Bevacizumabe or Triamcinolone for Persistent Diabetic Macular Edema (BEVATAAC)
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|ClinicalTrials.gov Identifier: NCT02985619|
Recruitment Status : Completed
First Posted : December 7, 2016
Last Update Posted : October 12, 2018
|First Submitted Date ICMJE||December 1, 2016|
|First Posted Date ICMJE||December 7, 2016|
|Last Update Posted Date||October 12, 2018|
|Actual Study Start Date ICMJE||July 21, 2016|
|Actual Primary Completion Date||April 14, 2017 (Final data collection date for primary outcome measure)|
|Current Primary Outcome Measures ICMJE
||Optical Coherence Tomography measurements in the central subfield thickness between baseline and 6 months 1st endpoint. [ Time Frame: 6 months. ]|
|Original Primary Outcome Measures ICMJE||Same as current|
|Change History||Complete list of historical versions of study NCT02985619 on ClinicalTrials.gov Archive Site|
|Current Secondary Outcome Measures ICMJE||Not Provided|
|Original Secondary Outcome Measures ICMJE||Not Provided|
|Current Other Pre-specified Outcome Measures||Not Provided|
|Original Other Pre-specified Outcome Measures||Not Provided|
|Brief Title ICMJE||Bevacizumabe or Triamcinolone for Persistent Diabetic Macular Edema|
|Official Title ICMJE||Randomized Trial Evaluating Bevacizumabe or Triamcinolone for Persistent Diabetic Macular Edema|
Background: Diabetic macular edema (DME) shows a sustained functional and morphologic response to anti-vascular endothelial growth factor (VEGF) drugs, but the optimal approach for persistent macular edema still in debate.
Purpose: To evaluate 24-week visual and anatomical effects of intravitreal bevacizumabe or triamcinolone in patients who had residual edema after 24-weeks to "pro re nata"(prn) intravitreal bevacizumabe therapy.
Methods: This study enrolled a total of 100 DME eyes. Each patient received "prn" bevacizumabe therapy throughout 24 weeks. At week 24, patients who had recurrent or persistent edema were randomized 1:1 to Group 1 (prn bevacizumane) or Group 2 (prn triamcinolone). Patients with no recurrent or persistent edema at week 24 were comprised Group 3 and continue received prn bevacizumabe. Prn treatment was administered when central subfield thickness of the macula (CST) > 300 µm and/or there were intraretinal cystoid spaces in the fovea. Study visits occurred every 4 weeks with the endpoint at week 48. At each visit, patients had an eye exam and CST, best-corrected visual acuity (BCVA), and intraocular pressure (IOP) were assessed. Fundus photography and fluorescein angiography were also performed at baseline, week 16, week 40, and week 48. Rescue therapy using laser photocoagulation could be administered at the discretion of the Investigators. All patients resumed standard care after exiting.
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 gave written informed consent before entering one year study and were evaluated 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 between June 21, 2016 and December 22, 2017 were invited to participate in the study. Recruiting phase considered the first 6 months.
Study Population. Inclusion criteria. Inclusion criteria were as follows: (1) Eligible participants were aged 18 years with diabetes mellitus (type 1 or 2); (2) center-involved DME, defined as a central subfield thickness >300 µm on SB-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 SB-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 was determined, subjects with center-involving DME were enrolled and underwent comprehensive ophthalmologic evaluation at baseline and every 4 weeks up to week 48. Patients received monthly prn 1.25 mg (0.05 cc) IVB throughout 24 weeks if central subfield thickness (CSFT) was greater than 300 µm. At week 24, patients who had recurrent or persistent edema (CSFT>300) were randomized 1:1 to Group 1 (prn IVB therapy) or Group 2 (quarterly IVT therapy). Randomization was done from binomial distribution with parameters that it enters as function arguments. Patients with no recurrent or persistent edema (CSFT≤300µm) at 24-week were comprised to Group 3 and continued receiving prn IVB therapy. If patient had edema in both eyes and the patient agreed to treat both eyes, 1 eye received the randomized treatment according to a computer-generated sequence and the contralateral eye received the other therapy option on the next day; thus if an eye was randomized to the IVB group I, the contralateral eye was allocated to the IVT group II and the reverse was also true.
Examination Procedures and follow-up. Each patient received a detailed ophthalmologic examination including measurement of BCVA according to the standardized ETDRS refraction protocol using a retroilluminated 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). Spectralis B-scan OCT evaluation (HRA-OCT; Heidelberg Engineering) was performed in all patients, and retinal thickness measurements were acquired using a standard 20, 15-degree raster scan protocol. CSFT values were calculated 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 were scheduled for follow-up examinations at monthly intervals. At these visits the BCVA was determined after ETDRS refraction and complete ophthalmic examination similar to baseline valuations with the exception of fluorescein angiography scheduled at baseline and week 36.
