Maintenance of Response To Transcranial Magnetic Stimulation (TMS) in Major Depressive Disorder (MDD) Using Monthly TMS Treatment
Phase: NA
Conditions: MDD
Sponsor: University of Missouri-Columbia

Page 1 of 11 
 
 
 
Maintenance Transcranial Magnetic Stimulation in Major Depressive Disorder   
 NCT04076644 
12/17/2019 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

Page 2 of 11 
BIOMEDICAL RESEARCH PROTOCOL 
UNIVERSITY OF MISSOURI 
 
Project Title:  Maintenance of response to Transcranial Magnetic Stimulation (TMS) in Major 
Depressive Disorder (MDD) using monthly TMS treatment  
IRB Number: 2013884 
Version Number: 3 
Version Date: 12/17/2019 
Principal Investigator:  Dr. Muaid Ithman 
Funding Source:  
 
Clinical Trial Phase: IV 
Clinicaltrials.gov Number:  
Study Drug/Study Device: Magventure/Magvita TMS machine 
 
 
 
 
 
Transcranial Magnetic Stimulation (TMS) has been established as an effective 
and safe method to treat Major Depressive Disorder (MDD).  Large randomized sham 
controlled trials (1,4), and over a decade of clinical use since it was FDA approved for 
acute treatment of MDD in 2008, has shown TMS to be a promising treatment after 
medications and psychotherapy have failed to alleviate depressive symptoms.  TMS is 
non-invasive, and uses a small but powerful pulsed magnetic field placed over the dorsa-
lateral-prefrontal-cortex (DLPFC), a part of the brain thought to be associated with 
depression.  In general, treatments are given 5 times for week for 4-6 weeks. This 
treatment protocol results in an effectiveness of roughly 2/3 of patients seeing a clinically 
significant benefit, while 1/3 of those patients experience a complete remission of their 
depressive symptoms (2).  TMS is also a relatively safe treatment and has very little if 
any side effects, the most common being a slight headache after the treatment (5,6).   
Given that treatment resistant MDD is a chronic disease with no known cure, 
management of symptoms mostly consists of trialing and failing medications whose 
positive effects on symptomology are of limited time course.  TMS is no different.  
Patients that respond or remit after a TMS course will most likely see a relapse in their 
depressive symptoms at some point after their acute TMS treatment course is completed 
(3,7,8).  The time course of response or remission after acute TMS treatment varies 
between individuals from weeks to years, and there is no way to predict the length of 
positive outcomes.  Research has shown that close to 40% of patients will see symptom 
worsening, and another 10% will have a relapse within 6 months post-acute treatment 
course (3). Interestingly, data and clinical evidence has shown that if a patient responds to 
TMS and relapses back into a depressive episode, a new TMS treatment course will 
provide the same benefits as the original TMS course (3).  In other words, if TMS works 
for the patient, it will most likely work again.  Given the relative safety and the fact the 
TMS is equally effective after a positive acute response, many clinicians and researchers 
I. 
Research Objectives/Background 

Page 3 of 11 
have questioned the current clinical protocol of waiting for a relapse to start treating with 
TMS.  Succinctly, should we be using TMS to maintain response? 
 
Research using TMS as a maintenance therapy has shown that remission and 
response have been extended out for longer periods after the acute treatment, however 
there has been a multitude of parameters, populations, and treatment protocols used 
which has led to mixed results.  These maintenance protocols studies include: as needed 
(10), use as a rescue (11), regular weekly or monthly intervals (10), and clustered 
treatments where multiple treatments are given in the same day (12).   
More recently, new acute TMS protocols, called theta-burst have been FDA 
cleared on some TMS machines for treating depression (9).  Both the original 10hz 
stimulation approved by the FDA in 2008, and the newer theta-burst stimulation are 
excitatory in nature, but little research has been completed to determine if newer theta-
burst protocols are as effective and safe in maintenance of the response compared to 
acute TMS treatment. Further, no work has been completed on how they compare to the 
clinical standard 10hz during a maintenance course of treatment.   
Hence, the main purpose of this study is to use TMS treatment to maintain 
patients that have responded or remitted from their depressive symptoms from the use of 
clinical TMS treatment, while off their antidepressant medication. A secondary objective 
is to see how the safety and effectiveness of this newer treatment protocol (theta-burst) is 
compared to prior treatment protocols in a maintenance regime, by comparing the theta-
burst to traditional 10hz TMS treatment protocols.  An additional tertiary purpose is to 
see if maintenance therapy treatment performed by a certified TMS technician can be 
performed without the need of TMS Attending supervision.  Given the relative safety of 
TMS, that TMS technicians are CPR certified, and highly experienced in understanding 
the safety of TMS, this particular objective would help to show the feasibility and 
possible economic benefit to patient and provider of not needing Attending supervision 
for TMS maintenance treatment.  
 
