A Comparison of Buprenorphine Versus Morphine in the Treatment of the Neonatal Ab

丁丙诺啡与吗啡治疗新生儿抗体的比较

• 批准号: 8634086
• 负责人: WALTER K KRAFT
• 金额: $ 47.17万
• 依托单位: THOMAS JEFFERSON UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-06-01 至 2016-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8634086
• 关键词: Adult; Affect; Analytical Chemistry; Automobile Driving; Benefits and Risks; Biology; Biometry; Birth; Blinded; Buprenorphine; Characteristics; Child; Clinical; Clinical Trials; Clinical Trials Cooperative Group; Complex; Consensus; Controlled Clinical Trials; Critical Illness; Data; Diarrhea; Discrimination; Disease; Dose; Double-Blind Method; Drug Kinetics; Exploratory/Developmental Grant for Diagnostic Cancer Imaging; Family; Funding; Genetic Polymorphism; Goals; Heterogeneity; Hospitalization; Hospitals; Individual; Infant; Intake; Intravenous; Investigation; Length; Length of Stay; Mass Spectrum Analysis; Measurement; Measures; Medical; Medication Management; Methadone; Methods; Modeling; Morphine; National Institute of Drug Abuse; Neonatal; Neonatal Abstinence Syndrome; Newborn Infant; Opioid; Opium Tincture; Oral; Oral Administration; Outcome; Parents; Patients; Pharmaceutical Preparations; Pharmacodynamics; Pharmacogenetics; Pharmacotherapy; Phase; Phase I Clinical Trials; Population; Pregnant Women; Property; Protocols documentation; Randomized; Randomized Controlled Trials; Relative (related person); Replacement Therapy; Reporting; Research; Resources; Risk; Safety; Sampling; Serum; Signs and Symptoms; Site; Solutions; Source; Symptoms; Testing; Therapeutic Index; Tremor; United States National Institutes of Health; Withdrawal; Withdrawal Symptom; addiction; arm; base; cohort; design; experience; feeding; genetic analysis; genetic risk factor; improved; in utero; meetings; neonate; open label; pharmacodynamic model; population based; postnatal; public health relevance; response; standard care; standard of care; therapy duration; treatment duration; treatment program

DESCRIPTION (provided by applicant): The Neonatal abstinence Syndrome (NAS) is a complex of signs and symptoms in the postnatal period associated with the sudden withdrawal of maternally transferred opioids. Optimal treatment for NAS has not been established, with only modest changes in treatment approaches over the past ~25 years. Despite the difficulties in conducting research in a vulnerable neonatal population, it is self-evident that successful advances in adult addiction be tested, validated, and transferred to infants with NAS. Administration of oral morphine is associated with lengths of treatment of 8-79 days in the hospital setting. We have performed the only clinical trial employing sublingual buprenorphine to treat NAS and have demonstrated a reduction in length of treatment from 33 to 22 days relative to standard of care morphine treatment. Our initial investigation, however, was a phase one, unblinded design. To meet level 1a evidence standards, a randomized controlled trial employing a subjective measurement driving the primary and secondary endpoints must have double blinding. The purpose of the current investigation is to test the central hypothesis that sublingual buprenorphine is more efficacious than oral morphine solution in the treatment of NAS. We specifically aim to demonstrate that sublingual buprenorphine has an efficacy advantage over morphine for the clinical endpoints of length of treatment and duration of hospitalization. From our initial investigations we have built a pharmacokinetic/pharmacodynamic (PK/PD) model. We will build upon this model, identify covariates that influence drug disposition, and optimize buprenorphine dose and interval of administration. We plan to also build a pharmacometric model of oral morphine in NAS. Our third major aim is to use pharmacogenetics to elucidate sources of variability in the need for pharmacologic treatment in NAS, and the differential response to opioid replacement therapy in this population. To reach achieve these aims, we propose a four year, randomized, blinded, double dummy, single site, parallel group clinical trial in which eighty term infants who require pharmacologic treatment for NAS will be randomized in a 1:1 ratio to each treatment arm. Sparse sampling for PK samples will be analyzed by use of mass spectroscopy. All infants at risk for NAS will have pharmacogenetic samples to allow for comparisons between treated and non-treated infants, as well as a discrimination of response to drug therapy. Patients will be drawn primarily from a well-established comprehensive treatment program for pregnant women treated with methadone for addiction. The research team assembled to perform the trial is extant. Comprehensive expertise to conduct the investigation exists vertically from parent intake, through birth, management of neonatal medical issues, clinical trial administration, analytic chemistry, genetic analysis, biostatistics, and pharmacometric analysis. It is through these investigations that we hope to better understand the biology of addiction, and ultimately improve the treatment options for infants at risk for NAS. PUBLIC HEALTH RELEVANCE: Newborns exposed to opioids prior to birth can show withdrawal symptoms that cause difficulty feeding, irritability, diarrhea, and tremors. This disease, called the Neonatal Abstinence Syndrome, is generally treated in the hospital with morphine for 4-6 weeks. Buprenorphine is a medication that is used to treat adults with addiction to opioids. We propose to see if buprenorphine is more effective than the standard treatment of morphine. Another goal is to investigate if there are inherited factors which make some babies react to treatment differently than others. Finally, we will measure levels of buprenorphine and morphine to see differences between adults and children, and to be able to pick the best dose of medication to use in treating this disease.

