A Phase 2b Trial of Lesion Network Mapping-Guided cTBS for Motor Recovery After Acute Ischemic Stroke

Official title

Lesion Network Mapping-Navigated Continuous Theta-Burst Stimulation for Motor Recovery in Acute Ischemic Stroke: A Randomized, Double-Blind, Sham-Controlled, Multicentre Phase 2b Trial: MASTRE-2

Overview

This Phase 2b study will evaluate whether lesion network mapping-guided continuous theta burst stimulation (cTBS) can improve recovery after acute ischemic stroke. The treatment uses each participant's brain imaging to identify individualized stimulation targets related to stroke symptoms. Participants will receive either active cTBS or a sham procedure in addition to standard stroke care. The study will assess the efficacy and safety of this personalized brain stimulation approach and support planning for future confirmatory trials.

Detailed description

Acute ischemic stroke can lead to persistent motor impairment despite standard medical treatment and rehabilitation. The early post-stroke period may provide an important window for modulating brain network plasticity and supporting functional recovery. Continuous theta burst stimulation (cTBS), a patterned form of repetitive transcranial magnetic stimulation, can modulate cortical excitability over a short stimulation period and may enhance recovery when applied to clinically relevant motor networks.

This Phase 2b study evaluates a personalized neuromodulation approach based on lesion network mapping. For each participant, the acute infarct lesion is identified on clinical brain imaging and mapped to a reference functional connectome to estimate lesion-associated brain networks. Candidate stimulation targets are selected from symptom-relevant cortical network nodes, with consideration of accessibility, safety, and electric-field modeling. Neuronavigation is used to guide coil placement and maintain targeting accuracy during treatment.

Active treatment consists of lesion network mapping-guided cTBS delivered to individualized cortical targets using a figure-8 coil under neuronavigation. Sham stimulation follows the same imaging-based target selection, electric-field modeling, positioning, and procedural workflow, but uses a sham coil designed to mimic the sensory and acoustic features of stimulation without delivering a therapeutic magnetic field. This approach is intended to maintain blinding of participants and outcome assessors while isolating the effect of active stimulation.

The study is designed to evaluate the efficacy and safety of individualized lesion network mapping-guided cTBS for recovery after acute ischemic stroke and to inform the design of future confirmatory trials.

Interventions

• Device LNM-navigated cTBS
  Individualized treatment targets are defined by outlining lesion areas on each patient's MRI and projecting them onto a normative functional connectivity map to identify symptom-specific connectivity disruptions within sensorimotor regions. Twice-daily treatments, administered over seven consecutive days, employ an "8"-shaped coil guided by neuronavigation for real-time targeting. For each target, a 40-second session delivers 600 pulses at an intensity of 80% of each participant's resting motor
• Device Sham cTBS
  Sham LNM-navigated cTBS follows the identical workflow, including MRI-based lesion mapping, target selection, electric-field modeling, and neuronavigation, but uses a sham figure-8 coil that mimics the sound and sensation of stimulation without generating a significant magnetic field. Participants receive two sham treatment sessions per day for seven consecutive days. Each session follows the same 40-second protocol timing and coil positioning as the active intervention, ensuring that participan

Primary outcome measures

• Proportion of patients achieving mRS 0-2 [Time frame: Day 90 post-randomization]
• Proportion experiencing serious adverse events (SAEs) [Time frame: Within 90 days post-randomization]

Secondary outcome measures (12)

• Distribution shift in modified Rankin Scale (mRS) score [Time frame: Day 90 post-randomization]
• Proportion of patients achieving mRS 0-1 [Time frame: Day 90 post-randomization]
• Change from baseline in National Institutes of Health Stroke Scale (NIHSS) total score at Day 7 [Time frame: Day 7 post-randomization]
• Change from baseline in Fugl-Meyer Assessment of Motor Recovery after Stroke motor score at Day 7 [Time frame: Day 7 post-randomization]
• Barthel Index for Activities of Daily Living score at Day 90 [Time frame: Day 90 post-randomization]
• EuroQol 5-Dimension 3-Level Questionnaire (EQ-5D-3L) utility index score [Time frame: Day 90 post-randomization]
• Early neurological deterioration [Time frame: 7 days post-randomisation]
• Proportion of participants with insomnia [Time frame: Within 7 days after randomization.]
• Proportion of participants with headache [Time frame: Within 7 days after randomization;]
• Proportion of participants with symptomatic intracranial hemorrhage [Time frame: Within 7 days after randomization.]
• All-Cause Mortality [Time frame: Within 90 days post-randomization]
• Proportion with symptomatic stroke (ischemic or hemorrhagic) [Time frame: Within 90 days post-randomization]

Eligibility criteria

Inclusion criteria

• Age 18-80 years.
• Ischemic stroke onset within the past 14 days.
• Unilateral, supratentorial ischemic stroke confirmed by CT or MRI.
• Pre-stroke modified Rankin Scale (mRS) score of 0-1.
• NIH Stroke Scale (NIHSS) total score 6-25, with item 1a ≤ 1 point, and at least one of items 5a, 5b, 6a, or 6b ≥ 2 points.
• Written informed consent signed by the patient or the patient's legally authorized representative.

Exclusion criteria

• Contraindications to TMS (e.g. cranial metallic foreign bodies, cardiac pacemaker, implanted drug pump, cochlear implant).
• History of epilepsy or seizure, intracranial hypertension, tumor, or other serious neurological disease.
• Midline shift or parenchymal mass effect on cranial CT or other imaging.
• CT or MRI evidence of bilateral acute cerebral infarction or infratentorial acute infarction (brainstem or cerebellum).
• Evidence of acute intracranial hemorrhage, including spontaneous intracerebral hemorrhage, epidural hematoma, subdural hematoma, intraventricular hemorrhage, or subarachnoid hemorrhage.
• Pre-stroke mRS ≥ 2.
• Systolic blood pressure ≥ 180 mmHg or diastolic blood pressure ≥ 110 mmHg despite antihypertensive treatment.
• Pregnant or breastfeeding women, or women planning pregnancy within 90 days.
• Severe psychiatric disorders or dementia (or other conditions) precluding informed consent or follow-up.
• Concomitant malignant tumor or severe systemic disease with life expectancy < 90 days.
• Participation in any other interventional clinical study within 30 days before randomization, or currently enrolled in such a study.

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

• Beijing Tiantan Hospital — Beijing

Publications

• Ding L, Liu H, Jing J, Jiang Y, Meng X, Chen Y, Zhao X, Niu H, Liu T, Wang Y, Li Z. Lesion Network Mapping for Neurological Deficit in Acute Ischemic Stroke. Ann Neurol. 2023 Sep;94(3):572-584. doi: 10.1002/ana.26721. Epub 2023 Jun 27. PMID 37314250

Identifiers

NCT: NCT07645560 · KY2025-087

Primary sources (government registries)

• ClinicalTrials.gov (US NIH)

View this study on ClinicalTrials.gov ↗