The Relivion® transcutaneous electrical nerve stimulator is indicated for the acute treatment of migraine with or without aura in patients 18 years of age or older. It is a prescription device to be self-used at home.

Device Description

The Relivion® is an external non-invasive neurostimulator designed for transcutaneous electrical nerve stimulation. The Relivion® headset integrates three pairs of output electrodes which come in contact with the subject's scalp at the forehead and occiput. The electrodes deliver the stimulation pulses produced by the headset's stimulation unit to the subject's scalp. The frontal electrodes stimulate the trigeminal (supraorbital and supratrochlear) nerve branches and the posterior electrodes stimulate the greater occipital nerve branches.

The Relivion® includes single-use replaceable electrode pads that are positioned on-top of the electrodes prior to treatment and are wetted by the user before use, in order to provide proper conductivity between the electrodes and the scalp.

The Relivion® is powered by a rechargeable battery and the headset incorporates an on-board user interface that enables the user to activate/deactivate the device and to adjust the stimulation intensity. Upon treatment activation, the treatment automatically runs and ends after 60 minutes or alternatively, the user can stop the treatment when desired.

The Relivion® can communicate via a low energy Bluetooth link with the Relivion® dedicated mobile application on the user's smartphone. The Relivion® mobile application is optional and it is used to display the device status and provide indications and alerts.

AI/ML Overview

The provided document is a 510(k) premarket notification for the Relivion® device, a transcutaneous electrical nerve stimulator for the acute treatment of migraine. It details the device's characteristics, performance data, and comparison to a predicate device (Cefaly® Acute).

Here's an analysis of the acceptance criteria and the study that proves the device meets them, based on the provided text:

Acceptance Criteria and Reported Device Performance

The acceptance criteria for the Relivion® device, as derived from the RIME study (the pivotal clinical trial for the commercial version of the device), focused on the efficacy of pain relief.

Acceptance Criteria (Primary Endpoint)	Reported Device Performance (RIME Study)
Proportion of subjects reporting reduction of migraine headache pain (i.e., pain relief) 2 hours post-treatment initiation from severe or moderate to mild or no pain, or from mild to no pain.	Active Group: 60% of subjects met the primary endpoint. Sham Group: 37% (mITT) / 36% (PP) of subjects met the primary endpoint. (p-value = 0.0180 (mITT) / 0.0135 (PP))
Secondary Endpoints (Superiority demonstrated for all three)
Pain Freedom rate at 2 hours post-treatment initiation without use of rescue medication.	Active Group: 46.00% Sham Group: 11.86% (p-value <0.0001)
Improvement in MBS (Migraine Burden Scale) 2-hours post-treatment initiation without use of rescue medication.	Active Group: 80.56% Sham Group: 60.00% (p-value 0.0466)
Reduction in pain level 1-hour post-treatment initiation without use of rescue medication.	Active Group: -0.6 (-28.7%) Sham Group: -0.3 (-14.4%) (p-value 0.0121)

Study Details Proving Acceptance Criteria are Met

The primary study cited to demonstrate the Relivion® device's efficacy and safety for its intended use (the commercial version for which clearance is sought) is the RIME study.

