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.