Implant for Augmentation of Cerebral Blood Flow Trial-1 (ImpACT-1). A single-arm feasibility study evaluating the safety and potential benefit of the Ischemic Stroke System for treatment of acute ischemic stroke

Background The Ischemic Stroke System is a novel device designed to deliver stimulation to the sphenopalatine ganglion(SPG).The SPG sends parasympathetic innervations to the anterior cerebral circulation. In rat stroke models, SPG stimulation results in increased cerebral blood flow, reduced infarct volume, protects the blood brain barrier, and improved neurological outcome. We present here the results of a prospective, multinational, single-arm, feasibility study designed to assess the safety, tolerability, and potential benefit of SPG stimulation inpatients with acute ischemic stroke(AIS). Methods Patients with anterior AIS, baseline NIHSS 7–20 and ability to initiate treatment within 24h from stroke onset, were implanted and treated with the SPG stimulation. Patients were followed up for 90 days. Effect was assessed by comparing the patient outcome to a matched population from the NINDS rt-PA trial placebo patients. Results Ninety-eight patients were enrolled (mean age 57years, mean baseline NIHSS 12 and mean treatment time from stroke onset 19h). The observed mortality rate(12.2%), serious adverse events (SAE)incidence(23.5%) and nature of SAE were within the expected range for the population. The modified intention to treat cohort consisted of 84 patients who were compared to matched patients from the NINDS placebo arm. Patients treated with SPG stimulation had an average mRS lower by 0.76 than the historical controls(CMH test p = 0.001). Conclusion The implantation procedure and the SPG stimulation, initiated within 24hr from stroke onset, are feasible, safe, and tolerable. The results call for a follow-up randomized trial (funded by BrainsGate; clinicaltrials.gov number, NCT03733236).

Stroke is a leading cause of disability, death and health care expenditure. It is the second most common cause of death worldwide, exceeded only by heart disease, and the third most common cause in the US. [1,2] In the US there are an estimated over 700,000 strokes (500,000 are first attacks and 200,000 recurrent events) claiming more than 150,000 lives annually. [2][3][4] Stroke is caused by either an occlusion (ischemia) or hemorrhage within the cerebral circulation. Ischemic stroke constitutes 83 to 90 % of stroke cases in western countries. [2,10] Occlusion of the Middle Cerebral Artery (MCA) or its branches is the most common site of ischemia, or cerebral infarct, in the anterior circulation accounting for approximately 90% of infarcts and two thirds of all first strokes. Of MCA territory infarcts over 50% involve the superficial MCA territory (Alison Baird, MD, PhD, Anterior Circulation Stroke, eMedicine.com).
The functionally impaired region that surrounds the infarct core and is threatened by necrosis has been termed the ischemic penumbra. The penumbra, although physiologically impaired, is potentially salvageable tissue. In the early phase following stroke, there is prompt initial improvement in function as the pathologic processes including edema, hemorrhage, and blood pressure (BP) resolve. The time frame for recovery of function in these reversibly injured neurons is relatively short, accounting for improvement in the first several weeks. The later ongoing improvement in neurologic function occurs by a different set of mechanisms that allow structural and functional reorganization within the brain. The processes involved in this reorganization represent neuroplasticity 1 and may continue for many months. Restitution of partially damaged pathways and expansion of representational brain maps occur, implying recruitment of neurons not ordinarily involved in specific activity.
To date, intravenous recombinant tissue plasminogen activator (IV t-PA) and mechanical revascularization with the MERCI device are the only two approved interventional treatments for acute ischemic stroke. Both are primarily focused on reperfusion, i.e. aiming to restore artery patency and brain perfusion in order to reduce the volume of cerebral infarction which thereby reduces functional deficits. However, the use of those treatments is limited. In the US, only about 3% of ischemic stroke patients are treated with IV t-PA. The main determinant of eligibility for treatment is time since onset; the time window for IV t-PA is less than 3 hours from stroke onset and up to 8 hours for the use of the MERCI device. The main determinant of eligibility for treatment is time since onset; the time window for IV t-PA is less than 3 hours from stroke onset and up to 8 hours for the use of the MERCI device. Symptomatic hemorrhagic transformation of the infarction remains the primary concern with the administration of IV t-PA in the treatment of acute ischemic stroke; up to 5.2% incidence is reported, based on a meta-analysis of the post marketing open-label studies published by Glenn. [53] 1.2

