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.
Study Type
INTERVENTIONAL
Allocation
NON_RANDOMIZED
Purpose
TREATMENT
Masking
SINGLE
Enrollment
24
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.
Department of Rehabilitation Medicine, The First Affiliated Hospital of Fujian Medical University
Fuzhou, Fujian, China
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.
Time frame: 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.
Time frame: 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.
Time frame: Within 2 days after completing the 5-day LIFU treatment
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