 
 
 
The device used in this study is a Magventure/MagVita Transcranial Magnetic 
Stimulation device.  It is a FDA approved for treating Major Depressive Disorder in an acute 
treatment protocol.  The normal acute clinical treatment protocol consists of 36 treatments 
given over 6 weeks with a 3 week taper (totaling 9 weeks).  This study will be looking at a 
maintenance protocol and treating monthly, so there will be much less treatments 
comparatively.  There is no IDE required for this study since it is a FDA approved device and 
we will use FDA cleared treatment protocols.  More specific inclusion criteria are listed in 
the inclusion/exclusion section of the protocol. 
TMS is an electromagnet that uses a small precise, but powerful magnetic pulse delivered 
to the head corresponding to an area over the brain thought to have some role in the 
depressive symptoms associated with MDD.  This study will use the exact same protocols 
used in the acute treatment setting, except that treatments will be given monthly not daily 
(see methods section for reference). 
  There are currently 3 FDA cleared treatment protocols for acute clinical treatment 
associated with this device.  They consist of a 37 minute treatment, a 20min treatment, and a 
II. 
Drugs/Biologics/Devices 

Page 4 of 11 
3 minute treatment.  The 37 and 20 min treatment have similar treatment protocols and total 
3000 stimulations for each treatment.  Both of these protocols consist of a 10Hz stimulation 
for 4 secs with either 27 or 11 sec intertrain break with no stimulation respectively.  The 3 
minute protocol is different than the other two protocols and consists of 600 stimulations per 
treatment.  It’s parameters consist of a 50Hz triplet burst stimulation for 2 seconds with a 8 
second intertrain break with no stimulation.     
 
Dosage (or % of machine output) is determined by Motor Threshold which is described 
in the methods section of this protocol. 
 
This device will be used in this study because it is the current device used to treat patients 
for acute MDD in the UMHC Neuromodulation clinic, and the Neuromodulation clinic is 
where the subjects for the study will be recruited from.  
 
This study is open-label with no sham group used as a comparative group.  However, we 
will use a study arm that does not use a TMS treatment for maintenance and follow them for 
similar time frame as other study TMS treatment arms noting durability/length of response 
measures compared to other study treatment groups. 
 
 
 
Subjects will be recruited from the UMHC Neuromodulation clinic.  All subjects will 
already have completed an acute TMS treatment regime in the clinic.  This study will be 
looking at treating in the maintenance phase only, meaning they must previously have 
completed the acute clinical protocol (36 treatments).  Subjects will only come from the 
UMHC clinic, and must have responded or remitted from their depressive symptoms due to 
the TMS acute treatment.  No participants will be allowed into the study who were acutely 
treated outside the UMHC Neuromodulation clinic. 
As patients come close to the end of their acute clinical TMS treatment, they will be 
screened to see if their depressive scores have shown a clinically significant improvement, or 
if their symptoms have remitted (we already collect these scores clinically).  If their clinical 
scores show this inclusion criteria then they will be approached by study staff either through 
face to face or by letter in mail, letting them know we have a study looking at the efficacy of 
using TMS treatment to maintain their improvement they have attained in their clinical 
course of TMS treatment. 
If a potential subject is interested in learning more about the study a copy of the consent 
will be given or sent to them in the mail for them to review, and a consent appointment will 
be setup to meet with the study staff. 
 
 
 
 
 
 
When a potential subject is identified and after a copy of the consent is given to the 
potential subject for review, a consent appointment will be setup.  At the appointment an 
approved study team member will go over the privacy practices, HIPAA, and consent 
thoroughly, allowing the potential subject to ask questions and stressing that the signing 
of the consent is not a contract only a process, and that they can discontinue the study at 
III. 
Recruitment Process 
IV. 
Consent Process 

Page 5 of 11 
any time for any reason.  Then if the subject is interested in starting the study the 
approved team member will have the subject sign and date the HIPAA and consent.  
Then a copy of each signed document will be given to the subject.  A baseline visit will 
then be setup, or if time allows a baseline visit commence immediately following the 
signing of consent. 
 
