Huntington Disease
Conditions
Keywords
low intensity focused ultrasound, Huntington Disease, brain stimulation, ultrasonic stimulation
Brief summary
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.
Detailed description
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.
Interventions
DEVICELow-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. 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.
Sponsors
First Affiliated Hospital of Fujian Medical University
Study design
Allocation
NON_RANDOMIZED
Intervention model
SEQUENTIAL
Primary purpose
TREATMENT
Masking
SINGLE (Outcomes Assessor)
Eligibility
Sex/Gender
ALL
Age
18 Years to 75 Years
Healthy volunteers
No
Inclusion criteria
1. Aged 18 to 75 years (inclusive) 2. Genetically confirmed Huntington's disease with HTT CAG repeat length of 40 or greater 3. 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 4. Huntington's Disease Integrated Staging System stage 2 or 3 5. Willing to participate and provide informed consent 6. Have a reliable caregiver available 7. No severe cognitive impairment that would preclude reliable reporting of adverse events or efficacy during treatment
Exclusion criteria
1. History of self-injury, aggressive behavior, or unstable psychiatric disorders 2. History of head injury or neurosurgical procedure 3. Presence of intracranial implants, metallic foreign bodies, cochlear implants, or cardiac pacemakers 4. Severe systemic disease, pregnancy, or breastfeeding 5. Contraindications to magnetic resonance imaging, ultrasound, or anesthesia 6. 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 7. Severe brain atrophy with unclear external globus pallidus structure on MRI 8. Concurrent participation in another interventional clinical trial 9. Any other condition that, in the opinion of the investigator, would preclude participation
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Safety: Incidence of Dose-Limiting Toxicity (DLT) | 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) | 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 | 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. |
Countries
China
Contacts
CONTACTXin-Yuan Chen
CONTACTLi-Zhu Wu
Outcome results
None listed