Personalized Transcranial Magnetic Stimulation (TMS) for Metabolic Dysfunction and Alcohol-Related Liver Disease

Official title

Personalized Transcranial Magnetic Stimulation for Metabolic Dysfunction and Alcohol-Related Liver Disease (MetALD): A Prospective, Multicenter, Randomized, Double-Blind, Placebo-Controlled Clinical Trial

Overview

The goal of this clinical trial is to learn if repetitive Transcranial Magnetic Stimulation (rTMS), a non-invasive brain stimulation technique, works to treat Metabolic dysfunction-associated and alcohol-associated liver disease (MetALD). The main questions it aims to answer are: * Can rTMS effectively treat MetALD? * Is an individualized, precision-targeted rTMS approach more effective than the standard rTMS method? * What changes in brain activity are associated with the treatment? Researchers will compare three different types of stimulation: * Group A: Individualized rTMS targeting a deep brain reward area (the Nucleus Accumbens) based on each participant's brain scan (fMRI). * Group B: Standard rTMS applied using the traditional "5 cm" rule for positioning. * Group C: Sham (placebo) rTMS, which mimics the procedure but delivers no significant magnetic stimulation. Participants will: * Be randomly assigned to one of the three groups (A, B, or C). * Undergo an MRI brain scan before starting treatment. * Receive a total of 20 rTMS sessions, completing at least 4 sessions per week. * Have additional MRI scans and clinical assessments halfway through and immediately after the treatment course. * Attend follow-up visits at 1, 3, and 6 months after treatment completion to assess long-term effects.

Interventions

• Device Individually Targeted rTMS
  Participants will receive individualized transcranial magnetic stimulation (TMS) based on neuroimaging-guided localization of the nucleus accumbens (NAc). After the first MRI scan, participants will be randomized by an independent researcher responsible for data analysis. The individualized stimulation coordinates will be provided to the TMS operator before treatment. Intervention will be delivered using intermittent theta-burst stimulation (iTBS): the coil will be placed tangentially to the sc
• Device Conventional rTMS
  Conventional rTMS is applied to the left dorsolateral prefrontal cortex (DLPFC) using the standard 5 cm rule for scalp-based localization. Stimulation is delivered with intermittent theta-burst stimulation (iTBS) at 90% resting motor threshold (RMT), 3 pulses at 50 Hz per burst, repeated at 5 Hz, for a total of 1800 pulses per session. Each session lasts about 570 seconds. Participants complete 20 sessions over 4 weeks, with 2 sessions per day on 2 days per week.
• Device Transcranial Magnetic Stimulation Sham
  Sham rTMS is delivered using a sham coil or low-intensity stimulation (10% RMT) to mimic the clicking sounds and scalp sensations of active rTMS without producing cortical activation. The sham sessions are matched to the active treatment in frequency, duration, and total number: 20 sessions in 4 weeks (2 sessions/day, 2 days/week, 570 seconds per session).

Primary outcome measures

• Percent Change in Liver Fat Content (LFC) From Baseline to End of Treatment as Measured by Magnetic Resonance Imaging-Proton Density Fat Fraction (MRI-PDFF) [Time frame: From baseline to the end of treatment (Week 4)]

Secondary outcome measures (12)

• Change in Controlled Attenuation Parameter (CAP, dB/m) From Baseline as Assessed by Vibration-Controlled Transient Elastography (FibroScan® VCTE) [Time frame: From baseline to mid-treatment (Week 2), end of treatment (Week 4), and at 1-, 3-, and 6-month follow-up]
• Change in Liver Stiffness Measurement (LSM, kPa) From Baseline as Assessed by FibroScan® VCTE [Time frame: From baseline to mid-treatment (Week 2), end of treatment (Week 4), and at 1-, 3-, and 6-month follow-up]
• LFC From Baseline as Measured by MRI-PDFF [Time frame: From baseline to the end of treatment (Week 4)]
• Proportion of Participants Achieving ≥30% or ≥50% Reduction in LFC From Baseline [Time frame: From baseline to the end of treatment (Week 4)]
• Change in Serum Levels of Liver Enzymes (ALT, AST, ALP, GGT [U/L]) From Baseline [Time frame: baseline, mid-treatment (Week 2), end of treatment (Week 4), 1, 3, 6 months]
• Change in Serum Level of Albumin From Baseline [Time frame: baseline, mid-treatment (Week 2), end of treatment (Week 4), 1, 3, 6 months]
• Change in International Normalized Ratio (INR) From Baseline [Time frame: baseline, mid-treatment (Week 2), end of treatment (Week 4), 1, 3, 6 months]
• Change in Prothrombin Time (PT) From Baseline [Time frame: baseline, mid-treatment (Week 2), end of treatment (Week 4), 1, 3, 6 months]
• Change in Serum Level of Total Bilirubin (TBIL) From Baseline [Time frame: baseline, mid-treatment (Week 2), end of treatment (Week 4), 1, 3, 6 months]
• Proportion of Participants With ALT Reduction >17 U/L From Baseline [Time frame: baseline, mid-treatment (Week 2), end of treatment (Week 4), 1, 3, 6 months]
• Change in Glucose Metabolism Markers (HOMA-IR [Index]; HOMA-β [Index]) From Baseline [Time frame: baseline, mid-treatment (Week 2), end of treatment (Week 4), 1, 3, 6 months]
• Change in Glucose Metabolism Markers (HbA1c [%]) From Baseline [Time frame: baseline, mid-treatment (Week 2), end of treatment (Week 4), 1, 3, 6 months]

Eligibility criteria

Inclusion criteria

• Participants are able to understand the study protocol, requirements, and restrictions, are fully informed of potential adverse events, are willing to comply with follow-up visits, and voluntarily sign the informed consent form before enrollment.
• Meet the diagnostic criteria for MASLD according to the Guidelines for the Prevention and Treatment of Metabolic (Non-Alcoholic) Fatty Liver Disease (2024 Edition), and fulfill the European definition of MetALD with moderate alcohol consumption (20-50 g/day for women; 30-60 g/day for men).
• Age between 18 and 65 years.
• Body mass index (BMI) > 24 kg/m².
• No history of alcohol abuse.

Exclusion criteria

• Contraindications to magnetic resonance imaging (MRI) or transcranial magnetic stimulation (TMS).
• Mild cognitive impairment, defined as Montreal Cognitive Assessment (MoCA) score < 25.
• Severe comorbid somatic diseases or neurological disorders.
• History of psychiatric disorders, or current use of antipsychotic medications.
• Pregnant or breastfeeding women, or those planning pregnancy.
• Previous TMS treatment within the last 3 months.

Criteria are shown verbatim from the registry (in English). Final eligibility is always assessed by the study center.

Healthy volunteers: No

Study design

Allocation

Randomized

Model

Parallel assignment

Masking

Quadruple blind

Primary purpose

Treatment

Study locations

China · 1 center

• The Affiliated Hospital of Hangzhou Normal University — Hangzhou

Identifiers

NCT: NCT07399600 · SJP20250926

Primary sources (government registries)

• ClinicalTrials.gov (US NIH)

View this study on ClinicalTrials.gov ↗