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.

总结 下丘脑肥胖症（HO）是指下丘脑的大脑经常复杂化的大量体重增加 肿瘤的患有这种治疗无效的肥胖症的儿童有过高的代谢后遗症率 与其他健康的儿童相比，他们有类似的肥胖，后来经历了与肥胖有关的死亡率过高。 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，NCT 02664441），受试者接受艾塞那肽（一种胰高血糖素样肽-1受体） 与接受安慰剂的受试者相比，接受GLP 1 RA激动剂的受试者表现出更大的体脂减少。虽然这些结果 令人鼓舞的是，在50%的参与者中，BMI并没有随着exenetry而降低，这突出了解决 治疗无反应。我们团队测试的另一种药理学选择是鼻内催产素（OXT）， 在我们的案例研究中取得了成功，并保证了安全性。然而，在最近结束的一项交叉研究中， 我们观察到OXT引起的受试者内体重减轻标称值为-0.6 kg，无统计学显著性， 与安慰剂（NCT 02849743）相比，但建议对焦虑和冲动有益。这些试验 强调我们团队的经验和我们致力于开发证据支持的个性化 解决HO治疗无反应问题的方法。今后，我们将继续努力， 创新的序贯多重分配随机试验（SMART）设计。SMART是一种多阶段临床 试验，在每个阶段，个体根据累积的 关于对先前干预的反应的信息。HO特别适合作为非应答者的SMART 可受益于替代和/或组合干预。此外，SMART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 试点试验，我们的目标是收集有关芬特明/托吡酯（Ph/T），一个有前途的选择关键的初步数据 含有拟交感神经胺（Ph）与抑制食欲的癫痫药物（T）的组合， 被批准用于“普通”肥胖症，但从未在HO中进行过测试。HO患者的子集， 经历过暴食或白天过度嗜睡可能受益于Ph/T诱导的食欲下降 提高警惕。我们将对安全性、不良事件和剂量进行初步评估（目标1）， 以及在一项为期27周的平行组双盲II期随机安慰剂研究中的疗效（BMI降低%，目标2）， 在FDA批准的剂量滴定后，在12-25岁的HO个体中进行对照临床试验。我们将 还测量BMI下降5%或2.5%的个体比例，探索Ph/T的影响 身体脂肪，饮食，自主神经张力和认知，并将银行生物样本，为未来的机械 分析。与参与者和护理人员进行半结构化的离职面谈将有助于解释治疗反应 或无应答、不良事件经历和对试验参与的印象。接下来我们将设计一个 SMART包括GLP 1 RA、Ph/T和/或其他新疗法，如OXT单药治疗和/或联合治疗HO。