Randomized Trial Evaluating Bevacizumabe or Triamcinolone for Persistent Diabetic Macular Edema

Methods Study Design. The current study is a prospective randomized clinical trial registered at ClinicalTrials.gov (NCT02985619). The study protocol adhered to the tenets of the Declaration of Helsinki and was approved by the local Institutional Review Board, research ethics committee of School of Medicine of Ribeirão Preto at University of Sao Paulo. All patients will give inform consent signature before entering one year study and will evaluate in the Retina Section of Department of Ophthalmology, School of Medicine of Ribeirao Preto of the University of Sao Paulo with center-involved DME in at least 1 eye. Recruiting phase will be consider the first 6 months. All patients with diagnostic of DME in at least 1 eye from July 2016 to December 2016 will invite to participate in the study.

Study Population. Inclusion criteria. Inclusion criteria are as follows: (1) Eligible participants are age 18 years old with diabetes mellitus (type 1 or 2); (2) center-involved DME, defined as a central subfield thickness >300 µm on spectral domain optical coherence tomography (SD-OCT), despite of macular laser photocoagulation, cataract surgery and intraocular injection performed at least 4 months previously; (3) best-corrected ETDRS visual acuity (BCVA) measurement between 0.3 logMAR (Snellen equivalent: 20/32) and 1.3 logMAR (Snellen equivalent: 20/400); (4) signed informed consent. Exclusion criteria. Exclusion criteria were: (1) vitreo-macular traction on SD-OCT; (2) proliferative diabetic retinopathy needing panretinal photocoagulation (PRP) or anticipated to need PRP in the next 12 months; (3) macular capillary dropout on fluorescein angiography; (4) history of glaucoma or ocular hypertension (defined as an intraocular pressure higher than 25 mm Hg); (5) an ocular condition (other than diabetes) that, in the opinion of the investigator, might affect macular edema or alter visual acuity during the course of the study (eg, retinal vein occlusion, uveitis or other ocular inflammatory disease, neovascular glaucoma, etc); (6) systemic corticosteroid therapy; (7) any condition that, in the opinion of the investigator, might preclude follow-up throughout the study period; (8) Recent (within 3 months) thromboembolic events including acute myocardial infarction (MI) and cerebrovascular accident (CVA); (9) Other Clinical trial participation in the last 30 days.

Randomization and Intervention. After eligibility phase, subjects with center-involving DME will enroll and undergo comprehensive ophthalmologic evaluation at baseline and every 4 weeks up to week 48. Patients will receive monthly prn 1.25 mg (0.05 cc) IVB throughout 24 weeks if central subfield thickness (CSFT) will great than 300 µm. At week 24, patients who has recurrent or persistent edema (CSFT>300) will randomize 1:1 to Group 1 (prn IVB therapy) or Group 2 (quarterly IVT therapy). Randomization will be do from binomial distribution with parameters that it enters as function arguments. Patients with no recurrent or persistent edema (CSFT≤300µm) at 24-week will comprise to Group 3 and continue receiving prn IVB therapy. If patient have edema in both eyes and the patient agree to treat both eyes, 1 eye will receive the random treatment according to a computer-generate sequence and the contralateral eye will receive the other therapy option on the next day; thus if an eye was randomized to the IVB group I, the contralateral eye will allocate to the IVT group II and the reverse will also true.

Examination Procedures and follow-up. Each patient will receive a detailed ophthalmologic examination including measurement of BCVA according to the standardized ETDRS refraction protocol using a retroilluminate Lighthouse for the Blind distance visual acuity test chart (using modified ETDRS charts 1, 2, and R; Precision Vision, IL), as well as applanation tonometry, slit-lamp biomicroscopic examination, indirect fundus examination, and fluorescein angiography using high-resolution angiography (HRA; Heidelberg Engineering, Heidelberg, Germany). SD-OCT evaluation (HRA-OCT; Heidelberg Engineering) will be performe in all patients, and retinal thickness measurements will be acquire using a standard 20, 15-degree raster scan protocol. CSFT values will be calculate automatically as the average thickness of a central macular region 1000 mm in diameter centered on the patient's foveola by built-in Heidelberg software using retinal map analysis. Patients will schedule for follow-up examinations at monthly intervals. At these visits the BCVA will be determined after ETDRS refraction and complete ophthalmic examination similar to baseline valuations with the exception of fluorescein angiography schedule at baseline and week 36.

Antiglaucomatous eyedrops criteria. Intraocular pressure (IOP) ≥ 25 mmHg and/or 10mmHg increased from baseline measurement will be adopt to initiate anti-glaucomatous eyedrops.