Stroke, Acute
Conditions
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 who are ineligible for intravenous thrombolysis and 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 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.
Interventions
DEVICETranscranial Direct Current Stimulation
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.
OTHERSham Stimulation
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.
Sponsors
University of California, Los Angeles
Study design
Allocation
RANDOMIZED
Intervention model
SEQUENTIAL
Primary purpose
TREATMENT
Masking
TRIPLE (Subject, Caregiver, Outcomes Assessor)
Intervention model description
Traditional 3+3 (rule-based, modified Fibonacci) dose escalation design
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
1. New focal neurologic deficit consistent with AIS 2. NIHSS≥4 or NIHSS \<4 in the presence of disabling deficits 3. Age\>18; 4. Presence of any cortical vessel occlusion including ICA, branches of MCA, Anterior Cerebral artery (ACA), Posterior Cerebral artery (PCA), Posterior-Inferior cerebellar artery (PICA); 5. Presence of salvageable penumbra with Tmax\> 6 sec/ ischemic core volume (ADC \< 620 μm2/s or rCBF\< 30%) ≥ 1.2 6. Patient ineligible for IV tPA, per national AHA/ASA Guidelines 7. 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
1. Acute intracranial hemorrhage 2. Evidence of a large Ischemic core volume (ADC \< 620 μm2/s or rCBF\< 30%) ≥ 100 3. Presence of tDCS contraindications - electrically or magnetically activated intracranial metal and non-metal implants. 4. Severe MR contrast allergy or renal dysfunction with eGFR\<30ml/min, precluding MRI gadolinium or CT iodine contrast 5. Pregnancy 6. Signs or symptoms of acute myocardial infarction, including EKG findings, on admission 7. Suspicion of aortic dissection on admission 8. History of seizure disorder or new seizures with presentation of current stroke 9. 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 10. Concomitant experimental therapy 11. Preexisting scalp lesion at the site of the stimulation or presence of skull defects (may alter current flow pattern) 12. Preexisting coagulopathy, consist of platelet count of ≤ 100, INR ≥ 3, PTT ≥ 90.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Tolerability Outcome: Percentage of the Patients Completing the Protocol-assigned Stimulation Treatment | After 20 minutes of stimulation period | Percentage of the patients completing the protocol-assigned stimulation treatment |
| Feasibility Outcome: Speed With Which HD C-tDCS Was Implemented | Time from randomization to tDCS initiation assessed up to 30 minutes | 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. |
| Safety Outcome: Rate of Symptomatic Intracranial Hemorrhage (SICH) in the Active Treatment Arms Compared to Sham Arm | At 24-hour post-stimulation | 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. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Secondary Safety Outcome: Rate of Early Neurologic Deterioration in All Active Patients Compared to Sham Arm | During the 24-hour post-stimulation | Early neurological deterioration will be defined as worsening ≥ 4 on NIHSS during the 24-hour period after stimulation without intracranial hemorrhage. |
| Secondary Safety Outcome: Rate of Mortality in All Active Patients Compared to Sham Arm, | By day 90 post stimulation | Mortality will be defined as death or modified Rankin Scale of 6. |
| Secondary Safety Outcome: Rate of All Serious Adverse Events Occured During the 90 Days of Study Participation in All Active Patients Compared to Sham. | By day 90 post-stimulation | 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. |
Other
| Measure | Time frame | Description |
|---|---|---|
| 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. | At 2-hour and 24-hour post-stimulation | 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. |
| 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. | At day 90 post stimulation | Rate of modified Rankin Scale (mRS) of 0-2 |
Countries
United States
Participant flow
Pre-assignment details
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.
Participants by arm
| Arm | Count |
|---|---|
| High-definition Cathodal Transcranial Direct Current Stimulation High-definition Cathodal Transcranial Direct Current Stimulation | 7 |
| Sham Stimulation Sham Stimulation | 3 |
| Total | 10 |
Baseline characteristics
| Characteristic | Sham Stimulation | Total | High-definition Cathodal Transcranial Direct Current Stimulation |
|---|---|---|---|
| Age, Continuous | 77 Year STANDARD_DEVIATION 12 | 75 Year STANDARD_DEVIATION 9.6 | 75 Year STANDARD_DEVIATION 19.6 |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 1 Participants | 1 Participants | 0 Participants |
| Race (NIH/OMB) Black or African American | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) White | 2 Participants | 9 Participants | 7 Participants |
| Sex: Female, Male Female | 1 Participants | 6 Participants | 5 Participants |
| Sex: Female, Male Male | 2 Participants | 4 Participants | 2 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk |
|---|---|---|---|
| deaths Total, all-cause mortality | 0 / 3 | 2 / 4 | 1 / 3 |
| other Total, other adverse events | 1 / 3 | 0 / 4 | 0 / 3 |
| serious Total, serious adverse events | 1 / 3 | 2 / 4 | 2 / 3 |
Outcome results
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.
