Combination OZURDEX® & LUCENTIS® vs. OZURDEX® Monotherapy in Incomplete-Responders With Diabetic Macular Edema

1. Hypothesis

   Pseudophakic center-involved DME eyes with incomplete response to 3-6 anti-VEGF injections (i.e., RBZ, BCZ or IAI) will have similar visual acuity gains, as assessed with AUC analysis (change from baseline randomization (Time 0) BCVA letters through 24 weeks ± 1 week), with a combination treatment regimen consisting of RBZ (0.5 mg) and DEX implant (0.7 mg) vs. a monotherapy treatment regimen with DEX implant (0.7 mg).

2. Description of Study procedures:

   Screening (Visit 1): At this initial visit, the study doctor or delegate will explain the study to the patient, answer all of their questions, and will ask them to sign an informed consent form. If the patient agrees to participate in the study, the study doctor or delegate will perform routine examinations; ask them questions about their past medical history, current medical conditions, and all medication or treatments they are receiving. If the patient is female, they may have a urine pregnancy test performed. Patients will undergo your regular eye evaluations. If their glycosylated hemoglobin (HbA1a) level is not available within 12-15 weeks of Visit 1 an HbA1c test will be performed at screening. Patients will be assigned to one of two possible treatment regimens (1.) combination consists of LUCENTIS® (0.5 mg) followed by OZURDEX® (0.7 mg) 0-8 days later or (2.) OZURDEX® (0.7 mg) monotherapy. This visit will last approximately 1-2 hours. Patients will always have the choice of receiving both medications at the same time or split between 2 shorter visits.

   Baseline/Randomization (Visit 2): If patients are eligible to receive study treatment(s) they will be scheduled for a baseline randomization study visit to allow collection of eye exam data (intraocular pressure, inflammatory cells, abnormal blood vessels) and ocular coherence tomography OCT. This is the same type of eye exam and OCT patients typically undergo at a retina specialist's office. Additionally, patients will undergo a special vision test and an intravenous fluorescein angiogram to assess retinal circulation. This visit will last approximately 2 hours. The next study visit (Visit 3) will be scheduled in 4-5 weeks. Someone from your study doctor's office will contact the patient prior to the baseline visit to remind you of this next visit

   Week 4 (Visit 3): This study visit will allow collection of eye exam data, vision, eye pressure, and OCT. This visit will last approximately 1 hour. The next study visit (Visit 4) will be scheduled in 4-5 weeks. Someone from the study doctor's office will contact the patient prior to the visit to remind them of this next visit.

   Week 8 (Visit 4): This study visit will allow collection of eye exam data, vision, eye pressure, and OCT. This visit will last approximately 1 hour. The next study visit (Visit 5) will be scheduled in 4-5 weeks. Someone from the study doctor's office will contact the patient prior to the visit to remind them of this next visit.

   Week 12 (Visit 5): This study visit will allow collection of eye exam data, vision, eye pressure, and OCT. This visit will last approximately 1 hour. The next study visit (Visit 6) will be scheduled in 4-5 weeks. Someone from the study doctor's office will contact the patient prior to the visit to remind them of this next visit.

   Week 16 (Visit 6): This study visit will allow collection of eye exam data, vision, eye pressure, and OCT. This visit will last approximately 1-2 hours. At this visit, the study doctor will determine the need for retreatment with the patient's assigned study treatment regimen. If they do not receive treatment, it is because the initial treatments administered at the baseline (visit 2) are still working and patients will be re-assessed for retreatment at study visit 7. The next study visit (Visit 7) will be scheduled in 4-5 weeks. Someone from the study doctor's office will contact the patient prior to their visit to remind them of this next visit.

   Week 20 (Visit 7): This study visit will allow collection of eye exam data, vision, eye pressure, and OCT. This visit will last approximately 1-2 hours. At this visit, the study doctor will determine the need for retreatment with the patient's assigned study treatment regimen. If they do not receive treatment, it is because the initial treatments administered at the baseline (visit 2) are still working and patients will be re-assessed for retreatment at study visit 8. The next study visit (Visit 8) will be scheduled in 4-5 weeks. Someone from the study doctor's office will contact the patient prior to their visit to remind them of this next visit.

