(263 days)
The Monarch external Trigeminal Nerve Stimulation (eTNS) System is indicated for treatment of pediatric Attention Deficit Hyperactivity Disorder as a monotherapy in patients ages 7 through 12 years old who are not currently taking prescription ADHD medications. The device is used for patient treatment by prescription only and is intended to be used in the home under the supervision of a caregiver during periods of sleep.
The Monarch external Trigeminal Nerve Stimulation (eTNS) System is a non-invasive device that uses electrical signals to therapeutically stimulate the Trigeminal nerve. The primary components of the device are:
- The Monarch external pulse generator
- The Monarch NS-2 external (cutaneous) electrical patches, which are single use disposable patches worn on the forehead.
The device has two primary components A) an external pulse generator approximately the size of a cell phone, and B) the non-invasive electrical patch that patients apply to their forehead to receive therapy.
The Monarch eTNS System underwent two clinical studies to establish its effectiveness and safety.
1. Acceptance Criteria and Reported Device Performance
The primary acceptance criteria for effectiveness were based on the change in ADHD-IV Rating Scale (ADHD-RS) scores.
| Acceptance Criteria (Implicit from Study 2 Primary Endpoint) | Reported Device Performance (Study 2, Active Group vs. Sham) |
|---|---|
| Statistically significant improvement in ADHD-IV RS total score in the active group compared to the sham group after 4 weeks of treatment. | ADHD-RS Total Score: Active Group: Decreased from 34.1 at baseline to 23.4 at Week 4 (mean change of -10.7). Sham Group: Decreased from 33.7 at baseline to 27.5 at Week 4 (mean change of -6.2). The difference between active and sham groups was clinically meaningful and statistically significant (p < 0.05, though exact p-value for the primary endpoint comparison is not explicitly stated, significance is claimed). |
| Demonstration of a clinically meaningful treatment effect. | Cohen's d test: Demonstrated a medium effect size in ADHD-RS Total scores. CGI-I Scale: 52% of subjects in the active group improved by one or more points vs. 14% in the sham group (p=0.003 at Week 4). |
| Acceptable safety profile with no serious adverse events. | Safety: No serious adverse events reported in either study. All reported adverse events were mild to moderate in severity and reversible. Minor side effects included nightmares, headache, frequent urination, increased appetite, skin rash, and teeth clenching (some more prevalent in active group, some in sham or similar). No discontinuations due to these events. |
2. Sample Size and Data Provenance
Study 1 (eTNS-ADHD01):
- Test Set Sample Size: 24 subjects initiated treatment (22 completed at least to Week 4 for analysis).
- Data Provenance: Not explicitly stated, but clinical studies for FDA De Novo requests typically involve US-based participants. The study was open-label.
Study 2 (eTNS-ADHD02):
- Test Set Sample Size: 62 subjects enrolled and randomized (32 to active, 30 to sham). 59 subjects completed the 4-week double-blind treatment period (31 in active, 28 in sham). A subset of patients (18 initially) continued in an open-label extension for long-term data.
- Data Provenance: Not explicitly stated, but the demographics showing a diverse and representative US treatment population suggest a US origin. The study was prospective, randomized, and double-blind, sham-controlled.
3. Number of Experts and Qualifications for Ground Truth
The ground truth for the effectiveness endpoints (ADHD-RS and CGI-I) was based on clinical assessments by qualified personnel.
- Study 1: The pre-specified primary outcome measure was the investigator-completed ADHD-RS. This implies a trained clinical investigator assessed the ADHD-RS. Specific qualifications (e.g., number of years of experience, specific specialty) are not detailed in the provided text, beyond being "investigators."
- Study 2: The primary endpoint was also the ADHD-IV RS, and the CGI-I was a secondary endpoint. It is implied these were also assessed by clinical investigators. Again, specific qualifications of these experts are not explicitly detailed.
4. Adjudication Method for the Test Set
The information provided does not explicitly detail an adjudication method (like 2+1, 3+1, or none) for establishing ground truth for the test sets in either study. The ADHD-RS is an investigator-rated scale, implying a single assessment per participant rather than a consensus approach involving multiple independent raters with subsequent adjudication.
5. Multi-Reader Multi-Case (MRMC) Comparative Effectiveness Study
No MRMC comparative effectiveness study was performed or described. The studies conducted were clinical trials evaluating the device's therapeutic effect on patients, not studies comparing human reader performance with or without AI assistance in diagnostics. Therefore, an effect size of how much human readers improve with AI vs without AI assistance is not applicable here.
6. Standalone Performance (Algorithm Only)
The Monarch eTNS System is a medical device for therapy delivery, not a diagnostic algorithm. Therefore, a standalone performance study of an algorithm without human-in-the-loop performance is not applicable to this device. Its performance is measured by its therapeutic effect on patients, as demonstrated in clinical trials.
7. Type of Ground Truth Used
The ground truth for the effectiveness of the Monarch eTNS System was based on clinical assessment scales and their interpretation by clinical investigators/experts.
- Study 1 & 2: The primary effectiveness measure was the ADHD-IV Rating Scale (ADHD-RS) an assessment tool completed by clinicians to quantify ADHD symptoms.
- Study 1 & 2: Secondary effectiveness measures included the CGI-Improvement Scale (CGI-I), another clinician-rated scale to assess global improvement.
- Safety: Ground truth for safety was based on the reporting of adverse events by participants and/or caregivers, and their assessment by study investigators.
8. Sample Size for the Training Set
The provided document describes clinical trials (eTNS-ADHD01 and eTNS-ADHD02) which are typically used for validation of the device's safety and effectiveness. It does not mention a separate "training set" for an algorithm, as the Monarch eTNS system is a neuromodulation device, not an AI or machine learning diagnostic tool that requires a training set in the conventional sense. The studies serve as the evidence base for its clinical utility.
9. How Ground Truth for the Training Set Was Established
As mentioned above, the concept of a "training set" for an algorithm is not applicable to this device. The clinical trials served as the primary evidence collection for evaluating the device's performance, with ground truth established through validated clinical scales administered by investigators.
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DE NOVO CLASSIFICATION REQUEST FOR MONARCH ETNS SYSTEM
REGULATORY INFORMATION
FDA identifies this generic type of device as:
Transcutaneous electrical nerve stimulator for Attention Deficit Hyperactivity Disorder. A transcutaneous electrical nerve stimulator for Attention Deficit Hyperactivity Disorder (ADHD) is a prescription device that stimulates transcutaneously or percutaneously through electrodes placed on the forehead.
