K Number

Device Name

Modius Stress

Manufacturer

Neurovalens Limited

Date Cleared

2024-03-27

(243 days)

Product Code

QJQ OJO

Regulation Number

882.5800

Intended Use

Modius Stress is a non-invasive, home-use neurostimulation device that is indicated to treat the symptoms of Generalized Anxiety Disorder in adults aged 22 and older, when used for approximately 4 weeks. Durability of effect after 4 weeks has not been established.

Device Description

Modius Stress is a non-invasive transdermal neurostimulation device to treat the symptoms of Generalized Anxiety Disorder. The proposed mechanism of the device is through a technology known as Cranial Electrotherapy Stimulation (CES). It consists of a battery-powered device designed to transcutaneously deliver low-level electrical energy (up to 1.5mA) to the skin behind the ears, over the mastoid processes. The delivery of this neurostimulation is through two self-adhesive electrode pads. These pads are placed on the skin behind each ear (mastoid area). The intensity of the electric pulse can be adjusted up or down by the user. When turned on, the device delivers a small electrical impulse, and adjustments to the stimulation level may be made using the up and down buttons on the device, which are located just above the power button. The device can also be paused by pressing the power button twice. When finished the user removes the device and disposes of the electrode pads after each use. When the device is not being used it can be charged through a micro-USB cable. For safety reasons, it is not possible to recharge the battery while the device is in use in stimulation mode. The key components of the Modius Stress include the Modius Stress device (plastic enclosure and printed circuit board assembly (PCBA), stimulation pads (K210448 and K132588), skin cleansing wipes (K121655) and charging accessories. The PCBA consists of a microcontroller, USB connector, transformer driver, IO expander and EEPROM memory. The embedded software within the device manages overall functionality of the device from Stimulation Control, Power Management, and user interaction (Indication LED and Audio tones).

More Information

Contact

Type

Center

Panel

Date Received

Product Code

Subsequent Product Codes

Applicant Name (Manufacturer)

Device Name

Decision

Street 1

Street 2

City

State

Country Code

ZIP

Postal Code

Class Advise Committee

SSP Indicator

Third Party Reviewed

Expedited Review

Predicate Devices

K062284, K903014

Reference Devices

No reference devices were used in this submission.

AI/ML (Artificial Intelligence / Machine Learning)

No
The device description details a simple neurostimulation device with a microcontroller and basic embedded software for control and user interaction. There is no mention of AI/ML components, data processing for learning, or adaptive algorithms based on user input or physiological data. The performance studies are clinical trials evaluating the device's efficacy, not studies related to AI/ML model training or validation.

Therapeutic

Yes
The device is indicated to treat the symptoms of Generalized Anxiety Disorder, which directly addresses a medical condition.

Diagnostic

The device is indicated to treat the symptoms of Generalized Anxiety Disorder; it is a neurostimulation device, not one for diagnosing conditions.

SaMD (Software as a Medical Device)

The device description clearly states it consists of a battery-powered device, electrode pads, and charging accessories, indicating it is a hardware device with embedded software, not a software-only medical device.

IVD (In Vitro Diagnostic)

Based on the provided text, this device is not an IVD (In Vitro Diagnostic).

Here's why:

IVD Definition: In vitro diagnostics are tests performed on samples taken from the human body, such as blood, urine, or tissue, to detect diseases, conditions, or infections.
Device Function: The Modius Stress device is a neurostimulation device that delivers electrical energy to the skin. It is used to treat symptoms of Generalized Anxiety Disorder, not to diagnose or detect a condition through analysis of biological samples.

The description clearly states its function as a non-invasive treatment device, not a diagnostic tool.

PCCP (Predetermined Change Control Plan) Authorized

N/A

Overview

Intended Use / Indications for Use

Product codes (comma separated list FDA assigned to the subject device)

OJO

Device Description

It consists of a battery-powered device designed to transcutaneously deliver low-level electrical energy (up to 1.5mA) to the skin behind the ears, over the mastoid processes. The delivery of this neurostimulation is through two self-adhesive electrode pads. These pads are placed on the skin behind each ear (mastoid area). The intensity of the electric pulse can be adjusted up or down by the user. When turned on, the device delivers a small electrical impulse, and adjustments to the stimulation level may be made using the up and down buttons on the device, which are located just above the power button. The device can also be paused by pressing the power button twice. When finished the user removes the device and disposes of the electrode pads after each use. When the device is not being used it can be charged through a micro-USB cable. For safety reasons, it is not possible to recharge the battery while the device is in use in stimulation mode.

The key components of the Modius Stress include the Modius Stress device (plastic enclosure and printed circuit board assembly (PCBA), stimulation pads (K210448 and K132588), skin cleansing wipes (K121655) and charging accessories. The PCBA consists of a microcontroller, USB connector, transformer driver, IO expander and EEPROM memory. The embedded software within the device manages overall functionality of the device from Stimulation Control, Power Management, and user interaction (Indication LED and Audio tones).

Mentions image processing

Not Found

Mentions AI, DNN, or ML

Not Found

Input Imaging Modality

Not Found

Anatomical Site

skin behind the ears, over the mastoid processes.

Indicated Patient Age Range

adults aged 22 and older

Intended User / Care Setting

home-use

Description of the training set, sample size, data source, and annotation protocol

Not Found

Description of the test set, sample size, data source, and annotation protocol

Not Found

Summary of Performance Studies (study type, sample size, AUC, MRMC, standalone performance, key results)

Clinical testing of the Modius Stress device (MA1500) included two pivotal randomized controlled trials to evaluate the safety and efficacy of the Modius Stress device, for the treatment of anxiety.