Sample Size Used for the Test Set and Data Provenance:
- Test Set Sample Size: 131 patients (109 females and 22 males).
- Data Provenance: Patients were enrolled at 12 sites in the US and Israel. This indicates both prospective and multi-country data collection.
Number of Experts Used to Establish the Ground Truth for the Test Set and Qualifications of Those Experts:
- The document describes a sham-controlled clinical trial where patients' self-reported pain levels and other migraine-related symptoms (e.g., Migraine Burden Scale, MBS) constitute a significant portion of the "ground truth."
- While the study involved clinical sites and likely medical professionals overseeing the trial, the "ground truth" for the primary and secondary endpoints is based on patient-reported outcomes.
- No specific number or qualifications of experts establishing "ground truth" in terms of independent adjudication of outcomes are mentioned beyond what is inherent in the clinical trial design (e.g., investigators at the sites). The blinding assessment was done by reviewing subjects' feelings about the treatment, but not explicitly stated as "expert" ground truth for the clinical endpoints themselves.
Adjudication Method for the Test Set:
- The study was a prospective, randomized, parallel-group, sham-controlled clinical trial.
- To maintain blinding, "measures included concealed allocation, use of an identical sham device and the same treatment protocol in all the study stages: device training, self-practice period and treatment period."
- "Additionally, sham stimulation was set to a level well above the sensory threshold to further enhance subject's blinding."
- A "blinding assessment" was conducted, revealing that subjects' feelings regarding the treatment received did not influence the study outcome.
- The results were analyzed based on statistical comparison between the active and sham groups. This is a standard clinical trial design for efficacy measurement, and the "adjudication" is inherent in the blinded, randomized, controlled nature of the study and statistical analysis of patient-reported outcomes. There is no mention of a separate expert adjudication panel for individual case outcomes in the typical sense (e.g., 2+1 radiologist review).
If a Multi-Reader Multi-Case (MRMC) Comparative Effectiveness Study Was Done:
- No. This device is a direct-to-patient neuromodulation device for migraine treatment. The clinical evaluation focuses on patient outcomes (pain relief, pain freedom, MBS improvement) measured from the device's application, either active or sham, compared to baseline and between groups. It does not involve human readers interpreting images or data, hence an MRMC study is not applicable.
If a Standalone (Algorithm Only Without Human-in-the-Loop Performance) Was Done:
- The device functions as a standalone treatment device. Its performance is measured by its direct effect on migraine symptoms as reported by patients, not as an algorithm assisting a human in a diagnostic or interpretive task. The clinical study (RIME) inherently assesses the "standalone" performance of the device in a real-world use case (self-used at home).
The Type of Ground Truth Used:
- The ground truth used for evaluating the device's performance is patient-reported outcomes (PROs), specifically:
  - Migraine headache pain levels (from severe/moderate/mild to no pain at 2 hours).
  - Pain freedom (at 1 and 2 hours).
  - Improvement in Migraine Burden Scale (MBS) (at 1 and 2 hours).
  - Reduction in overall pain level (at 1 hour).
  - Absence of rescue medication use within the specified timeframe.
- In the context of the study design, these PROs serve as the clinical "ground truth" for assessing the device's efficacy.
The Sample Size for the Training Set:
- The document describes the Relivion® as a neurostimulator, not a machine learning or AI model that requires a "training set" in the computational sense.
- Therefore, there is no "training set" of data for an algorithm. The clinical studies (OS-TNS, SP-301, and RIME) are clinical trials to evaluate the device's safety and efficacy in human subjects.
How the Ground Truth for the Training Set Was Established:
- As there is no computational "training set" for an algorithm, this question is not applicable. The device's mechanism of action is transcutaneous electrical nerve stimulation, which is a physical intervention, not a data-driven model. The "ground truth" for previous clinical testing (OS-TNS and SP-301 studies) would have been established through similar patient-reported outcomes, following standard clinical trial methodologies and ethical guidelines (GCP, institutional ethics committees).

Summary

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February 16, 2021

Image /page/0/Picture/1 description: The image contains the logo of the U.S. Food and Drug Administration (FDA). On the left is the Department of Health & Human Services logo. To the right of that is the FDA logo, which is a blue square with the letters "FDA" in white. To the right of the blue square is the text "U.S. FOOD & DRUG ADMINISTRATION" in blue.

Neurolief Ltd. % Janice Hogan Partner Hogan Lovells US LLP 1735 Market Street, Suite 2320 Philadelphia, Pennsylvania 19103

Re: K203419

Trade/Device Name: Relivion Regulation Number: 21 CFR 882.5891 Regulation Name: Transcutaneous Electrical Nerve Stimulator to Treat Headache Regulatory Class: Class II Product Code: PCC Dated: November 19, 2020 Received: November 19, 2020

Dear Janice Hogan:

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 (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 located 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.