NEW REGULATION NUMBER: 21 CFR 882.5898
CLASSIFICATION: Class II
PRODUCT CODE: OGL
BACKGROUND
DEVICE NAME: Monarch eTNS System
SUBMISSION NUMBER: DEN180041
DATE OF DE NOVO: July 31, 2018
NeuroSigma, Inc. CONTACT: 10960 Wilshire Boulevard Suite 1910 Los Angeles. CA 90024
INDICATIONS FOR USE
The Monarch external Trigeminal Nerve Stimulation (eTNS) System is indicated for treatment of pediatric Attention Deficit Hyperactivity Disorder as a monotherapy in patients ages 7 through 12 years old who are not currently taking prescription ADHD medications. The device is used for patient treatment by prescription only and is intended to be used in the home under the supervision of a caregiver during periods of sleep.
LIMITATIONS
For prescription use only.
The device is contraindicated for use by patients with:
- Implanted cardiac and/or neurostimulation systems ●
- Implanted metallic or electronic device in their head 0
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The device should not be applied on the neck or chest, and it should not be used in the presence of electric monitoring equipment (e.g. cardiac monitors), in the bath or shower, or while operating machinery.
The long-term effects of using the Monarch eTNS System are unknown.
The device should only be applied to healthy, clean, intact skin.
PLEASE REFER TO THE LABELING FOR A MORE COMPLETE LIST OF WARNINGS, PRECAUTIONS AND CONTRAINDICATIONS.
DEVICE DESCRIPTION
The Monarch external Trigeminal Nerve Stimulation (eTNS) System is a non-invasive device that uses electrical signals to therapeutically stimulate the Trigeminal nerve. The primary components of the device are:
- The Monarch external pulse generator
- The Monarch NS-2 external (cutaneous) electrical patches, which are single use ● disposable patches worn on the forehead.
| NeuroSigma |
|---|
| Mirach |
| A) Pulse generator, electrode patch on forehead, and system as worn | B) Illustration of NS-2 Electrical Patch placed on forehead |
|---|---|
| --------------------------------------------------------------------- | ------------------------------------------------------------- |
The device has two primary components A) an external pulse generator approximately the size of a cell phone, and B) the non-invasive electrical patch that patients apply to their forehead to receive therapy.
Figure 1: Monarch eTNS System
The Monarch External Pulse Generator
The Monarch pulse generator generates an electrical stimulus for delivery to the patient's forehead. It is housed in a sealed protective case and powered by a rechargeable lithium polymer battery. Accessories include two spare batteries and a battery charging station. The stimulation parameters generated by the Monarch eTNS System are summarized in Table 1. All parameters are fixed except for amplitude is controlled by the patient's caregiver. Under a
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physician's supervision, the user can adjust the amplitude in 0.2mA increments, from 0 and 10 mA.
The Monarch NS-2 Electrical Patch
The Monarch eTNS patch attaches to the skin of the forehead by both hypoallergenic hydrogel and medical grade foam and adhesive and allows for bilateral stimulation of both the right and left supraorbital (SO) and supratrochlear (ST) branches of the trigeminal nerve (V1), located above the eyebrows in the forehead. The caretaker places the patch in the midline of the patient's forehead and applies the patch to the forehead directly above the eyebrows.
The gel, foam, and adhesive have undergone skin sensitization and histocompatibility studies in animals according to ISO 10993-1: Biological Evaluation of Medical Devices – Part 1: Evaluation and Testing. The electrical patch is connected to the pulse generator via a lead wire.
Stimulation Parameters:
Electrical Stimulation parameters generated by the Monarch eTNS System are summarized in the table below:
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| Parameter | Outcome |
|---|---|
| Waveform | Symmetrical Square Wave |
| Frequency of Stimulation | 120 Hz |
| Pulse Width | 250 $\mu$ Sec |
| Duration between pulses | 8 mSec |
| Maximum stimulus intensity | 10 mA, under patient control |
| Maximum Output Voltage | 5.36V |
| Hours of use | 7 – 9 hours, while asleep, as prescribed by treating physician |
| Cycling | 30 Sec ON: 1 Sec Ramp Down: 30 Sec OFF: 1 Sec Ramp Up |
| Net Charge per pulse | |
| Maximum current density | 1.4 mA.cm2 |
| Maximum average power density | 7.5 mW/cm2 |
| Maximum average current | 10 mA |
| Maximum Charge Density | 0.35 $\mu$ C/cm2 |
| Maximum Average power density | 7.5 mW/cm2 |
| Stimulating Surface Area of NS-2 Patch | 7.1 cm2 per electrode |
| Anatomical Target | Supraorbital (SO) and Supratrochlear (ST) nerves ofthe V1 division of the Trigeminal Nerve |
Table 1: Stimulation Parameters
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Principle of Operation:
The Monarch eTNS System treatment protocol is administered each night while the patient is sleeping, for 7 - 9 hours. The device is designed to provide non-invasive electrical stimulation of the trigeminal nerve. The trigeminal nerve is the largest cranial nerve and has three major sensory divisions of the face (V1, V2, V3), all of which are bilateral. The trigeminal nerve provides a direct connection to multiple brain structures implicated in ADHD and other neurologic and neuopsychiatric disorders. 1234
Image /page/4/Figure/2 description: The image contains three diagrams labeled A, B, and C. Diagram A shows the trigeminal nerve and its three branches: V1 (ophthalmic zone), V2 (maxillary zone), and V3 (mandibular zone). Diagram B shows the supraorbital and supratrochelar nerves on a skull. Diagram C shows the cortex and thalamus.
A) The Trigeminal nerve provides sensation to the face via three divisions (V1, V2, V3). eTNS stimulates the V1 division. B) The Supraorbital (SO) and Supratrochlear (ST) nerves are terminal branches of the V1 division. These four nerves, two on each side of the forehead, are the stimulation targets for eTNS. C) Path of the Trigeminal as it enters the brainstem at the Pons then makes connections in the medulla and midbrain before making connections in the thalamus and cortex. Figure 2: Anatomy of the Trigeminal Nerve
SUMMARY OF NONCLINICAL AND BENCH STUDIES
Biocompatibility, electrical safety, electromagnetic compatibility, battery safety, waveform verification. shelf life and software testing was required for the Monarch eTNS System.
