Low-Intensity Focused Ultrasound Stimulation of the External Globus Pallidus in Huntington's Disease: A Phase I/II Safety and Feasibility Trial
试验速览
- 阶段
- 不适用
- 状态
- 招募中
- 入组人数
- 24
- 试验地点
- 1
- 主要终点
- Safety: Incidence of Dose-Limiting Toxicity (DLT)
研究概览
简要总结
The purpose of this research study is to determine the optimal pulse repetition frequency of low-intensity focused ultrasound that is safe and effective in improving motor symptoms in patients with Huntington's disease.
详细描述
Huntington's disease is an autosomal dominant neurodegenerative disorder caused by HTT gene CAG repeat expansion. Early degeneration of striatal neurons projecting to the external globus pallidus (GPe) leads to abnormal basal ganglia circuitry and impaired motor control, resulting in involuntary movements and other motor symptoms. Current treatments are symptomatic only, with no disease-modifying therapies available. Deep brain stimulation targeting the globus pallidus has shown efficacy but is invasive and associated with significant adverse events.
Low-intensity focused ultrasound (LIFU) enables non-invasive, deep, and millimeter-precise neuromodulation. It has been applied in various neurological and psychiatric disorders with favorable safety and efficacy, demonstrating potential for neuromodulation of basal ganglia circuits.
This phase I/II adaptive dose-finding prospective interventional study evaluates the safety and efficacy of LIFU targeting the external globus pallidus in patients with Huntington's disease. Using MRI-derived individualized head models and real-time neuronavigation, the study employs a Bayesian optimal interval (BOIN) design with three pulse repetition frequencies: 10 Hz, 50 Hz, and 100 Hz. Patients are enrolled in sequential cohorts of three, with dose escalation guided by a utility-based approach integrating safety and efficacy data. Each patient receives ten LIFU sessions over five consecutive days, with two sessions daily. Motor function, cognitive function, functional assessments, and magnetic resonance imaging are evaluated before the first treatment session and after the final treatment session.
研究设计
- 研究类型
- Interventional
- 分配方式
- Non Randomized
- 干预模型
- Sequential
- 主要目的
- Treatment
- 盲法
- Single (Outcomes Assessor)
入排标准
- 年龄范围
- 18 Years 至 75 Years（Adult, Older Adult）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •Aged 18 to 75 years (inclusive)
- •Genetically confirmed Huntington's disease with HTT CAG repeat length of 40 or greater
- •Unified Huntington's Disease Rating Scale Total Maximal Chorea score of 8 or higher on a scale of 0 to 28, with higher scores indicating more severe chorea
- •Huntington's Disease Integrated Staging System stage 2 or 3
- •Willing to participate and provide informed consent
- •Have a reliable caregiver available
- •No severe cognitive impairment that would preclude reliable reporting of adverse events or efficacy during treatment
排除标准
- •History of self-injury, aggressive behavior, or unstable psychiatric disorders
- •History of head injury or neurosurgical procedure
- •Presence of intracranial implants, metallic foreign bodies, cochlear implants, or cardiac pacemakers
- •Severe systemic disease, pregnancy, or breastfeeding
- •Contraindications to magnetic resonance imaging, ultrasound, or anesthesia
- •Prior treatment with electroconvulsive therapy, transcranial magnetic stimulation, transcranial direct current stimulation, transcranial alternating current stimulation, or other neuromodulation therapies within the past 3 years
- •Severe brain atrophy with unclear external globus pallidus structure on MRI
- •Concurrent participation in another interventional clinical trial
- •Any other condition that, in the opinion of the investigator, would preclude participation
研究组 & 干预措施
10 Hz LIFU Group
Low-Intensity Focused Ultrasound (LIFU), PRF 10 Hz
干预措施: Low-Intensity Focused Ultrasound Stimulation（LIFU） (Device)
50 Hz LIFU Group
Low-Intensity Focused Ultrasound (LIFU), PRF 50 Hz
干预措施: Low-Intensity Focused Ultrasound Stimulation（LIFU） (Device)
100 Hz LIFU Group
Low-Intensity Focused Ultrasound (LIFU), PRF 100 Hz
干预措施: Low-Intensity Focused Ultrasound Stimulation（LIFU） (Device)
结局指标
主要结局
Safety: Incidence of Dose-Limiting Toxicity (DLT)
时间窗: At any point during or immediately following intervention on day of LIFUS application
DLT refers to the occurrence of any of the following six events during LIFU treatment: 1. Second-degree scalp burn; 2. Clinical seizure; 3. Worsening of chorea or new movement disorder; 4. Significant deterioration of the patient's mood or mental status (e.g., anxiety, depression, hallucinations, excessive sleepiness); 5. Severe autonomic dysfunction, such as marked blood pressure fluctuations, abnormal heart rate, or respiratory distress; 6. Imaging-related safety events: new or significantly enlarged brain edema, new microbleeds, new infarcts, or structural abnormalities in the treatment area on post-treatment cranial MRI compared with baseline, deemed clinically significant by both radiologists and clinicians.
Efficacy: Change in Unified Huntington's Disease Rating Scale Total Motor Score (UHDRS-TMS)
时间窗: Baseline and within 2 days after completing the 5-day LIFU treatment
The Unified Huntington's Disease Rating Scale Total Motor Score (UHDRS-TMS) evaluates motor impairment in Huntington's disease. Score range: 0-124 Higher scores indicate more severe motor impairment Response is defined as a reduction of ≥4 points from baseline.
Comprehensive Benefit-Risk: Utility
时间窗: Within 2 days after completing the 5-day LIFU treatment
Utility is a composite measure integrating dose-limiting toxicity (DLT) and efficacy response to quantify the overall benefit-risk balance for each dose group. During the trial, the Utility value for each dose group is dynamically calculated using the U-BOIN design platform. In Stage II, the Utility value determines dose allocation for subsequent cohorts. At study completion, the dose group with the highest Utility value is identified as the optimal biological dose.
次要结局
未报告次要终点
研究者
Xinyuan Chen
Attending Physician
First Affiliated Hospital of Fujian Medical University