Effect of Ranibizumab Versus Bevacizumab on the Macular Perfusion in Diabetic Macular Edema (REBEL)

February 15, 2023 updated by: Ayman Gehad Elnahry, Cairo University

Comparison of the Effect of Ranibizumab Versus Bevacizumab on the Macular Perfusion in Diabetic Macular Edema Using OCTA

The Early Treatment Diabetic Retinopathy Study (ETDRS) group founded guidelines for treating patients with clinically significant diabetic macular edema (DME) with focal/grid macular laser photocoagulation. Since then, macular laser, and steroids, were the main therapies for the treatment of DME until anti-vascular endothelial growth factors (anti-VEGF) drugs were developed after a growing body of scientific evidence implicated VEGF in the pathophysiologic process of DME.

Anti-VEGF drugs have been implicated in the treatment of DME. VEGF has been shown to play an important role in the occurrence of increased vascular permeability in DME. VEGF levels are significantly higher in patients with DME and extensive leakage than in patients with minimal leakage.

Many studies such as Diabetic Retinopathy Clinical Research [DRCR] Network studies, RESTORE Study, RISE and RIDE Research Group, and The BOLT Study have supported the use of anti-VEGF agents in the treatment of DME with better visual outcomes using anti-VEGF injections alone or in combination with other treatments.

Several ocular complications of intravitreal anti-VEGF injections have been reported including endophthalmitis, cataract, and retinal detachment. The different effects on macular perfusion between different anti-VEGFs have yet to be fully concluded with mixed conclusions that it increases or decreases or has no effect on perfusion of the macula in response to Anti-VEGF treatment. In many of these studies, however, patients with more ischemic retinas were not included. Retinal ischemia is a vital factor determining the diabetic retinopathy progression and prognosis.

Optical coherence tomography angiography (OCTA) detects blood flow by analyzing signal decorrelation between two sequential OCT cross-sectional scans at the same location. As it detects the movements of red blood corpuscles within the vessels, compared to the stationary retinal surroundings, which will result in signal disparity and imaging The split-spectrum amplitude-decorrelation angiography (SSADA) algorithm improves the signal to noise ratio. OCTA is considered a reliable tool in the detection and quantification of macular ischemia in diabetics.

In this study, the investigators aim to compare the effect of repeated intravitreal injections of ranibizumab and bevacizumab on the perfusion of different capillary layers in the macula of diabetic patients using OCTA.

Study Overview

Detailed Description

Diabetic retinopathy is the major cause of blindness in developed but also in developing countries. The disruption of the blood-retinal barrier and the subsequent accumulation of fluid in the intraretinal layers result in diabetic macular edema (DME), the leading cause of central vision loss in these patients.

The Early Treatment Diabetic Retinopathy Study (ETDRS) group founded guidelines for treating patients with clinically significant DME (CSME) with focal/grid macular laser photocoagulation. Since then, macular laser, and steroids, were the main therapies for treatment of DME until anti-vascular endothelial growth factors (anti-VEGF) drugs were developed after a growing body of scientific evidence implicated VEGF in the pathophysiologic process of DME.

Anti-VEGF drugs have been implicated in the treatment of DME. VEGF has been shown to play an important role in the occurrence of increased vascular permeability in DME. VEGF levels are significantly higher in patients with DME and extensive leakage than in patients with minimal leakage.

Many studies such as Diabetic Retinopathy Clinical Research [DRCR] Network studies, RESTORE Study, RISE and RIDE Research Group, and The BOLT Study have supported the use of anti-VEGF agents in the treatment of DME with better visual outcomes using anti-VEGF injections alone or in combination with other treatments.

DRCR network protocol T found statistically insignificant difference between ranibizumab and bevacizumab on visual acuity and central macular thickness in diabetic macular edema.

Several ocular complications of intravitreal anti-VEGF injections have been reported including endophthalmitis, cataract, and retinal detachment. The different effects on macular perfusion between different anti-VEGFs have yet to be fully concluded with mixed conclusions that it increases or decreases or has no effect on perfusion of macula in response to Anti-VEGF treatment.in many of these studies, however, patients with more ischemic retinas were not included. Retinal ischemia is a vital factor determining the diabetic retinopathy progression and prognosis.

Using ocular ultrasound some studies showed retinal arteriolar vasoconstriction in eyes treated with anti-VEGF, while others showed decreased blood flow velocities in all retro-bulbar arteries after intravitreal injection of anti-VEGF. This may indicate that anti-VEGF may have an effect on ocular perfusion.

Fluorescein angiography (FA) was the method used to assess changes in macular perfusion after anti-VEGF injections in most of the studies. Despite its clinical value, however, FA is known to have documented risks. Optical coherence tomography angiography (OCTA) is an excellent non-invasive modality to acquire high-resolution images of the retinal vasculature that can be utilized in the treatment of retinal disease 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.

OCTA detects blood flow by analyzing signal decorrelation between two sequential OCT cross-sectional scans at the same location. As it detects the movements of red blood corpuscles within the vessels, compared to the stationary retinal surroundings, which will result in signal disparity and imaging The split-spectrum amplitude-decorrelation angiography (SSADA) algorithm improves the signal to noise ratio. OCTA is considered a reliable tool in the detection and quantification of macular ischemia in diabetics.

In this study, the investigators aim to compare the effect of repeated intravitreal injections of ranibizumab and bevacizumab on the perfusion of different capillary layers in the macula of diabetic patients using OCTA.