BIOCOMPATIBILITY/MATERIALS
Patient contacting materials of the Monarch eTNS System are limited to the materials of the NS-2 electrode patch
| Patient ContactingDevice Component | Nature of TissueContact | Duration of Tissue Contact |
|---|---|---|
| NS-2 Electrical Patch /Hydrogel (MultistickMG-1500 AG600) | Skin Contact | 7 – 9 hours; During Sleep |
1 Nolte J. The Human Brain. An introduction to its functional anatomy. Mosby. 6thedition. 2009.
2 Caous CA, de Sousa Buck H, Lindsey CJ. Neuronal connections of the paratrigeminal nucleus. AutonNeurosci 2001; 94:14-24.
3 Grzanna R, Chee WK, Akeyson EW. Noradrenergic projections to brainstem nuclei: evidence for differential projections from noradrenergic subgroups. J Comp Neurol 1987; 263:76-91.
4 Krout KE, Belzer RE, Loewy AD. Brainstem projections to midline and intra-laminar thalamic nuclei of the rat. J Comp Neurol 2002; 448:53-101.
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| NS-2 Electrical Patch /adhesive foam(MTDID 22459 A3) | Skin Contact | 7 – 9 hours; During Sleep |
|---|---|---|
| -------------------------------------------------------------- | -------------- | --------------------------- |
Table 2: List of Patient-Contacting Materials
The electrode has limited duration (<24 hours) with intact skin. Therefore, per the FDA guidance "Use of International Standard ISO 10993-1, "Biological evaluation of medical devices - Part 1: Evaluation and testing within a risk management process"", and ISO 10993-1: Biological Evaluation of Medical Devices - Part 1: Evaluation and Testing, cvtotoxicity, sensitization, and irritation testing were performed for the electrode. The following table summarizes the tests performed and the results:
| Test Article | Test/Stand | Method | Results |
|---|---|---|---|
| Hydrogel(Multistick MG-1500 AG600) | IntracutaneousReactivity/ISO10993-10 | Intracutaneous toxicity inrabbits | PASS |
| Hydrogel(Multistick MG-1500 AG600) | Sensitization/ISO10993-10 | Guinea Pig closed pathsensitization | PASS |
| Hydrogel(Multistick MG-1500 AG600) | Cytotoxicity/ISO10993-5 | MEM Elusion | PASS |
| Medical Gradeadhesive foam(MTDID 22459 A3) | Irritation/ISO 10993-10 | Intracutaneous toxicity inrabbits | PASS |
| Medical Gradeadhesive foam(MTDID 22459 A3) | Sensitization/ISO10993-10 | Guinea Pig maximizationsensitization | PASS |
| Medical Gradeadhesive foam(MTDID 22459 A3) | Cytotoxicity/ISO10993-5 | MEM Elusion and AgaroseOverlay Method | PASS |
Table 3: Summary of Biocompatibility Testing Results
SHELF LIFE/STERILITY
The Monarch eTNS device and its accessories are not sterile. Cleaning and maintenance instructions for the system are included within the labeling.
The Shelf Life of the Monarch NS-2 electrodes is 3 years, as determined by accelerated and real-time age testing.
ELECTROMAGNETIC COMPATIBILITY (EMC) AND ELECTRICAL SAFETY
The Monarch eTNS system was tested to demonstrate conformance to the following electromagnetic compatibility, electrical, mechanical, and thermal safety standards:
- Electromagnetic Compatibility .
- o IEC 60601-1-2 Medical Electrical Equipment: Part 1-2: General Requirements for Safety - Section 2: Collateral Standard: Electromagnetic Compatibility - Requirements and Tests.
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- . Electrical, Mechanical, and Thermal Safety
- o IEC 60601-1:2012 Medical Electrical Equipment: Part 1: General Requirements for Basic Safety and Essential Performance.
- IEC 60601-1-11:2015 Medical Electrical Equipment Part 1-11: o Collateral Standard Requirements for Medical Electrical Equipment and medical electrical systems used in home healthcare environment.
- IEC 60601-2-10 Medical Electrical Equipment; Part 2-10: Particular о Requirements for the Safety of Nerve and Muscle Stimulators (2016).
- o Battery Safety
- o IEC 62133:2012 - Secondary cells and batteries containing alkaline or other non-acid electrolytes - Safety requirements for portable sealed secondary lithium cells, and for batteries made from them, for use in portable applications - Part 2: Lithium systems
SOFTWARE
Proprietary Software of the Monarch eTNS system was reviewed according to FDA Guidance document, "Guidance for the Content of Premarket Submissions for Software Contained in Medical Devices," issued May 11, 2005. The software was found to have a MODERATE level of concern. FDA review of the software documentation provided in support of the Monarch eTNS System was found to be acceptable.
PERFORMANCE TESTING - BENCH
The following tests were conducted to demonstrate device reliability:
- Battery Performance Testing: The device operated for the intended duration of ● use to demonstrate that the battery could power the system for this period of time.
- Stimulation Output Verification Testing: Output waveforms were captured using . an oscilloscope to demonstrate that the device can produce its intended stimulation parameters.
- . Electrode Testing: Electrical performance, adhesive integrity, and shelf life testing of the electrode was tested to ensure that its electrical performance and adhesive properties met specifications for the duration of its shelf life.
Performance Testing (Bench) was found to be acceptable
SUMMARY OF CLINICAL INFORMATION
Two clinical trials, eTNS-ADHD01 (Study 1) and eTNS-ADHD02 (Study 2), were conducted and each trial is summarized below.
Study 1 - eTNS-ADHD01 (NCT01388530) A.
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eTNS-ADHD01 was an open label trial reporting the outcomes of 24 children ages 7 through 14 with moderate to severe ADHD. Moderate to severe ADHD was defined as having a minimum score of 12 on both the inattentive and hyperactive and impulse subscales of the baseline ADHD Rating Scale (ADHD-RS) and a Clinical Global Impression-Severity (CGI-S) score at baseline of greater than 4. Patients underwent 8 weeks of nightly treatments with eTNS as a monotherapy. The primary effectiveness endpoint in this study was the ADHD-IV Rating Scale (ADHD-RS). Secondary and Exploratory endpoints included the following:
-
- CGI-Improvement Scale
-
- Conners Parent and Teachers Indexes
-
- Children Depression Inventory (CDI)
-
- Beck Depression Inventory (BDI)
-
- Manifest Anxiety Scale for Children (MASC)
-
- Brief Family Assessment Measure III (Brief FAM-III)
-
- Behavior Rating Inventory of Executive Functioning (BRIEF)
-
- Cognitive tests (ANT, SDRT, Go/No Go)
-
- Children's Sleep Habits Questionnaire
eTNS-ADHD01 was designed to obtain preliminary data on the acceptability, tolerability, and potential effectiveness of eTNS as an ADHD treatment. This 8-week trial duration was based on clinical trials of pharmaceutical treatments for ADHD as well as other clinical trials of eTNS for different neuropsychiatric indications that found significant effects after 8 weeks.
