An interventional study of Stimulation-Temperature-Oxygen-Positioning (STOP) Multimodal Neuroprotective Strategy and Guideline-Based Reperfusion Therapy and Standard Stroke-Unit Care in Acute Ischemic Stroke, sponsored by Second Affiliated Hospital, Zhejiang University, School of Medicine. Not yet recruiting. Open to participants aged 18 Years and older. Per ClinicalTrials.gov, last updated 2026-10-27.
Sponsored by Second Affiliated Hospital, Zhejiang University, School of Medicine · Not applicable, Interventional, and Treatment
Acute ischemic stroke may result in substantial disability despite timely reperfusion therapy because ischemic and reperfusion-related brain injury can continue before, during, and after restoration of blood flow. This investigator-initiated, prospective, multicenter, randomized, open-label, blinded-endpoint trial will evaluate whether a protocolized Stimulation-Temperature-Oxygen-Positioning (STOP) multimodal neuroprotective strategy added to guideline-based reperfusion therapy and stroke-unit care improves 90-day functional outcome compared with standard care alone.
A total of 380 adults with acute ischemic stroke treated with intravenous thrombolysis and/or endovascular therapy within 24 hours of symptom onset or last known well will be randomized in a 1:1 ratio to the STOP strategy plus standard care or standard care alone.
The STOP strategy comprises transcutaneous auricular vagus nerve stimulation, protocolized normothermia targeting a body temperature of 37.5 °C or lower, high-flow normobaric oxygen, and dynamic head positioning according to reperfusion treatment and recanalization status.
The primary outcome is the ordinal distribution of modified Rankin Scale scores at 90 days after randomization. Blinded assessors will evaluate functional outcomes, and a blinded central imaging core laboratory will adjudicate imaging outcomes.
Among participants with anterior-circulation large-vessel occlusion who undergo endovascular treatment and achieve successful reperfusion (final mTICI grade 2b-3), eligible and consenting participants may enter an embedded randomized substudy comparing selective intra-arterial hypothermia with no additional intra-arterial infusion. The second randomization will occur only after successful reperfusion has been confirmed.
Reperfusion therapy with intravenous thrombolysis and/or endovascular treatment is the cornerstone of acute ischemic stroke treatment. However, restoration of large-vessel blood flow does not necessarily result in complete tissue recovery. Persistent ischemic injury, microcirculatory dysfunction, neuroinflammation, blood-brain barrier disruption, cerebral edema, and hemorrhagic transformation may contribute to neurological injury before and after reperfusion.
The STOP strategy integrates four nonpharmacological neuroprotective interventions targeting complementary mechanisms. Participants assigned to the STOP group will receive transcutaneous auricular vagus nerve stimulation, protocolized temperature management, high-flow normobaric oxygen, and dynamic head positioning in addition to guideline-based reperfusion therapy and stroke-unit care. All trial interventions must be implemented without delaying intravenous thrombolysis, endovascular therapy, transfer, anesthesia, or other clinically indicated emergency treatment.
TaVNS will be initiated as early as practicable after randomization and may begin before, during, or after reperfusion treatment. The first stimulation session must begin no later than 24 hours after completion of the final reperfusion treatment. Stimulation will be applied to the left auricular region corresponding to the auricular branch of the vagus nerve, using a current intensity of 0.5 mA, frequency of 25 Hz, and pulse width of 200 μs for 20 minutes every 12 hours for five days, with 10 sessions planned. These parameters are based on the NUVISTA regimen. Heart rate, blood pressure, treatment tolerance, and auricular skin condition will be assessed around each session. Symptomatic bradycardia, clinically significant arrhythmia, substantial hemodynamic instability, or clinically relevant local skin injury will prompt interruption or discontinuation of the affected session. Start time, duration, delivered parameters, interruptions, and reasons for discontinuation will be recorded. Hospital discharge or transfer will not be delayed solely to complete the stimulation course; any uncompleted sessions will be documented as reduced treatment exposure rather than protocol withdrawal.