Study Type

Interventional

Enrollment (Actual)

5

Phase

  • Phase 4

Contacts and Locations

This section provides the contact details for those conducting the study, and information on where this study is being conducted.

Study Locations

      • Cairo, Egypt, 11956
        • Cairo University

Participation Criteria

Researchers look for people who fit a certain description, called eligibility criteria. Some examples of these criteria are a person's general health condition or prior treatments.

Eligibility Criteria

Ages Eligible for Study

18 years and older (Adult, Older Adult)

Accepts Healthy Volunteers

No

Genders Eligible for Study

All

Description

Inclusion Criteria:

  1. Patients ≥18 years old with type 1 or 2 diabetes mellitus with decreased BCVA due to center involving diabetic macular edema on spectral-domain optical coherence tomography.
  2. Patients with central macular thickness "CMT" of ≥ 300 micrometers

Exclusion Criteria:

  1. Ocular conditions that may affect macular perfusion (e.g. retinal vascular diseases, uveitis, vasculitis etc.)
  2. History of vitreo-retinal surgeries.
  3. Previous macular laser treatment
  4. Presence of epi-retinal membrane involving the macula or vitreo-macular traction.
  5. Media opacity preventing good image quality.
  6. Uncontrolled glaucoma.
  7. Thrombo-embolic events within 6 months
  8. Previous intravitreal injections of anti-VEGF

Study Plan

This section provides details of the study plan, including how the study is designed and what the study is measuring.

How is the study designed?

Design Details

  • Primary Purpose: Treatment
  • Allocation: Randomized
  • Interventional Model: Parallel Assignment
  • Masking: Double

Arms and Interventions

Participant Group / Arm
Intervention / Treatment
Active Comparator: Ranibizumab Group
Patients will receive monthly ranibizumab injections for 3 months.
Intravitreal injection of 0.3 mg/0.05 ml ranibizumab will be performed monthly for 3 months.
Other Names:
  • Lucentis
Active Comparator: Bevacizumab Group
Patients will receive monthly bevacizumab injections for 3 months.
Intravitreal injection of 1.25 mg/0.05 ml bevacizumab will be performed monthly for 3 months.
Other Names:
  • Avastin

What is the study measuring?

Primary Outcome Measures

Outcome Measure
Measure Description
Time Frame
Change in foveal avascular zone area
Time Frame: 0 and 3 months.
The change in the foveal avascular zone area will be compared between the two treatment arms as a measure of macular perfusion change.
0 and 3 months.
Change in vascular density of the superficial retinal capillary plexus
Time Frame: 0 and 3 months.
The change in the superficial retinal capillary plexus vascular density will be compared between the two treatment arms as a measure of macular perfusion change.
0 and 3 months.
Change in vascular density of the deep retinal capillary plexus
Time Frame: 0 and 3 months.
The change in the deep retinal capillary plexus vascular density will be compared between the two treatment arms as a measure of macular perfusion change.
0 and 3 months.

Secondary Outcome Measures

Outcome Measure
Measure Description
Time Frame
Change in best corrected visual acuity
Time Frame: 0 and 3 months
The change in best corrected visual acuity will be assessed following treatment with both drugs using standard Snellen charts.
0 and 3 months
Change in central macular thickness
Time Frame: 0 and 3 months
The change in central macular thickness will be assessed following treatment with both drugs using optical coherence tomography.
0 and 3 months
Change in intraocular pressure
Time Frame: 0 and 3 months
he change in intraocular pressure will be assessed following treatment with both drugs using Goldman applanation tonometry.
0 and 3 months
Change of severity of diabetic retinopathy
Time Frame: 0 and 3 months
The change in the severity of diabetic retinopathy will be assessed following treatment with both drugs using color fundus photographs and clinical examination.
0 and 3 months

Collaborators and Investigators

This is where you will find people and organizations involved with this study.

Investigators

  • Principal Investigator: Ayman G Elnahry, MD, PhD, Cairo University
  • Study Director: Karim M Abdelaty, MBBCH, National Eye Center
  • Study Chair: Ahmed A Abdel-Kader, MD, PhD, Cairo University
  • Study Chair: Ahmed A Mohalhal, MD, PhD, Cairo University

Publications and helpful links

The person responsible for entering information about the study voluntarily provides these publications. These may be about anything related to the study.

General Publications

Study record dates

These dates track the progress of study record and summary results submissions to ClinicalTrials.gov. Study records and reported results are reviewed by the National Library of Medicine (NLM) to make sure they meet specific quality control standards before being posted on the public website.

Study Major Dates

Study Start (Actual)

November 26, 2021

Primary Completion (Actual)

September 1, 2022

Study Completion (Actual)

November 1, 2022

Study Registration Dates

First Submitted

July 24, 2021

First Submitted That Met QC Criteria

August 3, 2021

First Posted (Actual)

August 5, 2021

Study Record Updates

Last Update Posted (Estimate)

February 16, 2023

Last Update Submitted That Met QC Criteria

February 15, 2023

Last Verified

February 1, 2023

More Information

Terms related to this study

Plan for Individual participant data (IPD)

Plan to Share Individual Participant Data (IPD)?

NO

Drug and device information, study documents

Studies a U.S. FDA-regulated drug product

Yes

Studies a U.S. FDA-regulated device product

No

product manufactured in and exported from the U.S.

Yes

This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.

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