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Anti-vascular endothelial growth factor (VEGF) drugs are the mainstay of therapy for diabetic macular edema (DME), substantially improving visual acuity for many diabetics worldwide, and proving effective for treatment of both non-proliferative and proliferative diabetic retinopathy.
Many studies such as Diabetic Retinopathy Clinical Research Network studies, RESTORE Study, and The BOLT Study have supported the use of different 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 effect of anti-VEGF drugs on macular perfusion has been inconclusive, with mixed reports of increase, decrease or no effect on perfusion in response to anti-VEGF treatment. In many of these studies, however, patients with more ischaemic 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 studies. Despite its clinical usefulness, however, FA is known to have documented risks. Optical coherence tomography angiography (OCTA) is a new noninvasive method of acquiring 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 the superficial and deep retinal capillary layers separately and the construction of microvascular flow maps.
Several studies have proved the reliability of OCTA in detecting and quantifying macular ischemia in diabetics.
In this study, investigators aim to evaluate the effect of repeated intravitreal injections of different Anti-VEGF agents on the perfusion of different capillary layers in the macula of diabetic patients using OCTA.
This is a prospective interventional study to evaluate the effect of repeated intravitreal injections of Anti-VEGF on macular perfusion in diabetic patients using optical coherence tomography angiography (OCTA).
Each patient will receive a detailed ophthalmologic examination including measurement of BCVA as well as applanation tonometry, undilated and dilated slit-lamp biomicroscopic examination and indirect fundus examination.
Duration of diabetes and its control through HbA1C measurement will be recorded for each patient.
Type 1 and 2 diabetic patients found to have BCVA worse than 6/6 and clinical evidence of macular edema will undergo SD OCT and FA.
Patients with center involved macula edema detected by SD OCT will be included in the study and will undergo baseline macular OCTA.
These patients will then undergo intravitreal injections of Anti-VEGF monthly for 3 months then OCTA will be repeated to evaluate changes in macular perfusion and SD OCT will be repeated to assess retinal thickness. Patients with center involving macular edema on SD-OCT after the first 3 injections will continue to receive intravitreal Anti-VEGF injections monthly until the edema subsides or the study duration ends. These patients then undergo a final macular OCTA for perfusion evaluation and SD OCT for thickness assessment.
OCTA will be performed with an Avanti RTVue XR system (Optovue, Inc., Fremont, CA, USA). Area of FAZ and capillary density at each capillary layer will be calculated before and after interventions using the OCTA machine software and ImageJ software.
All statistical analyses will be done using IBM SPSS v20.0 statistical software (IBM Corporation, NY, USA). Descriptive statistics will be calculated, and the data will be summarized as mean ± SD for numerical data, and as frequencies and percentages for categorical data.
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| Label | Type | Description | Intervention Names |
|---|---|---|---|
| Bevacizumab group | Experimental | Monthly intravitreal injection of 2.5 mg of Bevacizumab for at least 3 consecutive months. This is followed by treat and extend regimen after resolution of macular edema. |
|
| Name | Type | Description | Arm Group Labels | Other Names |
|---|---|---|---|---|
| Bevacizumab | Drug | Repeated intravitreal injections of Bevacizumab monthly |
|
| Measure | Description | Time Frame |
|---|---|---|
| FAZ Area Change | Effect of repeated intravitreal Anti-VEGF injections on Foveal Avascular Zone (FAZ) area measured using the freehand tool of ImageJ | At baseline and after 3-6 consecutive monthly injections. |
| Macular Capillary Density Change at Full Retinal Thickness | Effect of repeated intravitreal Anti-VEGF injections on macular capillary density using the change in the skeletonized vascular density and fractal dimension measured by ImageJ | At baseline and after 3-6 consecutive monthly injections. |
| Measure | Description | Time Frame |
|---|---|---|
| BCVA Change | Correlation of BCVA change with degree of capillary non-perfusion before and after injections | At baseline and after 3-6 consecutive monthly injections. |
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Inclusion Criteria:
Exclusion Criteria:
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| Name | Affiliation | Role |
|---|---|---|
| Khaled E El Rakhawy, PhD | Cairo University | Study Director |
| Karim A Raafat, PhD | Cairo University | Study Director |
| Ahmed AA Abdel Kader, PhD | Cairo University | Study Chair |
| Ayman GA Elnahry, MSc | Cairo University | Principal Investigator |
| Facility | Status | City | State | ZIP | Country | Contacts |
|---|---|---|---|---|---|---|
| Cairo University Faculty of Medicine | Cairo | Egypt |
| PubMed Identifier | Type | Citation | Retractions |
|---|---|---|---|
| 26959128 | Background | Ajlan RS, Silva PS, Sun JK. Vascular Endothelial Growth Factor and Diabetic Retinal Disease. Semin Ophthalmol. 2016;31(1-2):40-8. doi: 10.3109/08820538.2015.1114833. | |
| 20416952 | Background | 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 edema (BOLT study) 12-month data: report 2. Ophthalmology. 2010 Jun;117(6):1078-1086.e2. doi: 10.1016/j.ophtha.2010.03.045. Epub 2010 Apr 22. |
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This is the number of enrolled patients that completed the study.