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

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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 803) for devices or postmarketing safety reporting (21 CFR 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 4, Subpart A) for combination products; and, if applicable, the electronic product radiation control provisions (Sections 531-542 of the Act); 21 CFR 1000-1050.

Also, please note the regulation entitled, "Misbranding by reference to premarket notification" (21 CFR Part 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,

Patrick Antkowiak Acting Assistant Director DHT5B: Division of Neuromodulation and Physical Medicine Devices OHT5: Office of Neurological and Physical Medicine Devices Office of Product Evaluation and Quality Center for Devices and Radiological Health

Enclosure

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DEPARTMENT OF HEALTH AND HUMAN SERVICES
Food and Drug Administration

Indications for Use

Expiration Date: 06/30/2023 See PRA Statement below.

Form Approved: OMB No. 0910-0120

510(k) Number (if known) K203419

Device Name Relivion®

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)

CONTINUE ON A SEPARATE PAGE IF NEEDED.

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FORM FDA 3881 (6/20)

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510(k) SUMMARY

Image /page/3/Picture/1 description: The image shows the logo for Neuroleaf Brain Innovation. The logo consists of a stylized brain icon on the left and the text "Neuroleaf" above "Brain Innovation" on the right. The brain icon and text are all in a light blue color.

RELIVION®

Applicant Name:	Neurolief Ltd.12 Giborei Israel St.Netanya, Israel 4250412Tel: +972-9-3730288
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Contact Person: Michal Kedar-Datel Clinical & Regulatory Affairs Director Neurolief Ltd. Tel: +972-9-3730288

Date Prepared: November 19, 2020

Relivion® Trade Name:

Classification Name: 21 CFR 882.5891 Transcutaneous electrical nerve stimulator to treat headache

Product Code: PCC

Classification: Class II

Classification Panel: Neurology

Predicate Device: CEFALY Technology's Cefaly® Acute (K171446)

Intended Use/Indication for Use:

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Device Description:

Technological Characteristics:

The Relivion® treats migraines by stimulating the trigeminal and occipital nerve branches by a transcutaneous electrical nerve stimulation. Trigeminal and occipital electrical nerve stimulation induces neuromodulation of these nerve pathways and by that reduces pain associate with migraine and associated symptoms.

The Relivion® includes single-use, replaceable electrode pads that are positioned on-top of the headset electrodes and are wetted by the user before each use. Water releasing covers are located on the outer side of each back occipital electrode and are used to release moisture from the electrode pads to the scalp in order to provide proper electrical conductivity between the electrodes and the scalp.

The Relivion® headset adjusts to various head sizes and contours and can be worn comfortably. The headset includes two flexible arms that penetrate under the hair layers while the headset is worn.

The Relivion® headset incorporates an on-board user interface and can communicate via a low

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energy Bluetooth link with the Relivion® dedicated mobile application on the user's smartphone, which displays the device status and provides indications and alerts.

Performance Data:

Neurolief conducted several performance tests to demonstrate that the Relivion® device complies with performance standards and that it functions as intended.

Performance - Bench Testing: The Relivion® device underwent performance testing, including software validation and device verification tests. It was successfully verified that the Relivion® output parameters meet the product's specifications.

Electrical Safety and Electromagnetic Compatibility: in addition, the system was tested per the applicable electrical safety and electromagnetic compatibility standards listed below, and all results were passing.

. IEC 60601-1 Ed. 3.1, Medical Electrical Equipment - Part 1: General requirements for basic safety and essential performance.
IEC 60601-1-2 Ed. 4.0, Medical Electrical Equipment Part 1-2: General requirements for . safety - Collateral Standard: Electromagnetic Compatibility - Requirements and Tests.
IEC 60601-1-11 Ed. 2.0, Medical electrical equipment Part 1-11: 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
IEC 60601-2-10 Ed. 2.1, Medical electrical equipment Part 2-10: Particular requirements ● for the basic safety and essential performance of nerve and muscle stimulators
IEC 60601-1-6 Ed. 3.1, Medical electrical equipment Part 1-6: General requirements for . basic safety and essential Performance - Collateral Standard: Usability
IEC 62366 Ed. 1.0 Medical devices Part 1: Application of usability engineering to medical ● devices
IEC 62304 Ed. 1.1, Medical device software Software life-cycle processes .

