The Neurolutions IpsiHand Upper Extremity Rehabilitation System is indicated for use in chronic stroke patients (≥ 6 months post-stroke) age 18 or older undergoing stroke rehabilitation, to facilitate muscle re-education and for maintaining or increasing range of motion in the upper extremity.

Device Description

The Neurolutions IpsiHand Upper Extremity Rehabilitation System (a.k.a. Neurolutions System or IpsiHand System) detects goal-oriented brain activity using non-invasive EEG electrodes to allow a stroke patient to perform therapeutic exercises that they would otherwise not be able to perform, due to their impairment. The Neurolutions System consists of the Neurolutions Handpiece, a Tablet computer, and a Biometric Headset. Using a standard Windows Tablet as the patient interface, the System translates brain signals from the Biometric Headset into movement of the motor-driven Handpiece worn over the patient's hand and wrist. The motion of the Handpiece, in turn, opens and closes the patient's impaired hand. The combined action of these System components allows the stroke patient to perform physical therapy exercises that they would otherwise not be able to perform, due to their impairment. The Biometric Headset, which contains dry electroencephalographic (EEG) sensors, receives electrical signals from the motor or pre-motor cortex, predominantly of the unaffected hemisphere of the patient's brain, and in doing so, detects the patient's intentions to move their affected hand. These intentions to move are translated into motor movements of the Handpiece using software that drives a linear actuator contained inside of the Handpiece. The Handpiece opens and closes the hand using a 3-finger pincer grip mechanism designed to emulate the movement of grasping an object using the two forefingers and thumb in a grasping motion (one degree of freedom). The device functions as powered exercise equipment for the patient's hand using three separate modes: the main mode of therapy is referred to as the brain-computer interface (BCI) or 'thought' mode in which the patient's hand is opened or closed by the powered orthosis based on brain signals received from the Biometric headset; the second mode is referred to as a 'volitional' mode in which a patient actively opens and closes their hand with the System enabling independent range of motion; the third is a continuous passive motion (CPM) mode in which the System simply moves the patient's hand passively through a comfortable range of motion in a repetitive fashion. The Neurolutions System is designed for use in clinic or home settings as part of prescribed rehabilitation therapy.

AI/ML Overview

Acceptance Criteria and Device Performance for Neurolutions IpsiHand Upper Extremity Rehabilitation System

The Neurolutions IpsiHand Upper Extremity Rehabilitation System is an EEG-driven upper extremity powered exerciser indicated for use in chronic stroke rehabilitation. The device's safety and effectiveness were evaluated through a series of clinical investigations and non-clinical studies.

1. Table of Acceptance Criteria and Reported Device Performance

The regulatory information outlines several special controls which act as acceptance criteria. The summaries of non-clinical and clinical studies demonstrate how these criteria were met.