描述（由申请人提供）：新生儿戒断综合症（NAS）是产后期间与母体转移的阿片类药物突然戒断相关的一系列体征和症状。 NAS 的最佳治疗方法尚未确定，在过去约 25 年中治疗方法仅发生了微小的变化。尽管在脆弱的新生儿群体中进行研究存在困难，但不言而喻的是，成人成瘾方面的成功进展需要经过测试、验证并转移到患有 NAS 的婴儿身上。口服吗啡的住院治疗时间为 8-79 天。我们进行了唯一一项采用舌下含服丁丙诺啡治疗 NAS 的临床试验，并证明相对于标准吗啡治疗，治疗时间从 33 天缩短至 22 天。然而，我们最初的调查是第一阶段的非盲设计。为了满足 1a 级证据标准，采用主观测量驱动主要和次要终点的随机对照试验必须采用双盲。当前研究的目的是检验舌下含服丁丙诺啡治疗 NAS 比口服吗啡溶液更有效的中心假设。我们的具体目的是证明舌下含服丁丙诺啡在治疗时间和住院时间的临床终点方面比吗啡具有疗效优势。根据我们的初步研究，我们建立了药代动力学/药效学 (PK/PD) 模型。我们将在此模型的基础上，确定影响药物处置的协变量，并优化丁丙诺啡剂量和给药间隔。我们还计划在 NAS 中建立口服吗啡的药理学模型。我们的第三个主要目标是利用药物遗传学来阐明 NAS 药物治疗需求的变异来源，以及该人群对阿片类药物替代治疗的差异反应。为了实现这些目标，我们提议进行一项为期四年的随机、盲法、双模拟、单中心、平行组临床试验，其中 80 名需要 NAS 药物治疗的足月婴儿将按 1:1 的比例随机分配到每个治疗组。 PK 样品的稀疏采样将通过质谱法进行分析。所有有 NAS 风险的婴儿都将获得药物遗传学样本，以便对接受治疗和未接受治疗的婴儿进行比较，并区分对药物治疗的反应。患者将主要来自针对接受美沙酮成瘾治疗的孕妇的完善综合治疗计划。为进行试验而组建的研究小组仍然存在。进行调查的综合专业知识垂直存在，从父母的接收、出生、新生儿医疗问题的管理、临床试验管理、分析化学、遗传分析、生物统计学和药理学分析。正是通过这些研究，我们希望更好地了解成瘾的生物学原理，并最终改善有 NAS 风险的婴儿的治疗选择。 公共卫生相关性：出生前接触阿片类药物的新生儿可能会出现戒断症状，​​导致喂养困难、烦躁、腹泻和颤抖。这种疾病称为新生儿戒断综合症，通常在医院用吗啡治疗 4-6 周。丁丙诺啡是一种用于治疗成人阿片类药物成瘾的药物。我们建议看看丁丙诺啡是否比吗啡的标准治疗更有效。另一个目标是调查是否存在遗传因素导致某些婴儿对治疗的反应与其他婴儿不同。最后，我们将测量丁丙诺啡和吗啡的水平，以了解成人和儿童之间的差异，并能够选择治疗这种疾病的最佳药物剂量。