Preoperative Bevacizumab and Ziv-Aflibercept Administration in PDR Subjects Undergoing PPV

Comparison of Interval Variation and Dosage in Preoperative Bevacizumab and Ziv-Aflibercept Administration in Proliferative Diabetic Retinopathy Undergoing Vitrectomy

To compare outcomes in subjects receiving different doses and treatment intervals of intravitreal bevacizumab or ziv-aflibercept preoperatively administered prior to undergoing vitrectomy for complications of proliferative diabetic retinopathy.

Study Overview

• Status: Completed
• Conditions: Diabetic Retinopathy
• Intervention / Treatment: Drug: Intravitreal bevacizumab or intravitreal ziv-aflibercept

Detailed Description

Severe vision loss in patients with proliferative diabetic retinopathy (PDR) frequently results from complications related to neovascularization and fibrovascular proliferation. Patients with PDR are typically considered candidates for pars plana vitrectomy (PPV) when non-clearing vitreous hemorrhaging, tractional retinal detachment (TRD) development or extensive fibrovascular proliferation occur. Visual prognosis is guarded in patients undergoing PPV with these advanced presentations of PDR because of the high rate of both intra-operative and postoperative complications. Intra-operative bleeding may result in poor visualization during PPV that increases total surgery time and ultimately leads to surgical failure, while recurrent/persistent postoperative vitreous hemorrhage may occur as high as 75% and hinder visual rehabilitation and monitoring of further disease progression.

Preoperative administration of bevacizumab (Avastin; Genentech, Inc, South San Francisco, California, USA), a full-length recombinant humanized monoclonal antibody targeting vascular endothelial growth factor (VEGF), has been reported in prospective clinical trials to decrease the overall surgery time, lower the rate of intra-operative complications, and reduce the occurrence of postoperative hemorrhaging in PDR patients with active neovascularization and/or extensive fibrovascular proliferation undergoing PPV. Furthermore, two meta-analysis studies examining published randomized controlled trials support the use of intravitreal bevacizumab (IVB) as a preoperative adjunct. Although IVB is widely used as a preoperative adjunct in patients with PDR undergoing PPV, little clinical data is available regarding the optimal timing of preoperative IVB administration or the most effective dose. In this randomized clinical study, we attempt to elucidate the most appropriate interval and dose for the administration of preoperative IVB in patients with PDR undergoing PPV for non-clearing vitreous hemorrhaging, TRD or extensive fibrovascular proliferation.

Ziv-aflibercept (Zaltrap, Regeneron) is a recombinant fusion protein that acts as a soluble decoy receptor and binds to VEGF-A, VEGF-B, and placental growth factor, similar to aflibercept (Eylea, Regeneron, Tarrytown, NY), which is FDA approved for intravitreal administration to treat various retinal diseases. At the dose of 1.25 mg/0.05 mL, ziv-aflibercept has been reported to safely and effectively treat neovascular macular degeneration and diabetic macular edema, similar in efficacy to bevacizumab. Presently, there are no reports regarding the effectiveness of preoperative ziv-aflibercept administration prior to PPV for PDR. In this randomized clinical trial, we also evaluate the effectiveness of ziv-aflibercept to bevacizumab, and attempt to elucidate the most appropriate interval for the administration of preoperative ziv-aflibercept in patients with PDR undergoing PPV for non-clearing vitreous hemorrhaging, TRD or extensive fibrovascular proliferation.

• Study Type: Interventional
• Enrollment (Actual): 568
• Phase: Not Applicable

Contacts and Locations

Study Locations

• Mexico
  • Nuevo Leon
    • Montemorelos, Nuevo Leon, Mexico
      • Hospital La Carlota

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 85 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

1. Subject age is 18-85 years.
2. Subject consents to study participation and is capable of 6 months of follow-up.
3. The subject has type I or II Diabetes Mellitus with active PDR in the study eye.
4. Best-corrected spectacle visual acuity (BCSVA) on the Snellen eye chart ranges from 20/40 to light perception with projection in the study eye.
5. The subject is determined to need a PPV because of reduced BCSVA principally from a non-clearing vitreous hemorrhage, TRD, fibrous proliferation, or a combination of the three. When non-clearing vitreous hemorrhage is the principal reason for PPV, the hemorrhage must have been present by subjective history for at least 3 months. When TRD is the principal reason for PPV, the TRD must be threatening (within one disc diameter) or involving the fovea. When fibrovascular proliferation is the principal reason for PPV, it must be extensive (>3 clock hours) and threatening (within one disc diameter) or involving the fovea.
6. Only one eye per patient is eligible for the study.