   Week 24 (Visit 8): This study visit will allow collection of eye exam data, vision, eye pressure, and OCT. Additionally; patients will undergo intravenous fluorescein angiogram to assess any changes in your retinal circulation status. This visit will last approximately 2 hours.

3. Post-Randomization Treatment

   Study eyes will be evaluated for retreatment at the week 16 and or week 20 study visits based on BCVA and CST. If an eye experiences a prior treatment-related AE, retreatment is at the discretion of the investigator.

   Retreatments will be deferred if:

   • BCVA letter score is ≥ 84 (20/20 or better) and the SD-OCT CST is \< the sex-specific SD-OCT cut-offs below:
   • Zeiss Cirrus: 290 µm in women and 305 µm in men

   Retreatments will be administered if:

   • VA letter score is \< 84 (worse than 20/20) and the SD-OCT CST is ≥ the sex-specific SD-OCT cut-offs below:
   • Zeiss Cirrus: 290 µm in women and 305 µm in men If at any time the investigators wish to treat the study eye(s) with a DME treatment that is different from the protocol treatment due to perceived failure or futility communication must be made with the other study investigator.

4. PATIENT WITHDRAWAL \& LOSS TO FOLLOW-UP

   A study participant has the right to withdrawal from the study at any time. If a study participant is considering withdrawal from the study, the lead investigator at each respective site should personally discuss with the subject the reasons for discontinuation and every effort should be made to accommodate the patient. Study participants who withdraw will be asked to have a final closeout visit at which time the testing described for the protocol visits will be performed. Study participants who have an AE related to a study treatment or procedure will be asked to continue in follow-up until the AE has resolved or stabilized.

5. Procedures to avoid perception undue influence

The lead investigator and co-investigators for each site will make initial contact in person with the patient. In the informed consent process, the study will be explained to the patients by a study coordinator and all questions of the patients will be answered. A consent form will be given and patients will be given as much time as they need. If needed, the patient may take home the consent form and decide later if they want to participate in the study. Additionally, if the patient cannot read and understand English, a consent form will be provided to them in a language that is understandable to them.

All patients will be assured that the standard of care will be given should the patients choose not to participate in the study. This information is included in the informed consent form and will help patients in their decision.

All patients will be instructed to contact the investigation if they have questions or concerns regarding the study.

7. Statistic Methods

Data will be analyzed using SPSS Statistics software, with the level of statistical significance set at p\<0.05.

A single center, 12 month pilot study randomizing 40 DME eyes from 30 subjects 1:1 to BCZ plus adjunctive DEX implant (i.e., BCZ (1.25 mg) at baseline and then monthly when retreatment criteria was met except at months 5 and 10 when DEX implant (0.7 mg) was administered 0.7 mg) or BCZ (1.25 mg monthly) demonstrated similar mean vision gains (+4.9 ± 12.3 ETDRS letters vs. +5.4 ± 10.7 ETDRS letters) but more effective resolution of central subfield thickness (30 ± 100 µm vs. 45 ± 107 µm) with the combination regimen (Maturi RK, 2013; ClinicalTrials.gov Identifier: NCT01309451 http://clinicaltrials.gov/ct2/show/record/NCT01309451). We estimate that a final sample size of at least 20 eyes per study arm is required. Assuming a third of the study eyes may be lost to follow-up we will require enrolment of 30 eyes per study arm.

9. Safety Reporting

All adverse events will be documented and appropriately described. The severity of the adverse event will be coded as mild, moderate, or severe; the association with the intervention will be coded as not related, possibly related or related. The determination of the severity and association will be decided by the principal investigator (PI). The PI for this study will also be acting as the safety monitor, reviewing all adverse events. All serious adverse events that are unexpected and potentially related to the research will be reported in an expedited manner to the research ethical board, the other participating centre and Health Canada.

10. Confidentiality 10.1 Data Confidentiality

All documents relating to the study, including the protocol and data collected during the trial, are the confidential property of the principal investigators.

10.2 Patient Confidentiality

The investigators will preserve the confidentiality of patients participating in the study by identifying them at all times by their study number and will not use patients' names on CRFs or other documentation.

Patients will only be identified on the study database and trial documentation by their assigned study number. All data will be handled in accordance with the Federal Personal Information Protection and Electronic Documents Act (effective January 1, 2004) and all applicable provincial privacy legislation.