Adaptive Design Study of NEST sTMS in Subjects With Major Depressive Disorder

Prospective, randomized, double-blind, sham-controlled, parallel group adaptive design study to confirm the safety and efficacy of sTMS in subject with Major Depressive Disorder (MDD) who have not responded to at least one antidepressant medication in the current episode. MDD was diagnosed according to DSM-IV criteria rendered by structured interview using the Mini International Neuropsychiatric Interview (MINI).

Subjects must have discontinued any antidepressant medication a minimum of 1 week prior to initiation of treatment with the active sTMS or sham device. Following wash-out of the antidepressant medication, an additional evaluation was performed to determine whether the protocol eligibility criteria were met before randomization and treatment.

Randomized subjects were treated 5 days per week for 6 weeks. Subjects who completed 6 weeks of double-blind treatment may have been eligible to receive up to 6 weeks of open-label treatment as clinically indicated during the follow-up phase of the study.

Follow-up evaluation visits were conducted during those six weeks, with frequency of the visits determined by the treatment choice during that time frame (open label subjects had weekly evaluation visits for 6 weeks).

• Synchronized Transcranial Magnetic Stimulation (sTMS) (Device): sTMS delivers brain stimulation via a continuous magnetic field created by the device and set to the individual patient's intrinsic alpha frequency (IAF).
• Sham Stimulation (Device): Sham stimulation is designed to look, sound and feel like the investigational device, but does not deliver magnetic stimulation to the brain.

Primary outcomes

• Incidence of Clinical Response (Reduction of At Least 50% in Baseline HAMD-17 Score) in Per-Protocol Population [Baseline (Day 0) to End of Weeks 1, 2, 3, 4, 5, 6]: Number of participants at the end of each treatment week who saw a reduction of at least 50% in baseline Hamilton Depression Rating Scale (HAMD-17) scores from baseline to week 6, compared between the active treatment and sham-controlled groups. The Hamilton Depression Rating Scale (HAMD-17) system asks 17 questions to rank subject on a scale ranges between 0-52, with higher numbers indicating more severe symptoms. 0-7 is generally accepted to be within the normal range (or in remission), while a score of 20 or higher indicates moderate to severe depression.

Secondary outcomes

• Mean Change (SD) in HAMD-17 Scores From Baseline to End of Treatment [Baseline (Day 0) and End of Weeks 1, 2, 3, 4, 5, 6]: Change from the baseline in HAMD-17 total score from baseline to week 6, compared between the active treatment and sham-controlled groups. The Hamilton Depression Rating Scale (HAMD-17) system asks 17 questions to rank subject on a scale ranges between 0-52, with higher numbers indicating more severe symptoms. 0-7 is generally accepted to be within the normal range (or in remission), while a score of 20 or higher indicates moderate to severe depression.
• Mean Change (SD) in MADRS Scores From Baseline to End of Treatment in the Per-Protocol Population [Baseline (Day 0) and End of Weeks 1, 2, 3, 4, 5, 6]: Change from the baseline in Montgomery-Asberg Depression Rating Scale (MADRS) total score from baseline to week 6, compared between the active treatment and sham-controlled groups. The MADRS scale ranges between 0-54, with higher numbers indicating more severe symptoms. 0-6 is generally accepted to be within the normal range (or in remission), 7-19 represents mild depression, while a score of 20 or higher indicates moderate to severe depression.
• Responder Analysis: Mean Change (SD) in HAMD-17 Scores From Baseline to End of Treatment in Per-Protocol Patients With Individual Alpha Frequency Greater Than 9.8 Hz [Baseline (Day 0) and End of Weeks 1, 2, 3, 4, 5, 6]: Measure of change in mean (SD) of HAMD-17 scores from baseline to end of treatment in per-protocol patients with an Individual alpha frequency (IAF) of greater than 9.8Hz. The Hamilton Depression Rating Scale (HAMD-17) system asks 17 questions to rank subject on a scale ranges between 0-52, with higher numbers indicating more severe symptoms. 0-7 is generally accepted to be within the normal range (or in remission), while a score of 20 or higher indicates moderate to severe depression.
• Mean Change (SD) in HAMD-17 Scores From Baseline to Week 6 of Open-Label Treatments [Baseline (sTMS Week 6/Sham Baseline) and End of Weeks 7, 8, 9, 10, 11, 12]: Change in HAMD-17 total score during 6 weeks of open-label treatment, compared between the active treatment and sham-controlled groups. The Hamilton Depression Rating Scale (HAMD-17) system asks 17 questions to rank subject on a scale ranges between 0-52, with higher numbers indicating more severe symptoms. 0-7 is generally accepted to be within the normal range (or in remission), while a score of 20 or higher indicates moderate to severe depression.
• Incidence of Clinical Response (Reduction of At Least 50% in Baseline HAMD-17 Score) in Open-Label Per-Protocol Population [Baseline (sTMS Week 6/Sham Baseline) and End of Weeks 7, 8, 9, 10, 11, 12]: Number of participants seeing reduction of at least 50% in baseline Hamilton Depression Rating Scale (HAMD-17) scores during 6 weeks of open-label treatment, compared between the active treatment and sham-controlled groups. The Hamilton Depression Rating Scale (HAMD-17) system asks 17 questions to rank subject on a scale ranges between 0-52, with higher numbers indicating more severe symptoms. 0-7 is generally accepted to be within the normal range (or in remission), while a score of 20 or higher indicates moderate to severe depression.