 
 
 
Inclusion Criteria: 
- 
Must have recently (within 4 weeks) completed an acute TMS course (full 36 
treatments) at the UMHC Neuromodulation clinic 
- 
Must have clinically responded to the acute TMS treatment course (≥50% 
improvement according to the clinical depressive scale used - usually the 
PHQ-9)  
- 
Must be able sign consent 
- 
Must have a current address and phone number 
- 
Must have current mental health care provider, either psychiatrist or general 
practioner who they see for mental health symptom management 
- 
Must be able to taper off antidepressant medication within 2 months of 
signing consent of study (treatment group only) 
 
Exclusion Criteria: 
- 
Subject that has not completed a full acute treatment course, including taper 
- 
Subjects that have changed anything that may not make them safe for TMS, 
which are (all changes will be reviewed by study MD, and will not necessarily 
be excluded possibly depending on severity): 
o Any new metal near head 
o Any new medical devices that cannot be removed 
o Any new pregnancies (verbally confirmed) 
o Seizures that occurred post-acute TMS treatment 
o Any uncontrolled cardiovascular disease 
o Any new head trauma 
o Any new illness causing injury to brain 
o Any new medications which cannot be altered or lowered that may be 
contraindicated for TMS treatment 
o Any drug or alcohol use deemed by the study doctor as unsafe for 
TMS treatment 
- 
 Subjects unwilling to sign consent or follow study procedures 
- 
 Subjects with known extended travel plans which may affect study 
procedures and scheduled TMS treatment 
 
 
 
 
V. 
Inclusion/Exclusion Criteria 
VI. 
Number of Subjects 

Page 6 of 11 
For this study we are looking to enroll 120 subjects broken down between 2 different 
treatment arms in the following way: 
 
 
 
The number of subjects we expect to enroll is based on our current UMHC 
Neuromodulation clinic patient flow.  The average patient clinic flow is 100 per year and using 
these numbers the study should be able to complete within 1-2 years.  We expect that at least 
20% of our expected enrolled may drop out of study for varies reasons (moved, loss of interest, 
unexpected reasons) hence the total expected completed being 100.  60 subjects in each arm will 
allow for a balanced study. 
 
 
 
This is an open-label non-blinded study, for patients that have already completed 
an acute TMS course of therapy and have responded or remitted from their depressive 
symptoms according to their routine care clinical assessments (PHQ-9, or QIDS).  There 
is no sham treatment in this study, but we will be using a study arm that does not receive 
TMS treatment in order to compare to an active TMS study arm.   
 
All subjects will complete 3 non-treatment visits (consent, baseline, end of study 
visit) and if a subject is in the treatment arm and additional 60 visits (over the course of 
year).  Additionally, a subject that is in the treatment arm will completed a PHQ-9, and 
IDS at baseline visit, and the beginning and end of each monthly treatment block.  If a 
subject is in the non-treatment arm they will complete 15 total visits consisting of a 
consent, baseline, 12 assessment visits (for PHQ-9 & IDS testing) and an end treatment 
visit.  For these individuals, a PHQ-9 and IDS will be completed at the baseline visit and 
at each monthly assessment visit. 
 
Subjects in the active TMS treatment arm will be tapered off their antidepressant 
medication as soon as they have signed consent according to the study doctor’s direction.  
Subjects in the TMS active arm will remain antidepressant medication free for the 
duration of the study. If these subjects deteriorate during course of the study they will be 
removed from the study and normal clinical care will resume.  They will complete a 
PHQ-9 and QIDS at this time.  Their data will be used in the final analysis of study.  
Deterioration or relapse will be determined by the study doctor clinical judgement. 
VII. 
Study Procedures/ Design/Treatment Plan 

