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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.
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.
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| Label | Type | Description | Intervention Names |
|---|---|---|---|
| Transcranial Direct Current Stimulation | Active Comparator | Transcranial Direct Current Stimulation |
|
| Sham Stimulation | Sham Comparator | Sham Stimulation |
|
| Name | Type | Description | Arm Group Labels | Other Names |
|---|---|---|---|---|
| Transcranial Direct Current Stimulation | Device | 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. |
| 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 |
| 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, |
| Measure | Description | Time Frame |
|---|---|---|
| Per-protocol Exploratory Imaging Efficacy Outcome of Imaging Biomarkers of Neuroprotection and Collateral Enhancement Excluding One Patient With no Penumbra at Baseline on Imaging Core Review and One Patient With Septic Embolization as Stroke Cause. | By comparing the baseline MR/CT imaging with the MR/CT imaging at 2-hour (early) and 24-hour (final) post-stimulation, the following were measured: 1) Final penumbra salvage proportion, 2) Final hypoperfusion lesion reduction, 3) Early relative quantitative cerebral blood volume (qrCBV) enhancement. |
Inclusion criteria:
9) A signed informed consent is obtained from the patient or patient's legally authorized representative
Exclusion criteria
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| Name | Affiliation | Role |
|---|---|---|
| Mersedeh Bahr Hosseini, MD | University of California, Los Angeles | Principal Investigator |
| Facility | Status | City | State | ZIP | Country | Contacts |
|---|---|---|---|---|---|---|
| University of California- Los Angeles (UCLA) | Los Angeles | California | 90095 | United States |
| PubMed Identifier | Type | Citation | Retractions |
|---|---|---|---|
| 37342040 | Derived | Bahr-Hosseini M, Nael K, Unal G, Iacoboni M, Liebeskind DS, Bikson M, Saver JL; TESSERACT Trial Group. High-definition Cathodal Direct Current Stimulation for Treatment of Acute Ischemic Stroke: A Randomized Clinical Trial. JAMA Netw Open. 2023 Jun 1;6(6):e2319231. doi: 10.1001/jamanetworkopen.2023.19231. |
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The first 4 patients (3 Active and 1 Sham) were assigned to Tier 1 (1mA of C-tDCS for 20 min) of the study, and the next 6 patients (4 Active and 2 Sham) were assigned to Tier 2 (2mA of C-tDCS for 20 min) of the study.
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| ID | Title | Description |
|---|---|---|
| FG000 | High-definition Cathodal Transcranial Direct Current Stimulation (HD C-tDCS)-Tier 1 | The first 4 patients were randomized to 1mA of HD C-tDCS for 20 min vs. sham stimulation in a 3:1 ratio. A total of 3 patients received active stimulation. |
| FG001 | High-definition Cathodal Transcranial Direct Current Stimulation (HD C-tDCS)-Tier 2 | The next 6 patients were randomized to 2mA of HD C-tDCS for 20 min vs. sham stimulation in a 3:1 ratio. A total of 4 patients received active stimulation. |
| FG002 | Sham Stimulation | Sham Stimulation Sham Stimulation: A total of 3 patients were enrolled in the Sham arm at Tier 1 and 2. Patients in sham arm had the cap and electrodes in place but without any delivery of electrical stimulation. |
| Title | Milestones | Reasons Not Completed | ||||||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Overall Study |
|
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| ID | Title | Description |
|---|---|---|
| BG000 | High-definition Cathodal Transcranial Direct Current Stimulation | High-definition Cathodal Transcranial Direct Current Stimulation |
| BG001 | Sham Stimulation | Sham Stimulation |
| Units | Counts |
|---|---|
| Participants |
|
| Title | Description | Population Description | Parameter Type | Dispersion Type | Unit of Measure | Calculate Percentage | Denominator Units Selected | Denominators | Classes |
|---|---|---|---|---|---|---|---|---|---|
| Age, Continuous | Mean |
| Type | Title | Description | Population Description | Reporting Status | Anticipated Posting Date | Parameter Type | Dispersion Type | Unit of Measure | Calculate Percentage | Time Frame | Units Analyzed | Denominator Units Selected | Arm/Group Information | Denominators | Classes | Analyses |
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Primary | 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. | One SICH occurred in a Tir 2 patient due to a rupture of mycotic aneurysm causing subarachnoid hemorrhage. This misenrollment was later deemed to be a protocol deviation due to not meeting the entry criteria. | Posted | Count of Participants | Participants | At 24-hour post-stimulation |
|
Three months following the study enrollment
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| ID | Title | Description | Deaths (Affected) | Deaths (At Risk) | Serious Events (Affected) | Serious Events (At Risk) | Other Events (Affected) | Other Events (At Risk) |
|---|---|---|---|---|---|---|---|---|
| EG000 | Active Stimulation-Tier 1 | High-definition Cathodal Transcranial Direct Current Stimulation 1mA-20min |
| Term | Organ System | Source Vocabulary | Assessment Type | Notes | Statistical Information |
|---|---|---|---|---|---|
| Anticipated serious adverse events | Nervous system disorders | Systematic Assessment | 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, etc. |
| Term | Organ System | Source Vocabulary | Assessment Type | Notes | Statistical Information |
|---|---|---|---|---|---|
| Anticipated AE | Nervous system disorders | Systematic Assessment | Anticipated adverse events were defined as AEs that are commonly reported and anticipated with tDCS application, such as minor tingling, itchiness, scalp redness, and burning sensation |
