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: 10677537
• 负责人: Mikhail I. Nemenov
• 金额: $ 50.27万
• 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/10677537
• 关键词: Age; American; Analgesics; Axon; Biological Markers; Blinded; Brain; C Fiber; 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; 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应用程序的目的是选择 持续的神经性疼痛（ON）和提供作为FDA生物标志物是分析性和初始临床验证 终点和其他工具（最佳）分类响应生物标志物，用于外周表现疼痛的功效 自发外围ONP是一种常见的症状，通常是最衰弱的特征 外周神经病，严重程度影响生活质量。 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。 在大多数患者中导致阿片类药物处方的治疗 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 针对这些纤维的响应生物标志物。 基于C和和和和和和和和和使用二极管激光器选择的生物标志物签名 这些纤维（DLSS）。 负责DLSS的外围化学。 跨皮肤深度介导的神经性疼痛，同时评估替代措施 OFN DLSS远端损失也唤起CMI介导的皮肤血压 可以量化的CMI激活。 根据其对神经性疼痛的周围起源的特异性，定义的反应生物标志物 优化的DLSS测量CMI：响应响应比和耀斑将与 周围珍贵的周围ONP患者报告的神经性疼痛强度的变化 表演神经性疼痛医学。 我们计划确认DLSS措施与对疼痛信任的反应程度显着相关 使用局部利多卡因贴片。 从预处理基线期过渡到用利多卡因或反学的随机治疗 安慰剂补丁，清洗和交替的手臂。 每日使用视觉模拟量表疼痛的报告将跟踪参与者正在进行的自发疼痛的严重程度。 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 治疗引导。如果满足预设的G/No-Go标准 在盲，随机平行的手臂研究中的斑块和安慰剂治疗。 神经性疼痛变为杂交主要终点，c：该项目的比例可以传递。 对外周活动神经性疼痛医学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。 在早期药物试验中，氨甲酸安慰剂效应并改善统计能力，并促进您 开发有效的外周作用神经性疼痛治疗。 FDA认证的疼痛生物标志物。