A Study of Ranibizumab Injection in Subjects With Clinically Significant Macular Edema (ME) With Center Involvement Secondary to Diabetes Mellitus (RISE)

A Phase III, Double-masked, Multicenter, Randomized, Sham Injection-controlled Study of the Efficacy and Safety of Ranibizumab Injection in Subjects With Clinically Significant Macular Edema With Center Involvement Secondary to Diabetes Mellitus

This study is a Phase III, double-masked, multicenter, randomized, sham injection-controlled study of the efficacy and safety of ranibizumab injection in patients with clinically significant macular edema with center involvement (CSME-CI) secondary to diabetes mellitus (Type 1 or 2). This study is identical in design to study NCT00473382 (Protocol ID FVF4168g).

The open-label extension phase of the study was stopped after receiving FDA approval of the study drug (ranibizumab) for diabetic macular edema.

This study is composed of 3 phases: (1) A 24-month controlled treatment period (monthly treatment with ranibizumab 0.3 mg, ranibizumab 0.5 mg, or sham injection) followed by (2) a 12-month treatment period in which patients randomized to the sham group who had not discontinued from treatment (still masked) could choose to receive monthly ranibizumab 0.5 mg while the 2 ranibizumab treatment groups continued on the same treatment they received in the first 2 years. Patients who had not discontinued treatment by Month 36 were eligible to continue treatment with ranibizumab 0.5 mg as needed (pro re nata, PRN) in (3) an extension phase of the study for up to 2 more years, resulting in up to 5 years possible total treatment time for some patients.

Inclusion Criteria:

• Willingness to provide written informed consent and, at U.S. sites, Health Insurance Portability and Accountability Act (HIPAA) authorization, and in other countries, as applicable according to national laws.
• Age ≥ 18 years.
• Diabetes mellitus (Type 1 or 2) .
• Retinal thickening secondary to diabetes mellitus (DME) involving the center of the fovea with central macular thickness ≥ 275 µm in the center subfield as assessed on optical coherence tomography (OCT).
• Best corrected visual acuity (BCVA) score in the study eye of 20/40 to 20/320 approximate Snellen equivalent using the Early Treatment Diabetic Retinopathy Study (ETDRS) protocol at an initial testing distance of 4 meters.
• Decrease in vision determined to be primarily the result of DME and not to other causes.
• For sexually active women of childbearing potential, use of an appropriate form of contraception (or abstinence) for the duration of the study.
• Ability (in the opinion of the investigator) and willingness to return for all scheduled visits and assessments.

Exclusion Criteria:

• History of vitreoretinal surgery in the study eye.
• Panretinal photocoagulation (PRP) or macular laser photocoagulation in the study eye within 3 months of screening.
• Previous use of intraocular corticosteroids in the study eye (eg, triamcinolone acetonide [TA]) within 3 months of screening.
• Previous treatment with anti-angiogenic drugs in either eye (pegaptanib sodium, anecortave acetate, bevacizumab, ranibizumab, etc) within 3 months of the Day 0 (first day of treatment) visit.
• Proliferative diabetic retinopathy (PDR) in the study eye, with the exception of inactive, regressed PDR.
• Iris neovascularization, vitreous hemorrhage, traction retinal detachment, or preretinal fibrosis involving the macula in the study eye.

Concurrent Ocular Conditions

• Vitreomacular traction or epiretinal membrane in the study eye.
• Ocular inflammation (including trace or above) in the study eye.
• History of idiopathic or autoimmune uveitis in either eye.
• Structural damage to the center of the macula in the study eye that is likely to preclude improvement in VA following the resolution of macular edema, including atrophy of the retinal pigment epithelium (RPE), subretinal fibrosis, 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 (CNV) of any cause (eg, age-related macular degeneration (AMD), ocular histoplasmosis, or pathologic myopia).
• Concurrent disease in the study eye that would compromise visual acuity or require medical or surgical intervention during the study period.
• Cataract surgery in the study eye within 3 months, yttrium-aluminum-garnet (YAG) laser capsulotomy within the past 2 months, or any other intraocular surgery within the 90 days preceding Day 0.
• Aphakia or absence of the posterior capsule in the study eye.
• Uncontrolled glaucoma or previous filtration surgery in the study eye.
• Spherical equivalent of the refractive error in the study eye of more than -8 diopters myopia.
• Evidence at examination of infectious blepharitis, keratitis, scleritis, or conjunctivitis in either eye or current treatment for serious systemic infection.
• Uncontrolled blood pressure.
• History of cerebral vascular accident or myocardial infarction within 3 months prior to Day 0.
• Uncontrolled diabetes mellitus.
• Renal failure requiring dialysis or renal transplant.
• Participation in an investigational trial within 30 days prior to screening that involved treatment with any drug (excluding vitamins and minerals) or device.
• History of other disease, metabolic dysfunction, physical examination finding, or clinical laboratory finding giving reasonable suspicion of a disease or condition that contraindicates the use an investigational drug, might affect interpretation of the results of the study, or renders the subject at high risk from treatment complications.
• Pregnancy or lactation.
• History of allergy to fluorescein.
• History of allergy to ranibizumab injection or related molecule.