Study Design:
Both studies were randomised, double blinded, sham-controlled trials, one of which was conducted in the UK and the other in India.
The UK study was undertaken from July 2022 to April 2023 and has been registered at https://clinicaltrials.gov (ClinicalTrials.gov Identifier: NCT05907967).
The study in India was conducted from October 2022 to June 2023 and has also been registered at ClinicalTrials.gov (Identifier: NCT05845658).
In both studies, adults with a General Anxiety Disorder 7th edition (GAD-7) score of 10 or higher were recruited.
In the UK study, both groups were advised to use their allocated devices for 30 minutes per day for a four-week duration at home.
In the India study, both groups were asked to complete 20 stimulation sessions (30 minutes duration) at a rate of ~3-5 sessions per week at the Department of Physiology at R.D. Gardi Medical College.

Primary Effectiveness Endpoint:
The efficacy of the Modius Stress device was quantified by change in GAD-7 score at baseline and week 4 in the UK study, and when each participant finished their 20 stimulation sessions in the India study, between the Modius Stress group and sham control group.

Primary Safety Endpoint:
In both studies, an evaluation of the safety of the Modius Stress device was quantified by the occurrence in adverse events between the Modius Stress group and sham control group.

UK Study Results:

Sample Size: A total of 87 eligible participants (female, n=65) were recruited and randomised to the Modius Stress group (n=43) or the sham control group (n=44). 84 participants were included in the primary safety endpoint analysis and 84 (ITT) / 75 (Complete case) in the primary effectiveness endpoint analysis.
Effectiveness: The ITT (multiple imputation (MI) and baseline carried forward (BOCF)) and complete case analyses demonstrated that the Modius Stress group had a greater reduction in GAD-7 score compared with the sham control group; however, the mean difference among the groups was not statistically different.
- ITT (MI) mean difference: -1.45 (95% CI: -3.37, 0.47), P=0.139
- ITT (BOCF) mean difference: -0.71 (95% CI: -2.57, 1.14), P=0.445
- Complete Case mean difference: -1.18 (95% CI: -3.12, 0.77), P=0.233
- More participants in the Modius Stress group achieved a 4 point or more reduction in GAD-7 (complete case analysis: 27 out of 36 [75%] vs 20 out of 39 [51%]).
Safety: A total of 7 Adverse Events were reported, 5 by the Modius Stress group and 2 by the sham control group. All were minor, caused minimal discomfort, and self-resolved. No serious adverse events were reported.

India Study Results:

Sample Size: A total of 60 eligible participants were recruited and randomised to the Modius Stress group (n=34) or the sham control group (n=26). 60 participants were included in the primary safety endpoint analysis and 60 (ITT) / 59 (Complete case) in the primary effectiveness endpoint analysis.
Effectiveness: The study met the primary endpoint. The Modius Stress group had a mean reduction in GAD-7 score of -7.44 (p= 10 at baseline.
Results:
- UK subgroup: Modius Stress had a 7.44 (95% CI: -8.87, -6.00) reduction in GAD-7, sham had 5.36 (95% CI: -7.06, -3.66) reduction.
- India subgroup: Modius Stress had a 6.67 (95% CI: -7.93, -5.40) reduction in GAD-7, control had 1.90 (95% CI: -4.20, 0.40) reduction.

Key Metrics (Sensitivity, Specificity, PPV, NPV, etc.)

Not Found. Key metrics mentioned are GAD-7 score reduction and percentage of participants achieving a 4-point or more reduction in GAD-7.

Predicate Device(s): If the device was cleared using the 510(k) pathway, identify the Predicate Device(s) K/DEN number used to claim substantial equivalence and list them here in a comma separated list exactly as they appear in the text. List the primary predicate first in the list.

CES Ultra, K062284, Alpha-Stim® CS, K903014

Reference Device(s): Identify the Reference Device(s) K/DEN number and list them here in a comma separated list exactly as they appear in the text.

No reference devices were used in this submission.

Predetermined Change Control Plan (PCCP) - All Relevant Information for the subject device only (e.g. presence / absence, what scope was granted / cleared under the PCCP, any restrictions, etc).

Not Found

Regulation Number and Section

§ 882.5800 Cranial electrotherapy stimulator.

(a)
Identification. A cranial electrotherapy stimulator is a prescription device that applies electrical current that is not intended to induce a seizure to a patient's head to treat psychiatric conditions.(b)
Classification. (1) Class II (special controls) when intended to treat insomnia and/or anxiety. The special controls for this device are:(i) A detailed summary of the clinical testing pertinent to use of the device to demonstrate the effectiveness of the device to treat insomnia and/or anxiety.
(ii) Components of the device that come into human contact must be demonstrated to be biocompatible.
(iii) The device must be designed and tested for electrical safety and electromagnetic compatibility (EMC) in its intended use environment.
(iv) Appropriate software verification, validation, and hazard analysis must be performed.
(v) The technical parameters of the device, including waveform, output mode, pulse duration, frequency, train delivery, maximum charge, and energy, must be fully characterized and verified.
(vi) The labeling for the device must include the following:
(A) The intended use population and the intended use environment;
(B) A warning that patients should be monitored by their physician for signs of worsening;
(C) A warning that instructs patients on how to mitigate the risk of headaches, and what to do should a headache occur;
(D) A warning that instructs patients on how to mitigate the risk of dizziness, and what to do should dizziness occur;
(E) A detailed summary of the clinical testing, which includes the clinical outcomes associated with the use of the device, and a summary of adverse events and complications that occurred with the device;
(F) Instructions for use that address where to place the electrodes, what stimulation parameters to use, and duration and frequency of treatment sessions. This information must be based on the results of clinical studies for the device;
(G) A detailed summary of the device technical parameters, including waveform, output mode, pulse duration, frequency, train delivery, and maximum charge and energy; and
(H) Information on validated methods for reprocessing any reusable components between uses.
(vii) Cranial electrotherapy stimulator devices marketed prior to the effective date of this reclassification must have an amendment submitted to the previously cleared premarket notification (510(k)) demonstrating compliance with these special controls.
(2) Class III (premarket approval) when intended to treat depression.
(c) Date premarket approval application (PMA) or notice of completion of product development protocol (PDP) is required. A PMA or notice of completion of a PDP is required to be filed with the Food and Drug Administration on or before March 19, 2020, for any cranial electrotherapy stimulator device with an intended use described in paragraph (b)(2) of this section, that was in commercial distribution before May 28, 1976, or that has, on or before March 19, 2020, been found to be substantially equivalent to any cranial electrotherapy stimulator device with an intended use described in paragraph (b)(2) of this section, that was in commercial distribution before May 28, 1976. Any other cranial electrotherapy stimulator device with an intended use described in paragraph (b)(2) of this section shall have an approved PMA or declared completed PDP in effect before being placed in commercial distribution.

