Development of Lofexidine as a First-line Non-Opioid Pharmacologic Treatment for Neonatal Opioid Withdrawal Syndrome

开发洛非西定作为新生儿阿片类药物戒断综合征的一线非阿片类药物治疗

基本信息

批准号：
10320676
负责人：
Kristen Leann Gullo
金额：
$ 535.33万
依托单位：
USWM, LLC
依托单位国家：
美国
项目类别：
财政年份：
2021
资助国家：
美国
起止时间：
2021-09-30 至 2024-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10320676
关键词：
Adrenergic Agonists Adult Adverse event Affect American Benefits and Risks Biological Availability Birth Blood specimen Brain Caring Chemistry Child Childhood Clinical Clinical Research Clinical Trials Clinical Trials Data Monitoring Committees Collaborations Cytoplasmic Granules Data Databases Development Distress Dose Double-Blind Method Drug Kinetics Electrocardiogram Enrollment Epidemic Evaluation Exposure to Formulation Funding GMP lots General Population Goals Health Care Costs Healthcare Systems Hospitalization Hospitals Incidence Infant Inpatients Investigation Label Length Length of Stay Measures Monitor Morphine Narcotics National Institute of Drug Abuse Neonatal Neonatal Abstinence Syndrome Opioid Oral Orphan Patients Pharmaceutical Preparations Pharmacological Treatment Pharmacology Pharmacotherapy Phase Phase III Clinical Trials Population Pregnant Women Process Production Program Development Publishing Randomized Recommendation Regimen Reporting Research Research Design Risk Safety Sample Size Severities Signs and Symptoms Site Symptoms System Tablets Technology Transfer Treatment Protocols United States Food and Drug Administration Ventilatory Depression Weight Withdrawal Symptom Work base care costs clinical development cohort cost design effectiveness measure efficacy evaluation efficacy study efficacy trial improved in utero inpatient service lofexidine neonate neurodevelopment non-opioid analgesic novel therapeutics off-label use open label opioid abuse opioid epidemic opioid therapy opioid use opioid use disorder opioid withdrawal pharmacokinetic model placebo controlled study programs public health emergency research clinical testing response safety assessment safety study scale up standard of care treatment risk volunteer

Adrenergic Agonists Adult Adverse event Affect American Benefits and Risks Biological Availability Birth Blood specimen Brain Caring Chemistry Child Childhood Clinical Clinical Research Clinical Trials Clinical Trials Data Monitoring Committees Collaborations Cytoplasmic Granules Data Databases Development Distress Dose Double-Blind Method Drug Kinetics Electrocardiogram Enrollment Epidemic Evaluation Exposure to Formulation Funding GMP lots General Population Goals Health Care Costs Healthcare Systems Hospitalization Hospitals Incidence Infant Inpatients Investigation Label Length Length of Stay Measures Monitor Morphine Narcotics National Institute of Drug Abuse Neonatal Neonatal Abstinence Syndrome Opioid Oral Orphan Patients Pharmaceutical Preparations Pharmacological Treatment Pharmacology Pharmacotherapy Phase Phase III Clinical Trials Population Pregnant Women Process Production Program Development Publishing Randomized Recommendation Regimen Reporting Research Research Design Risk Safety Sample Size Severities Signs and Symptoms Site Symptoms System Tablets Technology Transfer Treatment Protocols United States Food and Drug Administration Ventilatory Depression Weight Withdrawal Symptom Work base care costs clinical development cohort cost design effectiveness measure efficacy evaluation efficacy study efficacy trial improved in utero inpatient service lofexidine neonate neurodevelopment non-opioid analgesic novel therapeutics off-label use open label opioid abuse opioid epidemic opioid therapy opioid use opioid use disorder opioid withdrawal pharmacokinetic model placebo controlled study programs public health emergency research clinical testing response safety assessment safety study scale up standard of care treatment risk volunteer

