Effects of Intravitreal Ranibizumab for Macular Edema With Nonproliferative Diabetic Retinopathy

Nonproliferative Diabetic Retinopathy Clinical Trial

Official title:

Prospective, Single-center, Six-month Study of Intravitreal Ranibizumab for Macular Edema With Nonproliferative Diabetic Retinopathy: Effects on Microaneurysm Turnover and Non-perfused Retinal Area

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT02834663
• Other study ID #: CRFB002DKR03T
• Status: Completed
• Phase: Phase 4
• Start date: August 2016
• Est. completion date: December 2019

Study information

• Verified date: May 2020
• Source: Wonkwang University Hospital
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial Summary

Title of study:

Effects of Ranibizumab to delay or regression non-proliferative diabetic retinopathy(NPDR) with DME assessed by microaneurysm changes: A pilot study Objectives Diabetic retinopathy (DR) is a major cause of visual impairment. Anti-vascular endothelial growth factors have demonstrated therapeutic benefits in diabetic macular edema (DME). We aimed to prospectively analyze the effects of early intensive treatment using intravitreal ranibizumab (IVR) injections in nonproliferative diabetic retinopathy patients with macular edema.

Primary objective:

To investigate other efficacy endpoints including other visual acuity, anatomical change in mild-to-moderate NPDR with DME after intravitreal Ranibizumab injection from baseline through 6 months after treatment.

Secondary objectives:

To compare microvascular changes assessed by microaneurysm counts and perifoveal non-perfusion area changes and safty in eyes of mild-to-moderate NPDR with DME after intravitreal Ranibizumab injection from baseline through 6 months after treatment.

Description:

Title of study:

Effects of Ranibizumab to delay or regression non-proliferative diabetic retinopathy(NPDR) with DME assessed by microaneurysm changes: A pilot study

Study Rationale:

Diabetic retinopathy is the leading disease that causes acquired vision loss after 20 by making diabetic macular edema and neovascularization. In recent young generation, as prevalence of type 2 diabetes is growing, the burden of sight-threatening retinopathy is increasing on trend.1 Pathologically, angiogenesis is a main cause that destroys the structure of the eye and induces the visual function disorder as VEGF playing an important role in increasing the migration and proliferation of endothelial cells and increasing the permeability of the blood vessels.2,3 VEGF is made from the endothelial cells of retinal tissue, perivascular cells, pigment endothelial cells by hypoxia. And hypoxic condition of intraocular tissues is a key regulator of intra ocular angiogenesis by VEGF, the balance between VEGF and angiogenesis inhibitors determines the neovascular proliferation in diabetic retinopathy.4 VEGF is also inducing the expression of cell-to-cell contact molecule (intracellular adhesion molecule-1, ICM-1) and the adhesion of leukocytes to help the inflammatory response5, as mediator which destroys the blood retinal barrier, affecting the protein of tight junctions, making a microaneurysm and increasing permeability of capillary, that makes the liquid leakage and macular edema.5,6 Microanuerysm is the earliest clinical manifestations, the saccular local lesion that perivascular cells protruding in damaged areas on the capillary wall. According to Stitt AW et al9, diabetic microaneurysm is non-functioning extrusion of the vascular system from the deep part of inner retinal capillary plexus.

It is sometimes disappeared by being blocked with blood clots, on the other hand, new microanerysm is occurred in the other vascular bed structure.

