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

This is a 24-week, prospective, multi-center, open-label, randomized, investigator-initiated pilot study to explore the effects of RBZ (0.5 mg) plus DEX implant (0.7 mg) PRN combination therapy (n = 30) vs. DEX implant PRN monotherapy (n = 30) in pseudophakic eyes with center-involved DME that have demonstrated prior incomplete response to 3-6 anti-VEGF treatments.

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.

Eligibility Criteria:
Inclusion Criteria:

1. Type 1 or 2 diabetic patients
2. Pseudophakic (or phakic without cataract;\<1+ nuclear sclerosis) lens status with intact posterior lens capsule and / or Nd:YAG laser capsulotomy that in the investigator's opinion is not likely to permit dislocation of DEX implant into the anterior chamber
3. Center-involved DME \> 250 µm
4. Baseline BCVA between 20/40 - 20/320
5. Duration of DME ≤ 9 months
6. Glycosylated haemoglobin (HbA1c) levels ≤ 11%
7. Eyes with intraocular pressure (IOP) ≤ 21 and / or treatment with \< 2 topical IOP-lowering medications (eyes with history of previous angle -closure or similar conditions that have been successfully treated with either laser or surgical intervention are allowed as long as the visual fields and optic nerves have been stable for \> 1 year prior to study entry and the patient has been and can be safely dilated)
8. Demonstrated incomplete response to 3-6 prior intravitreal anti-VEGFs (AVASTIN®, LUCENTIS®, or EYLEA®; administered every 4 ± 2 weeks over 12-36 weeks (or 3-9 months)); incomplete response is defined herein as a treatment effect resulting in:

   1. \< 20% reduction in central subfield thickness (CST) by SD-OCT compared to the baseline first RBZ injection, or
   2. \< 5-letter increase in visual acuity compared to the baseline first RBZ injection and/or
   3. the opinion of the treating ophthalmologist additional anti-VEGF monotherapy is not deemed likely to provide further therapeutic benefit
9. If both eyes qualify investigators may enrol bilaterally, with one eye receiving the RBZ plus DEX implant combination regimen and the other receiving the DEX implant monotherapy regimen
10. Written informed patient consent

Exclusion Criteria:

1. Patients with active or suspected ocular or periocular infections including most viral diseases of the cornea and conjunctiva, including active epithelial herpes simplex keratitis (dendritic keratitis), vaccinia, varicella, mycobacterial infections, and fungal diseases.
2. Patients with known hypersensitivity to any components of RBZ or DEX implant
3. Patient has suffered from a stroke or trans-ischemic attack (TIA) in the last 6 months
4. Patients using topical anti-inflammatory medication for the duration of the study
5. Patients with ACIOL (Anterior Chamber Intraocular Lens) and rupture of the posterior lens capsule
6. Prior panretinal or macular laser treatments
7. Previous vitrectomy
8. Any ocular condition that in the opinion of the investigator would not permit improvement of visual acuity with resolution of ME (e.g., foveal atrophy, pigment abnormalities, dense subfoveal hard exudates and/or poor foveal architecture suggestive of photoreceptor loss)
9. Patients with retinal diseases, other than diabetes that can affect ME
10. HbA1c levels \> 11%
11. Eyes with a history of advanced glaucoma (optic nerve head change consistent with glaucoma damage and / or glaucomatous visual field loss), uncontrolled ocular hypertension (baseline IOP \> 21 mmHg despite use of ≥ 2 topical IOP-lowering medication)
12. Eyes with a history of steroid response (i.e., increase of ≥ 5 mmHg IOP following topical steroid treatment)
13. Eyes with demonstrated response to 3-6 prior monotherapy intravitreal anti-VEGF (i.e., AVASTIN®, LUCENTIS® or EYLEA® administered every 4 ± 2 weeks over 12-36 weeks (or 3-9 months)); response is defined herein as a treatment effect resulting in:

    1. ≥ 20% reduction in CST by SD-OCT from baseline first anti-VEGF injection,
    2. ≥ 5-letter increase in visual acuity since the baseline first anti-VEGF injection and/or,
    3. the opinion of the treating ophthalmologist additional anti-VEGF monotherapy is deemed likely to provide further therapeutic benefit
14. Female patients who are pregnant, breast feeding, or are unable to attend the scheduled follow-up study visits
15. Patients who are unable to attend scheduled follow-up visits throughout the 24-week study
16. Use of systemic steroid, anti-VEGF or pro-VEGF treatment within 4 months prior to enrolment or anticipated use during the study (these drugs are prohibited from use during the study)