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项目摘要

PROJECT SUMMARY: An alarming increase in the rate of opioid abuse among the general population has resulted in a public health emergency since 2017. The striking rise in opioid use disorder has affected Americans broadly, including pregnant women with a resulting increase in infants born suffering from opioid withdrawal or Neonatal Opioid Withdrawal Syndrome (NOWS). The NOWS epidemic has led to significant increases in healthcare costs and burden on the healthcare system due to increased length of hospital stay and level of required care. In 2016, a normal infant averaged 3 days of hospital care post-birth costing $15,000, whereas an infant born with NOWS averaged 16.4 days of inpatient care costing $70,000. Currently, there are no FDA-approved medications available for treatment of NOWS. Current approaches to pharmacotherapy rely on the off-label use of opioids and other agents. Opioid therapy contributes to the extended hospitalization of NOWS infants as continuous monitoring for safety observations is necessary due to the risk of respiratory depression. Through a successful collaboration with NIDA, USWM developed lofexidine for the mitigation of opioid withdrawal symptoms in adults. The Food and Drug Administration (FDA) approved lofexidine tablets (LUCEMYRA®) for this indication in May 2018. Due to the anticipated utility of lofexidine for the treatment of opioid withdrawal in children, USWM has initiated a development program evaluating lofexidine for neonate patient use. Initial requirements to begin clinical trials of lofexidine for NOWS have been agreed upon with the FDA and include nonclinical safety studies, development of a pediatric-specific formulation, and an evaluation of the pharmacokinetics (PK) of the pediatric formulation in healthy adults. Through a strategic alliance with NIDA, USWM has completed or is on track to complete all prerequisites to initiate clinical testing in NOWS prior to the anticipated start of funding for the current application. USWM now proposes to extend the co-development program through investigation of the safety and efficacy of the new pediatric formulation of lofexidine in NOWS. The goal of this project is to develop lofexidine as a first-line medication for the treatment of NOWS. Use of a well-characterized, safe and effective neonatal formulation of a non-opioid therapy is expected to result in fewer patients requiring opioids and/or reduce opioid dose/duration, permitting safer treatment with shorter hospital stays. The scope of the proposed research includes chemistry, manufacturing and control (CMC) activities and the clinical development program required to support registration of the pediatric formulation for mitigation of withdrawal symptoms in patients with NOWS. Key milestones of the program include: i) a technology transfer and manufacturing activities to support late phase clinical trial material (CTM) production (UG3 Aim 1), ii) a first- in-neonate PK and dose-response study in NOWS to support dose selection and pivotal study design decisions (UG3 Aims 2 & 3), iii) manufacture of Phase 3 CTM and completion of the CMC registration package (UH3 Aim 1), and iv) a pivotal study to establish safety and efficacy of lofexidine for use in NOWS (UH3 Aims 2 & 3).

项目摘要：普通民众中阿片类药物滥用率的令人震惊的增加导致了公共卫生自2017年以来的出现。阿片类药物使用障碍的惊人崛起影响了美国人，包括孕妇因阿片类药物戒断或新生儿阿片类药物而导致的婴儿增加戒断综合征（现在）。现在的流行病已导致医疗成本显着上升和由于住院时间增加和所需护理水平，医疗保健系统负担负担。 2016年，正常婴儿平均三天出生后的医院护理费用为$ 15,000，而生于现在的婴儿平均16.4天的住院护理费用为70,000美元。目前，没有FDA批准的药物可用于现在的治疗。当前药物治疗的方法取决于标签的卵子的使用和其他代理商。阿片类药物疗法有助于延长现在的婴儿的住院治疗由于呼吸抑郁症的风险，需要监测安全观察结果。通过与NIDA的成功合作，USWM开发了Lofexidine用于缓解阿片类药物的戒断成人的症状。食品药品监督管理局（FDA）批准了洛芬己定片（Lucemyra®）该指示在2018年5月。由于洛芬二胺预期用于治疗阿片类药物的效用儿童，USWM启动了一项开发计划，评估了洛芬己定以用于新生儿患者的使用。最初的现在已经与FDA商定了现在开始对洛夫己二氨酸进行临床试验的要求非临床安全研究，小儿特异性公式的开发以及评估健康成年人的儿科配方的药代动力学（PK）。通过与NIDA的战略联盟， USWM已完成或有望完成所有先决条件，以在Nows中启动临床测试预计当前申请的资金开始。 USWM现在提议扩展共同开发通过投资NOW的新小儿配方的安全和效率的投资。该项目的目的是开发洛芬己定作为现代治疗的一线药物。使用预计非阿片类药物治疗的特征良好，安全有效的新生儿公式将导致更少需要阿片类药物和/或减少阿片类药物剂量/持续时间的患者，可以通过较短的医院进行安全治疗留下来。拟议研究的范围包括化学，制造和控制（CMC）活动以及支持小儿配方的注册所需的临床发展计划以减轻现在患者的戒断症状。该计划的关键里程碑包括：i）技术转移和制造活动以支持后期临床试验材料（CTM）生产（UG3 AIM 1），ii） NOWS中的静脉内PK和剂量反应研究支持剂量选择和关键研究设计决策（UG3目标2和3），iii）制造3阶段CTM并完成CMC注册软件包（UH3 AIM 1）和iv）一项关键研究，以建立洛芬己定的安全性和效率以供诺（UH3 AIMS 2＆3）。