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

• Sponsor: Wave Neuroscience (Industry)
• Overall Status: Completed
• CT.gov ID: NCT03288714
• Collaborator: (none)
• Enrollment: 121
• Locations: 14
• Arms: 2
• Actual Duration (Months): 18.1
• Patients Per Site: 8.6
• Patients Per Site Per Month: 0.5

Study Details

Study Description

Brief Summary

This is a double-blind, sham controlled, multi-center study to confirm the safety and efficacy of synchronized transcranial magnetic stimulation (sTMS) for the treatment of patients currently experiencing an episode of depression who have failed to respond to at least one (1) antidepressant medication. Patients will be randomly assigned to either active or sham therapy and will undergo daily treatments for a period of time. Following completion of blinded treatments, patients may be eligible for a course of open label treatments.

Condition or Disease	Intervention/Treatment	Phase
Depressive Disorder; Depression; Depressive Disorder, Major; Depressive Episode; Major Depressive Disorder	Device: Synchronized Transcranial Magnetic Stimulation (sTMS); Device: Sham Stimulation	N/A

Detailed Description

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).

Study Design

• Study Type: Interventional
• Actual Enrollment: 121 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Intervention Model Description: Sham ControlledSham Controlled
• Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
• Masking Description: Double-Blind
• Primary Purpose: Treatment
• Official Title: A Prospective, Multicenter, Double-Blind, Sham-Controlled Adaptive Design Study to Confirm the Safety and Efficacy of NEST sTMS in Subjects With Major Depressive Disorder Who Have Not Responded to at Least One Antidepressant Medication in the Current Episode
• Actual Study Start Date: Nov 27, 2017
• Actual Primary Completion Date: Mar 1, 2019
• Actual Study Completion Date: Jun 1, 2019

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Active sTMS Synchronized Transcranial Magnetic Stimulation (sTMS) treatments to be administered using an active device 5 times per week for six treatment weeks.	Device: Synchronized Transcranial Magnetic Stimulation (sTMS); 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 Comparator: Sham Stimulation Sham treatments to be administered using a sham device 5 times per week for six treatment weeks.	Device: Sham Stimulation; Sham stimulation is designed to look, sound and feel like the investigational device, but does not deliver magnetic stimulation to the brain.

Outcome Measures

Primary Outcome Measures

1. 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 Outcome Measures

1. 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.

2. 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.

3. 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.

4. 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.

5. 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.

Eligibility Criteria

Criteria

• Ages Eligible for Study: 22 Years to 65 Years
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

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

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Kadima Neuropsychiatry Institute	La Jolla	California	United States	92037
2	UCLA Westwood - Semel Institute for Neuroscience and Human Behavior	Los Angeles	California	United States	90024
3	Stanford University	Stanford	California	United States	94305
4	Emory University	Atlanta	Georgia	United States	30329
5	Sheppard Pratt Health System	Baltimore	Maryland	United States	21204
6	Beth Israel Deaconess Medical Center	Boston	Massachusetts	United States	02215
7	Mayo Clinic	Rochester	Minnesota	United States	55905
8	Washington University/Barnes Jewish Hospital	Saint Louis	Missouri	United States	63110
9	New York University	New York	New York	United States	10016
10	Laureate Institute for Brain Research	Tulsa	Oklahoma	United States	74136
11	University of Pennsylvania	Philadelphia	Pennsylvania	United States	19104
12	Butler Hospital	Providence	Rhode Island	United States	02906
13	University of Texas Southwestern Medical Center	Dallas	Texas	United States	75390
14	Brain Health Consultants	Houston	Texas	United States	77046

Sponsors and Collaborators

• Wave Neuroscience

Investigators

• Principal Investigator: Andrew Leuchter, MD, University of California, Los Angeles

Study Documents (Full-Text)

• Study Protocol - Jan 7, 2018
• Statistical Analysis Plan - Jan 26, 2018

More Information

Publications

None provided.

