Macular Perfusion Changes After Anti-VEGF Versus Targeted Retinal Photocoagulation in Proliferative Diabetic Retinopathy

Phase 4

Completed

• Conditions: Diabetic Retinopathy; Proliferative Diabetic Retinopathy; Vascular Endothelial Growth Factor Overexpression
• Interventions: Drug: Bevacizumab Injection; Procedure: Targeted retinal photocoagulation; Procedure: Standard pan-retinal photocoagulation

• Registration Number: NCT04674254
• Lead Sponsor: Cairo University

Brief Summary

Diabetic retinopathy (DR) is the most common microvascular complication of diabetes mellitus (DM), while proliferative diabetic retinopathy (PDR) is the principal cause of severe visual loss in patients with diabetes. Since 1981, Panretinal photocoagulation (PRP) has been a standard of treatment for PDR. However, PRP can be associated with adverse effects, including visual field constriction, decreased night vision, and worsening of coexisting diabetic macular edema (DME). For this reason, some authors have advocated targeted treatment with PRP. Targeted retinal laser photocoagulation (TRP) is designed to treat areas of retinal capillary non-perfusion and intermediate retinal ischemic zones in PDR that may spare better-perfused tissue from laser-induced tissue scarring.

Protocol S by Diabetic Retinopathy Clinical Research Network (DRCR.net) has shown that patients that receive ranibizumab as anti-vascular endothelial growth factor (anti-VEGF) therapy with deferred PRP are non-inferior regarding improving in visual acuity to those eyes receiving standard prompt PRP therapy for the treatment of PDR.

Retinal ischemia is an important factor in the progression and prognosis of diabetic retinopathy. Regarding the effect of anti-VEGF drugs on macular perfusion, several studies have shown mixed results with an increase, decrease, or no effect on perfusion in response to anti-VEGF treatment. In many of these studies, however, patients with more ischemic retinas were not included. Fluorescein angiography (FA) was the method used to assess changes in macular perfusion after anti-VEGF injections in most of the clinical trials. Despite its clinical usefulness, however, FA is known to have documented risks. Optical coherence tomography angiography (OCTA) in macular perfusion evaluation in these cases was recommended by some investigators. Several studies have proved the reliability of OCTA in detecting and quantifying macular ischemia in diabetics.

The investigators aim to compare changes in the macular perfusion in patients with PDR after treatment with anti-VEGF therapy versus TRP versus Standard PRP using OCTA.

Detailed Description

Diabetic retinopathy (DR) is the most common microvascular complication of diabetes mellitus (DM), while proliferative diabetic retinopathy (PDR) is the principal cause of severe visual loss in patients with diabetes.

Since 1981, PRP has been a standard of treatment for PDR. However, PRP can be associated with adverse effects, including visual field constriction, decreased night vision, and worsening of coexisting diabetic macular edema (DME). for this reason, some authors have advocated targeted treatment with PRP. Targeted retinal laser photocoagulation (TRP) is designed to treat areas of retinal capillary non-perfusion and intermediate retinal ischemic zones in PDR that may spare better-perfused tissue from laser-induced tissue scarring.

Protocol S by DRCR.net has shown that patients that receive ranibizumab as anti-vascular endothelial growth factor (anti-VEGF) therapy with deferred PRP are non-inferior regarding improving in visual acuity to those eyes receiving standard prompt PRP therapy for the treatment of PDR. However, the effect of both treatment modalities on macular perfusion has been inconclusive with no studies comparing the effect of both.

Regarding the effect of anti-VEGF drugs on macular perfusion, several studies have shown mixed results with an increase, decrease, or no effect on perfusion in response to anti-VEGF treatment. In many of these studies, however, patients with more ischemic retinas were not included. Retinal ischemia is an important factor in the progression and prognosis of diabetic retinopathy.

Fluorescein angiography (FA) was the method used to assess changes in macular perfusion after anti-VEGF injections in most of the clinical trials. Despite its clinical usefulness, however, FA is known to have documented risks and is being replaced by optical coherence tomography angiography (OCTA) in macular perfusion evaluation in these cases.

OCTA is a new noninvasive method of acquiring high-resolution images of the retinal vasculature that can be utilized in the management and study of retinal diseases without the need for dye injection. It allows the visualization of both the superficial and deep retinal capillary layers separately and the construction of microvascular flow maps allowing quantitative analysis of vascular parameters.

OCTA uses high-speed OCT scanning to detect the flow of blood by analyzing signal decorrelation between two sequential OCT cross-sectional scans repeated at the same location. Because of the movement of erythrocytes within a vessel, compared to stationary areas of the surrounding retina, only perfused blood vessels will result in signal decorrelation, leading to their imaging. The split-spectrum amplitude-decorrelation angiography (SSADA) algorithm improves the signal to noise ratio.

