Study of 2.0 mg Ranibizumab in Subjects With Ischemic Central Retinal Vein Occlusion (RAVE2)

Study Overview
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Brief Summary
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The RAVE 2 trial is a phase I, open label, 12-month trial of intravitreal ranibizumab 2.0 mg in patients with ischemic CRVO who have been either previously treated with ranibizumab or treatment naïve.

Detailed Description
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The most devastating complication of ischemic CRVO is the development of anterior segment neovascularization and the resulting morbidity from neovascular glaucoma. This complication appears to be directly correlated with intraocular VEGF levels. Currently there is no proven treatment to decrease the formation of rubeosis. Current management of the disease consists of pan-retinal photocoagulation once significant anterior segment neovascularization becomes manifest. This treatment destroys peripheral retina (with peripheral retinal field) and presumably works by eventually lowering ocular VEGF levels which causes secondary regression of rubeosis. As ranibizumab blocks VEGF, this treatment when delivered intraocularly may prevent neo-vascular glaucoma while preserving peripheral visual fields in this patient population. A higher dose of ranibizumab may allow for both a longer duration of treatment effect and potentially more efficacy leading to better outcomes for patients that are somewhat treatment resistant and need continual therapy. Nonclinical and early clinical data indicate that higher doses of ranibizumab up to and including 2.0 mg are safe and tolerated by patients.

Official Title
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A Phase I Open Label Study of the Safety, Tolerability and Efficacy of 2.0 mg Ranibizumab in Subjects With Ischemic Central Retinal Vein Occlusion (RAVE2)

Conditions
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Ischemia, Retinal Vein Occlusion, Pathologic Processes, Retinal Diseases, Eye Diseases

Intervention / Treatment
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* Drug: ranibizumab


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Subjects will be eligible if the following criteria are met: Ability to provide written informed consent and comply with study assessments for the full duration of the study Age > 18 years For patients previously treated with ITV ranibizumab (Cohort 1): 6 or more intravitreal injections of ranibizumab with presence of persistent edema after a minimum of 6 ranibizumab injections followed in RAVE 1. For treatment naïve (Cohort 2): Ischemic CRVO within 3 months of enrollment as per the following inclusion criteria Three of the following clinical tests must be present to demonstrate ischemic CRVO: VA 20/200 or worse RAPD 0.9 LU or worse Loss of 1-2e isopter on Goldmann Visual field (Kwon et al. 2001) ERG demonstrating b wave amplitude less than 60% of A wave Capillary nonperfusion greater than 50 DA Exclusion Criteria: Subjects who meet any of the following criteria will be excluded from this study: IOP over 30 mm Hg Any previous retinal laser photocoagulation to the study eye in treatment naive Any previous intravitreal injection in study eye (triamcinolone or other) in treatment naive Any previous vitrectomy in study eye (posterior or anterior associated with vitreous loss in cataract surgery) Intracapsular cataract extraction (posterior capsule needs to be present) Previous history of retinal detachment in study eye Any previous radiation treatments to head/ neck Inability to assess iris neovascularization (corneal opacity precluding gonioscopy) Significant cardiovascular disease or cancer that would prevent follow-up visits or completion of the 12 month study Significant diabetic retinopathy in the fellow eye (diabetic macular edema, proliferative diabetic retinopathy, or high-risk non-proliferative diabetic retinopathy) Pregnancy (positive pregnancy test) Participation in another simultaneous medical investigator or trial Ocular disorders in the study eye that may confound interpretation of study results, including retinal detachment, macular hole, or choroidal neovascularization of any cause (e.g., DME 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 study period Aphakia or absence of the posterior capsule in the study eye Previous violation of the posterior capsule is also excluded unless it occurred as a result of YAG laser posterior capsulotomy in association with prior, posterior chamber intraocular lens implantation History of idiopathic or autoimmune uveitis in either eye Structural damage to the center of the macula in the study eye preexisting to CRVO 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) Vitreomacular traction or epiretinal membrane in the study eye evident biomicroscopically or by OCT Ocular inflammation (including trace or above) in the study eye Infectious blepharitis, keratitis, scleritis, or conjunctivitis (in either eye) or current treatment for serious systemic infection Spherical equivalent of the refractive error in the study eye of more than -8 diopters myopia (For patients who have had refractive or cataract surgery in the study eye, pre-operative spherical equivalent refractive error of more than -8 diopters myopia is not allowed) Systemic Conditions Uncontrolled Blood pressure exceeding diastolic pressure of 100 mm Hg (sitting) during the screening period Uncontrolled diabetes mellitus Renal failure requiring dialysis or renal transplant Pregnancy (positive pregnancy test) or lactation Premenopausal women not using adequate contraception. The following are considered effective means of contraception: surgical sterilization or use of oral contraceptives, barrier contraception with either a condom or diaphragm in conjunction with spermicidal gel, an IUD, or contraceptive hormone implant or patch. Any other condition that the investigator believes would pose a significant hazard to the subject if the investigational therapy were initiated Participation in another simultaneous medical investigation or trial History of other disease, metabolic dysfunction, physical examination finding, or other findings 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 render the subject at high risk from treatment complications Other History of allergy to fluorescein, not amenable to treatment Inability to obtain fundus photographs or fluorescein angiograms of sufficient quality to be analyzed and graded by the central reading center Inability to comply with study or follow up procedures History of allergy to humanized antibodies or any component of the ranibizumab formulation

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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Accepts Healthy Volunteers

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Non-Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: Treatment Experienced (Cohort 1<br>Previously treated with 6 or more intravitreal ranibizumab with persistent edema followed in RAVE 1 (FVF3348s). Cohort 1 patients will receive 1 dose of ranibizumab 2.0 mg, followed by PRN based on pre-defined retreatment criteria | Drug: ranibizumab<br>* Ranibizumab is formulated as a sterile solution aseptically filled in a sterile 3-mL stoppered glass vial. Each vial contains 0.5 mL of 40 mg/mL (2.0-mg dose level) ranibizumab aqueous solution.<br>* Other names: Lucentis;|
| Active Comparator: Treatment Naive (Cohort 2)<br>Treatment naïve. Cohort 2 patients will receive 6 doses of ranibizumab 2.0 mg, followed by PRN based on pre-defined re-treatment criteria. | Drug: ranibizumab<br>* Ranibizumab is formulated as a sterile solution aseptically filled in a sterile 3-mL stoppered glass vial. Each vial contains 0.5 mL of 40 mg/mL (2.0-mg dose level) ranibizumab aqueous solution.<br>* Other names: Lucentis;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Mean Change in logMAR | Mean change from baseline in ETDRS NCVA. | 12 months. | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Incidence and Severity of Adverse Events (Ocular and Non-ocular). | Incidence and severity of adverse events (ocular and non-ocular) from baseline through 12 months will be evaluated. | 12 months | 
| Neovascularization Development | Percent of patients that develop neovascularization of the iris, optic nerve and/or elsewhere. | 12 months | 
| Mean Change in Central Foveal Volume | Mean change in Central Foveal Volume on High Resolution OCT | 12 months | 
| Changes, by Disc Areas, of Capillary Non-perfusion in the Periphery | Changes, by disc areas, of capillary non-perfusion in the periphery (evaluated by wide-field fluorescein angiography) at 3, 6, 9 and 12 months from baseline. | 12 months | 
| Goldman Visual Field Changes | Goldman Visual Field changes at 6 and 12 months from baseline | 12 months | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Ischemic, Central, Retinal, Vein, Occlusion, Ranibizumab, Lucentis, CRVO, ISCRVO