Eye Center, Medical Center, Faculty of Medicine, University of Freiburg, Freiburg, Germany.
Department of Ophthalmology, University of Bonn, Bonn, Germany.
JAMA Pediatr. 2018 Mar 1;172(3):278-286. doi: 10.1001/jamapediatrics.2017.4838.
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.
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.
All infants received 1 baseline ranibizumab injection per eye. Reinjections were allowed in case of ROP recurrence after at least 28 days.
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.
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.
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.
clinicaltrials.gov Identifier: NCT02134457 and clinicaltrialsregister.eu Identifier: 2013-002539-13.
目的：抗血管内皮生长因子（VEGF）治疗是一种治疗早产儿视网膜病变（ROP）的新方法。关于剂量、疗效和安全性的数据不足。
方法：在德国 9 所学术医疗中心进行了一项随机、多中心、双盲、研究者发起的试验，比较了雷珠单抗的两种剂量（0.12mg 与 0.20mg）在双侧侵袭性后部 ROP 患儿中的应用，ROP 分期为 1 期伴+病变、2 期伴+病变或 3 期伴或不伴 I 区+病变；或 ROP 分期 3 期伴后部二区+病变。患者于 2014 年 9 月至 2016 年 8 月间入组。共筛选了 20 名婴儿，19 名被随机分配。
参与者：所有婴儿每只眼接受 1 次基线雷珠单抗注射。如果在至少 28 天后 ROP 复发，则允许进行再注射。
主要结局和措施：主要终点是 24 周时无需抢救治疗的婴儿人数。关键次要终点包括时间相关分析、生理性血管化进展和血浆 VEGF 水平。ROP 分期通过光凝记录并由专家委员会进行审查。
结果：共有 19 名患有 ROP 的婴儿入组（9 名[47.4%]为女性；首次治疗时的中位[范围]胎龄为 36.4[34.7-39.7]周），其中 3 名在研究期间死亡（0.12mg 组 1 名，0.20mg 组 2 名）。在幸存的婴儿中，0.12mg 组 8 名（88.9%）（17 只眼[94.4%]）和 0.20mg 组 6 名（85.7%）（13 只眼[92.9%]）不需要抢救治疗。两种雷珠单抗剂量在控制急性 ROP 方面同样有效（Cochran-Mantel-Haenszel 分析；优势比，1.88；95%CI，0.26-13.49；P=0.53）。0.12mg 组的视网膜内血管化更优。两组的 VEGF 血浆水平均未发生系统性改变。
结论和相关性：本初步研究表明，雷珠单抗在控制急性 ROP 方面有效，标准成人剂量的 24%（0.12mg）与 40%（0.20mg）同样有效。0.12mg 雷珠单抗治疗后外周视网膜血管化更优，表明较低的剂量可能更有利。血浆 VEGF 水平不变表明雷珠单抗的全身药物暴露有限。
试验注册：clinicaltrials.gov 标识符：NCT02134457 和 clinicaltrialsregister.eu 标识符：2013-002539-13。
