Efficacy and Safety of Transcranial Temporal Interference Stimulation of the Cerebellar Dentate Nucleus Using Individualized Head Modeling in Patients With Spinocerebellar Ataxia Type 3
试验速览
- 阶段
- 不适用
- 状态
- 尚未招募
- 入组人数
- 24
- 试验地点
- 1
- 主要终点
- Safety: Incidence of Dose-Limiting Toxicity (DLT)
研究概览
简要总结
The purpose of this research study is to identify the optimal biological dose for tTIS that targets DN in SCA3 while achieving the best possible balance between therapeutic efficacy and safety.
详细描述
Spinocerebellar ataxia type 3 (SCA3), also known as Machado-Joseph disease, is an autosomal dominant neurodegenerative disorder caused by CAG repeat expansion in the ATXN3 gene. Selective degeneration of neurons in the cerebellar dentate nucleus (DN) leads to abnormal cerebellar outflow circuitry and impaired motor control, resulting in progressive gait ataxia, dysarthria and other motor symptoms. Current treatments are symptomatic only, with no disease-modifying therapies available. Deep brain stimulation targeting the dentate nucleus has shown efficacy but is invasive and associated with significant adverse events.
Transcranial temporal interference stimulation (tTIS) enables non-invasive, deep and spatially precise neuromodulation. It has been applied in various neurological and psychiatric disorders with favorable safety and efficacy, demonstrating potential for neuromodulation of deep cerebellar circuits.
This phase I/II adaptive dose-finding prospective interventional study evaluates the safety and efficacy of tTIS targeting the cerebellar dentate nucleus in patients with spinocerebellar ataxia type 3. Using MRI-derived individualized head models and real-time neuronavigation, the study employs a utility-based Bayesian optimal interval (U-BOIN) design with three difference frequencies: 30 Hz, 40 Hz, and 70 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 tTIS sessions over two consecutive weeks, with one session daily. Motor function, balance function, activities of daily living, and multimodal magnetic resonance imaging are evaluated before the first treatment session and after the final treatment session.
研究设计
- 研究类型
- Interventional
- 分配方式
- Non Randomized
- 干预模型
- Sequential
- 主要目的
- Treatment
- 盲法
- Single (Outcomes Assessor)
入排标准
- 年龄范围
- 18 Years 至 75 Years（Adult, Older Adult）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •A physician-diagnosed SCA3 according to diagnostic criteria, with definite clinical symptoms and confirmed genetic testing;
- •Age 18-75 years;
- •Baseline total score of SARA: 8-30 points (inclusive); SARA gait function subscore: 2-6 points (inclusive);
- •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.
排除标准
- •History of seizures or convulsions, or a seizure within 6 months prior to enrolment;
- •History of severe traumatic brain injury or intracranial neurosurgery;
- •Presence of cardiac pacemakers, cochlear implants, intracranial implanted electronic devices, or other MRI-contraindicated ferromagnetic implants;
- •Severe cognitive impairment (Mini-Mental State Examination [MMSE] score ≤ 9) or severe visual, auditory, or speech dysfunction preventing cooperation with scale assessments and study procedures;
- •Pregnant or lactating women, or women of childbearing age not using reliable contraception;
- •Previous neuromodulation treatment (e.g., rTMS or tDCS) within the past year;
- •Skin breakdown or inflammation at the electrode placement site, or known allergy to conductive gel or electrode patch adhesives;
- •Currently participating in other interventional clinical trials, or planning to participate in other trials that might affect the outcome assessment of this study during the study period.
研究组 & 干预措施
40 Hz Difference Frequency tTIS
Transcranial Temporal Interference Stimulation (tTIS) uses a difference frequency (Δf) of 40 Hz.
干预措施: Transcranial Temporal Interference Stimulation (tTIS) (Device)
30 Hz Difference Frequency tTIS
Transcranial Temporal Interference Stimulation (tTIS) uses a difference frequency (Δf) of 30 Hz.
干预措施: Transcranial Temporal Interference Stimulation (tTIS) (Device)
70 Hz Difference Frequency tTIS
Transcranial Temporal Interference Stimulation (tTIS) uses a difference frequency (Δf) of 70 Hz.
干预措施: Transcranial Temporal Interference Stimulation (tTIS) (Device)
结局指标
主要结局
Safety: Incidence of Dose-Limiting Toxicity (DLT)
时间窗: At any point during or immediately following intervention on day of tTIS application
DLT event is defined as any one of the following 5 categories: 1. Grade Ⅱ (moderate) or higher adverse events per the NCI-CTCAE grading criteria\[1\] that require topical or non-invasive intervention, such as skin burns (skin breakdown, blister formation); 2. Clinically observable seizures during stimulation; 3. Severe headache with vomiting, confusion, or severe dizziness leading to syncope; 4. Severe sleep disturbance with psychiatric abnormalities (anxiety, depression, hallucinations, etc.); 5. New brain lesions on imaging, or decreased apparent diffusion coefficient (ADC) values in the subcortex beneath the stimulation site. References \[1\] Antal A, et al. Low intensity transcranial electric stimulation: Safety, ethical, legal regulatory and application guidelines (2017-2025: An update) - endorsed by the European Society for Brain Stimulation (ESBS) and by the International Federation for Clinical Neurophysiology (IFCN). Clin Neurophysiol. 2026. 184: 2111436
Efficacy: To assess the proportion of patients with SARA improvement (decrease) of at least 1.5 from baseline after 5 days
时间窗: Baseline and within 24 hours after completing the 5-day tTIS treatment
The Scale for the Assessment and Rating of Ataxia (SARA) evaluates the severity of ataxia symptoms, including gait, posture, speech, and limb kinetic functions. Score range: 0-40 Higher scores indicate more severe ataxia. Response is defined as a reduction of ≥1.5 points from baseline.
Comprehensive Benefit-Risk: Utility
时间窗: Within 24 hours after completing the 5-day tTIS 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.
次要结局
未报告次要终点
研究者
Xinyuan Chen
Principal Investigator
First Affiliated Hospital of Fujian Medical University