Summary

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March 27, 2024

Neurovalens Ltd. Jason Mckeown, MD CEO 8 Carmagrim Road Ballymena, County Antrim BT44 8BP United Kingdom

Re: K232253

Trade/Device Name: Modius Stress Regulation Number: 21 CFR 882.5800 Regulation Name: Cranial electrotherapy stimulator Regulatory Class: Class II Product Code: OJO Dated: February 26, 2024 Received: February 26, 2024

Dear Dr. McKeown:

We have reviewed your section 510(k) premarket notification of intent to market the device referenced above and have determined the device is substantially equivalent (for the indications for use stated in the enclosure) to legally marketed predicate devices marketed in interstate commerce prior to May 28, 1976, the enactment date of the Medical Device Amendments, or to devices that have been reclassified in accordance with the provisions of the Federal Food, Drug, and Cosmetic Act (the Act) that do not require approval of a premarket approval application (PMA). You may, therefore, market the device, subject to the general controls provisions of the Act. Although this letter refers to your product as a device, please be aware that some cleared products may instead be combination products. The 510(k) Premarket Notification Database available at https://www.accessdata.fda.gov/scripts/cdrh/cfdocs/cfpmn/pmn.cfm identifies combination product submissions. The general controls provisions of the Act include requirements for annual registration, listing of devices, good manufacturing practice, labeling, and prohibitions against misbranding and adulteration. Please note: CDRH does not evaluate information related to contract liability warranties. We remind you, however, that device labeling must be truthful and not misleading.

If your device is classified (see above) into either class II (Special Controls) or class III (PMA), it may be subject to additional controls. Existing major regulations affecting your device can be found in the Code of Federal Regulations, Title 21, Parts 800 to 898. In addition, FDA may publish further announcements concerning your device in the Federal Register.

Additional information about changes that may require a new premarket notification are provided in the FDA guidance documents entitled "Deciding When to Submit a 510(k) for a Change to an Existing Device" (https://www.fda.gov/media/99812/download) and "Deciding When to Submit a 510(k) for a Software Change to an Existing Device" (https://www.fda.gov/media/99785/download).

Your device is also subject to, among other requirements, the Quality System (QS) regulation (21 CFR Part 820), which includes, but is not limited to, 21 CFR 820.30, Design controls; 21 CFR 820.90, Nonconforming product; and 21 CFR 820.100, Corrective and preventive action. Please note that regardless of whether a change requires premarket review, the QS regulation requires device manufacturers to review and approve changes to device design and production (21 CFR 820.30 and 21 CFR 820.70) and document changes and approvals in the device master record (21 CFR 820.181).

Please be advised that FDA's issuance of a substantial equivalence determination does not mean that FDA has made a determination that your device complies with other requirements of the Act or any Federal statutes and regulations administered by other Federal agencies. You must comply with all the Act's requirements, including, but not limited to: registration and listing (21 CFR Part 807); labeling (21 CFR Part 801); medical device reporting of medical device-related adverse events) (21 CFR Part 803) for devices or postmarketing safety reporting (21 CFR Part 4, Subpart B) for combination products (see https://www.fda.gov/combination-products/guidance-regulatory-information/postmarketing-safety-reportingcombination-products); good manufacturing practice requirements as set forth in the quality systems (OS) regulation (21 CFR Part 820) for devices or current good manufacturing practices (21 CFR Part 4, Subpart A) for combination products; and, if applicable, the electronic product radiation control provisions (Sections 531-542 of the Act); 21 CFR Parts 1000-1050.

Also, please note the regulation entitled, "Misbranding by reference to premarket notification" (21 CFR 807.97). For questions regarding the reporting of adverse events under the MDR regulation (21 CFR Part 803), please go to https://www.fda.gov/medical-device-safety/medical-device-reportingmdr-how-report-medical-device-problems.

For comprehensive regulatory information about mediation-emitting products, including information about labeling regulations, please see Device Advice (https://www.fda.gov/medicaldevices/device-advice-comprehensive-regulatory-assistance) and CDRH Learn (https://www.fda.gov/training-and-continuing-education/cdrh-learn). Additionally, you may contact the Division of Industry and Consumer Education (DICE) to ask a question about a specific regulatory topic.

See the DICE website (https://www.fda.gov/medical-device-advice-comprehensive-regulatoryassistance/contact-us-division-industry-and-consumer-education-dice) for more information or contact DICE by email (DICE@fda.hhs.gov) or phone (1-800-638-2041 or 301-796-7100).

