Intravitreal Injections of Ziv-aflibercept for Macular Diseases

Diabetic Macular Edema Clinical Trial

Official title:

Intravitreal Injections of Ziv-aflibercept for Macular Diseases: Diabetic Macular Edema, Wet AMD and Macular Edema Secondary to Vein Occlusons

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT02556723
• Other study ID #: RetinaCLINIC
• Status: Completed
• Phase: N/A
• First received: September 18, 2015
• Last updated: October 1, 2016
• Start date: September 2014
• Est. completion date: September 2016

Study information

• Verified date: October 2016
• Source: Retina Clinic, Sao Paulo, Brazil
• Contact: n/a
• Is FDA regulated: No
• Health authority: Brazil: Ethics Committee
• Study type: Interventional

Clinical Trial Summary

Diabetic macular edema (DME), wet-AMD and macular edema secondary to vein occlusions are the leading cause of blindness in developed countries. Several therapies have been studied as such laser treatment and intravitreal injections of corticosteroids or anti-VEGF drugs. In terms of public health the long term treatment with the current available drugs is very expensive and new therapies with the same or better effect should be investigated. This study intends to evaluate the efficacy and safety of intravitreal injections of ziv-aflibercept for the treatment of patients with DME, wet-AMD and macular edema secondary to vein occlusions.

Description:

Twenty consecutive patients with DME, wet-AMD and macular edema secondary to vein occlusions will be enrolled. A complete examination including full-field ERG, visual acuity, central retinal thickness (CRT) and evaluation of systemic and ocular complications will be performed before and 24 weeks after intravitreal injections of ziv-aflibercept. The twenty patients will be submitted to 6 consecutive intravitreal injections of ziv-aflibercept with a 4 week interval.

The safety and efficacy of Eylea in the treatment of macular edema following CRVO were assessed in 2 randomized, multicenter, double- masked, sham-controlled studies: COPERNICUS and GALILEO. A total of 358 patients were treated and evaluable for efficacy (217 with Eylea) in the two studies. In both, patients were randomly assigned in a 3:2 ratio to either 2 mg Eylea administered every 4 weeks, or sham injections (control group) administered every 4 weeks for a total of 6 injections. After 6 monthly injections, patients continued to receive Eylea treatment during weeks 24 to 52 only if they met pre-specified retreatment criteria (PRN), except for patients in the sham control group in the GALILEO study who continued to receive sham injections through week 52. In the COPERNICUS study, after 6 months, 56% of patients receiving Eylea 2 mg monthly gained at least 15 letters of BCVA from baseline, as measured by ETDRS, compared to 12% of patients receiving sham injections (p<0.01), the primary endpoint of the study. Patients receiving Eylea 2 mg monthly gained, on average, 17.3 letters of vision compared to a mean loss of 4.0 letters with sham control injections (p<0.01), a secondary endpoint.

Ziv-aflibercept or zaltrap6 (Sanofi-Aventis US, LLC, Bridgewater, NJ/Regeneron Pharmaceuticals, Inc, Tarrytown, NY) is FDA approved for the treatment of metastatic colorectal cancer. During Bascom Palmer Eye Institute's Angiogenesis, Exudation, and Degeneration February 2014 conference, Michel Eid Farah, João R. Dias, Fernando M. Penha, and Eduardo B. Rodrigues investigated the safety of ziv-aflibercept in vitro and in vivo. In vitro toxicity was verified using ARPE-19 cultured cells exposed to anti-angiogenic vs balanced salt solution (BSS) for 10 minutes. Viability was assessed by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay, which evaluates cell viability by mitochondrial activity. No signs of cell toxicity were observed, and cell viability was similar for ziv-aflibercept, aflibercept, and BSS. For the in vivo study, they tested 1 injection of 0.05 mL ziv-aflibercept vs aflibercept in the right eyes of 18 rabbits, 9 eyes in each group. BSS was injected in the fellow eyes and served as control. After the injections, all animals were examined by funduscopy, SD-OCT), and ERG at baseline, 24 hours, and 7 days. Aqueous, vitreous, and serum samples were collected at baseline, 24 hours, and 7 days for pH and osmolarity analysis. The animals were sacrificed and the eyes were enucleated for morphologic study by light and electron microscopy. No abnormalities were found at 24 hours or 7 days after intravitreal injection of either drug when assessed by fundus exam and SD-OCT, ERG, and histology as well as transmission microscopy. There were also no changes in osmolarity in the aqueous humor or vitreous samples in any group after 24 hours and 1 week.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 60
• Est. completion date: September 2016
• Est. primary completion date: September 2015
• Accepts healthy volunteers: No
• Gender: Both
• Age group: 18 Years and older