• Responsible Party: Wave Neuroscience
• ClinicalTrials.gov Identifier: NCT03288714
• Other Study ID Numbers: NND-3002
• First Posted: Sep 20, 2017
• Last Update Posted: Sep 5, 2021
• Last Verified: Aug 1, 2021

• Individual Participant Data (IPD) Sharing Statement: No
• Plan to Share IPD: No
• Studies a U.S. FDA-regulated Drug Product: No
• Studies a U.S. FDA-regulated Device Product: Yes
• Product Manufactured in and Exported from the U.S.: No
• Keywords provided by Wave Neuroscience: Transcranial Magnetic Stimulation; TMS; sTMS
• Additional relevant MeSH terms: Disease; Depression; Depressive Disorder; Depressive Disorder, Major

Study Results

Participant Flow

Recruitment Details	Participants were recruited through local referral networks, as well as online study descriptions, printed flyers, and radio advertisements approved by Institutional Review Boards (IRB). Recruitment was accomplished through initial interview and in-person screening assessments determining eligibility.
Pre-assignment Detail	Following enrollment and completion of informed consent, participants were randomized to a treatment arm. Participants were instructed to discontinue any current antidepressant medication a minimum of 1 week prior to initiation of treatment, and confirmation of eligibility was completed after the wash-out.

Arm/Group Title	Active sTMS	Sham Stimulation
Arm/Group Description	Synchronized Transcranial Magnetic Stimulation (sTMS) treatments to be administered using an active device 5 times per week for six treatment weeks. Synchronized Transcranial Magnetic Stimulation (sTMS): 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 treatments to be administered using a sham device 5 times per week for six treatment weeks. Sham Stimulation: Sham stimulation is designed to look, sound and feel like the investigational device, but does not deliver magnetic stimulation to the brain.
Period Title: Overall Study
STARTED	59	62
COMPLETED	49	59
NOT COMPLETED	10	3

Baseline Characteristics

Arm/Group Title	Active sTMS	Sham Stimulation	Total
Arm/Group Description	Synchronized Transcranial Magnetic Stimulation (sTMS) treatments to be administered using an active device 5 times per week for six treatment weeks. Synchronized Transcranial Magnetic Stimulation (sTMS): 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 treatments to be administered using a sham device 5 times per week for six treatment weeks. Sham Stimulation: Sham stimulation is designed to look, sound and feel like the investigational device, but does not deliver magnetic stimulation to the brain.	Total of all reporting groups
Overall Participants	46	57	103
Age (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	45 (11.3)	46.1 (13.0)	45.6 (12.15)
Sex: Female, Male (Count of Participants)
Female	32 69.6%	43 75.4%	75 72.8%
Male	14 30.4%	14 24.6%	28 27.2%
Race/Ethnicity, Customized (Count of Participants)
Asian	3 6.5%	3 5.3%	6 5.8%
Black or African American	4 8.7%	4 7%	8 7.8%
Hispanic	4 8.7%	5 8.8%	9 8.7%
American Indian/Alaska Native	0 0%	1 1.8%	1 1%
White	34 73.9%	44 77.2%	78 75.7%
Other	1 2.2%	0 0%	1 1%
Region of Enrollment (participants) [Number]
United States	46 100%	57 100%	103 100%
Education Level (Count of Participants)
Some high school or less	0 0%	1 1.8%	1 1%
High school diploma	2 4.3%	3 5.3%	5 4.9%
Vocational school	3 6.5%	0 0%	3 2.9%
Some college	15 32.6%	12 21.1%	27 26.2%
College degree	15 32.6%	25 43.9%	40 38.8%
Professional or graduate degree	11 23.9%	16 28.1%	27 26.2%

Outcome Measures

1. Primary Outcome

Title	Incidence of Clinical Response (Reduction of At Least 50% in Baseline HAMD-17 Score) in Per-Protocol Population
Description	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.
Time Frame	Baseline (Day 0) to End of Weeks 1, 2, 3, 4, 5, 6

Outcome Measure Data

Analysis Population Description

121 subjects were randomized into the study. Of those, 13 subjects dropped out of the study for various reasons and 5 were excluded from per-protocol analysis, as they failed to meet protocol requirements. Per-protocol analysis was performed on the remaining 103 subjects.

Arm/Group Title	Active sTMS	Sham Stimulation
Arm/Group Description	Synchronized Transcranial Magnetic Stimulation (sTMS) treatments to be administered using an active device 5 times per week for six treatment weeks. Synchronized Transcranial Magnetic Stimulation (sTMS): 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 treatments to be administered using a sham device 5 times per week for six treatment weeks. Sham Stimulation: Sham stimulation is designed to look, sound and feel like the investigational device, but does not deliver magnetic stimulation to the brain.
Measure Participants	46	57
Week 1	5 10.9%	2 3.5%
Week 2	7 15.2%	10 17.5%
Week 3	9 19.6%	12 21.1%
Week 4	11 23.9%	10 17.5%
Week 5	12 26.1%	16 28.1%
Week 6	11 23.9%	12 21.1%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Active sTMS, Sham Stimulation
	Comments	Null hypothesis is that the active sTMS treatment group does not differ from the sham group with respect to the proportion of patients with clinical response at Week 6.
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	.814
	Comments
	Method	Fisher Exact
	Comments	The proportion of patients is compared across treatment groups using Fisher's Exact.

