Department of Ophthalmology, University of Bonn, Bonn, Germany.
Retinal Consultants of Arizona, Phoenix, Arizona; USC Eye Institute, Keck School of Medicine, University of Southern California, Los Angeles, California.
Ophthalmology. 2016 May;123(5):1080-9. doi: 10.1016/j.ophtha.2015.12.030. Epub 2016 Feb 20.
To assess the safety and efficacy of different doses of RTH258 applied as single intravitreal administration compared with ranibizumab 0.5 mg in patients with neovascular age-related macular degeneration (AMD).
Six-month, phase 1/2, prospective, multicenter, double-masked, randomized, ascending single-dose, active-controlled, parallel-group study.
A total of 194 treatment-naive patients, aged ≥50 years, with primary subfoveal choroidal neovascularization secondary to AMD.
Patients received a single intravitreal injection of RTH258 0.5 mg (n = 11), 3.0 mg (n = 31), 4.5 mg (n = 47), or 6.0 mg (n = 44), or ranibizumab 0.5 mg (n = 61).
The primary efficacy end point was the change from baseline to month 1 in central subfield thickness (CSFT) measured by spectral-domain optical coherence tomography. The secondary efficacy end point was the duration of treatment effect measured as time from the initial injection to receipt of post-baseline therapy (PBT) guided by protocol-defined criteria. Adverse events (AEs) were recorded throughout the study.
RTH258 demonstrated noninferiority compared with ranibizumab in mean change in CSFT from baseline to month 1 for the 4.5- and 6.0-mg dose groups (margin: 40 μm, 1-sided alpha 0.05). The difference in CSFT change at month 1 comparison with ranibizumab was 22.86 μm (90% confidence interval [CI], -9.28 to 54.99) and 19.40 μm (95% CI, -9.00 to 47.80) for RTH258 4.5 and 6 mg, respectively. The median time to PBT after baseline therapy was 60 and 75 days for patients in the RTH258 4.5- and 6.0-mg groups, respectively, compared with 45 days for ranibizumab. Changes in best-corrected visual acuity with RTH258 were comparable to those observed with ranibizumab. The most frequent AEs reported for the RTH258 groups were conjunctival hemorrhage, eye pain, and conjunctival hyperemia; the majority of these events were mild in intensity.
This first-in-human study of RTH258 demonstrated noninferiority in the change in CSFT at 1 month for the 4.5- and 6.0-mg doses compared with ranibizumab and an increase of 30 days in the median time to PBT for the 6.0-mg dose. There were no unexpected safety concerns, and the results support the continued development of RTH258 for the treatment of neovascular AMD.
评估不同剂量 RTH258 单次玻璃体内给药与雷珠单抗 0.5mg 治疗新生血管性年龄相关性黄斑变性（AMD）患者的安全性和疗效。
6 个月、1/2 期、前瞻性、多中心、双盲、随机、递增单剂量、活性对照、平行组研究。
共 194 例未经治疗的患者，年龄≥50 岁，原发性黄斑下脉络膜新生血管化继发于 AMD。
患者接受单次玻璃体内注射 RTH258 0.5mg（n=11）、3.0mg（n=31）、4.5mg（n=47）或 6.0mg（n=44），或雷珠单抗 0.5mg（n=61）。
主要疗效终点为基线至第 1 个月时通过谱域光学相干断层扫描（OCT）测量的中心视网膜下厚度（CSFT）的变化。次要疗效终点为治疗效果的持续时间，定义为根据方案标准接受基线后治疗（PBT）的初始注射时间。整个研究过程中均记录不良事件（AE）。
与雷珠单抗相比，RTH258 在第 1 个月时 CSFT 的平均变化在 4.5mg 和 6.0mg 剂量组中具有非劣效性（差值：40μm，单侧α值 0.05）。第 1 个月时 CSFT 变化与雷珠单抗的比较差异分别为 22.86μm（90%置信区间[CI]：-9.28 至 54.99）和 19.40μm（95%CI：-9.00 至 47.80），RTH258 的 4.5mg 和 6.0mg 组分别为 22.86μm（90%CI：-9.28 至 54.99）和 19.40μm（95%CI：-9.00 至 47.80）。与雷珠单抗相比，接受 RTH258 治疗的患者基线后治疗后至 PBT 的中位时间分别为 60 天和 75 天，而雷珠单抗为 45 天。RTH258 治疗后的最佳矫正视力变化与雷珠单抗观察到的变化相当。报告的 RTH258 组最常见的不良事件为结膜下出血、眼痛和结膜充血；这些事件大多数为轻度。
这是首例 RTH258 人体研究，结果表明，与雷珠单抗相比，4.5mg 和 6.0mg 剂量组在第 1 个月时 CSFT 的变化具有非劣效性，6.0mg 剂量组至 PBT 的中位时间延长 30 天。没有出现意外的安全性问题，结果支持继续开发 RTH258 用于治疗新生血管性 AMD。