Time frame: Time from randomization to tDCS initiation assessed up to 30 minutes
Population: The time from enrollment to HD C-tDCS initiation in the last 4 enrolled patients.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Active Stimulation-Tier 1 | Feasibility Outcome: Speed With Which HD C-tDCS Was Implemented | 12.5 minutes |
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.
Time frame: At 24-hour post-stimulation
Population: 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.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Active Stimulation-Tier 1 | Safety Outcome: Rate of Symptomatic Intracranial Hemorrhage (SICH) in the Active Treatment Arms Compared to Sham Arm | 0 Participants |
| Active Stimulation-Tier 2 | Safety Outcome: Rate of Symptomatic Intracranial Hemorrhage (SICH) in the Active Treatment Arms Compared to Sham Arm | 1 Participants |
| Sham Stimulation | Safety Outcome: Rate of Symptomatic Intracranial Hemorrhage (SICH) in the Active Treatment Arms Compared to Sham Arm | 0 Participants |
Primary
Tolerability Outcome: Percentage of the Patients Completing the Protocol-assigned Stimulation Treatment
Percentage of the patients completing the protocol-assigned stimulation treatment
Time frame: After 20 minutes of stimulation period
Population: Rate of patients completing the protocol assigned stimulation
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Active Stimulation-Tier 1 | Tolerability Outcome: Percentage of the Patients Completing the Protocol-assigned Stimulation Treatment | 3 Participants |
| Active Stimulation-Tier 2 | Tolerability Outcome: Percentage of the Patients Completing the Protocol-assigned Stimulation Treatment | 4 Participants |
| Sham Stimulation | Tolerability Outcome: Percentage of the Patients Completing the Protocol-assigned Stimulation Treatment | 3 Participants |
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.
Time frame: By day 90 post-stimulation
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Active Stimulation-Tier 1 | Secondary Safety Outcome: Rate of All Serious Adverse Events Occured During the 90 Days of Study Participation in All Active Patients Compared to Sham. | 3 Participants |
| Active Stimulation-Tier 2 | Secondary Safety Outcome: Rate of All Serious Adverse Events Occured During the 90 Days of Study Participation in All Active Patients Compared to Sham. | 2 Participants |
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.
Time frame: During the 24-hour post-stimulation
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Active Stimulation-Tier 1 | Secondary Safety Outcome: Rate of Early Neurologic Deterioration in All Active Patients Compared to Sham Arm | 1 Participants |
| Active Stimulation-Tier 2 | Secondary Safety Outcome: Rate of Early Neurologic Deterioration in All Active Patients Compared to Sham Arm | 0 Participants |
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.
Time frame: By day 90 post stimulation
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Active Stimulation-Tier 1 | Secondary Safety Outcome: Rate of Mortality in All Active Patients Compared to Sham Arm, | 2 Participants |
| Active Stimulation-Tier 2 | Secondary Safety Outcome: Rate of Mortality in All Active Patients Compared to Sham Arm, | 1 Participants |
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
Time frame: At day 90 post stimulation
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Active Stimulation-Tier 1 | 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. | 3 Participants |
| Active Stimulation-Tier 2 | 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. | 2 Participants |
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.
Time frame: At 2-hour and 24-hour post-stimulation
| Arm | Measure | Group | Value (MEDIAN) |
|---|---|---|---|
| Active Stimulation-Tier 1 | 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. | Final penumbra salvage proportion percentage | 66 percentage change from baseline |
| Active Stimulation-Tier 1 | 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. | Final hypoperfusion lesion proportion percentage change | -100 percentage change from baseline |
| Active Stimulation-Tier 1 | 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. | Early qrCBV percentage change | 64 percentage change from baseline |
| Active Stimulation-Tier 2 | 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. | Final penumbra salvage proportion percentage | 0 percentage change from baseline |
| Active Stimulation-Tier 2 | 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. | Final hypoperfusion lesion proportion percentage change | 325 percentage change from baseline |
| Active Stimulation-Tier 2 | 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. | Early qrCBV percentage change | -4 percentage change from baseline |