Exclusion Criteria:

1. Subject is known to have a significant retinal/optic nerve disease otherwise unrelated to Diabetes Mellitus, which in the opinion of the examiner is responsible for two or more lines of reduced BCSVA (macular degeneration, optic neuritis, glaucoma, amblyopia, etc.) in the study eye.
2. Subject is known to have macular ischemia, which in the opinion of the examiner, is responsible for two or more lines of reduced BCSVA in the study eye.
3. Subject has a significant corneal opacity, which in the opinion of the examiner, is responsible for two or more lines of reduced BCSVA (corneal scar, ectasia, etc.) in the study eye.
4. Subject is known to have had a macula-involving retinal detachment for greater than 6 months in the study eye.
5. Subject has had a previous vitrectomy (anterior or PPV) in the study eye.
6. Subject has uncontrolled neovascular glaucoma (intraocular pressure > 30 mmHg despite medical/surgical treatment) in the study eye.
7. Subject received systemic or intravitreal anti-VEGF treatment to the study eye within 3 months of anticipated study enrollment.
8. Subject has uncontrolled hypertension (systolic > 200 mmHg or diastolic > 120 mmHg) despite adherence to a multiple anti-hypertensive medication regimen.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Double

Number of Arms

9

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Active Comparator: A; Study Group A: Subjects receive 2.5 mg intravitreal bevacizumab 1-3 days prior to vitrectomy.	Drug: Intravitreal bevacizumab or intravitreal ziv-aflibercept; Intravitreal bevacizumab or intravitreal ziv-aflibercept is given preoperatively at various time intervals and doses.
Active Comparator: B; Study Group B: Subjects receive 2.5 mg intravitreal bevacizumab 5-10 days prior to vitrectomy.	Drug: Intravitreal bevacizumab or intravitreal ziv-aflibercept; Intravitreal bevacizumab or intravitreal ziv-aflibercept is given preoperatively at various time intervals and doses.
Active Comparator: C; Study Group C: Subjects receive 1.25 mg intravitreal bevacizumab 1-10 days prior to vitrectomy.	Drug: Intravitreal bevacizumab or intravitreal ziv-aflibercept; Intravitreal bevacizumab or intravitreal ziv-aflibercept is given preoperatively at various time intervals and doses.
Active Comparator: D; Study Group D: Subjects receive 0.625 mg intravitreal bevacizumab 1-10 days prior to vitrectomy.	Drug: Intravitreal bevacizumab or intravitreal ziv-aflibercept; Intravitreal bevacizumab or intravitreal ziv-aflibercept is given preoperatively at various time intervals and doses.
Active Comparator: E; Study Group E: Subjects receive 2.5 mg intravitreal bevacizumab 1-10 days prior to vitrectomy.	Drug: Intravitreal bevacizumab or intravitreal ziv-aflibercept; Intravitreal bevacizumab or intravitreal ziv-aflibercept is given preoperatively at various time intervals and doses.
Active Comparator: F; Study Group F: Subjects receive 1.25 mg intravitreal ziv-aflibercept 1-10 days prior to vitrectomy.	Drug: Intravitreal bevacizumab or intravitreal ziv-aflibercept; Intravitreal bevacizumab or intravitreal ziv-aflibercept is given preoperatively at various time intervals and doses.
Active Comparator: G; Study Group G: Subjects receive 1.25 mg intravitreal ziv-aflibercept 1-3 days prior to vitrectomy.	Drug: Intravitreal bevacizumab or intravitreal ziv-aflibercept; Intravitreal bevacizumab or intravitreal ziv-aflibercept is given preoperatively at various time intervals and doses.
Active Comparator: H; Study Group H: Subjects receive 1.25 mg intravitreal ziv-aflibercept 5-10 days prior to vitrectomy.	Drug: Intravitreal bevacizumab or intravitreal ziv-aflibercept; Intravitreal bevacizumab or intravitreal ziv-aflibercept is given preoperatively at various time intervals and doses.
Active Comparator: I; Study Group I: Subjects receive 1.25 mg intravitreal ziv-aflibercept 1-10 days prior to vitrectomy, and then receive 1.25 mg intravitreal ziv-aflibercept at the completion of the vitrectomy.	Drug: Intravitreal bevacizumab or intravitreal ziv-aflibercept; Intravitreal bevacizumab or intravitreal ziv-aflibercept is given preoperatively at various time intervals and doses.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Visual Acuity	Change in BCSVA from baseline	6 months

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Complications	Rate of complications (intra-operative and postoperative)	6 months
Time	Total surgery time	1 day

Collaborators and Investigators

• Sponsor: Panhandle Eye Group, LLP
• Investigators: Study Chair: Sloan Rush, MD, panhandle eye group

Study record dates

Study Major Dates

• Study Start (Actual): October 1, 2015
• Primary Completion (Actual): January 4, 2019
• Study Completion (Actual): January 4, 2019

Study Registration Dates

• First Submitted: October 27, 2015
• First Submitted That Met QC Criteria: October 27, 2015
• First Posted (Estimate): October 28, 2015

Study Record Updates

• Last Update Posted (Actual): December 3, 2021
• Last Update Submitted That Met QC Criteria: November 20, 2021
• Last Verified: November 1, 2021

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Cardiovascular Diseases; Vascular Diseases; Eye Diseases; Endocrine System Diseases; Diabetic Angiopathies; Diabetes Complications; Diabetes Mellitus; Retinal Diseases; Diabetic Retinopathy; Physiological Effects of Drugs; Antineoplastic Agents; Antineoplastic Agents, Immunological; Angiogenesis Inhibitors; Angiogenesis Modulating Agents; Growth Substances; Growth Inhibitors; Bevacizumab; Aflibercept
• Other Study ID Numbers: 4