NeuroStar Advanced Therapy System (All previously cleared models)

K231926 · Neuronetics, Inc. · OBP · Mar 22, 2024 · Neurology

Device Facts

• Record ID: K231926
• Device Name: NeuroStar Advanced Therapy System (All previously cleared models)
• Applicant: Neuronetics, Inc.
• Product Code: OBP · Neurology
• Decision Date: Mar 22, 2024
• Decision: SESE
• Submission Type: Traditional
• Regulation: 21 CFR 882.5805
• Device Class: Class 2
• Attributes: Therapeutic

Intended Use

NeuroStar Advanced Therapy is indicated as an adjunct for the treatment of Major Depressive Disorder (MDD) in adolescent patients (15-21).

Device Story

NeuroStar Advanced Therapy System is a computerized, electromechanical transcranial magnetic stimulation (TMS) device. It delivers non-invasive magnetic pulses to the left dorsolateral prefrontal cortex (DLPFC) to induce electrical currents, causing localized axonal depolarization and neuronal activation. The system comprises a mobile console, treatment chair, head support, electromagnetic coil, and TrakStar data management software. Used in clinics and hospitals by trained operators, the device provides adjunctive treatment for MDD. By stimulating targeted brain regions, it aims to alleviate depressive symptoms. Healthcare providers use the system's output to manage treatment protocols, with clinical decision-making supported by standardized stimulation parameters. The device benefits patients by providing a non-invasive therapeutic option for MDD.

Clinical Evidence

Evidence includes a retrospective analysis of real-world data (RWD) from 1,169 adolescent patients (12-21) and a systematic literature review of 14 studies. In the RWD study, 77.8% of patients met success criteria (p<0.0001), with a mean PHQ-9 score reduction of -10.0. Literature studies (RCTs and open-label) consistently showed statistically significant improvements in depression scores (HAM-D, CDRS-R) and remission rates, with effect sizes often categorized as large. The device was well-tolerated with no serious adverse events reported.

Technological Characteristics

Transcranial magnetic stimulator using a biphasic figure-8 ferromagnetic core coil. Energy source: power console. Connectivity: Wi-Fi/Ethernet to TrakStar. Materials: standard medical-grade, ISO 10993-1 compliant. Standards: ISO 13485:2016, IEC 60601-1, IEC 60601-1-2. Stimulation: 1-30 PPS, 185 µS pulse width, 135 V/m nominal field strength. No sterilization required.

Indications for Use

Indicated for adjunct treatment of Major Depressive Disorder (MDD) in adolescent patients aged 15-21.

Regulatory Classification

Identification

A repetitive transcranial magnetic stimulation system is an external device that delivers transcranial repetitive pulsed magnetic fields of sufficient magnitude to induce neural action potentials in the prefrontal cortex to treat the symptoms of major depressive disorder without inducing seizure in patients who have failed at least one antidepressant medication and are currently not on any antidepressant therapy.

Special Controls

*Classification.* Class II (special controls). The special control is FDA's “Class II Special Controls Guidance Document: Repetitive Transcranial Magnetic Stimulation System.” See § 882.1(e) for the availability of this guidance document.

Predicate Devices

• NeuroStar Advanced Therapy System (K230029)

Reference Devices

• NeuroStar Advanced Therapy System (K083538)
• NeuroStar Advanced Therapy System (K130233)
• NeuroStar Advanced Therapy System (K133408)
• NeuroStar Advanced Therapy System (K160703)
• NeuroStar Advanced Therapy System (K161519)
• NeuroStar Advanced Therapy System (K201158)
• NeuroStar Advanced Therapy System (K213543)
• NeuroStar Advanced Therapy System (K222230)

Submission Summary (Full Text)

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March 22, 2024

Neuronetics, Inc. Robin Fatzinger, RAC Sr. Director, Regulatory & Medical Affairs 3222 Phoenixville Pike Malvern, PA 19355

Re: K231926

Trade/Device Name: NeuroStar Advanced Therapy System Regulation Number: 21 CFR 882.5805 Regulation Name: Repetitive transcranial magnetic stimulation system Regulatory Class: Class II Product Code: OBP Dated: February 23, 2024 Received: February 23, 2024

Dear Robin Fatzinger:

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.

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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 (QS) 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 ([e-mail]) or phone [phone] or 301-796-7100).

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Sincerely,

# Robert Kang -S

for Pamela Scott, MS 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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## Indications for Use

510(k) Number (if known)

K231926

Device Name NeuroStar Advanced Therapy System

Indications for Use (Describe)

NeuroStar Advanced Therapy is indicated as an adjunct for the treatment of Major Depressive Disorder (MDD) in adolescent patients (age 15-21).

