Transcranial Direct Current Stimulation as a Neuroprotection in Acute Stroke

Study Overview
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Brief Summary
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This proposal is a prospective, single-center, dose-escalation safety, tolerability, feasibility and potential efficacy study of transcranial direct current stimulation (tDCS) in acute stroke patients with substantial salvageable penumbra due to a large vessel occlusion who are ineligible for intravenous thrombolysis and endovascular therapy.

Detailed Description
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This is a single center, sham-controlled, dose escalation study where cathodal tDCS is delivered to threatened but not yet irreversibly damaged (penumbral) tissue in patients with large vessel occlusion who are not eligible for blood flow restoring recanalization procedures. Patients will be randomized in a 3:1 design, to cathodal versus sham (control) stimulation, 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 Electrical Stimulation in Stroke EaRly After Onset Clinical Trial

Conditions
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Stroke, Acute

Intervention / Treatment
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* Device: Transcranial Direct Current Stimulation
* Other: Sham Stimulation


Participation Criteria
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Eligibility Criteria
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Inclusion criteria: New focal neurologic deficit consistent with AIS NIHSS≥4 or NIHSS <4 in the presence of disabling deficits Age>18; Presence of any cortical vessel occlusion including ICA, branches of MCA, Anterior Cerebral artery (ACA), Posterior Cerebral artery (PCA), Posterior-Inferior cerebellar artery (PICA); Presence of salvageable penumbra with Tmax> 6 sec/ ischemic core volume (ADC < 620 μm2/s or rCBF< 30%) ≥ 1.2 Patient ineligible for IV tPA, per national AHA/ASA Guidelines Patient ineligible for endovascular therapy per AHA/ASA national Guidelines - one or more of: poor prestroke functional status (mRS score >1), mild neurological symptoms (NIHSS <6), large ischemic core (ASPECTS <6), thrombectomy not technically performable due to severe vessel tortuosity, cervical artery chronic occlusion, or other unfavorable angioarchitectural features that preclude endovascular access to the target intracranial vessel. 8) Subject is able to be treated with tDCS within 24 hours of last known well time; 9) A signed informed consent is obtained from the patient or patient's legally authorized representative Exclusion criteria Acute intracranial hemorrhage Evidence of a large Ischemic core volume (ADC < 620 μm2/s or rCBF< 30%) ≥ 100 Presence of tDCS contraindications - electrically or magnetically activated intracranial metal and non-metal implants. Severe MR contrast allergy or renal dysfunction with eGFR<30ml/min, precluding MRI gadolinium or CT iodine contrast Pregnancy Signs or symptoms of acute myocardial infarction, including EKG findings, on admission Suspicion of aortic dissection on admission History of seizure disorder or new seizures with presentation of current stroke 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 Preexisting scalp lesion at the site of the stimulation or presence of skull defects (may alter current flow pattern) Preexisting coagulopathy, consist of platelet count of ≤ 100, INR ≥ 3, PTT ≥ 90.

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>Transcranial Direct Current Stimulation | Device: Transcranial Direct Current Stimulation<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>* Other names: C-tDCS;|
| Sham Comparator: Sham Stimulation<br>Sham Stimulation | Other: 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 cap and electrodes in place, and sham switch moved but without prolonged delivery of electrical stimulation.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Safety Outcome: Rate of Symptomatic Intracranial Hemorrhage (SICH) in the Active Treatment Arms Compared to Sham Arm | The presence of SICH will be assessed on 24-hour post-stimulation scan. SICH will be defined as an intracranial parenchymal hemorrhage, subarachnoid hemorrhage, or intraventricular hemorrhage with an increase of 4 or more points on the National Institute of Health Stroke Scale (NIHSS) within 24 hours of stimulation.The treatment will be considered to have exhibited adequate safety if tDCS results in lower or equivalent rates of SICH compared to sham. The NIHSS is a validated quantitative assessment tool to measure stroke-related neurological deficits and ranges from 0 (no neurological deficits) to a maximum of 42, indicative of a very severe level of impairment. | At 24-hour post-stimulation | 
| Feasibility Outcome: Speed With Which HD C-tDCS Was Implemented | The median time from enrollment to HD C-tDCS initiation in the last 4 enrolled patients included three Active-Tier 2 patients and one sham. | Time from randomization to tDCS initiation assessed up to 30 minutes | 
| Tolerability Outcome: Percentage of the Patients Completing the Protocol-assigned Stimulation Treatment | Percentage of the patients completing the protocol-assigned stimulation treatment | After 20 minutes of stimulation period | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Secondary Safety Outcome: Rate of Early Neurologic Deterioration in All Active Patients Compared to Sham Arm | Early neurological deterioration will be defined as worsening ≥ 4 on NIHSS during the 24-hour period after stimulation without intracranial hemorrhage. | During the 24-hour post-stimulation | 
| Secondary Safety Outcome: Rate of Mortality in All Active Patients Compared to Sham Arm, | Mortality will be defined as death or modified Rankin Scale of 6. | By day 90 post stimulation | 
| Secondary Safety Outcome: Rate of All Serious Adverse Events Occured During the 90 Days of Study Participation in All Active Patients Compared to Sham. | A serious adverse event is any adverse event that is fatal, is life-threatening, 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. | By day 90 post-stimulation |