Software Testing: The software was also subject to verification and validation testing, and results demonstrated that the system performed as intended. Cybersecurity risks were also identified and addressed.

Biocompatibility: The Relivion® is a device that contacts intact skin surface for a limited time (<24 hours). The patient-contacting components of the device headset and electrode pads were tested for

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cytotoxicity, sensitization, and irritation or intracutaneous reactivity as defined for surface devices in the FDA guidance (2020) and ISO 10993-1: 2009. Based on results of the conducted testing, the final device was determined to be biocompatible for its intended use.

Human Factors Usability Study: The device was also subject to formative and summative Human Factors testing, and results demonstrated that users could complete all essential tasks using the provided labeling with acceptable residual risk.

Performance - Clinical Testing: Two previous versions of Neurolief's device were used in preliminary prospective studies.

The OS-TNS Study was conducted at Meir Medical Center, Israel. The study assessed the safety and efficacy of combined occipital and supraorbital neurostimulation for treatment of migraine. It was approved by the institution's ethics committee on June 5, 2014 and the Israeli Ministry of Health Ethical committee and was concluded in November 2015. This clinical investigation was conducted in accordance with good clinical practice (GCP) as described in ISO 14155. Adults suffering from episodic migraine, aged 21-62 years, were enrolled. Subjects were randomly allocated in a 1:1 ratio to receive active or sham occipital and supraorbital stimulation. The primary endpoint was defined based on relative change (%) in VAS pain score from baseline to end of treatment without using pain medication. 30 patients treated one acute migraine episode with active device (N=15) or sham device (N=15). At the end of treatment there was a significant reduction of the average Pain VAS score in the treatment group vs. an increase in Pain VAS score in the control group (-79.2% vs. +14.9%, respectively; P=0.0002). Pain-free response rates significantly favored the active device at 2-hours (P=0.0031) and at 24-hours (P<0.05) post treatment. Superiority of the active device was also shown for functional disability (P=0.0004) and photophobia (P=0.002). No device-related serious adverse events were recorded.

The SP-301 Study was a prospective, randomized, double-blind, parallel-group, placebo-controlled investigation conducted to evaluate the clinical performance and safety of a self-administered abortive treatment for migraine headache using combined occipital and supraorbital transcutaneous nerve stimulation. The study was conducted at the Laniado Medical Center in Israel and approved by the Laniado Helsinki committee on February 8, 2018. The first patient enrollment was February 22, 2018, and the study concluded on November 2018. This clinical investigation was conducted in accordance with good clinical practice (GCP) as described in ISO 14155. Fifty-five (55) patients were randomized to either the active or placebo groups. To maintain blinding, measures included concealed allocation, use of an identical sham device and the same treatment protocol in all the study stages: device training, self-practice period and treatment period. Additionally, sham stimulation was set to a level well above the sensory threshold to further enhance subject's blinding. Subjects were instructed to use the device during 1 migraine episode within 14 weeks after a practice run in their home. Additionally, subjects were asked not to take any pain medication prior to treatment and until 2 hours post treatment. Mean pain intensity decreased significantly more in the treatment group than in the sham group at 1-hour (group difference: 41.4%; p=0.0002) and at 2-hours (group difference: 32.8%; p=0.0324) and 24-hours (group difference: 36.2%; p=0.0220). Responders rate

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was also statistically significantly higher in the treatment group than in the sham group at 1-hour (66.7% vs. 20%, p=0.0014), 2-hours (66.7% vs. 32%, p= 0.0227) and 24-hours (78.3% vs. 48%, p= 0.0401). No Serious Adverse Events (SAEs) were reported throughout the study period. Safety data collected by the research team was recorded and reported to the sponsor. Safety monitoring, including device related assessment was performed by qualified sponsor personnel in consultation with the study PI. Post hoc review was conducted by an independent medical advisor. There were no complaints of unpleasant stimulation sensation during or within 24 hours after the treatment.