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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| 510(k) Number: | K231926 |
|---------------------|-----------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|
| Date Prepared: | 21 March 2024 |
| Applicant: | Neuronetics, Inc.<br>3222 Phoenixville Pike<br>Malvern, PA 19355 |
| Primary Contact: | Robin Fatzinger, RAC<br>AVP, Regulatory and Medical Affairs<br>Phone: [phone]<br>Email: [e-mail] |
| Secondary Contact: | Cory Anderson<br>Sr. VP, R&D and Clinical<br>Phone:<br>Email: [e-mail] |
| Device Trade Names: | NeuroStar, NeuroStar TMS Therapy System, NeuroStar Advanced Therapy<br>System, NeuroStar Advanced Therapy for Mental Health |
| Device Common Name: | Transcranial Magnetic Stimulator |
| Classification: | 21 CFR 882.5805 |
| Product Code: | OBP |
| Predicate Devices: | Primary Predicate - NeuroStar Advanced Therapy System: K230029<br>Reference Predicates - NeuroStar Advanced Therapy System: K083538,<br>K130233, K133408, K160703, K161519, K201158, K213543, and K222230 |

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#### Device Description

The NeuroStar Advanced Therapy System is a transcranial magnetic stimulation device. Specifically, it is a computerized, electromechanical medical device that produces and delivers non-invasive magnetic fields to induce electrical currents targeting specific regions of the cerebral cortex. Transcranial magnetic stimulation (TMS) is a non-invasive technique used to apply brief magnetic pulses to the brain. The pulses are administered by passing high currents through an electromagnetic coil placed adjacent to a patient's scalp. The pulses induce an electric field in the underlying brain tissue. When the induced field is above a certain threshold and is directed in an appropriate orientation relative the brain's neuronal pathway, localized axonal depolarizations are produced, thus activating neurons in the targeted brain region.

The NeuroStar System consists of a combination of hardware, disposable, and consumable supplies, which are required for the operation of the system. The basic configuration includes the following components:

- Mobile Console
- System Software
- Treatment Chair
- Head Support System
- MT Cap
- . D-Tect MT Accessory
- TrakStar Data Management

#### Indications for Use:

NeuroStar Advanced Therapy is indicated as an adjunct for the treatment of Major Depressive Disorder (MDD) in adolescent patients (15-21).

#### Technological Characteristics and Substantial Equivalence:

NeuroStar TMS Therapy system has previously obtained FDA clearance for treatment of major depressive disorder in adult patients who have failed to receive satisfactory improvement from prior antidepressant medication in the current episode (K083538, K133408, K160703, K161519, K201158, K213543, and K222230).

Neuronetics has provided real-world clinical data that provides evidence that when used as an adjunct, NeuroStar Advanced Therapy has the same safety and efficacy profile in the adolescent population (15-21) as in the adult population and therefore the subject device is substantially equivalent to the predicate device that was cleared under K083538, K130233, K133408, K160703, K161519, K201158, K213543, and K222230. Neuronetics has implemented minor labeling changes to update the indications for use and clinical summaries. None of these changes alter the technical specifications for the subject device.

The components of and mechanisms of operation for the subject device are identical to the previously cleared predicate device, NeuroStar Advanced Therapy System (K083538, K130233, K133408, K160703, K161519, K201158, K213543, and K222230). The performance characteristics, including the

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Electrical and Magnetic Field Distribution testing are the same as the previously cleared NeuroStar Advanced Therapy System. The subject device has the following similarities to the predicate NeuroStar Advanced Therapy System:

- Principles of operation
- Design for delivery of Transcranial Magnetic Stimulation (TMS)
- Materials
- Stimulation parameters (frequency, train duration, interval, number of trains, number of pulses, and total duration

The proposed changes for the NeuroStar Advanced Therapy System are limited to labeling updates, specifically for the NeuroStar Advanced Therapy System to be used as an adjunct for the treatment of Major Depressive Disorder (MDD) in adolescent patients (15-21). The proposed change is supported by information submitted in this premarket notification and with the following rationale:

- The subject device is substantially equivalent to the FDA-cleared Primary Predicate Device, NeuroStar Advanced Therapy System, cleared by FDA under K230029. The subject device is also substantially equivalent to the Reference Predicate Devices previously cleared by FDA under K083538, K130233, K133408, K160703, K161519, K201158, K213543, and K222230.
- The subject device changes remain limited to labeling revisions, in support of the adjunct treatment of adolescent patients (15 -21). No other changes are made to the device or product labeling.

Clinical data has been provided to support the substantial equivalence of the subject NeuroStar Advanced Therapy System in terms of safety and effectiveness for the expanded patient population. Therefore, the NeuroStar TMS Therapy System with the proposed changes to the product labeling is substantially equivalent to the and predicate device.

#### Non-Clinical Testing:

There have been no changes to the hardware or software of the subject device and therefore no nonclinical testing was required.

#### Performance Standards:

The NeuroStar Advanced Therapy System has been previously tested and conforms with the following standards:

- ISO 13485:2016
- IEC60601-1
- IEC60601-1-2

Additionally, the contents of this 510(k) complies with the FDA Guidance Document: "Class II Special Controls Guidance Document: Repetitive Transcranial Magnetic Stimulation (rTMS) Systems - Guidance for Industry and Food and Drug Administration Staff". Prior non-clinical performance testing of the components of NeuroStar Advanced Therapy System was conducted as required according to the standards listed above. All system components have been previously cleared by the FDA.

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#### Clinical Performance Data:

Clinical performance data was provided to support the safety and effectiveness of the NeuroStar Advanced Therapy System device for use as an adjunct for the treatment of Major Depressive Disorder (MDD) in adolescent patients (15-21).