Sex: All, ages: 22 Years to 65 Years

Inclusion Criteria:

* Current episode of Major Depressive Disorder
* Inadequate response to at least one antidepressant medication in the current episode (Treatment Resistant Depression)
* Investigator able to identify IAF using EEG
* Willingness and ability to adhere to treatment schedule (5 treatments per week for six weeks)

Exclusion Criteria:

* Unable to unwilling to give informed consent
* Diagnosed with excluded conditions or treatment histories
* Currently hospitalized due to severity of depression symptoms
* Use of prohibited medications (as defined by protocol) within specified time frame of randomization
* Use of certain cardiac devices
* Use of certain intracranial devices
* Currently pregnant or unwilling to practice acceptable means of birth control, and women who are breastfeeding

Participant flow

Outcome results

• Incidence of Clinical Response (Reduction of At Least 50% in Baseline HAMD-17 Score) in Per-Protocol Population (Primary), Count of participants, Participants: Active sTMS 5; Sham Stimulation 2 (p .814)
• Mean Change (SD) in HAMD-17 Scores From Baseline to End of Treatment (Secondary), Mean, score on HAMD-17 scale: Active sTMS 22.96 +/- 2.81; Sham Stimulation 22.04 +/- 4.01 (p .872)
• Mean Change (SD) in MADRS Scores From Baseline to End of Treatment in the Per-Protocol Population (Secondary), Mean, score on MADRS scale: Active sTMS 31.89 +/- 4.57; Sham Stimulation 30.72 +/- 5.64 (p .641)
• Responder Analysis: Mean Change (SD) in HAMD-17 Scores From Baseline to End of Treatment in Per-Protocol Patients With Individual Alpha Frequency Greater Than 9.8 Hz (Secondary), Mean, score on HAMD-17 scale: Active sTMS (IAF > 9.8Hz) 23.68 +/- 2.65; Sham Stimulation (IAF>9.8Hz) 21.91 +/- 3.50 (p .032)
• Mean Change (SD) in HAMD-17 Scores From Baseline to Week 6 of Open-Label Treatments (Secondary), Mean, score on HAMD-17 scale: Active sTMS 16.50 +/- 4.69; Sham Stimulation 16.76 +/- 5.35 (p .015)
• Incidence of Clinical Response (Reduction of At Least 50% in Baseline HAMD-17 Score) in Open-Label Per-Protocol Population (Secondary), Count of participants, Participants: Active sTMS 12; Sham Stimulation 9 (p .028)

Adverse events

Time frame: All subjects screened at Screening, Baseline, and each Evaluation Visit (End of Weeks 1, 2, 3, 4, 5, 6; if continuing open-label 7, 8, 9, 10, 11, 12)

Serious adverse events by term

Other adverse events by term

Limitations and caveats: * Sham device used exaggerated vibration at the IAF which may have provided active treatment in the form of trigeminal nerve stimulation * Short wash-out period may have negatively impacted results. * Short treatment duration may limit efficacy

• Study Protocol (PDF, 2018-01-07)
• Statistical Analysis Plan (PDF, 2018-01-26)

• Andrew Leuchter, MD, Principal investigator, University of California, Los Angeles