Duloxetine to Prevent Oxaliplatin-Induced Chemotherapy-Induced Peripheral Neuropathy: A Randomized, Double-Blind, Placebo-Controlled Phase II to Phase III Study

度洛西汀预防奥沙利铂引起的化疗引起的周围神经病变：一项随机、双盲、安慰剂对照的 II 期至 III 期研究

• 批准号: 10543540
• 负责人: Ellen Mary Lavoie Smith
• 金额: $ 29.19万
• 依托单位: UNIVERSITY OF ALABAMA AT BIRMINGHAM
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-01-10 至 2024-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10543540
• 关键词: Academy; Address; Adverse event; Affect; Aftercare; Brief Pain Inventory; Cancer Survivor; Chemotherapy-induced peripheral neuropathy; Clinical; Clinical Trials; Colorectal Cancer; Common Terminology Criteria for Adverse Events; Community Clinical Oncology Program; Data; Diagnosis; Disease; Distress; Dose; Double-Blind Method; Fingers; Goals; Hand; Health; Impairment; Institute of Medicine (U.S.); Knowledge; Lead; Lower Extremity; Malignant Neoplasms; Measures; Medicine; Mental Depression; Multicenter Studies; National Cancer Institute; Numbness; Pain; Patients; Pattern; Peripheral Nervous System Diseases; Persons; Phase; Placebo Control; Placebos; Prevention; Prevention trial; Preventive treatment; Quality of life; Questionnaires; Randomized; Randomized, Controlled Trials; Rattus; Recommendation; Reporting; Research; Research Design; Resources; Risk; Safety; Severities; Site; Sleep disturbances; Symptoms; Testing; Toes; Toxic effect; Treatment-Related Cancer; United States; Upper Extremity; arm; chemotherapy; chronic neuropathic pain; chronic pain management; design; disability; dosage; duloxetine; experience; falls; foot; functional disability; non-opioid analgesic; oxaliplatin; pain relief; pain score; patient population; phase 2 study; phase 3 study; phase III trial; pre-clinical; prevent; preventive intervention; programs; response; side effect

In the United States in 2017, most of the 135,000 people diagnosed with colorectal cancer received oxaliplatin to treat stage II-IV disease. About 70% of patients develop oxaliplatin-induced peripheral neuropathy (OIPN) that is characterized by upper and lower extremity numbness (N) and tingling (T), which can persist for years. Painful OIPN develops after N and T in 30% of patients. OIPN (N, T, and pain) poses a major health risk because it is associated with impaired function, falls, depression, impaired sleep, poor quality of life, and is a common reason for chemotherapy dose reductions. A critical gap in our scientific knowledge is that no known preventive interventions for OIPN exist. To address this gap, our overall objective is to test whether duloxetine prevents oxaliplatin-induced N, T, and pain, using a sequential Phase II to Phase III design that will be conducted via the National Cancer Institute (NCI) Community Oncology Research Program (NCORP), a large, multisite research network with access to diverse patient populations. Duloxetine will be tested in this study based on evidence of its efficacy for established OIPN from two clinical trials (Yang et al, 2012; Smith et al., 2013), and our pre-clinical data showing that duloxetine prevents painful OIPN in rats. We will first conduct a randomized, 3-arm, double-blind, placebo-controlled, non-comparative, multi-center study (N = 171) to screen two daily doses of duloxetine—30 mg and 60 mg—to prevent OIPN (N, T, and pain). If duloxetine is shown to be clinically active in the Phase II study, we will proceed to a randomized, double-blind, placebo-controlled, multi-center Phase III study to compare what appears to be the most promising duloxetine dose to placebo. To maximize the use of patient resources, the Phase II data from patients who either completed treatment with placebo (n = 54) or the most promising duloxetine dose (n = 54) will be pooled with data obtained from new Phase III trial accruals to the placebo (n = 70) and most promising duloxetine dose arms (n = 70), respectively (N = 248). We will use pre-established stopping rules to determine the optimal dose based on the proportions of patients who do not develop N, T, and pain, and adverse event severity. The two primary hypotheses in the Phase III study are that the most promising duloxetine dose will be more effective than placebo to prevent 1) N, T, & pain during oxaliplatin treatment and 2) chronic neuropathic pain one month after treatment. The temporal patterns of OIPN and functional impairment will be assessed for 18 months after oxaliplatin treatment. This study addresses the NCI Cancer Moonshot goal to minimize cancer treatment-associated debilitating side effects, and the priority recommendation outlined in the Institute of Medicine's Relieving Pain in America report regarding the need for non-opioid treatments for chronic pain. By addressing these priorities, we expect to make a major advancement in the field of symptom prevention, including pain, by identifying a well-tolerated, widely available, non-opioid, preventive intervention for a distressing and debilitating chemotherapy side effect experienced by millions of cancer survivors, for which no good treatment exists.