Sincerely,

Pamela D. Scott -S

Pamela Scott, MS Assistant Director DHT5B: Division of Neuromodulation and Rehabilitation Devices OHT5: Office of Neurological and Physical Medicine Devices Office of Product Evaluation and Quality Center for Devices and Radiological Health

Enclosure

Indications for Use

510(k) Number (if known) K232253

Device Name

Modius Stress

Indications for Use (Describe)

Type of Use (Select one or both, as applicable)
-------------------------------------------------

☑ Prescription Use (Part 21 CFR 801 Subpart D)
☐ Over-The-Counter Use (21 CFR 801 Subpart C)

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This 510(k) Summary is submitted in accordance with 21 CFR Part 807, Section 807.92.

l. Submitter

Neurovalens Limited 8 Carmagrim Road Portglenone County Antrim BT44 8BP United Kingdom

Contact person/ official correspondence:

Dr Jason McKeown CEO Neurovalens Ltd. Tel: +44 (0) 7412508707 Email: Jason.mckeown@neurovalens.com

Device ll.

Name of Device: Modius Stress Common or usual name: Modius Stress Classification name: Cranial Electrotherapy Stimulator (CES) Regulatory Class: II Product Code: QJQ Regulation number: 882.5800 Classification panel: Neurology

III. Predicate devices

Primary predicate device

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01 Version Page 2 of 34

Modius Stress K232253 Summary

CES Ultra, K062284 Secondary predicate device Alpha-Stim® CS, K903014

No reference devices were used in this submission.

Device description IV.

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01 Version 3 of 34 Page

Modius Stress K232253 Summary

Biocompatibility testing in accordance with the endpoints of ISO 10993-1 to be addressed for a surface medical device, with prolonged: > 24 hours less than 30 days contact duration, demonstrated good biocompatibility for all components of the Modius Stress device.

Device Usage

Using the Modius Stress device has demonstrated an improvement in the symptoms of Generalized Anxiety Disorder (GAD).

After using Modius Stress there are usually no physical limitations imposed so most users can resume normal activities immediately. Some users may have a response that affect their ability to perform potentially hazardous tasks, such as operating a motor vehicle or heavy machinery for up to several hours after treatment. However, no significant lasting side effects have been reported.

V. Indications for use

VI. Comparison of the technological characteristics with the predicate device

Modius Stress is substantially equivalent with respect to indications for use, stimulation parameters (i.e., current levels, frequencies, pulse width and amplitude) and electrode placement to the predicate devices CES Ultra (cleared by K062284), and Alpha-Stim® CS (cleared by K903014). 2

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Table 1. Summary of substantial equivalence

Property	Proposed Device	Primary Predicate	Secondary Predicate	Comment
Device	Modius Stress	CES Ultra	Alpha-Stim® CS	N/A
Indications for Use	Modius Stress is a non-invasive, home-use
neurostimulation device
that is indicated to treat
the symptoms of
Generalized Anxiety
Disorder in adults aged
22 and older, when used
for approximately 4
weeks. Durability of
effect after 4 weeks has
not been established.	The CES Ultra is
indicated for the
treatment of insomnia,
depression or anxiety	The Alpha-Stim® 100 is a
precision medical
instrument used for the
management of pain,
anxiety, depression, and/or
insomnia.	Predicate devices are indicated for the
treatment of anxiety and in the case of
Modius Stress for symptoms of Generalized
Anxiety Disorder.
Target Population	Adults 22 and older	Adults	Adults	N/A
Environment	Home	Home	Home	N/A
Waveform	Symmetrical Biphasic
Rectangular Wave	Symmetrical Biphasic
Rectangular Wave	Symmetrical Biphasic
Rectangular Wave	Identical
Current Intensity Range	0 $ µ $ A – 1500 $ µ $ A	0 $ µ $ A – 1500 $ µ $ A
continually adjustable	0 $ µ $ A – 500 $ µ $ A	Modius Stress and the CES Ultra have near
identical current intensity ranges

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Modius Stress K232253 Summary

Property	Proposed Device	Primary Predicate	Secondary Predicate	Comment

Pulse Width Range	2.5ms	2ms	250ms - 1s	Pulse width varies depending on frequency
range
Number of electrodes	Two	Two	Two
				Identical

Electrode placement	Mastoid		Head – earlobes	The Modius Stress electrodes are placed on
		Mastoid or earlobes		mastoids. CES Ultra also supports mastoid only
				electrode placement
Power Source	3.75 Lithium Polymer	9V Alkaline Battery	2 x AAA NiMH
	Battery
Frequency	100Hz	100Hz	0.5Hz, 1.5Hz, 100Hz
Treatment Range	30 min	30min, 60min or	10min, 20min, 60 min or	Modius Stress maximum treatment time is within
		continuous	continuous	the range of the predicates
Unit Controls	Built into the device	Built into the device	Built into the device	Identical
Dimensions	16.5cm x 15.1cm x	13.5cm x 6.4cm x	9.8cm x 6.3cm x 2cm	Modius Stress is larger than the predicate
	6.6cm	3.3cm		devices
Enclosure	Plastic	Plastic	Plastic	Identical

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Table 2. Safety Information Comparison

| | Property | Proposed Device
Modius Stress | Primary Predicate
CES Ultra | Secondary Predicate
Alpha-Stim® CS | Comment |
|-------------------|------------------------------|----------------------------------------------|-------------------------------------------|-------------------------------------------|------------------------------------------------------------|
| Electrical Safety | | Complies with IEC
60601-1 | Complies with IEC
60601 | Complies with
IEC 60601 | The proposed device and predicate devices are
identical |
| EMC | | Complies with IEC
60601-1-2 | Complies with IEC
60601-1-2 | Complies with IEC
60601-1-2 | The proposed device and predicate devices are
identical |
| Software | Level
of
Concern | Moderate | Moderate | Moderate | The proposed device and predicate devices are
identical |
| | Verification &
Validation | Complies with
FDA Guidance
Requirement | Complies with FDA
Guidance Requirement | Complies with FDA
Guidance Requirement | |
| Biocompatibility | | Complies with ISO
10993 | Complies with ISO
10993 | Complies with
ISO 10993 | The proposed device and predicate devices are
identical |

