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，13.5万名被诊断为结直肠癌的患者中，大多数人接受了奥沙利铂治疗 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) 这是以上肢和下肢麻木(N)和刺痛(T)为特征的，可持续多年。 在30%的患者中，疼痛的OIPN发生在N和T之后。OIPN(N、T和疼痛)构成主要的健康风险 因为它与功能受损、跌倒、抑郁、睡眠受损、生活质量差有关，是一种 减少化疗剂量的常见原因。我们科学知识中的一个关键差距是没有人知道 存在对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 预防奥沙利铂引起的N、T和疼痛，采用序贯II期到III期设计，将 由国家癌症研究所(NCI)社区肿瘤学研究计划(NCORP)进行，该计划是一个大型、 多站点研究网络，可接触到不同的患者群体。度洛西汀将在这项研究中进行测试 基于来自两个临床试验(Yang等人，2012；Smith等人， 2013)，我们的临床前数据显示度洛西汀可以预防大鼠疼痛的OIPN。我们将首先进行一次 随机、三臂、双盲、安慰剂对照、非对照、多中心研究(N=171)以进行筛查 每天服用两剂度洛西汀-30毫克和60毫克-以预防OIPN(N、T和疼痛)。如果度洛西汀被显示为 在第二阶段的临床研究中，我们将继续进行随机、双盲、安慰剂对照、 多中心第三阶段研究，比较最有希望的度洛西汀剂量与安慰剂。至 最大限度地利用患者资源，来自完成治疗的患者的II期数据 安慰剂(n=54)或最有希望的度洛西汀剂量(n=54)将与新的 第三阶段试验分别增加到安慰剂(n=70)和最有希望的度洛西汀剂量组(n=70) 248例。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 没有发生N、T和疼痛的患者，以及不良事件的严重性。该模型中的两个主要假设 第三阶段的研究是，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)治疗后1个月出现慢性神经病理性疼痛。世俗的 奥沙利铂治疗18个月后将评估OIPN的类型和功能损害。这 研究解决了NCI癌症登月的目标，将癌症治疗相关的衰弱副作用降至最低 效果，以及医学研究所在美国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必要性。通过处理这些优先事项，我们预计将 在包括疼痛在内的症状预防领域取得重大进展，确定一种耐受性良好的、 广泛使用的、非阿片类药物的预防性干预，用于治疗令人痛苦和虚弱的化疗副作用 数以百万计的癌症幸存者经历过这种情况，目前还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.