The clinical performance data was based on a large-scale analysis of real-world data (RWD) of 1,169 patients, as well as a literature review.

#### Evidence of Safety and Efficacy in the Use of TMS as an Adjunctive Treatment for Adolescent Patients with MDD: Real-World Data

A large-scale retrospective analysis of real-world data (RWD) derived from the TrakStar registry data of 1,169 per protocol adolescent patients (age 12-21) who received the standard NeuroStar treatment protocol for MDD over a span of 15 years, beginning in 2008. This RWD was collected from patients across 347 TMS centers in the US. These 1,169 patient records were analyzed to determine the difference in measures of depression (PHQ-9 scores) over a pre-post TMS treatment interval of 6 weeks. (TrakStar (2023) Adolescent Study).

An additional 1,006 (45%) adolescent patients in the TrakStar database were not included due to insufficient available data. When compared for average age, gender distribution, type of site at which the patient was treated, and the U.S. geographical location of the sites, there were no statistically significant differences found between the two groups.

Eligible subjects in the TrakStar patient database were selected for analysis according to the following protocol-specified selection criteria.

#### Inclusion Criteria

- . Primary diagnosis of Major Depressive Disorder (MDD), according to DSM-4/ICD-9 or DSM-5/ICD-19 criteria applicable on the date treatment with NeuroStar Advanced Therapy begins.
- 12 to 21 years of age.
- Male or female.
- Treatment with NeuroStar Advanced Therapy.
- Treatment start-date of November 1, 2008, or later.
- . Treatment end date on or before the date on which the retrospective study sample is extracted from the TrakStar database.
- Per Protocol Subjects: Subject received a course of a minimum of 20 treatments with NeuroStar Advanced Therapy.
- l Intent to Treat (ITT) Subjects: Subject received at least one treatment with NeuroStar Advanced Therapy.
- Treatment with NeuroStar Advanced Therapy to the left dorsolateral prefrontal cortex (DLPFC) only.
- Treatment with NeuroStar Advanced Therapy according to standardized NeuroStar Advanced Therapy treatment protocols of DASH and/or Standard as per the original clinical study that supported FDA clearance of NeuroStar Advanced Therapy to reduce depression in adults suffering from MDD.

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- Each of GAD-7 and PHQ-9 scores available at each of pre-treatment (defined as the closest score available within 7 days prior to administration of the first treatment) and posttreatment (defined as the closest score available within ± 7 days of the date of the last treatment) evaluations for the single NeuroStar Advanced Therapy course.
- . Subjects with moderate or greater depression prior to NeuroStar Advanced Therapy (pretreatment), defined as a score on the Physician Health Questionnaire-9 (PHQ-9) ≥ 10 within 7 days prior to the first treatment.
- Subjects with moderate or greater anxiety symptoms prior to NeuroStar Advanced Therapy . (pre-treatment), defined as a score on the Generalized Anxiety Disorder-7 (GAD-7) ≥ 10 within 7 days prior to the first treatment.

#### Exclusion Criteria

- Gap in NeuroStar Advanced Therapy treatment due to COVID of > 14 continuous days, where applicable.
- . More than one DLPFC treatment session on the same day.

Patients included in this RWD study had a primary diagnosis of MDD, had received at least 20 treatments with NeuroStar Advanced Therapy to the left dorsolateral prefrontal cortex (DLPFC) and were required to exhibit baseline moderate or greater depression, defined as a score on the Physician Health Questionnaire-9 (PHQ-9) ≥ 10. The mean patient age was 19.2 years (min.12, max. 21), and 60.8% were female.

The primary endpoint was defined as the proportion of the per protocol population that met the Individual Success Criteria. The primary endpoint was met as 77.8% (95% CI: 72.8%, 83.0%) of the primary per protocol analysis population met the Individual Subject Success Criteria, with the lower limit of the 95% confidence interval exceeding the pre-established Overall Study Success Criteria of a minimum 50% by 22.79%. This proportion was found to be statistically significant at p<0.0001. The mean change in PHQ-9 scores from baseline to endpoint was -10.0 ± 6.6 and 30.0% attained remission of MDD symptoms defined as post-treatment PHQ-9 of <5. Due to the smaller number of patients, aged 12 - 14 years old (n=10), the final cleared indication for adolescents is age 15 – 21 years old.

A graphical representation of the per protocol change in PHQ-9 category of depression severity rating from pre-treatment to post-treatment is provided in Figure 1 below.

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Image /page/9/Figure/0 description: The image is a bar graph that shows the change in PHQ-9 category of depression severity. The x-axis shows the depression severity, and the y-axis shows the percent. The graph shows the pre-treatment and post-treatment percentages for each category of depression severity. For example, the pre-treatment percentage for severe depression is 51.1, and the post-treatment percentage is 9.4.

Figure 1. Change in PHQ-9

#### Literature Review

A systematic literature search was performed to identify all available published research evaluating use of TMS therapy for the intended patient population of adolescents to enable a thorough descriptive evaluation of findings. The systematic literature search was opened to identification of available published literature inclusive of randomized controlled trials, open-label trials, and retrospective studies.