The results of these studies demonstrated that combined occipital and supraorbital transcutaneous nerve stimulation (OSTNS) is a safe and highly effective treatment for the treatment of migraine and may serve as a safe, fast acting treatment method.

The device was also subject to a prospective, randomized, parallel-group, sham-controlled clinical trial- the RIME study. The device used in the RIME study is the commercial version for which the company is seeking clearance. The study included 131 patients (109 females and 22 males) having migraine attacks with or without aura. Patients were enrolled at 12 sites in the US and Israel. The study was initiated in November 2018 and concluded in August 2020. The US study sites of the investigation complied with 21 CFR parts 50, 56, and 812 and the OUS clinical investigations were conducted in accordance with good clinical practice (GCP) as described in 21 CFR 812.28(a)(1). To maintain blinding, measures included concealed allocation, use of an identical sham device and the same treatment protocol in all the study stages: device training, self-practice period and treatment period. Additionally, sham stimulation was set to a level well above the sensory threshold to further enhance subject's blinding. These measures were proven to be effective as the blinding assessment revealed that the subjects' feeling regarding the treatment received did not influence the study outcome. Baseline demographics were consistent with the migraine population in terms of age, 83% (109/131) of the participants were females. The mean age was 40.3 years gender, etc. (SD=12.7). The mean age of migraine onset was 18.6 (SD=8.54) years and ranged from 4 to 50. 62.6% (82/131) of the subjects had migraine without aura, 37.4% (49/131) had migraine with aura, 26.7% (35/131) of the subjects were using migraine preventive medication at baseline. Statistical analysis showed no significant differences between the US and Israeli populations.

The primary outcome was the proportion of subjects reporting reduction of migraine headache pain (i.e., pain relief) 2 hours post treatment initiation from severe or moderate to mild or no pain, or from mild to no pain. Pain relief at 2 hours post-treatment was found statistically significantly higher in the active group than in the sham group: 60% of subjects in the active group compared to 37% (p value=0.0180) (mITT) or 36% (p value=0.0135)(PP) in the sham group met the primary endpoint, with similar between-group differences of 23% and 24% (mITT and PP, respectively). All statistical tests for the between-group difference were statistically significant in both populations. Therefore, the study was deemed successful.

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Image /page/8/Figure/0 description: The image is a bar graph that compares the reduction in pain at 2-hours between an active treatment and a sham treatment. The y-axis represents the percentage of pain reduction, while the x-axis represents the study arm. The active treatment shows a 60% reduction in pain, while the sham treatment shows a 37.29% reduction in pain. The Chi-Square test p-value is 0.0180.

Figure 1: Pain relief 2 Hours Post-Treatment - mITT

Furthermore, the active arm was superior to the sham arm for all 3 secondary endpoints, as follows:

Pain Freedom rate at 2 hours post-treatment initiation without use of rescue medication . (46.00% vs. 11.86% for active and sham arms, respectively, p-value: <0.0001).
. Improvement in MBS 2-hours post-treatment initiation without use of rescue medication (80.56% vs. 60.00% for active and sham arms, respectively, p-value: 0.0466).
. Reduction in pain level - 1-hour post-treatment initiation without use of rescue medication (-0.6 (-28.7%) vs. -0.3 (-14.4%) for active and sham arms, respectively, p-value: 0.0121).

In addition, the active arm was superior to the sham arm in the following additional parameters:

. Complete MBS Freedom 1- and 2-hours post-treatment initiation without use of rescue medication.
. Pain Freedom at 1-hour post-treatment initiation without use of rescue medication.
. Pain and MBS Relief at 1- and 2-hours post-treatment initiation without use of rescue medication.
Complete symptoms Free (Pain and MBS)- 1- and 2-hours post-treatment initiation without ● use of rescue medication.
. Sustained 2-24 hours headache Pain Relief and Pain Freedom without use of rescue medication.
. Pain Relief and Pain Freedom consistency of response across multiple treated episodes.