Augmenting Brain Perfusion
An alternative therapeutic approach in ischemic stroke, whenever early recanalization cannot be achieved, is augmentation of brain perfusion through the collateral circulation. The cerebral collateral circulation refers to the subsidiary network of vascular channels that stabilize cerebral blood flow when principal conduits fail. The collateral circulation is a critical determinant of cerebral perfusion pressure in acute cerebral ischemia as is caused by stroke. [24] The quality of the process of collateral recruitment depends on the caliber and patency of primary pathways that may rapidly compensate for decreased blood flow and the adequacy of secondary collateral routes. Experimental data on middle cerebral artery occlusion in rats demonstrates the temporal dependence of collateral development. [25] The hemodynamic effects of the collateral circulation may also be important in maintaining perfusion to penumbral regions. [26] Additionally, perfusion itself may enhance angiogenesis, which may further stimulate collateral growth at the periphery of an ischemic region. [27] Although numerous theoretical arguments suggest a possible beneficial effect of augmenting brain perfusion by increasing collateral blood flow to the brain, current management of cerebrovascular disease has not focused on this as a therapeutic approach in stroke treatment.
Preliminary data suggest that induced hypertension in acute ischemic stroke may be associated with a reduction in hypoperfused tissue on perfusion-weighted MR scans, and may potentially improve outcome. [28][29][30] . The mechanism of improved function is assumed to be the enhanced cerebral perfusion.
There remains a pressing need for developing additional therapies for the treatment of acute ischemic stroke at a longer therapeutic window as well as for an improvement in outcome during the rehabilitation phase. For the acute phase, the therapeutic focus is in limiting the ischemic insult by restoration or alleviation of the Cerebral Blood Flow (CBF). Other interventions, referring to a time point much later after onset of stroke, are intended to help in the rehabilitation process and in particular to intervene in the process of brain plasticity. The mechanism of improved function is assumed to be the enhanced cerebral perfusion. The two most plausible forms of plasticity are collateral sprouting of new synaptic connections and unmasking of previously latent functional pathways. This would be clinically presented as functional improvements. Experimental evidence indicates that plasticity can be altered by several external conditions, including pharmacologic agents, electrical stimulation, and environmental stimulation.

The Role of Stimulation of the Sphenopalatine Ganglion in Ischemic Stroke
The sphenopalatine ganglion (SPG), classically known to be the source of parasympathetic innervations to the nasal and eye mucosa and the lacrimal gland, is now recognized also as the source of parasympathetic innervations to the brain vasculature. The location of the SPG is shown in Figure  1.3-1.  Stimulation of this ganglion induces vasodilatation of the ipsilateral, intradural arteries of the anterior circle of Willis in normal rats, cats, dogs, monkeys and human. The neurotransmitters released by the postganglionic fibers include nitric oxide (NO), vasoactive intestinal polypeptide (VIP), and acetylcholine, as well as other peptides of the VIP family such as peptide histidine isoleucine and its human form, peptide histidine methionine. [38][39][40][41][42][43] NO and VIP are known vasodilators of cerebral arteries in vitro. Vascular dilation in vitro and increases in cerebral blood flow (CBF) in vivo in response to SPG stimulation are blocked by antagonists of NO and VIP antiserum. There appears to be sufficient evidence in the literature which supports coupling between NO, vascular endothelial growth factor (VEGF) and angiogenesis, indicating that NO is involved in the regulation of progenitor cells and neurogenesis in the adult brain. Administration of NO in animal stroke models was shown to increase CBF to the ischemic territory, reduce the tissue damage resulting from focal Ischemia and enhance neurogenesis. [54] 1. It was previously demonstrated, that the duration and magnitude of the pulse provided by the BrainsGate System using the NeuroPath™ IS System electrode may differentially affect neuronal networks that are activated down stream by the SPG stimulation.
BrainsGate has completed a vast amount of pre-clinical studies to demonstrate the effects of SPG stimulation in animals with cerebral ischemia. The stroke model utilized by BrainsGate consists of an occlusion of the Middle Cerebral Artery (MCAo), a commonly used model for generating cerebral ischemic stroke in rats. Functional impairment has been attained by a transient (tMCAo) or a permanent (pMCAo) occlusion resulting into neurological deficits and long-term or permanent motor dysfunction. The consequence of either mode of occlusion has been assessed in terms of infarct size, and neurological and cognitive improvement using verified scoring systems.
Studies were aimed at specifying and optimizing the electrical pulse regimen for SPG stimulation as well as the treatment duration. Specific aims included: • Identification of the appropriate stimulation profile for the stroke application.
• Assessment of short and long term effects as measured by cerebral blood flow (CBF), infarct size and neurological improvement; follow up duration lasted up to 35 days.
• Evaluation of the therapeutic window following stroke onset; from immediate stimulation post stroke up to treatment 24 hours post stroke.
• Selection of suitable treatment regimen (i.e. treatment duration, and number of stimulations per day). • The [60"/12"] stimulation profile is the most suitable paradigm for further research in ischemic stroke.
• Short term efficacy is demonstrated after one 5 min train of SPG stimulation, and following long lasting stimulation (up to 10 h). Evaluation of efficacy parameters showed an increase in CBF, a decrease in infarct volume and improvement in neurological function as measured by a series of behavioral tests detailed in the literature.
• Improvement of the above parameters can be shown after extended delays (3 h and 24 h) following occlusion.
• Repetitive SPG stimulation attenuated neurological deficit and reduced infarct size after 24 h following occlusion.
• Enhanced cognitive and neurological functions were found in both tMACo and pMACo animals as a result of SPG stimulation.