Acceptance Criteria (Special Controls)	Reported Device Performance and Study Findings
(1) Clinical performance testing must demonstrate that the device performs as intended under anticipated conditions of use. Testing must capture any adverse events observed during clinical use and must demonstrate that the EEG signal can be translated into intended motion.	Studies QRS-0008, ORS-0012, and ORS-0013 (preliminary) all evaluated clinical performance: * QRS-0008: Demonstrated statistically significant improvement in ARAT (mean 6.6 points, 6/10 subjects exceeded MCID). Secondary outcomes (COPM, Motricity Index, grip strength) also significantly improved. Minor fatigue reported in 1 subject; no patient injury or adverse events. * ORS-0012: From baseline to 12 weeks, patients (n=17) demonstrated a mean improvement of (b) (9) in UEFM with a SD of (b) (4) (p < 0.0001). Mean ARAT improvement at 12 weeks was (0)(4) with SD of (b) (4). Mean change in motricity was (6) (4) points with SD of (b) (4) (p < .0001). Mean increase in gross grasp was (b) (4) pounds with SD of (b) (4). Mean change in AMAT scores was (b) (4) points (SD (b) (4) and p < 0001). Observed adverse events were minor fatigue/discomfort (1 case) and skin redness (1 case), both resolved. * ORS-0013 (preliminary): From baseline to 12 weeks, patients (n=12) demonstrated a mean improvement of (0) (4) with a SD of (b) (4) (p < 0.0001). Supports feasibility of EEG signal recording and control of the hand orthosis. * Meta-analysis: Compared to historical controls receiving standard care, IpsiHand showed clinically meaningful improvements (FM-UE MCID is 5.25 points), whereas standard care alone did not. * EEG Signal Translation: The device description explicitly states: "The Biometric Headset... receives electrical signals from the motor or pre-motor cortex... and in doing so, detects the patient's intentions to move their affected hand. These intentions to move are translated into motor movements of the Handpiece..." This core function was evaluated in Phase 1 of ORS-0008, ORS-0012, and ORS-0013 to ensure participants could control the BCI.
(2) Software verification, validation, and hazard analysis must be performed.	The sponsor provided documentation acceptable for software and firmware with a "Moderate" Level of Concern (LoC), as outlined in FDA guidance. The primary risk (delay of treatment due to software/firmware malfunction or failure) was addressed.
(3) Performance data must demonstrate the electromagnetic compatibility, electrical safety, battery safety, and wireless compatibility of the device.	EMC & Electrical Safety: Tested according to IEC 60601-1:2005 (compliant), IEC 60601-1-2:2014, and IEC 60601-1-11:2015. Wireless: Evaluated against ANSI/AAMI/IEC 60601-1-2 (4th edition) for immunity and emissions for Wi-Fi and Bluetooth. Despite lack of wireless coexistence testing, a General Precaution warning and troubleshooting section were added to labeling. Battery Safety: Rechargeable lithium-ion Handpiece battery reviewed to IEC 62133 Edition 2.0 2012-12 as part of IEC 60601-1:2005 + A1:2012 evaluation.
(4) The device components that contact the patient must be demonstrated to be biocompatible.	Biocompatibility evaluation for the Biometric Headset and Neurolutions System Handpiece (surface device, < 24-hour contact) was conducted per ISO 10993-1:2009. Tests included Cytotoxicity (ISO 10993-5:2009), Sensitization Test (ISO 10993-10:2010), and Intracutaneous Reactivity (ISO 10993-10:2010). One component (inner rings) showed cytotoxicity but passed sensitization and irritation, deemed acceptable as low risk. All other components met prespecified acceptance criteria.
(5) Performance data must validate the reprocessing instructions for the reusable components of the device.	Cleaning and disinfection methods were validated in accordance with AAMI TIR12:2010 by Nelson Labs. Demonstrations of low-level disinfection for clinic (multiple patient use) and factory reprocessing were successful. Validated instructions provided in labeling. Risk of cross-contamination is further ameliorated by disposable protective covers.
(6) Labeling must include: (i) Instructions on fitting the device to the patient; (ii) Information on how the device operates and the typical sensations experienced during treatment; and (iii) Reprocessing instructions.	The User Manual meets 21 CFR Part 801.109. Labeling includes instructions on navigating software, fitting the device, device operation, typical sensations, and cleaning for home and clinical use. Additionally, it informs users about 6-month durability data and that not all patients achieve clinically meaningful benefit (33.3% did not in one trial).

2. Sample Size Used for the Test Set and Data Provenance

The primary clinical evidence comes from three studies (QRS-0008, ORS-0012, ORS-0013) that served as the "test set" for the device's clinical performance.

QRS-0008: 10 chronic hemiparetic stroke survivors.
ORS-0012: 24 subjects progressed to Phase 2 (the therapeutic phase), with 17 completing the study protocol and 12 completing the 6-month durability visit.
ORS-0013 (Preliminary): 13 chronic hemiparetic stroke survivors, with 12 completing 12 weeks of therapy.

Data Provenance: All three studies were:

Prospective and Non-Randomized.
Self-controlled: Patients served as their own controls, with baseline measurements compared to post-treatment measurements.
Country of Origin: Not explicitly stated for all sites, but ORS-0013 was conducted at Washington University IRB in St. Louis, MO, indicating a US origin. The others are also implied to be within the US given the FDA submission context.

3. Number of Experts Used to Establish the Ground Truth for the Test Set and Qualifications of Those Experts

The ground truth in these studies was based on established clinical assessments of motor function and impairment. These assessments (e.g., ARAT, UEFM, Motricity Index, grip strength) are performed by trained clinical specialists. The document does not specify the exact number of experts or their specific qualifications (e.g., years of experience as a neurologist or physical therapist), beyond referring to "clinical specialist" in ORS-0013. However, the use of recognized, standardized clinical outcome measures implies that these assessments were performed by qualified personnel.

4. Adjudication Method for the Test Set

The studies used retrospective self-comparison (baseline vs. post-treatment for each patient) as the primary method to assess improvement. There is no mention of an independent expert adjudication panel for individual patient outcomes from the clinical assessment tools. The interpretation of the aggregated data and the overall clinical meaningfulness was part of the sponsor's analysis and FDA's review.

5. If a Multi-Reader Multi-Case (MRMC) Comparative Effectiveness Study Was Done

No, a Multi-Reader Multi-Case (MRMC) comparative effectiveness study was not explicitly mentioned or performed in the context of human readers improving with AI vs. without AI assistance. The Neurolutions System is a direct brain-computer interface therapy device, not an AI-assisted diagnostic tool that aids human interpretation of medical images or data. The "AI" here refers to the BCI algorithm that translates brain signals into device movement.