Through these changes, the investigators know the course of a diabetic retinopathy and it is known that the generation rate of microaneurysm is associated with the clinically significant progression of macular edema (CSME) in mild-to-moderate nonproliferative diabetic retinopathy .10,11 In addition, the number of microanerysm is an important prognostic indicator which can estimate the progression or regression of diabetic retinopathy, as predicting whether becoming better or worse in diabetic retinopathy.12 Kohner and Sleightholm13 describe this concept at first time in 1986, its association with the number of microvascular flow and the severity of diabetic retinopathy. In recent years it is reported that measuring the number of microaneurysm and the turnover rate associated with the appearance or disappearance of microaneurysm, are predictors in progression of diabetic retinopathy and macular edema.14 To delay the progression of diabetic retinopathy and to improve macular edema, the laser photocoagulation have been the important role.15 Although the laser photocoagulation have had treatment effect in the diabetic retinopathy by reducing the amount of VEGF in micraneurysm and by degenerating the neovascularization after laser therapy, there was a problem that has many limitations - peripheral visual field defects, night blindness, progression of macular edema etc., and that the disease does not cured in a good time because of limits of laser therapy due to cataract, vitreous hemorrhage and turbidity. As an alternative method to solve these limitations, there is an anti-VEGF therapy.6 According to a previous study result, intraocular injection of Bevacizumab inhibits occurring of neovascularization by blocking the VEGF receptor .17 Recently, several studies have been reported that when injected intravitreal anti-VEGF, macular edema is improved and neovascularization is inhibited, by reducing the leakage of neovascularization.3 Especially, Leicht SF et al18 reported the number of microaneurysms and turnover rate in NPDR(non-proliferative diabetic retinopathy) patients injected with Ranibizumab. And the result showed entire number of the microaneurysms and turnover rate are decreased, which could be mean the regression of diabetic retinopathy and it could decide the therapeutic effect.

On this study, through the fluorescein fundus angiography, the average number of microaneurysms was significantly decreased after intravitreal injection of anti-VEGF therapy (p<0.05). The decrease of 35.70±24.79% in the treatment group was statistically higher than 13.95±38.21% in the control group of the fellow eye (p<0.05).

The result is found because decreased concentration of intravitreal VEGF inhibits the progression of diabetic retinopathy, such as endothelial cell proliferation and endothelial cell damage on retinal capillary and perivascular cells.

Sjølie AK et al12 reported up-regulation of VEGF occuring microaneurysms causes endothelial cell proliferation and inflammation and effusion reaction, so anti-VEGF is effective in early diabetic retinopathy. But there is less effectiveness in late diabetic retinopathy as it reaches the non-changing point. Also Kohner EM et al19 reported diabetic retinopathy lesions are reversible and could be delayed in early diabetic retinopathy.

So far, changes of microaneurysms in late diabetic retinopathy is uncertain, and if there would be a finding according to anti-VEGF therapy, the investigators could get a clue of surrogate marker which represents treatment results in diabetic retinopathy.

This study was designed to find the clinical evaluation and reduction rate through fluorescein angiography as microaneurysm examination tools to research NPDR with DME treatment results assessed by microaneurysm counts, timely monitored with anti-VEGF therapy.

Objectives To evaluate the effects of intravitreal Ranibizumab injection on microvascular changes in eyes of mild-to-moderate NPDR with DME.

Primary objective:

To investigate other efficacy endpoints including other visual acuity, anatomical change in mild-to-moderate NPDR with DME after intravitreal Ranibizumab injection from baseline through 6 months after treatment.

Secondary objectives:

To compare microvascular changes assessed by microaneurysm counts and perifoveal non-perfusion area changes and safty in eyes of mild-to-moderate NPDR with DME after intravitreal Ranibizumab injection from baseline through 6 months after treatment.

Primary and secondary endpoints:

Primary endpoint:

To compare other visual acuity, anatomical changes after intravitreal Ranibizumab injection from baseline through 6 months after treatment.

i) The changes in best corrected visual acuity (BCVA) using ETDRS chart. ii) The central macular thickness - Circle Diameters : 1 mm ETDRS by spectralis OCT ; Heidelberg Engineering.

Secondary endpoints:

To compare microaneurysmal changes and perifoveal non-perfusion area and safty after intravitreal Ranibizumab injection from baseline through 6 months after treatment.

i) The total number of microaneurysm by fundus photo using Retmarker DR(version 1.0.2) software.

ii) The microaneurysm formation rate : Number of new MAs detected/month. iii) The microaneurysm disappearance rate : Number of MAs that resolved/month. iv)The microaneurysm turnover. v) Perifoveal non-perfusion area in FAG (mm²) using ImageJ software (version 1.52a) by FAG image.

vi) Safety parameters : Systemic adverse events (MI, CVA, etc), Ocular adverse events (retinal detachment, RPE tear, endophthalmitis, uveitis, vitreous hemorrhage, subretinal hemorrhage, cataract , IOP elevation, etc).

