Brain-based and clinical phenotyping of pain pharmacotherapy in knee OA

膝关节 OA 疼痛药物治疗的脑基和临床表型

基本信息

批准号：
10735060
负责人：
Apkar Vania Apkarian
金额：
$ 72.37万
依托单位：
NORTHWESTERN UNIVERSITY AT CHICAGO
依托单位国家：
美国
项目类别：
财政年份：
2023
资助国家：
美国
起止时间：
2023-08-15 至 2028-07-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10735060
关键词：
Aftercare Age Anatomy Anxiety Attention Back Behavioral Biochemical Biological Markers Blinded Brain Brain imaging C-reactive protein Caring Characteristics Clinic Clinical Clinical Data Clinical Trials Collection Data Degenerative polyarthritis Development Disease Emotional Etiology Exposure to Formulation Funding Opportunities Future Goals Image Individual Inflammation Intervention Joints Knee Knee Osteoarthritis Magnetic Resonance Imaging Measures Mental Depression Modality Modeling Naproxen Nociception Non-Steroidal Anti-Inflammatory Agents Norepinephrine Pain Pain intensity Parents Participant Pathway interactions Patient Outcomes Assessments Patient Selection Patient risk Patients Peripheral Personality Persons Pharmaceutical Preparations Pharmacotherapy Phenotype Physiological Placebo Effect Placebos Prognostic Factor Prognostic Marker Property Prospective Studies Psychological Factors Psychometrics Questionnaires Randomized Randomized, Controlled Trials Research Project Grants Risk Sensory Serotonin Serum Site Specificity Spinal Cord Testing Therapeutic Therapeutic Agents Therapeutic Intervention Validation Work arm brain based brain circuitry central sensitization chronic pain clinical biomarkers clinical outcome measures clinical phenotype conditioning cost effective daily pain demographics design duloxetine emotional functioning epidemiology study improved indexing individual patient individual variation inhibitor innovation machine learning prediction neurosensory novel therapeutics opioid use osteoarthritis pain pain perception pain relief patient oriented patient response patient variability personalized medicine pharmacologic predictive modeling prognostic prognostication prospective psychologic radiological imaging randomized trial research clinical testing response response biomarker reuptake sex side effect specific biomarkers success treatment response

项目摘要

ABSTRACT This proposal is in response to the funding opportunity Research Project Grant (Parent R01 Clinical Trial Required), FOA number PAR-20-183. This proposal aims to identify specific biomarkers in individual people with osteoarthritis (OA) pain that will allow definition of responder phenotypes distinct for different therapeutic interventions. A mechanistic, prospective randomized trial will be undertaken, treating people having moderate to severe OA pain with either naproxen (a non-steroidal anti-inflammatory agent (NSAID)), duloxetine (a selective serotonin-norepinephrine reuptake inhibitor) or placebo in a 1:1:1 ratio. Randomization will be stratified by sex and prior opioid use. Naproxen, duloxetine and placebo are known to have different mechanisms of action and work at different sites in the pain pathway. Hence, it would be expected that these distinctions would be reflected in differences in individuals who would respond to each of these interventions. To this end, during the study we will collect a wide variety of biomarkers including demographics (sex, age), clinical outcome measures, questionnaires of patient-reported outcomes, neurosensory status (quantitative sensory testing indices), serum- based biomarkers, and joint and brain imaging. The treatment for each participant and collection of biomarkers will occur during an initial 6-week period and then be repeated after a 4-week washout to account for the known within-patient variability. The results obtained will permit the identification of responders (defined by 30% or greater improvement in pain from baseline with other thresholds also evaluated), and the correlation of biomarker status at baseline to response. We will then build a model to define the responder phenotype for each intervention, first using only clinical data and secondly using both clinical and MRI-based brain data. The latter will permit a further understanding of the mechanisms involved in modulation of the pain pathways by each of the agents. Particular attention will be given to treatment by sex interactions. The characterization of responder phenotypes to NSAID, duloxetine and placebo will allow for the practice of personalized medicine, providing the right drug to the right patient, enhancing therapeutic success, and reducing the risks involved with being treated with ineffective drugs having serious potential side effects. In addition, this approach will allow for more targeted and more efficient development of potential new therapeutic agents to treat OA pain.

抽象的该提案是为了响应资助机会研究项目补助金（母公司 R01 临床试验）必需），FOA 编号 PAR-20-183。该提案旨在识别个体中的特定生物标志物骨关节炎 (OA) 疼痛，这将允许定义不同治疗方法的不同反应者表型干预措施。将进行一项机制性、前瞻性随机试验，治疗患有中度疾病的人使用萘普生（一种非甾体抗炎药 (NSAID)）、度洛西汀（一种选择性血清素-去甲肾上腺素再摄取抑制剂）或安慰剂，比例为 1:1:1。随机分组将按性别分层以及之前使用阿片类药物。已知萘普生、度洛西汀和安慰剂具有不同的作用机制，并且在疼痛通路的不同部位发挥作用。因此，预计这些区别将得到反映对每种干预措施做出反应的个人存在差异。为此，我们在研究过程中将收集各种生物标志物，包括人口统计数据（性别、年龄）、临床结果指标、患者报告的结果、神经感觉状态（定量感觉测试指数）、血清基于生物标志物以及关节和大脑成像。每个参与者的治疗和生物标志物的收集将在最初的 6 周期间发生，然后在 4 周的清洗后重复以考虑已知的情况患者内部的变异性。获得的结果将允许识别响应者（定义为 30% 或疼痛较基线有更大改善，还评估了其他阈值），以及生物标志物的相关性响应基线状态。然后我们将建立一个模型来定义每个的响应者表型干预，首先仅使用临床数据，其次使用临床和基于 MRI 的大脑数据。后者将有助于进一步了解每种疼痛途径调节所涉及的机制代理商。将特别关注通过性互动进行的治疗。响应者的特征 NSAID、度洛西汀和安慰剂的表型将允许个体化医疗的实践，提供对正确的患者使用正确的药物，提高治疗成功率，并降低治疗风险无效药物具有严重的潜在副作用。此外，这种方法将允许更有针对性的以及更有效地开发治疗骨关节炎疼痛的潜在新治疗药物。