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

从2009-2013年，附表二阿片类药物可待因、奥施康定和芬太尼的使用率下降 值得注意的是，这三种药物的价格都下降了约14.0%。与之形成鲜明对比的是，曲马多的使用情况为附表四 控制物质，增长32.5%。附表四物质滥用和危害的可能性很低 相对于附表二的物质，而曲马多的偶然性趋势已经减少了相对 不安全的第二类阿片类药物。曲马多是一种弱阿片类药物-辅助性药物，被认为是 比附表二阿片类药物(如羟考酮、替喷妥钠)具有更好的安全性和更少的滥用可能性。 不幸的是，曲马多有一个严重的缺陷。曲马多需要新陈代谢激活才能有效， 而那些代谢能力较差的人(PM)无法获得止痛效果。“真实世界”事件 在临床实践中，CYP2D6 PM的状态被证明高达1/3。曲马多耐药是由于 CYP2D6 PM状态是一个缺陷，会对患者护理造成重大负面影响，并且 侵蚀了曲马多作为附表二阿片类药物更安全替代品的全部效用。有一种重要的需求 “改良曲马多”具有相同的固有安全性，但对所有患者都有效。 他们的新陈代谢状态。地美拉莫尔是Syntrix公司开发的一种新型混合机制止痛药，即 一种由曲马多活性代谢物的对映体组成的阿片-辅助止痛药组合物。 地美他多与曲马多提供相同的净药理作用，但与曲马多不同 其活性需要通过细胞色素P450-2D6的代谢。Desmetramadol广泛增加了曲马多的效用， 是否会利用并加速改变相对不安全的附表II的趋势 阿片类药物。40例健康受试者的1b期随机、双盲、安慰剂对照、双交叉试验 比较20毫克的安全性、口服稳态药代动力学和止痛活性的受试者 地美他莫和50毫克曲马多最近完成了。1b阶段试验成功展示了 20毫克地美他莫与50毫克曲马多的生物等效性，并且地美他多产生了显著的 止痛与安慰剂相比，与曲马多一样有效。最近与FDA的一次会议明确提供了 NDA批准指南，这需要地美他莫剂量比例的临床证据，以及 口服给药后食物摄入量对系统地美他莫血药浓度的影响。在这 SBIR快速通道、地美他莫剂量比例和食品效应将按照 美国食品和药物管理局。这项SBIR快速通道建议将进行第一阶段随机单剂量口服，四期交叉 调查地美他莫剂量比例(10毫克、20毫克和30毫克)和食物效应(30毫克)的过度研究 Mg)。这项住院一期临床试验的成功将为以下项目提供直接支持 地美他莫作为一种新型混合机制止痛药的临床研究进展。

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.