The design, methods, and results of the phase 2 intravitreal bevacizumab for DME trial, a multi-center randomized clinical trial conducted by the DRCR.net at 36 clinical sites in the United States, have been published.14
The study enrolled 121 subjects at 36 different sites by 47 different retina specialists. As the current study relates only to baseline data from this trial, only the pertinent eligibility criteria and aspects of the study design relevant to the current study are summarized here. The entire protocol is available on the public site at http://drcr.net
Eligible subjects were at least 18 years old with type 1 or type 2 diabetes. The pertinent eligibility criteria for the study eye included: (1) definite retinal thickening due to DME involving the center of the macula based on clinical exam, (2) OCT central subfield thickness ≥ 275 microns, (3) no history of treatment for DME within the prior 3 months and (4) no panretinal photocoagulation (PRP) within the prior 4 months or an anticipated need for PRP in the 6 months following randomization. A subject could contribute only one study eye.
Standard ETDRS 7-field film color stereoscopic fundus photographs were obtained at baseline only of the study eye of each study participant and forwarded to the DRCR.net Reading Center at the University of Wisconsin-Madison for grading by trained readers who were masked to all clinical data, including clinician assessment of diabetic retinopathy level. Occasionally fundus photographs of both eyes were submitted; photographs of non-study eyes were not available to the graders. Photographs were each graded independently by each of 2 of the 6 graders assigned to DRCR.net color photograph grading. Disagreements by one or more retinopathy severity levels were resolved by a senior grader. The graders used standardized definitions for various characteristics of diabetic retinopathy and standard photographs to assess the severity of these characteristics in the 7 photographic fields and derived a composite ETDRS level score of 20, 35, 43, 47, 53, 60–61, 65, 71 or 75.13, 15
These levels correspond to the following classifications for diabetic retinopathy severity: 1) microaneurysms only, 2) mild non-proliferative diabetic retinopathy (NPDR), 3) moderate NPDR, 4) moderately severe NPDR, 5) severe NPDR, 6) mild proliferative diabetic retinopathy (PDR), 7) moderate PDR, and 8) high-risk PDR.
Clinicians were asked to grade diabetic retinopathy severity level at baseline in each eye of all study participants as one of the following levels: a) microaneurysms only, b) mild/moderate NPDR, c) severe NPDR (4-2-1 rule), and d) PDR or prior PRP or both. For eyes in category (d) presence/extent of PRP scars and of new vessels/vitreous or preretinal hemorrhage was also recorded. With the exception of required mydriasis, no specific protocol for the examinations was provided, but the principal methods used for ophthalmoscopy were slit-lamp biomicroscopy with a hand-held lens and binocular indirect ophthalmoscopy. Except for the 4-2-1 rule defining severe NPDR (severe intraretinal hemorrhages and microaneurysms in at least 4 quandrants, definite venous beading in at least 2 quandrants, or moderate intraretinal microvascular abnormalities in at least 1 quandrant), no specific definitions were provided to the clinicians for the severity levels with the presumption that their general ophthalmic fund of knowledge would suffice to differentiate these categories.
For comparison with clinician grading, Reading Center categories were collapsed to match those used by the clinicians as determined by the authors; Reading Center categories for mild, moderate and moderately severe NPDR were combined as were categories for mild, moderate and high-risk PDR. The clinician versus Reading Center grading comparison was not planned until follow-up on all patients had been completed. The current study is comprised of a retrospective analysis of data available and collected prospectively within the phase 2 study protocol.
Photographs were not available for 3 subjects, leaving 118 subjects for analysis. All photographs for which there was any disagreement in the gradings by the clinician compared with the Reading Center were re-reviewed by one of us (MDD) in order to ascertain potential reasons for the disagreements. Of the 118 eyes, 4 were initially classified as non-gradable by the Reading Center because of poor photographic quality, but on review for this manuscript could be assigned a retinopathy severity level and were included in the analysis (reviewer was aware of clinician’s grading at the time of re-review).
Percent agreement and the unweighted kappa statistic were computed, comparing the clinician and Reading Center gradings.