6. If a Standalone (i.e., Algorithm Only Without Human-in-the-Loop Performance) Was Done

Yes, in a way. The core function of the device is the "brain-computer interface (BCI) or 'thought' mode" where "the patient's hand is opened or closed by the powered orthosis based on brain signals received from the Biometric headset." This represents the device (algorithm and hardware) performing its intended function based solely on the patient's brain signals, without direct human intervention in each movement. The clinical studies (especially Phase 1 of QRS-0008, ORS-0012, and ORS-0013) inherently demonstrated the standalone performance of the BCI in detecting intentions and driving the handpiece. The "human-in-the-loop" aspect is the patient's brain activity providing the input.

7. The Type of Ground Truth Used

The ground truth used was primarily clinical assessment scores from recognized, validated scales performed by clinical specialists. These include:

Action Research Arm Test (ARAT)
Fugl-Meyer Upper Extremity (UEFM)
Canadian Occupational Performance Measure (COPM)
Motricity Index
Grip Strength
Active Range of Motion (AROM)
Modified Ashworth Scale

These are considered objective measures of functional motor outcomes and impairment.

8. The Sample Size for the Training Set

The document does not explicitly delineate a "training set" in the conventional machine learning sense for the BCI algorithm. The development of the BCI algorithm itself would have involved data collection for signal processing and pattern recognition. However, the regulatory submission focuses on the clinical studies (QRS-0008, ORS-0012, ORS-0013) that served as the validation and effectiveness studies using human participants. If "training set" refers to the initial development of the BCI's core functionality, that information is not provided here. The three clinical studies mentioned served to demonstrate the device's efficacy in real-world use rather than to train the underlying BCI algorithm.

9. How the Ground Truth for the Training Set Was Established

As noted above, specific details about a "training set" for the BCI algorithm in the context of this submission are not provided. However, for such BCI systems, the ground truth for training would typically involve:

Intentional Movement Observation: Patients would perform specific movements (e.g., attempt to open/close hand) while EEG signals are simultaneously recorded. The intent to move or the actual movement (if physically possible) would serve as the "ground truth label" for the corresponding brain signals.
Motor Imagery Tasks: Patients would imagine performing movements, and associated brain patterns would be recorded and labeled.
Expert Observational Data: Clinical specialists observing and documenting patient movement or attempted movement in conjunction with EEG data.

Without specific details, it is inferred that the BCI algorithm was developed using standard BCI training methodologies where intentional or imagined movements are correlated with EEG patterns.

Summary

{0}------------------------------------------------

DE NOVO CLASSIFICATION REQUEST FOR NEUROLUTIONS IPSIHAND UPPER EXTREMITY REHABILITATION SYSTEM

REGULATORY INFORMATION

FDA identifies this generic type of device as:

Electroencephalography (EEG)-driven upper extremity powered exerciser. An EEG-driven upper extremity powered exerciser is a non-invasive prescription device intended for rehabilitation by driving movement or exercise of an impaired upper extremity in response to the detection of purpose oriented electrical activity produced by the patient's brain.

NEW REGULATION NUMBER: 21 CFR 890.5420

CLASSIFICATION: Class II

PRODUCT CODE: QOL

BACKGROUND

DEVICE NAME: Neurolutions IpsiHand Upper Extremity Rehabilitation System

SUBMISSION NUMBER: DEN200046

DATE DE NOVO RECEIVED: July 23, 2020

SPONSOR INFORMATION:

Neurolutions, Inc. 1101 Pacific Ave, Suite 300 San Cruz, California 95060

INDICATIONS FOR USE

The Neurolutions IpsiHand Upper Extremity Rehabilitation System is indicated as follows:

LIMITATIONS

The sale, distribution, and use of the Neurolutions System are restricted to prescription use in accordance with 21 CFR 801.109.

{1}------------------------------------------------

The Neurolutions System is contraindicated for use in patients having any of the following conditions:

. Severe spasticity or rigid contractures in the wrist and/or digits that would prevent the Neurolutions Handpiece from being properly fit or positioned for use.
. Skull defects due to craniotomy or craniectomy.

The safety and effectiveness of Neurolutions System therapy has not been evaluated in the following patient populations:

Patients with Dementia, or who are too cognitively impaired to understand tasks
Patients with severe, receptive aphasia who have difficulty understanding written or spoken language, or who are unable to follow written instructions
Patients with severe unilateral visual inattention (neglect) that would visually limit use of the Tablet

The Neurolutions System should be used with caution in patients with nerve or sensory impairment that may limit or interfere with the patient's ability to sense pain in response to potential pressure points on the Neurolutions Handpiece.

