Phentermine/Topiramate in children, adolescents, and young adults with hypothalamic obesity: a pilot and feasibility study

芬特明/托吡酯治疗下丘脑肥胖儿童、青少年和年轻人：一项试点和可行性研究

• 批准号: 10734754
• 负责人: SHANA ERIN MCCORMACK
• 金额: $ 36.17万
• 依托单位: SEATTLE CHILDREN'S HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-08-01 至 2026-05-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10734754
• 关键词: Address; Adolescent; Adolescent and Young Adult; Adult; Adverse event; Affect; Age; Agonist; Anxiety; Biological; Body Weight decreased; Body fat; Body mass index; Brain Neoplasms; Cardiometabolic Disease; Caregivers; Case Study; Child; Childhood Brain Neoplasm; Clinical Trials; Cognition; Combined Modality Therapy; Cross-Over Studies; Data; Desire for food; Disease; Dose; Double-Blind Method; Drug usage; Dual-Energy X-Ray Absorptiometry; Eating; Eating Behavior; Energy Metabolism; Epilepsy; Event; Excess Mortality; Excessive Daytime Sleepiness; Exclusion Criteria; FDA approved; Fatigue; Feasibility Studies; Foundations; Froehlich' s Syndrome; Future; GLP-I receptor; Goals; Health; Heterogeneity; Hyperphagia; Hypothalamic Neoplasms; Hypothalamic structure; Impairment; Impulsivity; Individual; Injury; Intervention; Interview; Magnetic Resonance Imaging; Maintenance; Maximum Tolerated Dose; Measures; Metabolic; Mission; Multi-Institutional Clinical Trial; National Institute of Diabetes and Digestive and Kidney Diseases; Obesity; Oral; Outcome; Oxytocin; Participant; Persons; Pharmaceutical Preparations; Phase; Phentermine; Physical activity; Pilot Projects; Placebo Control; Placebos; Pre-Clinical Model; Procedures; Protocols documentation; Randomized; Regulation; Reporting; Research; Resistance; Safety; Sample Size; Sampling; Sequential Multiple Assignment Randomized Trial; Stimulant; Structure; Suggestion; Survivors; Sympathomimetic Amines; Testing; Therapeutic Intervention; Titrations; Visceral fat; Weight Gain; Withdrawal; alertness; arm; attenuation; biomarker identification; capsule; design; dose individualization; exenatide; experience; impression; improved; inclusion criteria; individual response; innovation; metabolic phenotype; metabolic rate; mortality risk; novel therapeutics; obesity treatment; personalized approach; personalized therapeutic; pharmacologic; phase 2 study; pilot trial; placebo controlled trial; prevent; programs; randomized placebo-controlled clinical trial; recruit; response; safety assessment; sibutramine; stimulant use; subcutaneous; success; topiramate; treatment effect; treatment planning; treatment response; treatment strategy; trial design

SUMMARY Hypothalamic obesity (HO) refers to the substantial weight gain that often complicates hypothalamic brain tumors. Children with this treatment-recalcitrant form of obesity have excess rates of metabolic sequelae compared to otherwise healthy children with similar obesity, and later experience excess mortality related to cardiometabolic disease. Our team has made important progress in recent trials. In our 36-week placebo- controlled trial (ECHO, NCT02664441), participants receiving exenatide, a glucagon-like peptide-1 receptor agonist (GLP1RA), demonstrated a larger reduction in body fat than those receiving placebo. While these results are encouraging, in 50% of participants, BMI did not decrease with exenatide, highlighting the need to address treatment non-response. Another pharmacologic option tested by our team is intranasal oxytocin (OXT), which has had success in our case studies and reassuring safety. However, in a recently concluded cross-over study, we observed a nominal, not statistically significant, within-subject weight loss of -0.6 kg attributable to OXT as compared to placebo (NCT02849743), but suggestions of benefit for anxiety and impulsivity. These trials highlight our team's experience and our commitment to developing evidence-supported, individualized approaches to address the problem of treatment non-response in HO. In future, we envision pursuing an innovative sequential multiple assignment randomized trial (SMART) design. A SMART is a multi-staged clinical trial where at each stage, individuals are re-randomized to the next intervention based on accumulated information about response to the previous intervention. HO is particularly suited to a SMART as non-responders may benefit from alternative and/or combination interventions. Moreover, the SMART allows for the identification of biomarkers, such as hypothalamic injury on MRI, to support optimal and efficient treatment planning. In this pilot trial, our objective is to gather key preliminary data about phentermine/topiramate (Ph/T), a promising option containing a sympathomimetic amine (Ph) combined with an appetite-suppressive epilepsy drug (T) that is FDA- approved for “common” obesity but has never been tested in HO. The subset of individuals with HO who experience hyperphagia or excess daytime sleepiness may benefit from the Ph/T-induced decrease in appetite and increase in alertness. We will make preliminary assessments of safety, adverse events and dosing (Aim 1), as well as efficacy (% BMI loss, Aim 2) in a 27-week parallel-arm double-blinded Phase 2 randomized placebo- controlled clinical trial in 12-25-year-old individuals with HO, following the FDA-approved dose titration. We will also measure the proportion of individuals who experience 5% or 2.5% decrease in BMI, explore effects of Ph/T on body fat, eating, autonomic tone, and cognition, and will bank biological samples for future mechanistic analyses. Semi-structured exit interviews with participants and caregivers will help to explain treatment response or non-response, experience of adverse events, and impressions of trial participation. We will next design a SMART to include GLP1RA, Ph/T, and/or other novel therapies like OXT alone and/or in combination for HO.