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With respect to safety, safety monitoring, including device related assessment was performed by qualified sponsor personnel in consultation with the study PI and the medical advisor. In the ITT analysis set, 21 AE's were reported in 10 subjects, 8 in the active arm (incidence: 11.94%, 8/67), and 2 in the sham arm (incidence: 3.13% (2/64). None of the adverse events were serious, 7 AE's were considered moderate (4 in the active arm and 3 in the sham arm), and the other 14 were mild. 16 AE's were considered as at least possibly related to the study device (7 in 5 subjects randomized to active arm; 9 in 2 subjects in the sham arm). All the reported AEs were fully reversible and resolved without intervention. The nature of the observed events in the active group were anticipated and very similar to other nerve stimulators for migraine, including adverse events that are directly related to the neuromodulatory action of the device such as transient scalp numbness sensation, tingling and twitching. The rate and severity of events was as anticipated and similar to other previously cleared devices. An initial device malfunction resulted in exclusion of the first 50 cases from the above analysis. Because the malfunction resulted in failure to deliver stimulation, these patients were not analyzed for efficacy but were analyzed for safety, and the results were consistent with those reported for the ITT population.

Although COVID-19 resulted in interruption of study enrollment and early termination, FDA guidance was followed in the completion and analysis of study results in light of the pandemic and met the study hypothesis, as presented above, supporting substantial equivalence.

Substantial Equivalence:

The following table compares the Relivion® device to the predicate devices with respect to intended use, technological characteristics and principles of operation, providing detailed information regarding the basis for the determination of substantial equivalence.

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Table 1: Neurolief, Ltd.'s Relivion® Substantial Equivalence

