Ranibizumab and Peripheral Scatter Laser in Patients With Diabetic Macular Edema and Peripheral Nonperfusion

Study Overview
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Brief Summary
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To investigate the role of ranibizumab and angiographically-directed peripheral scatter laser therapy in patients with clinically-significant diabetic macular edema (CSME) and peripheral nonperfusion. We propose a novel treatment of CSME in a subgroup of patients defined by a combination of ultrawide-field angiography (UWFA) and optical coherence tomography (OCT). Within this classification scheme, patients with CSME are subdivided by the presence of: 1) focal macular leakage, 2) vitreomacular interface traction, and/or 3) peripheral nonperfusion. The successful treatment of diabetic macular edema would be dictated by pathophysiology-directed therapy based on this classification. The subgroup of interest for this clinical trial is characterized by diabetic macular edema, peripheral nonperfusion on UWFA, and the absence of macular traction on OCT. This group of patients has previously not been well recognized or characterized due to limitations in previous, standard angiographic evaluation of the retinal periphery. We postulate that this subcategory represents one with a high rate of failure of accepted therapies given persistence of the basic pathophysiologic mechanism for CSME, namely ischemia-induced production of Vascular Endothelial Growth Factor (VEGF) from the retinal periphery. This also represents a population of patients with likely recurrence of CSME despite treatment with anti-VEGF therapy alone for the same reason.

Detailed Description
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Diabetic retinopathy is a leading cause of moderate and severe visual loss in developed countries. It is of paramount socioeconomic impact as the prevalence of diabetes is sharply increasing, diabetic macular edema is the leading cause of vision loss in working age patients, it is a significant cause of vision loss in patients older than 65 years of age, it frequently affects patients bilaterally, and the costs of therapy are increasing. Diabetic macular edema (DME) is the most common cause of vision loss in diabetic retinopathy. The pathophysiology of DME is complex and multifactorial. Chronic hyperglycemia, protein kinase C (PKC) formation, free radical accumulation, advanced glycation end-product (AGE) proteins, and ischemia-driven release of vascular endothelial growth factor (VEGF) are some of the better understood factors that contribute to chronic retinal arterial and capillary damage and increased permeability. The RIDE and RISE Studies demonstrated the superiority of anti-VEGF monotherapy with ranibizumab over sham therapy, when all groups were allowed to receive macular laser therapy after month 3 based on predefined criteria. Furthermore, other studies have demonstrated VEGF inhibitors to be beneficial for DME, either as monotherapy or in combination with macular laser. The benefit of VEGF antagonists in treating DME validates that the VEGF pathway is a key target. The need for repeated anti-VEGF injections to maintain the benefit of treatment begs the question whether persistent peripheral retinal ischemia may be driving VEGF production in at least a subset of patients with DME. Fluorescein angiographic studies of the mid- and far-periphery of diabetic patients by Shimizu in the 1980's demonstrated areas of peripheral retinal nonperfusion in diabetic patients. These findings have been reproduced and substantiated more recently utilizing a novel, commercially-available imaging system for ultrawide-field angiography (UWFA) that employs a scanning laser ophthalmoscope and an ellipsoidal mirror. We investigated whether patients with diabetic macular edema associated with peripheral nonperfusion on UWFA would have improved visual acuity, resolution of retinal thickening on OCT, and durability of therapy using a novel strategy of a single intravitreal injection of Ranibizumab, a VEGF-A inhibitor + UWFA-guided peripheral Scatter Laser, or RaScaL. A second goal of the study was to guide DME treatment by the imaging signature of UWFA and OCT.

Official Title
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Ranibizumab (rhuFab V2) and Scatter Laser Photocoagulation in Treatment of Patients With Clinically-significant Diabetic Macular Edema With Peripheral Retinal Nonperfusion (RaScaL)

Conditions
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Diabetic Macular Edema

Intervention / Treatment
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* Drug: intravitreal injection of ranibizumab
* Procedure: peripheral laser
* Drug: intravitreal injection of triamcinolone acetonide
* Procedure: macular laser


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 Patient related considerations: • Patients with Type I or Type II diabetes Disease related considerations: Study eye with clinically significant diabetic macular edema characterized by macular edema, peripheral nonperfusion, and absence of macular traction on clinical exam, UWFA, and OCT. Study eye with best corrected visual acuity between 20/40 (≤ 73 letters on Early Treatment of Diabetic Retinopathy Study (ETDRS) chart and 20/320 (≥ 19 letters on ETDRS chart) Other considerations Patient able to complete all study visits Female patients must be using two forms of contraception Exclusion Criteria: 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 Intra Uterine Device, or contraceptive hormone implant or patch. Prior enrollment in the study 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 Therapy with intravitreal triamcinolone, pegaptanib, ranibizumab, or bevacizumab within the previous 3 months Previous panretinal scatter laser photocoagulation Previous pars plana vitrectomy Visually-significant significant cataracts as primary reason for vision loss Uncontrolled or advanced glaucoma Patients on more than one anti-glaucoma agent Myocardial infarction or cerebrovascular accident within 6 months Subjects with poor glycemic control that have initiated intensive insulin treatment or plan to do so in the next 4 months

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: Double


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Treatment group<br>single intravitreal injection of ranibizumab (0.5 mg in 0.1 cc) peripheral laser to areas of retinal nonperfusion on ultra-widefield fluorescein angiography | Drug: intravitreal injection of ranibizumab<br>* intravitreal injection of 0.5 mg ranibizumab<br>* Other names: treatment arm;Procedure: peripheral laser<br>* ultra-widefield fluorescein angiography guided peripheral laser<br>* Other names: treatment arm;|
| Active Comparator: Control Group<br>single intravitreal injection of triamcinolone acetonide (4.0 mg in 0.1 cc) macular laser per treatment criteria | Drug: intravitreal injection of triamcinolone acetonide<br>* intravitreal injection of 4.0 mg triamcinolone acetonide<br>* Other names: control arm;Procedure: macular laser<br>* macular laser to areas of retinal thickening or leakage<br>* Other names: control arm;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Mean Change in Best Corrected Visual Acuity (BCVA), as Assessed by the Number of Letters Read Correctly on the ETDRS Eye Chart at a Starting Test Distance of 4 Meters From Baseline to Month 6. |  | 6 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Mean Central Foveal Thickness (CFT) on Optical Coherence Tomography (OCT) in Microns at 6 Months |  | 6 months | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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diabetic macular edema