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.
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
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
Sequential
Low-Intensity Focused Ultrasound Stimulation（LIFU）
DeviceThis 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.
Safety: Incidence of Dose-Limiting Toxicity (DLT)
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)
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
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.
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
Clinical Global Impression of Change (CGI-C)
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
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
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
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