Diabetic Macular Edema
Conditions
Keywords
diabetic macular edema
Brief summary
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
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.
Interventions
intravitreal injection of 0.5 mg ranibizumab
PROCEDUREperipheral laser
ultra-widefield fluorescein angiography guided peripheral laser
DRUGintravitreal injection of triamcinolone acetonide
intravitreal injection of 4.0 mg triamcinolone acetonide
PROCEDUREmacular laser
macular laser to areas of retinal thickening or leakage
Sponsors
Retina Associates of Florida, P.A.
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
DOUBLE (Subject, Investigator)
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
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
Design outcomes
Primary
| Measure | 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
| Measure | Time frame |
|---|---|
| Mean Central Foveal Thickness (CFT) on Optical Coherence Tomography (OCT) in Microns at 6 Months | 6 months |
Countries
United States
Participant flow
Recruitment details
We included 30 treatment-naïve eyes of 22 patients (8 bilateral patients) aged ≥ 18 years of age, with Type 1 or 2 diabetes mellitus and visual impairment secondary to diabetic macular edema associated with peripheral nonperfusion on Ultra Widefield Fluorescein Angiography (UWFA).
Pre-assignment details
Treatment naive patients
Participants by arm
| Arm | Count |
|---|---|
| Treatment Group 1 ranibizumab and scatter laser | 11 |
| Comparative Group 1 Intravitreal triamcinolone with macular laser | 11 |
| Total | 22 |
Baseline characteristics
| Characteristic | Comparative Group 1 | Treatment Group 1 | Total |
|---|---|---|---|
| Age, Categorical <=18 years | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical >=65 years | 0 Participants | 1 Participants | 1 Participants |
| Age, Categorical Between 18 and 65 years | 11 Participants | 10 Participants | 21 Participants |
| Age, Continuous | 58.3 years STANDARD_DEVIATION 6.5 | 57.7 years STANDARD_DEVIATION 7.5 | 58.0 years STANDARD_DEVIATION 7.4 |
| Region of Enrollment United States | 11 participants | 11 participants | 22 participants |
| Sex: Female, Male Female | 5 Participants | 5 Participants | 10 Participants |
| Sex: Female, Male Male | 6 Participants | 6 Participants | 12 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — |
| other Total, other adverse events | 0 / 11 | 0 / 11 |
| serious Total, serious adverse events | 0 / 11 | 0 / 11 |
Outcome results
Primary
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
Population: We included 30 treatment-naïve eyes of 22 patients (8 bilateral patients) aged ≥ 18 years of age, with Type 1 or 2 diabetes mellitus and visual impairment secondary to diabetic macular edema associated with peripheral nonperfusion on UWFA.
| Arm | Measure | Value (MEAN) |
|---|---|---|
| Treatment Group 1 | 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. | 13 Letters of visual acuity on ETDRS chart |
| Comparative Group 1 | 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. | 10 Letters of visual acuity on ETDRS chart |
Secondary
Mean Central Foveal Thickness (CFT) on Optical Coherence Tomography (OCT) in Microns at 6 Months
Time frame: 6 months
| Arm | Measure | Value (MEAN) |
|---|---|---|
| Treatment Group 1 | Mean Central Foveal Thickness (CFT) on Optical Coherence Tomography (OCT) in Microns at 6 Months | 270 units on a scale (microns) |
| Comparative Group 1 | Mean Central Foveal Thickness (CFT) on Optical Coherence Tomography (OCT) in Microns at 6 Months | 350 units on a scale (microns) |