#### Literature Search Methodology

God: The systematic literature search was intended to identify and collate all available and relevant published research evaluating use of TMS Therapy to treat adolescent patients for the symptoms of depression, with a focus on published research evaluating application of the NeuroStar device and other figure 8 coil technology devices to perform a thorough descriptive analysis of current findings of available relevant literature.

Selection Criteria: The parameters for the literature search, as listed below, were intentionally predetermined to be broad to capture all potentially relevant literature:

- . Study Treatment: NeuroStar Therapy per standard protocol (left DLPFC) or rTMS Therapy with a figure 8 coil over the left DLPFC comparable to NeuroStar Therapy.
- . Patient/Subject Population: Adolescents covering the age range of 12 to 21 years, inclusive, who received treatment for symptoms of depression and/or anxiety.
- . Outcome Assessments:
- An outcome measure of depression, any scale (mandatory)
- An outcome measure of anxiety, any scale (preferred)
- Review Timeline: November 2008 to January 2024
- Search Terms:
- Device: transcranial magnetic stimulation, TMS, rTMS, NeuroStar, Neuronetics, Figure 8 coil.
- Condition: depression, depressive disorder, MDD, major depressive disorder, depressive

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episode,

- Population: adolescent, teen, teenager, child, children, childhood, young adult.
- Indication: antidepressant, antidepressant therapy, antidepressant medication, depression medication, Escitalopram, Lexapro, Fluoxetine, Prozac, selective serotonin reuptake inhibitors, ડડ્ઠા.
- . Search Sources: The pre-determined sources searched per the above selection criteria were the following:
- PubMed
- Medline
- Embase
- Central
- Google Scholar

Tables 1 and 2 summarize the studies from the literature search.

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| Study | Study Design and<br>Treatment | Population | Sample<br>Size | Outcome<br>Measure(s) | Study Results | Effect Size<br>Hedges' g<br>(between<br>groups) | | | | | | | | | | | | | | | | | | | | | | | | | | | |
|----------------------|-----------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|------------------------|----------------|-----------------------|---------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|-------------------------------------------------|--|--|--|--|--|--|--|--|--|--|--|--|--|--|--|--|--|--|--|--|--|--|--|--|--|--|---------------------------------------|
| Ren and Pu<br>(2022) | • RCT:<br>• Active: Active TMS +<br>Sertraline vs.<br>• Control: Sertraline<br>only<br>• Active TMS: LDLPFC;<br>10 Hz; 90%MT; 2,000<br>pulses per session; 4<br>weeks<br>• Sertraline:<br>– 8 - 12 yrs.: 25mg/d<br>– 12 – 18 yrs.: 50<br>mg/d | • Age (yrs.): 8-<br>18 | 107 | • HAMD-24 | Mean change in scores on the HAMD-24 from baseline to endpoint (week 4)<br>for each of the control and active treatment groups, and the significance of<br>the difference in the change between the two groups is shown below.<br><br>HAMD-24 Baseline Week 4 Mean Change Active TMS +<br>antidepressant 55.32 ±<br>6.35 15.33 ± 2.03 -39.87<br>(p<0.0001) Antidepressant only 55.25 ±<br>5.89 36.75 ±3.76 -18.50<br>(p<0.0001) The 21.27-point difference in the mean change in HAMD-24 Total score at endpoint relative to baseline in favor of active over control was statistically significant at p<0.005 at end of week 4.<br>HAMD-24 % reductions at week 4 relative to baseline are shown below for each of the study groups:<br>HAMD-24 Active TMS +<br>antidepressant Antidepressant only ≥75% reduction 16% 11% ≥50% reduction 16% 13% ≥25% reduction 13% 15% <25% (no improvement) 5% 11% Conclusion: HAMD-24 total depression scores decreased significantly for both the active and control treatment groups at week 8 relative to baseline. The finding of a significant decrease for the control group is not surprising; however, given that the subjects in this study were not taking any medication prior to study entry, and therefore a treatment effect component of medication implementation was to be expected. However, the 21.37-point difference in depression improvement in favor of the active group is supportive of the enhanced effect of TMS as an adjunct to antidepressant therapy. Note there was no sham device to account for a potential device placebo effect. | | | | | | | | | | | | | | | | | | | | | | | | | | | | HAMD-24<br>-7.15<br>CI [-8.21, -6.08] |

