The Efficacy of Intravitreal Aflibercept Injection in Improvement of Retinal Nonperfusion in Diabetic Retinopathy

The Efficacy of Intravitreal Aflibercept Injection in Improvement of Retinal Nonperfusion in Patients With Diabetic Retinopathy

Retinal nonperfusion drives vision-threatening complications such as pathological neovascularization, which can lead to neovascular glaucoma, vitreous hemorrhage, or tractional retinal detachments and macular edema in diabetic retinopathy. Thus, decreasing nonperfusion area with aid of anti-VEGF agents might be a useful way to prevent deteriorating course of diabetic retinopathy. The main purpose of this study is to determine the efficacy of intravitreal aflibercept injection in improvement of retinal nonperfusion and identify associated factors in patients with nonproliferative diabetic retinopathy with moderate retinal nonperfusion.

Study Overview

• Status: Completed
• Conditions: Diabetic Retinopathy
• Intervention / Treatment: Drug: Intravitreal Aflibercept injection

Detailed Description

Retinal nonperfusion drives vision-threatening complications such as pathological neovascularization, which can lead to neovascular glaucoma, vitreous hemorrhage, or tractional retinal detachments and macular edema in various retinal vascular diseases including diabetic retinopathy and retinal vein occlusion. Silva et al revealed that retinal nonperfusion area was correlated highly with diabetic retinopathy severity in their recent paper. It should be clarified that retinal nonperfusion is not synonymous with retinal ischemia, which implies tissue hypoxia, but is a useful surrogate.

Retinal nonperfusion has known to be associated with the production of vascular endothelial factor (VEGF). Recently, Campochiaro et al reported that neutralization of VEGF using ranibizumab improved macular edema and reversed the worsening of retinal nonperfusion in patients with retinal vein occlusion and diabetic macular edema. The precise mechanism for improved perfusion in the VEGF treated eye is uncertain. The authors suggested that VEGF exacerbates retinal ischemia by increasing leukostasis, and intravitreal anti-VEGF agents may break the feedback loop, allowing reperfusion to occur. There might be a portion of circulation that is closed but not permanently, and this reversible closure is modulated by VEGF.

The study by Campochiaro et al, however, was limited in that they reviewed retinal nonperfusion within a template consisting of the Early Treatment Diabetic Retinopathy subfields mainly confined to posterior pole of the fundus. Wide-field retinal imaging is an imaging technique that allows a view of almost 200° of the fundus in a single image. It has been well shown that wide-field scans allow the detection of peripheral pathology that may be missed on 75 degrees of achieved by montaging the Early Treatment Diabetic Retinopathy Study 7-standard fields.

To investigators knowledge, there has been no previous study evaluating the longitudinal change of retinal nonperfusion after aflibercept treatment in a larger area of the retina by taking advantage of the 200° field of view in diabetic retinopathy. The main purpose of this study is to determine the efficacy of intravitreal aflibercept injection in improvement of retinal nonperfusion and identify associated factors in patients with nonproliferative diabetic retinopathy with moderate retinal nonperfusion.

• Study Type: Interventional
• Enrollment (Actual): 38
• Phase: Phase 2

Contacts and Locations

Study Locations

• South Korea
  • Seoul
    • Seoul, Seoul, South Korea, 05505
      • Asan Medical Center

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

• A subject must meet the following criteria to be eligible for inclusion in the study:

  1. Adults ≥ 18 years with type 1 or 2 diabetes mellitus
  2. Patients diagnosed as nonproliferative diabetic retinopathy with retinal nonperfusion (Ischemic index >20%) Severe nonproliferative diabetic retinopathy - Early proliferative diabetic retinopathy
  3. Willing and able to comply with clinic visits and study-related procedures
  4. Provide a signed informed consent form

Exclusion Criteria:

• A subject who meets any of the following criteria will be excluded from the study.

  1. Systemic exclusion criteria 1. Renal failure requiring hemodialysis or peritoneal dialysis within 6 months prior to baseline or anticipated need for hemodialysis, peritoneal dialysis at any time during the study 2. Acute cardiovascular events (acute myocardiac infarction and/or cerebral infarction) within 1 year before Visit 1 3. Blood HbA1c level greater than 12% at Visit 0
  2. Ocular exclusion criteria
  1. Diabetic macular edema involving the center of the macula (Defined as the area of the center subfield of OCT, Heidelberg Spectralis: ≥305 in women; ≥320 in men) in the study eye
  2. Presence of rubeosis (neovascularization of the iris or the angle) in the study eye
  3. Any current or history of retinal diseases that affects visual acuity in the study eye
  4. Previous treatment of panretinal photocoagulation
  5. Previous treatment with anti-VEGF in study eye within 6 months before Visit 1
  6. Previous treatment with intraocular or periocular corticosteroids in the study eye within 6 months before Visit 1
  7. Previous history of intraocular surgery other than cataract surgery in the study eye
  8. Cataract surgery within 3 months before Visit 1 in the study eye
  9. Yttrium-aluminium-garnet (YAG) capsulotomy in the study eye within 1 month before Visit 1
  10. Aphakia in the study eye
  11. Elevated intraocular pressure (≥ 22 mmHg) in spite of using topical IOP lowering agents at Visit 1 or a diagnosis of glaucoma (Visual field defect corresponding to glaucomatous optic neuropathy) in the study eye
  12. Presence of a visually significant cataract in the study eye
  13. BCVA score < 34 letters in the fellow eye
  14. Hypersensitivity to aflibercept
  15. Ocular or periocular infection
  16. Active intraocular inflammation

