Evaluation Of Intravitreal Aflibercept For The Treatment Of Severe Nonproliferative Diabetic Retinopathy Results From The Panorama Randomized Clinical Trial

IMPORTANCE Proactive treatment of nonproliferative diabetic retinopathy (NPDR) reduces the risk of progression to vision-threatening complications.OBJECTIVE To evaluate vascular endothelial growth factor blockade therapy with intravitreal aflibercept injections in eyes with severe NPDR without diabetic macular edema (DME).DESIGN, SETTING, AND PARTICIPANTS The Study of the Efficacy and Safety of Intravitreal Aflibercept for the Improvement of Moderately Severe to Severe Nonproliferative Diabetic Retinopathy (PANORAMA) was a double-masked 100-week randomized clinical trial conducted in multiple centers worldwide. The study included 402 adults with Diabetic Retinopathy Severity Scale (DRSS) level 47 or 53 with no DME and best-corrected visual acuity of 20/40 or better.INTERVENTIONS Intravitreal injections of aflibercept, 2 mg, every 16 weeks after 3 initial monthly doses and one 8-week interval (aflibercept 2q16 group); intravitreal injections of aflibercept, 2 mg, every 8 weeks after 5 initial monthly doses, with pro re nata (PRN) dosing beginning at week 56 (aflibercept 2q8/PRN group); or sham injections (control group).MAIN OUTCOMES AND MEASURES Proportions of eyes with a 2-step or greater improvement in DRSS level, vision-threatening complications, and center-involved DME from baseline to weeks 24, 52, and 100.RESULTS Among 402 participants (1 eye per participant), the mean (SD) age was 55.7 (10.5) years; 225 (56.0%) were male, and 310 (77.1%) were White. A total of 135 were randomized to the aflibercept 2q16 group, 134 to the aflibercept 2q8/PRN group, and 133 to the control group. At 24 weeks, treatment with aflibercept resulted in a 2-step or greater improvement in DRSS level in 157 of 269 eyes (58.4%) in the combined aflibercept groups vs 8 of 133 eyes (6.0%) in the control group (adjusted difference, 52.3%; 95% CI, 45.2%-59.5%; P < .001). At 52 weeks, 88 of 135 eyes (65.2%) in the aflibercept 2q16 group (adjusted difference, 50.1%; 95% CI, 40.1%-60.1%) and 107 of 134 eyes (79.9%) in the aflibercept 2q8/PRN group (adjusted difference, 64.8%; 95% CI, 55.8%-73.9%) compared with 20 of 133 eyes (15.0%) in the control group (P < .001 for both comparisons) showed a 2-step or greater improvement in DRSS level. Fewer eyes treated with aflibercept vs sham injections developed vision-threatening complications and/or center-involved DME through week 100 (22 of 135 eyes [16.3%] in the 2q16 group [adjusted difference, -34.2%; 95% CI, -44.6 to -23.8] and 25 of 134 eyes [18.7%] in the 2q8/PRN group [adjusted difference, -31.7%; 95% CI, -42.5 to -20.9] compared with 67 of 133 eyes [50.4%] in the control group; P < .001 for both comparisons). No new safety signals were identified.CONCLUSIONS AND RELEVANCE In this study, significantly more eyes with moderately severe to severe NPDR that were treated with aflibercept showed a 2-step or greater improvement in DRSS level at 24, 52, and 100 weeks, and significantly fewer eyes treated with aflibercept vs sham developed vision-threatening complications and center-involved DME. Outcomes on the DRSS between year 1 and 2 emphasize the need for ongoing vascular endothelial growth factor suppression and adherence.This randomized clinical trial evaluates whether treatment with intravitreal aflibercept vs sham injections results in anatomic improvement from baseline through 100 weeks in eyes with moderately severe to severe nonproliferative diabetic retinopathy and no diabetic macular edema.Question Does treatment of moderately severe to severe nonproliferative diabetic retinopathy (NPDR) with intravitreal aflibercept injections result in 2-step or greater improvement on the Diabetic Retinopathy Severity Scale in more eyes, fewer vision-threatening complications, and fewer center-involved diabetic macular edema events from baseline through 100 weeks compared with sham injections?Findings In this randomized clinical trial of 402 patients with moderately severe to severe NPDR without diabetic macular edema, more eyes treated with intravitreal aflibercept injections showed a 2-step or greater improvement on the Diabetic Retinopathy Severity Scale at 24, 52, and 100 weeks, with significantly fewer vision-threatening complications and center-involved diabetic macular edema events. No differences in mean change in best-corrected visual acuity at weeks 52 and 100 were observed.Meaning In this study, anatomic improvement was more likely to occur in eyes with moderately severe to severe NPDR that were treated with intravitreal aflibercept injections; in year 2, fixed dosing appeared necessary to maintain anatomic benefit.