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Modius Stress K232253 Summary

Table 3. Technical Information for the Modius Stress Output parameters

	Modius Stress	CES Ultra	Alpha-Stim CS
510(k) Number	K232253	K024377	K903014
Device Name	Modius Stress	CES ultra	Alpha-Stim CS
Manufacturer	Neurovalens Ltd	Neuro-Fitness LLC	Electromedical Products
Inc.
Power Sourcet	3.75 Lithium Polymer
Battery	9V Alkaline Battery	2 x AAA NiMH
-Method of Line Current Isolation	DC:DC transformer	N/A Non Rechargeable	N/A Non-Rechargeable
- Patient Leakage Current (as per ANSI/AAMI 60601-1)	0μA	Unknown	Unknown
-Normal Condition (μΑ)	0-1500μΑ	0-1500μΑ	0-500μΑ
-Single Fault Condition (μA)	2.3μA	Unknown	1.3mA
Average DC current through the electrodes when the device is on but no
pulses are being delivered (µA)	0μA	Unknown	Unknown
Number of output channels	1	1	1
-If more than one channel, is the stimulus delivered to
each channel synchronous or alternating between each channel?	N/A	N/A	N/A
-If more than one channel, describe method of channel isolation	N/A	N/A	N/A
Software/Firmware/Microprocessor Control	Yes	Yes	Yes
Automatic Overload Trip?	No	No	No
		Modius Stress	CES Ultra	Alpha-Stim CS
Automatic Shut Off?		Yes	Yes	Yes
User Override Control?		Yes	Yes	Yes
Mode or Program Name		Stimulation mode	Stimulation mode	Stimulation/Treatment
Mode
Waveform (e.g., pulsed monophasic, biphasic)		Biphasic	Biphasic	Biphasic
Shape (e.g., rectangular, spike, rectified sinusoidal)		Rectangular	Rectangular	Rectangular
Maximum Output Voltage (volts) (+/-1%)		750mV @500 Ω	Unknown	@500 Ω
		3V @ 2 kΩ	Unknown	@ 2 kΩ
		15V @10 kΩ	Unknown	@10 KΩ
Maximum Output Current (specify units) (+/-2%)		1500μA @500 Ω	Unknown	500μA @ 500 Ω
		1500μA @ 2 kΩ	1.5mA @ 2kΩ	@ 2 kΩ
		1500μA @10 kΩ	Unknown	@10 KΩ
Duration of primary (depolarizing) phase† (msec)		10ms	10ms	2000ms, 1000ms, 10ms
Pulse Duration†† (msec)		5ms	5ms	1000ms, 500ms, 5ms
Frequency†† (Hz) [or Rate†† (pps)]		100Hz	100Hz	0.5Hz, 1Hz, 100Hz
	For interferential modes only: Beat Frequency† (Hz)
	For multiphasic waveforms Symmetrical phases?
only:	Phase Duration† (include units),
(state range, if applicable), (both phases, if
asymmetrical)	Not Applicable for these devices

		Modius Stress	CES Ultra	Alpha-Stim CS
	Net Charge (microcoulombs (mC) per pulse) (If zero, state method of achieving zero net charge.)	3.75μC @2k Ω /
3.75 μC @ 500 Ω	0.75μC @500 Ω	300μC, 150 μC, 1.5 μC
	Maximum Phase Charge, (μC)	3.75μC @2k Ω /
3.75 μC @ 500 Ω	0.75μC@ 2 kΩ	600μC @ 500Ω
Maximum Current Density,††† (mA/cm², r.m.s.)		0.75mA /cm² @500 Ω	1.91mA/cm² @500 Ω	~1.2mA/cm² @ 500Ω
Maximum Average Current (average absolute value), mA		1.5mA @500 Ω
1.5mA @ 2kΩ	3.07mA/cm² @ 2 kΩ	Unknown
	Maximum Average Power Density, ††† (W/cm²), (using smallest electrode conductive surface area)	0.28mW/cm² @500Ω
2.24mW/cm² @2kΩ	9.19mW/cm² @2 kΩ	Unknown
Burst Mode††† (i.e., pulse trains):	(a) Pulses per burst	2	2	2, 2, 2
	(b) Bursts per second	100	100	0.5, 1, 100
	(c) Burst duration (seconds)	0.01	0.01 (10ms)	2, 1, 0.01s
	(d) Duty Cycle: Line (b) x Line (c)	0.5 (50%)	0.2(20%)	0.5 (50%)
ON Time (seconds)		5ms	10ms	1sec, 0.5sec, 10ms
OFF Time (seconds)		5ms	40ms	1sec, 0.5sec, 10ms
Output value
Load conditions	Modius stress	CES Ultra	Alpha Stim CS
Output value at 500Ω, 2kΩ and 10kΩ	1.5mA at all loads	1.5mA at all loads	0.6mA at all loads
Electrode surface
area in cm2	Conductive Area (16mm diameter)
2.0cm2	Ear clips
Diameter 7.9mm
0.5cm2 Area	1.5cm Diameter
1.77cm2
Current density	500Ω
0.75mA/cm2,

