Transcranial Direct Current Stimulation in Acute Ischemic Stroke Treatment

Study Overview
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Brief Summary
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This prospective interventional single center randomized sham controlled dose-escalation study will assess safety, tolerability, feasibility and potential efficacy of transcranial direct current stimulation (tDCS) in acute stroke patients with substantial salvageable penumbra due to a large vessel occlusion who are ineligible for endovascular therapy (EVT). Patients will be randomized in a 3:1 design, to cathodal versus sham (control) tDCS, at each six designed dose tiers. The dose tiers will be increasing in both intensity and duration of the stimulation. The occurrence of symptomatic intracranial hemorrhage will determine the pace of the escalation through the dose tiers.

Official Title
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Transcranial Direct Current Stimulation in Acute Ischemic Stroke Treatment - Safety and Feasibility Trial

Conditions
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Stroke

Intervention / Treatment
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* Device: Soterix Medical 1X1 tDCS stimulator (active C-tDCS)
* Device: Soterix Medical 1X1 tDCS stimulator (sham stimulation)


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Age > 18 years. New focal neurologic deficit consistent with acute ischemic stroke. Baseline NIHSS ≥ 4 or NIHSS < 4 in the presence of disabling deficits (e.g. aphasia) Presence of acute occlusion of ICA or MCA (including MCA peripheral cortical branches) according to clinical picture and baseline CTA/CTP scan. Presence of salvageable penumbra with Tmax > 6 sec/ ischemic core volume (rCBF < 30%) ≥ 1.2 on baseline CTP scan. Patient is ineligible for EVT per current national guidelines (Cerebrovascular Section of Czech Neurological Society ČLS JEP). Subject is able to be treated with tDCS within 24 hours of last known well time. A signed informed consent is obtained from the patient or patient's legally authorized representative (point 30 of Declaration of Helsinki). Exclusion Criteria: Acute intracranial hemorrhage including suspected subarachnoid hemorrhage. Other than ischemic cause of acute neurological deficit (stroke mimics:postparoxysmal Todd´s palsy, metabolic cause, tumor, meningoencephalitis etc.). Evidence of a large Ischemic core volume on baseline CTP: volume of rCBF<30% ≥ 100ml. Subacute or chronic subdural hematoma or hygroma. Intra-axial malignant brain tumor. History of spontaneous ICH in the past. History of seizure disorder or new seizures with presentation of current stroke. History of intracranial surgery. Presence of tDCS contraindications: skin lesion at the site of stimulation (open wound, acute inflammation of skin or subcutaneous tissue, burns etc.); skull defect at the site of stimulation (e.g. skull fracture, postcraniectomy); implanted electric device (pacemaker, ICD, DBS, cochlear implant etc.); presence of metal material in head (e.g. metal stent, clamps etc.). Thrombocytopenia < 100 000/ul. INR > 3,0. Heparin or LMWH therapy in last 48 hours with aPTT increased more than 1,5 times over limit of the laboratory. History of acute overdose by DOAC. Known congenital or acquired increased bleeding propensity. Suspected or confirmed pregnancy. Known CT iodine contrast allergy. Known renal dysfunction (eGFR<30 ml/min.). Signs or symptoms of acute myocardial infarction, including ECG findings, on admission. Suspicion of aortic dissection on admission. Evidence of any other major life-threatening or serious medical condition that would prevent completion of the study protocol including attendance at the 3-month follow-up visit. Concomitant experimental therapy.

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Sequential Assignment
Interventional Model Description: Traditional 3+3 (rule-based, modified Fibonacci) dose escalation design
Masking: Triple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: Transcranial Direct Current Stimulation<br> | Device: Soterix Medical 1X1 tDCS stimulator (active C-tDCS)<br>* Patients will be randomized to active treatment (C-tDCS) vs sham stimulation in a 3:1 ratio. There will be 6 dose tiers, reflecting increasing intensity and duration of stimulation: Tier 1 - 1 mA, single 20 - min cycle; Tier 2- 2 mA, single 20 min cycle; Tier 3 - 1 mA, 2 cycles of 20 min/20 min off; Tier 4- 2 mA, 2 cycles of 20 min/20 min off; Tier 5 - 1 mA, 3 cycles of 20 min/20 min off; Tier 6 - 2 mA, 3 cycles of 20 min/20 min off.<br>|
| Sham Comparator: Sham Stimulation<br> | Device: Soterix Medical 1X1 tDCS stimulator (sham stimulation)<br>* Patients will be randomized to active treatment (C-tDCS) vs sham stimulation in a 3:1 ratio. Patients in the sham stimulation arm at all the tiers will have the headgear and electrodes in place, and the switch for sham stimulation will be on, i.e. no prolonged electrical stimulation will be delivered.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Primary safety outcome: the rate of symptomatic intracranial hemorrhage (SICH) in the active treatment arm compared to sham arm, and between higher and lower dose tiers. | The presence of SICH will be assessed on 24-hour post-stimulation non-contrast CT scan. SICH will be defined as an intracranial hemorrhage with an increase of ≥ 4 points on the National Institute of Health Stroke Scale (NIHSS) within 24h after stimulation. In case of sudden worsening of neurostatus anytime within first 24 hours after stimulation, first follow-up CT will be performed immediately (earlier). The treatment will be considered to have exhibited adequate safety if tDCS results in lower or equivalent rates of SICH compared to sham. | At 24-hour post-stimulation | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Secondary safety outcome: the rate of asymptomatic intracranial hemorrhage (AICH) in the active treatment arm compared to sham arm, and between higher and lower dose tiers. | The AICH will be defined as an intracranial hemorrhage on 24h post-stimulation non-contrast CT scan that is not associated with NIHSS worsening ≥ 4 within 24 hours after stimulation.The treatment will be considered to have exhibited adequate safety if tDCS results in lower or equivalent rates of AICH compared to sham. | At 24-hour post-stimulation | 
| Secondary safety outcome: the rate of early neurologic deterioration in the active treatment arm compared to sham arm, and between higher and lower dose tiers. | Early neurological deterioration will be defined as worsening ≥ 4 on NIHSS during the 24-hour period after stimulation without intracranial hemorrhage. The treatment will be considered to have exhibited adequate safety if tDCS results in lower or equivalent rates of early neurological deterioration compared to sham. | During the 24-hour post-stimulation | 
| Secondary safety outcome: the rate of mortality in the active treatment arm compare to sham arm, and between higher and lower dose tiers. | Mortality will be defined as death or modified Rankin Scale of 6. The treatment will be considered to have exhibited adequate safety if tDCS results in lower or equivalent rates of mortality compared to sham. | By day 90 post stimulation | 
| Secondary safety outcome: the rate of all serious adverse events occurring during the 90 days of study participation in the active treatment arm compare to sham arm, and between higher and lower dose tiers. | A serious adverse event is any adverse event that is fatal, is lifethreatening, is permanently or substantially disabling, requires or prolongs hospitalization, or requires medical or surgical intervention to prevent one of the above outcomes. The rate of serious adverse events will be compared between the active treatment and sham patients, and between higher and lower dose tiers.The treatment will be considered to have exhibited adequate safety if tDCS results in lower or equivalent rates of serious adverse events compared to sham. | By day 90 post-stimulation | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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stroke, transcranial direct current stimulation, tDCS, neuroprotection