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NCT Number: NCT07743866

Optimizing Parameters of Transcranial Temporal Interference Stimulation for Spinocerebellar Ataxia Type 3

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.

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Key information

Conditions

Spinocerebellar Ataxia Type 3 Ataxia Brain Diseases Central Nervous System Diseases Cerebellar Ataxia Cerebellar Diseases Congenital, Hereditary, and Neonatal Diseases and Abnormalities Dyskinesias Genetic Diseases, Inborn Heredodegenerative Disorders, Nervous System Machado-Joseph Disease Nervous System Diseases Neurodegenerative Diseases Neurologic Manifestations Spinal Cord Diseases Spinocerebellar Ataxias Spinocerebellar Degenerations

Age range

18 year–75 year

Sex eligibility

All sexes

Study type

Interventional

Phase

Not applicable

Primary location

Department of Rehabilitation Medicine, The First Affiliated Hospital of Fujian Medical University

Fuzhou, Fujian, China

Location contact

Xin-Yuan Chen

CONTACT

[email protected]

+86 15005065282

About this study

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.

Who can participate

Healthy volunteers accepted: No

Only the study team can determine whether someone qualifies for participation.

Inclusion criteria

  • 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.

Exclusion criteria

  • 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.

Treatment and study plan

Transcranial temporal interference stimulation (tTIS)

Device

Participants assigned to this intervention arm receive transcranial temporal interference stimulation (tTIS) with a difference frequency (Δf) of 30Hz/40Hz/70 Hz.

Before treatment, individualized electric field modeling is performed based on each participant's 3D-T1 MRI data to optimize electrode placement and stimulation parameters. The stimulation target is the bilateral cerebellar dentate nuclei. A personalized finite element head model is generated, and electrode positions are determined through simulation-based optimization to achieve focused interference electric fields at the target region.

During each treatment session, tTIS is delivered using two carrier frequencies of 2000 Hz and 2030Hz/2040Hz/2070 Hz, with a current intensity of 2.0 mA (zero-to-peak). Each session lasts 20 minutes. Treatment is administered twice daily, 5 days per week, for a total of 10 sessions.

Primary outcomes

  1. Safety: Incidence of Dose-Limiting Toxicity (DLT)

    Time frame: 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:

    • 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);
    • Clinically observable seizures during stimulation;
    • Severe headache with vomiting, confusion, or severe dizziness leading to syncope;
    • Severe sleep disturbance with psychiatric abnormalities (anxiety, depression, hallucinations, etc.);
    • 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

  2. Efficacy: To assess the proportion of patients with SARA improvement (decrease) of at least 1.5 from baseline after 5 days

    Time frame: 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.

  3. Comprehensive Benefit-Risk: Utility

    Time frame: 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.

Other outcomes

  1. The International Cooperative Ataxia Rating Scale (ICARS)

    Time frame: Baseline and within 24 hours after completing the 5-day tTIS treatment

    The International Cooperative Ataxia Rating Scale (ICARS) assesses the severity of cerebellar ataxia across four subscales: posture and gait disturbances, limb kinetic functions, speech disorders, and oculomotor disorders.

    Total score range: 0-100 Higher scores indicate more severe ataxia impairment.

  2. The European Quality of Life 5-Dimension (EQ-5D)

    Time frame: Baseline and within 24 hours after completing the 5-day tTIS treatment

    The European Quality of Life 5-Dimension Utility Index Score (EQ-5D Utility Index) assesses health-related quality of life across five dimensions: mobility, self-care, usual activities, pain/discomfort, and anxiety/depression.

    Participants' health states are described using a five-digit code, with values ranging from 11111 (no problems in any dimension) to 33333 (extreme problems in all dimensions). The health state code is converted into a utility index score using population-specific preference weights. The score is anchored at 1.0 for full health, with lower values indicating poorer health status; values below 0 may occur for health states considered worse than death depending on the applicable value set.

  3. Patient Global Impression of Change (PGI-C)

    Time frame: Within 24 hours after completing the 5-day tTIS treatment

    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

  4. Clinical Global Impression of Change (CGI-C)

    Time frame: Within 24 hours after completing the 5-day tTIS treatment

    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

  5. Change in Multimodal Magnetic Resonance Imaging (MRI) Parameters

    Time frame: Baseline and within 24 hours after completing the 5-day tTIS treatment

    Multimodal magnetic resonance imaging (MRI), including structural MRI (sMRI), resting-state fMRI (rs-fMRI) and diffusion tensor imaging (DTI), is performed to evaluate cerebral structural and functional alterations.

  6. Functional Near-Infrared Spectroscopy (fNIRS) assesses hemodynamic changes

    Time frame: Baseline and within 24 hours after completing the 5-day tTIS treatment

    Functional Near-Infrared Spectroscopy (fNIRS) assesses hemodynamic changes by measuring regional cerebral oxygenation in the cerebellar and motor cortical regions.

    Changes in oxygenation signals reflect alterations in regional neural activity through neurovascular coupling.

Study contacts

Contact information is provided by the study sponsor or research team.

Kai-Xiong Chen

CONTACT

[email protected]

+86 15280096886

Xin-Yuan Chen

CONTACT

[email protected]

+86 15005065282

Sponsors and collaborators

Lead sponsor

First Affiliated Hospital of Fujian Medical University

Other

Registry information

Official study title

Efficacy and Safety of Transcranial Temporal Interference Stimulation of the Cerebellar Dentate Nucleus Using Individualized Head Modeling in Patients With Spinocerebellar Ataxia Type 3

Important dates

Study start
2026
Primary completion
2026
Study completion
2027
First posted
Aug 4, 2026
Registry last updated
Aug 5, 2026

OpenTrials presents study information sourced from ClinicalTrials.gov. The official registry record should be consulted for the latest information.

View the official ClinicalTrials.gov record (opens in a new tab)

This listing is for discovery and informational purposes only. It is not medical advice, does not guarantee that a study is recruiting, and does not determine eligibility. Contact the study team and a qualified healthcare professional when considering participation.

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