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• Beneficial effects can be observed up to 4 weeks after the MCA occlusion, and may be attributed to either the long-term influence of SPG stimulation, or to a long-term rehabilitation process.
• The most efficient treatment duration was demonstrated when the treatment lasted for 3 or 6 h. When the stimulation period increased to 10 h or decreased to 1 h, the beneficial effects diminished.

The Evaluation of Safety of SPG Stimulation in Animal Studies
BrainsGate performed several studies in animals to evaluate specific parameters and aspects of the safety of SPG stimulation. These studies are identified in Table 1.4-2. In summary, through the use of well-defined animal models for ischemic stroke, BrainsGate has demonstrated that cerebral blood flow is increased as a result of SPG stimulation. Additionally, in animals with permanent occlusion of the middle cerebral artery, SPG stimulation appears to be associated with a small increase in recovery of neurological function, and a substantial reduction of brain infarct volume. In animals with transient ischemia, there was a substantial recovery of motor and cognitive abilities as a result of SPG stimulation.

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Additionally, the safety studies demonstrate no long-term adverse events as a result of SPG stimulation at stimulation levels (i.e. duration, stimulation on/off times, and current levels) in excess of those utilized to demonstrate efficacy in the ischemia stroke model. Short term effects on weight gain, open field tests, and cognitive ability were observed in SPG stimulated rats; all effects were reversible within 9 weeks after the termination of stimulation. Furthermore, there were no histopathologic findings of an adverse nature.
Based on these studies, it is concluded that SPG stimulation may have a therapeutic role in the treatment of patients following ischemic stroke, supported by a positive benefit to risk assessment.

Previous Clinical Experience
The first clinical studies utilizing BrainsGate technology were initiated in Europe in 2004. These Studies investigated the device operation using different stimulation regimen, as a controlled method for destruction the Blood-Brain-Barrier by stimulating the SPG.
In these Pilot feasibility studies, the Neuropath™ System was used to improve the bioavailability of the chemotherapeutic agent, Paclitaxel, which normally does not penetrate the CNS. The study population was Glioblastoma Multiform (GBM) patients with histological evidence of GBM. In these patients, disease recurrence was documented, and the tumor was inoperable. The primary objective of the study was to assess safety of the device implantation procedure and the stimulation protocol. Efficacy parameters including the increase in cerebral blood flow, drug level contained in the cerebral spinal fluid (CSF) and S100 protein were established as secondary objectives. In addition, follow-up on tumor response was performed.
To date, the NeuroPath™ System has been implanted in ten (10) GBM patients in Europe: six in Hungary, three in Croatia and one in Germany.
Clinical data obtained from these subjects includes: • The clinical response to SPG stimulation (i.e. tolerance to stimulation); • Safety parameters including anticipated and unanticipated adverse events; related and unrelated to the device and the procedure; • And, efficacy parameters as specified above; In summary, the implantation procedure in patients with GBM, followed by the specific protocol of SPG electrical stimulation, was shown to be safe and tolerable. During the stimulation protocol, only minor symptoms were observed on the stimulated side of the head. As mentioned above, those symptoms are expected while the SPG is stimulated. Moreover, BrainsGate and its Clinical Investigators view the appearance of these minor symptoms as positive indicators of a successful SPG stimulation session. During the clinical use of the NeuroPath™ System in patients with GBM, there have been no device-related serious adverse events.
Feasibility for the treatment of GBM was further demonstrated quantitatively by evidence of cerebral vasodilatation, elevation in S100 protein and elevation in drug levels in CSF, all indicators of enhanced drug delivery across the blood brain barrier.

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These results, coupled with the findings of minimal adverse events, suggest that SPG stimulation possesses clinical utility and may be used under controlled conditions in a clinical study involving subjects impaired by ischemic stroke. Furthermore, with implementation of device and procedural improvements, BrainsGate believes that the device-related adverse events experienced in these early clinical trials for GBM may be further mitigated.
Risk analysis can be found in the Investigator Brochure.

