The Ranibizumab for Edema of the mAcula in Diabetes-2 (READ-2) Study

The READ-2 Study is a phase 2 randomized, multi-center clinical trial to be conducted under an investigator-initiated investigational new drug (IND). The study aims to enroll 126 patients, who will be randomized into 3 different groups. The primary objectives of the READ-2 Study are: (a) to obtain data on the bioactivity and dose interval effects of intravitreal ranibizumab (RBZ) alone, as well as in combination with laser photocoagulation, on retinal thickness and visual acuity in subjects with DME; and (b) to obtain additional safety and bioactivity data to aid in the design of a phase 3 clinical trial to evaluate ranibizumab as a therapeutic option for patients with DME The study consists of a 2-week screening period (Days -14 to 0), a 6-month treatment period with a primary time endpoint, and a 18-month follow-up and treatment period with secondary time endpoints. Consented subjects will enter the 14-day screening period to determine eligibility. Serum chemistry and hematology testing, urinalysis, pregnancy testing, and macular thickness measurements based on optical coherence tomography (OCT) will be performed. Screening will also include VA, ophthalmic examination and fluorescein angiography (FA) entry criteria.

Patients who have ETDRS visual acuity of 20/40 or worse, but better than or equal to 20/320 due to foveal thickening from macular edema secondary to diabetes (type 1 or 2) and who meet eligibility criteria will be eligible to enroll in the study. Baseline foveal thickness by OCT must be at least 250, which is often associated with VA of 20/40 or worse and which provides sufficient thickening so that a treatment effect is easily detectable (Nguyen et al. 2004). Approximately 126 patients with DME will be enrolled in this study from all clinical sites in the study. Every effort will be made to recruit and enroll eligible patients from men and women of all ethnic and social backgrounds. Patients who meet entry criteria will be able to enroll in the study until the quota of patients has been achieved.

Inclusion:

• Signed informed consent and authorization of use and disclosure of protected health information
• Age greater than 18 years
• Diagnosis of diabetes mellitus (type 1 or type 2) and serum HbA1c greater than 5.5% within 12 months of randomization
• Retinal thickening secondary to diabetes mellitus (diabetic macular edema) involving the center of the fovea.
• Diagnosis must be confirmed by OCT images
• Foveal thickness of greater than 250, as assessed by OCT
• Best corrected visual acuity score in the study eye of 20/40 to 20/320 inclusive (Snellen equivalents using the ETDRS protocol at a distance of 4 meters). Only one eye will be treated in the study. If both eyes are eligible, the investigator will select the eye to be enrolled. Visual acuity in the non-study eye must be greater than 20/800.
• In the opinion of the investigator, decreased vision in the study eye is due to foveal thickening from DME and not from other obvious causes.
• In the opinion of the investigator, laser photocoagulation can be withheld for at least 30 days after the patient has enrolled in the study

Exclusion criteria

• Panretinal photocoagulation or macular photocoagulation within 3 months of study entry in the study eye
• Use of intraocular or periocular injection of steroids in the study eye (e.g., triamcinolone) within 3 months of study entry
• Previous participation in a study and receipt of anti-angiogenic drugs (pegaptanib sodium, ranibizumab, anecortave acetate, protein kinase C inhibitor, etc.) within 2 months of study entry
• Eyes in which the investigators do not feel appropriate to do any additional laser photocoagulation
• Proliferative diabetic retinopathy in the study eye, with the exceptions of inactive, fibrotic proliferative diabetic retinopathy that has regressed following pan-retinal laser photocoagulation or tufts of neovascularization elsewhere (NVE) less than one disc area with no vitreous hemorrhage
• Vitreomacular traction or epiretinal membrane in the study eye evident biomicroscopically or by OCT
• Structural damage to the center of the macula in the study eye likely to preclude improvement in visual acuity following the resolution of macular edema, including atrophy of the retinal pigment epithelium, subretinal fibrosis, laser scar(s), macular ischemia, or organized hard exudate plaque
• Ocular disorders in the study eye that may confound interpretation of study results, including retinal vascular occlusion, retinal detachment, macular hole, or choroidal neovascularization of any cause (e.g., age related macular degeneration (AMD), ocular histoplasmosis, or pathologic myopia)
• Concurrent disease in the study eye that could compromise visual acuity or require medical or surgical intervention during the first 6-month study period
• Eyes which are likely to need cataract surgery and intraocular lens implantation within the first 6 months of the study
• Cataract surgery in the study eye within 3 months of study entry; Yttrium-Aluminum-Garnet (YAG) laser capsulotomy within 2 months of study entry; or any other intraocular surgery within 3 months preceding Day 0.
• History of vitreoretinal surgery in the study eye within 3 months of study entry
• Uncontrolled glaucoma (defined as intraocular pressure greater than 30 mm Hg despite treatment with anti-glaucoma medications)
• Uncontrolled diabetes mellitus, as evidenced by glycosylated hemoglobin (HbA1c) value greater than 12%
• Premenopausal women not using adequate contraception
• Any women who are pregnant
• International normalized ratio (INR) greater than or equal to 3.0 (e.g. due to current treatment with warfarin). The use of aspirin or other anticoagulants is not an exclusion
• History of gastrointestinal bleeding within 2 months of study enrollment
• History of major gastrointestinal, cardiothoracic, gynecological, genitourinary, or orthopedic surgeries within 2 months of study enrollment
• History of cerebral vascular accident, myocardial infarction, transient ischemic attacks within 6 months of study enrollment
• Any patients who are on renal dialysis