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：慢性腹痛是慢性的标志 胰腺炎（CP），有50-80％的患者寻求医疗护理以控制疼痛。而几个 管理选项可能可用，结果常常令人失望，阿片类药物 仍然是治疗的中流。阿片类药物诱导的痛觉过敏（OIH）可能发生，这种现象 导致剂量升级，似乎部分归因于阿片类药物对疼痛的影响 相关的电压门控钠通道。 lacosamide块并稳定这些通道 并可能抑制OIH的影响。这可能会导致疼痛控制的改善，并减少 Opioid使用。在神经性疼痛的临床前和临床试验中，lacosamide降低了疼痛评分 并且耐受性良好。但是，没有数据评估lacosamide在CP中的使用 患者。目的：1。评估添加的安全性，耐受性和限制性毒性 可疑和定义的疼痛CP受试者中的lacosamide至阿片类药物治疗； 2。评估 试验研究的可行性在这些受试者中增加了阿片类药物疗法的可行性。 作为探索目的，我们将评估将Lacosamide添加到阿片类药物治疗中的效率 治疗CP引起的腹痛。方法：这是使用贝叶斯的1阶段试验 最佳间隔（BOIN）设计以找到最大耐受剂量（MTD）。目标剂量 - MTD的限制毒性（DLT）率为ɸ= 0.3，最大样本量为24。 样本量较小，预期的相对短研究期以及患者招募的潜力 几个临床中心，预计所有数据将在研究的36个月内征收 引发。意义：这项研究将产生有关安全性，毒性和 LACOSAMIDE在CP患者中的剂量限制毒性。预计Lacosamide会证明 安全且耐受性良好。然后，这项试验研究的结果将支持一个阶段的程序 2评估添加到阿片类药物治疗中的lacosamide效率以减轻腹痛的试验 来自CP。