Eligibility

Inclusion Criteria:

• Adults = 18 years with type 1 or 2 diabetes mellitus

• BCVA varying from 20/62 to 20/400 (Snellen chart) - equivalent 0.49 to 1.30 logMAR - caused by DME

• Central Retinal Thickness on OCT (Heildelberg Engineering, Heidelberg, Germany ) of 275 mm or more

Exclusion Criteria:

• Laser photocoagulation within the previous 6 months

• Previous intraocular anti-VEGF or corticosteroid injection

• Previous systemic anti-VEGF or receptor tyrosine kinase inhibitor therapy

• Vitreomacular traction or epiretinal membrane producing any traction on the macula on SD-OCT scan

• Angiographic evidence of macular ischemia defined as foveal avascular zone greatest linear dimension of more than 1000 mm or severe perifoveal capillary loss

• Previous cataract, trabeculectomy or vitrectomy

• Aphakia

• External ocular infections

• Glaucoma (IOP of > 21 mmHg or regular use of more than 2 IOP lowering drugs)

• Likelihood of needing intraocular surgery within 6 months

• Proliferative diabetic retinopathy with any evidence of retinal traction

• Systemic conditions that precluded trial enrollment included glycosylated hemoglobin of more than 10.0%

• Past medical history of chronic renal failure requiring either dialysis or kidney transplantation

• Blood pressure of more than 160/90 mmHg

• an arteriothrombotic event within 6 months before randomization, including myocardial infarction, acute congestive heart failure or other cardiac event, and stroke or transient ischemic attack

• Pregnancy or breastfeeding.

Study Design

Endpoint Classification: Safety/Efficacy Study, Intervention Model: Single Group Assignment, Masking: Open Label, Primary Purpose: Treatment

Related Conditions & MeSH terms

• Age Related Macular Degeneration
• Branch Retinal Vein Occlusion With Macular Edema
• Central Retinal Vein Occlusion With Macular Edema
• Diabetic Macular Edema
• Edema
• Macular Degeneration
• Macular Edema
• Retinal Vein Occlusion

Intervention

Drug:
• Intravitreal injections of ziv-aflibercept
All subjects will receive intravitreal injections of ziv-aflibercept under sterile conditions at baseline, 4 weeks, 8 weeks, 12 weeks, 16 weeks, and 20 weeks. No topical or systemic antibiotics will be prescribed (pre- injection or postinjection).

Locations

Country	Name	City	State
Brazil	Retina Clinic / UNIFESP	São Paulo

Sponsors (2)

Lead Sponsor	Collaborator
Retina Clinic, Sao Paulo, Brazil	Federal University of São Paulo

Country where clinical trial is conducted

Brazil, 

References & Publications (17)

Arevalo JF, Sanchez JG, Fromow-Guerra J, Wu L, Berrocal MH, Farah ME, Cardillo J, Rodríguez FJ; Pan-American Collaborative Retina Study Group (PACORES). Comparison of two doses of primary intravitreal bevacizumab (Avastin) for diffuse diabetic macular ede — View Citation

Cunningham ET Jr, Adamis AP, Altaweel M, Aiello LP, Bressler NM, D'Amico DJ, Goldbaum M, Guyer DR, Katz B, Patel M, Schwartz SD; Macugen Diabetic Retinopathy Study Group. A phase II randomized double-masked trial of pegaptanib, an anti-vascular endothelia — View Citation

de Oliveira Dias JR, Badaró E, Novais EA, Colicchio D, Chiarantin GM, Matioli MM, Verna C, Penha FM, Barros NM, Meyer CH, Farah ME, Rodrigues EB. Preclinical investigations of intravitreal ziv-aflibercept. Ophthalmic Surg Lasers Imaging Retina. 2014 Nov-D — View Citation

de Oliveira Dias JR, Xavier CO, Maia A, de Moraes NS, Meyer C, Farah ME, Rodrigues EB. Intravitreal injection of ziv-aflibercept in patient with refractory age-related macular degeneration. Ophthalmic Surg Lasers Imaging Retina. 2015 Jan;46(1):91-4. doi: — View Citation

