Ranibizumab 0.5mg and 2.0mg to Treat Diabetic Macular Edema in Patients With Poor Response to Bevacizumab

Study Overview
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Brief Summary
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This is an open-label, Phase I/II study of intravitreally administered ranibizumab either 0.5-mg and/or 2.0-mg in subjects with clinical, angiographic, and ocular coherence tomography (OCT) evidence of diabetic retinopathy with associated diabetic macular edema following bevacizumab therapy. Thirty patients will be enrolled in this study. Consented, enrolled subjects will receive multiple open-label intravitreal injections of 0.5 mg ranibizumab administered every 30 days (±7 days) for 3 injections during the mandatory treatment phase (Day 0, Month 1, and Month 2). Subjects with complete resolution of diabetic macular edema after 3 intravitreal injections of 0.5 mg ranibizumab will be treated as necessary with 0.5 mg ranibizumab to treat recurrent macular edema for an additional 9 months (12 months from Day 0). The intent is to administer additional ranibizumab treatment if there is evidence of disease activity documented on OCT (e.g., intra-retinal fluid, subretinal fluid and/or cystic changes). Subjects with residual diabetic macular edema following 3 intravitreal injections of 0.5 mg ranibizumab will be receive 3 intravitreal injections of 2.0 mg ranibizumab administered every 30 days (±7 days) for 3 injections at the Month 3, Month 4, and Month 5 study visits. Beginning at the Month 6 study visit, subjects with complete resolution of diabetic macular edema following 3 intravitreal injections of 2.0 mg ranibizumab will treated as necessary with 2.0 mg ranibizumab injections only to treat recurrent macular edema for an additional 6 months (12 months from Day 0). Subjects with residual diabetic macular edema following 3 consecutive intravitreal injections of 2.0 mg ranibizumab will be treated as necessary with 2.0 mg ranibizumab to treat persistent or recurrent macular edema for an additional 6 months (12 months from Day 0). Focal photocoagulation or intravitreal triamcinolone may be administered at the physician's discretion as an adjunct to ranibizumab injections beginning at Month 6 through Month 12 of the study. All subjects will make monthly visits for 12 months for evaluation of safety and efficacy. All subjects will have their first injection of ranibizumab on Day 0 and undergo a safety visit one week (±2 days) after the first injection. At subsequent visits, the subject will have a safety evaluation at the monthly scheduled follow-up visit prior to any intravitreal injection. Subjects will be contacted by the site personnel 1-2 days after each injection to elicit reports of decreased vision or pain or unusual new ocular symptoms in the study eye.

Official Title
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Open Label, Phase I/II, Residual Edema Evaluation With 0.5mg and 2.0mg Ranibizumab Formulations (REEF)

Conditions
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Diabetic Macular Edema

Intervention / Treatment
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* Drug: Ranibizumab


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Ability to provide written informed consent and comply with study assessments for the full duration of the study Age > 18 years Diagnosis of diabetes mellitus (type 1 or 2)Any one of the following will be considered to be sufficient evidence that diabetes is present:Current regular use of insulin for treatment of diabetes or current regular use of oral anti-hyperglycemia agent for the treatment of diabetes Clinical evidence of retinal thickening due to macular edema involving the center of the macula, associated with diabetic retinopathy. Previous history of two consecutive intravitreal bevacizumab injections for the treatment of diabetic macular edema with documented incomplete resolution of central subfield thickening by OCT (consecutive injections administered < 7 weeks apart and within the past 12 months). Central diabetic macular edema present on clinical examination and OCT testing with central 1mm subfield thickness greater than 300 microns as measured on SD-OCT. Visual acuity score greater than or equal to 19 letters (20/400) and less than or equal to 73 letters (20/40) by the ETDRS visual acuity protocol. Media clarity, pupillary dilation and patient cooperation sufficient to allow OCT testing and retinal photography Exclusion Criteria: Pregnancy (positive pregnancy test) or known to be pregnant; also pre-menopausal women not using adequate contraception. Participation in another ocular investigation or trial simultaneously Blood pressure > 180/110 (systolic above 180 OR diastolic above 110) Any condition that, in the opinion of the investigator, would preclude participation in the study (e.g. chronic alcoholism, drug abuse) Evidence of vitreoretinal interface abnormality after ocular exam or OCT that may be contributing to the macular edema An eye that, in the investigator's opinion, has no chance of improving in visual acuity following resolution of macular edema (e.g. presence of subretinal fibrosis or geographic atrophy) Presence of another ocular condition that may affect the visual acuity or macular edema during the course of the study (e.g. AMD, uveitis, Irvine-Gas) Evidence of neovascularization of the iris or retina Evidence of central atrophy or fibrosis in the study eye Presence of substantial cataract, one that might decrease the vision by 3 or more lines of vision at sometime during the study. History of vitreous surgery in the study eye History of cataract surgery within 6 months of enrollment. History of YAG capsulotomy within 2 months of enrollment. Visual acuity <20/400 in the fellow eye Uncontrolled glaucoma (pressure >30) despite treatment with glaucoma medications. History of cerebral vascular accident or myocardial infarction within 3 months prior to Day 0.

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: 0.5mg and 2.0mgRanibizumab<br>Three consecutive intravitreal ranibizumab 0.5mg injections followed by three consecutive intravitreal ranibizumab 2.0mg injections if specific criteria is met. | Drug: Ranibizumab<br>* 0.05ml of 0.5mg or 2.0mg ranibizumab injected intravitreally<br>* Other names: Lucentis;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Overall Mean Change in Visual Acuity Scores at Month 6 Compared to Baseline | To determine the mean change in the best-corrected visual acuity on an ETDRS visual acuity chart at a starting distance of 4 meters from baseline to 6 months. | baseline and 6 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Mean Change in 1-mm Central Subfield (CST) Thickness as Measured by OCT at Month 6 Compared to Baseline | To determine the mean change in central 1-mm subfield thickness as measured by spectral-domain OCT from baseline to 6 months . | baseline and 6 months | 
| Qualitative Assessment of Diabetic Macular Edema (DME) | To compare the percentage of subjects with compete or partial/no resolution of diabetic macular edema in response to the ranibizumab 0.5 and 2.0 mg doses. | Baeline and 6 months | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Diabetes, Macula, Edema, Retina