rTMS for Military TBI-related Depression

Study Overview
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Brief Summary
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This study aims to compare different types of repetitive transcranial magnetic stimulation (rTMS) that may alleviate depressive symptoms in United States Military Service Members with a history of concussion.

Detailed Description
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In United States Military personnel, rates of depression may increase after mild traumatic brain injury, or concussion. rTMS may hold a therapeutic potential for alleviating symptoms of depression after concussion. This study is a randomized, double-blind, Bayesian adaptive trial aimed at comparing the safety, efficacy, and tolerability of various rTMS protocols in Military Service Members with depressive symptoms and a history of concussion.

Official Title
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ADEPT: Adaptive Trial for the Treatment of Depressive Symptoms Associated With Concussion Using Repetitive Transcranial Magnetic Stimulation Protocols

Conditions
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Depressive Symptoms, Mild Traumatic Brain Injury, Concussion, Mild

Intervention / Treatment
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* Device: Repetitive Transcranial Magnetic Stimulation (rTMS)
* Device: Sham rTMS


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Age 18-50 at the time of consent Current or former US military service member eligible for care at a military treatment facility Able to provide written, informed consent in English History of concussion (mild TBI), > 6 months, but < 20 years prior to consent, as defined by: positive loss of consciousness of <30 minutes as confirmed by TBI screener and/or medical records and/or; positive alteration of consciousness of <24 hours as confirmed by TBI screener and/or medical records and/or; positive post-traumatic amnesia of 0 to 1 day as confirmed by TBI screener and/or medical records Baseline MADRS >13 Maintained a steady psychotropic medication regimen for six weeks and a steady behavioral therapy regimen for twelve weeks prior to enrollment in the study participants will be urged to maintain their medication and behavioral therapy regimen throughout the study, unless otherwise recommended by their personal physician changes in medication and/or behavioral therapy regimens will be reviewed and assessed with the study team before participants can continue their enrollment Female participants with child-bearing potential must agree to use an effective method of birth control during the course of the study. For the purposes of this study, acceptable forms of birth control include: abstinence Surgical sterilization (hysterectomy, tubal ligation, vasectomy for male partners) condoms diaphragm birth control pill or patch intrauterine device (IUD) Under the care of a primary care and/or behavioral health provider Exclusion Criteria: Elevated risk of seizures at the time of rTMS including any of the following: History of unprovoked seizures or any seizure within 24 hours of sustaining a concussion(s) or other head injury regardless of whether it was determined to have been related to concussion Family history of two or more unprovoked seizures in a first degree relative (parent, sibling, or child) History of moderate or severe TBI based on TBI screener and/or medical records History of penetrating TBI based on TBI screener and/or medical records Intracranial lesion (such as intracranial tumor or intraparenchymal hemorrhage) that, in the opinion of the investigator, would be unsafe with MRI or TMS, or that would produce an artifact that would compromise the integrity of data Currently taking medication or other substances (such as tricyclic antidepressants or neuroleptics) that, in the opinion of the investigator, lowers the seizure threshold Contra-indications to awake 3T MRI without contrast at the time of Baseline MRI History of severe or recent uncontrolled heart disease Presence of a cardiac pacemaker or intracardiac lines Any implant, prosthesis, or other permanent alteration of the body (i.e., implanted neurostimulators and medication pumps) that, in the opinion of the investigator, would be unsafe with MRI or TMS, or that would produce an artifact that would compromise the integrity of data Presence of rapidly progressive illnesses such as late-stage cancer, neurodegenerative conditions, major organ failure, etc. History of bipolar disorder or schizophrenia spectrum disorders Current evidence of substance-induced mood disorder, active psychosis, or depression, secondary to general medical illness other than TBI Concomitant or lifetime history of receiving open-label TMS Concomitant or recent history (within 6 months prior to enrollment) of receiving other neurostimulatory treatment, including but not limited to transcranial direct current (tDCS), transcranial alternating current (tACS), alpha stim, or electroconvulsive therapy Unilateral or bilateral upper extremity amputation or other condition precluding motor threshold calibration Suicide attempt within six months prior to enrollment Unable to complete timeline of the study Severe claustrophobia interfering with medication/sedation-free 3T closed-bore MRI Any considerations that, in the opinion of the investigator, may adversely affect participant safety, participation, or the scientific validity of the data being collected (e.g., severe or controlled uncontrolled substance abuse, inability to remain on a steady neurotropic medication and/or behavioral therapy regimen over the course of the randomization phase of the study, planned hospitalization half-way through the initial randomization period, limited life expectancy, prisoners, or others who have legally restricted freedom of movement and participants, etc.)

