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.

2009-2013年，附表2阿片类药物可待因、奥施康定和芬太尼的使用率下降