A Study Evaluating Dosing Regimens for Treatment With Intravitreal Ranibizumab Injections in Subjects With Macular Edema Following Retinal Vein Occlusion

This study consisted of 2 study periods, a 7-month fixed treatment period, followed by an 8-month alternate dose regimen period. Subjects could receive up to a maximum of 15 monthly injections of ranibizumab 0.5 mg during the study, 7 injections (Day 0 and at 6 monthly visits) in the fixed treatment period and a maximum of 8 injections in the alternate dose regimen period. During the fixed treatment period, subjects received 7 monthly intravitreal ranibizumab 0.5 mg injections. During the alternate dose regimen period, from Month 7 through Month 14, subjects were evaluated monthly to determine whether they achieved the study-specific visual acuity and spectral-domain optical coherence tomography (VA-OCT) stability criteria. Subjects continued to receive monthly ranibizumab 0.5 mg monthly injections until the VA-OCT stability criteria were first met. Upon meeting the VA-OCT stability criteria for the first time during the alternate dose regimen period, subjects were randomly assigned in a 1:1 ratio to one of 2 dose regimens, the PRN (pro re nata, "as-needed") or the Monthly regimen.

PRN randomized subjects: Subjects received no injection at the randomization visit and at future monthly visits where the VA-OCT stability criteria were met and received a ranibizumab 0.5 mg injection at future monthly visits if the VA-OCT stability criteria were not met.

Monthly randomized subjects: Subjects continued to receive ranibizumab 0.5 mg injections at each monthly visit.

Monthly non-randomized subjects: Subjects who did not meet the VA-OCT stability criteria at any month from Month 7 through Month 14 were not randomized and received 8 monthly intravitreal ranibizumab 0.5 mg injections.

Inclusion criteria

• For sexually active women of childbearing potential, use of an appropriate form of contraception (or abstinence) for the duration of the study.

Ocular Inclusion Criteria (Study Eye)

• Foveal center-involved macular edema secondary to branch retinal vein occlusion (BRVO) (including hemi-retinal retinal vein occlusion [HRVO]) or central retinal vein occlusion (CRVO).
• Best corrected visual acuity (BCVA) using Early Treatment Diabetic Retinopathy Study (ETDRS) charts of 20/40 to 20/320 (Snellen equivalent) in the study eye.
• Mean central subfield thickness > 300 µm on 2 spectral-domain optical coherence tomography measurements (screening and Day 0 [first day of treatment]).

Exclusion criteria

• History of cerebral vascular accident or myocardial infarction within 3 months prior to Day 0.
• History of any systemic anti-vascular endothelial growth factor (VEGF) or pro-VEGF treatment within 6 months prior to Day 0.
• History of allergy to fluorescein.
• History of allergy to ranibizumab injection or related molecule.
• Relevant systemic disease that may be associated with increased systemic VEGF levels. History of successfully treated malignancies is not an exclusion criterion.
• Uncontrolled blood pressure.
• Pregnancy or lactation.
• Daily use of oral corticosteroids to treat a chronic condition.
• Required treatment with injectable corticosteroids to treat a musculoskeletal condition.
• Participation in an investigational trial within 30 days prior to Day 0 that involved treatment with any drug or device that has not received regulatory approval at the time of study entry.

Ocular Exclusion Criteria (Study Eye)

• Prior episode of retinal vein occlusion (RVO).
• Brisk afferent pupillary defect.
• History of any previous intravitreal anti-VEGF therapy for RVO in the study eye.
• History of previous therapeutic treatment for RVO, other than anti-VEGF therapy, within 4 months prior to the screening visit, including any intraocular corticosteroids.
• History of previous surgical treatment for RVO, including radial optic neurotomy or sheathotomy.
• History or presence of age-related macular degeneration (AMD) (dry form graded as Age-Related Eye Disease Study [AREDS] Stage 2 or higher or wet form).
• History of laser photocoagulation for macular edema within 4 months prior to Day 0.
• History of panretinal scatter photocoagulation or sector laser photocoagulation within 4 months prior to Day 0 or anticipated within the next 4 months following Day 0.
• History of pars plana vitrectomy.
• History of intraocular surgery within 2 months prior to Day 0 or anticipated within the next 7 months following Day 0.
• History of yttrium-aluminum-garnet (YAG) capsulotomy performed within 2 months prior to Day 0.
• Previous filtration surgery in the study eye.
• History of herpetic ocular infection.
• History of ocular toxoplasmosis.
• History of rhegmatogenous retinal detachment.
• History of idiopathic central serous chorioretinopathy.
• Evidence upon examination of vitreoretinal interface disease either on clinical examination or spectral-domain optical coherence tomography (SD-OCT), thought to be contributing to macular edema.
• Presence of an ocular condition that, in the opinion of the investigator, might affect macular edema or alter visual acuity during the study.
• Visually significant hemorrhage obscuring the fovea and felt to be a major contributor to reduced visual acuity. The subject should be followed and when the hemorrhage in the fovea clears to the point that it is no longer a major contributor to reduced visual acuity, the subject may be screened for the study.
• Presence of a substantial cataract that, in the opinion of the investigator, is likely to be decreasing visual acuity by 3 lines or more.
• Intra-ocular pressure (IOP) ≥ 30 mmHg. If a subject's IOP is ≥ 30 mmHg, that subject will be referred for glaucoma treatment and may be re-screened after 1 month.
• Evidence upon examination of pseudoexfoliation.
• Aphakia.
• Evidence upon examination of external ocular infection, including conjunctivitis, chalazion, or significant blepharitis.
• Evidence upon examination of any diabetic retinopathy, defined as eyes of diabetic patients with more than one microaneurysm outside the area of the vein occlusion (inclusive of both eyes).
• Other relevant ocular disease that may be associated with increased intraocular VEGF levels.
• Improvement of ≥ 10 letters on best-corrected visual acuity ETDRS score between screening and Day 0.