Do DV, Schmidt-Erfurth U, Gonzalez VH, Gordon CM, Tolentino M, Berliner AJ, Vitti R, Rückert R, Sandbrink R, Stein D, Yang K, Beckmann K, Heier JS. The DA VINCI Study: phase 2 primary results of VEGF Trap-Eye in patients with diabetic macular edema. Ophth — View Citation

Ferrara N. Vascular endothelial growth factor: basic science and clinical progress. Endocr Rev. 2004 Aug;25(4):581-611. Review. — View Citation

Gray A, Clarke P, Farmer A, Holman R; United Kingdom Prospective Diabetes Study (UKPDS) Group. Implementing intensive control of blood glucose concentration and blood pressure in type 2 diabetes in England: cost analysis (UKPDS 63). BMJ. 2002 Oct 19;325(7 — View Citation

Holash J, Davis S, Papadopoulos N, Croll SD, Ho L, Russell M, Boland P, Leidich R, Hylton D, Burova E, Ioffe E, Huang T, Radziejewski C, Bailey K, Fandl JP, Daly T, Wiegand SJ, Yancopoulos GD, Rudge JS. VEGF-Trap: a VEGF blocker with potent antitumor effe — View Citation

Intensive blood-glucose control with sulphonylureas or insulin compared with conventional treatment and risk of complications in patients with type 2 diabetes (UKPDS 33). UK Prospective Diabetes Study (UKPDS) Group. Lancet. 1998 Sep 12;352(9131):837-53. E — View Citation

Ishida S, Usui T, Yamashiro K, Kaji Y, Ahmed E, Carrasquillo KG, Amano S, Hida T, Oguchi Y, Adamis AP. VEGF164 is proinflammatory in the diabetic retina. Invest Ophthalmol Vis Sci. 2003 May;44(5):2155-62. — View Citation

Klein R, Knudtson MD, Lee KE, Gangnon R, Klein BE. The Wisconsin Epidemiologic Study of Diabetic Retinopathy XXIII: the twenty-five-year incidence of macular edema in persons with type 1 diabetes. Ophthalmology. 2009 Mar;116(3):497-503. doi: 10.1016/j.oph — View Citation

Mansour AM, Al-Ghadban SI, Yunis MH, El-Sabban ME. Ziv-aflibercept in macular disease. Br J Ophthalmol. 2015 Aug;99(8):1055-9. doi: 10.1136/bjophthalmol-2014-306319. Epub 2015 Feb 12. — View Citation

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. Opht — View Citation

Nguyen QD, Shah SM, Khwaja AA, Channa R, Hatef E, Do DV, Boyer D, Heier JS, Abraham P, Thach AB, Lit ES, Foster BS, Kruger E, Dugel P, Chang T, Das A, Ciulla TA, Pollack JS, Lim JI, Eliott D, Campochiaro PA; READ-2 Study Group. Two-year outcomes of the ra — View Citation

Shaw JE, Sicree RA, Zimmet PZ. Global estimates of the prevalence of diabetes for 2010 and 2030. Diabetes Res Clin Pract. 2010 Jan;87(1):4-14. doi: 10.1016/j.diabres.2009.10.007. Epub 2009 Nov 6. — View Citation

Stratton IM, Cull CA, Adler AI, Matthews DR, Neil HA, Holman RR. Additive effects of glycaemia and blood pressure exposure on risk of complications in type 2 diabetes: a prospective observational study (UKPDS 75). Diabetologia. 2006 Aug;49(8):1761-9. Epub — View Citation

The effect of intensive treatment of diabetes on the development and progression of long-term complications in insulin-dependent diabetes mellitus. The Diabetes Control and Complications Trial Research Group. N Engl J Med. 1993 Sep 30;329(14):977-86. — View Citation

* Note: There are 17 references in all — Click here to view all references

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Multifocal electroretinogram responses at Week 24 and 48		24 and 48 weeks	No
Secondary	Change From Baseline in Best Corrected Visual Acuity (BCVA) as Measured by Snellen Letter Score at Week 24 and 48		24 and 48 weeks	No
Secondary	Change From Baseline in Central Retinal Thickness (CRT) at Week 24 and 48 as Assessed on Optical Coherence Tomography (OCT)		24 and 48 weeks	No