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 50 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Sequential Assignment
Interventional Model Description: Bayesian-adaptive trial design
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Arm 1<br>Active rTMS/Individualized Connectome Targeting (ICT)/Bilateral/Standard rTMS protocol | Device: Repetitive Transcranial Magnetic Stimulation (rTMS)<br>* Active rTMS<br>|
| Experimental: Arm 2<br>Active rTMS/ICT/Bilateral/Theta Burst Stimulation (TBS) rTMS protocol | Device: Repetitive Transcranial Magnetic Stimulation (rTMS)<br>* Active rTMS<br>|
| Experimental: Arm 3<br>Active rTMS/ICT/Unilateral/Standard rTMS protocol | Device: Repetitive Transcranial Magnetic Stimulation (rTMS)<br>* Active rTMS<br>|
| Experimental: Arm 4<br>Active rTMS/ICT/Unilateral/TBS rTMS protocol | Device: Repetitive Transcranial Magnetic Stimulation (rTMS)<br>* Active rTMS<br>|
| Experimental: Arm 5<br>Active rTMS/Structural targeting/Bilateral/Standard rTMS protocol | Device: Repetitive Transcranial Magnetic Stimulation (rTMS)<br>* Active rTMS<br>|
| Experimental: Arm 6<br>Active rTMS/Structural targeting/Bilateral/TBS rTMS protocol | Device: Repetitive Transcranial Magnetic Stimulation (rTMS)<br>* Active rTMS<br>|
| Experimental: Arm 7<br>Active rTMS/Structural targeting/Unilateral/Standard rTMS protocol | Device: Repetitive Transcranial Magnetic Stimulation (rTMS)<br>* Active rTMS<br>|
| Experimental: Arm 8<br>Active rTMS/Structural targeting/Unilateral/TBS rTMS protocol | Device: Repetitive Transcranial Magnetic Stimulation (rTMS)<br>* Active rTMS<br>|
| Experimental: Arm 9<br>Active rTMS/Scalp targeting/Bilateral/Standard rTMS protocol | Device: Repetitive Transcranial Magnetic Stimulation (rTMS)<br>* Active rTMS<br>|
| Experimental: Arm 10<br>Active rTMS/Scalp targeting/Bilateral/TBS rTMS protocol | Device: Repetitive Transcranial Magnetic Stimulation (rTMS)<br>* Active rTMS<br>|
| Experimental: Arm 11<br>Active rTMS/Scalp targeting/Unilateral/Standard rTMS protocol | Device: Repetitive Transcranial Magnetic Stimulation (rTMS)<br>* Active rTMS<br>|
| Experimental: Arm 12<br>Active rTMS/Scalp targeting/Unilateral/TBS rTMS protocol | Device: Repetitive Transcranial Magnetic Stimulation (rTMS)<br>* Active rTMS<br>|
| Sham Comparator: Sham 1<br>Sham rTMS/Scalp targeting/Bilateral laterality/Standard rTMS protocol | Device: Sham rTMS<br>* Sham comparator to active rTMS<br>|
| Sham Comparator: Sham 2<br>Sham rTMS/Scalp targeting/Bilateral laterality/TBS rTMS protocol | Device: Sham rTMS<br>* Sham comparator to active rTMS<br>|
| Sham Comparator: Sham 3<br>Sham rTMS/Scalp targeting/Unilateral/Standard rTMS protocol | Device: Sham rTMS<br>* Sham comparator to active rTMS<br>|
| Sham Comparator: Sham 4<br>Sham rTMS/Scalp targeting/Unilateral/TBS rTMS protocol | Device: Sham rTMS<br>* Sham comparator to active rTMS<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Change from Baseline in Montgomery-Asberg Depression Rating Scale (MADRS) Scores | Change in Montgomery-Asberg Depression Rating Scale scores from baseline to post-intervention between groups. The Scale is designed to measure depression severity and consists of 10 items, each of which is scored on a Likert scale from 0 (item not present or normal) to 6 (severe or continuous presence of the symptoms), for a total possible score of 60. Higher scores represent a more severe condition. | Baseline to post-intervention, within 10 working days of the final rTMS session | 
