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

Diabetic Retinopathy Clinical Trial

Official title:

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

Clinical Trial Details — Status: Recruiting

Administrative data

• NCT number: NCT03006081
• Other study ID #: FLOW_001
• Status: Recruiting
• Phase: Phase 2
• First received: December 5, 2016
• Last updated: December 29, 2016
• Start date: May 2016
• Est. completion date: June 2018

Study information

• Verified date: December 2016
• Source: Asan Medical Center
• Contact: Yoon Jeon Kim, MD
• Phone: 82-2-3010-3680
• Email: anne215[@]gmail.com
• Is FDA regulated: No
• Health authority: South Korea: Ministry of Food and Drug Safety
• Study type: Interventional

Clinical Trial Summary

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.

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.

Recruitment information / eligibility

• Status: Recruiting
• Enrollment: 40
• Est. completion date: June 2018
• Est. primary completion date: June 2017
• Accepts healthy volunteers: No
• Gender: Both
• Age group: 18 Years and older

Eligibility

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 Design

Intervention Model: Single Group Assignment, Masking: Open Label, Primary Purpose: Treatment

Related Conditions & MeSH terms

• Diabetic Retinopathy
• Retinal Diseases

Intervention

Drug:
• Intravitreal Aflibercept injection
Six number of injections at baseline, 1M, 2M, 3M, 4M, and 5M

Locations

Country	Name	City	State
Korea, Republic of	Asan medical center	Olympicro 43 gil 88, Seoul

Sponsors (1)

Lead Sponsor	Collaborator
Asan Medical Center

Country where clinical trial is conducted

Korea, Republic of, 

References & Publications (3)

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. — View Citation

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. — View Citation

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. — View Citation

Outcome

Type	Measure	Description	Time frame	Safety issue
Other	Safety outcome; Adverse effect of intravitreal aflibercept (Eylea) injection	Ocular and systemic adverse event	1 year	Yes
Primary	Improvement of retinal nonperfusion	Mean changes (%) of retinal nonperfusion (Ischemic index) from baseline	1 year	No
Secondary	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	No
Secondary	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	No
Secondary	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	No
Secondary	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	No
Secondary	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	No