2kΩ
0.75mA/cm2

10kΩ
0.75mA/cm2 | 500Ω
1.91mA/cm2

2kΩ
3.07mA/cm2

10kΩ
Unknown | 500Ω
1.2mA/cm2

2kΩ
Unknown

10kΩ
Unknown | |
| Charge density | 500Ω
1.87µC – Per Pulse

2kΩ
1.87µC – Per Pulse

10kΩ
1.87µC – Per Pulse | 500Ω
Unknown

2kΩ
Unknown

10kΩ
Unknown | 500Ω
Unknown

2kΩ
Unknown

10kΩ
Unknown | |
| Power density | 500Ω,
0.56mW/cm2

2kΩ
2.24mW/cm2

10kΩ
11.19mW/cm2 | 500Ω,
Unknown

2kΩ
9.19ma/cm2

10kΩ
Unknown | 500Ω,
Unknown

2kΩ
Unknown

10kΩ
Unknown | |
| Max phase charge
(pulse width x peak current) | 500Ω,
3.75 µC – Per Pulse

2kΩ
3.75 µC – Per Pulse

10kΩ
3.75 µC – Per Pulse | 500Ω,
Unknown

2kΩ
0.75 µC

10kΩ
Unknown | 500Ω,
600 µC

2kΩ
Unknown

10kΩ
Unknown | |
| Max phase charge density (pulse width x peak current) / electrode surface area | 500Ω
1.87µC – Per Pulse

2kΩ
1.87µC – Per Pulse | 500Ω
Unknown

2kΩ
Unknown | 500Ω
Unknown

2kΩ
1.12mW/cm²

10kΩ
5.6mW/cm² | 500Ω,
Unknown

2kΩ
9.19mW/cm²

10kΩ
Unknown | 500Ω,
Unknown

2kΩ
Unknown

10kΩ
Unknown | |

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Page 8 of 34

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Modius Stress K232253 Summary

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Modius Stress K232253 Summary

Table 4. Comparison of Device Outputs

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Modius Stress K232253

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VII. Performance Data

Non-clinical tests

The Modius Stress was evaluated for its safety and effectiveness based on the following testing:

Table 5: Non-clinical tests

Test Name	Test Description	Results
Device Ship/Transport
Testing	Ensure device, enclosed in the selected shipping container,
meets ASTM D4169 specifications.	Passed
Biocompatibility Testing	Testing and analysis of the Modius Stress device has
demonstrated compliance to ISO 10993-1: Biological
evaluation of medical devices - Guidance	Passed
Electrical Safety	The Modius Stress device was tested to confirm that it met
the applicable standards for electrical safety (IEC 60601-1)	Passed
EMC	The Modius Stress device was tested to confirm that it met
the applicable standards for electromagnetic compatibility
(EMC) (IEC 60601-1-2)	Passed
Usability Testing	Modius Stress was assessed with regards to usability for
compliance with IEC 62366 - Medical devices - Application
of usability engineering to medical devices	Passed
Maximum Current &
Phase Charge Testing	The Maximum Current & Phase Charge Testing was to detail
the Max Current / Power output of the system under different
load conditions and determine the Max Phase Charge, Max
Current Density and Max Power Density of the Modius
Stress device.	Passed
System Verification and
Validation Testing	The system verification and validation testing was performed
to verify the hardware and firmware of the Modius Stress
Device	Passed

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Modius Stress K232253 Summary

Labeling

The labeling for the device includes the intended use population and the intended use environment; warning that patients should be monitored by their physician for signs of worsening; A warning that instructs patients on how to mitigate the risk of headaches, and what to do should a headache occur; a warning that instructs patients on how to mitigate the risk of dizziness, and what to do should dizziness occur; a detailed summary of the clinical testing, which includes the clinical outcomes associated with the use of the device, and a summary of adverse events and complications that occurred with the device; Instructions for use that address where to place the electrodes, what stimulation parameters to use, and duration and frequency of treatment sessions based on the results of clinical studies for the device; A detailed summary of the device technical parameters, including waveform, output mode, pulse duration, frequency, train delivery, and maximum charge and energy; and Information on validated methods for reprocessing any reusable components between uses.

Software Verification and Validation Testing

Software verification and validation testing were conducted, and documentation was provided as recommended by FDA's Guidance for Industry and FDA Staff, "Guidance for the Content of Premarket Submissions for Software Contained in Medical Devices."

The software for this device was considered as a "moderate" level of concern, since a failure or latent design flaw could directly result in minor injury to the patient or a failure or latent flaw could indirectly result in minor injury to the patient or operator through incorrect or delayed information or through the action of a care provider.

Animal Studies

No animal studies were conducted as part of submission to prove substantial equivalence.

Clinical Studies

CES devices collectively demonstrate a class effect of CES for treating anxiety and/or insomnia. However, it cannot be concluded, based on available information alone, that specific CES devices or stimulation parameters are effective for treating anxiety and/or insomnia. As such, individuals using this device should work with the prescribing medical provider to

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determine the best treatment settings to use. As such, please see General CES Summary below for a general summary of pertinent clinical literature that has been published using various combinations of CES devices, stimulation settings, and electrode positions.

General CES Summary (January 01, 1970, to November 2022)

As of November 2022, 33 studies investigated the impact of Cranial Electrotherapy Stimulation (CES) on anxiety (14 randomized controlled trials (RCTs), 13 observational studies, 2 metaanalysis, and 4 reviews). Of the RCTs that were evaluated, some trials reported superiority of CES treatment versus placebo (Rosenthal, S H et al. 1972) (Philip, P et al. 1991) (Lee, S H, et al. 2013) (Sousa, A D et al. 1975) (Gibson, T H et al. 1987) (Ryan, J J. et al. 1976) (Kim, J, et al. 2021) or control (Kanq, H W, et al. 2020) (Park, B S, et al. 2022) in reducing anxiety symptoms, while other studies demonstrated no impact on anxiety (Levitt, E A et al. 1975) (Passini, F G et al. 1976) (Scallet, A, et al. 1976) (13). One study noted transient improvement in symptoms (Hearst, E D, et al. 1974). The majority of observational studies reported a positive association between CES treatment and reduction in anxiety symptoms (Flemenbaum, A et al. 1974,) (Overcash, S J. et al 1999) (Rosenthal, S et al. 1970) (Rosenthal, S H et al. 1970) (Smith, R B et al. 1999) (Ryan, J J et al. 1977) (Matteson, M T et al. 1986) (Morriss, R, et al. 2019) (Morriss, R, et al. 2020) (Bystritsky, A, et al. 2008). One observational study reported that CES was as effective as usual care (Royal, S, et al., 2022). Only 2 observational studies reported that CES did not have a significant impact on anxiety based on clinical assessment and standard inventories (Moore, J A, et al. 1975) (Von Richthofen et al 1980). A meta-analysis of 10 studies evaluating the effectiveness of cranial stimulation in treating depression noted an effect on anxiety as a secondary study outcome compared to sham (Cheng, Y, et al. 2022). Another meta-analysis of 14 RCTs evaluating the effectiveness of cranial stimulation indicated that CES versus sham treatment was associated with significantly improved anxiety (Klawansky, S, et al. 1995).