2. Secondary Outcome

Title	Mean Change (SD) in HAMD-17 Scores From Baseline to End of Treatment
Description	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.
Time Frame	Baseline (Day 0) and End of Weeks 1, 2, 3, 4, 5, 6

Outcome Measure Data

Analysis Population Description

121 subjects were randomized into the study. Of those, 13 subjects dropped out of the study for various reasons and 5 were excluded from per-protocol analysis, as they failed to meet protocol requirements. Per-protocol analysis was performed on the remaining 103 subjects.

Arm/Group Title	Active sTMS	Sham Stimulation
Arm/Group Description	Synchronized Transcranial Magnetic Stimulation (sTMS) treatments to be administered using an active device 5 times per week for six treatment weeks. Synchronized Transcranial Magnetic Stimulation (sTMS): 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 treatments to be administered using a sham device 5 times per week for six treatment weeks. Sham Stimulation: Sham stimulation is designed to look, sound and feel like the investigational device, but does not deliver magnetic stimulation to the brain.
Measure Participants	46	57
Baseline	22.96 (2.81)	22.04 (4.01)
Change from Baseline to Week 1	-5.30 (5.14)	-4.33 (3.60)
Change from Baseline to Week 2	-6.63 (4.99)	-6.65 (4.93)
Change from Baseline to Week 3	-7.76 (5.48)	-7.74 (5.54)
Change from Baseline to Week 4	-7.61 (5.63)	-7.93 (6.19)
Change from Baseline to Week 5	-7.93 (5.81)	-7.95 (6.56)
Change from Baseline to Week 6	-7.57 (5.50)	-6.81 (6.48)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Active sTMS, Sham Stimulation
	Comments	Null hypothesis is that the active sTMS treatment group does not differ from the sham group with respect to the proportion of patients with clinical response at Week 6.
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	.872
	Comments
	Method	ANCOVA
	Comments	P-value is from analysis of covariance adjusting for baseline.

3. Secondary Outcome

Title	Mean Change (SD) in MADRS Scores From Baseline to End of Treatment in the Per-Protocol Population
Description	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.
Time Frame	Baseline (Day 0) and End of Weeks 1, 2, 3, 4, 5, 6

Outcome Measure Data

Analysis Population Description

121 subjects were randomized into the study. Of those, 13 subjects dropped out of the study for various reasons and 5 were excluded from per-protocol analysis, as they failed to meet protocol requirements. Per-protocol analysis was performed on the remaining 103 subjects.

Arm/Group Title	Active sTMS	Sham Stimulation
Arm/Group Description	Synchronized Transcranial Magnetic Stimulation (sTMS) treatments to be administered using an active device 5 times per week for six treatment weeks. Synchronized Transcranial Magnetic Stimulation (sTMS): 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 treatments to be administered using a sham device 5 times per week for six treatment weeks. Sham Stimulation: Sham stimulation is designed to look, sound and feel like the investigational device, but does not deliver magnetic stimulation to the brain.
Measure Participants	46	57
Baseline	31.89 (4.57)	30.72 (5.64)
Change from Baseline to Week 1	-6.02 (8.25)	-5.39 (5.80)
Change from Baseline to Week 2	-7.91 (7.46)	-8.63 (8.20)
Change from Baseline to Week 3	-10.76 (8.57)	-9.47 (9.19)
Change from Baseline to Week 4	-8.89 (9.81)	-10.12 (9.04)
Change from Baseline to Week 5	-9.11 (8.64)	-10.81 (8.88)
Change from Baseline to Week 6	-9.52 (8.75)	-9.77 (9.56)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Active sTMS, Sham Stimulation
	Comments	The null hypothesis is that the active sTMS treatment group does not differ
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	.641
	Comments
	Method	ANCOVA
	Comments	P-value is from analysis of covariance adjusting for baseline.

4. Secondary Outcome

Title	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
Description	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.
Time Frame	Baseline (Day 0) and End of Weeks 1, 2, 3, 4, 5, 6

Outcome Measure Data

Analysis Population Description

Subjects in the per-protocol group with IAF greater than 9.8 Hz.

