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

疼痛性周围神经病的新型反应生物标志物特征的发现和验证

• 批准号: 10357531
• 负责人: Mikhail I. Nemenov
• 金额: $ 100.02万
• 依托单位: LASMED, LLC
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-09-01 至 2025-08-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10357531
• 关键词: Age; American; Analgesics; Axon; Biological Markers; Blinded; Brain; C Fiber; Categories; Certification; Characteristics; Cholesterol; Clinical; Cross-Over Studies; Crossover Design; Cutaneous; Data; Development; Diabetes Mellitus; Disease; Distal; Double-Blind Method; Etiology; Fiber; Flare; Foot Injuries; Hereditary Disease; Hybrids; Infection; Lasers; Lead; Length; Lidocaine; Lidocaine Patch; Limb structure; Measures; Mediating; Mediation; Metabolic syndrome; Methods; Morbidity - disease rate; Nerve; Nerve Fibers; Neuropathy; Nociceptors; Obesity; Outcome; Pain; Pain intensity; Pain management; Painless; Participant; Patients; Peripheral; Peripheral Nerves; Peripheral Nervous System Diseases; Pharmaceutical Preparations; Pharmacologic Substance; Phase; Placebo Effect; Placebos; Polyneuropathy; Population; Prediabetes syndrome; Proteins; Quality of life; Randomized; Recording of previous events; Reporting; Sensory; Severities; Signal Transduction; Skin; Specificity; Standardization; Symptoms; Techniques; Testing; Time; Utah; Validation; Visual; Visual Analogue Pain Scale; Vitamin Deficiency; active method; analog; arm; base; biomarker signature; chemotherapy; density; diabetic; disability; effective therapy; foot; improved; injured; irritation; novel; novel marker; pain patient; pain reduction; painful neuropathy; prescription opioid; primary endpoint; prospective; response; response biomarker; sensory neuropathy; specific biomarkers; spontaneous pain; tool; transmission process; treatment arm; treatment duration; treatment group; treatment response; validation studies

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.

项目摘要 此R61/R33应用的目的是优化新颖的响应生物标志物的特征 持续的神经性疼痛（ONP），并作为FDA生物标志物提供了分析和初始临床验证 终点和其他工具（最佳）分类响应生物标志物，以便于外周表现疼痛 治疗。自发外围ONP是一种经常表现的症状，通常是最令人衰弱的功能 周围感觉神经病，严重影响生活质量。痛苦的周围神经病（PN），是否是否 特发性或与化学疗法（化学疗法诱导的多神经病）和其他药物相关的糖尿病， 代谢综合征或遗传性疾病遭受了美国人群6-10％的困扰。缺乏有效 在大多数PN患者中导致阿片类药物处方的治疗，导致发病。发展 由于缺乏实用性，可以阻碍减少自发周围伤害感受器传播的药物 对这些纤维的反应生物标志物。我们有一个新的外围ONP的初步证据 基于对C和Aδ伤害感受器评估的生物标志物签名，使用二极管激光选择性刺激 这些纤维（DLSS）。皮肤C纤维的自发活性，主要是C机械不敏感的纤维（CMI） 负责外围ONP的调解。 DLSS允许评估赞助商活跃的CMI纤维 跨皮肤深度介导的神经性疼痛，而对Aδ纤维的评估可提供替代测量 PN盘状轴突丢失。 DLSS还唤起CMI介导的皮肤血管舒张耀斑，特定的，客观 可以量化的CMI激活的度量。我们建议将DLSS措施发展为新颖的措施 定义的反应生物标志物基于其对神经性疼痛周围起源的特异性。我们假设 结合CMI的优化DLSS测量：Aδ响应比和耀斑将与 周围治疗后，周围ONP患者报告的神经性疼痛强度的变化 作用神经性止痛药。 我们计划确认DLSS测量与对疼痛治疗的反应程度显着相关 使用局部利多卡因补丁。 R61将执行四部分双盲随机跨界研究 从预处理基线期过渡到用利多卡因或相同的随机治疗 安慰剂补丁，冲洗和替代手臂。 DLSS度量将在每个阶段之前和之后获得。两次 每天使用视觉模拟量表疼痛的报告将跟踪正在进行的赞助商的严重性。 混合生物标志物将区分安慰剂和主动治疗臂，将与 利多卡因期间神经性疼痛减轻的程度，但在安慰剂期不会改变或不变 治疗引线。如果满足了预设的G/No-GO标准，则随后的R33验证将比较利多卡因 在盲，随机平行的手臂研究中的斑块和安慰剂治疗。当与患者结合报告时 神经性疼痛变为杂交主要终点，c：Aδ比可能。这个项目将提供第一个 对周围活性神经性止痛药的反应的实用机械生物标志物签名， 准备进行先进的前瞻性临床验证研究。 DLSS响应生物标志物具有 改善安慰剂作用并改善早期药物试验的统计能力，并促进 开发有效的外周作用神经性疼痛治疗。它可能会提供第一个神经疗法 FDA认证的疼痛生物标志物。