Phase 1 and 2 studies of sublingual dexmedetomidine, an alpha 2 adrenergic agonist, for treating opioid withdrawal

舌下含服右美托咪定（一种 α2 肾上腺素能激动剂）用于治疗阿片类药物戒断的 1 期和 2 期研究

• 批准号: 10478324
• 负责人: SANDRA D COMER
• 金额: $ 331.22万
• 依托单位: NEW YORK STATE PSYCHIATRIC INSTITUTE DBA RESEARCH FOUNDATION FOR MENTAL HYGIENE, INC
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-08-01 至 2024-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10478324
• 关键词: Adrenergic Agonists; Adverse effects; Affinity; Agitation; Anxiety; Binding; Biological Assay; Blood Pressure; Bradycardia; Buprenorphine; Bypass; Clinical; Data; Development; Dexmedetomidine; Dose; Double-Blind Method; Dropout; Drops; Drug Metabolic Detoxication; Effectiveness; Exhibits; Fentanyl; Film; Future; Heart Rate; Human; Hypertension; Hypotension; Inpatients; Liver; Measures; Metabolism; Monitor; Naltrexone; Opiate Addiction; Opioid; Opioid agonist; Outpatients; Participant; Patient Self-Report; Patients; Pharmaceutical Preparations; Phase; Phase II/III Trial; Physical Dependence; Placebo Control; Placebos; Play; Public Health; Randomized; Receptors, Adrenergic, alpha-2; Respiration; Role; Safety; Sedation procedure; Serious Adverse Event; Signs and Symptoms; Site; Sleep; Sleep disturbances; Suboxone; Substance Withdrawal Syndrome; Symptoms; Testing; Time; United States Food and Drug Administration; United States National Institutes of Health; Withdrawal; Withdrawal Symptom; abuse liability; associated symptom; clinically significant; compare effectiveness; craving; design; efficacy study; heroin use; illicit drug use; improved; innovation; lofexidine; non-opioid analgesic; opioid epidemic; opioid overdose; opioid tapering; opioid use; opioid use disorder; opioid withdrawal; overdose death; phase III trial; placebo controlled study; primary endpoint; response; safety testing; secondary endpoint; side effect; success; synthetic opioid

Project Summary The current epidemic of Opioid Use Disorder (OUD) is a severe public health crisis in the US, and in response, the National Institutes of Health (NIH) is supporting development of innovative medications for treating OUD. The withdrawal symptoms associated with cessation of opioid use are serious obstacles to initiating opioid blockers (naltrexone) and may pose difficulties in transitioning patients to other medications for treating opioid use disorder (MOUD), such as buprenorphine. The FDA approval of the alpha-2-adrenergic agonist lofexidine has made a significant contribution to ameliorating OUD withdrawal, but only 40% of subjects became opioid free in a pivotal study. This study was conducted prior to the widespread availability of the potent synthetic opioid fentanyl, so the effectiveness of lofexidine in treating opioid withdrawal in fentanyl-dependent patients is unclear. BioXcel has developed another alpha-2-adrenergic agonist dexmedetomidine as a sublingual (SL) film (BXCL501). BXCL501 is potentially superior to alternatives such as opioid tapering because it is a non-opioid with minimal abuse potential, and at doses that reduce opioid withdrawal symptoms, it has minimal adverse effects on respiration, hypotension, hypertension, bradycardia, and sedation. Furthermore, it avoids potential liver complications due to bypassing first-pass metabolism. Data collected during a recently completed multiple ascending dose safety and preliminary efficacy study showed that the highest dose of BXCL501 tested reduced anxiety and improved sleep disturbances, which are symptoms that are typically not well treated with lofexidine. In the proposed studies, BXCL501 will be tested for its ability to decrease the signs and symptoms of opioid withdrawal across multiple sites through two Specific Aims: 1 (UG3). A Phase 1b randomized, double- blind, placebo-controlled safety, optimal dose finding, and preliminary efficacy inpatient study (n=160), and 2 (UH3). A Phase 2b randomized, double-blind, placebo-controlled outpatient study comparing the safety and efficacy of BXCL501 to placebo and lofexidine (n=300). Two Go/No-Go criteria for moving from the UG3 to the UH3 phases are: 1) BXCL501 is shown to reduce withdrawal symptoms (total SOWS score) more than 30% compared to the SOWS score of subjects receiving placebo. 2) No more than one serious adverse event attributed to BXCL501 among the subjects receiving active BXCL at the minimum dose identified to exhibit at least a 30% reduction in withdrawal symptoms. Our positive clinical findings with BXCL501 and strong investigative team promise high success for bringing this new treatment to market.

项目摘要 当前的阿片类药物使用障碍（OUD）流行是美国的严重公共卫生危机，并且作为回应， 美国国立卫生研究院（NIH）正在支持开发用于治疗OUD的创新药物。 与停止阿片类药物使用有关的戒断症状是引发阿片类药物的严重障碍 阻滞剂（纳曲酮），可能在转变为治疗阿片类药物的其他药物方面遇到困难 使用障碍（MOUD），例如丁丙诺啡。 FDA批准了α-2-肾上腺素能激动剂洛芬定丁 已经为改善OUD撤离做出了重大贡献，但只有40％的受试者成为阿片类药物 在关键研究中免费。这项研究是在有效合成的广泛可用性之前进行的 阿片类药物芬太尼，因此洛芬氨基氨酸在芬太尼依赖性患者中治疗阿片类药物戒断的有效性是 不清楚。 Bioxcel开发了另一种α-2-肾上腺素能激动剂右美托胺作为舌下膜（SL）膜 （BXCL501）。 BXCL501可能优于阿片类药物等替代品，因为它是一种非阿片类药物 由于滥用的潜力最小，并且减少阿片类药物戒断症状的剂量，它的不利影响最小 关于呼吸，低血压，高血压，心动过缓和镇静。此外，它避免了潜在的肝脏 由于绕过第一频繁代谢而引起的并发症。在最近完成的多个过程中收集的数据 上升剂量安全性和初步疗效研究表明，测试的最高剂量的BXCL501 减轻焦虑和改善的睡眠障碍，这通常是症状 Lofexidine。在拟议的研究中，BXCL501的降低体征和症状的能力将进行测试 通过两个特定目的在多个地点撤回阿片类药物：1（ug3）。 1B阶段随机，双重 盲，安慰剂控制的安全性，最佳剂量发现和初步疗效住院研究（n = 160），2 （UH3）。 2B期随机，双盲，安慰剂对照的门诊研究，比较安全性和 BXCL501对安慰剂和Lofexidine的功效（n = 300）。两个GO/No-Go从UG3转移到的标准 UH3阶段是：1）显示BXCL501可减少戒断症状（总母猪得分）超过30％ 与接受安慰剂的受试者的母猪分数相比。 2）不超过一个严重的不利事件 在接受活性BXCL的受试者中归因于BXCL501的最小剂量。 戒断症状至少减少了30％。我们对BXCL501和强大的积极临床发现 调查团队承诺将这种新待遇推向市场的成功很高。