Phase II Combination Steroid and Anti-VEGF for Persistent DME

Study Overview
=================
Brief Summary
-----------------
Although anti-vascular endothelial growth factor (VEGF) therapy is generally effective as treatment for center-involved diabetic macular edema (DME), a substantial proportion of anti-VEGF-treated eyes with DME do not achieve vision of 20/20 or complete resolution of retinal thickening. Indeed, over 50% of ranibizumab-treated eyes did not achieve a 2 or more line improvement in visual acuity from baseline at 2 years in Protocol I, a previous DRCR.net (Diabetic Retinopathy Clinical Research Network) study. Furthermore, 27% of ranibizumab-treated eyes still had central subfield (CSF) thickness on time-domain optical coherence tomography (OCT) ≥ 300 at 1 year, and more than 40% of ranibizumab-treated eyes did not achieve complete resolution of retinal thickening (< 250 microns) by 2 years. Thus, there is a need for alternative or additional treatments that will improve vision by reducing retinal edema in eyes with persistent DME following previous anti-VEGF therapy. Intravitreal steroid is not as efficacious as ranibizumab in eyes with DME overall, but it has been shown to have a positive effect for DME in some eyes and might add benefit in eyes that are already receiving anti-VEGF. The main objective of this study is to assess the short-term effects of combination steroid+anti-VEGF therapy on visual acuity and retinal thickness on OCT in comparison with that of continued anti-VEGF therapy alone in eyes with persistent central-involved DME and visual acuity impairment despite previous anti-VEGF treatment. This study will provide important information for the design of a future confirmatory phase III clinical trial on the efficacy of combination steroid and anti-VEGF in eyes with persistent DME and vision impairment following previous anti-VEGF therapy. The primary outcome for efficacy will be the mean change in visual acuity at 24 weeks. Each study eye is required to complete a 12-week run-in phase. The run-in phase will identify study eyes that truly have persistent DME despite anti-VEGF therapy by requiring an additional 3 injections while also collecting standardized visual acuity and OCT measurements. At the enrollment, 4-week and 8-week visits of the run-in phase, enrolled eyes will receive an intravitreal injection of ranibizumab 3mg. Then at the 12-week run-in visit, if the eye still has persistent DME, it will be randomized to receive either intravitreal sham+intravitreal ranibizumab 0.3 or intravitreal dexamethasone+intravitreal ranibizumab 0.3 injections. The randomized study duration is 24 week, during which a protocol visit takes place every month. The combination injections of sham+ranibizumab or dexamethasone +ranibizumab will be given at the randomization visit (baseline) and at the 12-week visit after randomization. In between, an intravitreal injection of ranibizumab only will be given to study eyes at the 4, 8, 16 and 20 week visits.

Official Title
-----------------
Short-term Evaluation of Combination Corticosteroid+Anti-VEGF Treatment for Persistent Central-Involved Diabetic Macular Edema Following Anti-VEGF Therapy

Conditions
-----------------
Diabetic Macular Edema

Intervention / Treatment
-----------------
* Drug: intravitreal ranibizumab 0.3 mg
* Drug: dexamethasone intravitreal implant
* Procedure: Sham injection