Antiglaucomatous eyedrops criteria. Intraocular pressure (IOP) ≥ 25 mmHg and/or 10mmHg increased from baseline measurement were adopted to initiate anti-glaucomatous eyedrops.
Intravitreal Injection. All injections were performed using topical proparacaine drops under sterile conditions (eyelid speculum and povidone-iodine). Topical antibiotics were not used before the day of injection. Before the injection was performed, the eyelids were scrubbed with 10% povidone-iodine, and 5% povidone-iodine drops were applied to the conjunctiva. The time between application of 5% povidone-iodine solution to the conjunctiva and administration of the intravitreal injection was 2 minutes. Povidone-iodine was applied to the conjunctiva directly over the intended injection site.21-24 Care was taken in all cases to insure that the needle did not touch the lids or lashes. Bevacizumab (1.25 mg/0.05 cc; F. Hoffmann- La Roche Ltd., Basel, Switzerland) or Triamcinolone (1.20 mg/ 0.03 cc; Opthaac, Ophthalmos, São Paulo, Brazil) was injected into the vitreous cavity using a 29-gauge 0.5- inch needle inserted through the superotemporal pars plana 3.0-3.5 mm posterior to the limbus.25 After the injection, central retinal artery perfusion was confirmed with indirect ophthalmoscopy. Patients were instructed to instill 1 drop of 0.3% ciprofloxacin into the injected eye 4 times daily for 1 week after the procedure.
Retreatment Protocol. Retreatment with the originally assigned treatment was performed monthly if central subfield thickness was greater than 300 µm.
Rescue Therapy. If, after 3 consecutive injections, there was not a reduction in central subfield thickness of at least 10% and/or an increase in BCVA of at least 5 letters compared with baseline, the patient could continue to receive the same intravitreal medication for an additional 3 consecutive visits or quit.
Outcomes. Primary outcome measure: Mean change in CSFT from baseline to week 48. Secondary outcomes measures: Mean change in BCVA from baseline to week 48; mean change in IOP at any visit; lens status changes, mean number of intravitreous injections Sample Size. Sample size and powering were based on a previous clinical trial on bevacizumab use for diabetic macular edema30, where a mean change observed in central subfield thickness from baseline was 130 mm with a standard deviation of 122 μm. Therefore, to have 80% power to detect a difference of 50 μm between central subfield thickness change found in both groups, the sample size required in each group was 25 eyes. Thirty eyes per treatment group were required if one assumed a 10% dropout rate. With this sample size, there is a 20% chance for a failure to detect a true mean difference of at least 50 μm between the treatment groups (type I error), or for an incorrect conclusion that a difference of at least 50 μm exists between the treatment groups (type II error).
Statistical Analysis. BCVA and central subfield thickness measured at each follow-up visit were compared with baseline BCVA and CSFT values for within- and between-group comparisons, which were performed using multiple analysis of variance (MANOVA) for repeated measurements. Proportions of eyes with central subfield thickness ≤ 300 mm were compared using the likelihood ratio x2 test. In addition, a multivariate analysis comparing BCVA and CSFT outcomes in the prn-IVB group and qIVT group was performed, considering number of injections, baseline BCVA, and CSFT as effects. A statistically significant effect was defined if P < .05, and a trend towards significance was reported if P < .1. Statistical analyses were performed using JMP 10.0.0 (2010; SAS Institute Inc, Cary, North Carolina, USA) software.
|Study Type ICMJE||Interventional|
|Study Phase ICMJE||Phase 2
|Study Design ICMJE||Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
|Condition ICMJE||Diabetic Macular Edema|
|Study Arms ICMJE||
|Publications *||Not Provided|
* Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
|Recruitment Status ICMJE||Completed|
|Actual Enrollment ICMJE
|Original Actual Enrollment ICMJE||Same as current|
|Actual Study Completion Date ICMJE||December 21, 2017|
|Actual Primary Completion Date||April 14, 2017 (Final data collection date for primary outcome measure)|
|Eligibility Criteria ICMJE||
|Ages ICMJE||18 Years and older (Adult, Older Adult)|
|Accepts Healthy Volunteers ICMJE||Yes|
|Contacts ICMJE||Contact information is only displayed when the study is recruiting subjects|
|Listed Location Countries ICMJE||Not Provided|
|Removed Location Countries|
|NCT Number ICMJE||NCT02985619|
|Other Study ID Numbers ICMJE||1.599.864|
|Has Data Monitoring Committee||Yes|
|U.S. FDA-regulated Product||Not Provided|
|IPD Sharing Statement ICMJE||
|Responsible Party||Murilo Wendeborn Rodrigues Junior, University of Sao Paulo|
|Study Sponsor ICMJE||University of Sao Paulo|
|Collaborators ICMJE||Not Provided|
|Investigators ICMJE||Not Provided|
|PRS Account||University of Sao Paulo|
|Verification Date||May 2018|
ICMJE Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP