Implant for Augmentation of Cerebral Blood Flow Trial, Effectiveness and Safety in a 24 Hour Window

Study Overview
=================
Brief Summary
-----------------
The primary objective of the study is to assess the safety and effectiveness of SPG stimulation with the ISS in patients with an acute ischemic stroke in the anterior circulation initiated within 24 hours from stroke onset.

Detailed Description
-----------------
A multi-center, multinational, randomized, blinded, sham control, adjunctive to Standard of Care, parallel arm study and will include ongoing Data Safety and Monitoring Board (DSMB) review of accumulated safety data. Screening: Since the treatment should be initiated within 24 hours from stroke onset, the screening window is limited and all procedures should be performed within this window.Subjects with Acute Ischemic Stroke will be screened upon arrival to the hospital. Since the treatment should be initiated between 8 and 24 hours from stroke onset, the screening window is limited and all procedures should be performed as soon as possible. All screened patients will be identified by patient number and will sign the informed consent prior to any study procedure initiation. Period 1: Day 1-5 Day 1- Eligible subjects will be randomized to: Group 1: Implantation and ISS Stimulation during five consecutive days & Standard of Care Group 2: Sham Implantation and Sham Stimulation during five consecutive days & Standard of Care Subjects will be transferred to the implantation procedure facility and the implantation/sham implantation will be performed by a trained physician. After implantation, active/sham stimulation will be administered in daily 4-hour sessions, beginning immediately following the placement procedure and continuing for 5 consecutive days. Day 5 / Day of Discharge. Following the last ISS /Sham Stimulation, explantation will be performed and the patients will be evaluated for safety and effectiveness. Subjects will continue with Standard of Care as needed and will be released from the hospital upon investigator's judgment. Period 2: Day of Discharge - 89±7 days During this period both groups (ISS Stimulation and Sham Control) will be treated according to Standard of Care either at the hospital, rehabilitation center or at home. Scheduled visits will be performed on day 30±7 and day 60 ±7, which will include safety and effectiveness assessments. Final Visit Day 90±7 days: The final visit will be performed at the study site and will include safety and effectiveness evaluations. Patients will be contacted by study personnel via telephone on Day 180±7 and on Day 360±7 in order to assess their quality of life status.

Official Title
-----------------
A Multicenter, Randomized, Double Blind, Sham Control, Parallel Arm Trial to Assess Effectiveness and Safety of the Ischemic Stroke System ISS, as an Adjunct to Standard of Care in Subjects With Acute Ischemic Stroke

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

Intervention / Treatment
-----------------
* Device: Active Sphenopalatine Ganglion (SPG) Stimulation
* Device: Sham Sphenopalatine Ganglion (SPG) Stimulation


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria: Age: Between 40 years and 80 years for male and 85 for female subjects Clinical diagnosis of an acute ischemic stroke in the Carotid, Middle or Anterior Cerebral Artery territories Imaging findings demonstrating signs of ischemia in the anterior circulation, consistent with the clinical diagnosis Baseline NIHSS ≥ 7 and ≤ 18 within 2 hours prior to implantation. Ability to initiate treatment within 8- 24 hours from stroke onset Signed informed consent from patient him/herself or legally authorized representative if applicable Exclusion Criteria: Intracranial hemorrhage or hemorrhagic transformation Massive stroke Acute ischemic stroke in the posterior circulation Minor stroke Treated with IV-tPA (intravenous tissue Plasminogen Activator) ,IA-tPA (intra-arterial tissue Plasminogen Activator) or neurothrombectomy devices for the current stroke Previous stroke in the last 6 months or pre-existing disability Patients with bleeding propensity or any condition in the oral cavity that prevents implantation Clinical signs and symptoms or imaging evidence of bilateral stroke. Treated with IV-tPA ,IA-tPA or neurothrombectomy devices for the current stroke. Known cerebral arteriovenous malformation, cerebral aneurysm. Clinical suspicion of septic embolus. Uncontrolled hypertension (systolic >185 mmHg and/or diastolic >110 mmHg) Serious systemic infection. Women known to be pregnant or having a positive or indeterminate pregnancy test. Patients with other implanted neural stimulator/ electronic devices (pacemakers). Life expectancy < 1 year from causes other than stroke.

Ages Eligible for Study
-----------------
Minimum Age: 40 Years
Maximum Age: 85 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: Parallel Assignment
Masking: Triple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: Active Stimulation<br>Implantation/ISS Stimulation during 5 consecutive days & Standard of Care (SoC). Day 1: First stimulation initiated within 24 hours from stroke onset, following implantation completion. All subjects will be treated according to SoC for treatment of Acute Ischemic Stroke. Day 2-4: ISS Stimulation treatment sessions repeated daily. Each treatment will be initiated within 18-26 hours from the preceding treatment. Day 5: Following completion of the last ISS Stimulation treatment session, imaging performed for assessing Injectable Neuro Stimulator (INS) positioning and/or lesion. Implant removal procedure will then be performed. Subsequently, patients will be evaluated for safety and effectiveness. Subjects will continue with SoC as needed and discharged from the hospital based on the judgment of the study investigator. | Device: Active Sphenopalatine Ganglion (SPG) Stimulation<br>* SPG stimulation and standard of care. During all study periods, patients will receive Standard of Care in accordance to the general management of ischemic stroke and secondary prevention, following the guidelines of the American Heart Association/American Stroke Association and of the European Stroke Organization (ESO), including the use of antiplatelets, management of secondary stroke, dyslipidemia, hypertension, diabetes and counseling regarding smoking cessation. Off-label uses of drugs and devices should not occur during any of the study periods.<br>* Other names: Standard of Care;|
| Sham Comparator: Sham Stimulation<br>Sham Implantation and Sham Stimulation during 5 consecutive days & Standard of Care (SoC). Day 1: First Sham stimulation initiated within 24 hours from stroke onset, following Sham implantation procedure. All subjects will be treated according to SoC for treatment of Acute Ischemic Stroke. Day 2-4: Sham Stimulation sessions repeated daily. Each Sham Stimulation will be initiated within 18-26 hours from the preceding treatment. Day 5: Following completion of the last Sham Stimulation session, imaging performed for lesion assessment. Sham Implant removal will then be performed. Subsequently, patients will be evaluated for safety and effectiveness. Subjects will continue with SoC as needed and discharged from the hospital based on the judgment of the study investigator. | Device: Sham Sphenopalatine Ganglion (SPG) Stimulation<br>* Sham SPG stimulation and standard of care. During all study periods, patients will receive Standard of Care in accordance to the general management of ischemic stroke and secondary prevention, following the guidelines of the American Heart Association/American Stroke Association and of the European Stroke Organization (ESO), including the use of antiplatelets, management of secondary stroke, dyslipidemia, hypertension, diabetes and counseling regarding smoking cessation. Off-label uses of drugs and devices should not occur during any of the study periods.<br>* Other names: Standard of Care;|

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

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Sliding Dichotomy modified Rankin Scale (mRS) at 3 months | The primary efficacy endpoint is improvement beyond expectations on the modified Rankin Scale at 3 months (sliding dichotomy), assessed in primary populations of: modified intention to treat (mITT) confirmed cortical involvement (CCI), defined as baseline NIHSS ≥ 10 and signs of cortical involvement in baseline imaging (at least one of the following ASPECT regions: M1-M6, Insular Cortex) Type I Error is controlled at an overall level of 0.05 (two-sided) using the Hochberg method. | 90 days±7 days | 

 Terms related to the study
=================
Keywords Provided by Centre Hospitalier Valida
-----------------
acute ischemic stroke, randomized clinical trial, effectiveness, safety