Importance Anti–vascular endothelial growth factor (VEGF) therapies are a novel treatment option in retinopathy of prematurity (ROP). Data on dosing, efficacy, and safety are insufficient. Objective To investigate lower doses of anti-VEGF therapy with ranibizumab, a substance with a significantly shorter systemic half-life than the standard treatment, bevacizumab. Design, Setting, and Participants This randomized, multicenter, double-blind, investigator-initiated trial at 9 academic medical centers in Germany compared ranibizumab doses of 0.12 mg vs 0.20 mg in infants with bilateral aggressive posterior ROP; ROP stage 1 with plus disease, 2 with plus disease, or 3 with or without plus disease in zone I; or ROP stage 3 with plus disease in posterior zone II. Patients were recruited between September 2014 and August 2016. Twenty infants were screened and 19 were randomized. Interventions All infants received 1 baseline ranibizumab injection per eye. Reinjections were allowed in case of ROP recurrence after at least 28 days. Main Outcomes and Measures The primary end point was the number of infants who did not require rescue therapy at 24 weeks. Key secondary end points included time-to-event analyses, progression of physiologic vascularization, and plasma VEGF levels. Stages of ROP were photodocumented and reviewed by an expert committee. Results Nineteen infants with ROP were enrolled (9 [47.4%] female; median [range] postmenstrual age at first treatment, 36.4 [34.7-39.7] weeks), 3 of whom died during the study (1 in the 0.12-mg group and 2 in the 0.20-mg group). Of the surviving infants, 8 (88.9%) (17 eyes [94.4%]) in the 0.12-mg group and 6 (85.7%) (13 eyes [92.9%]) in the 0.20-mg group did not require rescue therapy. Both ranibizumab doses were equally successful in controlling acute ROP (Cochran-Mantel-Haenszel analysis; odds ratio, 1.88; 95% CI, 0.26-13.49; P = .53). Physiologic intraretinal vascularization was superior in the 0.12-mg group. The VEGF plasma levels were not systematically altered in either group. Conclusions and Relevance This pilot study demonstrates that ranibizumab is effective in controlling acute ROP and that 24% of the standard adult dose (0.12 mg) appears equally effective as 40% (0.20 mg). Superior vascularization of the peripheral retina with 0.12 mg of ranibizumab indicates that the lower dose may be favorable. Unchanged plasma VEGF levels point toward a limited systemic drug exposure after ranibizumab. Trial Registration clinicaltrials.gov Identifier: NCT02134457 and clinicaltrialsregister.eu Identifier: 2013-002539-13.

中文翻译：

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比较替代雷珠单抗剂量在早产儿视网膜病变中的安全性和有效性

重要性 抗血管内皮生长因子 (VEGF) 疗法是早产儿视网膜病变 (ROP) 的一种新型治疗选择。关于剂量、功效和安全性的数据不足。目的 研究使用雷珠单抗进行较低剂量的抗 VEGF 治疗，雷珠单抗是一种全身半衰期明显短于标准治疗贝伐单抗的物质。设计、设置和参与者 这项随机、多中心、双盲、由研究者发起的试验在德国 9 个学术医疗中心进行，比较了双侧侵袭性后路 ROP 婴儿的雷珠单抗 0.12 mg 和 0.20 mg 剂量；ROP 分期 1 加病，2 加病，或 3 区加病或不加病；或 ROP 3 期伴后区 II 加病。患者是在 2014 年 9 月至 2016 年 8 月期间招募的。筛选了 20 名婴儿，随机分配了 19 名婴儿。干预 所有婴儿每只眼睛接受 1 次基线雷珠单抗注射。如果在至少 28 天后 ROP 复发，则允许再次注射。主要结果和措施 主要终点是在 24 周时不需要抢救治疗的婴儿数量。关键的次要终点包括事件发生时间分析、生理血管化进展和血浆 VEGF 水平。ROP 的各个阶段都被记录下来并由专家委员会审查。结果 招募了 19 名患有 ROP 的婴儿（9 名 [47.4%] 女性；首次治疗时的中位 [范围] 月经后年龄，36.4 [34.7-39.7] 周），其中 3 名在研究期间死亡（0.12 毫克组中的一名和0.20 毫克组中有 2 人）。在存活婴儿中，0.12 毫克组中有 8 名（88.9%）（17 只眼 [94.4%]）和 6 名（85.7%）（13 只眼 [92. 9%]) 在 0.20 毫克组不需要救援治疗。两种雷珠单抗剂量在控制急性 ROP 方面同样成功（Cochran-Mantel-Haenszel 分析；优势比，1.88；95% CI，0.26-13.49；P = .53）。0.12-mg 组的生理性视网膜内血管化效果更好。两组的 VEGF 血浆水平均未发生系统性改变。结论和相关性 该初步研究表明，雷珠单抗可有效控制急性 ROP，并且 24% 的标准成人剂量 (0.12 mg) 似乎与 40% (0.20 mg) 等效。0.12 mg 雷珠单抗对周边视网膜的良好血管化表明较低的剂量可能是有利的。未改变的血浆 VEGF 水平表明雷珠单抗后全身药物暴露有限。试验注册clinicaltrials.gov 标识符：