Methodology:

single center, prospective, interventional, one arm, pilot study

Evaluation Participants will be evaluated with a full ocular examination at each visit (VA measurement, tonometry, slit lamp exam). Fluorescein angiography (FA) will be performed at baseline, at 3 months after baseline and at the last visit(6 months after baseline), and OCT will be performed monthly (baseline and 1, 2, 3, 4, 5, 6 months from baseline).

The MAs and perifoveal non-perfused areas in individual retinas were evaluated at 6 months using fundus photography and FA imaging. The Retmarker (version 1.0.2 by Retmarker Ltd, Coimbra, Portugal) software was used for automatic measurement and analysis of changes in number and extent of MAs on fundus photographs and to calculate the total number and turnover of MAs.

Perifoveal non-perfused area was estimated using the early FA image (from each of the three examinations) in which both the vascular arch and the non-perfused area were clearly visualized. Subsequently, the ImageJ software (version 1.25a 23/04/2018 by ImageJ, USA) was used for scaling each image to 200 µm and for equalizing the contrast and sensitivity of each picture to the maximum possible extent, by auto-adjustment of brightness and contrast. The raw red-green-blue (RGB) images were then converted to 8-bit images, with the threshold set for optimal visualization of the non-perfused area. The same threshold was applied to all images of the same patient.

Result analysis The investigators compare the differences between at baseline, at 3 month, and at 6 month. Statistical analyses will be performed using SPSS ver.18.0 (SPSS Inc., Chicago, Il, USA). Kolmogorov-Smirnov test was applied to test for normality of sample group data. the paired T-test was used for comparative statistical analysis of these parameters. (BCVA, CRT, total number of MAs, MA formation rate, MA disappearance rate, MA turnover, and perifoveal non-perfused area)

Recruitment information / eligibility

• Status: Completed
• Enrollment: 25
• Est. completion date: December 2019
• Est. primary completion date: February 2019
• Accepts healthy volunteers: No
• Gender: All
• Age group: 40 Years and older

Eligibility

Inclusion Criteria:

• Patients (Male & female) =40 years of age

• Type 2 DM

• Best corrected visual acuity = 20/200 (Snellen equivalent using Early Treatment Diabetic Retinopathy Study chart)

• central retinal thickness of =300 µm on optical coherence tomography

• nonproliferative diabetic retinopathy (NPDR) with diabetic macular edema

Exclusion Criteria:

• proliferative diabetic retinopathy

• Vitreous hemorrhage

• previous history of vitreoretinal surgery, post-cataract operation status (=4 months before participation in this study)

• prior treatment with anti-VEGF drugs, intraocular corticosteroids, and/or retinal laser application

• Uncontrolled hypertension.

• Uncontrolled glaucoma.

• If both eyes met the study inclusion criteria, the more severely affected eye was selected

Related Conditions & MeSH terms

• Diabetic Retinopathy
• Macular Edema
• Nonproliferative Diabetic Retinopathy
• Retinal Diseases

Intervention

Drug:
• Lucentis
Local anesthesia with T-caine with Saline irrigation. Routine eye drap was done by potadine-cotton ball. Lucentis injected to vitreous cavity, finally dressing.

Locations

Country	Name	City	State
n/a

Sponsors (2)

Lead Sponsor	Collaborator
Wonkwang University Hospital	Novartis Korea Ltd.

References & Publications (19)

Crawford TN, Alfaro DV 3rd, Kerrison JB, Jablon EP. Diabetic retinopathy and angiogenesis. Curr Diabetes Rev. 2009 Feb;5(1):8-13. Review. — View Citation

Ferrara N, Hillan KJ, Gerber HP, Novotny W. Discovery and development of bevacizumab, an anti-VEGF antibody for treating cancer. Nat Rev Drug Discov. 2004 May;3(5):391-400. Review. — View Citation

Hammes HP. Pericytes and the pathogenesis of diabetic retinopathy. Horm Metab Res. 2005 Apr;37 Suppl 1:39-43. Review. — View Citation

Han XX, Guo CM, Li Y, Hui YN. Effects of bevacizumab on the neovascular membrane of proliferative diabetic retinopathy: reduction of endothelial cells and expressions of VEGF and HIF-1a. Mol Vis. 2012;18:1-9. Epub 2012 Jan 1. — View Citation

