A phase 1/2 trial to evaluate the pharmacokinetics, safety, and efficacy of NI-03 in patients with chronic pancreatitis: study protocol for a randomized controlled trial on the assessment of camostat treatment in chronic pancreatitis (TACTIC)
A phase 1/2 trial to evaluate the pharmacokinetics, safety, and efficacy of NI-03 in patients with chronic pancreatitis: study protocol for a randomized controlled trial on the assessment of camostat treatment in chronic pancreatitis (TACTIC)
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DOI：
10.1186/s13063-019-3606-y
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发表时间：
2019-08-14
期刊：
影响因子：
2.5
通讯作者：
Hart, Phil A.
中科院分区：
文献类型：
--
作者：
Ramsey, Mitchell L.;Nuttall, Janet;Hart, Phil A.
慢性胰腺炎（CP）是一种进行性的纤维炎性疾病，其特征是酶的自激活和随后的腺泡细胞纤维化替代。很大一部分患者出现疼痛，这可能是由于许多原因，包括神经周围炎症、疼痛信号的中枢处理改变、实质结构变化和导管阻塞。目前尚无获批的CP相关疼痛的药物治疗方案。NI-03（甲磺酸卡莫司他）是一种口服丝氨酸蛋白酶抑制剂，可降低胰腺酶活性，在日本已广泛用于治疗CP相关疼痛。目前的研究将评估NI-03在美国减少CP相关疼痛的安全性和有效性。方法本研究分为两个阶段。首先，将进行I期研究，以确定单次给药（100、200或300 mg）后1周内的药代动力学和安全性特征。随后，将进行一项II期研究，包括一项双盲、随机、对照试验（RCT）。该随机对照试验将评估在28天内每日三次给予的三种剂量的NI-03中的每一种与安慰剂相比的功效。在双盲期之前将进行为期7天的单盲导入期，以评估基线疼痛特征。主要疗效结局是研究期终末7天内与基线相比的每日最差疼痛评分（数字评定量表为0-10）的平均值。次要疗效结局包括阿片类药物剂量和生活质量指标的变化，以及至首次静脉镇痛补救的时间。将记录不良事件。讨论NI-03已在日本成功且安全地用于治疗CP相关疼痛。本研究的目的是在美国人群中使用严格的RCT评估NI-03的安全性和有效性。这项研究可能填补一个重要的临床空白，为CP相关疼痛提供一种有效的药物治疗选择。
Background Chronic pancreatitis (CP) is a progressive, fibro-inflammatory disease characterized by enzymatic autoactivation and subsequent fibrotic replacement of acinar cells. A significant proportion of patients develop pain, which may be due to many causes, including perineural inflammation, altered central processing of pain signals, parenchymal structural changes, and ductal obstruction. Currently there are no approved medical treatment options for CP-associated pain. NI-03 (camostat mesilate) is an orally administered serine protease inhibitor that reduces pancreatic enzyme activity and has been widely used for the treatment of CP-associated pain in Japan. The current study will assess the safety and efficacy of NI-03 for reduction of CP-associated pain in the USA. Methods The current study consists of two phases. First, a phase I study will be performed to establish the pharmacokinetics and safety profile over a 1-week period following a single dose (100, 200, or 300 mg). Subsequently, a phase II study will be performed consisting of a double-blind, randomized, controlled trial (RCT). This RCT will evaluate the efficacy of each of the three doses of NI-03 given three times daily compared to placebo over 28 days. A 7-day, single-blind, run-in period will precede the double-blind phase to assess baseline pain characteristics. The primary efficacy outcome is the average of worst daily pain scores (numeric rating scale of 0-10) over the terminal 7 days of the study period compared to baseline. Secondary efficacy outcomes include change in opioid dose and quality of life measures, and time to first rescue intravenous analgesic. Adverse events will be recorded. Discussion NI-03 has been used successfully and safely in Japan to treat CP-associated pain. The aim of the current study is to assess the safety and efficacy of NI-03 using a rigorous RCT in a population in the USA. This study may fill an important clinical gap to provide an effective medical treatment option for CP-associated pain.