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| ID | Title | Description |
|---|---|---|
| FG000 | Bevacizumab Group | Monthly intravitreal injection of Bevacizumab for at least 3 consecutive months. This is followed by treat and extend regimen after resolution of macular edema. Bevacizumab: Repeated intravitreal injections of Bevacizumab monthly |
| Title | Milestones | Reasons Not Completed | |||||||||||||||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Overall Study |
|
|
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| ID | Title | Description |
|---|---|---|
| BG000 | Bevacizumab Group | Monthly intravitreal injection of Bevacizumab for at least 3 consecutive months. This is followed by treat and extend regimen after resolution of macular edema. Bevacizumab: Repeated intravitreal injections of Bevacizumab monthly |
| Units | Counts |
|---|---|
| Participants |
|
| Title | Description | Population Description | Parameter Type | Dispersion Type | Unit of Measure | Calculate Percentage | Denominator Units Selected | Denominators | Classes |
|---|---|---|---|---|---|---|---|---|---|
| Age, Categorical | Count of Participants |
| Type | Title | Description | Population Description | Reporting Status | Anticipated Posting Date | Parameter Type | Dispersion Type | Unit of Measure | Calculate Percentage | Time Frame | Units Analyzed | Denominator Units Selected | Arm/Group Information | Denominators | Classes | Analyses | ||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Primary | FAZ Area Change | Effect of repeated intravitreal Anti-VEGF injections on Foveal Avascular Zone (FAZ) area measured using the freehand tool of ImageJ | Patients with adequate image quality | Posted | Mean | Standard Deviation | mm^2 | At baseline and after 3-6 consecutive monthly injections. |
|
|
3 months
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| ID | Title | Description | Deaths (Affected) | Deaths (At Risk) | Serious Events (Affected) | Serious Events (At Risk) | Other Events (Affected) | Other Events (At Risk) |
|---|---|---|---|---|---|---|---|---|
| EG000 | Bevacizumab Group | Monthly intravitreal injection of Bevacizumab for at least 3 consecutive months. This is followed by treat and extend regimen after resolution of macular edema. Bevacizumab: Repeated intravitreal injections of Bevacizumab monthly |
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| Term | Organ System | Source Vocabulary | Assessment Type | Notes | Statistical Information |
|---|---|---|---|---|---|
| Subconjunctival hemorrhage | Eye disorders | Non-systematic Assessment |
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| Title | Organization | Phone | Extension | |
|---|---|---|---|---|
| Dr. Ayman Elnahry | Cairo University | 00201224927604 | ayman_elnahri@hotmail.com |
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| Type | Includes Protocol | Includes SAP | Includes ICF | Document Label | Document Date | Document Uploaded Date | Document File Name |
|---|---|---|---|---|---|---|---|
| Prot | Yes | No | No | Study Protocol | Apr 3, 2017 | Dec 25, 2019 | Prot_000.pdf |
| SAP | No | Yes | No | Statistical Analysis Plan | May 16, 2019 | Jan 13, 2020 | SAP_001.pdf |
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| ID | Term |
|---|---|
| D000068258 | Bevacizumab |
| ID | Term |
|---|---|
| D061067 | Antibodies, Monoclonal, Humanized |
| D000911 | Antibodies, Monoclonal |
| D000906 | Antibodies |
| D007136 | Immunoglobulins |
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| 2866759 | Background | Photocoagulation for diabetic macular edema. Early Treatment Diabetic Retinopathy Study report number 1. Early Treatment Diabetic Retinopathy Study research group. Arch Ophthalmol. 1985 Dec;103(12):1796-806. |
| 16508438 | Background | Avery RL. Regression of retinal and iris neovascularization after intravitreal bevacizumab (Avastin) treatment. Retina. 2006 Mar;26(3):352-4. doi: 10.1097/00006982-200603000-00016. No abstract available. |
