Discovery and Validation of a Novel Response Biomarker Signature for Painful Peripheral Neuropathy

项目摘要 此R61/R33应用程序目的是优化一种新的外周血细胞反应生物标志物特征 持续神经病理性疼痛(ONP)，并提供其作为FDA生物标志物的分析和初步临床验证 终端和其他工具(最佳)外周作用疼痛疗效的分类反应生物标记物 心理治疗。自发性外周ONP是一种常见的表现症状，通常是最令人虚弱的特征 周围感觉神经病，严重影响生活质量。痛性周围神经病(PN) 特发性的，或与化疗(化疗引起的多发性神经病)和其他药物相关的，糖尿病， 代谢综合征或遗传性疾病困扰着6%-10%的美国人口。缺乏有效的 在大多数PN患者中，治疗导致阿片类药物处方，并导致发病率。发展中的 减少外周伤害性感受器自发传递的药物因缺乏实用的药物而受阻 这些纤维特有的反应生物标记物。我们有初步证据证明一种新的外周ONP 基于使用半导体激光选择性刺激的C和Aδ伤害性感受器评估的生物标志物特征 这些纤维(DLss)。皮肤C纤维，主要是C机械不敏感纤维(CMI)的自发活动 负责外围ONP的调解工作。DLSS允许评估自发活动的CMI纤维- 介导的跨皮肤深度神经病理性疼痛，而Aδ纤维的评估提供了一种替代措施 PN远端轴突丢失。DLSS还能引起CMI介导的皮肤血管扩张，这是一种特定的、客观的 可以量化的CMI激活的度量。我们建议将DLSS度量作为一种新的最佳 根据神经病理性疼痛的外周起源的特异性，定义了反应生物标志物。我们假设 将CMI：Aδ响应率和FLARE相结合的优化DLSS测量将显著相关 外周治疗后外周ONP患者神经病理性疼痛强度的变化 代理神经性止痛药。 我们计划证实DLSS测量与疼痛治疗的反应程度显著相关 使用局部利多卡因贴片。R61将进行四部分双盲随机交叉研究 从治疗前的基线阶段过渡到利多卡因或相同剂量的随机治疗 安慰剂贴片、洗涤剂和替代手臂。将在每个阶段之前和之后获得DLSS措施。两次 使用视觉模拟评分的每日疼痛报告将跟踪参与者持续自发疼痛的严重程度。 混合生物标记物将区分安慰剂和积极治疗药物，将显著相关 利多卡因期间神经病理性疼痛减轻的程度，但在安慰剂期或无 治疗开始了。如果满足预设的G/No-Go标准，则后续的R33验证将比较利多卡因 一项随机、盲法平行对照研究中的贴片和安慰剂治疗。当与报告的患者结合时 神经病理性疼痛改变为混合主要终点，C：Aδ比率可能。该项目将提供第一个 对外周活性神经性疼痛药物反应的实用机械生物标记物标记， 为先进的前瞻性临床验证研究做好准备。DLSS反应生物标记物有可能 改善早期药物试验中的安慰剂效应和提高统计能力，并促进 开发有效的外周作用的神经病理性疼痛治疗方法。它可能会提供第一种神经病原体 FDA认证的疼痛生物标记物。

Project Abstract The purpose of this R61/R33 application is to optimize a novel response biomarker signature of peripheral ongoing neuropathic pain (ONP) and provide its analytical and initial clinical validation as an FDA Biomarkers EndpointS and other Tools (BEST) categorical Response biomarker for efficacy of peripherally acting pain therapy. Spontaneous peripheral ONP is a frequent presenting symptom, and often the most debilitating feature of peripheral sensory neuropathy, severely impacting quality of life. Painful peripheral neuropathy (PN), whether idiopathic, or associated with chemotherapy (chemotherapy induced polyneuropathy) and other drugs, diabetes, metabolic syndrome or hereditary disease afflicts 6-10% of the US population. There is a lack of effective treatment leading to opioid prescription in most PN patients, with resulting morbidity. Development of medications that reduce spontaneous peripheral nociceptor transmission is hindered by lack of a practical Response biomarker specific for these fibers. We have preliminary evidence for a novel peripheral ONP biomarker signature based on assessment of C and Aδ nociceptors using a diode laser to selectively stimulate these fibers (DLss). Spontaneous activity of cutaneous C fibers, mainly C mechano-insensitive fibers (CMi), are responsible for mediation of peripheral ONP. DLss allows assessment of spontaneously active CMi fiber- mediated neuropathic pain across cutaneous depth, while assessment of Aδ fibers provides a surrogate measure of PN distal axonal loss. DLss also evokes CMi mediated cutaneous vasodilatative flare, a specific, objective measure of CMi activation that can be quantified. We propose to develop DLss measures as a novel BEST defined Response biomarker based on its specificity for peripheral origin of neuropathic pain. We hypothesize that an optimized DLss measure combining CMi: Aδ response ratio and flare will significantly correlate with change in reported neuropathic pain intensity in peripheral ONP patients, following treatment with peripherally acting neuropathic pain medications. We plan to confirm that DLss measures are significantly correlated with extent of response to pain treatment using a topical lidocaine patch. The R61 will perform a four part double-blind randomized crossover study transitioning from a pretreatment baseline phase, to randomized treatment with either lidocaine or an identical placebo patch, washout, and alternate arm. DLss measures will be obtained before and after each phase. Twice daily report of pain using a visual analogue scale will track severity of ongoing spontaneous pain in participants. The hybrid biomarker will distinguish between placebo and active treatment arms, will significantly correlate with extent of neuropathic pain reduction during lidocaine, but will not change during the placebo phase or no- treatment lead in. If preset G/No-Go criteria are met, the subsequent R33 validation will then compare lidocaine patch and placebo treatment in a blinded, randomized parallel arm study. When combined with patient reported change in neuropathic pain into a hybrid primary endpoint, C:Aδ ratio may. This project will deliver the first practical mechanistic biomarker signature of Response to peripherally active neuropathic pain medications, ready for advanced prospective clinical validation studies. The DLss Response biomarker has the potential to ameliorate placebo effect and improve statistical power in early Phase pharmaceutical trials, and facilitate the development of effective, peripherally acting neuropathic pain treatments. It may provide the first neuropathic pain biomarker for FDA certification.