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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.
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.
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| Label | Type | Description | Intervention Names |
|---|---|---|---|
| 10 Hz LIFU Group | Experimental | Low-Intensity Focused Ultrasound (LIFU), PRF 10 Hz |
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| 50 Hz LIFU Group | Experimental | Low-Intensity Focused Ultrasound (LIFU), PRF 50 Hz |
|
| 100 Hz LIFU Group | Experimental | Low-Intensity Focused Ultrasound (LIFU), PRF 100 Hz |
|
| Name | Type | Description | Arm Group Labels | Other Names |
|---|---|---|---|---|
| Low-Intensity Focused Ultrasound Stimulation（LIFU） | Device | 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. Based on observed DLTs, the next cohort's dose is determined (escalate/stay/de-escalate). Stage II: When any dose group reaches 6 participants or the highest dose is explored, safety and efficacy data are integrated to calculate a utility value. Subsequent cohorts are assigned to the dose group with the highest utility value. The study stops when any dose group reaches 12 participants or total enrollment reaches 24. Not all three dose levels may be utilized. Allocation is not fixed a priori. |
| Measure | Description | Time Frame |
|---|---|---|
| Safety: Incidence of Dose-Limiting Toxicity (DLT) | DLT refers to the occurrence of any of the following six events during LIFU treatment:
| 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) | 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. | Baseline and within 2 days after completing the 5-day LIFU treatment |
| Comprehensive Benefit-Risk: Utility | 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. | Within 2 days after completing the 5-day LIFU treatment |
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| Measure | Description | Time Frame |
|---|---|---|
| Patient Global Impression of Change (PGI-C) | The Patient Global Impression of Change (PGI-C) is a patient-reported scale assessing perceived change in overall condition after treatment. Score range: 1-7 Lower scores indicate greater improvement | Within 2 days after completing the 5-day LIFU treatment |
| Clinical Global Impression of Change (CGI-C) |
Inclusion Criteria:
Exclusion Criteria:
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| Name | Role | Phone | Extension | |
|---|---|---|---|---|
| Xin-Yuan Chen | Contact | +86 15005065282 | fychenxinyuan@fjmu.edu.cn | |
| Li-Zhu Wu | Contact | +86 18459867658 | 1809225097@qq.com |
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| Facility | Status | City | State | ZIP | Country | Contacts |
|---|---|---|---|---|---|---|
| Department of Rehabilitation Medicine, The First Affiliated Hospital of Fujian Medical University | Recruiting | Fuzhou | Fujian | China |
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| ID | Term |
|---|---|
| D006816 | Huntington Disease |
| ID | Term |
|---|---|
| D001480 | Basal Ganglia Diseases |
| D001927 | Brain Diseases |
| D002493 | Central Nervous System Diseases |
| D009422 | Nervous System Diseases |
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The Clinical Global Impression of Change (CGI-C) is a clinician-rated scale assessing overall change in the patient's clinical status. Score range: 1-7 Lower scores indicate greater improvement |
| Within 2 days after completing the 5-day LIFU treatment |
| Change in Unified Huntington's Disease Rating Scale Chorea Score | The UHDRS Chorea Score evaluates severity of choreiform movements. Score range: 0-28 Higher scores indicate more severe chorea | Baseline and within 2 days after completing the 5-day LIFU treatment |
| Change in Symbol Digit Modalities Test (SDMT) | The Symbol Digit Modalities Test (SDMT) is a cognitive assessment of processing speed and attention. Score range: 0-110 (number of correct matches within 90 seconds) Higher scores indicate better cognitive function | Baseline and within 2 days after completing the 5-day LIFU treatment |
| Change in Controlled Oral Word Association Test (COWAT) | The Controlled Oral Word Association Test (COWAT) assesses verbal fluency and executive function. Score range: 0-unlimited (total number of words generated across three trials, each 60 seconds) Higher scores indicate better verbal fluency and executive function | Baseline and within 2 days after completing the 5-day LIFU treatment |
| Change in Stroop Interference Test Score | The Stroop Interference Test assesses cognitive inhibition and executive function. Score range: 0-unlimited (number of correct responses on the interference task within a time limit) Higher scores indicate better cognitive function | Baseline and within 2 days after completing the 5-day LIFU treatment |
| Change in Functional Independence Scale | The Functional Independence Scale assesses a patient's level of independence in daily activities. Score range: 0-100 Higher scores indicate greater independence | Baseline and within 2 days after completing the 5-day LIFU treatment |
| Change in Total Functional Capacity (TFC) | The Total Functional Capacity (TFC) scale is a component of the Unified Huntington's Disease Rating Scale (UHDRS) that assesses functional capacity. Score range: 0-13 Higher scores indicate better functional capacity | Baseline and within 2 days after completing the 5-day LIFU treatment |
| Change in Functional Assessment Score | The Functional Assessment Score is a component of the Unified Huntington's Disease Rating Scale (UHDRS) that assesses the patient's ability to perform specific tasks. Score range: 0-25 Higher scores indicate better functional ability | Baseline and within 2 days after completing the 5-day LIFU treatment |
| Change in Serum Neuron-Specific Enolase (NSE) | Serum Neuron-Specific Enolase (NSE) is a biomarker of neuronal injury. Unit of measure: ng/mL Higher levels indicate more neuronal damage | Baseline and within 2 days after completing the 5-day LIFU treatment |
| Change in Multimodal Magnetic Resonance Imaging (MRI) Parameters | Change from baseline in structural and functional brain connectivity metrics as assessed by multimodal MRIto evaluate the neuromodulatory effects of LIFU. | Baseline and within 2 days after completing the 5-day LIFU treatment |
| D003704 | Dementia |
| D002819 | Chorea |
| D020820 | Dyskinesias |
| D009069 | Movement Disorders |
| D020271 | Heredodegenerative Disorders, Nervous System |
| D019636 | Neurodegenerative Diseases |
| D030342 | Genetic Diseases, Inborn |
| D009358 | Congenital, Hereditary, and Neonatal Diseases and Abnormalities |
| D003072 | Cognition Disorders |
| D019965 | Neurocognitive Disorders |
| D001523 | Mental Disorders |