A Pilot Study of Transcutaneous Auricular Vagus Nerve Stimulation for the Treatment of Idiopathic Nephrotic Syndrome in Children

经皮耳迷走神经刺激治疗儿童特发性肾病综合征的初步研究

• 批准号: 10516390
• 负责人: Christine B Sethna
• 金额: $ 35.38万
• 依托单位: FEINSTEIN INSTITUTE FOR MEDICAL RESEARCH
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-08-15 至 2025-07-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10516390
• 关键词: 17 year old; Action Potentials; Address; Adherence; Affect; Aftercare; Age; Animals; Antibodies; Antibody Formation; Attenuated; Autoantibodies; B-Lymphocytes; Child; Chronic; Clinical Trials; Confidence Intervals; Data; Devices; Diabetes Mellitus; Disease; Double-Blind Method; Dyslipidemias; Edema; Enrollment; Etiology; Evaluation; Exposure to; Fibrinogen; Future; Goals; Growth; Hypertension; Immune; Immune response; Immune system; Immunologic Markers; Immunosuppressive Agents; Infection; Inflammatory; Kidney; Knowledge; Lead; Measures; Mediating; Methods; Mission; Monitor; Multi-Institutional Clinical Trial; National Institute of Diabetes and Digestive and Kidney Diseases; Nephrotic Syndrome; Organ; Outcome; Participant; Pathogenesis; Pathway interactions; Pharmaceutical Preparations; Pilot Projects; Placebos; Process; Proteins; Proteinuria; Protocols documentation; Randomized; Reflex action; Regulatory T-Lymphocyte; Relapse; Renal glomerular disease; Reperfusion Injury; Research; Resistance; Resources; Rheumatoid Arthritis; Role; Safety; Sample Size; Serum; Signal Transduction; Site; Specific qualifier value; Spleen; Steroid therapy; Steroid-resistant idiopathic nephrotic syndrome; Steroids; Systemic Lupus Erythematosus; TNF gene; Testing; Time; Vagus nerve structure; base; cell motility; confirmatory clinical trial; cytokine; design; efficacy outcomes; feasibility testing; immunoregulation; innovation; interest; monocyte; nephrin; nephrotoxicity; novel; patient safety; podocyte; randomized placebo controlled trial; recruit; response; side effect; treatment response; trial comparing; vagus nerve stimulation

PROJECT SUMMARY/ABSTRACT Children with nephrotic syndrome, especially those that have frequent relapses (FRNS) or are resistant to steroid therapy (SRNS), are exposed to prolonged courses of steroids and other immunosuppressant medications. Given the adverse side effect profiles and variable efficacy of these medications, there is an urgent need to identify novel and safe therapies to treat nephrotic syndrome in children. Stimulation of the vagus nerve, which can be activated non-invasively by transcutaneous auricular vagus nerve stimulation (taVNS), modulates the immune system by the inflammatory reflex and spleen. taVNS has become a therapy of interest for treating chronic immune-mediated illnesses. The central hypothesis is that activation of the inflammatory reflex via taVNS modulates the immune response, attenuates relapses and proteinuria, and reduces reliance on immunosuppressant medications in children with nephrotic syndrome. The overarching goal is to conduct a large scale, multicenter clinical trial to investigate the efficacy and safety of taVNS in the treatment of nephrotic syndrome in children. To optimally prepare for this larger clinical trial, the objective of this proposal is to conduct pilot clinical trials to evaluate the feasibility and tolerability of taVNS for the treatment of nephrotic syndrome in children and generate preliminary data to guide power calculations for a future larger study. In this context, the specific aims of this proposal are: (Aim 1) To determine the feasibility of protocol implementation and tolerability of taVNS in the treatment of nephrotic syndrome in children; (Aim 2) To establish proof of concept and generate effect sizes for treatment response outcomes in children with nephrotic syndrome randomized to taVNS therapy compared with sham therapy; (Aim 3) To investigate the effects of taVNS on immune markers in children with nephrotic syndrome. The proposed pilot study will enroll 30 children with FRNS and 10 children with SRNS age 3-17 years from two sites in two parallel, double-blinded, randomized placebo-controlled trials comparing five minutes of daily taVNS use with sham therapy for 26 weeks. To test for feasibility and tolerability of the clinical trial, the process of recruitment, adherence , device functionality, time and resource utilization, and safety monitoring will be examined. Using pre-specified proof- of-concept criteria, preliminary data gathered from this pilot study will then be used to determine whether a subsequent larger main trial should move forward. Further, immune markers including serum and monocyte- stimulated cytokines and anti-nephrin antibodies will be measured in order to characterize the immunomodulatory effect of taVNS therapy. To this end, accomplishing the goals of this pilot study will provide preliminary data that will inform the design of and strengthen the implementation of a planned larger clinical trial. Providing these preliminary data that are essential to conduct a large-scale trial will address a significant knowledge gap and will pave the way for evaluation of an innovative, non-pharmacologic, non-invasive, steroid-sparing approach to the treatment of idiopathic nephrotic syndrome in children.

项目概要/摘要 患有肾病综合征的儿童，尤其是那些经常复发（FRNS）或对药物有抵抗力的儿童 类固醇治疗 (SRNS)，长期接受类固醇和其他免疫抑制剂治疗 药物。鉴于这些药物的不良副作用和不同的疗效，有一个 迫切需要找到治疗儿童肾病综合征的新颖且安全的疗法。刺激 迷走神经，可以通过经皮耳廓迷走神经刺激非侵入性地激活 (taVNS)，通过炎症反射和脾脏调节免疫系统。 taVNS 已成为一种疗法 对于治疗慢性免疫介导的疾病具有重要意义。中心假设是激活 通过 taVNS 的炎症反射调节免疫反应，减轻复发和蛋白尿，以及 减少肾病综合征儿童对免疫抑制剂药物的依赖。首要的 目标是进行大规模、多中心临床试验，以研究 taVNS 在治疗中的有效性和安全性 治疗小儿肾病综合征。为了为这项更大规模的临床试验做好最佳准备，目标是 该提案旨在进行试点临床试验，以评估 taVNS 的可行性和耐受性 治疗儿童肾病综合征并生成初步数据以指导功率计算 未来更大规模的研究。在此背景下，本提案的具体目标是：（目标 1）确定 taVNS治疗儿童肾病综合征的方案实施和耐受性； （目标 2） 建立概念验证并生成肾病儿童治疗反应结果的效应大小 与假治疗相比，随机接受 taVNS 治疗的综合征； （目标 3）调查效果 taVNS 对肾病综合征儿童免疫标志物的影响。拟议的试点研究将招募 30 名儿童 在两个平行、双盲、 随机安慰剂对照试验对 26 名患者每天使用 5 分钟的 taVNS 与假治疗进行了比较 几周。测试临床试验、招募过程、依从性的可行性和耐受性 ， 设备 功能、时间和资源利用率，以及 将检查安全监测。使用预先指定的证明- 根据概念标准，从该试点研究中收集的初步数据将用于确定是否 后续更大规模的主要试验应该继续进行。更远， 免疫标记物，包括血清和单核细胞 将测量受刺激的细胞因子和抗去氧肾上腺素抗体，以表征 taVNS 治疗的免疫调节作用。为此，实现本试点研究的目标将提供 初步数据将为计划的更大规模临床的设计和加强实施提供信息 审判。提供这些对于进行大规模试验至关重要的初步数据将解决一个重要问题 知识差距，并将为评估创新的、非药物的、非侵入性的、 治疗儿童特发性肾病综合征的类固醇节约方法。