Intravitreal Ranibizumab for Vitreous Hemorrhage Due to Proliferative Diabetic Retinopathy (N)

Study Overview
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Brief Summary
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This study is being conducted to determine if intravitreal injections of ranibizumab decrease the proportion of eyes in which vitrectomy is performed compared with saline injections in eyes presenting with vitreous hemorrhage from proliferative diabetic retinopathy.

Detailed Description
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In mild to moderate cases of vitreous hemorrhage, panretinal photocoagulation (PRP) is performed when possible to achieve regression of new vessels or at least stabilization of the neovascularization with no further growth in order to decrease the probability of subsequent vitreous hemorrhage while spontaneous absorption of the hemorrhage occurs. In cases in which the hemorrhage is too dense to apply PRP, vitrectomy is considered to remove the hemorrhage and provide a clear media for application of PRP (often as endolaser photocoagulation) as well as eliminate extensive neovascularization and relieve traction retinal detachments. Pars plana vitrectomy was introduced in the 1970s as a surgical intervention in diabetes for non-clearing vitreous hemorrhage, traction retinal detachment or very severe proliferative diabetic retinopathy (PDR). The goal of vitrectomy in such eyes is to remove the hemorrhage and provide a clear media for application of PRP (often as endolaser photocoagulation) as well as eliminate extensive neovascularization and relieve traction retinal detachments. Many advances in instrumentation and technique have resulted in a dramatic reduction in complications over the last few decades, but surgical complications remain including the following: neovascular glaucoma, retinal detachment, fibrinoid syndrome, endophthalmitis and hypotony with subsequent phthisis bulbi. Recovery for the subject can take up to 6 weeks. Increased vascular endothelial growth factor (VEGF) levels have been demonstrated in the retina and vitreous of human eyes with diabetic retinopathy, especially PDR. VEGF has been demonstrated to increase vessel permeability by increasing the phosphorylation of tight junction proteins, and has been shown to increase retinal vascular permeability in in vivo models. Anti-VEGF therapy, therefore, may represent a useful therapeutic modality which targets the underlying pathogenesis of PDR while vitreous hemorrhage clears to facilitate the placement of PRP, potentially avoiding vitrectomy. This study is designed to determine if intravitreal injections of ranibizumab will facilitate clearing of vitreous hemorrhage and avoidance of vitrectomy and its potential complications. Compared with a surgical intervention, use of an intravitreal agent associated with fewer vitrectomies would be preferable because of the reduced costs, reduced time to treatment, reduced intervention time, relatively low risk of side effects, and reduced recovery time. An intravitreal agent also would be a useful alternative for patients who are unwilling to undergo surgery. Furthermore, the study will determine the safety of this medication in the setting of PDR.

Official Title
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An Evaluation of Intravitreal Ranibizumab for Vitreous Hemorrhage Due to Proliferative Diabetic Retinopathy

Conditions
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Vitreous Hemorrhage, Proliferative Diabetic Retinopathy

Intervention / Treatment
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* Drug: Ranibizumab
* Drug: Saline