### Table 1. Summary of Published Randomized Controlled Studies

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| Study | Study Design<br>and Treatment | Population | Sample<br>Size | Outcome<br>Measure(s) | Study Results | Effect Size<br>Hedges' g<br>(between<br>groups) | | | | | | | | | | | | |
|------------------------|-----------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|---------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|----------------------------------------|-----------------------|------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|-------------------------------------------------|--|--|--|--|--|--|--|--|--|--|--|------------------------------------------|
| Chen. et al.<br>(2022) | • Prospective RCT<br>• Active: rTMS:<br>- left DLPFC<br>- 90% MT<br>- 60 trains of 4 secs on<br>and 15 secs off<br>- 10 Hz<br>- 2400 pulses<br>- 5 days/week for 2<br>weeks + sertraline<br>50mg daily for 4<br>weeks<br>• Control: sertraline<br>50mg daily for 4<br>weeks | • MDD:<br>- First<br>episode<br>• Age (yrs):<br>- Active: Mean ±<br>SD: 14.65 ±<br>2.34<br>Range: 12-18<br>- Control: Mean<br>+ SD: 15.39 ±<br>2.44<br>Range: 12-18<br>• Gender:<br>- Active: 85%<br>female<br>Control: 78%<br>female | Total: 97<br>Active: 48<br>Control: 49 | • HAM-D<br>• CDRS-R | Mean change in scores on the respective scales from baseline to endpoint<br>(week 4) for each of the control and active treatment groups, and the<br>significance of the difference in the change between the two groups is shown<br>below for the HAM-D and CDRS-R.<br><br>Active Control Change HAM-D -10.54 -6.27 p < 0.001 CDRS-R -27.73 -4.23 p < 0.001<br>Conclusion: Mean decreases in depression scores were statistically<br>significantly greater for subjects in the active than in the control group,<br>supporting the that active TMS as an adjunct to medication is superior to<br>medication alone according to two distinct depression measures. There were<br>no reported adverse events in this study with the exception of transient pain<br>at the treatment site. Note there was no sham device to account for a<br>potential device placebo effect. | | | | | | | | | | | | | HAM-D<br>-2.555<br>CI: [-3.137, -1.973] |
| Lu et al.<br>(2020) | • RCT:<br>• Active: Sertraline +<br>active TMS vs.<br>• Control: Sertraline +<br>sham TMS<br>• Active TMS: LDLPFC<br>10 Hz 80% MT for 2<br>weeks.<br>• Sertraline: Started at<br>25 mg/day and<br>titrated to effect to<br>max of 100-150<br>mg/day. | • Age (yrs.): 12 -<br>18<br>• Subjects were<br>medication-<br>free prior to<br>study start and<br>experiencing<br>their first<br>depressive<br>episode, | 116 | • HAMD-24 | Mean change in scores on the HAMD-24 from baseline to endpoint (for each<br>of the control and active treatment groups, and the significance of the<br>difference in the change within each group is shown below.<br><br>HAMD-24 Baseline Endpoint Mean Change Active TMS<br>+ Sertraline 27.12 ± 3.24 13.02 ± 3.63 -14.10<br>(p<0.0001) Sham TMS<br>+ Sertraline 26.67 ± 3.45 19.57 ± 3.96 -7.10<br>(p<0.0001)<br>Conclusion: HAMD-24 total depression scores decreased significantly for both<br>the active and sham treatment groups. The finding of a significant decrease<br>for the sham group is not surprising; however, given that the subjects in this<br>study were not taking any medication prior to study entry. However, the 7-<br>point difference in depression improvement in favor of the active group was<br>statistically significant at p<0.0001, clearly demonstrating and supporting the<br>enhanced effect of TMS as an adjunct to antidepressant therapy over<br>antidepressant therapy alone. | | | | | | | | | | | | | HAMD-24<br>-4.028<br>CI: [-4.825,-3.232] |

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| Study | Study Design and Treatment | Population | Sample Size | Outcome Measure(s) | Study Results | Effect Size Hedges' g (between groups) | | | | | | | | | | | | | | | | | | | | | | | | | | | |
|-------------------|-----------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|---------------------------------------------------------------------------------------------------------------------------------------|-------------|--------------------|---------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|----------------------------------------|--|--|--|--|--|--|--|--|--|--|--|--|--|--|--|--|--|--|--|--|--|--|--|--|--|--|---------------------------------|
| Qui et al. (2021) | RCT: Active: Active TMS + Sertraline/ aripiprazole vs. Control: Sertraline/ aripiprazole only Active TMS: LDLPFC 10 Hz 6 weeks 80%MT sertraline: 25 - 100 mg/d aripiprazole from 2mg/d to 5mg/d (for patients with psychotic symptoms). | Age (yrs.): 13 – 19. HAMD-24 ≥ 35 First onset, unipolar depressive episode No prior anti-depressants, antipsychotics, or ECT therapy. | 100 | HAMD-24 | Mean change in scores on the HAMD-24 from baseline to endpoint (week 8) for each of the control and active treatment groups, and the significance of the difference in the change within each group is shown below.<br><br>HAMD-24 Baseline Week 8 Mean Change Active TMS + antidepressant 43.00 ± 2.96 7.86 ± 1.60 -35.14 (p<0.0001) Antidepressant only 44.10 ± 2.85 13.00 ± 1.59 -31.10 (p<0.0001)<br>HAMD-24 % reductions at week 8 relative to baseline are shown below.<br><br>HAMD-24 Active TMS + antidepressant Antidepressant only ≥75% reduction 21% 15% ≥50% reduction 19% 12% ≥25% reduction 11% 7% <25% (no improvement) 3% 12%<br><b>Conclusion:</b> HAMD-24 total depression scores decreased significantly for both the active and control treatment groups at week 8 relative to baseline, although the magnitude of the change was greater for the active group relative to control. The finding of a significant decrease for the control group is not surprising; however, given that the subjects in this study were not taking any medication prior to study entry. However, the 4-point difference in depression improvement in favor of the active group clearly demonstrates and supports the enhanced effect of TMS as an adjunct to antidepressant therapy over antidepressant therapy alone. Note there was no sham device to account for a potential device placebo effect. | | | | | | | | | | | | | | | | | | | | | | | | | | | | HAMD-24 -2.01 CI [-2.49, -1.54] |