1. Study 1
Patients in eTNS-ADHD01 used the Neurosigma NS-2 disposable patch and the EMS 7500 Transcutaneous Electrical Nerve Stimulator (TENS) device. The EMS 7500 used the same electrical output parameters as the Monarch eTNS System. Each NS-2 electrical patch was used for a single, nightly treatment session and disposed of in the morning.
2. Background and Trial Design
ADHD diagnosis was based on the DSM-IV criteria for ADHD. Once inclusion/exclusion criteria were met, participants had a pre-treatment visit to assess baseline ADHD symptom severity on the ADHD-RS scale and several measures of cognition. Following the baseline visit, subjects initiated nightly therapy with eTNS. Parents/Caregivers were instructed to start treatment shortly before sleep. The disposable patch was applied to the center of the subject's forehead, just above the eyebrows, and connected to the external stimulator via the lead wire. Parents/Caregivers were instructed to increase the current to the point of perceptibility, and to keep it at that level throughout the night. Upon waking, subjects removed the patch and went about their normal daily activities. Patients were required not to use any ADHD medications at baseline and throughout the study.
After initiating therapy with eTNS, participants returned for 8 weekly clinic visits, which included repeated assessment of behavioral response. tolerability, and compliance. Treatment compliance was measured daily with a parent completed compliance diary and weekly by clinical interviews conducted at study visits. Visits at weeks 4 and 8 also
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included repeated measurements of cognitive outcomes. Additionally, teacher rating of ADHD symptoms were collected when available at baseline, week 4 and week 8. The pre-specified primary outcome measure was the investigator completed ADHD-RS.
Statistical Analysis 3.
Participation rates and treatment compliance were determined based on all participants deemed eligible at screening. The safety population included all participants with at least one night's exposure to eTNS. The treatment population included all participants with outcome data at Week 4 which was the first post-baseline point at which primary behavioral and cognitive outcomes were obtained.
4. Results
A total of 29 individuals were screened for participation. Of those screened 25 met inclusion/exclusion criteria. Twenty-four subjects initiated eTNS treatment as there was an early termination for 1 subject for which no other information was provided. Two participants dropped out prior to visit 4, and one dropped out after visit 4. According to daily treatment diaries from subjects that completed the trial, nightly treatment compliance was 100%. The Safety Analysis was based on the 24 participants with any exposure to eTNS. Treatment Analysis was based on the 22 participants with baseline and visit 4 data. Participant demographics is summarized in the below table:
| Sample Size (N) | 24 |
|---|---|
| Sex | 92% male, 8% female |
| Age: Mean (SD), Range | 10.3 (2.1) 7-14 years |
| Full Scale IQ: Mean (SD), Range | 100.7 (12.7) 75-127 |
| Race | |
| White | 75 % |
| African American | 13 % |
| Asian | 13 % |
| Ethnicity | |
| Non-Hispanic | 54 % |
| Hispanic | 46 % |
| ADHD Subtype | |
| Inattentive | 8% |
| Hyperactive/Impulsive | 4% |
| Combined | 88% |
| Comorbidity (%) | |
| Oppositional Defiant Disorder | 46% |
*Safety population based on all participants exposed to TNS
Table 4: eTNS-ADHD01 Participant Characteristics
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88% met criteria for the combined subtype of ADHD. 46% had comorbid oppositional defiant disorder (ODD).
Safety a)
A total of 13 adverse events (AE) were reported during the 8-week pilot trial. Of these, 2 events (eye twitching and headache) were deemed as potentially related to the evaluated treatment. The eye twitch resolved with alternative placement of forehead electrodes. Two patient reported headache, which were resolved without additional intervention. Table 5 presents adverse events reported during the study and Table 6 summarizes side effects which were rated on at least one visit as being "moderate" or "severe".
| Event | Number ofIncidents | Related orPossibly Related* | Unrelated* | % ParticipantsReporting |
|---|---|---|---|---|
| Asthma | 1 | 0 | 1 | 4.2% |
| Eye Twitch | 1 | 1 | 0 | 4.2% |
| Gagging | 1 | 0 | 1 | 4.2% |
| Headache | 4 | 2 | 2 | 16.7% |
| Inguinal Hernia | 1 | 0 | 1 | 4.2% |
| Nasal Congestion | 1 | 0 | 1 | 4.2% |
| Sore Throat | 2 | 0 | 2 | 8.3% |
| Swallowed Tack | 1 | 0 | 1 | 4.2% |
| Tingles in Head | 1 | 0 | 1 | 4.2% |
- Determination made by study investigators
Table 5: Adverse Events (N=24)
| Side Effect | % Participants Reporting | Number of Incidents |
|---|---|---|
| Trouble concentrating ** | 92 | 22 |
| Trouble sitting still ** | 71 | 17 |
| Poor concentration ** | 71 | 17 |
| Feeling nervous or hyper | 58 | 14 |
| Poor memory ** | 46 | 11 |
| Irritable | 42 | 10 |
| Trouble Sleeping | 29 | 7 |
| Stuffy nose | 24 | 6 |
| Nightmares or other sleepingdisturbances | 21 | 5 |
| Feeling drowsy or sleepy | 21 | 5 |
| Weakness or fatigue | 21 | 5 |
| Headache | 13 | 3 |
| Diminished mentalacuity/sharpness | 13 | 3 |
| Apathy/emotional indifference | 13 | 3 |
| Feeling strange or unreal | 8 | 2 |
| Drooling or increased salivation | 8 | 2 |
| Muscle twitching or movements | 8 | 2 |
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| Slurred speech | 8 | 2 |
|---|---|---|
| Stomach or abdominaldiscomfort | 8 | 2 |
| Excess sweating | 8 | 2 |
| Weight gain | 8 | 2 |
| Difficulty finding words | 8 | 2 |
| Blurred vision | 4 | 1 |
| Dry mouth | 4 | 1 |
| Rapid heartbeat | 4 | 1 |
| Hyperventilation | 4 | 1 |
| Difficulty starting urination | 4 | 1 |
| Frequent need to urinate | 4 | 1 |
| Appetite decreased | 4 | 1 |
| Appetite increased | 4 | 1 |
| Skin rash or allergy | 4 | 1 |
| Hair thinning/loss | 4 | 1 |
Table 6: Moderate and Severe Side Effects Based on SAFTEE Rating Scale (N = 24)
Effectiveness b)
Results are summarized in Table 6 and Figure 5. The change in ADHD-RS results are presented for baseline, week 4, and week 8. The mean score on ADHD-RS was 32.6 at baseline versus 18.2 at week 4 and 17.3 at week 8.