Protocolized temperature management will begin promptly after randomization and continue until 72 hours after completion of the final reperfusion treatment. The target body temperature is ≤37.5°C. For participants treated with IVT alone, the 72-hour period will be anchored to completion of thrombolytic administration; for participants undergoing direct EVT or bridging therapy, it will be anchored to completion of the EVT procedure. Body temperature will be measured at least every 4 hours during the intervention period, with additional measurements when clinically indicated. The measurement site and method will be recorded and, whenever feasible, kept consistent within an individual participant. A temperature >37.5°C will trigger prompt evaluation for infection and other causes of fever and protocol-directed temperature-lowering treatment using antipyretic medication, physical cooling, or both, according to clinical circumstances. Repeated or additional cooling measures may be used when temperature remains above the target. Temperature measurements, interventions, and subsequent response will be recorded. Induction of systemic therapeutic hypothermia is not part of the STOP strategy.
Normobaric oxygen therapy will begin as early as practicable after randomization, preferably before or at initiation of reperfusion treatment, without delaying standard treatment. Nonintubated participants will receive oxygen through a high-concentration reservoir mask at a flow rate of 10 L/min. Participants who are intubated or mechanically ventilated will receive an inspired oxygen fraction of 1.0. Oxygen therapy will continue for four hours from initiation, irrespective of the final reperfusion grade. Peripheral oxygen saturation and respiratory status will be monitored throughout treatment, with oxygen saturation maintained at ≥94%. Clinically significant carbon dioxide retention, worsening respiratory status, or substantial intolerance will prompt adjustment or discontinuation as clinically indicated. Oxygen-delivery device, flow rate, ventilator settings when applicable, start and stop times, and treatment interruptions will be recorded.
Positioning will be adapted to the reperfusion pathway and, for participants undergoing EVT, to the final degree of reperfusion. Participants treated with IVT without subsequent EVT will be maintained in a 0° supine position for 24 hours after completion of thrombolysis. Participants undergoing EVT, including those receiving bridging therapy, will be maintained in a 0° supine position while awaiting thrombectomy and during transfer when feasible. After EVT, participants with successful reperfusion, defined as modified Thrombolysis in Cerebral Infarction (mTICI) grade ≥2b, will be positioned with approximately 30° head elevation for the subsequent 24 hours, whereas those with mTICI \<2b will be placed at approximately -20° Trendelenburg position for the subsequent 24 hours when clinically safe and tolerated. For participants managed in a flat or head-down position, development of symptomatic intracranial hemorrhage (sICH), parenchymal hematoma (PH), progressive cerebral edema or raised intracranial pressure, vomiting or aspiration, clinically important respiratory compromise, or another safety concern will prompt discontinuation of the prescribed position and elevation to approximately 30° or another clinically appropriate position. Brief interruptions for feeding, nursing care, diagnostic procedures, rehabilitation, or other necessary clinical activities are permitted. Actual head position, cumulative exposure time, interruptions, and reasons for protocol-directed modification will be recorded.
Participants assigned to the control group will receive guideline-based reperfusion therapy and standard stroke-unit care. Clinically indicated oxygen therapy, antipyretic treatment, positioning changes, rescue therapy, and other necessary treatment will not be withheld.
Among participants with anterior-circulation large-vessel occlusion treated with endovascular therapy, those who achieve successful reperfusion (final mTICI grade 2b-3) and meet the substudy safety criteria may undergo a second centrally concealed 1:1 randomization, stratified by the main-trial STOP assignment, to selective intra-arterial hypothermia or no additional intra-arterial infusion. Participants with vessel perforation, contrast extravasation, definite or strongly suspected procedural intracranial hemorrhage, another serious interventional complication, or another condition considered by the treating interventionist to make additional intra-arterial infusion unsafe will not undergo the second randomization. Additional informed consent may be obtained before EVT on a conditional basis, but eligibility will be reassessed and randomization performed only after EVT has been completed and successful reperfusion confirmed. Participants assigned to hypothermia will receive 300 mL of 0.9% saline at 4 °C through a guiding or intermediate catheter supplying the reperfused vascular territory, infused at 30 mL/min for 10 minutes as soon as practicable after successful reperfusion. Participants assigned to the control group will receive no additional intra-arterial saline infusion. No pre-reperfusion cooling bolus or additional fallback infusion is planned.
2,612 studies on the registry are indexed under Ischemic Stroke; 971 are open to participants now.
This study's planned enrollment of 380 is above the median of 120 across 1,776 interventional studies indexed under Ischemic Stroke.
