A Novel Approach to Stimulant-Induced Weight Suppression and its Impact on Growth

一种抑制兴奋剂体重的新方法及其对生长的影响

• 批准号: 8282802
• 负责人: WILLIAM E PELHAM
• 金额: $ 56.27万
• 依托单位: FLORIDA INTERNATIONAL UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-07-01 至 2015-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8282802
• 关键词: Academy; Acceleration; Address; Adherence; Adolescence; Adolescent; Adolescent Psychiatry; Adult; Adverse effects; Adverse event; Age; American; Anorexia; Appetite Depressants; Attention deficit hyperactivity disorder; Behavior Therapy; Body Weight decreased; Cells; Child; Child Psychiatry; Childhood; Chronic; Clinical Treatment; Combined Modality Therapy; Control Groups; DRD4 gene; Data; Deceleration; Disease; Dose; Drug Industry; Drug Prescriptions; Early identification; Early treatment; Energy Intake; Evaluation; Evidence based treatment; Failure; Genetic; Genotype; Goals; Growth; Health Benefit; Healthcare; Height; Holidays; Home environment; Hour; Industry; Intervention; Investigation; Late Effects; Lead; Mental disorders; Methylphenidate; Monitor; Nursery Schools; Parents; Patients; Pharmaceutical Preparations; Pharmacological Treatment; Positioning Attribute; Preparation; Preventive Intervention; Public Health; Randomized; Randomized Controlled Trials; Recovery; Regimen; Reporting; Research; Risk; Risk Estimate; Running; Safety; Schedule; School-Age Population; Schools; Secondary to; Seminal; Site; Supplementation; Symptoms; Techniques; Therapeutic Effect; Time; Weight; Work; Youth; active control; arm; combat; common treatment; control trial; design; dopamine transporter; dosage; drug efficacy; energy balance; experience; falls; functional disability; innovation; novel strategies; prepuberty; prevent; public health relevance; randomized trial; response; restoration; social stigma; standard of care; success; treatment adherence

DESCRIPTION (provided by applicant): The most recent results from the MTA and PATS found that daily stimulant therapy with a 12 hour methylphenidate (MPH) regimen produced sustained growth deficits. In the MTA, there was as 1.7 inch difference in subjects medicated before and during the MTA vs. those never medicated. This difference persisted as long as medication was used, out to age 18. In PATS, one year of stimulant treatment at conservative doses produced a 20% reduction in expected height gain. This deceleration continued almost unabated over the next two years of medication use. Hence, there now appears to be evidence of concerning and persistent stimulant-induced growth suppression (SIGS). There were two major limitations of these findings. First, both used short acting stimulants, which are no longer the standard of care for pediatric ADHD. Extended release (ER) stimulants are the treatment of choice, but their longer therapeutic effects and ease of use may increase the chances of weight loss. Second was the failure to keep children in their assigned treatment cells past 14 months, thereby losing the effects of random assignment. In addition, anorexia and weight loss are two of the most commonly experienced adverse events with stimulants and are the side effects most likely to lead to treatment discontinuation. For a daily treatment, adherence is critical for success, and drug tolerability is a significant predictor of adherence. Even before PATS and the MTA, there was sizable stigma over the use of stimulants for ADHD, largely due to concerns about their long term safety in children. For these reasons, it is imperative to precisely estimate the risks of SIGS, examine the underlying mechanisms and develop treatments for it. While drug holidays and caloric supplementation are two common treatments for SIGS, there has been little systematic investigation of either. It is unknown if they are effective or feasible. Therefore, using a randomized adaptive design, we will evaluate the efficacy and feasibility of these two practices vs. routine monitoring of growth in 180 prepubertal children with ADHD. The study will address the limitations of prior work by using an ER MPH product and by keeping subjects in their assigned cells for 30 months. An additional 50 subjects will be treated solely with behavioral therapies to evaluate for growth abnormalities associated with ADHD. The study will assess will the risk of SIGS with ER stimulants and the underlying mechanisms while providing evidenced-based treatments for its management. Weight loss is a common side effect experienced by many of the millions of school-aged children prescribed stimulants that can lead to discontinuation of treatment. Now, there is evidence from PATS and the MTA that stimulants can lead to sustained and concerning growth suppression in children continuously treated with them throughout their childhood. This study holds substantial public health benefit as it will be the first randomized controlled trial for the treatment of stimulant induced growth suppression. In addition, it will enhance the understanding of growth abnormalities associated with ADHD vs. those secondary to persistent use of extended release stimulants as well as the mechanisms behind stimulant induced growth suppression.

描述（由申请人提供）：MTA 和 PATS 的最新结果发现，每日 12 小时哌醋甲酯 (MPH) 方案的刺激疗法会产生持续的生长缺陷。在 MTA 中，MTA 之前和期间服用药物的受试者与从未服用药物的受试者之间存在 1.7 英寸的差异。只要使用药物，这种差异就会一直持续到 18 岁。在 PATS 中，保守剂量的兴奋剂治疗一年后，预期身高增加减少了 20%。在接下来的两年中，药物使用的减速几乎没有减弱。因此，现在似乎有证据表明存在令人担忧和持续的兴奋剂诱导的生长抑制（SIGS）。这些发现有两个主要局限性。首先，两者都使用短效兴奋剂，这不再是儿科多动症的标准治疗方法。缓释（ER）兴奋剂是首选治疗方法，但其较长的治疗效果和易用性可能会增加减肥的机会。其次是在过去 14 个月内未能将儿童留在指定的治疗室中，从而失去了随机分配的效果。此外，厌食和体重减轻是兴奋剂最常见的两种不良事件，也是最有可能导致治疗中断的副作用。对于日常治疗，依从性对于成功至关重要，而药物耐受性是依从性的重要预测因素。甚至在 PATS 和 MTA 之前，使用兴奋剂治疗 ADHD 就存在相当大的耻辱，这主要是由于担心它们对儿童的长期安全性。由于这些原因，必须准确估计 SIGS 的风险，检查其潜在机制并开发治疗方法。虽然药物假期和热量补充是 SIGS 的两种常见治疗方法，但对这两种方法的系统研究却很少。目前尚不清楚它们是否有效或可行。因此，我们将使用随机适应性设计，评估这两种做法与常规监测 180 名患有 ADHD 的青春期前儿童生长的有效性和可行性。该研究将通过使用 ER MPH 产品并将受试者保留在指定的牢房中 30 个月来解决先前工作的局限性。另外 50 名受试者将仅接受行为疗法治疗，以评估与 ADHD 相关的生长异常。该研究将评估 ER 兴奋剂发生 SIGS 的风险及其潜在机制，同时为其管理提供循证治疗。体重减轻是数百万学龄儿童服用兴奋剂所经历的常见副作用，可能导致治疗停止。现在，PATS 和 MTA 的证据表明，对于在整个童年时期持续接受兴奋剂治疗的儿童来说，兴奋剂可能会导致持续且令人担忧的生长抑制。这项研究具有重大的公共健康益处，因为它将是第一个治疗兴奋剂诱导的生长抑制的随机对照试验。此外，它将增强对与 ADHD 相关的生长异常与持续使用缓释兴奋剂继发的生长异常以及兴奋剂诱导生长抑制背后机制的理解。