Arm/Group Title	Active sTMS (IAF > 9.8Hz)	Sham Stimulation (IAF>9.8Hz)
Arm/Group Description	Synchronized Transcranial Magnetic Stimulation (sTMS) treatments to be administered using an active device 5 times per week for six treatment weeks. Synchronized Transcranial Magnetic Stimulation (sTMS): sTMS delivers brain stimulation via a continuous magnetic field created by the device and set to the individual patient's intrinsic alpha frequency (IAF), subgroup of those participants were found to be greater than 9.8Hz	Sham treatments to be administered using a sham device 5 times per week for six treatment weeks. Sham Stimulation: Sham stimulation is designed to look, sound and feel like the investigational device, but does not deliver magnetic stimulation to the brain. All patients analyzed and compared with other belonging to same subgroup of those with IAF greater than 9.8Hz.
Measure Participants	19	33
Baseline	23.68 (2.65)	21.91 (3.50)
Change from Baseline to Week 1	-7.05 (6.11)	-4.12 (3.32)
Change from Baseline to Week 2	-8.32 (5.75)	-6.15 (4.27)
Change from Baseline to Week 3	-10.11 (5.37)	-7.70 (4.22)
Change from Baseline to Week 4	-9.89 (4.74)	-6.97 (4.88)
Change from Baseline to Week 5	-9.53 (6.01)	-6.97 (6.14)
Change from Baseline to Week 6	-9.47 (5.11)	-5.18 (5.72)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Active sTMS, Sham Stimulation
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	.032
	Comments	Alpha level: .05
	Method	ANCOVA
	Comments	P-value is from analysis of covariance adjusting for baseline

5. Secondary Outcome

Title	Mean Change (SD) in HAMD-17 Scores From Baseline to Week 6 of Open-Label Treatments
Description	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.
Time Frame	Baseline (sTMS Week 6/Sham Baseline) and End of Weeks 7, 8, 9, 10, 11, 12

Outcome Measure Data

Analysis Population Description

Of the 103 subjects in the original per-protocol group, 83 continued to open-label treatment for analysis.

Arm/Group Title	Active sTMS	Sham Stimulation
Arm/Group Description	Synchronized Transcranial Magnetic Stimulation (sTMS) treatments to be administered using an active device 5 times per week for six treatment weeks. Synchronized Transcranial Magnetic Stimulation (sTMS): 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 treatments to be administered using a sham device 5 times per week for six treatment weeks. Sham Stimulation: Sham stimulation is designed to look, sound and feel like the investigational device, but does not deliver magnetic stimulation to the brain.
Measure Participants	38	45
sTMS Active Treatment Week 6/Sham Baseline	16.50 (4.69)	16.76 (5.35)
Change from Baseline to Open-Label Week 1 (Active Week 7/Sham Week 1)	-8.82 (5.34)	-3.98 (5.53)
Change from Baseline to Open-Label Week 2 (Active Week 8/Sham Week 2)	-9.36 (5.96)	-3.69 (5.17)
Change from Baseline to Open-Label Week 3 (Active Week 9/Sham Week 3)	-9.09 (6.58)	-4.29 (5.25)
Change from Baseline to Open-Label Week 4 (Active Week 10/Sham Week 4)	-10.68 (7.34)	-4.51 (5.92)
Change from Baseline to Open-Label Week 5 (Active Week 11/Sham Week 5)	-12.34 (6.54)	-5.47 (5.71)
Change from Baseline to Open-Label Week 6 (Active Week 12/Sham Week 6)	-12.72 (6.97)	-6.42 (5.01)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Active sTMS, Sham Stimulation
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	.015
	Comments	Alpha level: .05
	Method	ANCOVA
	Comments	P-value is from analysis of covariance adjusting for baseline

6. Secondary Outcome

Title	Incidence of Clinical Response (Reduction of At Least 50% in Baseline HAMD-17 Score) in Open-Label Per-Protocol Population
Description	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.
Time Frame	Baseline (sTMS Week 6/Sham Baseline) and End of Weeks 7, 8, 9, 10, 11, 12

Outcome Measure Data

Analysis Population Description

Of the 103 subjects in the original per-protocol group, 83 continued to open-label treatment for analysis.