Browse Ischemic Stroke studies →Second Affiliated Hospital, Zhejiang University, School of Medicine is the lead sponsor of 99 studies on the registry; 67 are open to participants now.
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Informed consent
Before you join, the study team explains what taking part involves — its purpose, what happens, the risks and possible benefits — and answers your questions, so you can decide freely. Consent is usually recorded on a form (the informed consent form, ICF) signed by you or, where the law allows, by someone legally authorised to decide for you.
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Clinically significant
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Participants receive the protocolized STOP multimodal neuroprotective strategy in addition to guideline-based reperfusion therapy and stroke-unit care. The STOP strategy comprises transcutaneous auricular vagus nerve stimulation, protocolized normothermia, high-flow normobaric oxygen, and dynamic head positioning. Each component may be modified, interrupted, or discontinued for prespecified safety reasons. Trial procedures must not delay reperfusion therapy or other clinically necessary treatment.
Other: Stimulation-Temperature-Oxygen-Positioning (STOP) Multimodal Neuroprotective Strategy
Participants receive guideline-based reperfusion therapy and standard stroke-unit care. Intravenous thrombolysis and/or endovascular therapy are performed according to contemporaneous national and institutional standards. Oxygen therapy, antipyretic treatment, positioning changes, and other rescue treatments are provided when clinically indicated, but no protocolized STOP bundle is mandated.
Other: Guideline-Based Reperfusion Therapy and Standard Stroke-Unit Care
The STOP strategy comprises four protocolized nonpharmacological interventions added to guideline-based care: (1) taVNS to the left auricular vagus nerve region (0.5 mA, 25 Hz, 200 μs, 20 min every 12 h for 5 days; first session as early as feasible and within 24 h after final reperfusion treatment); (2) temperature management targeting body temperature ≤37.5 °C through 72 h after final reperfusion treatment; (3) high-flow normobaric oxygen initiated as early as possible, preferably before or at reperfusion treatment, at 10 L/min by reservoir mask in non-intubated patients or FiO2 1.0 in intubated patients, for 4 h; and (4) dynamic head positioning: IVT-only patients will remain supine (0°) for 24 h. EVT patients will remain supine (0°) before thrombectomy when feasible. After EVT, patients with mTICI ≥2b will receive 30° head elevation, while those with mTICI \<2b will receive -20° Trendelenburg positioning for 24 h, when clinically safe and tolerated.
Participants receive guideline-based reperfusion therapy, including intravenous thrombolysis and/or endovascular therapy when clinically indicated, together with standard stroke-unit care according to contemporary national and institutional guidelines. Standard care may include physiological monitoring and management, antithrombotic and lipid-lowering therapy, management of cerebral edema, dysphagia and aspiration precautions, venous thromboembolism prevention, rehabilitation, clinically indicated oxygen therapy, antipyretic treatment, positioning adjustments, and other rescue treatments. Clinically necessary treatment will not be withheld because of trial participation.
Distribution of disability across the modified Rankin Scale at 90 days
The modified Rankin Scale (mRS) is a 7-category global disability scale ranging from 0 (no symptoms) to 6 (death); lower scores indicate better functional status. The full ordinal distribution will be assessed by a trained evaluator blinded to treatment allocation.
Time frame: Day 90 after randomization
Functional independence at 90 days
Proportion of participants with an mRS score of 0-2. The mRS ranges from 0 (no symptoms) to 6 (death); lower scores indicate better functional status.
Time frame: Day 90 after randomization
Excellent functional outcome at 90 days
Proportion of participants with an mRS score of 0-1. The mRS ranges from 0 (no symptoms) to 6 (death); lower scores indicate better functional status.
Time frame: Day 90 after randomization
National Institutes of Health Stroke Scale score at 24 hours
The National Institutes of Health Stroke Scale (NIHSS) score ranges from 0 to 42; higher scores indicate greater neurological deficit.
Time frame: 24 hours after randomization
National Institutes of Health Stroke Scale score at Day 7
The National Institutes of Health Stroke Scale (NIHSS) score ranges from 0 to 42; higher scores indicate greater neurological deficit.
Time frame: Day 7 after randomization
Change in National Institutes of Health Stroke Scale score from baseline to 24 hours
Change calculated as the 24-hour NIHSS score minus the baseline score. The NIHSS ranges from 0 to 42; higher scores indicate greater neurological deficit, so a negative change indicates improvement.