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| Study | Study Design and<br>Treatment | Population | Sample<br>Size | Outcome<br>Measure(s) | Study Results | Effect Size<br>Hedges' g<br>(between<br>groups) | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | |
|-----------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|---------------------------------|------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|---------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|-------------------------------------------------|--|--|--|--|--|--|--|--|--|--|--|--|--|--|--|--|--|--|--|--|--|--|--|--|--|--|--|--|--|--|--|--|--|--|--------------------------------------------------|
| Pan, F. et al.<br>(2020) | • Prospective, double-<br>blind RCT.<br>• Subjects randomized<br>to escitalopram<br>oxalate (10mg/d) in<br>combination with<br>either active or sham<br>rTMS.<br>• Left-sided DLPFC<br>based on MRI data.<br>• rTMS treatment for 7<br>continuous days<br>• 120 trains of 5 s<br>duration<br>• 10 Hz w/ inter-train<br>intervals of 15 s<br>• 100% resting MT<br>• Total 6,000 pulses<br>per session | • Treatment<br>naïve MDD<br>patients with<br>suicidal<br>ideation<br>• Age (yrs)<br>Active<br>18.14±3.94<br>Sham<br>21.43±6.79<br>• Gender (M/F)<br>Active<br>2/19<br>Sham<br>5/16 | 42<br>Active: 21<br>Control: 21 | • HAMD-24<br>• MADRS<br>• Beck Scale for<br>Suicide<br>Ideation (BSI)<br>• Wisconsin<br>Card Sorting<br>Test (WCST)<br>• Continuous<br>Performance<br>Test (CPT)<br>• Stroop Color-<br>Word Test<br>(SCWT) | Mean change in scores on each of the HAMD-24, MADRS, and BSI for each of<br>the active and sham control study groups from baseline to endpoint (Day 7) is<br>shown in the table below.<br>Active TMS +<br>escitalopram<br>(n=21) Sham TMS +<br>escitalopram<br>(n=21) F p HAMD-24<br>Baseline mean<br>scores 38.33±7.93 35.76 ± 8.85 0.992 0.327 Baseline to<br>Day 7 Change -19.19±8.72 -4.48±6.27 36.682 <0.001 MADRS<br>Baseline mean<br>scores 37.14±7.18 36.43±4.87 0.377 0.708 Baseline to<br>Day 7 Change -19.67±9.22 -4.33±6.53 37.997 <0.001 BSI<br>Baseline mean<br>scores 19±5.94 21.48±5.91 -1.354 0.183 Baseline to Day<br>7 Change -14.76±7.22 -4.71±5.30 37.553 <0.001 | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | HAMD-24<br>-2.117 (Large)<br>CI [-2.878, -1.356] |
| Conclusion: Statistically significant decreases in depression ratings were<br>attained for each of the HAMD-24, MADRS, and BSI assessment scales<br>following 7 continuous days of treatment with Active rTMS + escitalopram<br>versus Sham rTMS + escitalopram (p<0.0001) with no serious adverse events<br>noted. Two adolescents displayed symptoms of hypomania after day 4 of<br>treatment and were excluded from completing the study; however, It could<br>not definitely be determined whether the hypomania was related to the TMS<br>treatment, the escitalopram, or the combination therapy. Mild, transient<br>adverse reactions, such as headache and tiredness, occurred in only 4<br>subjects. The findings of this RCT clearly demonstrate and provide additional<br>support for the enhanced effect of TMS as an adjunct to antidepressant<br>therapy over antidepressant therapy alone. | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | |