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: N/A
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

1

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: 2mg intravitreal aflibercept injection; 2mg intravitreal aflibercept (Eylea) injection at baseline, 1M, 2M, 3M, 4M, and 5M	Drug: Intravitreal Aflibercept injection; Six number of injections at baseline, 1M, 2M, 3M, 4M, and 5M; Other Names: Eylea

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Improvement of retinal nonperfusion	Mean changes (%) of retinal nonperfusion (Ischemic index) from baseline	1 year

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
progression of diabetic retinopathy to proliferative diabetic retinopathy (PDR)	Number of patients who receive rescue treatment due to PDR and time to rescue treatment due to PDR	1 year
development of diabetic macular edema	Number of patients who receive rescue treatment due to DME and time to rescue treatment due to DME	1 year
Factors associated with the progression of retinal nonperfusion 1 (Functional)	- Visual acuity parameters: Mean changes of BCVA from baseline at every 3 month visit The proportion of subjects with gaining / losing ≥ 15letters or more in BCVA	1 year
Factors associated with the progression of retinal nonperfusion 2 (Anatomical)	- Optical coherence tomography (OCT) parameters: Mean changes of Central Retinal Thickness (CRT) from baseline at every 3 month visit Mean changes of Central Retinal Volume from baseline at every 3 month visit Mean change subfoveal choroidal thickness (SFChT) from baseline at every 3 month visit	1 year
Factors associated with the progression of retinal nonperfusion 3 (Anatomical)	- Fluorescein angiography (FA) parameters: Baselinenonperfusion area(Ischemic index) at posterior and peripheral retina Baseline degree of vascular leakage at posterior and peripheral retina	1year

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
Safety outcome; Adverse effect of intravitreal aflibercept (Eylea) injection	Ocular and systemic adverse event	1 year

Collaborators and Investigators

• Sponsor: Asan Medical Center
• Investigators: Principal Investigator: Young Hee Yoon, Asan Medical Center

Publications and helpful links

General Publications

• Silva PS, Cavallerano JD, Haddad NM, Kwak H, Dyer KH, Omar AF, Shikari H, Aiello LM, Sun JK, Aiello LP. Peripheral Lesions Identified on Ultrawide Field Imaging Predict Increased Risk of Diabetic Retinopathy Progression over 4 Years. Ophthalmology. 2015 May;122(5):949-56. doi: 10.1016/j.ophtha.2015.01.008. Epub 2015 Feb 19.
• Silva PS, Dela Cruz AJ, Ledesma MG, van Hemert J, Radwan A, Cavallerano JD, Aiello LM, Sun JK, Aiello LP. Diabetic Retinopathy Severity and Peripheral Lesions Are Associated with Nonperfusion on Ultrawide Field Angiography. Ophthalmology. 2015 Dec;122(12):2465-72. doi: 10.1016/j.ophtha.2015.07.034. Epub 2015 Sep 6.
• 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.ophtha.2014.03.021. Epub 2014 Apr 24.
• Kim YJ, Yeo JH, Son G, Kang H, Sung YS, Lee JY, Kim JG, Yoon YH. Efficacy of intravitreal AFlibercept injection For Improvement of retinal Nonperfusion In diabeTic retinopathY (AFFINITY study). BMJ Open Diabetes Res Care. 2020 Oct;8(1):e001616. doi: 10.1136/bmjdrc-2020-001616.

Study record dates

Study Major Dates

• Study Start (Actual): April 14, 2016
• Primary Completion (Actual): August 30, 2018
• Study Completion (Actual): August 30, 2018

Study Registration Dates

• First Submitted: December 5, 2016
• First Submitted That Met QC Criteria: December 29, 2016
• First Posted (Estimated): December 30, 2016

Study Record Updates

• Last Update Posted (Estimated): December 2, 2025
• Last Update Submitted That Met QC Criteria: November 25, 2025
• Last Verified: December 1, 2018

More Information

Terms related to this study

• Keywords: Aflibercept; Retinal nonperfusion
• Additional Relevant MeSH Terms: Endocrine System Diseases; Vascular Diseases; Cardiovascular Diseases; Diabetes Mellitus; Eye Diseases; Diabetic Angiopathies; Diabetes Complications; Retinal Diseases; Diabetic Retinopathy; Physiological Effects of Drugs; Antineoplastic Agents; Angiogenesis Inhibitors; Angiogenesis Modulating Agents; Growth Substances; Growth Inhibitors; aflibercept
• Other Study ID Numbers: FLOW_001

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: YES