As with use of any medical device, there are risks associated with treatment using the Neurolutions System. Some patients may experience any of the following adverse events during use of the device.

· Fatigue, discomfort and/or headache associated with device use
· Skin redness or pressure point(s) associated with the mechanical hand exerciser

Durability testing has not been completed beyond 6-months, persistence of benefits beyond 6-months post device use are currently unknown.

PLEASE REFER TO THE LABELING FOR A COMPLETE LIST OF WARNINGS, PRECAUTIONS AND CONTRAINDICATIONS.

DEVICE DESCRIPTION

{2}------------------------------------------------

The Neurolutions System shown in the figure below, consists of the Neurolutions Handpiece, a Tablet computer, and a Biometric Headset.

Image /page/2/Picture/1 description: A person is wearing a hand rehabilitation device. The device is blue and black and is attached to the person's hand and wrist with straps. The device appears to be designed to help the person move their fingers and hand. The person's hand is resting on a black surface.

Neurolutions Handpiece

Image /page/2/Picture/3 description: The image shows a white tablet with a Windows operating system displayed on the screen. The tablet is positioned at a slight angle, showcasing the screen and the thin profile of the device. The Windows interface is visible, featuring the start menu and various application icons, suggesting the tablet is in active use or standby mode.

Tablet

Image /page/2/Picture/5 description: The image shows a black headset with multiple sensors attached to it, placed on a transparent head model. The headset has a central circular pad on top, with several smaller circular sensors extending outwards and downwards. The sensors appear to be positioned to make contact with the head. The transparent head model is featureless, allowing the headset and sensors to be clearly visible.

Biometric Headset

Using a standard Windows Tablet as the patient interface, the System translates brain signals from the Biometric Headset into movement of the motor-driven Handpiece worn over the patient's hand and wrist. The motion of the Handpiece, in turn, opens and closes the patient's impaired hand. The combined action of these System components allows the stroke patient to perform physical therapy exercises that they would otherwise not be able to perform, due to their impairment. The Biometric Headset, which contains dry electroencephalographic (EEG) sensors, receives electrical signals from the motor or pre-motor cortex, predominantly of the unaffected hemisphere of the patient's brain, and in doing so, detects the patient's intentions to move their affected hand. These intentions to move are translated into motor movements of the Handpiece using software that drives a linear actuator contained inside of the Handpiece. The Handpiece opens and closes the hand using a 3-finger pincer grip mechanism designed to emulate the movement of grasping an object using the two forefingers and thumb in a grasping motion (one degree of freedom).

The device functions as powered exercise equipment for the patient's hand using three separate modes: the main mode of therapy is referred to as the brain-computer interface (BCI) or 'thought' mode in which the patient's hand is opened or closed by the powered orthosis based on brain signals received from the Biometric headset; the second mode is referred to as a 'volitional' mode in which a patient actively opens and closes their hand with the System enabling independent range of motion; the third is a continuous passive motion (CPM) mode in which the System simply moves the patient's hand passively through a comfortable range of motion in a repetitive fashion.

The Neurolutions System is designed for use in clinic or home settings as part of prescribed rehabilitation therapy.

SUMMARY OF NONCLINICAL/BENCH STUDIES

BIOCOMPATIBILITY/MATERIALS

Only the Biometric Headset and Neurolutions System Handpiece are considered patientcontacting components of the System. The sponsor tested (6) samples each of the loop

{3}------------------------------------------------

straps, orthosis padding, headset top foam padding and headset ear pad covers, which are patient-contacting throughout the therapy. However, the orthosis housing, EEG electrode components, plastic components of the finger tray and thumb rest, chargers, and the polycarbonate components of the biometric headset were not tested, as these components are in contact with the skin for a brief period and represent a low risk. The tablet was also not tested for biocompatibility, as it is an off-the-shelf consumer electronics device that is in contact with the patient only when initiating or updating the therapy program, thus posing a low risk for biocompatibility issues.

The biocompatibility evaluation for the Biometric Headset and Neurolutions System Handpiece was conducted in accordance with the International Standard ISO 10993-1: 2009 "Biological Evaluation of Medical Devices Part-1: Evaluation and Testing Within a Risk Management Process". The Biometric Headset and Neurolutions System Handpiece are categorized as a surface device in limited (< 24 hours) contact of the skin. Assessment of the device included the following tests:

Cytotoxicity (ISO 10993-5:2009) ●
. Sensitization Test (ISO 10993-10:2010)
Intracutaneous Reactivity (ISO 10993-10:2010) ●

The inner rings passed sensitization and irritation testing but demonstrated some cytotoxicity. It appears likely that the Silver/Silver Chloride (manufactured from (b) (4) fine silver) that is deposited on the Acrylonitrile Butadiene Styrene (ABS D100) base material for the inner sensor electrode is the cause for the failure. This appears to be a low risk and was determined to be acceptable. All other components met the prespecified acceptance criteria for all tests.