| Measure | Study Week Least Square Means | |||||
|---|---|---|---|---|---|---|
| Baseline | Week 4 | Week 8 | F | d/f | p value | |
| ADHD-RS-Total | 32.6 | 18.2 | 17.3 | 42.45 | 2/340 | <.0001 |
| ADHD-RS-Inattentive Subscale | 17.8 | 10.9 | 10.1 | 30.25 | 2/40 | <.0001 |
| ADHD-RS-Hyper/Imp Subscale | 14.8 | 7.3 | 7.3 | 30.31 | 2/40 | <.0001 |
Table 7: ADHD-IV RS Scale Results
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Image /page/11/Figure/0 description: The image is a line graph that shows the change in ADHD-RS scores over time. The x-axis represents time, with labels for Baseline, Week 4, and Week 8. The y-axis represents the ADHD-RS score, ranging from 0 to 35. There are three lines on the graph, representing ADHD-RS Total, ADHD-RS - Inattentive, and ADHD-RS - Hyper/Imp. The ADHD-RS Total score decreases from about 33 at baseline to about 17 at Week 8. The ADHD-RS - Inattentive score decreases from about 18 at baseline to about 10 at Week 8. The ADHD-RS - Hyper/Imp score decreases from about 15 at baseline to about 7 at Week 8.
Figure 3: ADHD-RS Results
Feasibility Study Results c)
No serious adverse events were reported, and the treatment was well tolerated in this feasibility study. Preliminary mean scores improved from 32.6 points at baseline to 18.2 points at Week 4 and 17.3 points at Week 8.
Study 1 Limitations d)
Additional factors to be considered in determining a reasonable assurance of safety and effectiveness includes the small sample size, open label studies may cause an overestimation of the treatment effect due to investigator and subject ratings. Also, open label studies do not assess the magnitude of the placebo response, the effect of changes in medications or the contribution of other treatments.
Study 2 - eTNS-ADHD02 (NCT02155608) B.
Background and Trial Design 1.
eTNS-ADHD02 was a double blind, randomized, sham controlled trial of the external trigeminal nerve stimulation (eTNS) for the treatment of pediatric ADHD. The purpose of this study was to evaluate the safety and effectiveness findings of eTNS-ADHD01. The primary endpoint was the ADHD-IV RS. Secondary endpoints included:
- . CGI-I
The primary endpoint was measured at 4 weeks based on results from eTNS-ADHD01. Patients in this trial were not permitted to take medications for ADHD to ensure the
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effectiveness of the device could be assessed without confounding variation due to medication. Prior to device therapy, patients were requested to stay off medication for at least a week.
Subjects were randomized 1:1 to either the active treatment or sham stimulation groups. Subjects randomized to the sham group received a Monarch eTNS system identical in appearance and graphical user interface to the active device. However, stimulation was routed through an internal resistor instead of the adhesive electrical patch. This ensured that the rechargeable battery still drained appropriately and required the subject to recharge it after each nightly therapy session to maintain the study blind. To further protect study blinding, subjects were counseled during enrollment that stimulation may not be perceptible, and all patients received an "early impression questionnaire" at their Week 1 visit to determine if there were statistically significant differences in impressions of treatment.
Each night parents/caregivers were instructed to apply a patch to their forehead, turn on the device and increase stimulation to the maximum tolerable level. Once this maximum level was reached, patients were instructed to reduce it by 0.1 mA. Compliance was assessed during the weekly visit by reviewing the subject diaries.
Subjects were instructed to begin their eTNS therapy each night before sleep. Initiation of therapy consisted of applying the NS-2 electrical patch to the midline of the subject's forehead just above the eyebrows, subsequently followed by setting the amplitude to a comfortable level. Stimulation was then applied throughout the night while the subject was sleeping.
Enrollment 2.
79 subjects were screened for trial participation. Of these, 13 failed to meet trial inclusion criteria, 2 met exclusion criteria, and 2 were lost to follow up prior to the baseline visit. 62 subjects were enrolled and randomized (32 to the active group and 30 to the sham group). Of these, 3 terminated the study early, but did participate in at least one efficacy assessment. 59 subjects completed the 4week double blind treatment period (31 in the active group and 28 in the sham group).
3. Accountability
Of the 62 subjects randomized in the study, 94% of active subjects and 83% of sham subjects reported complete compliance data for each endpoint at the 4 weeks follow up visit. The following table presents patient compliance with the study.
4. Demographics
A summary of subject demographics is presented in table 9. Sixty-three percent (63%) of subjects had the combined subtype of ADHD, 34% had the inattentive subtype, and 3% had the hyperactive/impulsive subtype. In addition, subject demographics show that the population evaluated was diverse and representative of the intended US treatment population.
