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

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 在临床实践中，CYP 2D 6 PM状态的比例高达1/3。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。地美曲马多是一种新型混合机制镇痛药，由Syndrome开发， 由曲马多活性代谢物的对映体组成的阿片样物质-辅助镇痛剂组合。 地美曲马多提供与曲马多相同的净药理学，但与曲马多相反， 需要通过CYP 2D 6代谢才能发挥其活性。地美曲马多广泛增加曲马多的效用， 将利用并加速处方趋势从相对不安全的附表II的转变 阿片类药物一项在40名健康受试者中进行的1b期随机、双盲、安慰剂对照、双交叉试验 比较20 mg的安全性、口服稳态药代动力学和镇痛活性的受试者 最近完成了去甲曲马多和50 mg曲马多。1b期试验成功证明了 20 mg地美曲马多与50 mg曲马多生物等效， 与安慰剂相比，镇痛与曲马多一样有效。最近与FDA的一次会议提供了明确的 NDA批准指南，需要地美曲马多剂量比例性的临床证据，以及 口服给药后食物摄入对全身去甲曲马多血浆水平的评价。在这 SBIR快速通道、地美曲马多剂量比例性和食物效应将按照 FDA.该SBIR快速通道提案将进行1期随机单次口服给药，4个阶段交叉给药， 研究地美曲马多剂量比例（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以下方面提供直接支持 地美曲马多作为一种新型混合机制镇痛药的持续临床开发。

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. Desmetramadol is a novel mixed-mechanism analgesic developed by Syntrix that is an opioid-adjunct analgesic combination consisting of the enantiomers of the active metabolite of tramadol. Desmetramadol provides the same net pharmacology as tramadol, but in contrast to tramadol, does not require metabolism by CYP2D6 for its activity. Desmetramadol 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 desmetramadol and 50 mg tramadol was recently completed. The Phase 1b trial successfully demonstrated that 20 mg desmetramadol was bioequivalent to 50 mg tramadol, and that desmetramadol 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 desmetramadol dose-proportionality, and the evaluation of food intake on systemic desmetramadol plasma levels following oral administration. In this SBIR Fast-Track, desmetramadol 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 desmetramadol 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 desmetramadol's continued clinical development as a novel mixed-mechanism analgesic.