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| Study | Study Design and Treatment | Population | Sample Size | Outcome Measure(s) | Study Results | Effect Size Hedges' g (within group) | | | | | | | | | | | | |
|---------------------------|------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|-----------------------------------------------------------------------------------------------------|-------------|---------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|----------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|--------------------------------------|--|--|--|--|--|--|--|--|--|--|--|-----------------------------------|
| Wall, C. et al.<br>(2016) | • Open-label, single-arm.<br>• Left-sided DLPFC rTMS Therapy per standard treatment protocol.<br>• 120% MT<br>• 10 Hz<br>• ITI: 26s<br>• duration: 4s<br>• 3,000 pulses<br>• 30 sessions, 5/wk over 6-8 wks. | • TRMDD<br>• Age (yrs):<br>- Mean ± SD: 15.9 ± 1.1<br>- Range: 13.9-17.4<br>60% male | 10 | • Children's Depression Rating Scale-Revised (CDRS-R)<br>• Quick Inventory of Depressive Symptomatology-- Adolescent (17 Item) - Self Report (QIDS-A17-SR)<br>Clinical Global Impression's Scale - Severity (CGI-S) | Change in mean assessment scores from baseline to treatment end (30 days) and from baseline to 6-months post-treatment were statistically significant for all measures:<br>CDRS-R QIDS-A17-SR CGI-S 30 days -21.1 (p<0.005) -4.0 (p<0.05) -2.0 (p<0.005) 6 months -23.0 (p<0.05) -5.7 (p<0.05) -2.4 (p<0.005) Conclusion: TMS treatment resulted in statistically significant improvements in depression for this group of adolescents that was sustained through 6 months post-treatment, supporting the long-term efficacy of TMS Therapy as an adjunct to antidepressant therapy for the treatment of depressive symptoms in the adolescent patient population. Furthermore, there were no adverse events or tolerability issues with the treatment reported for any subject. | | | | | | | | | | | | | -1.671 (Large)<br>[-2.597,-0.745] |
| Wall, C. et al.<br>(2011) | • Open-label, single-arm.<br>• Left-sided DLPFC rTMS Therapy per standard NeuroStar treatment protocol.<br>• 120% MT<br>• 10 Hz<br>• ITI: 26s<br>• duration: 4s<br>• 3,000 pulses<br>• 30 sessions, 5/wk over 6-8 wks. | MDD<br>Age (yrs):<br>- Mean ± SD: 16.5 ± 1.18<br>Range: 14.6-17.8<br>87.5% female (7 of 8 subjects) | 8 | • CDRS-R<br>• QIDS-A17-SR<br>• CGI-S- | Change in mean assessment scores from baseline to treatment end (30 days) and from baseline to 6-months post-treatment were statistically significant for all measures:<br>CDRS-R QIDS-A17-SR CGI-S 30 days -33.3±7.3 (p<0.005) -6.4±2.8 (p<0.001) -2.3±1.0 (p<0.001) 6 months -33.1±3.8 (p<0.0001) -7.6±2.1 (p<0.0001) -2.7±1.0 (p<0.001) Conclusion: TMS treatment resulted in statistically significant improvements in depression for this group of adolescents that were sustained through 6 months post-treatment, supporting the long-term efficacy of TMS Therapy as an adjunct to antidepressant therapy for the treatment of depressive symptoms in the adolescent patient population. Additionally, TMS treatment was well tolerated by the subjects, and no serious adverse events occurred. Of special note, three (3) of the subjects reported suicidal ideation at baseline which improved during the treatment course. | | | | | | | | | | | | | -4.243<br>[-6.411, -2.075] |

## Table 2. Supportive Single-Arm Studies from the Literature

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| Study | Study Design and<br>Treatment | Population | Sample<br>Size | Outcome<br>Measure(s) | Study Results | Effect Size<br>Hedges' g<br>(within group) |
|-------------------------|-----------------------------------------------------------------------------------------------------------------------|-----------------------------------------------------------------------------------------------------------------------------------------------------------------------|----------------|------------------------------------------------------------------------------------------------------------------------------------------------------------|-------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|--------------------------------------------|
| Dhami. et al.<br>(2019) | • Open-label, single-<br>arm.<br>• iTBS left DLPFC<br>• cTBS right DLPFC--<br>80% MT<br>• 10 sessions over 2<br>weeks | • MDD single or<br>recurrent<br>• Mean ATHF<br>$3.0 \pm 2.2$<br>• Age (yrs):<br>- Mean $\pm$ SD:<br>$20.9 \pm 2.6$<br>- Range:<br>16-24<br>• 50% male /<br>50% female | 20 | • CDRS-R<br>• HRSD-17<br>• Beck<br>Depression<br>Inventory (BDI-<br>II)<br>• Quality of Life<br>Enjoyment and<br>Satisfaction<br>Questionnaire<br>(QLES-Q) | Primary efficacy assessment of the change in mean rating from baseline to<br>treatment end (2 weeks) on the HDRS-17 was found to be statistically<br>significant, as with all other secondary assessments.<br>Mean change and significance of the change for all study assessments at<br>treatment end (2 weeks) relative to baseline:<br>• HDRS-17: M -8.90 (p < 0.0001)<br>• BDI-II: -13.1 (p<0.005)<br>• Q-LES-I: -38.35 (p<0.0005)<br>• CDRS-R: -25.3 (p<0.05)<br>Conclusion: TMS therapy in adolescents with one or more failed medications<br>in the current treatment episode resulted in statistically significant<br>improvements in depression and quality of life. | -1.965<br>[-2.705, -1.225] |