Parameter	Neurolief Ltd.'sRelivion®(Subject Device)	CEFALY Technology'sCefaly® Acute(Predicate Device)	Comparison
General Characteristics
510(k) number	Pending	K171446	N/A
Classification	21 CFR § 882.5891	21 CFR § 882.5891	Same
Product Code	PCC	PCC	Same
Product Class	Class II	Class II	Same
Regulation Name	Transcutaneous Electrical NerveStimulator to Treat Headache	Transcutaneous Electrical NerveStimulator to Treat Headache	Same
Indications for Use	The Relivion® transcutaneous electrical nervestimulator is indicated for the acute treatment ofmigraine with or without aura in patients 18years of age or older. It is a prescription deviceto be self-used at home.	Cefaly® Acute is indicated forthe acute treatment of migrainewith or without aura in patients18 years of age or older.	Same(Both devices areintended for self-administered, athome use)
Technology	Transcutaneous ElectricalNerve Stimulator	TranscutaneousElectrical NerveStimulator	Same
Invasiveness	Non-Surgical	Non-Surgical	Same
Electrode Locations	Forehead and Occiput	Forehead	Similar(Forehead location isthe same for bothdevices; addition ofocciput location doesnot raise newquestions—seebelow.)
Parameter	Neurolief Ltd.'sRelivion®(Subject Device)	CEFALY Technology'sCefaly® Acute(Predicate Device)	Comparison
Nerves over whichelectrodes are placed	Supratrochlear and supraorbital branches ofthe trigeminal nerve bilaterally and theoccipital nerves	Supratrochlear and supraorbitalbranches of the trigeminal nervebilaterally	Similar(Relivion® treats theoccipital nerves inaddition to thetrigeminal nerve, butthe therapeutic effectis the same)
Energy	Electric	Electric	Same
Power Source	Rechargeable Li-Po 3.7 V Battery	Rechargeable LiPo 3.7 Vbattery	Same
Software-controlled	Yes, 1 fixed program	Yes, 1 fixed program	Same
Constant Current	Yes	Yes	Same
Constant Voltage	No	No	Same
Software Function	Controls the output of the deviceand device indicators	Controls the output of thedeviceand device indicators	Same
Timer Settings	Yes	Yes	Same
Patient overridecontrol method	On/Off button	On/Off button	Same
Button Types	On/Off Button and buttons to adjust intensityof electrical stimulus	On/Off Button and buttons toadjust intensity of electricalstimulus	Same
Functional features	Visual and auditory indicators inform theuser when the device is on vs. off and helpthem troubleshoot if it is not workingproperly (e.g., indicates if device isactive/non-active, low battery indicationand if electrical connection between deviceand skin is unacceptable)	Visual and auditoryindicators inform theuser when the device ison vs. off and help themtroubleshoot if it is notworking properly (e.g.,indicates if device isactive/non-active , low	Same
Parameter	Neurolief Ltd.'sRelivion®(Subject Device)	CEFALY Technology'sCefaly® Acute(Predicate Device)battery indication and ifelectrical connectionbetween device and skinis unacceptable)	Comparison
Bluetooth Capable	Yes	No	Different
Associated mobileapplication todisplay devicestatus, treatmentduration, andbattery status	Yes	No	(Relivion® includes amobile app andBluetooth capability,but these features donot alter thetherapeutic effect)
Max leakage current	None (battery operated)	None (battery operated)	Same
Electrodes	Relivion® electrode	Cefaly® electrode	Similar(Each device uses itsown designatedelectrode, but thecomponents performsimilarly, asestablished by benchtesting)
Indicator display:Unit functioning	Yes	Yes	Same
Low batteryindicator	Yes	Yes	Same
Standards:IEC 60601-1	Yes	Yes	Same
IEC 60601-1-2	Yes	Yes	Same
IEC 60601-1-6	Yes	Yes	Same
IEC 60601-1-11	Yes	Yes	Same
Parameter	Neurolief Ltd.'sRelivion®(Subject Device)	CEFALY Technology'sCefaly® Acute(Predicate Device)	Comparison
IEC 60601-2-10	Yes	Yes	Same
IEC 62366	Yes	Yes	Same
Weight	90 gr	12 gr	Different(The difference inweight is notclinically relevant tothe treatment)
Dimensions	209mm x 128mm x 39mm	55 mm x 40 mm x 15 mm	Different(The difference insize is not clinicallyrelevant to thetreatment)
Housing materials	Plastic PA + Silicone	Plastic PC	Similar(Manufacturing thedevice housing fromPlastic PA andSilicon rather thanPlastic PC does notraise differentquestions of safetyand effectiveness)
Maximum TimeDevice Used	60 minutes	60 minutes	Same
Net Charge (µC) perpulse	0	0	Same
Parameter	Neurolief Ltd.'sRelivion®(Subject Device)	CEFALY Technology'sCefaly® Acute(Predicate Device)	Comparison
Pulse Duration(µsec)	850	505	Similar(Differences in thestimulationparameters wereevaluated in theclinical testing, andthe results confirmedthat the devices haveequivalent safety andefficacyperformance)
Frequency (Hz)	80	100
Maximum outputvoltage (V): @500ohms @2000 ohms@10000 ohms	3 front electrodes / 6 back electrodes12 front electrodes / 24 back electrodes60 front electrodes / 100 back electrodes	83260
Maximum outputcurrent (mA): @500ohms @2000 ohms@10000 ohms	6 front electrodes /12 back electrodes6 front electrodes /12 back electrodes6 front electrodes /10 back electrodes	16166
Max PhaseAmplitude	6 mA front electrodes/ 12 mA backelectrodes; with a load of a 4.7 uFcapacitor parallelwith 2.2K ohms resistance	16 mAwith a load of a 4.7 uFcapacitor parallel with2.2K ohms resistance
Maximum phasecharge (µC) @500Ω	4.8	4
Maximum CurrentDensity, (mA/cm²,r.m.s.) @500Ω	1.93 front electrodes/ 2.78 back electrodes	2.37
Maximum AveragePower Density,(W/cm²) @500Ω	0.0000116 front electrodes /0.000034 back electrodes	0.000047
Maximum AverageCurrent (averageabsolute value, mA)@500Ω	0.38 front electrodes / 0.76 back electrodes	0.8
Phase rise time	5 µS	2 µS
Modulation OptionsAmplitudeFrequency Duration	0- 12 mAFixed @ 80 Hz330- 400 µS	0-16 mAFixed @ 100 HzFixed @ 250 µS
Phase decay time	2 µS	2 µS	Same
Parameter	Neurolief Ltd.'sRelivion®(Subject Device)	CEFALY Technology'sCefaly® Acute(Predicate Device)	Comparison
Ramp ModulationsRamp UpRamp Down	ManuallyManually	14 minutes1 minute	Different(Relivion®'s use ofmanual rampmodulation does notraise differentquestions of safetyand effectiveness)