| Change from Baseline in Montgomery-Asberg Depression Rating Scale (MADRS) Scores in a Subgroup | Change in Montgomery-Asberg Depression Rating Scale scores between groups from Baseline to post-intervention in participants who complete ≥80% of rTMS sessions. The Scale is designed to measure depression severity and consists of 10 items, each of which is scored on a Likert scale from 0 (item not present or normal) to 6 (severe or continuous presence of the symptoms), for a total possible score of 60. Higher scores represent a more severe condition. | Baseline to post-intervention, within 10 working days of the final rTMS session | 
| Change in Montgomery-Asberg Depression Rating Scale (MADRS) Scores from Baseline to 6-month follow-up | Change in Montgomery-Asberg Depression Rating Scale scores from baseline to 6-month follow-up between groups. The Scale is designed to measure depression severity and consists of 10 items, each of which is scored on a Likert scale from 0 (item not present or normal) to 6 (severe or continuous presence of the symptoms), for a total possible score of 60. Higher scores represent a more severe condition. | Baseline to 6 months | 
| Comparison of Treatment Response or Remission in Montgomery-Asberg Depression Rating Scale (MADRS) Scores | Comparison of proportion of participants in each condition achieving treatment response ≥50% improvement in MADRS) or remission (MADRS ≤10) | Baseline to post-intervention, within 10 working days of the final rTMS session | 
| Comparison of Duration of Remission of Depressive Symptoms in Montgomery-Asberg Depression Rating Scale (MADRS) Scores | Comparison of duration of remission of depressive symptoms in Montgomery-Asberg Depression Rating Scale (MADRS) Scores between groups assessed monthly during follow-up | Follow-up Period, from 1-6 months after the final rTMS session | 
| Comparison of Frequency of Adverse Events | Comparison of AEs between groups | Baseline to post-intervention, within 10 working days of the final rTMS session | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Comparison of Change in Inventory of Depressive Symptomatology-Self Report (IDS-SR) Scores from Baseline to post-intervention | Change in Inventory of Depressive Symptomatology-Self Report scores between groups. The Report is a 30-item self-report depressive symptom severity rating scale, with each question on a scale of 0 to 4; and a score range between 0 to 84, with a higher score reflecting higher symptom severity in depression. | Baseline to post-intervention, within 10 working days of the final rTMS session | 
| Comparison of Change in Symptoms of Major Depressive Disorder Scale (SMDDS) Scores from Baseline to Post-intervention | Change in Symptoms of Major Depressive Disorder Scale scores between groups. The Scale is a 16-question scale, with each question using a rating scale between 0 (Not at all or Never) to 4 (Extremely or Always); the total score ranges from 0 to 60 with a higher score indicating more severe depressive symptomatology. | Baseline to post-intervention, within 10 working days of the final rTMS session | 
| Comparison of Change in Inventory of Depressive Symptomatology-Self Report (IDS-SR) Scores from Baseline to 6-month follow-up | Change in Inventory of Depressive Symptomatology-Self Report scores between groups. The Report is a 30-item self-report depressive symptom severity rating scale, with each question on a scale of 0 to 4; and a score range between 0 to 84, with a higher score reflecting higher symptom severity in depression | Baseline to 6-month follow-up | 
| Comparison of Change in Symptoms of Major Depressive Disorder Scale (SMDDS) Scores from Baseline to 6-month follow-up | Change in Symptoms of Major Depressive Disorder Scale scores between groups. The Scale is a 16-question scale, with each question using a rating scale between 0 (Not at all or Never) to 4 (Extremely or Always); the total score ranges from 0 to 60 with a higher score indicating more severe depressive symptomatology. | Baseline to 6-month follow-up | 