摘要 下丘脑肥胖(HO)指的是体重大幅增加，这通常会使下丘脑变得复杂 肿瘤。这种治疗顽固性肥胖的儿童代谢后遗症的发生率过高。 与其他健康的儿童相比，他们有类似的肥胖，并且后来经历了与 心脏代谢疾病。我们的团队在最近的试验中取得了重要进展。在我们36周的安慰剂中- 对照试验(ECHO，NCT02664441)，参与者接受胰升糖素样肽-1受体艾塞那肽的治疗 激动剂(GLP1RA)比那些接受安慰剂的人显示出更大的体脂减少。虽然这些结果 令人鼓舞的是，在50%的参与者中，体重指数没有随着埃塞那肽的下降而下降，这突出了解决以下问题的必要性 治疗无反应。我们团队测试的另一个药理选择是鼻腔内催产素(OXT)，它 在我们的案例研究和令人放心的安全方面取得了成功。然而，在最近结束的一项交叉研究中， 我们观察到可归因于OXT AS的标称的、没有统计意义的受试者内体重减轻-0.6公斤 与安慰剂(NCT02849743)相比，但建议有益于焦虑和冲动。这些试验 突出我们团队的经验和我们致力于开发有证据支持的、个性化的 解决HO治疗无反应问题的方法。在未来，我们设想追求一种 创新的序贯多分配随机试验(SMART)设计。SMART是一个多阶段的临床 试验中，在每个阶段，个体被重新随机分配到基于累积的下一次干预 有关对先前干预的反应的信息。Ho特别适合作为非响应者的聪明人 可能受益于替代和/或组合干预措施。此外，SMART还允许识别 生物标志物，如MRI上的下丘脑损伤，以支持最佳和有效的治疗计划。在这 在试点试验中，我们的目标是收集有关苯特明/托吡酯(Ph/T)的关键初步数据，这是一种有希望的选择 含有交感神经胺(Ph)和食欲抑制癫痫药物(T)，这是FDA- 被批准为“普通”肥胖症，但从未在胡志明市进行过测试。具有Ho Who的个体的子集 Ph/T引起的食欲下降可能有助于体验吞噬过多或日间过度嗜睡 并提高警觉性。我们将对安全性、不良事件和剂量进行初步评估(目标1)， 以及在27周的平行臂双盲2期随机安慰剂中的疗效(BMI损失百分比，AIM 2)- 在12-25岁HO患者中进行的对照临床试验，遵循FDA批准的剂量滴定。我们会 还测量BMI下降5%或2.5%的个体比例，探索Ph/T的影响 关于身体脂肪、饮食、自主神经和认知的研究，并将为未来的机械学储存生物样本 分析。对参与者和照顾者的半结构化离职访谈将有助于解释治疗反应 或无反应，不良事件的经历，以及参与试验的印象。接下来，我们将设计一种 明智地包括GLP1RA、Ph/T和/或其他新疗法，如OXT单独和/或联合治疗HO。