Optimizing Parameters of Low-Intensity Focused Ultrasound for Pallidal Modulation in Huntington's Disease

Официальное название

Low-Intensity Focused Ultrasound Stimulation of the External Globus Pallidus in Huntington's Disease: A Phase I/II Safety and Feasibility Trial

Обзор

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.

Подробное описание

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.

Вмешательства

• Устройство Low-Intensity Focused Ultrasound Stimulation（LIFU）
  This is not a traditional three-arm parallel trial but a Stage I/II dose-finding study using an adaptive design. Participants are dynamically assigned to three pulse repetition frequency levels (10 Hz, 50 Hz, 100 Hz) based on predefined rules, rather than fixed randomization. The study adopts a two-stage utility-based Bayesian optimal interval (U-BOIN) design: Stage I: Dose decisions are based solely on dose-limiting toxicity (DLT) incidence. Participants are enrolled in cohorts of three. Base

Первичные конечные точки

• Safety: Incidence of Dose-Limiting Toxicity (DLT) [Срок оценки: At any point during or immediately following intervention on day of LIFUS application]
• Efficacy: Change in Unified Huntington's Disease Rating Scale Total Motor Score (UHDRS-TMS) [Срок оценки: Baseline and within 2 days after completing the 5-day LIFU treatment]
• Comprehensive Benefit-Risk: Utility [Срок оценки: Within 2 days after completing the 5-day LIFU treatment]

Критерии участия

Критерии включения

• 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

Критерии исключения

• 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

Критерии приведены из реестра в оригинале (на английском). Окончательную оценку соответствия проводит исследовательский центр.

Здоровые добровольцы: Нет

Дизайн исследования

Распределение

Нерандомизированное

Модель

Последовательный дизайн

Маскирование

Простое слепое

Основная цель

Лечение

Центры проведения

Китай · 1 центр

• Department of Rehabilitation Medicine, The First Affiliated Hospital of Fujian Medical Uni — Фучжоу

Идентификаторы

NCT: NCT07513844 · MRCTA,ECFAH of FMU[2025]738-1

Первоисточники (государственные реестры)

• ClinicalTrials.gov (NIH, США)

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