| 16849623 | Background | Chapman JA, Beckey C. Pegaptanib: a novel approach to ocular neovascularization. Ann Pharmacother. 2006 Jul-Aug;40(7-8):1322-6. doi: 10.1345/aph.1G604. Epub 2006 Jul 18. |
| 19646547 | Background | Zhang X, Bao S, Hambly BD, Gillies MC. Vascular endothelial growth factor-A: a multifunctional molecular player in diabetic retinopathy. Int J Biochem Cell Biol. 2009 Dec;41(12):2368-71. doi: 10.1016/j.biocel.2009.07.011. Epub 2009 Jul 29. |
| 26795548 | Background | Hwang TS, Gao SS, Liu L, Lauer AK, Bailey ST, Flaxel CJ, Wilson DJ, Huang D, Jia Y. Automated Quantification of Capillary Nonperfusion Using Optical Coherence Tomography Angiography in Diabetic Retinopathy. JAMA Ophthalmol. 2016 Apr;134(4):367-73. doi: 10.1001/jamaophthalmol.2015.5658. |
| 26903223 | Background | 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. |
| 26338819 | Background | 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 Sep 4. |
| 25317632 | Background | Spaide RF, Klancnik JM Jr, Cooney MJ. Retinal vascular layers imaged by fluorescein angiography and optical coherence tomography angiography. JAMA Ophthalmol. 2015 Jan;133(1):45-50. doi: 10.1001/jamaophthalmol.2014.3616. |
| 3523356 | Background | 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. |
| 19563370 | Background | Bonnin P, Pournaras JA, Lazrak Z, Cohen SY, Legargasson JF, Gaudric A, Levy BI, Massin P. Ultrasound assessment of short-term ocular vascular effects of intravitreal injection of bevacizumab (Avastin((R)) ) in neovascular age-related macular degeneration. Acta Ophthalmol. 2010 Sep;88(6):641-5. doi: 10.1111/j.1755-3768.2009.01526.x. |
| 19560206 | Background | Papadopoulou DN, Mendrinos E, Mangioris G, Donati G, Pournaras CJ. Intravitreal ranibizumab may induce retinal arteriolar vasoconstriction in patients with neovascular age-related macular degeneration. Ophthalmology. 2009 Sep;116(9):1755-61. doi: 10.1016/j.ophtha.2009.03.017. Epub 2009 Jun 27. |
| 22250209 | Background | 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. |
| 22330964 | Background | 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. Ophthalmology. 2012 Apr;119(4):789-801. doi: 10.1016/j.ophtha.2011.12.039. Epub 2012 Feb 11. |
| 21459215 | Background | Mitchell P, Bandello F, Schmidt-Erfurth U, Lang GE, Massin P, Schlingemann RO, Sutter F, Simader C, Burian G, Gerstner O, Weichselberger A; RESTORE study group. The RESTORE study: ranibizumab monotherapy or combined with laser versus laser monotherapy for diabetic macular edema. Ophthalmology. 2011 Apr;118(4):615-25. doi: 10.1016/j.ophtha.2011.01.031. |
| 32411431 | Derived | 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 Ophthalmol. 2020 Apr 27;2020:5814165. doi: 10.1155/2020/5814165. eCollection 2020. |
| Participants |
|
| Age, Continuous | Mean | Standard Deviation | Years |
|
| Sex: Female, Male | Count of Participants | Participants |
|
| Race (NIH/OMB) | Count of Participants | Participants |
|
| Region of Enrollment | Number | participants |
|
| Participants |
|
|
| Primary | Macular Capillary Density Change at Full Retinal Thickness | Effect of repeated intravitreal Anti-VEGF injections on macular capillary density using the change in the skeletonized vascular density and fractal dimension measured by ImageJ | Patients with adequate image quality | Posted | Mean | Standard Deviation | percentage of vascularity | At baseline and after 3-6 consecutive monthly injections. |
|
|
|
| Secondary | BCVA Change | Correlation of BCVA change with degree of capillary non-perfusion before and after injections | Patients with good image quality | Posted | Mean | Standard Deviation | Logmar | At baseline and after 3-6 consecutive monthly injections. |
|
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| 0 |
| 31 |
| 0 |
| 31 |
| 18 |
| 31 |
| Ocular irritation | Eye disorders | Non-systematic Assessment |
|
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| D007162 |
| Immunoproteins |
| D001798 | Blood Proteins |
| D011506 | Proteins |
| D000602 | Amino Acids, Peptides, and Proteins |
| D012712 | Serum Globulins |
| D005916 | Globulins |