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.

Trial Registration ClinicalTrials.gov Identifier: NCT02718326

重要性 非增殖性糖尿病视网膜病变 (NPDR) 的积极治疗可降低进展为威胁视力的并发症的风险。

目的 评价玻璃体腔注射阿柏西普对无糖尿病黄斑水肿（DME）的重度NPDR眼血管内皮生长因子阻断治疗的疗效。

设计、设置和参与者 玻璃体内阿柏西普改善中重度至重度非增殖性糖尿病视网膜病变 (PANORAMA) 的疗效和安全性研究是一项在全球多个中心进行的双盲 100 周随机临床试验。该研究包括 402 名糖尿病视网膜病变严重程度量表 (DRSS) 47 或 53 级且没有 DME 且最佳矫正视力为 20/40 或更高的成年人。

干预措施 玻璃体内注射阿柏西普 2 毫克，在 3 次初始每月剂量和 1 次 8 周间隔后每 16 周注射一次（阿柏西普 2q16 组）；玻璃体内注射阿柏西普 2 毫克，在 5 次初始每月给药后每 8 周注射一次，从第 56 周开始使用 pro renata (PRN) 给药（阿柏西普 2q8/PRN 组）；或假注射（对照组）。

主要结果和测量 从基线到第 24、52 和 100 周，DRSS 水平、视力威胁并发症和中心受累 DME 改善 2 步或更多的眼睛比例。

结果 在 402 名参与者中（每名参与者 1 只眼），平均 (SD) 年龄为 55.7 (10.5) 岁；225 人 (56.0%) 为男性，310 人 (77.1%) 为白人。共有 135 人被随机分配到阿柏西普 2q16 组，134 人被随机分配到阿柏西普 2q8/PRN 组，133 人被随机分配到对照组。在 24 周时，阿柏西普联合治疗组 269 只眼中的 157 只眼（58.4%）与对照组 133 只眼中的 8 只眼（6.0%）相比，阿柏西普治疗使 DRSS 水平改善了 2 步或更多（调整后的差异， 52.3%；95% CI，45.2%-59.5%；P < .001)。在 52 周时，阿柏西普 2q16 组 135 只眼中有 88 只眼（65.2%）（调整后的差异，50.1%；95% CI，40.1%-60.1%）和阿柏西普 2q8/PRN 组 134 只眼中的 107 只眼（79.9%） （调整后的差异，64.8%；95% CI，55.8%-73.9%）与对照组 133 只眼中的 20 只眼（15.0%）相比（两项比较P  < .001）显示 DRSS 改善了 2 步或更多等级。与假注射相比，接受阿柏西普治疗的眼睛在第 100 周内出现威胁视力的并发症和/或中心受累的 DME（2q16 组 135 只眼中的 22 只眼 [16.3%] [调整后差异，-34.2%；95% CI，-44.6 2q8/PRN 组 134 只眼中有 25 只眼 [18.7%] [调整后差异，-31.7%；95% CI，-42.5 至 -20.9]，而对照组 133 只眼中有 67 只眼 [50.4%]组；P < .001 对于两个比较）。没有发现新的安全信号。

结论和相关性 在这项研究中，在 24、52 和 100 周，接受阿柏西普治疗的中重度至重度 NPDR 的眼睛显着增加了 2 步或更多，而接受阿柏西普治疗的眼睛明显少于假治疗。出现威胁视力的并发症和中心受累的 DME。第 1 年和第 2 年 DRSS 的结果强调需要持续的血管内皮生长因子抑制和依从性。

试验注册 ClinicalTrials.gov 标识符：NCT02718326