The MOOD Study - External Combined Occipital and Trigeminal Nerve Stimulation (eCOT-NS) for the Treatment of Major Depressive Disorder (MDD)

The MOOD Study - External Combined Occipital and Trigeminal Nerve Stimulation (eCOT-NS) for the Treatment of Major Depressive Disorder (MDD)

The MOOD study will evaluate the safety and efficacy of a noninvasive, self-administered external Combined Occipital and Trigeminal Neurostimulation (eCOT-NS) treatment for Major Depressive Disorder (Relivion®DP).

This is a prospective, multi-center, 2-arm randomized, double-blind, parallel-group, sham-controlled study.

The study will include the following stages:

1. Screening, Eligibility evaluation and Randomization to Relivion®DP vs. Sham control (1:1 randomization) (Baseline - Day 0).
2. Daily treatment period: Active/Sham (Group A/B) treatment protocol (Baseline to end of 8 weeks).
3. Open label phase: Active treatment period of additional 8 weeks.

After completion of the open label period the subject's participation in the study will be over.

The study will include the following study visits & phases:

• Visit 1- Screening (Day (-14)-0) - Screening & Preliminary Eligibility Assessment.
• Visit 2- Baseline (Day (-4)-0) - Eligibility, baseline assessment, Randomization to Relivion®DP vs. Sham control (1:1 randomization) and training.
• Double blind phase (Day 0 to day 56±7)- 5-7 days a week treatment: Active/Sham (Group A/B) treatment protocol.
• Visit 3- Follow Up Visit (day 28±7)- MDD assessment.
• Visit 4- End of Double-Blind phase (day 56±7)- MDD assessment.
• Open label phase- Active treatment period: According to HDRS response in DB phase, in between Maintenance treatment 3-4 times a week and up to 5-7 days a week of intensified treatment (Day 56±7 to day 112±7)
• Visit 5- follow up visit (day 84±7) - MDD assessment.
• Visit 6- End of study (day 112±7)- MDD assessment and end of study.

Inclusion Criteria:

1. Males and females 18-70 years of age:

   1. Up to 124 randomized subjects aged 22-70
   2. Up to 36 randomized subjects aged 18-21

2. Primary diagnosis of unipolar major depressive disorder by DSM-V criteria.

3. Current MDD episode lasts up to three years.

4. Score on the Hamilton Depression Rating Scale (HDRS21) ≥ 20

5. Symptoms of current major depressive episode that, as determined by the Investigator, for the current episode and according to the Antidepressant Treatment Resistance Form (ATRF) or Antidepressant Treatment Intolerance Form (ATIF):

   • Did not respond or have insufficiently responded by less than 50% improvement; dose and duration defined & rated at minimum confidence level 3 on the ATRF;
   • Did not respond or has insufficiently responded to at least one but no more than four adequate trials of antidepressant medications (4 ≥ ATRF ≥1) or
   • Did not respond or has insufficiently responded due to poor tolerability to at least two inadequate antidepressant medication trials (ATIF ≥2).

6. Subject must be on at least one (1) antidepressant medication (minimum therapeutic dose not required if tolerability precluded further dose titration) and is willing to remain on the same daily dose of antidepressant medication(s) for a minimum of 28 days prior to randomization and thereafter for the duration of the study.

7. For subjects receiving current depression focused psychotherapy: psychotherapy initiated at least 1 month prior to baseline visit with a stable frequency of visits regimen, in the opinion of the Investigator.

8. Subject is able to provide written Informed Consent and is capable of complying with the specified study requirements, as determined by the Investigator.

9. Subject has cognitive and/or motor skills needed to operate a smartphone and can be contacted by phone, as determined by the Investigator.

Exclusion Criteria:

1. History of intracranial surgery.
2. Current denervation in one or more of the following: the supraorbital or supratrochlear branches of the trigeminal nerve, or the greater occipital branch of the occipital nerve.
3. An implanted neurostimulators or any implanted metallic or electronic device in the head, a cardiac pacemaker or an implanted or wearable defibrillator, except for dental implants.
4. Skin lesion, scars, or inflammation at the region of the stimulating electrodes.
5. Subjects with a history of traumatic brain injury (TBI), defined as a disruption in the normal function of the brain that can be caused by a bump, blow, or jolt to the head, or penetrating head injury, within 3 months of study enrollment.
6. Pregnancy or Lactation.
7. Women of reproductive age not using a reliable contraceptive method as determined by the Investigator.
8. In the opinion of the Investigator, subjects with a psychiatric history consistent with, suspicious for, or diagnostic of, bipolar depression or depression associated with psychosis.
9. Borderline personality disorder, defined by DSM-V criteria, that in the judgement of the Investigator is likely to complicate the assessment of clinical response to study treatments or limits the patient's ability to comply with study procedures
10. Subjects who, within one (1) year of study enrollment, have a history consistent with, suspicious for or diagnostic of, any of the following: psychosis, psychotic disorder, schizophrenia or schizoaffective disorder, in the opinion of the Investigator.
11. Subjects who demonstrate or have a history of any cognitive disorder or impairment, memory loss, dementia, confusion or delirium that, in the opinion of the Investigator, may compromise the integrity of the study data or impact the ability of the subject to comply with the study requirements.
12. Past 12 months active suicidal intent or plan as defined by a "yes" answer to Q4 or Q5 on the Columbia-Suicide Severity Rating Scale, (C-SSRS) or with a history of suicide attempt in the past twelve months.
13. Subjects currently (past month) meeting diagnostic criteria for Obsessive-Compulsive Disorder or post-traumatic stress disorder and that is their primary diagnosis.
14. Subjects meeting the DSM-V criteria for alcohol use disorder or other substance use disorder (not including tobacco/nicotine) within six (6) months prior to study enrollment.
15. The subject has any past or present medical condition, disease, illness, disorder or injury that, in the opinion of the Investigator, may reduce or hinder the subject's ability to fully comply with all study requirements for the duration of the study or may confound the integrity of the study data.
16. Participation in a previous study with the Relivion®DP or the Relivion® device.
17. Treatment with Transcranial Magnetic Stimulation (TMS) in the past 6 months.
18. Current treatment with any other approved or investigational brain stimulation therapies (i.e. Vagus or trigeminal nerve Stimulation, tDCS, TES).
19. Failure to receive clinical benefit from an adequate trial of ECT in the current or a past depressive episode in the opinion of the Investigator.
20. Subject having received Botox treatment in the head or neck region within 90 days prior to study enrollment.
21. Subject having received supraorbital or occipital nerve blocks within 1 month prior to enrollment.
22. Head circumference smaller than 51 centimeters or larger than 60 centimeters.
23. Current neurological condition or disease which, in the opinion of the investigator, is likely to manifest a depressive syndrome or symptoms that would substantially confound the diagnosis or serial assessment of major depressive disorder.
24. Subjects participating in other clinical trials evaluating experimental treatments or procedures.