CLINICAL PHARMACOKINETICS AND SAFETY TRIALS IN DOWN SYNDROME

唐氏综合症的临床药代动力学和安全性试验

• 批准号: 10274297
• 负责人: MARA BECKER
• 金额: $ 229.87万
• 依托单位: DUKE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-09-12 至 2025-06-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10274297
• 关键词: Address; Adult; Affect; Age; Alzheimer' s disease risk; Alzheimer' s disease therapeutic; Anatomy; Appearance; Attention deficit hyperactivity disorder; Best Pharmaceuticals for Children Act; Biological; Caregivers; Celiac Disease; Characteristics; Child; Childhood; Childhood Leukemia; Chromosome 21; Clinical; Clinical Research; Clinical Trials; Clinical Trials Network; Conduct Clinical Trials; Congenital Abnormality; Coronary Arteriosclerosis; Cytotoxic agent; Data; Data Collection; Development; Diabetes Mellitus; Disease; Dose; Down Syndrome; Drug Kinetics; Drug usage; Elderly; Enrollment; Evaluation; Face; Gastroesophageal reflux disease; General Population; Goals; Health; Hearing; Heart Abnormalities; Hypertension; Hypothyroidism; Immunologics; Individual; Infrastructure; Intellectual functioning disability; Intestinal Atresia; Investigation; Knowledge; Longevity; Medical; Minimal Risk Study; Muscle Tonus; Muscle hypotonia; National Institute of Child Health and Human Development; National Institute on Aging; Neurologic; Obesity; Outcome Measure; Participant; Patient Recruitments; Patients; Persons; Pharmaceutical Preparations; Pharmacodynamics; Pharmacogenomics; Pharmacology; Physicians; Physiology; Placebo Effect; Pneumonia; Population; Problem behavior; Procedures; Pulmonary Hypertension; Quality of life; Research; Research Design; Research Personnel; Resources; Risk; Safety; Sampling; Seizures; Solid Neoplasm; Stratification; Study models; Testing; Time; Training Programs; United States National Institutes of Health; Vision; autism spectrum disorder; base; cohort; comorbidity; design; drug development; drug disposition; drug metabolism; individualized medicine; infancy; infection risk; leukemia; malignant breast neoplasm; novel therapeutics; off-patent; patient population; patient registry; programs; recruit; research study; response; standard of care; trial design; young adult

Background and Significance: Down syndrome is a condition in which a person is born with an extra copy of chromosome 21. The condition is associated with intellectual disability, a characteristic facial appearance, and weak muscle tone (hypotonia), particularly in infancy. People with Down syndrome may have a variety of birth defects; about half of all affected children are born with a heart defect, and some also have intestinal atresias. Individuals with Down syndrome have an increased risk of developing several medical conditions, including childhood leukemias, hearing and vision problems, gastroesophageal reflux, diabetes, obesity, hypothyroidism, and celiac disease. The rate of Attention Deficit/Hyperactivity Disorder (ADHD) is three to five times higher than in the general population, and other neurological conditions such as seizures, autism, and behavioral problems are also more common in those with Down syndrome. Individuals with Down syndrome have an increased risk of infections such as pneumonia, due in part to immunological differences, airway anatomical factors, and comorbidities such as heart defects and pulmonary hypertension. About half of adults with Down syndrome develop Alzheimer’s Disease (AD), and the risk increases with advancing age (generally starting around the mid-50s or later). At the same time, people with Down syndrome are “protected” from other common conditions in the adult population, such as hypertension, coronary artery disease, and most forms of solid tumors such as breast cancer. Despite increases in lifespan among individuals with Down syndrome, opportunities for them to participate in medication trials have been hampered by difficulties in recruiting large enough clinical cohorts, limited knowledge of appropriate endpoints and outcome measures for this population, lack of stratification to identify positive responses to medications above placebo effects, and lack of resources to sustain a clinical trials program for the long-term that would allow new therapeutics to be tested. One of the potential barriers to drug development trials for drugs to be used by people with Down syndrome is the limited and/or lack of knowledge of how these individuals may metabolize drugs, including basic knowledge about pharmacokinetics (PK), pharmacodynamics (PD) and pharmacogenomics (PGx) in Down syndrome populations. For example, children with Down syndrome require lower doses of cytotoxic drugs to treat their leukemia. NIH’s new INvestigation of Co-occurring conditions across the Lifespan to Understand Down syndromE (INCLUDE) project may help to address some of these questions. The project is a comprehensive, trans-NIH strategy to address critical health and quality-of-life needs for individuals with Down syndrome. The main goals of the INCLUDE project are: to support clinical trials on conditions and diseases that disproportionately affect people with Down syndrome, both to accelerate the development of new therapies tailored to their physiology; as well as include individuals with Down syndrome in ongoing clinical trials. A separate activity under the auspices of the National Institute on Aging is providing clinical trials infrastructure to studies of anti-AD therapeutics in Down syndrome. A patient registry known as DS-Connect® is supported by NICHD and has been used to recruit for clinical research studies and clinical trials (https://DSConnect.nih.gov). The Best Pharmaceutical for Children Act (BPCA) Pediatric Trials Network (PTN) is strategically poised to address the NICHD’s goals of including participants with Down syndrome in new or ongoing clinical trials through existing clinical trials networks. The purpose of this task order is to leverage the infrastructure of the PTN to provide an additional platform for the inclusion of individuals with Down syndrome into pharmacology-based clinical trials conducted under the BPCA Clinical Program. Scope and Scientific Rationale The primary goal of this task order is to recruit this patient population into the PTN Opportunistic study model. The Opportunistic study design involves the study of dosing and safety of multiple medications prescribed by physicians to their patients. The research will be to determine if the doses of medications given to individuals with Down syndrome are appropriate and safe. A second goal, to be interwoven with the first, is to develop a training program for clinical researchers, both within the PTN and including experts in conducting research in Down syndrome, that will provide bi-directional guidance in trial design, recruitment, and engagement specifically in this population. The purpose of a clinical study is to characterize the PK, PD, and PGx of understudied off-patent drugs administered to children and potentially young adults (ages 18-25 years) with Down syndrome who are receiving drugs per standard of care as prescribed by their treating caregiver. In order to understand drug disposition and metabolism, biological samples will be collected from participants. The opportunistic design of this study will allow for a minimal risk study, an expanded enrollment net, evaluation of off-patent drugs, and capitalization on procedures performed per standard of care to maximize study efficiency and data collection and minimize potential harm to participants. The data collected through this initiative will provide valuable PK, dosing, and safety information for drugs used in this population.

