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

2017年在美国，135，000名被诊断患有结直肠癌的人中的大多数接受了奥沙利铂 来治疗II-IV期疾病约70%的患者发生奥沙利铂诱导的周围神经病变（OIPN） 其特征在于上下肢麻木（N）和刺痛（T），其可持续数年。 30%的患者在N和T后出现疼痛性OIPN。OIPN（N，T和疼痛）构成主要健康风险 因为它与功能受损、福尔斯、抑郁、睡眠障碍、生活质量差有关， 化疗剂量减少的常见原因。我们科学知识中的一个关键空白是， 存在OIPN的预防干预措施。为了解决这一差距，我们的总体目标是测试度洛西汀是否 预防奥沙利铂诱导的N、T和疼痛，采用II期至III期设计， 通过国家癌症研究所（NCI）社区肿瘤学研究计划（NCORP）进行，这是一个大型， 多站点研究网络，可访问不同的患者人群。本研究将对度洛沙汀进行检测 基于来自两项临床试验的其对已建立的OIPN的功效的证据（Yang等人，2012; Smith等人， 2013），我们的临床前数据显示度洛西汀可预防大鼠疼痛性OIPN。我们将首先进行一次 筛选的随机化、3组、双盲、安慰剂对照、非比较、多中心研究（N = 171） 每日两次剂量的度洛沙汀-30 mg和60 mg-预防OIPN（N、T和疼痛）。如果显示度洛沙汀 在II期研究中具有临床活性，我们将进行一项随机、双盲、安慰剂对照， 多中心III期研究，以比较似乎是最有希望的度洛沙汀剂量与安慰剂。到 最大限度地利用患者资源，II期数据来自完成治疗的患者， 安慰剂（n = 54）或最有希望的度洛沙汀剂量（n = 54）将与从新的 III期试验分别累积至安慰剂组（n = 70）和最有希望的度洛塞汀剂量组（n = 70） （N = 248）。我们将使用预先建立的停止规则来确定基于比例的最佳剂量 未发生N、T和疼痛的患者的比例以及不良事件严重程度。两个主要的假设 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， 2）奥沙利铂治疗期间的疼痛和2）治疗后一个月的慢性神经性疼痛。时间 在奥沙利铂治疗后18个月内评估OIPN和功能损害的模式。这 一项研究提出了NCI癌症登月计划的目标，即最大限度地减少癌症治疗相关的衰弱性副作用 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求。通过处理这些优先事项，我们希望 在症状预防领域取得重大进展，包括疼痛，通过确定一种耐受性良好， 广泛使用的非阿片类药物预防性干预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所经历的，没有很好的治疗方法。

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.