2017年在美国，135,000名被诊断患有结直肠癌的人中大部分接受了奥沙利铂治疗 用于治疗 II-IV 期疾病，约 70% 的患者会出现奥沙利铂引起的周围神经病变 (OIPN)。 其特点是上肢和下肢麻木 (N) 和刺痛 (T)，可持续数年。 30% 的 OIPN（N、T 和疼痛）患者在 N 和 T 后出现疼痛 OIPN，构成重大健康风险。 因为它与功能受损、跌倒、抑郁、睡眠受损、生活质量差有关，并且是一种 我们科学知识中的一个关键差距是没有已知的化疗剂量减少的常见原因。 为了弥补这一差距，我们的总体目标是测试度洛西汀是否存在。 使用连续的 II 期至 III 期设计来预防奥沙利铂引起的 N、T 和疼痛，该设计将 通过美国国家癌症研究所 (NCI) 社区肿瘤​​学研究计划 (NCORP) 进行，该计划是一项大型、 本研究将测试可接触不同患者群体的多地点研究网络。 基于两项临床试验的其对已建立的 OIPN 的功效证据（Yang 等人，2012 年；Smith 等人， 2013），我们的临床前数据表明度洛西汀可以预防大鼠的疼痛性 OIPN。 随机、三组、双盲、安慰剂对照、非比较、多中心研究 (N = 171) 进行筛选 每日两次服用度洛西汀（30 毫克和 60 毫克）以预防 OIPN（N、T 和疼痛）。 在 II 期研究中处于临床活跃状态，我们将进行一项随机、双盲、安慰剂对照、 多中心 III 期研究比较了最有希望的度洛西汀剂量与安慰剂。 最大限度地利用患者资源，完成治疗的患者的 II 期数据 安慰剂 (n = 54) 或最有希望的度洛西汀剂量 (n = 54) 将与从新获得的数据进行汇总 III 期试验分别针对安慰剂 (n = 70) 和最有希望的度洛西汀剂量组 (n = 70) (N = 248)。我们将使用预先制定的停止规则来根据比例确定最佳剂量。 未出现 N、T 和疼痛的患者的比例以及不良事件的严重程度是两个主要假设。 III 期研究表明，最有希望的度洛西汀剂量将比安慰剂更有效地预防 1) N、 T，奥沙利铂治疗期间的疼痛和 2) 治疗后 1 个月的慢性神经性疼痛。 奥沙利铂治疗后 18 个月内将评估 OIPN 和功能障碍的模式。 研究解决了 NCI 癌症登月计划的目标，即尽量减少癌症治疗相关的衰弱副作用 效果以及美国医学研究所缓解疼痛报告中概述的优先建议 关于慢性疼痛的非阿片类药物治疗的需要，我们期望通过解决这些优先事项。 通过确定耐受性良好的药物，在包括疼痛在内的症状预防领域取得重大进展 广泛使用的非阿片类药物预防性干预措施，用于治疗令人痛苦和衰弱的化疗副作用 数以百万计的癌症幸存者都经历过这种情况，但目前尚无良好的治疗方法。