Laboratory Testing
The

Intended Use and Indication
The NeuroPath™ IS System is intended for electrical stimulation of the Spheno-Palatine Ganglion (SPG) to augment cerebral perfusion and aid in the management of ischemic cerebral stroke, i.e. improving neurological deficits, of ischemic stroke patients, who are not eligible for reperfusion therapy.
The system is designed to enable repetitive continuous sessions of electrical stimulation of the sphenopalatine ganglion (SPG) for 7 days following acute ischemic stroke. It is assumed, based on the literature and the BrainsGate pre clinical work, that usage of the system and the treatment regimen is safe, and tolerable.
Patients receiving the stimulation treatment are expected to show an improvement in their ischemic stroke status. The improvement is expected to be demonstrated by the augmentation of cerebral blood flow during and immediately after stimulation; reduction of the lesion measures and consequently improvement of the neurological deficits. As such, the treatment with the device may therefore provide a solution for acute ischemic stroke patients, who cannot benefit from early recanalization therapies.
The suggested hypothetical mechanism of action discusses the option that the enhancement of endogenous neurogenesis via enhanced release of NO and VIP, occurs due to better perfusion status; this sequentially boosts the physiological process of brain plasticity and results in improvement in the functional deficits despite artery occlusion.
The NeuroPath IS System provides an opportunity of stimulation during the penumbra phase and later in the early sub acute phase to augment cerebral perfusion. Resulting in the opportunity to

NeuroPath TM Description
The NeuroPath™ IS System is comprised of two major components: The Implantable Neural Stimulator (INS) The Energy Delivery Control Subsystem (EDC).

A The Transmitter
B The EDC is further divided into three parts: • The Transmitter • The Driver • The Controller A surgical kit provided with the NeuroPath™ IS System, facilitates the INS implantation procedure.

The Transmitter
The Transmitter is used to relay energy between the EDC Subsystem and the Implantable Neural Stimulator (INS). The Transmitter is a single-patient reusable device component that requires cleaning before each use. The Transmitter is mechanically held in place facing the INS receiver inside the oral cavity.

The Driver
The Driver is the interface between the Controller and the Transmitter. It is physically connected to the Transmitter and communicates with the Controller in a wireless fashion. This communication consists first of loading with the stimulation parameters by the physician/healthcare provider, followed by exchanging information and data during treatment. The Driver is reusable.

The Controller
The Controller, an off-the-shelf, hand-held computer, fitted with custom Microsoft© Windows based software, controls the stimulation pattern and the stimulation timing, and collects and archives the log files of the treatment sessions. During the operational phase, the Controller communicates with the Driver via a Bluetooth© communication protocol for the purpose of beginning a treatment session, verifying correct operation and logging data for the treatment sessions. The Controller is powered by an internal battery that is charged by a standard AC medical grade power supply that is supplied with the system. The Controller is reusable. The INS is composed of three major areas (see Figure 2  The stimulating controller does not need to be installed. For complete instructions on the operation of the NeuroPath™ IS System refer to the NeuroPath™ IS System Physician Manual.

Necessary Training
The usage of the NeuroPath™ IS System is composed of two processes: 1. The implantation procedure.
In this pilot study, the insertion procedure will be performed by the local surgeons following a training session, and under the supervision of a BrainsGate surgeon who is trained and experienced in the implementation surgical procedure.
The stimulation procedure requires a trained person to be present during the session. During the first stimulation procedures BrainsGate representative will be present, and will assist the investigator with the operation of the NeuroPath™ IS System.

2.5
The Surgical Kit The surgical accessory kit is composed of custom made tools intended for use in the preparation of the greater palatine canal for insertion of the Implantable Neural Stimulator (INS). Other tools supplied are conventional surgical tools intended to facilitate exposure of the greater palatine canal and aid in the overall procedure. The custom-made tools supplied as part of the surgical kit consist of: 1. A set of rounded trockars ranging in diameter from 1.00 to 2.00 mm (in 0.1 mm increments), with a tip angle of 10.° 2. A stylet with a finely sharpened tip (1.3 mm in diameter) for initial penetration into the greater palatine canal. 3. A palatometer, dedicated tool used to locate the entrance of the greater palatine canal.

General
The system is designed to enable repetitive continuous sessions of electrical stimulation of the SPG for 7 days following acute ischemic stroke event. Patients receiving the stimulation treatment are expected to show an improvement in their ischemic stroke status. The improvement is expected to be demonstrated by the augmentation of cerebral blood flow during and immediately after stimulation.
Reduction of the lesion measures and consequently improvement of the neurological deficits are expected to be demonstrated later on during the follow up period. .
The suggested hypothetical mechanism of action discuss the option that the enhancement of endogenous neurogensis via enhanced release of NO and VIP, occurs due to better perfusion status; this sequentially boosts the physiological process of brain plasticity resulting in improvement in the functional deficits despite artery occlusion.