Haritoglou C, Kernt M, Neubauer A, Gerss J, Oliveira CM, Kampik A, Ulbig M. Microaneurysm formation rate as a predictive marker for progression to clinically significant macular edema in nonproliferative diabetic retinopathy. Retina. 2014 Jan;34(1):157-64. doi: 10.1097/IAE.0b013e318295f6de. — View Citation

Hoeben A, Landuyt B, Highley MS, Wildiers H, Van Oosterom AT, De Bruijn EA. Vascular endothelial growth factor and angiogenesis. Pharmacol Rev. 2004 Dec;56(4):549-80. Review. — View Citation

Horii T, Murakami T, Nishijima K, Sakamoto A, Ota M, Yoshimura N. Optical coherence tomographic characteristics of microaneurysms in diabetic retinopathy. Am J Ophthalmol. 2010 Dec;150(6):840-8. doi: 10.1016/j.ajo.2010.06.015. Epub 2010 Sep 19. — View Citation

Kohner EM, Sleightholm M. Does microaneurysm count reflect severity of early diabetic retinopathy? Ophthalmology. 1986 May;93(5):586-9. — View Citation

Kohner EM, Stratton IM, Aldington SJ, Turner RC, Matthews DR. Microaneurysms in the development of diabetic retinopathy (UKPDS 42). UK Prospective Diabetes Study Group. Diabetologia. 1999 Sep;42(9):1107-12. — View Citation

Leicht SF, Kernt M, Neubauer A, Wolf A, Oliveira CM, Ulbig M, Haritoglou C. Microaneurysm turnover in diabetic retinopathy assessed by automated RetmarkerDR image analysis--potential role as biomarker of response to ranibizumab treatment. Ophthalmologica. 2014;231(4):198-203. doi: 10.1159/000357505. Epub 2014 Mar 19. — View Citation

Liinamaa MJ, Savolainen MJ. High vitreous concentration of vascular endothelial growth factor in diabetic patients with proliferative retinopathy using statins. Ann Med. 2008;40(3):209-14. doi: 10.1080/07853890701749209. — View Citation

Noma H, Funatsu H, Yamasaki M, Tsukamoto H, Mimura T, Sone T, Hirayama T, Tamura H, Yamashita H, Minamoto A, Mishima HK. Aqueous humour levels of cytokines are correlated to vitreous levels and severity of macular oedema in branch retinal vein occlusion. Eye (Lond). 2008 Jan;22(1):42-8. Epub 2006 Jul 7. — View Citation

Nunes S, Pires I, Rosa A, Duarte L, Bernardes R, Cunha-Vaz J. Microaneurysm turnover is a biomarker for diabetic retinopathy progression to clinically significant macular edema: findings for type 2 diabetics with nonproliferative retinopathy. Ophthalmologica. 2009;223(5):292-7. doi: 10.1159/000213639. Epub 2009 Apr 16. — View Citation

Photocoagulation treatment of proliferative diabetic retinopathy. Clinical application of Diabetic Retinopathy Study (DRS) findings, DRS Report Number 8. The Diabetic Retinopathy Study Research Group. Ophthalmology. 1981 Jul;88(7):583-600. — View Citation

Ribeiro ML, Nunes SG, Cunha-Vaz JG. Microaneurysm turnover at the macula predicts risk of development of clinically significant macular edema in persons with mild nonproliferative diabetic retinopathy. Diabetes Care. 2013 May;36(5):1254-9. doi: 10.2337/dc12-1491. Epub 2012 Nov 30. — View Citation

Roy S, Ha J, Trudeau K, Beglova E. Vascular basement membrane thickening in diabetic retinopathy. Curr Eye Res. 2010 Dec;35(12):1045-56. doi: 10.3109/02713683.2010.514659. Epub 2010 Oct 7. Review. — View Citation

Sjølie AK, Klein R, Porta M, Orchard T, Fuller J, Parving HH, Bilous R, Aldington S, Chaturvedi N. Retinal microaneurysm count predicts progression and regression of diabetic retinopathy. Post-hoc results from the DIRECT Programme. Diabet Med. 2011 Mar;28(3):345-51. doi: 10.1111/j.1464-5491.2010.03210.x. — View Citation

