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: 10019014
• 负责人: MARA BECKER
• 金额: $ 299.92万
• 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 2022-09-11
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10019014
• 关键词: Address; Adult; Affect; Age; Alzheimer' s Disease; Alzheimer' s disease risk; Anatomy; Appearance; Attention deficit hyperactivity disorder; Best Pharmaceuticals for Children Act; Biological; Caregivers; Celiac Disease; Characteristics; Child; Childhood; Childhood Leukemia; Chromosomes, Human, Pair 21; Clinical; Clinical Research; Clinical Trials; Clinical Trials Network; Comorbidity; 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; Legal patent; 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; Therapeutic; Time; Training Programs; United States National Institutes of Health; Vision; autism spectrum disorder; base; cohort; 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.

背景和意义： 唐氏综合症是一个人天生有额外的染色体副本的疾病。这种情况与智力障碍，特征性的面部外观和弱肌肉张力（肌肉张力）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。大约一半的受影响儿童天生患有心脏缺陷，有些人也有肠闭幕。唐氏综合症患者患有多种医疗状况的风险增加，包括儿童白血病，听力和视力问题，胃食管反射X，糖尿病，肥胖，甲状腺功能减退症和腹腔疾病。注意力缺陷/多动症（ADHD）的率是普通人群的三到五倍，而其他神经系统疾病（例如癫痫发作，自闭症和行为问题）也更为常见。唐氏综合症患者患感染的风险增加，例如肺炎，部分原因是免疫学差异，气道解剖因素以及合并症，例如心脏缺陷和肺动脉高压。大约一半的唐氏综合症成年人患有阿尔茨海默氏病（AD），风险随着年龄的增长而增加（通常在50年代中期或更高版本开始）。同时，患有唐氏综合症的人“受到保护”，不受成年人口的其他常见状况，例如高血压，冠状动脉疾病以及大多数形式的实体瘤，例如乳腺癌。 尽管唐氏综合症患者之间的寿命增加，但他们参加药物试验的机会受到了困难的阻碍，招募了足够大的临床群体，对适当的终点的了解有限，并且缺乏对该人群的分层措施，无法确定对药物效应的积极反应，并缺乏对长期进行临床试验的资源来进行新的疗法，从而使他们无法进行新的治疗。 唐氏综合症患者使用的药物使用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/或缺乏知识，包括有关药代动力学（PK），药物动力学（PD）（PD）和药物基因组学（PGX）（PGX）（PGX）在唐氏综合症群中。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其白血病。 NIH对整个生命周期的同时发生条件的新调查，以了解唐氏综合症（包括）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的策略，可满足唐氏综合症患者的关键健康和生活质量需求。包含项目的主要目标是：支持对疾病和疾病的临床试验，这些疾病和疾病不成比例地影响唐氏综合症患者，以加速旨在量身定制的符合其生理学的新疗法；以及包括唐氏综合症的个体在正在进行的临床试验中。国家老化研究所的主持下的一项单独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支持称为DS-Connect®的患者注册表，并已用于招募临床研究和临床试验（https://dsconnect.nih.gov）。 《儿童法案》（BPCA）儿科试验网络（PTN）的最佳药物是战略中毒，以解决NICHD的目标，即包括唐氏综合症的参与者 在新的或正在进行的临床试验中，通过现有的临床试验网络。 该任务订单的目的是利用PTN的基础设施，为将唐氏综合症的个体纳入基于BPCA临床计划进行的基于药理学的临床试验提供了额外的平台。 范围和科学原理 该任务顺序的主要目标是将该患者人群招募到PTN机会研究模型中。机会性研究设计涉及对医生为患者开出的多种药物的剂量和安全性的研究。该研究将是确定给唐氏综合症患者服用药物剂量是否合适且安全。 与第一个交织在一起的第二个目标是针对PTN内的临床研究人员制定培训计划，包括在唐氏综合症中进行研究专家，该计划将在该人群中专门为试验设计，招聘和参与方面提供双向指导。临床研究的目的是表征PK，PD和PGX的特征，该PK，PGX的受理专利药物和潜在的年轻人（18-25岁）和唐氏综合症的可能年轻人（年龄在18-25岁）中，这些药物正在接受治疗护理人员所规定的每个护理标准。为了了解药物处理和代谢，将从参与者那里收集生物样品。这项研究的机会设计将允许进行最小的风险研究，扩大的入学净网，评估非照料药物以及对按照护理标准执行的程序进行资本化，以最大程度地提高研究效率和数据收集，并最大程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中使用的药物提供有价值的PK，剂量和安全信息。