A Phase 1 Randomized Single Oral Dose Four Period Cross-Over Study Investigating Omnitram Dose Proportionality and Food Effect in Normal Human Subjects

一项 1 期随机单次口服剂量四期交叉研究，调查 Omnitram 剂量比例和食物对正常人类受试者的影响

• 批准号: 10029002
• 负责人: STUART J KAHN
• 金额: $ 120.48万
• 依托单位: SYNTRIX BIOSYSTEMS, INC.
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-06-01 至 2022-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10029002
• 关键词: Absence of pain sensation; Adopted; Adverse effects; Analgesics; Antidepressive Agents; CYP2D6 gene; Cause of Death; Centers for Disease Control and Prevention (U.S.); Cessation of life; Child; Clinic; Clinical; Cocaine; Codeine; Collaborations; Cross-Over Studies; Cross-Over Trials; Dose; Double-Blind Method; Drug Kinetics; Eating; Enrollment; Evaluation; FDA approved; Fentanyl; Food; Genetic; Grant; Guidelines; Health; Heroin; Hydrocodone; Incidence; Individual; Metabolic; Metabolic Activation; Metabolism; Methods; Morphine; National Institute of Drug Abuse; Norepinephrine; Opiate Addiction; Opioid; Opioid Analgesics; Opioid agonist; Oral; Oral Administration; Overdose; Oxycodone; Pain management; Patient Care; Patients; Persons; Pharmaceutical Preparations; Pharmacology; Phase; Phase I Clinical Trials; Phase Ib Trial; Physicians; Placebos; Plasma; Protocols documentation; Randomized; Reporting; Resistance; Respiratory Failure; Risk; Safety; Schedule; Schedule II opioids; Small Business Innovation Research Grant; Tapentadol; Therapeutic; Tramadol; Validation; Ventilatory Depression; chronic pain; clinical development; clinical practice; cost; dosage; enantiomer; human subject; improved; interest; meetings; milligram; novel; nursing mothers; pain relief; prescription opioid; reuptake; side effect; success; trend

From 2009-2013 the utilization of the Schedule II opioids codeine, OxyContin and fentanyl declined significantly, down about 14.0% for all three drugs. In sharp contrast, the use of tramadol, a Schedule IV controlled substance, increased 32.5%. Schedule IV substances have low potential for abuse and harm relative to Schedule II substances, and the fortuitous trend to tramadol has reduced the use of the relatively unsafe Schedule II opioids dramatically. Tramadol is a weak opioid-adjunct combination that is recognized as having a better safety profile and less abuse potential than Schedule II opioids (e.g., oxycodone, tapentadol). Unfortunately, tramadol suffers from a critical shortcoming. Tramadol requires metabolic activation for efficacy, and individuals who are CYP2D6 poor metabolizers (PMs) fail to obtain pain relief. The “real world” incidence of CYP2D6 PM status in clinical practice has been shown to be as high as 1 in 3. Tramadol resistance due to CYP2D6 PM status is a shortcoming that results in a significant negative impact on patient care, and that erodes the entire utility of tramadol as a safer alternative to Schedule II opioids. There exists a significant need for an “improved tramadol” that would have the same inherent safety but be effective in all patients irrespective of their metabolic status. Omnitram is a novel mixed-mechanism analgesic developed by Syntrix that is an opioid-adjunct analgesic combination consisting of the enantiomers of O-desmethyltramadol, the active metabolite of tramadol. Omnitram provides the same net pharmacology as tramadol, but in contrast to tramadol, does not require metabolism by CYP2D6 for its activity. Omnitram broadly increases the utility of tramadol, and would leverage and accelerate the shift in prescribing trends away from the relatively unsafe Schedule II opioids. A Phase 1b randomized, double-blind, placebo-controlled, double cross-over trial in 40 healthy subjects that compared the safety, oral steady-state pharmacokinetics, and analgesic activity of 20 mg Omnitram and 50 mg tramadol was recently completed. The Phase 1b trial successfully demonstrated that 20 mg Omnitram was bioequivalent to 50 mg tramadol, and that Omnitram produced significant analgesia compared to placebo, being as effective as tramadol. A recent meeting with the FDA provided clear guidance towards NDA approval, which requires clinical evidence of Omnitram dose-proportionality, and the evaluation of food intake on systemic Omnitram plasma levels following oral administration. In this SBIR Fast-Track, Omnitram dose-proportionality and food-effect will be evaluated as mandated by the FDA. This SBIR Fast- Track proposal will conduct a Phase 1 randomized single oral dose, four period cross-over study investigating Omnitram dose-proportionality (10 mg, 20 mg and 30 mg) and food-effect (30 mg) in normal human subjects. Success in this in-patient Phase 1 clinical trial will provide direct support for Omnitram's continued clinical development as a novel mixed-mechanism analgesic.

从2009年至2013年，附表II阿片类可待因，Oxycontin和Fentanyl的利用率下降 值得注意的是，所有三种药物的下降约为14.0％。形成鲜明对比的是，使用曲马多，附表IV 受控物质增加了32.5％。附表IV物质对滥用和伤害的潜力较低 相对于附表II物质以及曲马多的偶然趋势降低了相对的使用 不安全的附表II阿片类药物急剧。曲马多是一种弱阿片类药物的组合，被认为是 比附表II阿片类药物（例如羟考酮，tapentadol）具有更好的安全性和更少的滥用潜力。 不幸的是，曲马多遭受了严重的缺点。曲马多需要代谢激活，以便于 CYP2D6不良代谢物（PMS）的个体无法缓解疼痛。 “现实世界”事件 临床实践中的CYP2D6 PM状态已显示出高达3中的1个。 CYP2D6 PM状态是一个缺点，会对患者护理产生重大负面影响，并且 侵蚀了曲马多的整个效用，作为附表II阿片类药物的更安全替代品。存在很大的需求 对于“改进的曲马多”，它具有相同的固有安全性，但在所有患者中都有效 他们的代谢状况。 Omnitram是一种新型的混合机制镇痛药，由Syntrix开发 阿片类药物的镇痛作用，由O-甲基甲二醇的映异构体组成，活性 曲马多代谢物。 Omnitram提供了与Tramadol相同的净药理学，但与 曲马多不需要CYP2D6代谢其活性。 Omnitram广泛增加了 曲马多（Tramadol），并将利用和加速处方趋势的转变，从相对不安全 附表II阿片类药物。 1B期随机，双盲，安慰剂对照，双重交叉试验40 比较安全性，口服稳态药代动力学和20 mg的镇痛活性的健康受试者 Omnitram和50 mg Tramadol最近完成了。 1B期试验成功证明了20 MG Omnitram与50 mg Tramadol的生物等效性，并且Omnitram产生了明显的镇痛作用 与安慰剂相比，与曲马多一样有效。最近与FDA的会议提供了明确的指导 迈向NDA批准，这需要综合剂量 - 比例的临床证据，并评估 口服治疗后全身综合血浆水平的食物摄入量。在此SBIR快速轨道中， Omnitram剂量折叠性和食品效应将按照FDA的要求进行评估。这个sbir fast- 跟踪提案将进行1期随机单口服剂量，四个时期的跨界研究 在正常人受试者中，综合剂量折叠性（10 mg，20 mg和30 mg）和食物效应（30 mg）。 在此住院1阶段1临床试验中的成功将为Omnitram持续的临床提供直接支持 发展是一种新型的混合机制镇痛药。