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

工程摘要 该R61/R33应用的目的是优化外周血淋巴细胞的新型响应生物标志物特征。 持续神经性疼痛（ONP），并提供其作为FDA生物标志物的分析和初步临床验证 终点和其他工具（BEST）外周作用性疼痛疗效的分类缓解生物标志物 疗法自发性外周ONP是一种常见的症状，通常是最衰弱的特征 周围感觉神经病变严重影响生活质量疼痛性周围神经病变（PN），是否 特发性的，或与化疗有关的（化疗引起的多发性神经病）和其他药物，糖尿病， 代谢综合征或遗传性疾病折磨着6-10%的美国人口。缺乏有效 在大多数PN患者中，治疗导致阿片类药物处方，并导致发病。发展 减少自发性外周伤害感受器传递的药物由于缺乏实用的 对这些纤维有特异性反应的生物标志物。我们有初步证据表明， 基于使用二极管激光选择性刺激C和Aδ伤害感受器评估的生物标志物特征 这些纤维（DLss）。皮肤C纤维的自发活动，主要是C机械不敏感纤维（CMi）， 负责外围ONP的调解。DLss允许评估自发活性CMi纤维- 介导的神经病理性疼痛，而Aδ纤维的评估提供了替代措施 PN远端轴突缺失的症状DLss还引起CMi介导的皮肤血管舒张性发作，这是一种特异性、客观的 可以量化的CMi激活的量度。我们建议发展DLss措施作为一种新的最佳 基于其对神经性疼痛的外周起源的特异性定义的响应生物标志物。我们假设 结合CMi：Aδ响应比和耀斑的优化DLss测量将与 外周ONP患者中报告的神经病理性疼痛强度在外周药物治疗后的变化 神经性疼痛药物 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将进行一项四部分双盲随机交叉研究 从治疗前基线阶段过渡到使用利多卡因或相同的 安慰剂贴剂、洗脱期和替代组。在每个阶段之前和之后将获得DLss测量值。两次 使用视觉模拟量表每日报告疼痛将跟踪参与者中持续自发性疼痛的严重程度。 混合生物标志物将区分安慰剂组和活性治疗组，将显著相关于 利多卡因治疗期间神经性疼痛减轻的程度，但在安慰剂治疗期间不会改变或无变化。 治疗导入。如果满足预设G/No-Go标准，则随后的R33验证将比较利多卡因 在一项设盲、随机化平行组研究中使用贴剂和安慰剂治疗。当与患者报告相结合时 神经病理性疼痛的变化可能成为混合型主要终点，C：Aδ比值可能。该项目将提供第一个 对外周活性神经性疼痛药物的反应的实际机制生物标志物特征， 准备进行先进的前瞻性临床验证研究。DLss反应生物标志物有可能 改善安慰剂效应，提高早期药物试验的统计功效， 开发有效的外周作用神经性疼痛治疗。它可能是第一个神经性的 疼痛生物标志物的FDA认证。

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.