Implantation of the Implantable Neural Stimulator (INS)
The implantation of the INS in the treatment of ischemic stroke is intended to be performed by a surgen such as Otolaryngologists, Maxillofacial Surgeons or Neurosurgeons who will receive specialized training by BrainsGate. The participating surgeons will be trained to perform the procedure on cadavers before attempting in a clinical setting. Implantation of the INS takes approximately 20 minutes to complete.
The following section provides an overview of the surgical procedure for the implantable component (INS) of the Neuropath™ IS System.
1. The patient is locally anesthetized.
2. The entrance to the Greater Palatine canal is located using standard procedures well known to dentists which routinely deliver anesthesia injections into the canal.
3. An incision is made adjacent to the canal entrance within 5 mm.
4. The canal is exposed, and a path is created alongside the canal with the aid of surgical tools.
5. The INS is surgically inserted via the greater palatine canal, such that the stimulating tip rests adjacent to the SPG and its receiving end is situated underneath the mucosa of the Palatine process of the maxilla bone or potentially of the Alveolar process of the maxilla bone. Positioning is obtained by introducing the INS until the distal stimulating tip reaches the superior boundary of the Sphenopalatine fossa.
6. The incision is sutured or glued.
7. The Implantable Neural Stimulator (INS) will be removed at the end of the treatment portion of the study, i.e. between 7 -28 days after implantation.

Stimulation with the Neuropath™
Immediately (up to 15 minutes) following implantation, the Transmitter is placed in the patient's mouth such that it is aligned with the Implantable Neural Stimulator (INS) receiver. There are predefined stimulation parameters which are set in the Controller during manufacturing (frequency, stimulation times etc). Then, there are stimulating parameters which could be set in the Controller by the Physician (pulse width, stimulation intensity). In any case, the patient has no control over the setting of the stimulation parameters. Upon activation, the Controller transmits the stimulation parameters to the Adaptor. The energy for the stimulation is driven by an energy source and electronic driver within the Adaptor. The Adaptor conveys the energy via a linear connection cable to the Transmitter. Finally, the Transmitter then transmits the energy to the Implantable Neural Stimulator (INS), electrically stimulating the SPG. Stimulus strength will be administered at an approximate range of 2 mA ± 1.
The rationale for selecting the stimulation parameters of the NeuroPath™ IS System is based upon two primary sources. 2,3 Both address the parameters of nerve stimulators, although neither with respect to the CNS. These standards are considered to be the closest relevant to the NeuroPath™ IS System. Listed below is a summary of the key safety and performance requirements of each.
b. Pulse width: 1 to 2,000 microseconds (µsec).   In this pilot feasibility study, the NeuroPath™ IS System will be used to assess the feasibility and safety during treatment initiated up to 24 hours following acute ischemic stroke in a comparison method.
The study population will be acute ischemic patients. The system is designed to enable repetitive continuous sessions of electrical stimulation of the sphenopalatine ganglion (SPG) for 7 days following acute ischemic stroke.
A total of 30 (thirty) patients with acute ischemic stroke (within the last 24 hours) will be enrolled to this study. The patients who will be enrolled to the treatment group will undergo an implantation procedure in which the NeuroPath™ IS System will be inserted into the SPG by using a minimal invasive approach; thereafter the stimulation treatments will begin and will continue 7 days. The patient should stay in the hospital for the whole treatment duration. The patients who will be enrolled to the control group will receive a standard medical care without a stimulation procedure.
A follow-up session will take place for up to 90 days post enrollment to the trial to both groups.
The entire process is expected to result in an improvement in the patient's neurological deficits and functional status after the ischemic stroke.

Summary of Study Design
Hypothesis: The use of the NeuroPath™ IS System is safe and tolerable when use for cerebral ischemia treatment.
The use of the NeuroPath TM IS System will augment cerebral perfusion and aid in the management of ischemic cerebral stroke, i.e. improving neurological deficits of ischemic stroke patients.

Design:
A Pilot, prospective, comparison, multi center, study

No. of Subjects:
A total of 30 subjects will participant the trial and will be compared in ration 1:1.
Study duration and Follow-up: The overall length of treatment will be 7 days, with daily stimulation sessions of 3 hours duration.

Endpoints:
1. Rate of intra-procedural and post-procedural adverse events.
2. Improvement of cerebral perfusion during and immedialty after stimulation 3. Improvement of neurological scale performed to ischemic stroke patients at different time points.

Study Design
This is a pilot study designed as an open label, comparison, multi-center study. The primary objective of this study is to demonstrate feasibility and safety of the device and the procedure.
The treatment group will be treated with the NeuroPath IS System as an adjunct to conventional non thrombolytics medical care.
The control group will be treated with a standard medical care.

Primary
The objective of this pilot study is the assessment of the feasibility and the safety of the NeuroPath IS System in patients who have experienced an acute ischemic stroke in the MCA territory.

