Purpose

To investigate whether the riboflavin dosing frequency affects corneal cross-linking efficacy or safety, given that isotonic riboflavin solution is viscous and each installation coats the corneal surface with a film that absorbs some of the incident ultraviolet A light.

Design

Prospective, randomized, single-center equivalence trial.

Participants

Patients with progressive keratoconus or ectasia after refractive surgery (n = 510).

Methods

One eye per patient was prospectively randomized to 2-minute or 5-minute riboflavin dosing intervals with standard corneal cross-linking (epithelial removal and 30-minute irradiation with 3 mW/cm² ultraviolet A light). Block randomization resulted in comparable representation of keratoconus and ectasia after refractive surgery in the 2 treatment arms. Treatment equivalence was assessed using the 2 one-sided test. Fellow eyes (n = 207) were treated with 5-minute dosing and considered in the safety analysis.

Main Outcome Measures

The primary hypothesis was equivalent change in the topography-derived maximum keratometry value from baseline to 6 months with 2-minute vs. 5-minute dosing. A ±0.75-diopter margin of equivalence for the treatment difference between dosing regimens was considered clinically relevant. Adverse events and changes from baseline to 6 months in corrected distance visual acuity (CDVA), uncorrected distance visual acuity, and minimum corneal thickness were assessed.

Results

The mean reduction in maximum keratometry from baseline was equivalent with 2-minute and 5-minute riboflavin dosing intervals at 6 months (0.97 and 0.76 diopters, respectively; 90% confidence interval for treatment difference, −0.23 to 0.66; per-protocol population). With both dosing intervals, the mean improvement in CDVA was 0.07 logarithm of the minimum angle of resolution or 3.5 letters at 6 months. Of the 635 study and fellow eyes examined at 6 months, 134 (21%) gained and 32 (5%) lost 2 or more lines of CDVA. Three eyes (0.4%) developed sterile infiltrates, 1 (0.1%) had delayed epithelial healing with dendrites, and 3 (0.4%) had recurrent epithelial defects. Three eyes (0.4%) were re-treated.

Conclusions

The 2 riboflavin dosing regimens produced equivalent reduction in the maximum keratometry value, with a favorable safety profile.

中文翻译：

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角膜交联核黄素给药频率治疗圆锥角膜和角膜裂孔的前瞻性随机试验

目的

为了研究核黄素的给药频率是否影响角膜交联功效或安全性，考虑到等渗的核黄素溶液是粘性的，并且每个装置都在角膜表面覆盖一层吸收某些入射紫外线A光的膜。

设计

前瞻性，随机，单中心等效性试验。

参加者

屈光手术后进行性圆锥角膜或扩张的患者（n = 510）。

方法

每名患者的一只眼睛按标准角膜交联（上皮去除和3 mW / cm ²紫外线A光照射30分钟）随机分配至2分钟或5分钟核黄素给药间隔。在2个治疗组中，屈光手术后，区组随机分组可得出圆锥角膜和扩张的可比代表。使用2单侧测试评估治疗等效性。用5分钟的剂量对同一个眼睛（n = 207）进行治疗，并在安全性分析中予以考虑。

主要观察指标

主要假设是在2分钟和5分钟的剂量下，从基线到6个月的地形派生最大角膜曲率测量值的等效变化。给药方案之间治疗差异的等效屈光度为±0.75屈光度，被认为具有临床意义。评估了不良事件以及从基线到6个月的矫正远视力（CDVA），未矫正远视力和最小角膜厚度的变化。

结果

最大角膜测定法相对于基线的平均减少量相当于6个月时2分钟和5分钟的核黄素给药间隔（分别为0.97和0.76屈光度；治疗差异的90％置信区间为-0.23至0.66；按协议人群） 。在两个给药间隔中，CDVA的平均改善为最小分辨角的0.07对数或6个月时为3.5个字母。在6个月内检查的635例研究和同伴眼中，有134例（21％）得了眼，有32例（5％）失去了2根或更多根CDVA。三只眼（0.4％）出现无菌浸润，1眼（0.1％）延迟了树突上皮愈合，3眼（0.4％）复发了上皮缺损。再治疗三只眼（0.4％）。

结论

两种核黄素给药方案在最大角膜测定值上均等降低，并具有良好的安全性。