Ranibizumab and Peripheral Scatter Laser in Patients With Diabetic Macular Edema and Peripheral Nonperfusion (RaScaL)
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.
|Diabetic Macular Edema||Drug: intravitreal injection of ranibizumab Procedure: peripheral laser Drug: intravitreal injection of triamcinolone acetonide Procedure: macular laser||Phase 2|
|Study Design:||Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Double (Participant, Investigator)
Primary Purpose: Treatment
|Official Title:||Ranibizumab (rhuFab V2) and Scatter Laser Photocoagulation in Treatment of Patients With Clinically-significant Diabetic Macular Edema With Peripheral Retinal Nonperfusion (RaScaL)|
- 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. [ Time Frame: 6 months ]
- Mean Central Foveal Thickness (CFT) on Optical Coherence Tomography (OCT) in Microns at 6 Months [ Time Frame: 6 months ]
|Study Start Date:||February 2008|
|Study Completion Date:||August 2011|
|Primary Completion Date:||July 2011 (Final data collection date for primary outcome measure)|
Experimental: Treatment group
Drug: intravitreal injection of ranibizumab
intravitreal injection of 0.5 mg ranibizumab
Other Name: treatment armProcedure: peripheral laser
ultra-widefield fluorescein angiography guided peripheral laser
Other Name: treatment arm
Active Comparator: Control Group
Drug: intravitreal injection of triamcinolone acetonide
intravitreal injection of 4.0 mg triamcinolone acetonide
Other Name: control armProcedure: macular laser
macular laser to areas of retinal thickening or leakage
Other Name: control arm
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.
Please refer to this study by its ClinicalTrials.gov identifier: NCT00815360
|United States, Florida|
|Retina Associates of Florida|
|Tampa, Florida, United States, 33609|
|Principal Investigator:||Ivan J Suner, MD||Retina Associates of Florida|