Arm/Group Title	Active sTMS	Sham Stimulation
Arm/Group Description	Synchronized Transcranial Magnetic Stimulation (sTMS) treatments to be administered using an active device 5 times per week for six treatment weeks. Synchronized Transcranial Magnetic Stimulation (sTMS): 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 treatments to be administered using a sham device 5 times per week for six treatment weeks. Sham Stimulation: Sham stimulation is designed to look, sound and feel like the investigational device, but does not deliver magnetic stimulation to the brain.
Measure Participants	38	45
Open Label Week 1 (Active Week 7/Sham Week 1)	12 26.1%	9 15.8%
Open Label Week 2 (Active Week 8/Sham Week 2)	17 37%	9 15.8%
Open Label Week 3 (Active Week 9/Sham Week 3)	14 30.4%	10 17.5%
Open Label Week 4 (Active Week 10/Sham Week 4)	19 41.3%	10 17.5%
Open Label Week 5 (Active Week 11/Sham Week 5)	23 50%	10 17.5%
Open Label Week 6 (Active Week 12/Sham Week 6)	20 43.5%	12 21.1%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Active sTMS, Sham Stimulation
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	.028
	Comments	Alpha level: .05
	Method	Fisher Exact
	Comments	The proportion of patients is compared across treatment groups using Fisher's Exact.

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)
Adverse Event Reporting Description	All adverse events were entered by study personnel verbatim based on patient reports. Any adverse event occurring before randomization occurred was not included in the final report.
Arm/Group Title	Active sTMS		Sham Stimulation
Arm/Group Description	Synchronized Transcranial Magnetic Stimulation (sTMS) treatments to be administered using an active device 5 times per week for six treatment weeks. Synchronized Transcranial Magnetic Stimulation (sTMS): 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 treatments to be administered using a sham device 5 times per week for six treatment weeks. Sham Stimulation: Sham stimulation is designed to look, sound and feel like the investigational device, but does not deliver magnetic stimulation to the brain.
All Cause Mortality
	Active sTMS		Sham Stimulation
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/59 (0%)		0/62 (0%)
Serious Adverse Events
	Active sTMS		Sham Stimulation
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	2/59 (3.4%)		0/62 (0%)
General disorders
Anaphylactic Reaction (peanut allergy)	1/59 (1.7%)		0/62 (0%)
Psychiatric disorders
Hospitalization (Suicidal Ideation)	1/59 (1.7%)		0/62 (0%)
Other (Not Including Serious) Adverse Events
	Active sTMS		Sham Stimulation
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	35/59 (59.3%)		43/62 (69.4%)
Eye disorders
Visual Disturbance	3/59 (5.1%)		5/62 (8.1%)
Gastrointestinal disorders
Diarrhea	3/59 (5.1%)		3/62 (4.8%)
Nausea	6/59 (10.2%)		2/62 (3.2%)
GI Infection	0/59 (0%)		2/62 (3.2%)
General disorders
Dizziness	3/59 (5.1%)		1/62 (1.6%)
Cramping	0/59 (0%)		2/62 (3.2%)
Oral Herpes	2/59 (3.4%)		0/62 (0%)
Blepharospasm	2/59 (3.4%)		1/62 (1.6%)
Hypersensitivity	0/59 (0%)		2/62 (3.2%)
Muscle Twitching	2/59 (3.4%)		0/62 (0%)
Nasopharyngitis	0/59 (0%)		2/62 (3.2%)
Musculoskeletal and connective tissue disorders
Neck Pain	7/59 (11.9%)		3/62 (4.8%)
Jaw Discomfort	2/59 (3.4%)		0/62 (0%)
Musculoskeletal Pain	0/59 (0%)		2/62 (3.2%)
Back Pain	2/59 (3.4%)		2/62 (3.2%)
Shoulder Pain	2/59 (3.4%)		0/62 (0%)
Nervous system disorders
Headache	23/59 (39%)		28/62 (45.2%)
Paraesthesia	1/59 (1.7%)		5/62 (8.1%)
Psychiatric disorders
Insomnia	5/59 (8.5%)		8/62 (12.9%)
Anxiety	1/59 (1.7%)		2/62 (3.2%)
Respiratory, thoracic and mediastinal disorders
Respiratory Infection	10/59 (16.9%)		10/62 (16.1%)
Skin and subcutaneous tissue disorders
Application Site Discomfort	3/59 (5.1%)		2/62 (3.2%)

Limitations/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

More Information

Certain Agreements

Principal Investigators are NOT employed by the organization sponsoring the study.

There is NOT an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.