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| Study | Study Design and Treatment | Population | Sample Size | Outcome Measure(s) | Study Results | Effect Size Hedges' g (within group) | | | | | | | | | | | | |
|-------------------------|--------------------------------------------------------------------------------------------------------------------------------------------------------|----------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|-------------|--------------------------------------------|------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|--------------------------------------|--|--|--|--|--|--|--|--|--|--|--|---------------------------------|
| Zhang, T. et al. (2019) | • Open label: 3-arm (Adolescents, Adults, and Older Adults)<br>• Left DLPFC<br>• 120% MT<br>• 10 Hz<br>• ITI: 12s<br>• 2,400 pulses 20 sessions, 4/wks | • Mood and anxiety disorders.<br>• Baseline score inclusion criteria -HAM-D: ≥ 14 - HAM-A ≥ 10<br><b>Adolescents</b> :<br>• n=42<br>• Age (yrs):<br>Mean ± SD: 14.6 ± 2.0<br>Range: 10-17<br>- 69% female<br><b>Adults</b> :<br>• n=27<br>• Age (yrs):<br>Mean ± SD: 39.3 ± 13.1<br>Range: 18-59<br>- 56% male<br><b>Older Adults</b> :<br>• n=48<br>• Age (yrs):<br>Mean ± SD: 71.7 ± 7.1<br>Range: 60-80<br>- 56% female | 42 | • Hamilton Depression Rating Scale (HAM-D) | Outcome assessments occurred after 2 weeks (mid-treatment) and 4 weeks (end of treatment) relative to baseline for the following, with results shown in the table below:<br>• HAM-D Treatment Response (TR), defined as ≥ 50% decrease in total score.<br>• HAM-D Remission Rates (RR), defined as endpoint score <7,.<br>HAM-D Adolescent 2wk/4wk Adult 2wk/4wk Older Adult 2wk/4wk TR 71%/100% 50%/100% 43.7%/76.2% RR 48.4%/86.7% 34.6%/53.8% 8.3%/33.3%<br>Conclusion: While all age groups demonstrated improvement in depression symptoms following rTMS therapy, subjects in the adolescent group demonstrated statistically significant superior outcomes to those of subjects in each of the adult and older groups at both 2 week and 4 week assessments. There were no serious adverse events reported throughout the study duration. Only transient mild headache and musculoskeletal discomfort were noted. | | | | | | | | | | | | | -2.073 (Large) [-2.607, -1.540] |

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| Study | Study Design and Treatment | Population | Sample Size | Outcome Measure(s) | Study Results | Effect Size<br>Hedges' g<br>(within group) | | | | | | | | |
|-------------------------|--------------------------------------------------------------------------------------------------|-----------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|-------------|--------------------|----------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|--------------------------------------------|--|--|--|--|--|--|--|----------------------------|
| Zhang, T. et al. (2020) | Open label Left or Right DLPFC 120% MT 10 Hz or 1 Hz ITI: 12s 2,400 pulses<br>20 sessions, 4/wks | Anxiety disorders. Baseline score inclusion criteria<br>–HAM-D: ≥ 14<br>– HAM-A ≥ 10 <b>Adolescents:</b> n=42 Age (yrs):<br>Mean ± SD: 15.2 ± 1.6 57% female <b>Adults:</b> n=35 Age (yrs):<br>Mean ± SD: 44.6 ± 12.6 60% female <b>Older Adults:</b> n=70 Age (yrs):<br>Mean ± SD: 71.4 ± 6.8 56% female | 42 | HAMD-17 | Primary assessment occurred at 4 weeks post-treatment relative to baseline.<br>Baseline Week 4 Change HAM-D 14.31 ± 5.60 3.23 ± 1.74 F = 61.470,<br>p < 0.001 Conclusion: All age groups demonstrated improvement in depression and anxiety symptoms with rTMS, but subjects in the Adolescent group demonstrated statistically significant superior outcomes to those of subjects in each of the Adult and Older Groups, respectively. Furthermore, there was only one adverse event in the adolescent group which was mild and transient (dizziness). | | | | | | | | | -2.191<br>[-2.746, -1.636] |

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| Study | Study Design and<br>Treatment | Population | Sample<br>Size | Outcome<br>Measure(s) | Study Results | Effect Size<br>Hedges' g<br>(within group) |
|-----------------------------------|-----------------------------------------------------------------------------------------------------------------------------------------------------------------|----------------------------------------------------------------------------------------------------------------|----------------|--------------------------------------------------------------|------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|--------------------------------------------|
| MacMaster,<br>F. et al.<br>(2019) | • Open-label, single-<br>arm.<br>• Left-sided DLPFC<br>• 120% MT<br>• 10 Hz<br>• ITI: 26s<br>• 75 trains<br>• 3,000 pulses<br>• 15 sessions, 5/wk for<br>3 wks. | • Moderate -<br>severe TRMDD<br>• Age (yrs):<br>- Mean ± SD:<br>17.57 ± 1.98<br>- Range: 13-<br>21<br>53% male | 32 | • HAM-D<br>• CDRS<br>• Beck<br>Depression<br>inventory (BDI) | Primary assessment at treatment end relative to baseline:<br>• HAM-D TR: > 50% decrease in score: 56%<br>• HAM-D RR: Endpoint score ≤ 7: 44%<br>• Mean change in HAM-D from baseline to endpoint: -10.87<br>(p < 0.0001)<br>Additional outcomes were also statistically significant for baseline to<br>endpoint change:<br>• CDRS: -13.64 (p<0.0001)<br>• BDI: -13.90 (p<0.0001)<br>Conclusion: 3 measures of depression each demonstrated statistically<br>significant improvement post-treatment relative to baseline. There were<br>only mild to moderate adverse events reported which were self-limiting<br>(headache and neck pain) with no serious adverse events reported. | -1.779<br>CI [-2.331, -1.228] |

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| Study | Study Design and<br>Treatment | Population | Sample<br>Size | Outcome<br>Measure(s) | Study Results | Effect Size<br>Hedges' g<br>(within group) | | | | | | | | | | | | | | | | | | | | | | | | |
|---------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|-----------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------|----------------------------------------------------------------------------------------------------------------------------------------|----------------|---------------------------------------------------------------------------------------------------------------------|-------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------…