Transcranial Direct Current Stimulation as a Neuroprotection in Acute Stroke Before and After Thrombectomy

Study Overview
=================
Brief Summary
-----------------
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 before and after endovascular therapy.

Detailed Description
-----------------
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 undergoing recanalization procedure. 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. All patients will be receiving the first dose (stimulation cycle) after the recanalization procedure and patients at dose tiers 5-6 will also be receiving stimulation cycles before the recanalization procedure begins. The occurrence of symptomatic intracranial hemorrhage will determine the pace of the escalation through the dose tiers.

Official Title
-----------------
Transcranial Electrical Stimulation in Stroke EaRly After Onset Clinical Trial_ Bridging and Adjunctive Neuroprotection

Conditions
-----------------
Acute Ischemic Stroke

Intervention / Treatment
-----------------
* Device: Transcranial Direct Current Stimulation (tDCS)


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion criteria New focal neurologic deficit consistent with AIS Age≥18 NIHSS ≥ 4 ICA or M1 or M2 MCA occlusion on pre-thrombectomy MRA or CTA Onset (last-seen-well) time to randomization time within 24 hours Pre-stroke modified Rankin Scale≤ 3. Patient ineligible for IV tPA, per national AHA/ASA Guidelines. Having undergone endovascular thrombectomy with less than a complete reperfusion (<TICI 2c, 3) for receiving post-thrombectomy adjunct C-tDCS. Undergoing endovascular thrombectomy, per national AHA/ASA Guidelines for patients who are assigned to pre-thrombectomy bridging session at Tiers 5, 6. 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 ml Presence of tDCS contraindications - electrically or magnetically activated intracranial metal and non-metal implants. Pregnancy Severe contrast allergy or absolute contraindication to iodinated contrast preventing endovascular intervention. 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 a platelet count of ≤ 100, INR ≥ 3, PTT ≥ 90.

Ages Eligible for Study
-----------------
Minimum Age: 18 Years

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

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: Single


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Stimulation arm<br>Patients will be randomized to active treatment (C-tDCS) vs sham stimulation in a 3:1 ratio. There will be 6 dose tiers: Tier 1 - 1 mA, and Tier 2- 2 mA: Consist of a single stimulation cycle (20min) after the endovascular procedure (EVT) in patients with TICI<2c,3 and negative immediate post-EVT CT scan for definitive evidence of ICH. Tier 3 - 1 mA and Tier 4- 2mA consist of 2 treatment cycles after the EVT in patients with TICI<2c and 3, and negative immediate post-EVT CT scan for definitive evidence of ICH. Tier 5 - 1 mA and tier 6- 2 mA consist of 3 treatment cycles. The first cycle will be up to 20 min cycle, after initial imaging and prior to arterial puncture, the second and third cycles after EVT in patients with TICI<2c and 3 and negative immediate post-EVT CT scan for definitive evidence of ICH. | Device: Transcranial Direct Current Stimulation (tDCS)<br>* 20 minutes of Cathodal tDCS after +/- before endovascular thrombectomy (EVT)<br>|
| Sham Comparator: Sham arm<br>Patients in the sham stimulation arm at all the tiers will have the cap and electrodes in place, and sham switch moved but without delivery of electrical stimulation. | Device: Transcranial Direct Current Stimulation (tDCS)<br>* 20 minutes of Cathodal tDCS after +/- before endovascular thrombectomy (EVT)<br>|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Primary Safety Outcome- Number of Participants With Symptomatic Intracranial Hemorrhage (SICH) | Symptomatic intracranial hemorrhage (SICH) is defined as an increase of 4 or more points on the National Institute of Health Stroke Scale (NIHSS) total score within 24 hours of stimulation associated with parenchymal hematoma type 1 (PH1), parenchymal hematoma type 2 (PH2), remote intraparenchymal hemorrhage (RIH), subarachnoid hemorrhage (SAH), or intraventricular hemorrhage (IVH). The NIHSS is a 15-item neurologic examination stroke scale used to evaluate the effect of acute stroke on the levels of consciousness, language, neglect, visual-field loss, extraocular movement, motor strength, ataxia, dysarthria, and sensory loss. A trained observer rates the patent's ability to answer questions and perform activities. Ratings for each item are scored with 3 to 5 grades with 0 as normal, and there is an allowance for untestable items. Accordingly, 0 is the lowest and 42 is the highest total score possible. In the NIHSS, the higher the score, the more impaired a stroke patient is. | At 24-hour post-stimulation | 
| Primary Tolerability Outcome-Number of Participants Completing the Protocol-assigned Stimulation | The percentage of the patients completing the protocol-assigned stimulation treatment with no intolerability. | After 5 minutes of stimulation period | 
| Primary Feasibility Outcome- Assessing the Speed of Stimulation Implementation From Randomization. | The median times from randomization to bridging C-tDCS initiation and the time form end of endovascular thrombectomy procedure to adjunctive C-tDCS initiation in the last 10 enrolled patients. | Median time from randomization to tDCS initiation | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Secondary Safety Outcome-Number of Participants With Asymptomatic Intracranial Hemorrhage (AICH) | AICH is defined as intracranial hemorrhage not associated with National Institute of Health Stroke Scale (NIHSS) total score worsening of ≥ 4. The NIHSS is a 15-item neurologic examination stroke scale used to evaluate the effect of acute stroke on the levels of consciousness, language, neglect, visual-field loss, extraocular movement, motor strength, ataxia, dysarthria, and sensory loss. A trained observer rates the patent's ability to answer questions and perform activities. Ratings for each item are scored with 3 to 5 grades with 0 as normal, and there is an allowance for untestable items. Accordingly, 0 is the lowest and 42 is the highest total score possible. In the NIHSS, the higher the score, the more impaired a stroke patient is. | At 24-hour post-stimulation | 
| Secondary Safety Outcome-Number of Participants With Early Neurologic Deterioration | Worsening of total score ≥ 4 on NIHSS during the 24-hour period after stimulation, with or without intracranial hemorrhage. The NIHSS is a 15-item neurologic examination stroke scale used to evaluate the effect of acute stroke on the levels of consciousness, language, neglect, visual-field loss, extraocular movement, motor strength, ataxia, dysarthria, and sensory loss. A trained observer rates the patent's ability to answer questions and perform activities. Ratings for each item are scored with 3 to 5 grades with 0 as normal, and there is an allowance for untestable items. Accordingly, 0 is the lowest and 42 is the highest total score possible. In the NIHSS, the higher the score, the more impaired a stroke patient is. | At 24-hour post-stimulation | 
| Secondary Safety Outcome-Number of Participants With Mortality | Rate of mortality | At 90 days post-stimulation | 
| Secondary Safety Outcome-Number of Participants With All Serious Adverse Events (Anticipated and Unanticipated) | A serious adverse event (SAE) 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. Anticipated serious adverse events were defined as SAEs that are expected and related to acute ischemic stroke complications such as headache, stroke recurrence, pneumonia, systemic blood clots, Family withdrawal of care, etc. An unanticipated serious adverse event is an SAE that is not deemed an ischemic stroke complication and adjudicated as possibly related to study treatment. | At 90 days post-stimulation | 

 Terms related to the study
=================
Keywords Provided by Centre Hospitalier Valida
-----------------
Transcranial direct current stimulation, Bridging neuroprotection, Adjunctive neuroprotection