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

Diabetic Retinopathy Clinical Trial

— PROPER  

Official title:

Macular Perfusion Changes in Proliferative Diabetic Retinopathy Following Anti-VEGF Therapy Versus Targeted and Pan-retinal Photocoagulation Using Optical Coherence Tomography Angiography

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT04674254
• Other study ID #: MD-39-2021
• Status: Completed
• Phase: Phase 4
• Start date: March 30, 2021
• Est. completion date: March 15, 2023

Study information

• Verified date: January 2024
• Source: Cairo University
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial 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.

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.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 43
• Est. completion date: March 15, 2023
• Est. primary completion date: March 15, 2023
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years and older

Eligibility

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.

Related Conditions & MeSH terms

• Diabetic Retinopathy
• Proliferative Diabetic Retinopathy
• Retinal Diseases
• Vascular Endothelial Growth Factor Overexpression

Intervention

Drug:
• Bevacizumab Injection
Bevacizumab will be intravitreally injected every 4 weeks through 12 weeks then pro re nata thereafter for 12 months.

Procedure:
• Targeted retinal photocoagulation
Targeted retinal photocoagulation will be administered to nonperfused areas detected on fundus fluorescein angiography at baseline and repeated every 3 months as needed for 12 months.
• Standard pan-retinal photocoagulation
Standard pan-retinal photocoagulation will be applied to perfused and nonperfused areas of the retinal periphery at baseline and every 3 months as needed for 12 months.

Locations

Country	Name	City	State
Egypt	Faculty of Medicine, Cairo University	Giza

Sponsors (1)

Lead Sponsor	Collaborator
Cairo University

Country where clinical trial is conducted

Egypt, 

References & Publications (21)

Alagorie AR, Nittala MG, Velaga S, Zhou B, Rusakevich AM, Wykoff CC, Sadda SR. Association of Intravitreal Aflibercept With Optical Coherence Tomography Angiography Vessel Density in Patients With Proliferative Diabetic Retinopathy: A Secondary Analysis o — View Citation

Bradley PD, Sim DA, Keane PA, Cardoso J, Agrawal R, Tufail A, Egan CA. The Evaluation of Diabetic Macular Ischemia Using Optical Coherence Tomography Angiography. Invest Ophthalmol Vis Sci. 2016 Feb;57(2):626-31. doi: 10.1167/iovs.15-18034. — View Citation

Campochiaro PA, Wykoff CC, Shapiro H, Rubio RG, Ehrlich JS. Neutralization of vascular endothelial growth factor slows progression of retinal nonperfusion in patients with diabetic macular edema. Ophthalmology. 2014 Sep;121(9):1783-9. doi: 10.1016/j.ophth — View Citation

Elnahry AG, Abdel-Kader AA, Habib AE, Elnahry GA, Raafat KA, Elrakhawy K. Review on Recent Trials Evaluating the Effect of Intravitreal Injections of Anti-VEGF Agents on the Macular Perfusion of Diabetic Patients with Diabetic Macular Edema. Rev Recent Cl — View Citation

Elnahry AG, Abdel-Kader AA, Raafat KA, Elrakhawy K. Evaluation of Changes in Macular Perfusion Detected by Optical Coherence Tomography Angiography following 3 Intravitreal Monthly Bevacizumab Injections for Diabetic Macular Edema in the IMPACT Study. J O — View Citation

Elnahry AG, Abdel-Kader AA, Raafat KA, Elrakhawy K. Evaluation of the Effect of Repeated Intravitreal Bevacizumab Injections on the Macular Microvasculature of a Diabetic Patient Using Optical Coherence Tomography Angiography. Case Rep Ophthalmol Med. 201 — View Citation

Freiberg FJ, Pfau M, Wons J, Wirth MA, Becker MD, Michels S. Optical coherence tomography angiography of the foveal avascular zone in diabetic retinopathy. Graefes Arch Clin Exp Ophthalmol. 2016 Jun;254(6):1051-8. doi: 10.1007/s00417-015-3148-2. Epub 2015 — View Citation

Ghasemi Falavarjani K, Iafe NA, Hubschman JP, Tsui I, Sadda SR, Sarraf D. Optical Coherence Tomography Angiography Analysis of the Foveal Avascular Zone and Macular Vessel Density After Anti-VEGF Therapy in Eyes With Diabetic Macular Edema and Retinal Vei — View Citation

Hsieh YT, Alam MN, Le D, Hsiao CC, Yang CH, Chao DL, Yao X. OCT Angiography Biomarkers for Predicting Visual Outcomes after Ranibizumab Treatment for Diabetic Macular Edema. Ophthalmol Retina. 2019 Oct;3(10):826-834. doi: 10.1016/j.oret.2019.04.027. Epub — View Citation