Several studies have proved the reliability of OCTA in detecting and quantifying macular ischemia in diabetics.

The investigators aim to compare changes in the macular perfusion in patients with PDR without macular edema after treatment with anti-VEGF therapy versus TRP versus Standard PRP using OCTA.

Study Timeline

• Study First Submitted: 2020-12-06
• Study First Submitted QC: 2020-12-13
• Study First Posted: 2020-12-19
• Study Start: 2021-03-30
• Primary Completion: 2023-03-15
• Study Completion: 2023-03-15
• Status Verified: 2024-01
• Last Update Submitted: 2024-01-18
• Last Update Posted: 2024-01-19

Recruitment & Eligibility

• Status: COMPLETED
• Sex: All
• Target Recruitment: 43

Inclusion Criteria

1. Patients ≥ 18 years old
2. Type 1 or 2 diabetes mellitus
3. PDR
4. Central macular thickness less than 300 µm

Exclusion Criteria

1. Central macular thickness more than 300 µm
2. Previous retinal laser treatment
3. Ocular conditions that may affect macular perfusion (e.g. retinal vein occlusion, uveitis, vasculitis etc.)
4. Any previous treatment for diabetic macular edema.
5. Presence of epiretinal membrane involving the macula or vitreomacular traction
6. Media opacity such vitreous hemorrhage and dense cataract.
7. Patients with previous cataract surgery within the last 3 months.
8. Uncontrolled glaucoma
9. Thromboembolic events within 6 months
10. Tractional retinal detachment.

Study & Design

• Study Type: INTERVENTIONAL
• Study Design: PARALLEL

Arm && Interventions

Group	Intervention	Description
Anti-vascular endothelial growth factor agent	Bevacizumab Injection	Intravitreal injections of 1.25 mg/0.05 ml of Bevacizumab every 4 weeks through 12- week visit then pro re nata to complete 12 months according to Protocol S.
Targeted retinal photocoagulation	Targeted retinal photocoagulation	Targeted retinal photocoagulation guided by fundus fluorescein angiography will be administered after topical anesthesia, directed to areas of nonperfused peripheral retina plus a 1-disc area margin using the Mainster lens. Subsequent treatments if needed will be delivered at 3 monthly intervals for a minimum follow-up of 12 months. The extent of the laser applied will be determined based on areas of nonperfusion identified by fundus fluorescein angiography.
Standard pan-retinal photocoagulation	Standard pan-retinal photocoagulation	Standard pan-retinal photocoagulation will be performed at baseline and then every 3 months thereafter if needed, for a minimum follow-up period of 12 months. PRP will be performed at two consecutive sessions with adherence to the guidelines of the Early Treatment Diabetic Retinopathy Study Group. Following topical anesthesia, 1000 to 1200 laser spots will be applied to the retina at each session with a 532 nm frequency doubled Nd-YAG laser (VISULAS, Carl Zeiss, Germany) using a spot size of 300-500 μm. PRP will be applied in all 4 retina quadrants. The Mainster lens will be used. Retreatment will be done according to the Diabetic Retinopathy Clinical Research network protocol S classification for patients with stable, worsening, or with failure of regression of neovascularization.

Primary Outcome Measures

Name	Time	Method
Change in vascular density of the retinal capillary plexuses	0, 3, 6, 9, and 12 months	The change in retinal capillary vascular densities at different capillary layers will be compared between the different treatment arms as a measure of macular perfusion change.
Change in foveal avascular zone area	0, 3, 6, 9, and 12 months	The change in the foveal avascular zone area will be compared between the different treatment arms as a measure of macular perfusion change.

Secondary Outcome Measures

Name	Time	Method
Change in best corrected visual acuity	0, 3, 6, 9, and 12 months	The change in best corrected visual acuity will be assessed following treatment with each modality using standard Snellen charts.
Change in macular sensitivity	0, 3, 6, 9, and 12 months	The change in the macular sensitivity will be assessed following treatment with each modality using macular microperimetry.
Change in orbital blood flow	0, 3, 6, 9, and 12 months	The change in orbital blood flow will be assessed following treatment with each modality using orbital color duplex imaging.
Change in neovessels	0, 3, 6, 9, and 12 months	The change in neovessels following treatment with each modality will be evaluated clinically and by fundus fluorescein angiography and the response to treatment will be classified according to the criteria of protocol S of the DRCR network
Change in central macular thickness	0, 3, 6, 9, and 12 months	The change in central macular thickness will be evaluated following treatment with each modality using optical coherence tomography.

Trial Locations

Locations (1)

Faculty of Medicine, Cairo University; 🇪🇬 Giza, Egypt