Secondary
The secondary study's outcomes are related to the patient's status from the ischemic stroke.
These outcomes measures include the following: 1. Augmentation of perfusion and/or cerebral blood flow changes 2. Infract size/volume changes 3. Changes in the neurological and functional status.

3.5.1
Primary endpoint Those endpoints will include the assessment of the safety and feasibility of the device activation.

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For the safety analysis: the incidence of the procedure complications, Expected/Unexpected Adverse Events and SAE will be recorded For the feasibility analysis: the information will be collected. Patient's tolerability of the stimulation will be assessed. The outcome will be measured as the ability to maintain treatment in each session for the treatment length, and the compliance for the whole treatment period; i.e. each treatment session should be performed for at least 85% of the prescribed regimen and the compliance of the treatment should reach at least 85%. Reports will include questionnaires specifically designed to evaluate tolerance; and data regarding treatment compliance.

Secondary endpoint
Those are related to cerebral brain perfusion and the patient's status from the ischemic stroke. These outcomes measures include: A. cerebral perfusion (MRI perfusion/ CT perfusion and SPECT scan); B. cerebral blood flow velocity measured at the implant side (TCD); C. infract size/volume changes; D. and the changes in the neurological and functional status.

Study Duration and Timelines
The study will be performed in two (2) sites with the goal of enrolling 30 patients. Our estimation is that the site will enroll 4 patients per month with a total enrollment period of 4 months. The trial will involve an implantation of the NeuroPath TM IS System in 15 patients (treatment group), thereafter the patients will receive treatments for a duration of 7 days, with daily stimulation sessions of 3 hours duration. The additional 15 patients (control group) will receive a standard medical care without a stimulation procedure.
Follow-up will be performed to both groups at 30±5, 60±5 and at 90±5; aggregate trial duration will be ~100 days per patient.
Database cleaning and lock will take one month and final statistical analysis and report additional two months.

ELIGIBILITY CRITERIA
30 Patients with acute ischemic stroke (within the last 24 hours) who will meet the inclusion/exclusion criteria will be assigned by the physician in charge of the study ("Principal Investigator") to one of two groups: either a group that receives a treatment with the NeuroPath IS System or a group that does not receive a treatment with the NeuroPath IS System. (If patient does not fulfills Exclusion criteria #21 but the other criteria's are met, only than the patient will be assigned to the control group).

Inclusion criteria
All of the following must be answered YES in order to enroll a patient to this study:

Exclusion Criteria
Any one of the following will exclude the patient from participation in this study: 1. Time interval prior to treatment initiation in greater than twenty-four (24)  Patients with a condition precluding entry into the scanner (e.g. morbid obesity, claustrophobia, etc.)

Patient Enrollment
Informed Consent will be obtained and then eligibility screening will be assessed using Inclusion/ Exclusion criteria.
A patient who appears to meet ALL eligibility requirements will be asked to participate in the study.

Patient Identification
The patient identification number will be of 4 characters; the first two characters correspond to the site number, and the last three characters correspond to the patient number at the site, as follows: • Site number will be composed of two numbers; "01" • The patient CRF number will be composed of one character; "001", "002" etc. 4 This exclusion criteria may be disregarded if CT scan will be used as the imaging modality.

Variables Measured
The primary end point will be evaluated following and during each activation session.
• Expected/Unexpected Adverse Events and SAE will be evaluated during and immediately following the activation, as well as self reported (or otherwise obtained) absence of side effects between stimulations will be considered as a positive primary end point.
• Patient's tolerability of the stimulation will be assessed. The outcome will be measured as the ability to maintain treatment in each session for the treatment length, and the compliance for the whole treatment period The secondary end points will be measured as follows: • Cerebral Perfusion -Cerebral perfusion changes as measured by using imaging modalities (MRI/CT perfusion and/or SPECT) scan resulted from the stimulation. Recording will be performed for all treated patients, in a sample of the treatment sessions. It is required to performed at least 2 measures -during the first day of treatment and the last day of treatment.
• Cerebral Blood Flow -Cerebral blood flow velocity changes as measured by Transcranial Doppler (TCD) sonography resulted from the stimulation. Recording will be performed for all treated patients, in a sample of the treatment sessions. Recording will include the time before, during and following the stimulation session and will be compared.
• Infarct Status -Salvagable Areas, Infarct Size, and Infarct Volume-The stroke lesion volume will be assessed by T2 weighted and FLAIR (fluid-attenuated inversion recovery) MRI or CT scan.
Measurements will be performed at baseline and will be compared to the a follow up scan performed at at 60 days.
• Clinical Outcomes -Improvement of Neurological Status-Neurological assessment using the NIHSS and Modified Rankin scores will be performed.
NIHSS will be performed at baseline and during the first week; Modified Rankin scale will be performed prior to discharge.
A weekly assessment including both scales will be performed following discharge during the first 30 days. Additional follow up assessments will be performed at 60 and 90 days post enrollment to the trial.
During the follow up assessment visits all patients will be subject to additional outcomes assessment scales including the Rankin score and Barthel Assessment of Motor Recovery.

