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，附表二阿片类药物可待因、奥施康定和芬太尼的使用量下降 这三种药物均显著下降约14.0%。与此形成鲜明对比的是，使用曲马多，附表四 对照品增加32.5%。附表四物质滥用和危害的可能性较低 相对于附表二物质，曲马多的偶然趋势减少了相对 不安全的附表二阿片类药物。曲马多是一种弱阿片类药物辅助组合， 具有比附表II阿片类药物更好的安全性特征和更少的滥用可能性（例如，羟考酮、他喷他多）。 不幸的是，曲马多有一个严重的缺点。曲马多需要代谢活化才能发挥功效， 而CYP 2D 6弱代谢者（PM）不能获得疼痛缓解。“真实的世界”发生率 临床实践中CYP 2D 6 PM状态的比例已被证明高达三分之一。曲马多抵抗，由于 CYP 2D 6 PM状态是一个缺点，会对患者护理产生显著的负面影响， 削弱了曲马多作为附表II阿片类药物更安全替代品的全部效用。存在着重大的需求 一种“改良的曲马多”，具有相同的固有安全性，但对所有患者都有效， 他们的代谢状态。Omnitram是一种新型的混合机制镇痛药，由Syndrome开发， 阿片类辅助镇痛组合物，其由O-去甲基曲马多的对映体、活性 曲马多的代谢产物。Omnitram提供与曲马多相同的净药理学，但与曲马多相反， 曲马多的活性不需要通过CYP 2D 6代谢。Omnitram广泛地增加了 曲马多，并将利用和加速处方趋势的转变，从相对不安全的 附表二阿片类药物。一项在40名受试者中进行的1b期随机、双盲、安慰剂对照、双交叉试验 健康受试者，比较20 mg的安全性、口服稳态药代动力学和镇痛活性 最近完成了Omnitram和50 mg曲马多。1b期试验成功证明，20 50 mg的Omnitram与50 mg的曲马多具有生物等效性，并且Omnitram产生显著的镇痛作用 与安慰剂相比，与曲马多一样有效。最近与FDA的一次会议提供了明确的指导 NDA批准，这需要Omnitram剂量比例的临床证据，以及评估 口服给药后食物摄入对全身Omnitram血浆水平的影响。在这个SBIR快速通道中， 将按照FDA的要求评价Omnitram的剂量比例性和食物效应。这个SBIR快速- 跟踪提案将进行一项I期随机单次口服给药、四阶段交叉研究， 在正常人受试者中，Omnitram剂量比例（10 mg、20 mg和30 mg）和食物效应（30 mg）。 这项住院患者1期临床试验的成功将为Omnitram的持续临床研究提供直接支持。 开发为一种新型的混合机制镇痛药。