Time frame: Baseline and 24 hours after randomization
Change in National Institutes of Health Stroke Scale score from baseline to Day 7
Change calculated as the Day 7 NIHSS score minus the baseline score. The NIHSS ranges from 0 to 42; higher scores indicate greater neurological deficit, so a negative change indicates improvement.
Time frame: Baseline and Day 7 after randomization
Early neurological improvement at 24 hours
Proportion of participants with a decrease of at least 4 points in NIHSS score from baseline or an NIHSS score of 0-1 at 24 hours. The NIHSS ranges from 0 to 42; lower scores indicate less neurological deficit.
Time frame: 24 hours after randomization
Early neurological deterioration at 24 hours
Proportion of participants with an increase of at least 4 points in NIHSS score from baseline or death within 24 hours after randomization.
Time frame: 24 hours after randomization
All-cause mortality at 90 days
Proportion of participants who have died from any cause.
Time frame: Day 90 after randomization
Final infarct volume
Final infarct volume (mL) measured on follow-up CT or MRI, assessed by a blinded central imaging core laboratory.
Time frame: Day 3 to 7 after randomization
Infarct growth
Infarct growth (mL), calculated as final infarct volume minus baseline ischemic-core volume, among participants with reliable baseline ischemic-core measurements obtained from CT perfusion or diffusion-weighted MRI.
Time frame: Baseline and Day 3 to 7 after randomization
Cerebral edema score
Cerebral edema severity will be assessed on follow-up CT or MRI using a SITS-MOST-based 0-3 grading system: grade 0, no edema; grade 1, swelling involving ≤1/3 of the hemisphere; grade 2, swelling involving \>1/3 of the hemisphere; and grade 3, swelling with midline shift. For posterior fossa infarctions, grades 1-3 indicate focal swelling without compression, fourth ventricular or cisternal compression, and severe swelling with brainstem compression, obstructive hydrocephalus, or herniation, respectively. Assessments will be performed by a blinded central imaging core laboratory.
Time frame: From randomization through Day 7
Proportion of participants with cerebral mass effect
Maximum midline shift (mm) measured on follow-up CT or MRI as a quantitative Proportion of participants with cerebral mass effect on follow-up CT or MRI, defined as imaging evidence of sulcal effacement, ventricular compression, or midline shift attributable to ischemic brain swelling. All imaging findings will be assessed by a blinded central imaging core laboratory.
Time frame: From randomization through Day 7
Occurrence of any intracranial hemorrhage
Proportion of participants with any intracranial hemorrhage detected on follow-up CT or MRI, including hemorrhagic infarction, parenchymal hematoma, subarachnoid hemorrhage, or intraventricular hemorrhage, classified according to the Heidelberg Bleeding Classification.
Time frame: From randomization through Day 7
Occurrence of parenchymal hematoma type 1 (PH-1)
Proportion of participants with parenchymal hematoma type 1 (PH-1), defined as hematoma involving less than 30% of the infarcted area with mild space-occupying effect, based on follow-up brain imaging.
Time frame: From randomization through Day 7
Occurrence of parenchymal hematoma type 2 (PH-2)
Proportion of participants with parenchymal hematoma type 2 (PH-2), defined as hematoma involving more than 30% of the infarcted area with substantial space-occupying effect, based on follow-up brain imaging.
Time frame: From randomization through Day 7
Occurrence of symptomatic intracranial hemorrhage (sICH)
Proportion of participants with symptomatic intracranial hemorrhage (sICH), defined according to the European Cooperative Acute Stroke Study III (ECASS III) criteria as any intracranial hemorrhage detected on CT or MRI associated with neurological deterioration (an increase of ≥4 points in the National Institutes of Health Stroke Scale \[NIHSS\] score) or death, with the hemorrhage identified as the predominant cause of neurological deterioration.
Time frame: Within 36 hours after randomization
Occurrence of intervention-related adverse events
Proportion of participants experiencing adverse events considered possibly, probably, or definitely related to the multimodal neuroprotective interventions, including hypothermia, hypotension, hypoxemia, pulmonary complications, cardiac arrhythmias, and complications associated with intra-arterial cold saline infusion.
Time frame: From randomization through Day 90
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Second Affiliated Hospital, Zhejiang University, School of Medicine