Klein R, Klein BE, Moss SE, Davis MD, DeMets DL. The Wisconsin epidemiologic study of diabetic retinopathy. IV. Diabetic macular edema. Ophthalmology. 1984 Dec;91(12):1464-74. doi: 10.1016/s0161-6420(84)34102-1. — View Citation

Kozak I, Luttrull JK. Modern retinal laser therapy. Saudi J Ophthalmol. 2015 Apr-Jun;29(2):137-46. doi: 10.1016/j.sjopt.2014.09.001. Epub 2014 Sep 28. — View Citation

Lee R, Wong TY, Sabanayagam C. Epidemiology of diabetic retinopathy, diabetic macular edema and related vision loss. Eye Vis (Lond). 2015 Sep 30;2:17. doi: 10.1186/s40662-015-0026-2. eCollection 2015. — View Citation

Manousaridis K, Talks J. Macular ischaemia: a contraindication for anti-VEGF treatment in retinal vascular disease? Br J Ophthalmol. 2012 Feb;96(2):179-84. doi: 10.1136/bjophthalmol-2011-301087. — View Citation

Michaelides M, Kaines A, Hamilton RD, Fraser-Bell S, Rajendram R, Quhill F, Boos CJ, Xing W, Egan C, Peto T, Bunce C, Leslie RD, Hykin PG. A prospective randomized trial of intravitreal bevacizumab or laser therapy in the management of diabetic macular ed — View Citation

Muqit MM, Marcellino GR, Henson DB, Young LB, Patton N, Charles SJ, Turner GS, Stanga PE. Optos-guided pattern scan laser (Pascal)-targeted retinal photocoagulation in proliferative diabetic retinopathy. Acta Ophthalmol. 2013 May;91(3):251-8. doi: 10.1111 — View Citation

Nguyen QD, Brown DM, Marcus DM, Boyer DS, Patel S, Feiner L, Gibson A, Sy J, Rundle AC, Hopkins JJ, Rubio RG, Ehrlich JS; RISE and RIDE Research Group. Ranibizumab for diabetic macular edema: results from 2 phase III randomized trials: RISE and RIDE. Opht — View Citation

Nikkhah H, Ghazi H, Razzaghi MR, Karimi S, Ramezani A, Soheilian M. Extended targeted retinal photocoagulation versus conventional pan-retinal photocoagulation for proliferative diabetic retinopathy in a randomized clinical trial. Int Ophthalmol. 2018 Feb — View Citation

Riaskoff S. Photocoagulation treatment of proliferative diabetic retinopathy. Bull Soc Belge Ophtalmol. 1981;197:9-17. No abstract available. — View Citation

Wessel MM, Aaker GD, Parlitsis G, Cho M, D'Amico DJ, Kiss S. Ultra-wide-field angiography improves the detection and classification of diabetic retinopathy. Retina. 2012 Apr;32(4):785-91. doi: 10.1097/IAE.0b013e3182278b64. — View Citation

Writing Committee for the Diabetic Retinopathy Clinical Research Network; Gross JG, Glassman AR, Jampol LM, Inusah S, Aiello LP, Antoszyk AN, Baker CW, Berger BB, Bressler NM, Browning D, Elman MJ, Ferris FL 3rd, Friedman SM, Marcus DM, Melia M, Stockdale — View Citation

Yannuzzi LA, Rohrer KT, Tindel LJ, Sobel RS, Costanza MA, Shields W, Zang E. Fluorescein angiography complication survey. Ophthalmology. 1986 May;93(5):611-7. doi: 10.1016/s0161-6420(86)33697-2. — View Citation

* Note: There are 21 references in all — Click here to view all references

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Change in foveal avascular zone area	The change in the foveal avascular zone area will be compared between the different treatment arms as a measure of macular perfusion change.	0, 3, 6, 9, and 12 months
Primary	Change in vascular density of the retinal capillary plexuses	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.	0, 3, 6, 9, and 12 months
Secondary	Change in neovessels	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	0, 3, 6, 9, and 12 months
Secondary	Change in central macular thickness	The change in central macular thickness will be evaluated following treatment with each modality using optical coherence tomography.	0, 3, 6, 9, and 12 months
Secondary	Change in best corrected visual acuity	The change in best corrected visual acuity will be assessed following treatment with each modality using standard Snellen charts.	0, 3, 6, 9, and 12 months
Secondary	Change in macular sensitivity	The change in the macular sensitivity will be assessed following treatment with each modality using macular microperimetry.	0, 3, 6, 9, and 12 months
Secondary	Change in orbital blood flow	The change in orbital blood flow will be assessed following treatment with each modality using orbital color duplex imaging.	0, 3, 6, 9, and 12 months