Screening and enrollment
Patients with known acute ischemic stroke within the last 24 hours, who fulfill the eligibility criteria specified for this study (see inclusion/exclusion criteria).
The screening process will include the following: Patients classified to the implanted arm should be undergoing the implantation. The NeuroPath TM IS System will be implanted using a minimal invasive approach. Total procedure time will be ~20 minutes. The stimulation will be performed for a total 7 days, 3 hours daily.
The stimulation parameters of the NeuroPath™ IS System are based upon two primary sources . 3,4 (for additional information refer to section 2.7.3). Treatment Period will be performed ONLY during hospitalization.
Measurements and evaluation during hospitalization phase • Neurological and clinical assessments using standard scales o The NIHSS will be performed at 24 hours; 3 days post event and on day 7 (i.e. last treatment day). o The Modified Rankin Score will be performed prior to discharge as the baseline measurement o Barthel Index Assessment scale will be performed prior to discharge as the baseline measurement • SPECT scan or CT/MRI perfusion will be performed at day one of treatment phase and on the last day of treatment -7 th day.
• TCD Recordings -Transcranial Doppler (TCD) sonography will be performed within 3 treatment sessions; the measurement should be performed so recordings will be gathered prior to stimulation; during stimulation and immediately after stimulation has stopped.
• General clinical examination including ECG, BP and blood tests will be performed in accordance with best medical care practice during hospitalization, and prior to discharge o HR and BP will be recorded before, during and one hour post stimulation session. Such measurements will be done at day 1 and at least twice during the hospitalization period.
If not done during the hospitalization period, Patients will be invited for implant removal session; this must be done on between the 7 th to 28 th days of treatment.
Following that the patients will be invited to the clinic for 'a check up' visit at 48 to 72 hours following implant removal.

Follow Up Period
The period will include at least 4 visits -at 14+/-2; at 30+/-2; at 60+/-5 and at 90+/-5 days post enrollment; In each of the visit the investigator is required to performed the following assessments: • General clinical assessment.

Not related:
An adverse event has no temporal relationship to study device or has a much more likely alternative etiology.

Adverse Events Reporting
Each adverse event will be reported to BrainsGate. The severity scoring should comply with the Common Terminology Criteria for Adverse Events version 3.0 as possible.
Unanticipated adverse events and device related adverse events will be reported immediately (with in 24 hours) to BrainsGate both by fax on adverse event CRF page and by a telephone call.
Anticipated adverse events will be reported within five (5) days both by fax and by a telephone call.
All unanticipated and device related events will once reported to BrainsGate, undergo immediate review BrainsGate. If there is a technical problem that is deemed by BrainsGate, as such that there is a risk for the patient arising from it -all implantations that had not been carried out, will be halted, and all stimulation (if relevant) in patients that had been implanted will be halted, until a satisfactory resolution of the problem which had been reviewed by BrainsGate will be found and approved by BrainsGate. Device related adverse events will be reported to the all participant centers' Ethical committees promptly.
If the conclusion of BrainsGate is that there should be a change in the protocol as a result of the event reported as needed, it will be changed as soon as possible according to the regulations. If BrainsGate deems the problem to require immediate changes, all treatments will be suspended until such a change will take place. Events will be reported to the Ethical committee and to the local health authorities according to the rules and regulations.
In case of a serious or severe adverse event or in case of other emergency need the following contact should be used:

Rationale
This Pilot/safety and feasibility pilot study will comprise of 30 patients.
The study will be considered successful if a low incidence of procedure complications, expected/ unexpected adverse events and SAE.

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Secondary end points will be considered successful if a substantial percentage of the patients will show augmentation of cerebral brain perfusion during the whole length of the treatment protocol and improvement of neurological status can be demonstrated in those patients population.

Interim Analysis
As this study is non-statistical in nature, no statistical interim analysis will be performed and therefore there will be no early termination on statistical grounds.

Patient Incorporation Policy
All eligible participants in this study will be included in the analysis, which will not be statistical in nature due to the characteristic of the study.

Data Accountability
All the relevant clinical data and imaging will be collected from the study site by BrainsGate representative or BrainsGate designee during routine monitoring visits. These visits will be carried out to coincide with the implantation and the stimulation, and thereafter the follow-up data will be collected in less frequent monitoring visits. During those visits, all efforts will be made to complete missing data according to regulations. However, missing data, will not, if at all possible, exclude the patient from analysis.

