Clinical trial NCT03246152
Conditions: Diabetic Macular Edema Ischemic Maculopathy
Keywords: Anti-VEGF safety Ischemic Maculopathy Diabetic Macular Edema OCTA
Sponsor: Cairo University
Start date: 2017-10-23; Completion date: 2018-12-24
Enrollment: 31 participants; Allocation: NA; Intervention model: SINGLE_GROUP

Brief summary:
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.

Detailed description:
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.

Arms: arm 1: 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.
Interventions: intervention 1: Bevacizumab
Intervention descriptions: intervention 1: Repeated intravitreal injections of Bevacizumab monthly

Protocol documents:
Prot_000.pdf: 
Research Template 
1 
 
Final Version: 1/6/2016
 
 
Cover Page 
 
Evaluation of the Effect of Intravitreal Injections of 
Anti-VEGF on Macular Perfusion in Diabetic Patients 
Using OCTA (IMPACT) 
 
NCT03246152 
 
Upload date: 12/25/2019 
Review date: 4/3/2017 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


Research Template 
2 
 
Final Version: 1/6/2016
 
 
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1.  Proposed Study Title 
 Evaluation of the effect of repeated intravitreal injections of Anti-VEGF 
on macular perfusion in diabetic patients using optical coherence 
tomography angiography 
 
 
2. Background and Rationale 
Over the past few years, anti-vascular endothelial growth factor (VEGF) 
drugs have become 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.1 
The Early Treatment Diabetic Retinopathy Study (ETDRS) group founded 
guidelines for treating patients with clinically significant DME (CSME) with focal/grid 
macular laser photocoagulation.2 Since then, macular laser, and steroids, were the 
main therapies for treatment of DME until anti VEGF drugs were developed after a 
growing body of scientific evidence implicated VEGF in the pathophysiologic 
process of DME.3,4 
Several explanations are present for how VEGF results in the dysfunction of 
the blood–retinal barrier in patients with DME, including (1) being an important 
mediator for several proinflammatory mediators in diabetic retinopathy (e.g. 
cytokines); (2) the direct effects on tight junction-associated proteins (as B-catenin 
and occludin); and (3) induction of pericyte degeneration and depletion.5 
Many studies such as Diabetic Retinopathy Clinical Research [DRCR] 
Network studies, RESTORE Study,6 RISE and RIDE Research Group,7 and The 
BOLT Study8 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. 
One of these studies, The BOLT study, compared ETDRS macular laser 
treatment (MLT) to intravitreal bevacizumab in patients with persistent CSME. After 
2 years, the bevacizumab group had a median of 9 letters gained, compared to 2.5 
letters for the MLT group (p = 0.005).8 
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 


Research Template 
3 
 
Final Version: 1/6/2016
many of these studies, however, patients with more ischaemic retinas were not 
included.8,9 Retinal ischemia is an important factor in the progression and prognosis 
of diabetic retinopathy. 
Some studies showed sustained retinal arteriolar vasoconstriction in eyes 
treated with anti-VEGF,10 while others demonstrated using ultrasound decreased 
blood flow velocities in all retrobulbar arteries after intravitreal anti-VEGF 
injections.11 This could indicate that anti-VEGF agents may have an effect on the 
ocular perfusion. 
Fluorescein angiography (FA) was the method used to assess changes in 
macular perfusion after anti-VEGF injections in most of the studies.6,7,8 Despite its 
clinical usefulness, however, FA is known to have documented risks.12 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 both the superficial and deep retinal capillary layers separately and 
the construction of microvascular flow maps. 13 
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.14 
Several studies have proved the reliability of OCTA in detecting and 
quantifying macular ischemia in diabetics.14,15,16 
In our study, we aim to evaluate the effect of repeated intravitreal injections of 
Anti-VEGF on the perfusion of different capillary layers in the macula of diabetic 
patients using OCTA. 
 
 
 
3. Objectives 
 
To study the effect of repeated intravitreal injections of Anti-VEGF on 
macular perfusion in diabetic patients using optical coherence 
tomography angiography 
 
4. Study Design 
 
Prospective interventional study 
 
 
 


Research Template 
4 
 
Final Version: 1/6/2016
5. Ethical committee approval: Yes 
 
6. Study Methods 
 
Type 1 and 2 diabetic patients requiring intravitreal Anti-VEGF injections 
for treatment of center involving diabetic macular edema 
 
Inclusion criteria: 
1) Patients ≥ 18 years old with type 1 or 2 diabetes mellitus with 
decreased BCVA due to diabetic macular edema and center 
involvement by the edema on spectral domain optical coherence 
tomography (SD OCT) with any stage of diabetic retinopathy 
 
 
Exclusion criteria: 
1) Ocular conditions that may affect macular perfusion (e.g. retinal 
vascular diseases, uveitis, vasculitis etc.) 
2) History of vitreoretinal surgeries (excluding intravitreal injections) 
3) Any previous treatment for diabetic macular edema 
4) Presence of epiretinal membrane involving the macula or 
vitreomacular traction 
5) Media opacity preventing good image quality 
6) Uncontrolled glaucoma 
7) Thromboembolic events within 6 months 
 
 
Methodology in details 
 
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 


Research Template 
5 
 
Final Version: 1/6/2016
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.  
  
Possible Risk (mention if there is any risk or not) 
Risk of cataract, glaucoma, endophthalmitis, retinal detachment, central 
retinal artery occlusion and vitreous hemorrhage 
 
Primary outcomes 
 
1- Effect of repeated intravitreal Anti-VEGF injections on Foveal 
Avascular Zone (FAZ) area and capillary density as a measure of 
macular perfusion change at different capillary levels in the macula. 
 