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| Total Sample(N=62) | Active Group(n=32) | Sham Group(n=30) | P Value | |||||
|---|---|---|---|---|---|---|---|---|
| Age, Mean (SD) Years | 10.4 | (1.4) | 10.3 | (1.4) | 10.5 | (1.4) | 0.49 | |
| [Range] | [8.1-13.0] | [8.1-12.9] | [8.2-13.0] | |||||
| Height, Mean (SD) cm | 141.8 | (9.2) | 142.7 | (10.2) | 140.0 | (8.1) | 0.44 | |
| [Range] | [126.0-160.3] | [126.0-160.3] | [126.8-157.2] | |||||
| Weight, Mean (SD) kg | 37.3 | (11.1) | 38.4 | (12.4) | 36.0 | (9.4) | 0.41 | |
| [Range] | [23.3-77.0] | [23.3-77.0] | [23.5-67.2] | |||||
| Full Scale IQ, Mean (SD) | 108.9 | (13.2) | 110.4 | (12.3) | 107.3 | (14.2) | 0.35 | |
| [Range] | [81.0-144.0] | [87.0-134.0] | [81.0-144.0] | |||||
| Sex, n (%) | ||||||||
| Male | 40 | (65) | 20 | (63) | 21 | (70) | 0.38 | |
| Female | 22 | (35) | 13 | (40) | 9 | (3) | ||
| Race, n (%) | ||||||||
| White | 40 | (65) | 20 | (63) | 20 | (67) | 0.21 | |
| Total Sample(N=62) | Active Group(n=32) | Sham Group(n=30) | P Value | |||||
| Black | 4 | (6) | 4 | (13) | 0 | |||
| Asian | 10 | (16) | 5 | (16) | 5 | (17) | ||
| Mixed/Other | 8 | (13) | 3 | (9) | 5 | (17) | ||
| Ethnicity, n (%) | ||||||||
| Non-Hispanic | 52 | (84) | 27 | (84) | 25 | (83) | 0.91 | |
| Hispanic | 10 | (16) | 5 | (16) | 5 | (17) | ||
| ADHD Subtype, n (%) | ||||||||
| Combined | 39 | (63) | 22 | (69) | 17 | (57) | 0.60 | |
| Inattentive | 21 | (34) | 9 | (28) | 12 | (40) | ||
| Hyperactive/Impulsive | 2 | (3) | 1 | (3) | 1 | (3) | ||
| Comorbid Disorders, n (%) | ||||||||
| Oppositional Defiant | 20 | (32) | 11 | (34) | 9 | (30) | 0.71 | |
| Disruptive Mood Dysregulation | 17 | (27) | 10 | (31) | 7 | (23) | 0.49 | |
| Social Phobia | 10 | (16) | 7 | (21) | 3 | (10) | 0.20 |
| Table 8: Subject Demographics | |||
|---|---|---|---|
| Event | % of Participants Reporting Event During Study | ||
| Active (n=32) | Sham (n=30) | ||
| Hyperactive | 41 | 63 | |
| Drowsy | 22 | 13 | |
| Increased appetite | 19 | 7 | |
| Trouble sleeping | 19 | 17 | |
| Stuffy nose | 16 | 20 | |
| Clenching teeth | 13 | 7 | |
| Fatigue | 13 | 3 | |
| Headache | 13 | 3 | |
| Constipation | 9 | 7 | |
| Upper Respiratory Infection | 9 | 10 | |
| Apathy | 6 | 7 | |
| Frequent urination | 6 | 0 | |
| Nightmares | 6 | 3 | |
| Rhinitis | 6 | 6 | |
| Skin rash | 6 | 0 | |
| Stomachache | 6 | 3 | |
| Bronchitis | 3 | 0 | |
| Decreased appetite | 3 | 3 | |
| Frequent sweating | 3 | 3 | |
| Itching | 3 | 0 | |
| Lightheaded | 3 | 0 | |
| Muscle cramps | 3 | 3 | |
| Nausea | 3 | 0 | |
| Out of breath | 3 | 3 | |
| Rapid heartbeat | 3 | 0 | |
| Skin whitening/discoloration | 3 | 3 | |
| Tingling | 3 | 0 | |
| Tooth pain | 3 | 0 | |
| Vomiting | 3 | 0 | |
| Anxiety | 0 | 3 | |
| Difficulty finding words | 0 | 7 | |
| Feeling strange | 0 | 7 | |
| Mouth pain | 0 | 3 | |
| Muscle twitch | 0 | 7 | |
| Slurred speech | 0 | 3 | |
| Tremor | 0 | 3 | |
| Wrist sprain | 0 | 3 |
10
18
6
2
2
1
5. Results
Generalized Anxiety
Tourette's Syndrome
Any Anxiety
Enuresis
Encopresis
Motor Tic
Safety a)
There were no significant differences in vital signs between baseline and week 4 or between active and sham treatment groups. eTNS was well tolerated in all 62 subjects. Of the reported adverse events, all were mild to moderate in severity.
(16)
(29)
(12)
(3)
(3)
(2)
6
11
5
0
2
0
(19)
(3)
(16)
(6)
4
7
1
2
0
1
(13)
(23)
(3)
(7)
(3)
0.96
0.34
0.10
0.14
0.16
0.30
{14}------------------------------------------------
There were no serious adverse events (SAEs) associated with the use of the device.
Table 9: Safety Results - Adverse Events
b) Efficacy
Early Impressions Questionnaire (Blinding Assessment) (1)
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| Odds Ratio(Active vs.Sham) | 95%ConfidenceInterval | Wald Chi-Square df | P Value | |
|---|---|---|---|---|
| At this point, howsuccessfully do you thinkyour current TNS treatmentwill be in reducing yourchild's ADHD symptoms? | .93 | .76 - 1.15 | .451 | .50 |
| At this point, how much doyou really feel that TNStreatment will help reduceyour child's ADHDsymptoms? | .90 | .70 - 1.14 | .821 | .37 |
Table 10: Early Impression Questionnaire Results
All patients were assessed for blinding at the 1 week follow up visit using an Early Impression Questionnaire. Results demonstrated that there was no significant difference in caregiver expectations between active and sham groups regarding expectations of a positive treatment effect.
Primary Efficacy Endpoint (2)
The primary endpoint was the ADHD-IV Rating Scale. Upon completion of the 4-week blinded treatment protocol, the average ADHD-RS score in the active group decreased from 34.1 points at baseline to 23.4 points. Within the sham group, a decrease from 33.7 points at baseline to 27.5 points was recorded. As seen in Figure 5 below, both groups saw a decrease in ADHD-RS total score over Week 1 of the study. This was followed by ongoing improvement in the active group as compared to flattening of the curve in the sham group.
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Image /page/16/Figure/0 description: The image is a line graph comparing the ADHD-RS Total Score between Active and Sham eTNS groups over a 4-week period. The x-axis represents the week, ranging from 0 to 4, while the y-axis represents the ADHD-RS Total Score, ranging from 20 to 34. The Active group, represented by a solid blue line, shows a decrease in the ADHD-RS Total Score from approximately 32 at week 0 to around 23 at week 4. The Sham group, represented by a dashed orange line, also shows a decrease from approximately 33 at week 0 to around 28 at week 4, but the decrease is less pronounced than in the Active group.
