DA VINCI 2011

Methods	Parallel group RCT One eye per person, unclear how eye selected
Participants	Country: USA, Canada and Austria Number of people randomised: 221 (221 eyes) Average age: 64 years (range 40 to 86) Sex: 31% women Inclusion criteria: 18 years or older diabetes mellitus DMO involving the central macula defined as CRT ≥ 250 µm in the central subfield based on Stratus OCT BCVA letter score at 4 m of 73‐24 (Snellen equivalent: 20/40–20/320) measured by the ETDRS protocol women of childbearing potential were included only if they were willing to not become pregnant and to use a reliable form of birth control during the study period Exclusion criteria: (for study eye) history of vitreoretinal surgery PRP or macular laser photocoagulation or use of intraocular or periocular corticosteroids or anti‐angiogenic drugs within 3 months of screening vision decrease due to causes other than DMO PDR (unless regressed and currently inactive) ocular inflammation cataract or other intraocular surgery within 3 months of screening laser capsulotomy within 2 months of screening aphakia spherical equivalent of > −8 dioptres or any concurrent disease that would compromise VA or require medical or surgical intervention during the study period (in either eye) active iris neovascularisation vitreous haemorrhage traction retinal detachment preretinal fibrosis involving the macula visually significant vitreomacular traction or epiretinal membrane evident biomicroscopically or on OCT history of idiopathic or autoimmune uveitis structural damage to the center of the macula that is likely to preclude improvement in VA after the resolution of macular oedema uncontrolled glaucoma or previous filtration surgery infectious blepharitis, keratitis, scleritis, or conjunctivitis current treatment for serious systemic infection (systemic) uncontrolled diabetes mellitus uncontrolled hypertension history of cerebral vascular accident or myocardial infarction within 6 months renal failure requiring dialysis or renal transplant pregnancy or lactation history of allergy to fluorescein or povidone iodine only 1 functional eye ocular condition in the fellow eye with a poorer prognosis than the study eye
Interventions	Intervention: VEGF Trap‐Eye n = 177 (177 eyes) Comparator: laser photocoagulation n = 44 (44 eyes) "Patients were randomly assigned in a 1:1:1:1:1 ratio to 1 of 5 treatment regimens in 1 eye only: 0.5 mg VEGF Trap‐Eye every 4 weeks (0.5q4); 2 mg VEGF Trap‐Eye every 4 weeks (2q4); 2 mg VEGF Trap‐Eye for 3 initial monthly doses and then every 8 weeks, (2q8); 2 mg VEGF Trap‐Eye for 3 initial monthly doses and then on an as‐needed (PRN) basis (2 PRN); or macular laser treatment by the modified ETDRS protocol" Page 1820
Outcomes	Primary outcome: change in BCVA from baseline to week 24 (ETDRS chart at 4 m) Secondary outcomes: retinal thickness assessed by OCT safety and tolerability change in BCVA from baseline at week 52 proportion of eyes that gained at least 15 ETDRS letters in BCVA compared with baseline at weeks 24 and 52 the change in CRT (central subfield on OCT) from baseline to weeks 24 and 52 number of focal laser treatments given Follow‐up: 24 and 52 weeks
Notes	Date study conducted: December 2008 to June 2009 Funding: "Sponsored by Regeneron Pharmaceuticals, Inc., Tarrytown, New York." Conflict of interest: "The author(s) have made the following disclosure (s): Diana V. Do: Genentech (financial support), Regeneron Pharmaceuticals (financial support). Ursula Schmidt‐Erfuth: Alcon Labs (consultant, lecturer), Bayer Healthcare (consultant, lecturer), Novartis (consultant, lecturer), Regeneron Pharmaceuticals (lecturer), Pfizer (lecturer). Victor H. Gonzalez: Pfizer (consultant, lecturer), Genentech (lecturer), Eyetech (consultant, lecturer), Regeneron (lecturer). Carmelina M. Gordon: Allergan (consultant), Regeneron Pharmaceuticals (lecturer), Novartis (consultant, lecturer). Michael Tolentino: Genentech (consultant, lecturer), Eyetech (consultant, lecturer), Regeneron Pharmaceuticals (consultant, lecturer). Alyson J Berliner: Regeneron Pharmaceuticals (employee, equity owner). Robert Vitti: Regeneron Pharmaceuticals (employee, equity owner). Rene Rückert: Bayer Schering Pharma (employee). Rupert Sandbrink: Bayer Schering Pharma (employee). David Stein: Regeneron Pharmaceuticals (employee,equity owner). Ke Yang: Regeneron Pharmaceuticals (employee, equity owner). Karola Beckmann: Bayer Schering Pharma (employee). Jeff S.Heier: Genentech (consultant, lecturer), Regeneron Pharmaceuticals (consultant,lecturer), Fovea (consultant). Trial registration:NCT00789477
Risk of bias
Bias	Authors' judgement	Support for judgement
Random sequence generation (selection bias)	Low risk	"The randomization was handled by an IVRS vendor. The study statistician at REGENERON provided the randomization plan and reviewed and approved the dummy rand table. Study Data Management at REGENERON tested the randomization function extensively along with the Clinical team."
Allocation concealment (selection bias)	Low risk	"Sites called into IVRS to randomize patients and received the randomization number and drug kit assignment at the completion of the call. The site also received a confirmation email. Neither of these contained the actual randomization assignment. The randomization assignments were kept by the IVRS vendor in a secure, access‐controlled database and were delivered to REGENERON by the IVRS vendor at the primary endpoint database lock."
Blinding of participants and personnel (performance bias) All outcomes	Low risk	"To maintain participant masking, sham injections were performed on visits when an active dose was not given, and a sham laser was given to the VEGF Trap‐Eye groups at week 1. Study drug and sham injections and laser and sham laser treatments were performed by an unmasked physician who had no other role in the study except to assess adverse events (AEs) immediately posttreatment. Sham injections followed the active treatment protocol with the exception that no needle was attached to the syringe, and the syringe hub was gently applied to the sclera to mimic an injection. Sham laser consisted of placing a contact lens on the study eye and positioning the patient in front of the laser machine for the approximate duration of a laser treatment." Page 1820‐1
Blinding of outcome assessment (detection bias) All outcomes	Unclear risk	A separate masked physician was assigned to assess adverse events (AEs) and retreatment and rescue criteria and to supervise the masked assessment of efficacy. Every effort was made to ensure that all other study site personnel remained masked to treatment assignment to facilitate an unbiased assessment of efficacy and safety."
Incomplete outcome data (attrition bias) All outcomes	Low risk	"Two randomised patients did not receive treatment and 19 patients discontinued the study after receiving at least 1 treatment for the following reasons: lost to follow‐up (6 patients), withdrew consent (6 patients), death (3 patients), treatment failures (2 patients), AE (1 patient), and protocol deviation (1 patient). Discontinuations were evenly distributed among the 5 treatment groups." Page 1821 Comment: LOCF used
Selective reporting (reporting bias)	Low risk	Primary outcome declared and consistent with our review
Other bias	Low risk	No other bias identified
Overall risk of bias	Low risk	Low risk of bias for most items