Study Monitoring
Monitoring functions shall be performed in compliance with 21CFR §812.43(d) and 21CFR §812.46 The major function of the clinical monitor is to observe and assess the quality of the clinical study. For this study, qualified personnel will be appointed by BrainsGate Ltd.
Apart from assuming responsibility for the communication between the investigators and BrainsGate (BrainsGate Ltd..), the monitor's duties include on-site visits, participation in initial study sessions, review of Case Report Forms and other study documents and results.

On-Site Visits
On-site monitoring visits include pre-study visit, periodic visits, and final visit at the close of the study.
The pre-study visit is intended to review with the investigator the final approved version of the protocol and to assure that the investigator has obtained institutional approval for conducting the study, and has all study documentation, required records, and equipment on site.
Periodic visits are intended to assess adherence to the protocol, maintenance of records, reports and devices, and review of source documents for accuracy, completeness, and legibility.

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During these periodic visits the monitor is required to assess the progress of the study toward meeting study objectives and identify any concerns that stem from observations and review of patient records, study management documents, informed consent documents, and adverse events records.
At the close of the study, the monitor will make a final on-site visit to ensure that all study data has been properly completed and to have a closing meeting with the investigator and medical staff.
Reports of on-site visits should be generated by the monitor, as needed to inform BrainsGate of required corrective actions, resolution of concerns, completion of follow-up activities, and completion of assigned tasks.
At the close of the study, the monitor is required to prepare and provide with BrainsGate a final monitoring report.

Case Report Forms
Case Report Forms will be provided for each patient. On completion, Case Report Forms must be reviewed for completeness and accuracy, dated, and signed by the investigator.
Crossing out the incorrect information shall only make corrections of data on the Case Report Forms and writing the correct values next to those crossed out. Each correction must be initiated and dated by the investigator or an authorized assistant. In no instance may data be altered by use of correction fluid, erasures, etc.
*Case report forms will be sent via facsimile to BrainsGate or to its local representative every monitoring visit with an attached cover page.

Review of Study Documents
The monitor will review completed data forms and study documentation for accuracy, completeness, and protocol compliance. In particular, the monitor should: (1) Compare the Case Report Forms to original (source) documents to adequately evaluate accuracy and completeness of data.
(2) Review all Case Report Forms for errors, omissions, internal consistency, and signature and dates in the appropriate sections.
(3) Verify that a patient's written Informed Consent has been duly completed and signed for each subject prior to his/her participation in the study.
(4) Assume responsibility for any follow-up activities that result from review of study forms and documents.

Patient Confidentiality
All reports and communications relating to study subjects will identify the subject only by his/her trial I.D code. The investigator will complete subject identification on a confidential patient log, which will be used for purposes of patient tracking and follow-up. This will be treated in accordance with strict adherence to professional standards of confidentiality, and will be filed with adequate security and restricted accessibility.
Signed Informed Consent Forms bearing the full name and signature of patients represent confidential documents and should therefore be archived in the Investigator File.

Study Discontinuation
The study may be discontinued if: a) At any time, in the opinion of the Institutional Ethical Committee, the investigator, and/or the company, the study represents an unreasonable medical risk to patients.
b) The Sponsor decides to terminate the study due to company considerations.

Protocol Amendments
The protocol is not to be modified by the investigator without first obtaining review and agreement of BrainsGate.
Medically significant amendments to the protocol (e.g., changes that increase the risk or the inconveniences for the patient, inclusion of new categories of patients, etc.) must be approved by the local Ethical Committee prior to implementation.

Study Documentation and Data Management
The following data will be recorded pre, during and post-procedure on the Case Report Forms: (1) BASELINE FORM -to be used for screening patients for inclusion into the study and to record patient's demographic data as well as patient's medical history.
(2) PROCEDURE FORM -to be used to record procedural details, procedural complications, technical aspects of the system, and other relevant information related to the procedure.
(3) FOLLOW-UP FORM -to be used during the standard post-procedure checkup visit at the clinic to record the current condition of the patient, and occurrence of post-procedural complication if any.
(4) ADVERSE EVENT FORM -to be used for recording any complication that occurred during the study.
(5) EXIT FORM -to be used to record completion of study, pre-mature withdrawals, and/or lost to follow up cases.
All data collected in the CRF will be stored in a computer form (database). Data will be entered into a commercially available or validated system, using a double data entry (DDE) method. In case of changes to the data, the system should maintain an audit trial of all the changes.
The investigator will be responsible for keeping the following records: The investigator will arrange for the retention of these documents for a period of no less than three years after the latter of the following dates: the date of which the study is terminated or completed or; the date that the records are no longer required supporting marketing applications. The investigator should not relocate or dispose of any study documents before having obtained BrainsGate written permission.