SHELF LIFE/REPROCESSING/STERILITY

The Neurolutions System is not provided sterile and is not intended to be sterilized prior to use. The device consists of the following reusable components: a handpiece, a tablet, and a headset. Cleaning and disinfection methods were validated in accordance with AAMI TIR12:2010 (Designing, testing, and labeling reusable medical devices for reprocessing in health care facilities: A guide for device manufacturers). Testing was performed by Nelson Labs to demonstrate low-level disinfection of the Neurolutions System when used by different patients in a clinic setting (multiple patient use), and during factory reprocessing performed by Neurolutions, Inc. Validated cleaning and disinfection instructions have been provided for each of the three components.

The risk of contamination, particularly when the device is used between multiple patients in clinic use, is also ameliorated by the use of a legally marketed disposable protective cover that is worn as a barrier between the patient's skin and the Neurolutions Handpiece.

ELECTROMAGNETIC CAPABILITY & ELECTRICAL SAFETY

{4}------------------------------------------------

The Neurolutions System was tested according to the following FDA-recognized consensus standards:

IEC 60601-1:2005 (Modified to be equivalent to (AAMI/ANSI ES60601-. 1:2005/(R)2012 and C1:2009/(R)2012 and, A2:2010/(R)2012) "Medical Electrical Equipment; Part 1: General requirements for basic safety and essential performance." Results demonstrated that the device is compliant to this standard.
IEC 60601-1-2:2014 "Medical Electrical Equipment Part 1-2: General ● Requirements for Basic Safety and Essential Performance-Collateral Standard: Electromagnetic disturbances - Requirements and Tests."
IEC 60601-1-11:2015 "Medical electrical equipment: General requirements for . basic safety and essential performance – Collateral Standard: Requirements for medical electrical equipment and medical electrical systems used in the home healthcare environment."

Wireless

The Neurolutions System includes the following wireless technologies operating in the ISM band and has been evaluated against ANSI/AAMI/IEC 60601-1-2 (4th edition) for immunity and emissions appropriate for the healthcare and home environment.

Wi-Fi 802.11 b/g/n 2.4GHz
Bluetooth 2.1 2.4GHz

Although the sponsor provided wireless compatibility testing. they did not provide wireless coexistence testing. Thus, the sponsor added a General Precaution warning in the labeling explaining that the device may be susceptible to interference from common radio frequency (RF) devices and added a section in the troubleshooting to address such issues.

Battery testing

Evaluation of the product to IEC 60601-1:2005 + A1:2012 included review of 3rd party testing of sub-components such as the rechargeable lithium ion Handpiece battery to IEC 62133 Edition 2.0 2012-12.

SOFTWARE

The sponsor provided documentation acceptable for software and firmware with a "Moderate" Level of Concern (LoC), as outlined in the FDA guidance document "Guidance for the Content of Premarket Submissions for Software Contained in Medical Devices." issued May 11, 2005. The primary risk to patients is delay of treatment due to software/firmware malfunction or failure.

SUMMARY OF CLINICAL INFORMATION

A total of three separate clinical investigations were performed to evaluate the safety and effectiveness of the Neurolutions System. The first study (QRS-0008) was completed and the results published in Bundy et al. 2017, Contralesional Brain-Computer Interface Control of a Powered Exoskeleton for Motor Recovery in Chronic Stroke Survivors. The second study (ORS-0012) was completed, and the third study (QRS-0013) was on-going at the time of submission,

{5}------------------------------------------------

with preliminary analyses provided. Additionally, a meta-analysis was performed to provide further interpretation of the outcomes of these clinical investigations which utilized subject selfcontrols.

A. Treatment of Chronic Stroke with IpsiHand, Clinical Study (ORS-0008)

This feasibility study tested whether a powered hand orthosis driven by a brain-computer interface (BCI), using neural activity from the unaffected cortical hemisphere, could affect motor recovery in chronic hemiparetic stroke survivors. The study was a prospective, non-randomized, self-controlled study performed in two phases at one investigational site. Phase 1 was conducted to determine the feasibility of recording ipsilateral (contralesional) motor commands and to demonstrate the ability to use the signals to control a computer, and Phase 2 was intended to determine if the BCI-system can be used to impact rehabilitation was assessed by examining changes in commonly used functional motor scores.

Ten chronic (≥ 6 months) hemiparetic (Modified Ashworth Scale of 1+ or less of elbow flexion in the affected upper extremity) stroke survivors utilized the BCI IpsiHand System at home for 12 weeks. During this time, data was collected before, during, and upon completion of use of the Neurolutions IpsiHand System.