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria: Age ≥ 18 years i) Individuals <18 years old are not being included because DME is so rare in this age group that the diagnosis of DME may be questionable. Diagnosis of diabetes mellitus (type 1 or type 2) Any one of the following will be considered to be sufficient evidence that diabetes is present: Current regular use of insulin for the treatment of diabetes Current regular use of oral anti-hyperglycemia agents for the treatment of diabetes Documented diabetes by ADA (American Diabetes Association) and/or WHO (World Health Organization) criteria At least one eye meets the study eye criteria listed below. Fellow eye (if not a study eye) meets criteria. Able and willing to provide informed consent. Meets all of the following ocular criteria in at least the one eye: At least 3 injections of anti-VEGF drug (ranibizumab, bevacizumab, or aflibercept) within the prior 20 weeks. Visual acuity letter score in study eye ≤ 78 and ≥24 (approximate Snellen equivalent 20/32 to 20/320). On clinical exam, definite retinal thickening due to DME involving the center of the macula. OCT CSF thickness, within 8 days of enrollment: i) On Zeiss Cirrus ≥ 290 microns in women; ≥ 305 in men ii) On Heidelberg Spectralis: ≥ 305 microns in women; ≥ 320 in men Media clarity, pupillary dilation, and individual cooperation sufficient for adequate OCTs. Exclusion Criteria: An individual is not eligible if any of the following exclusion criteria are present: History of chronic renal failure requiring dialysis or kidney transplant. A condition that, in the opinion of the investigator, would preclude participation in the study (e.g., unstable medical status including blood pressure, cardiovascular disease, and glycemic control). Initiation of intensive insulin treatment (a pump or multiple daily injections) within 4 months prior to randomization or plans to do so in the next 4 months. Participation in an investigational trial within 30 days of enrollment that involved treatment with any drug that has not received regulatory approval for the indication being studied. Note: study participants cannot receive another investigational drug while participating in the study. Known allergy to any component of the study drugs (including povidone iodine prep). Blood pressure > 180/110 (systolic above 180 OR diastolic above 110). If blood pressure is brought below 180/110 by anti-hypertensive treatment, the individual can become eligible. Myocardial infarction, other acute cardiac event requiring hospitalization, stroke, transient ischemic attack, or treatment for acute congestive heart failure within 1 month prior to enrollment. Systemic steroid, anti-VEGF or pro-VEGF treatment within 4 months prior to enrollment or anticipated use during the study. These drugs cannot be used during the study. For women of child-bearing potential: pregnant or lactating or intending to become pregnant within the next 9 months. Women who are potential study participants should be questioned about the potential for pregnancy. Investigator judgment is used to determine when a pregnancy test is needed. Individual is expecting to move out of the area of the clinical center to an area not covered by another clinical center during the next 9 months. The following exclusions apply to the study eye only (i.e., they may be present for the non-study eye unless otherwise specified): Macular edema is considered to be due to a cause other than DME. An eye should not be considered eligible if: (1) the macular edema is considered to be related to ocular surgery such as cataract extraction or (2) clinical exam and/or OCT suggest that vitreoretinal interface abnormalities (e.g., a taut posterior hyaloid or epiretinal membrane) are the primary cause of the macular edema. An ocular condition is present such that, in the opinion of the investigator, visual acuity loss would not improve from resolution of macular edema (e.g., foveal atrophy, pigment abnormalities, dense subfoveal hard exudates, non-retinal condition, etc.). An ocular condition is present (other than DME) that, in the opinion of the investigator, might affect macular edema or alter visual acuity during the course of the study (e.g., vein occlusion, uveitis or other ocular inflammatory disease, neovascular glaucoma, etc.). Substantial posterior capsule opacity that, in the opinion of the investigator, is likely to be decreasing visual acuity by 3 lines or more (i.e., opacity would be reducing acuity to 20/40 or worse if eye was otherwise normal). History of intravitreal anti-VEGF drug within 21 days prior to enrollment. History of intravitreal or peribulbar corticosteroids within 3 months prior to enrollment. History of macular laser photocoagulation within 4 months prior to enrollment. History of panretinal (scatter) photocoagulation (PRP) within 4 months prior to enrollment or anticipated need for PRP in the 6 months following enrollment into run-in phase. Any history of vitrectomy.