Figure 4: Mean ADHD-RS Total Score by Time Point by Group
| Time Point | Active (N = 31) | Sham (N = 28) | ||
|---|---|---|---|---|
| Mean | SD | Mean | SD | |
| Baseline (Visit 0) | 34.06 | 6.64 | 33.7 | 7.21 |
| Week 1 (Visit 1) | 26.16 | 7.67 | 28.53 | 8.78 |
| Week 2 (Visit 2) | 24.74 | 9.01 | 27.54 | 7.84 |
| Week 3 (Visit 3) | 23.59 | 7.24 | 28.13 | 8.96 |
| Week 4 (Visit 4) | 23.39 | 7.88 | 27.5 | 8.08 |
Table 11: Mean ADHD-RS Total Score by Time Point and Group
Treatment effect size was determined using the Cohen's d test and demonstrated a medium effect in ADHD-RS Total scores.
{17}------------------------------------------------
Image /page/17/Figure/0 description: The image is a line graph comparing the total score of an active group versus a sham group over a period of two weeks. The x-axis represents the week, with values of 4 and 5, while the y-axis represents the total score, ranging from 0 to 35. The active group, represented by a solid red line, shows a gradual increase in total score from approximately 23 to 25 between weeks 4 and 5. The sham group, represented by a dotted blue line, maintains a relatively stable total score of around 28 across both weeks.
Figure 5: ADHD-RS Total Scores over Blinded Discontinuation Week - Active Vs. Sham TNS
In addition, long term data was collected for a subset of patients with clinically meaningful improvement on active eTNS treatment during Study 2. This was defined as those whose had a CGI-I score of ≤ 2. These patients were offered the opportunity to continue using the device for an additional 12 months in an open label extension phase. This opportunity was open to active group subjects following their initial 4 weeks of blinded treatment and to those of the sham group who chose to enter the cross over phase.
| Time Point | Number of Subjects | |
|---|---|---|
| Started inActive Group | Started inSham Group | |
| 3 Months | 10 | 8 |
| 6 Months | 5 | 3 |
| 9 Months | 4 | 2 |
| 12 Months | 2 | 1 |
Table 12: Long Term Data Accountability
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Image /page/18/Figure/0 description: This bar graph shows the scores of all extension subjects at baseline, 3 months, 6 months, 9 months, and 12 months. At baseline, the score was 35.4 with n=18. At 3 months, the score was 16.6 with n=18, at 6 months the score was 17.8 with n=8, at 9 months the score was 15.8 with n=6, and at 12 months the score was 16.7 with n=3. The mean baseline score for all study subjects was 33.9.
Figure 6: Mean ADHD-RS Total Score by Time Point in Open Label Extension
Secondary Efficacy Endpoints c)
Data from the CGI-I scale demonstrated a statistically significant result from eTNS treatment. After 4 weeks of study treatment, 52% of subjects in the active group improved by one or more points on the CGI-I scale versus 14% of subjects in the sham group. Additionally, data from weeks 1 – 4 of treatment show a steadily increasing improvement among subjects in the active group versus no significant change among subjects in the sham group.
Image /page/18/Figure/4 description: This image shows a bar graph comparing the active and sham groups. The graph shows that 25% of the active group improved, compared to 13% of the sham group. At week 4, 52% of the active group improved, compared to 14% of the sham group.
Figure 7: Percent of Group Reporting Improvement on CGI-I Scale
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| Active | Sham | |||||
|---|---|---|---|---|---|---|
| Week | Not Improvedn (%) | Improvedn (%) | Not Improvedn (%) | Improvedn (%) | $X^2_{df}$ | P Value |
| 1 | 24 (75) | 8 (25) | 26 (87) | 4 (13) | 1.351 | 0.25 |
| 2 | 19 (61) | 12 (34) | 22 (85) | 4 (15) | 3.811 | 0.05 |
| 3 | 16 (53) | 14 (47) | 22 (88) | 3 (12) | 7.671 | 0.006 |
| 4 | 15 (48) | 16 (52) | 24 (86) | 4 (14) | 9.121 | 0.003 |
- improved = CGI-I ≤2 ; not improved = CGI-I >2.
Table 13: CGI-I by Study Week
d) Study 2 Limitations
Additional factors to be considered in determining a reasonable assurance of safety and effectiveness includes the small sample size and the potential for unblinding subjects in the sham arm which may have resulted in patient bias and the outcomes reported for treatment groups. In addition, the design of Study 2 did not allow an assessment of the placebo response.
LABELING
The Monarch eTNS System Instructions for Use are consistent with the clinical data and cover all the hazards and other clinically relevant information that may impact use of the device. The labeling is sufficient and satisfies the requirements of 21 CFR § 801.109 Prescription devices. The Monarch eTNS System is contraindicated for the following uses:
The device is contraindicated for use by patients with:
- Implanted cardiac and/or neurostimulation systems ●
- . Implanted metallic or electronic device in their head
The following warnings and precautions are included within device labeling:
- The device should not be applied on the neck or chest, and it should not be used in the 0 presence of electric monitoring equipment (e.g. cardiac monitors), in the bath or shower, or while operating machinery.
- The long-term effects of using the Monarch eTNS System are unknown. ●
- The device should be used only as direct and be applied to healthy, clean, intact skin. o
The labeling also includes:
- Information on how the device operates and the typical sensations experienced during treatment;
- A detailed summary of the device technical parameters; ●
- A shelf life for the electrodes; ●
- Information in the Instructions for Use regarding how to place the device on the patient; and
- Cleaning instructions for the device.
RISKS TO HEALTH
{20}------------------------------------------------
The table below identifies the risks to health that may be associated with use of a transcutaneous nerve stimulator for Attention Deficit Hyperactivity Disorder (ADHD) and the measures necessary to mitigate these risks.
| Identified Risk | Mitigation Measures |
|---|---|
| Adverse tissue reaction | Biocompatibility evaluation |
| Injury or discomfort fromelectrical stimulation, includingburns and nerve damage | Electromagnetic compatibility testingElectrical, mechanical, and thermal safety testingNon-clinical performance testingSoftware verification, validation, and hazard analysisShelf life testingLabeling |
| Misuse that may result in devicefailure, user discomfort, orinjury | Labeling |
| Skin irritation or infection fromuse on broken skin | Labeling |
Table 14: Identified Risks to Health and Mitigation Measures
SPECIAL CONTROLS:
In combination with the general controls of the FD&C Act, the transcutaneous electrical nerve stimulator for Attention Deficit Hyperactivity Disorder (ADHD) is subject to the following special controls:
-
- The patient-contacting components of the device must be demonstrated to be biocompatible.
