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

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

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.

Study Overview

• Status: Not yet recruiting
• Conditions: Ischemic Stroke
• Intervention / Treatment: Device: LNM-navigated cTBS; Device: Sham cTBS

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.

• Study Type: Interventional
• Enrollment (Estimated): 60
• Phase: Phase 2

Contacts and Locations

• Study Contact: Name: Zixiao Li, MD; Email: lizixiao2008@hotmail.com
• Study Contact Backup: Name: Lingling Ding, MD; Phone Number: 008613552358752; Email: dinglingling@bjtth.org

Study Locations

• China
  • Beijing, China, 100070
    • Beijing Tiantan Hospital
    • Contact: Zixiao Li, MD; Email: lizixiao2008@hotmail.com
    • Contact: Lingling Ding, MD; Phone Number: 008613552358752; Email: dinglingling@bjtth.org
    • Principal Investigator: Zixiao Li, MD

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Adult; Older Adult
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

1. Age 18-80 years.
2. Ischemic stroke onset within the past 14 days.
3. Unilateral, supratentorial ischemic stroke confirmed by CT or MRI.
4. Pre-stroke modified Rankin Scale (mRS) score of 0-1.
5. 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.
6. Written informed consent signed by the patient or the patient's legally authorized representative.

Exclusion Criteria:

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

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Quadruple

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: LNM-navigated cTBS group; Patients receive two daily sessions for 7 consecutive days. Each session uses a figure-8 coil under neuronavigation to deliver 3-pulse bursts at 50 Hz, repeated at 5 Hz (continuous theta burst) for a total of 600 pulses in 40 seconds per target. Targets are individualized via lesion network mapping of the patient's acute infarct, selecting symptom-relevant network nodes. Stimulus intensity is set at 80% of the resting motor threshold.	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 threshold (RMT), administered as 3-pulse bursts at 50 Hz, repeated at a theta frequency of 5 Hz.
Sham Comparator: Sham cTBS group; Procedures mimic the active group in coil positioning, timing, navigation, acoustic noise, and session schedule, but use a sham coil that produces no effective magnetic field.	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 participants and assessors remain blinded while no effective pulses are delivered.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Proportion of patients achieving mRS 0-2		Day 90 post-randomization
Proportion experiencing serious adverse events (SAEs)	Proportion experiencing serious adverse events (SAEs), including seizures	Within 90 days post-randomization

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Distribution shift in mRS scores		Day 90 post-randomization
Proportion of patients achieving mRS 0-1		Day 90 post-randomization
National Institutes of Health Stroke Scale (NIHSS) total score	Change in National Institutes of Health Stroke Scale (NIHSS) total score from baseline to 7 days post-randomization.	Day 7 post-randomization
Fugl-Meyer Assessment (FMA) score	Change in Fugl-Meyer Assessment (FMA) score from baseline to 7 days post-randomization.	Day 7 post-randomization
Barthel Index of Activities of Daily Living score		Day 90 post-randomization
EQ-5D-5L	EuroQol five-dimensional five-level health questionnaire	Day 90 post-randomization
Early neurological deterioration	Proportion of patients with neurological deterioration (defined as a ≥4-point increase in NIHSS score) within 7 days post-randomisation.	7 days post-randomisation
Proportion of participants with insomnia	The proportion of participants with insomnia reported within 7 days after randomization.	Within 7 days after randomization.
Proportion of participants with headache	The proportion of participants with headache reported within 7 days after randomization;	Within 7 days after randomization;
Proportion of participants with symptomatic intracranial hemorrhage	The proportion of participants with symptomatic intracranial hemorrhage reported within 7 days after randomization.	Within 7 days after randomization.
All-Cause Mortality	Proportion of patients who died from any cause	Within 90 days post-randomization
Proportion with symptomatic stroke (ischemic or hemorrhagic)		Within 90 days post-randomization
Any Adverse Events (AEs)	Proportion experiencing any adverse events	Within 90 days post-randomization

Collaborators and Investigators

• Sponsor: Beijing Tiantan Hospital

Publications and helpful links

General 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.

Study record dates

Study Major Dates

• Study Start (Estimated): June 15, 2026
• Primary Completion (Estimated): September 30, 2027
• Study Completion (Estimated): December 30, 2027

Study Registration Dates

• First Submitted: June 9, 2026
• First Submitted That Met QC Criteria: June 9, 2026
• First Posted (Actual): June 12, 2026

Study Record Updates

• Last Update Posted (Actual): June 12, 2026
• Last Update Submitted That Met QC Criteria: June 9, 2026
• Last Verified: June 1, 2026

More Information

Terms related to this study

• Keywords: Motor function; Neuronavigation; Continuous theta-burst stimulation; Lesion network mapping; ishchemic stroke
• Additional Relevant MeSH Terms: Cerebrovascular Disorders; Brain Diseases; Central Nervous System Diseases; Nervous System Diseases; Vascular Diseases; Cardiovascular Diseases; Stroke; Ischemic Stroke
• Other Study ID Numbers: KY2025-087

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No