Subjects had a statistically significant improvement in the Action Research Arm Test (ARAT) of a mean 660 points (from (b) (4) points represents the Minimal Clinically Important Difference (MCID) in chronic stroke survivors. Six of the 10 subjects showed a difference exceeding the ARAT MCID. Secondary outcome measures including Canadian Occupational Performance Measure (COPM), Motricity Index, and grip strength also significantly improved.

No patient injury or adverse events have been reported in any subject; and only minor fatigue was reported in one (1) subject and was self-limiting.

B. IpsiHand Device Use in Stroke Patients to Assess Functional Motor Outcomes, Clinical Study (ORS-0012)

The study was a prospective, non-randomized, self-controlled study performed in two phases at two (2) investigational sites. The protocol allowed for enrollment of up to 20 adult (at least 18 vears of age) stroke survivors who sustained a cerebrovascular accident (CVA) six (6) or more months prior to the date of screening and who had moderate functional impairment of the right or left upper extremity as evidenced by screening assessments.

The goal of the study was to assess whether a motor-activity based BCI system (Neurolutions IpsiHand System) would provide rehabilitative benefits for stroke survivors. Forty-two subjects were evaluated against the inclusion criteria, and those 31 who met those criteria were assigned to Group 1 or Group 2. The study was carried out in two phases. In Phase 1, each participant (Group 1 and Group 2) completed up to three (3) sessions for recording EEG signals. by wearing a research-grade EEG Headset with EEG electrodes in place. The signals were recorded with BCI software. If the participant's EEG signals were adequate for controlling a BCI

{6}------------------------------------------------

mediated hand orthosis, the participant continued on to Phase 2. Of the 31 enrolled subjects, 7 did not meets the Phase 1 EEG criteria and 24 progressed to Phase 2, which evaluated whether a BCI system can be used to impact stroke rehabilitation. In Phase 2, each subject (Group 1 and Group 2) was issued a BCI-mediated hand orthosis and advised to use the device daily at home, a minimum of five out of seven consecutive days per week for a total of 12 weeks. Each subject had a motor assessment at 4 weeks, 8 weeks, and 12 weeks of device use. Based on progress achieved during the first 12 weeks of device use (if a subject achieved a 2-point improvement on UEFM from 8 to 12 weeks), clinical discretion, and other variables, some subjects agreed to continue using the Neurolutions System at home for up to 36 weeks. Seventeen subjects completed the study protocol, and 12 completed the 6-month durability visit.

All eligible subjects underwent the same assessments, except that Group 1 subjects completed functional MRI imaging (fMRI) to obtain structural, diffusion tensor imaging (DTI), resting state (rs) and task-based (tb) fMRI at the following specific time-points during Phase 2:

· Prior to using home BCI therapy to establish a baseline
· 12 weeks of home BCI therapy device use

All subjects were followed for an initial period of 12 weeks. Subjects who achieved motor progress, as evidenced by results of their motor assessments throughout their participation, were allowed to continue using the device at home for up to 36 weeks, or until progress plateaued (plateau was indicated by 'less than 2 points of Fugl Meyer change at the 12-week visit'). A total of eight subjects who qualified to continue with the study past 12 weeks, declined to continue for a number of reasons including personal/scheduling conflicts. or a desire to return to previous therapy.

The Fugl-Meyer - Upper Extremity (UEFM) was administered at baseline. during use of the device, and post treatment to assess motor impairment and functional movement of the affected upper extremity as related to the impact of BCI therapy.

From baseline to 12 weeks, patients (n=17) demonstrated a mean improvement of (b) (9) with a standard deviation (SD) of (b) (4) (two sided, one-sample t-test, p-value < 0.0001).

Twelve of the 17 subjects who completed at least 12-weeks of device use also completed a durability visit 6-months post device use. The mean improvement was (0)(4) points on the ARAT assessment at 12 weeks with a SD of (b) (4) (two-sided, one-sample t-test, p-value (b) (4)). The mean change from baseline to completion was (b) (4) (n=17). The mean change in motricity at 12 weeks for the study analysis (n=17) was (6) (4) points with a SD of (b) (4) (p <.0001). The mean increase in gross grasp was (b) (4) pounds with a SD of (b) (4)
change in AMAT scores was (b) (4) points (SD (b) (4) and p < 0001). . The mean

The only adverse events reported were one case of minor fatigue, discomfort (including headache) reported with device use following heart surgery and one case of skin redness indicative of a pressure point on the patient's thumb, which was resolved with re-emphasized training on thumb positioning.

