High Dose Aflibercept in Diabetic Macular Edema in Patients With Previous Vitrectomy

Summary

Patients with diabetic macular edema (DME) sometimes must undergo vitrectomy surgery (PPV) for diabetic and non-diabetic related issues. Patients may have improved DME with anti-VEGF therapy and ranibizumab has been found to reduce central macular thickness (CMT) with anti-VEGF therapy following vitrectomy. Those patients still require intravitreal injections but the pharmacokinetics of a vitrectomized eye are different than those eyes that have not undergone vitrectomy. The clearance of protein molecules is quicker in vitrectomized eyes so these patients may be more refractory to standard of care anti-VEGF therapy. In rabbit models, the half-life of both bevacizumab and ranibizumab were reduced by a factor 1.8 and 1.3, respectively, after pars plana vitrectomy. In a study examining intravitreal triamcinolone acetonide in human eyes, the half-life was found to be 18.6 days in non-vitrectomized eyes and 3.2 days in vitrectomized eyes, but there was considerable intrasubject variation. Patients with various disease states, including neovascular age-related macular degeneration (nAMD) have been managed with monthly anti-VEGF therapy successfully after vitrectomy surgery. Another study performed by the DRCR net showed that patients with DME treated with anti-VEGF are not affected in the long term if they had had a previous vitrectomy. High dose aflibercept may improve anatomic and visual outcomes in this patient population. Also, high dose aflibercept may allow for longer treatment intervals in these vitrectomized eyes.

Eligibility

Inclusion Criteria:

* A patient must meet the following criteria at both the screening and randomization visits (except where indicated) to be eligible for inclusion in the study:

  1. Men or women ≥18 years of age with type 1 or type 2 diabetes mellitus
  2. DME with central involvement in the study eye with CRT ≥320 μm on Spectralis.
  3. BCVA early treatment diabetic retinopathy study (ETDRS) letter score of 84 to 20 (approximate Snellen equivalent of 20/25 to 20/400) in the study eye with decreased vision determined to be primarily the result of DME
  4. Willing and able to comply with clinic visits and study-related procedures
  5. Provide informed consent signed by study patient or legally acceptable representative
  6. Have a previous history of vitrectomy surgery.

Exclusion Criteria:

* A patient who meets any of the following criteria at either the screening or randomization visits will be excluded from the study:

  1. Evidence of macular edema due to any cause other than diabetes mellitus in either eye
  2. Prior intravitreal investigational agents in the study eye (gene therapy, etc.) at any time
  3. IOP ≥28 mmHg in the study eye
  4. History of glaucoma filtration surgery in the past
  5. Evidence of infectious blepharitis, keratitis, scleritis , or conjunctivitis in either eye within 4 weeks (28 days) of the screening visit.
  6. Any intraocular inflammation/infection in either eye within 6 weeks (42 days) of the screening visit.
  7. History of idiopathic or autoimmune uveitis in the study eye
  8. Vitreomacular traction or epiretinal membrane in the study eye evident on biomicroscopy or OCT that is thought to affect central vision
  9. Current iris neovascularization, vitreous hemorrhage, or tractional retinal detachment visible at the screening assessments in the study eye
  10. History of corneal transplant or corneal dystrophy in study eye
  11. Any concurrent ocular condition in the study eye which, in the opinion of the investigator, could either increase the risk to the patient beyond what is to be expected from standard procedures of IVT injections, or which otherwise may interfere with the injection procedure or with evaluation of efficacy or safety.
  12. Structural damage to the center of the macula in the study eye that is likely to preclude improvement in BCVA following the resolution of macular edema including atrophy of the retinal pigment epithelium, subretinal fibrosis or scar, significant macular ischemia, or organized hard exudates
  13. Inability to obtain photographs, FA, or SD-OCT in the study eye, eg, due to media opacity, allergy to fluorescein dye, or lack of venous access
  14. History of other disease, metabolic dysfunction, physical examination finding, or clinical laboratory finding giving reasonable suspicion of a disease or condition that contraindicates the use of high dose aflibercept or that might affect interpretation of the results of the study or render the patient at high risk for treatment complications
  15. Uncontrolled diabetes mellitus as defined by hemoglobin A1c (HbA1c) \> 14%
  16. History of cerebrovascular accident or myocardial infarction within 24 weeks (168 days) of screening visit
  17. Known sensitivity to any of the compounds of the study formulation
  18. Participation in an investigational study within 30 days prior to screening visit that involved treatment with any drug (excluding vitamins and minerals) or device
  19. Pregnant or breastfeeding women
  20. Men or women of childbearing potential (WOCBP)\* who are unwilling to practice highly effective contraception prior to the initial dose/start of the first treatment and during the study.

Conditions2

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