Low-FREquency Deep TRanscranial Magnetic Stimulation in ACute Ischaemic StrokE within 48 Hours (RETRACE-I): rationale and design of a randomised, multicentre, open-label, blinded endpoint trial.

BACKGROUND: Acute ischaemic stroke often leads to significant disability and mortality. Secondary brain injury caused by post-stroke immune and inflammatory responses worsens outcomes. AIM: To assess the efficacy and safety of low-frequency deep transcranial magnetic stimulation (LF-dTMS), delivered with an H4 coil to target the insular and prefrontal cortex, and its potential effects on neuroimmune activity and recovery. DESIGN: This randomised, multicentre, open-label, parallel-group trial with blinded outcome assessment evaluates early LF-dTMS at 1 Hz using the H4 coil in adults with anterior-circulation acute ischaemic stroke treated within 48 hours of onset. Participants are randomly assigned in a 1:1 ratio to receive either standard care plus LF-dTMS or standard care alone. Active LF-dTMS is delivered as two sessions per day, 1200 pulses per session, for three consecutive days. STUDY OUTCOMES: The primary efficacy outcome is the growth in infarct volume from baseline to day 3, measured by diffusion-weighted MRI. The primary safety outcome is symptomatic intracranial haemorrhage within 3 days of treatment. Secondary outcomes include the modified Rankin Scale and serious adverse events at 90 days. Exploratory analyses in a predefined subgroup will involve dynamic plasma proteomics and single-cell RNA sequencing of peripheral mononuclear cells to understand immune responses (days 0, 3, 7), as well as resting-state functional MRI to evaluate the effects of neuromodulation on brain network connectivity. SUMMARY: This study will evaluate the feasibility, safety and preliminary efficacy of early LF-dTMS in acute stroke. It will provide proof-of-concept data on whether modulating post-stroke inflammation and neuroplasticity can improve outcomes. The findings will inform the design of a large definitive trial. TRIAL REGISTRATION NUMBER: NCT06064734.