| Comparison of Change in TBI Quality of Life Scale (TBI-QOL) Subtest Scores from Baseline to Post-intervention | Change in subtest scores between groups Anxiety ranges Raw Score (RS) 10-50, T-score 36.0-85.1; higher = worse Communication ranges RS 9-45, T-score 12.8-67.2; higher = better Depression ranges RS 10-50, T-score 38.3-82.6; higher = worse Emotional & Behavioral Dyscontrol ranges RS 10-50, T-score 33.1-84.6; higher = worse Executive Function range RS 10-50, T-score 12.3-58.0; higher = better Fatigue ranges RS 10-50, T-score 32.7-80.7; higher = worse General Concerns ranges RS 10-50, T-score 17.3-59.6; higher = better Grief - Loss ranges RS 9-45, T-score 32.9-75.0; higher = worse Headache ranges RS 10-50, T-score 38.9-72.6; higher = worse Independence ranges RS 8-40, T-score 21.2-66.2; higher = better Pain Interference ranges RS 10-50, T-score 40.4-78.8; higher = worse Resilience ranges RS 10-50, T-score 15.3-69.2; higher = better Self-Esteem ranges RS 10-50, T-score 20.0-64.9; higher = better Cognitive Function ranges RS 8-40, T-score 22.5-67.0; higher = better | Baseline to post-intervention, within 10 working days of the final rTMS session | 
| Comparison of Change in TBI Quality of Life Scale (TBI-QOL) Subtest Scores from Baseline to 6-month follow-up | Change in subtest scores between groups Anxiety ranges Raw Score (RS) 10-50, T-score 36.0-85.1; higher = worse Communication ranges RS 9-45, T-score 12.8-67.2; higher = better Depression ranges RS 10-50, T-score 38.3-82.6; higher = worse Emotional & Behavioral Dyscontrol ranges RS 10-50, T-score 33.1-84.6; higher = worse Executive Function range RS 10-50, T-score 12.3-58.0; higher = better Fatigue ranges RS 10-50, T-score 32.7-80.7; higher = worse General Concerns ranges RS 10-50, T-score 17.3-59.6; higher = better Grief - Loss ranges RS 9-45, T-score 32.9-75.0; higher = worse Headache ranges RS 10-50, T-score 38.9-72.6; higher = worse Independence ranges RS 8-40, T-score 21.2-66.2; higher = better Pain Interference ranges RS 10-50, T-score 40.4-78.8; higher = worse Resilience ranges RS 10-50, T-score 15.3-69.2; higher = better Self-Esteem ranges RS 10-50, T-score 20.0-64.9; higher = better Cognitive Function ranges RS 8-40, T-score 22.5-67.0; higher = better | Baseline to 6-month follow-up | 
| Comparison of Change in PTSD Checklist for DSM-5 (PCL-5) Scores from Baseline to Post-intervention | Change in PTSD Checklist for DSM-5 scores between groups. The Checklist is a self-reported measure of PTSD symptom severity, with a score range of 0-84 in which a higher score represents greater severity. | Baseline to post-intervention, within 10 working days of the final rTMS session | 
| Comparison of Change in PTSD Checklist for DSM-5 (PCL-5) Scores from Baseline to 6-month Follow-up | Change in PTSD Checklist for DSM-5 scores between groups. The Checklist is a self-reported measure of PTSD symptom severity, with a score range of 0-84 in which a higher score represents greater severity. | Baseline to 6-month follow-up | 
| Compliance Assessment | Proportion of participants who achieve at least 80% compliance, defined as having completed ≥16 rTMS sessions | Post-intervention, within 10 working days of the final rTMS session | 
| Comparison of Change in rsfMRI Connectivity from Baseline to Post-intervention | Compare change in rsfMRI connectivity, focusing on brain networks relevant to mood regulation between groups | Baseline to post-intervention, within 10 working days of the final rTMS session | 
| Comparison of Change in rsfMRI Connectivity from Baseline to 6-month Follow-up | Compare change in rsfMRI connectivity, focusing on brain networks relevant to mood regulation between groups | Baseline to 6-month follow-up |