{7}------------------------------------------------

C. Chronic Stroke Rehabilitation with Contralesional Brain Computer Interface, Preliminary Clinical Study Report (ORS-0013)

The third clinical investigation evaluating the Neurolutions System is currently being conducted with the approval of the Washington University IRB, located in St. Louis, MO. The clinical study (preliminary report provided in QRS-0013, Rev. B) is a prospective, non-randomized, selfcontrolled crossover study performed in two phases at one investigational site (St. Louis, MO).

Phase 1 of the study investigated the feasibility of recording electroencephalogram (EEG) signals from the affected and unaffected brain hemispheres and was intended to demonstrate the possibility of using these signals to control the motor output of a robotic hand orthosis (Handpiece). Phase 2 was the home use portion of the study, which assessed if the BCI system could be used to impact stroke rehabilitation. Subjects were enrolled into either Group 1 (additional fMRI assessment and range of motion (ROM) exercises, crossover group) or Group 2 (no fMRI or ROM).

Group 1 subjects underwent 12 weeks each of device use and the ROM Home Exercise Program (24 weeks total). For the first 12 weeks, half of the subjects used the Neurolutions IpsiHand System before the ROM home exercise program, and half of the subjects used the Neurolutions IpsiHand System after the ROM home exercise program. For the second 12 weeks, the subjects switched the treatment regimen regarding use of the investigational device before or after the ROM home exercise program.

The preliminary report presented results from 13 chronic hemiparetic stroke survivors who utilized the Neurolutions System in BCI-mode at home for 12- weeks. Three of the subjects are actively participating in the crossover portion (second treatment regimen) of the study. During the study, the clinical specialist collected data before, during, and upon completion of device use.

Based on this preliminary statistical analysis, from baseline to 12 weeks, on the patients who completed 12 weeks of therapy (n=12) demonstrated a mean improvement of (0) (4) with a SD of (b) (4) (two-sided, one sample t-test, p < 0.0001)

The results of Phase 1 of the study support the feasibility of recording EEG signals from the unaffected (contralesional) hemisphere and suggest that these signals can be used to control the motor output of a robotic hand orthosis (Handpiece). The results of Phase 2 of the study suggest that brain-controlled movement of the affected hand, through use of the Neurolutions InsiHand System, can positively impact rehabilitation by improving motor function.

To interpret the therapy outcomes of the Neurolutions IpsiHand System relative to a control intervention, an independent meta-analysis including studies published from 2000 to June 2020 was conducted of serial changes in terms of upper limb motor function for chronic stroke patients treated with standard rehabilitation care (as measured by Fugl-Meyer Upper Extremity Assessment, FM-UE). Analysis shows the effect size computed from serial differences, in terms of FM-UE assessment from a total 10 patients, ranges from (b) (4) to (0) (8) with an average change in FM-UE of (b) (4). Although small, this estimated average improvement can be hypothesized to originate from the training effect, or placebo effect, as some chronic stroke

{8}------------------------------------------------

patients treated with regular rehabilitation care will exhibit an improvement after periods of inactivity. Importantly, this small improvement is far below the Minimal Clinically Important Difference (MCID) scores for the FM-UE, which has been defined as an increase of 5.25 points from baseline in those patients in the chronic phase of stroke. The findings of this meta-analysis conclude that chronic stroke survivors do not demonstrate a clinically meaningful improvement in their motor function when receiving standard of care alone, as evidenced by the Fugl-Meyer assessment.

To date, there has been no patient injury or adverse events reported in any subject.

Pediatric Extrapolation

The Neurolutions IpsiHand Upper Extremity Rehabilitation System is indicated for patients age 18 and older. For medical devices, the FD&C Act defines patients before their 22nd birthday as pediatric patients. In this De Novo request, complete data from patients between 28-79 (mean age 57.9) were used to support the use of the device in adult patients. It was appropriate to indicate the device for individuals 18 and older because patients aged 18 to 21 do not carry additional differences or risks relative to the patient population studied, incidence of stroke and hemiparesis is present in the transitional adolescent population (pediatric sub-population) of 18-21 years of age, and this device has a likely benefit for this group.

LABELING

The labeling (User Manual) meets the requirements of 21 CFR Part 801.109 for prescription devices.

The labeling for providers and patients includes information describing the data collected with regard to the durability of the effects of device use. Namely, providers and patients are made aware that 6-month durability data were collected in a small cohort and the permanency of these gains beyond that window remain unknown.

Information in the labeling for providers and patients also describes the data collected with regard to the proportion of users that attained a clinically meaningful increased in the Fugl-Meyer with device use. Namely, 33.3% of patients who used the device as directed did not achieve a clinically meaningful increase in Fugl-Meyer score during the 12-week trial of device use. It is important that providers and patients be made aware that not all patients will experience a clinically meaningful benefit from device use.