Participation Criteria
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Eligibility Criteria
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Subject-level Criteria Inclusion To be eligible, the following inclusion criteria must be met: Age >= 18 years Diagnosis of diabetes mellitus (type 1 or type 2) At least one eye meets the study eye criteria listed below Able and willing to provide informed consent. Exclusion A subject is not eligible if any of the following exclusion criteria are present: A condition that, in the opinion of the investigator, would preclude participation in the study (e.g., unstable medical status including blood pressure, cardiovascular disease, and glycemic control). A condition that, in the opinion of the investigator, would preclude subject undergoing elective vitrectomy surgery if indicated during the study. Participation in an investigational trial that involved treatment with any drug within 30 days of randomization that has not received regulatory approval at the time of study entry. Known allergy to any component of the study drug. Blood pressure > 180/110 (systolic above 180 or diastolic above 110). Myocardial infarction, other cardiac event requiring hospitalization, stroke, transient ischemic attack, or treatment for acute congestive heart failure within 4 months prior to randomization. Systemic anti-VEGF or pro-VEGF treatment within 4 months prior to randomization. For women of child-bearing potential: pregnant or lactating or intending to become pregnant within the next 4 months. Subject is expecting to move out of the area of the clinical center to an area not covered by another clinical center during the 12 months of the study. Study Eye Criteria The subject must have at least one eye meeting all of the inclusion criteria and none of the exclusion criteria listed below. A subject can have only one study eye. If both eyes are eligible at the time of randomization, the study eye will be selected by the investigator and subject before randomization. The eligibility criteria for a study eye are as follows: Inclusion Vitreous hemorrhage causing vision impairment, presumed to be from proliferative diabetic retinopathy, and precluding completion of panretinal photocoagulation (or precluding assessment of completeness of prior PRP). Immediate vitrectomy not required (investigator and subject are willing to wait at least 8 weeks to see if hemorrhage clears sufficiently without having to proceed to vitrectomy). Visual acuity is light perception or better. Exclusion Prompt vitrectomy indicated, such as because of signs of rhegmatogenous retinal detachment or traction detachment involving the macula present on ultrasound. Exam evidence of neovascular glaucoma, angle neovascularization, or active neovascularization of the iris (small iris tufts not an exclusion). History of intravitreal anti-VEGF treatment for vitreous hemorrhage at any time in the past or for an indication other than vitreous hemorrhage in the past 2 months. History of major ocular surgery (including cataract extraction, scleral buckle, any intraocular surgery, etc.) within prior 4 months or major ocular surgery other than vitrectomy anticipated within the next 6 months following randomization. History of vitrectomy. History of yttrium aluminum garnet capsulotomy performed within 2 months prior to randomization. Aphakia. Uncontrolled glaucoma (in investigator's judgment). Exam evidence of severe external ocular infection, including conjunctivitis, chalazion, or substantial blepharitis.

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
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Triple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Placebo Comparator: Saline Injection<br>Saline injection at baseline, 4 and 8 weeks | Drug: Saline<br>* Saline injection of 0.5mg at baseline, 4 and 8 weeks<br>|
| Active Comparator: Ranibizumab<br>Intravitreal injection of 0.5 mg ranibizumab (Lucentis™) at baseline, 4 and 8 weeks | Drug: Ranibizumab<br>* Intravitreal injection of 0.5 mg ranibizumab (Lucentis™) at baseline, 4 and 8 weeks<br>* Other names: Lucentis;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Treatment or Failure Defined as Vitrectomy | The cumulative probabilities of vitrectomy by 16 weks (112 days) in each group were computed using the life-table method. The treatment group comparison was made using the log-rank test. Data were censored at the time point of the participant's last completed visit. | within 112 days of randomization | 
| Safety (Injected-related, Ocular Drug-related and Systemic Drug-related) |  | Baseline to 16 weeks | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Ability to Complete Panretinal Photocoagulation (PRP) in the Absence of Vitrectomy | The proportion of eyes with complete panretinal photocoagulation by 16 weeks in abscence of vitrectomy was computed using the life-table method and treatment groups were compared using the log-rank test. | within 112 days of randomization | 
| Extent of Vitreous Hemorrhage Measured by Optical Coherence Tomography Signal Strength | Optical coherence tomography signal strength was evaluated as a potential indicator of vitreous hemorrhage density in an exploratory analysis. This analysis included only eyes with Optical Coherence Tomography (OCT) signal strength equals to 0 at baseline. | 4, 8 and 12 weeks | 
| Visual Acuity Adjusted for the Baseline Acuity Regardless of Vitrectomy Status | Visual acuity was analyzed using a longitudinal mixed regression model adjusting for baseline visual acuity.Unit of measure is based on the E-ETDRS visual acuity letter score scale, 0-97, where 0 = worst and 97 = best. | 4, 8 and 12 weeks | 
| Visual Acuity Better Than 20/40 and no Vitrectomy Prior to the Visit |  | 4, 8 and 12 weeks | 
| Severe Visual Acuity Loss (Defined as <20/200) |  | 4,8 and 12 weeks | 
| Very Severe Visual Acuity Loss (Defined as <20/800) |  | 4,8 and 12 weeks | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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vitreous, hemorrhage, proliferative, diabetic, retinopathy, intravitreal, ranibizumab, Lucentis, saline, vitrectomy