Stitt AW, Gardiner TA, Archer DB. Histological and ultrastructural investigation of retinal microaneurysm development in diabetic patients. Br J Ophthalmol. 1995 Apr;79(4):362-7. — View Citation

Usui T, Ishida S, Yamashiro K, Kaji Y, Poulaki V, Moore J, Moore T, Amano S, Horikawa Y, Dartt D, Golding M, Shima DT, Adamis AP. VEGF164(165) as the pathological isoform: differential leukocyte and endothelial responses through VEGFR1 and VEGFR2. Invest Ophthalmol Vis Sci. 2004 Feb;45(2):368-74. — View Citation

* Note: There are 19 references in all — Click here to view all references

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	The Best Corrected Visual Acuity (BCVA)	BCVA was performed using the Early Treatment Diabetic Retinopathy Study (ETDRS) chart at baseline and 6 months. The BCVA compare the degree of improvement or worsening of vision at baseline and 6 months. (value at 6 months minus value at baseline)	6 months
Primary	Central Macular Thickness(CMT)	CRT was performed using OCT at each visit. The OCT measured at each visit was analyzed statistically. the CMT compare the degree of improvement or worsening of vision at baseline and 6 months. (value at 6 months minus value at baseline)	6 months
Secondary	The Total Number of Microaneurysm	The number of MAs in individual retinas were evaluated during 6 months using fundus photography and FA imaging. The Retmarker software was used for automatic measurement and analysis of changes in number and extent of MAs on fundus photographs and to calculate the total number and turnover of MAs. Changes in MAs were analyzed statistically. the total number of MAs compare the degree of improvement or worsening of vision at baseline and 6 months. (value at 6 months minus value at baseline)	6 months
Secondary	The Microaneurysm Formation Rate	number of new MAs detected/month The MAs in individual retinas were evaluated at 6 months using fundus photography. The Retmarker (version 1.0.2 by Retmarker Ltd, Coimbra, Portugal) software was used for automatic measurement and analysis of changes in number and extent of MAs on fundus photographs and to calculate the total number and turnover of MAs. MA turnover was calculated by adding the MA formation rate (number of new MAs detected/month) to the MA disappearance rate (number of MAs that resolved/month). The microaneurysm formation rate compare the degree of improvement or worsening of vision at baseline and 6 months. (value at 6 months minus value at baseline)	6 months
Secondary	The Microaneurysm Disappearance Rate	Number of MAs that resolved/month The MAs in individual retinas were evaluated at 6 months using fundus photography. The Retmarker (version 1.0.2 by Retmarker Ltd, Coimbra, Portugal) software was used for automatic measurement and analysis of changes in number and extent of MAs on fundus photographs and to calculate the total number and turnover of MAs. MA turnover was calculated by adding the MA formation rate (number of new MAs detected/month) to the MA disappearance rate (number of MAs that resolved/month). The microaneurysm disappearance rate compare the degree of improvement or worsening of vision at baseline and 6 months. (value at 6 months minus value at baseline)	6 months
Secondary	The Microaneurysm Turnover	The microaneurysm formation rate + The microaneurysm disappearance rate The MAs in individual retinas were evaluated at 6 months using fundus photography. The Retmarker (version 1.0.2 by Retmarker Ltd, Coimbra, Portugal) software was used for automatic measurement and analysis of changes in number and extent of MAs on fundus photographs and to calculate the total number and turnover of MAs. MA turnover was calculated by adding the MA formation rate (number of new MAs detected/month) to the MA disappearance rate (number of MAs that resolved/month). The microaneurysm turnover compare the degree of improvement or worsening of vision at baseline and 6 months. (value at 6 months minus value at baseline)	6 months
Secondary	Perifoveal Non-perfusion Area in FAG (mm²)	Using ImageJ software (version 1.52a) by FAG image. The Perifoveal non-perfusion area in FAG compare the degree of improvement or worsening of vision at baseline and 6 months. (value at 6 months minus value at baseline)	6 months
Secondary	Safety Parameters	Systemic adverse events (MI, CVA, etc), Ocular adverse events (retinal detachment, RPE tear, endophthalmitis, uveitis, vitreous hemorrhage, subretinal hemorrhage, cataract , IOP elevation, etc) at baseline and each visit.	6 months