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。奥美尼兰是Syntrix公司开发的一种新型混合机制止痛药，是一种 由O-去甲基曲马多的对映体组成的阿片-辅助止痛药组合物，活性 曲马多的代谢物。奥美尼兰提供与曲马多相同的净药理作用，但与 曲马多，其活性不需要通过CYP2D6代谢。Omnitram广泛地增加了 曲马多，并将利用并加速处方趋势的转变，远离相对不安全的 附表二阿片类药物。一项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健康受试者 奥美尼兰和50毫克曲马多最近完成了。1b阶段试验成功地证明了20 奥美尼兰的生物等效性相当于50 mg曲马多，且该奥美尼兰具有显著的止痛作用 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 获得NDA批准，这需要临床证据表明全硝胺的剂量比例，以及评估 口服后食物摄入量对全身性全氮显血浆水平的影响。在这个SBIR快速通道中， 根据FDA的要求，将对奥米尼兰的剂量比例和食品效应进行评估。这款SBIR Fast- Track Proposal将进行一项第一阶段随机单剂量、四期交叉研究 奥美尼兰在正常人中的剂量比例(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的继续临床提供直接支持 作为一种新的混合机制止痛药的开发。

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. 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.