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As described in the comparison table above, the subject Relivion® and the predicate Cefaly® Acute (K171446) share the same intended use and similar indications, technological characteristics, and same principles of operation. The minor differences in the technological characteristics do not alter the overall therapeutic effect of the device. Any differences between the Relivion® and its predicate (K171446) were carefully evaluated through performance testing. The Relivion® device underwent performance testing, including bench testing, clinical testing, software validation testing, electrical safety according to IEC 60601-1, electromagnetic compatibility testing according to IEC 60601-1-2 and other tests. These performance tests confirmed that the Relivion® complies with the same special controls and the same consensus and performance standards, on which FDA based its clearance of the Cefaly® Acute (K171446), and demonstrated that the differences in the technological characteristics between the subject and predicate device do not adversely impact performance and that the subject Relivion® is substantially equivalent to its predicate device (K171446).

Conclusions:

Therefore, based on the same intended use and similar indications, technological characteristics, and same principles of operation, the Relivion® device is substantially equivalent to its predicate device.

Regulation Number and Section

§ 882.5891 Transcutaneous electrical nerve stimulator to treat headache.

(a)
Identification. A transcutaneous electrical nerve stimulator to treat headache is a device used to apply an electrical current to a patient's cranium through electrodes placed on the skin.(b)
Classification. Class II (special controls). The special controls for this device are:(1) The patient-contacting components of the device must be demonstrated to be biocompatible.
(2) Appropriate analysis/testing must validate electromagnetic compatibility and electrical, mechanical, and thermal safety.
(3) The technical parameters of the device, including waveform, output modes, maximum output voltage and current (with 500, 2,000, and 10,000 ohm loads), pulse duration, frequency, net charge (µC) per pulse, maximum phase charge at 500 ohms, maximum current density (mA/cm
2 , r.m.s.), maximum average current (mA), maximum average power density (W/cm2 ), and the type of impedance monitoring system must be fully characterized.(4) Electrical performance, adhesive integrity, shelf life, reusability, and current distribution testing of the electrodes must be conducted.
(5) Appropriate software verification, validation, and hazard analysis must be performed.
(6) Clinical performance data must demonstrate that the device is safe and effective as a treatment for headache in the indicated patient population.
(7) Labeling must include the following:
(i) Appropriate contraindications such as not for use in subjects with an implanted metallic or electronic device in the head, a cardiac pacemaker, or an implanted or wearable defibrillator.
(ii) Appropriate warnings such as not to apply the device on the neck or chest, not to use the device in the presence of electronic monitoring equipment, not to use in the bath or shower, not to use while sleeping, not to use while driving, not to use while operating machinery.
(iii) Appropriate precautions such as the long-term effects of chronic use of the device are unknown.
(iv) A summary of the expected risks and benefits of using the device.
(v) A summary of the clinical performance data, including information on the patient population for which the device has and has not been demonstrated to be effective, and any adverse events and complications.
(vi) Information on how the device operates and the typical sensations experienced during treatment.
(vii) A detailed summary of the device technical parameters.
(viii) An expiration date/shelf life for the electrodes and the number of times they can be reused.
(ix) Disposal instructions.