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: 8264541
• 负责人: WALTER K KRAFT
• 金额: $ 47.11万
• 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/8264541
• 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）：新生儿禁欲综合征（NAS）是与母体转移的阿片类药物突然戒断有关的产后症状和症状的复合体。尚未确定NAS的最佳治疗，在过去的25年中，治疗方法的变化仅适度。尽管在脆弱的新生儿人群中进行研究很困难，但不言而喻的是，在成年成瘾方面的成功进展得到了测试，验证和转移到NAS婴儿的。口服吗啡的给药与医院环境中8-79天的治疗时间有关。我们进行了唯一采用舌下丁丙诺啡治疗NAS的临床试验，并且相对于护理吗啡治疗的标准，治疗时间从33天减少到22天。但是，我们的最初调查是第一阶段，无盲的设计。为了符合1A级证据标准，采用主观测量的随机对照试验驱动驱动原始终点和次要终点必须具有双重盲。当前研究的目的是检验中心假设，即舌下丁丙诺啡在NAS治疗中比口服吗啡溶液更有效。我们特别旨在证明舌下丁丙诺啡比吗啡具有治疗时间和住院持续时间的临床终点的功效优势。从我们的初步研究中，我们建立了一种药代动力学/药效学（PK/PD）模型。我们将基于该模型，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。我们计划在NAS中构建口服吗啡的药物计量模型。我们的第三个主要目的是使用药物遗传学来阐明NAS药物治疗需求的可变性，以及该人群中对阿片类药物替代疗法的差异反应。为了达到这些目标，我们提出了为期四年，随机，盲人，双假，单位，单位，平行组临床试验，其中需要NAS药物治疗的八十个学期婴儿将以1：1的比例随机分配。 PK样品的稀疏采样将通过使用质谱法分析。所有有NAS风险的婴儿都有药物遗传学样本，以允许治疗和未治疗的婴儿之间进行比较，并歧视对药物治疗的反应。患者将主要是从一项公认的综合治疗计划中汲取的，用于接受美沙酮成瘾治疗的孕妇。研究团队集会进行试验。进行调查的全面专业知识来自父母的摄入，通过出生，新生儿医学问题的管理，临床试验给药，分析化学，遗传分析，生物统计学和药物计量分析。正是通过这些调查，我们希望更好地了解成瘾的生物学，并最终改善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显示出戒断症状，​​这会导致喂养，烦躁，腹泻和震颤困难。这种疾病称为新生儿禁欲综合征，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年阿片类药物的药物。我们建议查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有遗传因素使某些婴儿对治疗的反应与其他因素不同。最后，我们将测量丁丙诺啡和吗啡的水平，以查看成人和儿童之间的差异，并能够选择最佳的药物来治疗这种疾病。