Similar findings were reported in a review that examined 34 controlled trials involving a total of 767 patients receiving CES and an additional 867 patients serving as controls (De Felice, E A. 1997). Twenty-six (Moore, J A, et al. 1975,) of 34 studies (77%) reported decreased anxiety after treatment with CES and the remaining 8 of 34 studies (24%) reported no such benefit. Two other reviews of trials using CES in patients with anxiety and depression concluded that CES may provide a modest benefit in the treatment of anxiety (31) (Brunyé, T

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Modius Stress K232253 Summary

T, et al. 2021). A fourth review found several small studies reporting decreased anxiety with CES use in patients with various conditions, including 1 small study in individuals with anxiety disorder (Freire, R C, et al. 2020). In studies that reported improvement in anxiety with use of CES, the reported stimulation parameters, electrode placement, and treatment schedule varied widely as listed below and were only evaluated in a small number of combinations. Please also note that not all CES devices are capable of providing the same stimulation parameters or combination of stimulation parameters.

Electrode placement:

. Over orbits and mastoids
. Over evelid and mastoids
. Over orbits and occiput
Earlobes
. Anterior and posterior regions of the head; in ear

Waveform:

. Square
. Rectangular
Monophasic ●
Bipolar, asymmetric, rectangular waves ●
. Sine wave
. Biphasic modified square wave
. Modified sine wave

Frequency:

. 100 Hertz (Hz)
350 Hz
0.5 Hz ●
. 10 Hz

Pulse Width:

0.7 millisecond (ms)
1 ms .
. 2 ms

Maximum current:

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. 0.01-4 milliamperes (mA)
Treatment schedule:
. 30 minutes, 5 times a week for 1-2 weeks
. 30-minute sessions twice a day
. single 20-minute session
5 times a week for 3 weeks ●
. 20 minutes a day for 2 days
. 60 minutes a day for 6-12 weeks
. 5 minutes
45 minutes daily for 3 weeks .

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Modius Stress – Clinical Studies

A summary of the clinical performance testing is given below with detailed information provided in Section 20.

Clinical testing of the Modius Stress device (MA1500) included two pivotal randomized controlled trials to evaluate the safety and efficacy of the Modius Stress device, for the treatment of anxiety. Originally a multi-site study was planned; however, logistical challenges prevented the research site in India from adhering to the precise study design outlined in the UK protocol. As a result, the studies are documented separately.

The stimulation sessions received at the India site were of the same duration (30 minutes) as the sessions participants completed at home in the UK. UK participants were instructed to use their device daily or no less than 5 times per week; however, at the India site, participants were asked to complete 20 stimulation sessions at a rate of ~3 -5 sessions per week. The difference in the treatment duration was to allow flexibility to facilitate the additional travel and time spent going to the India research site.

Study Design

Both studies were randomised, double blinded, sham-controlled trials, one of which was conducted in the UK and the other in India. The UK study was undertaken from July 2022 to April 2023 and has been registered at https://clinicaltrials.gov (ClinicalTrials.gov Identifier: NCT05907967). The UK study protocol (version 6.0, 25/11/2022) was approved at the UK site by East of England - Cambridge Central Research Ethics Committee (Ref: 22/EE/0009). The study in India was conducted from October 2022 to June 2023 and has also been registered at ClinicalTrials.gov (Identifier: NCT05845658). The Indian study protocol (version 1.0, 25/07/2022) was approved by the Institutional Ethics Committee – R.D.Gardi Medical College, Ujjain, Madhya Pradesh, India (Ref: 14/2022). Informed consent was obtained from all participants.

In both studies, adults with a General Anxiety Disorder 7th edition (GAD-7) score of 10 or higher (Spitzer et al., 2006) were recruited using social media advertising and were randomly

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Modius Stress K232253 Summary

allocated (1:1 allocation ratio) to receive the Modius Stress device (intervention group) or the sham device (active control group). In the UK study, both groups were advised to use their allocated devices for 30 minutes per day for a four-week duration at home. In the India study, both groups were asked to complete 20 stimulation sessions (30 minutes duration) at a rate of ~3-5 sessions per week at the Department of Physiology at R.D. Gardi Medical College.

The Modius stress and sham devices are identical in appearance and therefore neither the participant nor the clinical study team knew whether the Modius Stress device or sham device was allocated.

Primary Effectiveness Endpoint

The efficacy of the Modius Stress device was quantified by change in GAD-7 score at baseline and week 4 in the UK study, and when each participant finished their 20 stimulation sessions in the India study, between the Modius Stress group and sham control group.

Primary Safety Endpoint

In both studies, an evaluation of the safety of the Modius Stress device was quantified by the occurrence in adverse events between the Modius Stress group and sham control group.

