept Switch Protocol 3.0 12-6-19 71 CHAPTER 1 72 BACKGROUND INFORMATION AND STUDY SYNOPSIS 73 74 1.1 Background Information 75 1.1.1 Diabetic Retinopathy Complications and Public Health Impact 76 The age-adjusted incidence of diabetes mellitus in the United States has reportedly doubled in 77 recent history.1 Estimates suggest that by the year 2035, approximately
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