The labeling includes instructions explaining how users can navigate the software application to use the different modes of the device (Brain-Computer Interface, Volitional, and Continuous Passive Motion). Instructions for use includes information on fitting the device to the patient, how the device operates, and the typical sensations experienced during treatment.

The labeling also outlines the cleaning for home use and clinical use.

RISKS TO HEALTH

{9}------------------------------------------------

The table below identifies the risks to health that may be associated with use of the electroencephalography (EEG)-driven powered exerciser and the measures necessary to mitigate these risks.

Identified Risks to Health	Mitigation Measures
Device provides ineffective treatment,leading to worsening condition	Clinical performance testingSoftware verification, validation, and hazard analysisWireless compatibility testing
Unintended motion leading to injury	Software verification, validation, and hazard analysis
Thermal injury including burns andshock	Electromagnetic compatibility (EMC) testingElectrical safety testingBattery safety testingLabeling
Adverse tissue reaction	Biocompatibility evaluationLabeling
Cross contamination, leading toinfection or adverse tissue reaction	Reprocessing validationLabeling
Pain or discomfort including:• Headache• Fatigue• Skin redness	LabelingClinical performance testing

SPECIAL CONTROLS

In combination with the general controls of the FD&C Act, the electroencephalography (EEG)driven powered exerciser is subject to the following special controls:

(1) Clinical performance testing must demonstrate that the device performs as intended under anticipated conditions of use. Testing must capture any adverse events observed during clinical use and must demonstrate that the EEG signal can be translated into intended motion.
(2) Software verification, validation, and hazard analysis must be performed.
(3) Performance data must demonstrate the electromagnetic compatibility, electrical safety, battery safety, and wireless compatibility of the device.
(4) The device components that contact the patient must be demonstrated to be biocompatible.
(5) Performance data must validate the reprocessing instructions for the reusable components of the device.
(6) Labeling must include:
- (i) Instructions on fitting the device to the patient;
- (ii) Information on how the device operates and the typical sensations experienced during treatment; and
- (iii) Reprocessing instructions.

BENEFIT-RISK DETERMINATION

{10}------------------------------------------------

The risks of the device are based on data collected in the clinical studies described above. Namely, the studies included adverse events such as pain or discomfort due to headache and fatigue as well as adverse tissue reaction if the device was not positioned properly. Known risks for skin contacting devices include issues of biocompatibility, and when intended for multipatient use, there is a known risk of cross contamination. With devices of this type, malfunction due to electromagnetic interference or software faults can also pose risks such as thermal injury. unintended motion, or inability to treat due to device failure. None of the above are serious and all can be resolved quickly and easily by discontinuing use or adjusting the device.

The probable benefits of the device are also based on data collected in the clinical studies as described above. Improvements include improved upper extremity function as measured by the Action Research Arm Test (ARAT) and the upper extremity Fugl-Mever (UEFM) score, results that were statistically significant and clinically meaningful. There were also statistically significant improvements in Motricity Index and grip strength and a self-scored subjective measure of each subject's ability to use their affected arm in functional tasks. Improvements were observed in pinch strength, Modified Ashworth Scale and Active Range of Motion (AROM).

Sources of uncertainty in the benefits included the effect of concomitant use of Botox by some study participants, small sample sizes with an open label study design that does not control for the placebo effect, and limited follow up time to establish durability of treatment effect. The first was addressed using subgroup analysis showing that when the data were combined across studies there was a larger mean UEFM improvement in Botox patients ((b) (4) pts) than in non-Botox patients (0) (4) pts). The small sample size and lack of placebo control was addressed by pooling data and citing historical controls. Due to the limited follow up time, the sponsor includes in the labeling information on the durability of the treatment effect.

PATIENT PERSPECTIVES

This submission did not include specific information on patient perspectives for this device.

BENEFIT/RISK CONCLUSION

In conclusion, given the available information above, for the following indication statement:

The Neurolutions IpsiHand Upper Extremity Rehabilitation System is indicated for use in chronic stroke patients (> 6 months post-stroke) age 18 or older undergoing stroke rehabilitation, to facilitate muscle re-education and for maintaining or increasing range of motion in the upper extremity.

The probable benefits outweigh the probable risks for the Neurolutions IpsiHand Upper Extremity Rehabilitation System. The device provides benefits and the risks can be mitigated by the use of general controls and the identified special controls.

CONCLUSION

{11}------------------------------------------------

The De Novo request for the Neurolutions IpsiHand Upper Extremity Rehabilitation System is granted and the device is classified as follows:

Product Code: QOL Device Type: Electroencephalography (EEG)-driven upper extremity powered exerciser Regulation Number: 21 CFR 890.5420 Class: II

Regulation Number and Section

N/A