-
- Performance testing must demonstrate the electromagnetic compatibility and electrical, mechanical, and thermal safety of the device.
-
- Non-clinical performance testing must demonstrate that the device performs as intended under anticipated conditions of use. The following must be performed:
- a. Electrical performance testing must validate electrical output and duration of stimulation;
- b. Battery performance testing must be performed; and
- c. Adhesive integrity testing of the electrodes must be conducted.
-
- The technical parameters of the device including waveform, maximum output current and voltage, pulse duration, frequency, net charge per pulse, maximum current density, maximum average current, and maximum average power density must be fully characterized.
-
- Software verification, validation, and hazard analysis must be performed.
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-
- Shelf life testing of the electrodes must be performed to demonstrate continued package integrity and component functionality over the labeled shelf life.
-
- Labeling must include the following:
- a. A contraindication for patients with an implanted metallic or electronic device in the head, a cardiac pacemaker, or an implanted or wearable defibrillator;
- b. A warning that the device is only for use on clean, intact skin;
- c. Information on how the device operates and the typical sensations experienced during treatment;
- d. A detailed summary of the device technical parameters;
- A shelf life for the electrodes; e.
- Instructions for use, including placement of the device on the patient; and f.
- g. Cleaning instructions.
BENEFIT/RISK DETERMINATION
The risks of the Monarch eTNS Therapy System are based on data collected from two studies. No serious adverse events were reported in either study and all adverse events were minor with reversible effects. In Study 2, differences in side effects seen between patients in the active compared to the sham group included nightmares, headache, frequent urination, increased appetite, skin rash, and teeth clenching. However, none of the patients were reported to discontinue treatment based on headaches or any of the other adverse effects.
The probable benefits of the device are based on data collected from the randomized shamcontrolled trial that demonstrated a clinically meaningful and statistically significant improvement in the ADHD-RS total score over the 4-week treatment period. Data from both Study 1 and long term follow up portion of Study 2 indicates that there may be continued benefit beyond 4 weeks. However, this benefit was not studied in a controlled manner.
Additional factors considered in determining probable risks and benefits for the Monarch eTNS Therapy System include:
-
- Medications approved for ADHD provide a similar benefit but may have problematic side effects.
-
- Long term effects of eTNS therapy (beyond 4 weeks) has not been evaluated.
-
- Blinding was not assessed after the week 1 assessment in the one blinded trial.
Based on the results of the feasibility study and the randomized, sham controlled, clinical trial to support the use of a transcutaneous nerve stimulator for the treatment of ADHD in a pediatric population (ages 7 - 12, and assessment of the adverse event reported, we conclude that the benefits outweigh the probable risks.
Patient Perspectives
Patient and caregiver self-reported measures along with patient diaries were used to collect information on patient perspectives for this device.
{22}------------------------------------------------
Benefit/Risk Conclusion
In conclusion, given the available information above, the data support that for the previously stated indications for use, the probable benefits outweigh the probable risks for the Monarch eTNS System. The device provides benefits and the risks can be mitigated using general controls and the identified special controls.
CONCLUSION
The De Novo request for the Monarch eTNS Therapy System is granted and the device is classified under the following:
Product Code: QGL Device Type: Transcutaneous electrical nerve stimulator for Attention Deficit Hyperactive Disorder Class: II Regulation: 21 CFR 882.5898
REFERENCES
-
- Nolte J. The Human Brain. An introduction to its functional anatomy. Mosby. 6th edition. 2009.
-
- Caous CA, de Sousa Buck H, Lindsey CJ. Neuronal connections of the paratrigeminal nucleus. AutonNeurosci 2001; 94:14-24.
-
- Grzanna R, Chee WK, Akeyson EW. Noradrenergic projections to brainstem nuclei: evidence for differential projections from noradrenergic subgroups. J Comp Neurol 1987; 263:76-91.
-
- Krout KE, Belzer RE, Loewy AD. Brainstem projections to midline and intra-laminar thalamic nuclei of the rat. J Comp Neurol 2002; 448:53-101.
-
- McGough et al. An Eight-week. Open-trial. Pilot Feasibility Study of Trigeminal Nerve Stimulation in Youth With Attention-deficit/Hyperactivity Disorder. Brain Stimulation 8 (2015) 299-304.
-
- McGough JJ, Sturm A, Cowen J, Tung K, Salgari GC, Leuchter AF, Cook IA, Sugar CA, Loo SK. Double-Blind, Sham-Controlled, Pilot Study of Trigeminal Nerve Stimulation for Attention-Deficit/Hyperactivity Disorder. J Am Acad Child Adolesc Psychiatry. 2019 Apr;58(4):403-411.e3. doi: 10.1016/j.jaac.2018.11.013. Epub 2019 Jan 28.
§ 882.5898 Transcutaneous electrical nerve stimulator for attention deficit hyperactivity disorder.
(a)
Identification. A transcutaneous electrical nerve stimulator for attention deficit hyperactivity disorder (ADHD) is a prescription device that stimulates transcutaneously or percutaneously through electrodes placed on the forehead.(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) Performance testing must demonstrate the electromagnetic compatibility and electrical, mechanical, and thermal safety of the device.
(3) Non-clinical performance testing must demonstrate that the device performs as intended under anticipated conditions of use. The following must be performed:
(i) Electrical performance testing must validate electrical output and duration of stimulation;
(ii) Battery performance testing must be performed; and
(iii) Adhesive integrity testing of the electrodes must be conducted.
(4) The technical parameters of the device including waveform, maximum output current and voltage, pulse duration, frequency, net charge per pulse, maximum current density, maximum average current, and maximum average power density must be fully characterized.
(5) Software verification, validation, and hazard analysis must be performed.
(6) Shelf life testing of the electrodes must be performed to demonstrate continued package integrity and component functionality over the labeled shelf life.
(7) Labeling must include the following:
(i) A contraindication for patients with an implanted metallic or electronic device in the head, a cardiac pacemaker, or an implanted or wearable defibrillator;
(ii) A warning that the device is only for use on clean, intact skin;
(iii) Information on how the device operates and the typical sensations experienced during treatment;
(iv) A detailed summary of the device technical parameters;
(v) A shelf life for the electrodes;
(vi) Instructions for use, including placement of the device on the patient; and
(vii) Cleaning instructions.