Cibinetide Improves Corneal Nerve Fiber Abundance in Patients With Sarcoidosis-Associated Small Nerve Fiber Loss and Neuropathic Pain
Cibinetide Improves Corneal Nerve Fiber Abundance in Patients With Sarcoidosis-Associated Small Nerve Fiber Loss and Neuropathic Pain
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DOI：
10.1167/iovs.16-21291
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发表时间：
2017-05-01
影响因子：
4.4
通讯作者：
Brines, Michael
中科院分区：
文献类型：
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作者：
Culver, Daniel A.;Dahan, Albert;Brines, Michael
目的。结节病常常并发少量神经纤维丢失(SNFL)，这可以用角膜共焦显微镜(CCM)来定量。先前的研究表明，先天修复受体激动剂西比妥可以逆转角膜神经丢失。这项2b期、为期28天的随机试验对患有结节相关SNFL和神经病理性疼痛的受试者进行了评估，评估了西宾肽对角膜神经纤维面积和再生表皮内纤维(GAP-43(+))的影响，作为疾病改善、疼痛严重程度和功能容量(6分钟步行试验[6MWT])的替代终点。主要研究终点是28天时CNFA的变化。结果：在1、4和8毫克组，28天时安慰剂校正后的平均变化分别为109(95%可信区间[CI]，类似于429647)、697(159,1236；P=0.012)和431(类似于130992)。4 mg组表皮内GAP-43(+)纤维增多(P=0.035)。此外，CNFA的变化与GAP-43(+)(q=0.575；P=0.025)和6MWT(q=0.645；P+0.009)的变化相关。所有组的疼痛都有显著改善，有中到重度疼痛的受试者报告说，4毫克组的疼痛强度有临床意义的安慰剂纠正减少(P=0.157)。结论：西比妥显著增加了角膜和皮肤中小神经纤维的含量，与疾病改善效果一致。CNFA和其他临床疾病指标之间的关系支持将其用作评估神经病变的潜在疾病修改疗法的替代终点。
PURPOSE. Sarcoidosis frequently is complicated by small nerve fiber loss (SNFL), which can be quantified using corneal confocal microscopy (CCM). Prior studies suggest that the innate repair receptor agonist cibinetide reverses corneal nerve loss. This phase 2b, 28-day, randomized trial of 64 subjects with sarcoid-associated SNFL and neuropathic pain assessed the effect of cibinetide on corneal nerve fiber area (CNFA) and regenerating intraepidermal fibers (GAP-43(+)) as surrogate endpoints for disease modification, pain severity, and functional capacity (6-minute walk test [6MWT]).METHODS. Cibinetide (1, 4, or 8 mg/day) was compared to placebo. The primary study endpoint was a change in CNFA at 28 days.RESULTS. The placebo-corrected mean change from baseline CNFA (mu m(2)) at day 28 was 109 (95% confidence interval [CI], similar to 429, 647), 697 (159, 1236; P = 0.012), and 431 (similar to 130, 992) in the 1, 4, and 8 mg groups, respectively. Intraepidermal GAP-43(+) fibers increased in the 4 mg group (P = 0.035). Further, changes in CNFA correlated with changes in GAP-43(+) (q = 0.575; P = 0.025) and 6MWT (q = 0.645; P + 0.009). Pain improved significantly in all groups, with subjects having moderate-severe pain reporting a clinically meaningful placebocorrected decrease in pain intensity in the 4 mg group (P = 0.157).CONCLUSIONS. Cibinetide significantly increased small nerve fiber abundance in the cornea and skin, consistent with a disease modifying effect. The relationships between CNFA and other clinical measures of disease support its use as a surrogate endpoint to assess potential disease modifying therapies for neuropathy.