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