CLINICAL PHARMACOKINETICS AND SAFETY TRIALS IN DOWN SYNDROME

背景和意义： 唐氏综合症是一种人出生时就有额外的21号染色体拷贝的情况。这种情况与智力残疾、特有的面部外观和无力的肌肉张力(肌张力低下)有关，特别是在婴儿时期。唐氏综合症患者可能有各种各样的出生缺陷；所有受影响的儿童中约有一半出生时就有心脏缺陷，还有一些人还患有肠道闭锁。患有唐氏综合症的人患上几种疾病的风险更高，包括儿童白血病、听力和视力问题、胃食道反流、糖尿病、肥胖、甲状腺功能减退和乳糜泻。注意力缺陷/多动障碍(ADHD)的发病率是普通人群的三到五倍，其他神经疾病，如癫痫发作、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，部分原因是免疫差异、呼吸道解剖因素以及心脏缺陷和肺动脉高压等共病。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)，这种风险随着年龄的增长而增加(通常开始于55岁左右或更晚)。与此同时，患有唐氏综合症的人在成年人群中可以免受其他常见疾病的影响，如高血压、冠状动脉疾病和大多数实体肿瘤，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一直受到以下因素的阻碍：招募足够大的临床队列的困难，对这一群体的适当终点和结果衡量标准的有限了解，缺乏分层来确定对高于安慰剂效果的药物的积极反应，以及缺乏资源来维持允许测试新疗法的长期临床试验计划。 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有限和/或缺乏了解，包括唐氏综合症人群中的药代动力学(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新开展的了解唐氏综合症(INCLUDE)的共生疾病调查项目可能有助于解决其中的一些问题。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。该项目的主要目标是：支持对唐氏综合症患者造成不成比例影响的疾病和疾病的临床试验，加快开发适合唐氏综合症患者生理的新疗法；以及将唐氏综合症患者纳入正在进行的临床试验。由国家老龄研究所赞助的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。名为DS-CONNECT®的患者登记系统得到了NICHD的支持，已被用于临床研究和临床试验(https://DSConnect.nih.gov).)的招募 儿童最佳药物法案(BPCA)儿科试验网络(PTN)从战略上准备满足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。 此任务订单的目的是利用PTN的基础设施，为将唐氏综合症患者纳入根据BPCA临床计划进行的基于药理学的临床试验提供额外的平台。 范围和科学理论基础 此任务顺序的主要目标是将这些患者群体招募到PTN机会性研究模型中。机会性研究设计包括研究医生给患者开的多种药物的剂量和安全性。这项研究将确定唐氏综合症患者服用的药物剂量是否合适和安全。 与第一个目标交织在一起的第二个目标是为PTN内部的临床研究人员开发一个培训计划，其中包括进行唐氏综合症研究的专家，该计划将在试验设计、招募和参与方面提供双向指导，特别是在这一人群中。一项临床研究的目的是描述未被研究的非专利药物的PK、PD和PGx的特征，这些药物适用于患有唐氏综合症的儿童和潜在的年轻人(年龄18-25岁)，他们正在按照治疗照顾者开出的护理标准接受药物治疗。为了了解药物的处置和代谢，将从参与者那里收集生物样本。这项研究的机会主义设计将允许风险最低的研究、扩大的登记网络、对非专利药物的评估，以及根据护理标准进行的程序资本化，以最大限度地提高研究效率和数据收集，并将对参与者的潜在伤害降至最低。通过这一倡议收集的数据将为这一人群使用的药物提供有价值的PK、剂量和安全信息。

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.