Ages Eligible for Study
-----------------
Minimum Age: 18 Years

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Double


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: Sham + intravitreal ranibizumab 0.3 mg<br>Intravitreal ranibizumab will be given on the day of randomization. The sham injection will be given within 0-8 days of the ranibizumab injection. If the injections are given consecutively on the same day, the sham injection must be given first. Follow-up intravitreal injections of ranibizumab will be given up to every 4 weeks using defined treatment criteria. | Drug: intravitreal ranibizumab 0.3 mg<br>* Intravitreal injection of 0.3mg ranibizumab performed on the day of randomization and up to every 4 weeks using defined treatment criteria<br>* Other names: Lucentis;Procedure: Sham injection<br>* No injection is given. It is a sham injection to keep the participant masked. The sham injection will be given within 0-8 days of the ranibizumab injection. If the injections are given consecutively on the same day, the sham injection must be given first.<br>|
| Experimental: Intravitreal dexamethasone+intravitreal ranibizumab 0.3mg<br>The initial intravitreal ranibizumab injection will be given on the day of randomization. The dexamethasone intravitreal injection will be given within 0-8 days of the ranibizumab injection. If defined criteria are met, a second dexamethasone injection in combination with intravitreal ranibizumab (within 0-8 days) will be given at the 12 week visit. If the injections are given consecutively on the same day, the ranibizumab injection must be given first. | Drug: intravitreal ranibizumab 0.3 mg<br>* Intravitreal injection of 0.3mg ranibizumab performed on the day of randomization and up to every 4 weeks using defined treatment criteria<br>* Other names: Lucentis;Drug: dexamethasone intravitreal implant<br>* The dexamethasone intravitreal injection will be given within 0-8 days of the ranibizumab injection. If defined criteria are met, a second dexamethasone injection in combination with intravitreal ranibizumab (within 0-8 days) will be given at the 12 week visit. If the injections are given consecutively on the same day, the ranibizumab injection must be given first.<br>* Other names: Ozurdex;|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Mean Change in Visual Acuity Letter Score | At 24 weeks after randomization, mean change in visual acuity letter score, adjusted for visual acuity at time of randomization | 24 weeks after randomization | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| At 24 Weeks After Randomization, Number of Eyes With at Least 10 and at Least 15 Letter Gain (Increase) or Loss (Decrease) in E-ETDRS Letter Score Visual Acuity. | ETDRS (Early Treatment Diabetic Retinopathy Study) | 24 weeks weeks after randomization | 
| Visual Acuity Area Under the Curve (AUC) Between Randomization and 24 Weeks | Only included participants who completed the 24-week visit. Time points for which data were collected for this analysis include 0, 4 8,12, 16, 20, and 24 weeks post randomization. | 24 weeks after randomization | 
| Mean Change in OCT CSF Thickness, Adjusted for Thickness at Time of Randomization | Change in optical coherence tomography (OCT) central subfield thickness (in microns) was truncated to 3 standard deviations from the mean [-372, +201] (calculated using observed changes at 24 weeks combining all treatment groups), to minimize the effect of outliers. Two values were truncated in the sham + ranibizumab group: one on the negative end, and one on the positive end. | 24 weeks after randomization | 
| Number of Eyes With ≥1 and ≥2 logOCT Step Gain or Loss in CSF Thickness | Change in optical coherence tomography (OCT) central subfield (CSF) thickness (in microns) was truncated to 3 standard deviations from the mean [-372, +201] (calculated using observed changes at 24 weeks combining all treatment groups), to minimize the effect of outliers. Two values were truncated in the sham + ranibizumab group: one on the negative end, and one on the positive end. | 24 weeks after randomization | 
| Eyes With OCT CSF Thickness < the Gender-specific Spectral Domain OCT Equivalent of 250 Microns on Zeiss Stratus | Gender and OCT machine-specific values for OCT central subfield thickness (in microns) are defined as: <290 in women and <305 in men in Zeiss Cirrus; <305 in women and <320 in men in Heidelberg Spectralis | 24 weeks after randomization | 
| OCT CSF Thickness Area Under the Curve Between Randomization and 24 Weeks | Including participants who completed the 24-week visit. Time points for which data were collected for this analysis include 0, 4 8,12, 16, 20, and 24 weeks post randomization. | 24 weeks after randomization | 

 Terms related to the study
=================
Keywords Provided by Centre Hospitalier Valida
-----------------
Diabetic Macular Edema, Anti-vascular endothelial growth factor, Dexamethasone Intravitreal implant, Ranibizumab intravitreal injection