UK study results

A total of 87 eligible participants (female, n=65) were recruited and randomised to the Modius Stress group (n=43) or the sham control group (n=44). Nine participants withdrew from the study before the 4-week visit. Three of these participants withdrew (lost to follow-up, n=2 and self-withdrawal, n=1) prior to the baseline visit and therefore were not included in the Intention to treat (ITT) analysis (no baseline data and did not receive at least one stimulation session). The mean age of the sample was 30 years (age range: 18 to 69 years). One participant was aged over 65 years, and 14 participants were aged under 22 years.

Stage	Modius Stress Device	Sham control device	Total
Enrolment	43	44	87
Treatment	42	42	84

Table 6: Participant accountability (UK study)

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| Primary safety

endpoint analysis	42	42	84
Primary effectiveness
endpoint analysis	aIntention to treat= 42
bComplete case = 36	Intention to treat = 42
Complete case = 39	84
75

ª Intention to treat analysis was undertaken for all participants who were randomised and had baseline GAD-7 scores. * Complete case analysis was undertaken on all participants with available data at baseline and at the 4-week visit.

Effectiveness

The effect of the Modius Stress device on change in GAD-7 scores from baseline to the 4week visit is shown in Table 7 below. The ITT (multiple imputation (MI) and baseline carried forward (BOCF)) and complete case analyses demonstrated that the Modius Stress group had a greater reduction in GAD-7 score compared with the sham control group; however, the mean difference among the groups was not statistically different.

More participants in the Modius Stress group, compared with the sham control group, achieved a 4 point or more reduction in GAD-7 (Toussaint et al., 2020) from baseline to the 4week visit (complete case analysis: 27 out of 36 [75%] vs 20 out of 39 [51%]).

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Table 7. The effect of Modius Stress on GAD-7 scores according to randomization group (primary outcome) (UK Study)

Cohort	Modius Stress			Sham Control				P
	Baseline
Mean (SD)	4
weeks
Mean
(SD)	Within-group
mean change
(95% CI)	Baseline
Mean (SD)	4
weeks
Mean
(SD)	Within-group
mean change
(95% CI)	Between-group
difference
mean (95%
CI)a
ITT (MI)	11.36
(0.66)	5.95
(0.59)	-5.41
(-6.83, -3.99)	10.90
(0.54)	6.94
(0.59)	-3.96
(-5.25, -6.06)	-1.45
(-3.37, 0.47)	0.139
ITT (BOCF)	11.36
(4.27)	6.83
(4.03)	-4.52
(-5.91, -3.14)	10.90
(3.47)	7.10
(3.75)	-3.81
(-5.08, -2.54)	-0.71
(-2.57, 1.14)	0.445
Complete
Case	11.17
(4.32)	5.89
(3.20)	-5.28
(-6.75, -3.80)	11.15
(3.31)	7.05
(3.74)	-4.10
(-5.43, -2.78)	-1.18
(-3.12, 0.77)	0.233

ªBetween-group difference in GAD-7 scores from baseline to week 4 analysed using Independent Samples t-tests. ITT analysis (MI and BOCF) includes all participants randomized and who had baseline GAD-7 scores (Modius Stress, n=42 and sham control n=42). Three participants did not have baseline GAD-7 scores and were not included in the ITT analysis. Complete case analysis includes participants who had baseline and 4-week GAD-7 scores (Modius Stress n=36 and sham control n=39).

Safety

A total of 7 Adverse Events were reported during the 4-week study, 5 reported by the Modius Stress group and 2 reported by the sham control group. The adverse events were all minor, caused a minimal discomfort to participants, and all self-resolved during the period of the study. No serious adverse events were reported.

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Table 8. Number (%) of Adverse Events (Safety Data Analysis) according to Randomization Group (all participants, n=87) (UK Study)

| | | Total
n (%) | Modius Stress
n (%) | Sham Control
n (%) |
|----------------------------|---------------------------------------|----------------|------------------------|-----------------------|
| Nervous
System | Migraine | 1 (1) | 1 (1) | 0 (0) |
| Disorders | Sudden sharp
movements | 1 (1) | 0 (0) | 1 (1) |
| Ear Disorders | Cartilage swelling | 1 (1) | 1 (1) | 0 (0) |
| | Itchiness | 1 (1) | 1 (1) | 0 (0) |
| | Pressure in ears | 1 (1) | 1 (1) | 0 (0) |
| Mouth/ dental
disorders | Metallic fillings pulsing/
buzzing | 1 (1) | 0 (0) | 1 (1) |
| Other | Study related anxiety | 1 (1) | 1 (1) | 0 (0) |

Conclusion

Participants using the Modius Stress device, 5-7 times per week, had a 5.41 reduction in GAD-7 score, while participants using the sham control device had a 3.96 reduction in GAD-7 score. More participants using the Modius Stress device daily had a 4-point or more reduction in GAD-7 score when assessed at 4 weeks.

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India study results

A total of 60 eligible participants were recruited and randomised to the Modius Stress group (n=34) or the sham control group (n=26). One participant randomised to the sham control group withdrew from the study due to difficulty attending the research site for treatment and assessments. The mean age of the sample was 35.6 years. The age range was 19-70 years, with one participant aged over 65 years and two participants aged under 22 years.

Stage	Modius Stress Device	Sham control device	Total
Enrolment	34	26	60
Treatment	34	26	60
Primary safety endpoint
analysis	34	26	60
Primary effectiveness
endpoint analysis	aIntention to treat= 34
bComplete case = 34	Intention to treat = 26
Complete case = 25	60
59

Table 9: Participant accountability (India study)

case analysis was undertaken on all participants with available data at baseline and at end of study assessment.

Effectiveness

The study met the primary endpoint. The Modius Stress group had a mean reduction in GAD-7 score of -7.44 (p