 
Secondary outcome parameters 
1- Effect of intravitreal Anti-VEGF injections on microaneurysms and 
vascular changes in the superficial and deep capillary plexuses of the 
macula using OCTA 
2- Effect of intravitreal Anti-VEGF injections on choriocapillaris density 
using OCTA 


Research Template 
6 
 
Final Version: 1/6/2016
3- Correlation of BCVA with degree of capillary non-perfusion before 
and after injections 
 
Sample size (number of participants included) 
50 eyes 
Source of funding  (is there any source of funds or not) 
Self 
 
7. Time plan  
6 months from first injection 
 
 
 References: 
 
1. Radwan S. Ajlan, Paolo S. Silva & Jennifer K. Sun (2016) Vascular 
Endothelial Growth Factor and Diabetic Retinal Disease, Seminars in 
Ophthalmology, 31:1-2, 40-48, DOI: 10.3109/08820538.2015.1114833 
2. Early Treatment Diabetic Retinopathy Study Research Group. 
Photocoagulation for diabetic macular edema: Early Treatment Diabetic 
Retinopathy Study report number 1. Arch Ophthalmol 1985; 103:1796–806. 
3. Regression of retinal and iris neovascularization after intravitreal 
bevacizumab (Avastin) treatment. Retina 2006; 26:352– 4. 
4. Pegaptanib: a novel approach to ocular neovascularization. Ann 
Pharmacother 2006;40:1322– 6. 
5. Zhang X, Bao S, Hambly BD, et al. Vascular endothelial growth factor-A: A 
multifunctional molecular player in diabetic retinopathy. Int J Biochem Cell 
Biol 2009;41: 2368–2371. 
6. Mitchell P, Bandello F, Schmidt-Erfurth U; et al. RESTORE Study Group. The 
RESTORE Study: ranibizumab monotherapy or combined with laser versus 
laser monotherapy for diabetic macular edema. Ophthalmology 2011; 
118:615–25 
7. Nguyen QD, Brown DM, Marcus DM, et al. RISE and RIDE Research Group. 
Ranibizumab for diabetic macular edema: results from 2 phase III 
randomized trials: RISE and RIDE. Ophthalmology 2012;119:789–801. 
8. Michaelides M, Kaines A, Hamilton RD. 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; 
117:1078–1086 
9. Manousaridis K, Talks J. Macular ischaemia: a contraindication for anti-VEGF 
treatment in retinal vascular disease? Br J Ophthalmol 2012;96(2):179-84. 
10. 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; 116(9): 1755–1761. 
11. Bonnin P, Pournaras JA, Lazrak Z, et al. Ultrasound assessment of short 
term ocular vascular effects of intravitreal injection of bevacizumab 


Research Template 
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Final Version: 1/6/2016
(Avastin((R))) in neovascular age-related macular degeneration. Acta 
Ophthalmol 2010;88: 641–645. 
12. Yannuzzi LA, Rohrer KT, Tindel LJ, et al. Fluorescein angiography 
complication survey. Ophthalmology. 1986;93: 611–617. 
13. Spaide RF, Klancnik JM Jr, Cooney MJ. Retinal vascular layers imaged by 
fluorescein angiography and optical coherence tomography angiography. 
JAMA Ophthalmol. 2015;133:45–50. 
14. Freiberg, F.J., Pfau, M., Wons, J. et al, Optical coherence tomography 
angiography of the foveal avascular zone in diabetic retinopathy. Graefes 
Arch Clin Exp Ophthalmol. 2016;254:1051–1058. 
15. Bradley PD, Sim DA, Keane PA, et al. The evaluation of diabetic macular 
ischemia using optical coherence tomography angiography. Invest 
Ophthalmol Vis Sci. 2016;57(2):626–631. 
16. Hwang TS, Gao SS, Liu L, et al. Automated quantification of capillary 
nonperfusion using optical coherence tomography angiography in diabetic 
retinopathy. JAMA Ophthalmol. 2016;134(4):367–373. 
 
 
 

SAP_001.pdf: 
 
Cover Page 
Evaluation of the Effect of Intravitreal Injections 
of Anti-VEGF on Macular Perfusion in Diabetic 
Patients Using OCTA (IMPACT) 
NCT03246152 
 
Document date: 5/16/2019 
Upload date: 1/13/2020 
 
 
 
 
 
Statistical methods: 
Data were coded and entered using the statistical package SPSS 
(Statistical Package for the Social Sciences) version 25. Data was 
summarized using mean, standard deviation, median, minimum and 
maximum in quantitative data and using frequency (count) and relative 
frequency (percentage) for categorical data. Comparisons between 
quantitative variables were done using the non-parametric Kruskal-Wallis 
and Mann-Whitney tests. For comparison of serial measurements within 
same patients paired t test was used in normally distributed quantitative 
variables while non-parametric Wilcoxon signed rank test was used for 
non-normally 
distributed 
quantitative 
variables 
(Chan, 
2003a). 
Correlations between quantitative variables were done using Pearson or 
Spearman correlation coefficient (Chan, 2003b).  Linear regression 


analysis was done to predict changes in different parameters using 
baseline data (Chan, 2004). P-values less than 0.05 were considered as 
statistically significant. 
Ref:- 
Chan YH (2003a): Biostatistics102: Quantitative Data – Parametric 
& Non-parametric Tests. Singapore Med J.;44(8): 391-396.  
Chan YH (2003b): Biostatistics 104: Correlational Analysis. 
Singapore Med J.;44(12) : 614-619. 
Chan YH (2004): Biostatistics 201: linear regression analysis. 
Singapore Med J.;45(2): 55-61.