背景及意义： 唐氏综合症是一种患有先天性 21 号染色体额外拷贝的疾病。这种疾病与智力障碍、面部特征特征和肌张力弱（肌张力低下）有关，尤其是在婴儿期。患有唐氏综合症的人可能有多种出生缺陷；大约一半受影响的儿童出生时就有心脏缺陷，有些还患有肠闭锁。患有唐氏综合症的人患多种疾病的风险增加，包括儿童白血病、听力和视力问题、胃食管反流、糖尿病、肥胖、甲状腺功能减退和乳糜泻。注意力缺陷/多动症 (ADHD) 的发病率比普通人群高出三到五倍，而其他神经系统疾病，如癫痫、自闭症和行为问题，在唐氏综合症患者中也更常见。唐氏综合症患者感染肺炎等感染的风险增加，部分原因是免疫学差异、气道解剖因素以及心脏缺陷和肺动脉高压等合并症。大约一半患有唐氏综合症的成年人会患上阿尔茨海默病 (AD)，并且这种风险随着年龄的增长而增加（通常从 50 多岁左右开始）。与此同时，患有唐氏综合症的人可以“免受”成年人中其他常见疾病的影响，例如高血压、冠状动脉疾病和大多数形式的实体瘤（例如乳腺癌）。 尽管唐氏综合症患者的寿命有所延长，但他们参与药物试验的机会却受到阻碍，因为招募足够多的临床队列存在困难，对该人群的适当终点和结果测量的了解有限，缺乏分层来识别对高于安慰剂效应的药物的积极反应，以及缺乏长期维持临床试验计划以测试新疗法的资源。 唐氏综合症患者使用的药物开发试验的潜在障碍之一是对这些人如何代谢药物的了解有限和/或缺乏，包括唐氏综合症人群的药代动力学 (PK)、药效学 (PD) 和药物基因组学 (PGx) 的基本知识。例如，患有唐氏综合症的儿童需要较低剂量的细胞毒性药物来治疗他们的白血病。 美国国立卫生研究院 (NIH) 的新的“对整个生命周期中同时发生的情况进行调查以了解唐氏综合症 (INCLUDE)”项目可能有助于解决其中一些问题。该项目是一项全面的跨 NIH 战略，旨在满足唐氏综合症患者的关键健康和生活质量需求。 INCLUDE 项目的主要目标是： 支持对唐氏综合症患者影响较大的病症和疾病的临床试验，以加速针对其生理机能的新疗法的开发；以及将患有唐氏综合症的个体纳入正在进行的临床试验。在国家老龄化研究所的支持下，另一项活动正在为唐氏综合症的抗 AD 疗法研究提供临床试验基础设施。 NICHD 支持名为 DS-Connect® 的患者登记系统，并已用于招募临床研究和临床试验 (https://DSConnect.nih.gov)。 《儿童最佳药物法案》 (BPCA) 儿科试验网络 (PTN) 从战略上做好了准备，以实现 NICHD 纳入唐氏综合症参与者的目标 通过现有的临床试验网络进行新的或正在进行的临床试验。 该任务订单的目的是利用 PTN 的基础设施提供一个额外的平台，将唐氏综合症患者纳入 BPCA 临床计划下进行的基于药理学的临床试验。 范围和科学原理 该任务顺序的主要目标是将这些患者群体招募到 PTN 机会研究模型中。机会主义研究设计涉及医生向患者开出的多种药物的剂量和安全性研究。该研究将确定给予唐氏综合症患者的药物剂量是否适当且安全。 第二个目标与第一个目标交织在一起，是为 PTN 内部的临床研究人员以及开展唐氏综合症研究的专家制定培训计划，该计划将为专门针对该人群的试验设计、招募和参与提供双向指导。临床研究的目的是描述对患有唐氏综合症的儿童和潜在年轻人（18-25 岁）服用的正在研究的非专利药物的 PK、PD 和 PGx 的特征，这些儿童和潜在的年轻人（18-25 岁）正在按照治疗护理人员规定的护理标准接受药物。为了了解药物的分布和代谢，将从参与者身上收集生物样本。这项研究的机会主义设计将允许进行最小风险研究、扩大入组网、评估非专利药物以及利用按照护理标准执行的程序，以最大限度地提高研究效率和数据收集，并最大限度地减少对参与者的潜在伤害。通过该计划收集的数据将为该人群使用的药物提供有价值的 PK、剂量和安全性信息。