Safety, tolerability, and dose limiting toxicity of lacosamide in patients with painful chronic pancreatitis

拉科酰胺治疗疼痛性慢性胰腺炎的安全性、耐受性和剂量限制毒性

• 批准号: 10609935
• 负责人: Evan L Fogel
• 金额: $ 31.72万
• 依托单位: INDIANA UNIV-PURDUE UNIV AT INDIANAPOLIS
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-04-15 至 2025-03-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10609935
• 关键词: Abdominal Pain; Adjuvant; Adverse effects; Amino Acids; Anticonvulsants; Antidepressive Agents; Carbamazepine; Cardiovascular Physiology; Clinical; Clinical Trials; Data; Disease; Dose; Dose Limiting; FDA approved; Hyperalgesia; Knowledge; Maximum Tolerated Dose; Methods; Mission; Moods; National Institute of Diabetes and Digestive and Kidney Diseases; Neurons; Nociception; Opioid; Opioid Analgesics; Opioid Receptor; Outcome; Pain; Pain management; Patient Care; Patient Recruitments; Patients; Performance; Pharmaceutical Preparations; Pharmacologic Actions; Phase; Pilot Projects; Quality of life; Refractory; Respiratory physiology; Safety; Sample Size; Sodium Channel; Stimulus; TLR4 gene; Therapeutic; Toxic effect; allodynia; chronic abdominal pain; chronic pancreatitis; clinical center; design; drug action; efficacy evaluation; experience; gastrointestinal function; improved; medical attention; novel therapeutic intervention; opioid therapy; opioid use; oxcarbazepine; pain reduction; pain relief; pain score; painful neuropathy; persistent symptom; phase 1 study; phase I trial; phase II trial; preclinical trial; response; side effect; voltage

ABSTRACT: Background: Chronic abdominal pain is the hallmark symptom of chronic pancreatitis (CP), with 50-80% of patients seeking medical attention for pain control. While several management options are potentially available, outcomes are often disappointing, and opioids remain a mainstay of therapy. Opioid-induced hyperalgesia (OIH) may occur, a phenomenon resulting in dose escalation, and appears to be due in part to the effect of opioids on pain- associated voltage-gated sodium channels. Lacosamide blocks and stabilizes these channels and may inhibit the effects of OIH. This may result in improved pain control with a decrease in opioid use. In pre-clinical and clinical trials with neuropathic pain, lacosamide reduced pain scores and was well tolerated. There are no data, however, evaluating the use of lacosamide in CP patients. Aims: 1. To evaluate the safety, tolerability and dose-limiting toxicity of adding lacosamide to opioid therapy in subjects with suspected and definite painful CP; 2. To assess the feasibility of performance of a pilot study adding lacosamide to opioid therapy in these subjects. As an exploratory aim, we will assess the efficacy of adding lacosamide to opioid therapy for the treatment of abdominal pain due to CP. Methods: This is a Phase 1 trial, utilizing the Bayesian optimal interval (BOIN) design to find the Maximum Tolerated Dose (MTD). The target dose- limiting toxicity (DLT) rate for the MTD is ɸ = 0.3 and the maximum sample size is 24. Given the small sample size, anticipated relatively short study period and potential for patient recruitment at several clinical centers, it is anticipated that all data will be accrued within 36 months of study initiation. Significance: This study will generate new knowledge regarding the safety, toxicity and dose-limiting toxicity of lacosamide in CP patients. It is anticipated that lacosamide will prove to be safe and well-tolerated. The results of this pilot study will then support proceeding with a phase 2 trial assessing the efficacy of lacosamide added to opioid therapy to alleviate abdominal pain from CP.

摘要：背景：慢性腹痛是慢性腹痛的标志性症状， 胰腺炎（CP），50-80%的患者寻求医疗关注以控制疼痛。虽然若干 管理选择是可能的，结果往往令人失望，阿片类药物 仍然是治疗的支柱。阿片样物质诱导的痛觉过敏（OIH）可能会发生，这是一种现象 导致剂量递增，部分原因似乎是阿片类药物对疼痛的影响- 相关的电压门控钠通道。拉考沙胺阻断并稳定这些通道 并可抑制OIH的作用。这可能导致改善的疼痛控制， 阿片类药物使用在神经性疼痛的临床前和临床试验中，拉考沙胺降低了疼痛评分 并且耐受性良好。然而，没有数据评价拉考沙胺在CP中的使用 患者目的：1.评价加用地塞米松的安全性、耐受性和剂量限制性毒性， 拉考沙胺与阿片类药物治疗疑似和明确疼痛性CP的受试者; 2.评估 在这些受试者中进行在阿片类药物治疗中添加拉考沙胺的初步研究的可行性。 作为一个探索性的目的，我们将评估在阿片类药物治疗中加入拉考沙胺的疗效。 治疗CP引起的腹痛。方法：这是一项1期试验，利用贝叶斯 最佳间隔（BOIN）设计，以找到最大耐受剂量（MTD）。目标剂量- MTD的极限毒性（DLT）率为≤ 0.3，最大样本量为24。鉴于 样本量小，预期研究期相对较短，患者招募的可能性为 几个临床中心，预计所有数据将在研究的36个月内累积 入会仪式意义：这项研究将产生关于安全性、毒性和 拉考沙胺在CP患者中的剂量限制性毒性。预计拉考沙胺将被证明 安全且耐受良好。该试点研究的结果将支持继续进行一个阶段， 2项评估拉考沙胺加用阿片类药物治疗缓解腹痛的疗效的试验 从CP。