Clinical trial NCT02556723: Intravitreal Injections of Ziv-aflibercept for Macular Diseases
Official title: Intravitreal Injections of Ziv-aflibercept for Macular Diseases: Diabetic Macular Edema, Wet AMD and Macular Edema Secondary to Vein Occlusons
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: NA
Conditions: Diabetic Macular Edema
Age Related Macular Degeneration
Branch Retinal Vein Occlusion With Macular Edema
Central Retinal Vein Occlusion With Macular Edema
Lead sponsor: Retina Clinic, Sao Paulo, Brazil
Sponsor class: OTHER
Collaborators: name: Federal University of São Paulo
First posted: 2015-09-22
Enrollment: 60
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NA
Intervention model: SINGLE_GROUP
Primary purpose: TREATMENT

Brief 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.

Detailed 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.

Eligibility criteria: 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.

Primary outcomes:
measure: Multifocal electroretinogram responses at Week 24 and 48
timeFrame: 24 and 48 weeks
Secondary outcomes:
measure: Change From Baseline in Best Corrected Visual Acuity (BCVA) as Measured by Snellen Letter Score at Week 24 and 48
timeFrame: 24 and 48 weeks
measure: Change From Baseline in Central Retinal Thickness (CRT) at Week 24 and 48 as Assessed on Optical Coherence Tomography (OCT)
timeFrame: 24 and 48 weeks
Other outcomes:
Locations:
city: São Paulo
country: Brazil
facility: Retina Clinic / UNIFESP
Study officials:
affiliation: C.E.O.
name: André Maia, M.D.
role: STUDY_DIRECTOR
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