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| Title | Organization | Phone | Extension | |
|---|---|---|---|---|
| Dr. Mersedeh Bahr-Hosseini | Study's principal investigator | 3107941195 | MBahrHosseini@mednet.ucla.edu |
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| Type | Includes Protocol | Includes SAP | Includes ICF | Document Label | Document Date | Document Uploaded Date | Document File Name |
|---|---|---|---|---|---|---|---|
| Prot_SAP | Yes | Yes | No | Study Protocol and Statistical Analysis Plan | Jan 22, 2021 | Jun 7, 2023 | Prot_SAP_002.pdf |
| ICF | No | No | Yes | Informed Consent Form | Apr 8, 2021 | Mar 14, 2023 | ICF_001.pdf |
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| ID | Term |
|---|---|
| D020521 | Stroke |
| ID | Term |
|---|---|
| D002561 | Cerebrovascular Disorders |
| D001927 | Brain Diseases |
| D002493 | Central Nervous System Diseases |
| D009422 | Nervous System Diseases |
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| ID | Term |
|---|---|
| D065908 | Transcranial Direct Current Stimulation |
| ID | Term |
|---|---|
| D004599 | Electric Stimulation Therapy |
| D013812 | Therapeutics |
| D003295 | Convulsive Therapy |
| D013000 | Psychiatric Somatic Therapies |
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Traditional 3+3 (rule-based, modified Fibonacci) dose escalation design
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|
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| Sham Stimulation | Other | 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. |
|
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 |
| At 2-hour and 24-hour post-stimulation |
| Per-protocol Exploratory Clinical Efficacy Outcome: Rate of Functional Independence at 3-month in Active vs. Sham Excluding Two Patients, One With no Penumbra Was Present at Baseline on Imaging Core Review and One With Septic Embolization as Stroke Cause. | Rate of modified Rankin Scale (mRS) of 0-2 | At day 90 post stimulation |
| BG002 | Total | Total of all reporting groups |
| Year |
|
| Sex: Female, Male | Count of Participants | Participants |
|
| Race (NIH/OMB) | Count of Participants | Participants |
|
| OG000 |
| Active Stimulation-Tier 1 |
High-definition Cathodal Transcranial Direct Current Stimulation (1mA-20min) |
| OG001 | Active Stimulation-Tier 2 | High-definition Cathodal Transcranial Direct Current Stimulation (2mA-20min) |
| OG002 | Sham Stimulation | Sham Stimulation Sham Stimulation: 3 patients were enrolled in the Sham arm: Patients had the cap and electrodes in place but without any delivery of electrical stimulation. |
|
|
| Primary | 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. | The time from enrollment to HD C-tDCS initiation in the last 4 enrolled patients. | Posted | Median | Inter-Quartile Range | minutes | Time from randomization to tDCS initiation assessed up to 30 minutes |
|
|
|
| Primary | Tolerability Outcome: Percentage of the Patients Completing the Protocol-assigned Stimulation Treatment | Percentage of the patients completing the protocol-assigned stimulation treatment | Rate of patients completing the protocol assigned stimulation | Posted | Count of Participants | Participants | After 20 minutes of stimulation period |
|
|
|
| Secondary | 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. | Posted | Count of Participants | Participants | During the 24-hour post-stimulation |
|
|
|
| Secondary | 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. | Posted | Count of Participants | Participants | By day 90 post stimulation |
|
|
|
| Secondary | 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. | Posted | Count of Participants | Participants | By day 90 post-stimulation |
|
|
|
| Other Pre-specified | Per-protocol Exploratory Imaging Efficacy Outcome of Imaging Biomarkers of Neuroprotection and Collateral Enhancement Excluding One Patient With no Penumbra at Baseline on Imaging Core Review and One Patient With Septic Embolization as Stroke Cause. | By comparing the baseline MR/CT imaging with the MR/CT imaging at 2-hour (early) and 24-hour (final) post-stimulation, the following were measured: 1) Final penumbra salvage proportion, 2) Final hypoperfusion lesion reduction, 3) Early relative quantitative cerebral blood volume (qrCBV) enhancement. | Posted | Median | Inter-Quartile Range | percentage change from baseline | At 2-hour and 24-hour post-stimulation |
|
|
|
| Other Pre-specified | Per-protocol Exploratory Clinical Efficacy Outcome: Rate of Functional Independence at 3-month in Active vs. Sham Excluding Two Patients, One With no Penumbra Was Present at Baseline on Imaging Core Review and One With Septic Embolization as Stroke Cause. | Rate of modified Rankin Scale (mRS) of 0-2 | Posted | Count of Participants | Participants | At day 90 post stimulation |
|
|
|
| 0 |
| 3 |
| 1 |
| 3 |
| 1 |
| 3 |
| EG001 | Active Stimulation-Tier 2 | High-definition Cathodal Transcranial Direct Current Stimulation 2mA-20min | 2 | 4 | 2 | 4 | 0 | 4 |
| EG002 | Sham Stimulation | Sham Stimulation Patients in sham arm had the cap and electrodes in place but without any delivery of electrical stimulation. | 1 | 3 | 2 | 3 | 0 | 3 |
|
| Unanticipated serious adverse event | Nervous system disorders | Systematic Assessment | An unanticipated serious adverse event is an SAE that is not deemed an ischemic stroke complication and adjudicated as possibly related to study treatment |
|
|
| Unanticipated adverse event | Nervous system disorders | Systematic Assessment | An unanticipated adverse event is an AE that is not commonly reported with tDCS application |
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| D014652 | Vascular Diseases |
| D002318 | Cardiovascular Diseases |
| D004191 | Behavioral Disciplines and Activities |
| D004597 | Electroshock |
| D011580 | Psychological Techniques |
| Early qrCBV percentage change |
|