Page 7 of 11 
 
For subjects in the active TMS treatment arms, a dosing procedure (Motor 
Threshold) will need to be performed by any person the study PI delegates this authority 
to, each month immediately before the first treatment of each monthly treatment block.  
The Motor Threshold (MT) is used to determine the % TMS machine output or dosage, 
needed to treat.  The procedure consists of the TMS certified operator placing the TMS 
machine treatment coil on the patient’s head, corresponding to an area over the patients 
left Motor Cortex of his/her brain. Then the TMS machine intensity is turned up or down 
and the coil is moved around on patient’s head to determined how much energy is need to 
elicit a muscle twitch in the right abductor pollicis brevis muscle (APB).  Then a 
computer algorithm helps determine the correct intensity that should be used for the next 
5 treatments.  An additional computer algorithm uses head measurements of 
circumference, Nasion to Inion, and Tragus to Tragus, to determine where the TMS 
treatment coil will be located to treat over the Dorsolateral Prefrontal Cortex (DLPFC).  
This procedure must be completed each month prior to the monthly treatment block.   
 
If a patient drops out of the study for any reason their data up to that point will be 
retained and used, this will be discussed with the potential patient during the consent 
process, and described in the consent itself. 
 
The last treatment visit when a patient completes the treatment portion of the 
study or has finished their last monthly assessment visit if they are not in an active 
treatment arm, will be an end study visit (this could be the last treatment/assessment visit 
if time allows). At this visit the TMS MD will discuss end of study and possible future 
clinical care that maybe necessary for subject when they switch back over to clinical 
realm and are no longer part of the study. 
 
Study procedure plan is below: 

Page 8 of 11 
 
 
 
 
 
Study visit completion for TMS active arms form is below, subjects that are in non-active 
arm will not have the TMS treatment visits, but will do the monthly assessment visits: 
 
 

Page 9 of 11 
 
 
The machine and treatment protocols are the same used in the clinical setting, therefore 
the risks are the same.  The most common side effect/ risk is headache, superficial pain under 
treatment site, dental pain, eye pain, or facial muscle twitching.  These seem to well 
tolerated, and can occur during or after treatment.  These can be treated with over-the-counter 
pain medication (Tylenol, Ibuprophen).   
Another rare but serious risk is seizure.  Seizures are very rare and are thought to occur 
about 1in 30,000 treatments.  Subjects will have already gone through safety screens in order 
to get TMS treatment clinically, but nevertheless, another Transcranial Adult Safety Screen 
(TASS) will be done prior to starting treatment phase of study.  Study staff are trained in 
seizure occurrence during TMS and are also CPR certified. 
The study doctor will determine if patient participation should start or continue from 
these or any other subject problems that may occur, such as failure of TASS question 
throughout the study. 
If an adverse event, UP, or deviation occur study staff will fill out a study adverse event 
form, the AE event log, and will notify the MU IRB if required within 5 days of awareness of 
the event.  
 
 
 
 
 
 
It is not known whether TMS used in a monthly maintenance protocol will be beneficial in 
helping to extend out the subject’s acute response or remission, but it may be a possible 
benefit.  Additionally, this study will help add to the work of clinical and scientific 
community in this area of interest.  This data may also help future patients that have MDD 
and are trying to maintain their response. 
 
 
 
No compensation will be given for this study. 
 
 
 
 
There are no costs associated with this study either for the research or to participants.  The 
TMS machine is already part of the Neuromodulation Clinic. 
 
 
 
No DSMB is required for this study.  All adverse events will be reported on the 
AE study report form, the AE log, and local IRB protocol will dictate what needs to be 
submitted to MU IRB.  Because this is an internal study (no other sites), AEs and UP will 
immediately be known to study doctor.  He will determine if AEs are in the normal range 
VIII. Potential Risks/Adverse Events 
IX. 
Anticipated Benefits 
X. 
Compensation 
XII. 
Data Safety Monitoring Plan 
XI. 
Costs 

Page 10 of 11 
for TMS treatment, comparing to clinical experience and TMS safety data.  If they are 
found not to be, the he may pause the study to review protocols and procedures.     
All study data will be captured on paper then transferred over to an electronic 
database on a secured approved UM computer.  All data will coded so no patient data 
will be identifiable.  Study Consents and HIPAA that are signed will be stored in locked 
cabinet behind a locked door.  The key linking subject consent and subject codes will not 
be stored in same place as consents and coded data.  All coded data on paper will be 
placed in subject binder and stored in locked cabinet behind locked door.  All study data 
will be stored for length of time in accordance with UM IRB research data rules. 
 
 
 
 
1. NA 
 
 
 
 
1  O’Reardon, J. P., Solvason, H. B., Janicak, P. G., Sampson, S., Isenberg, K. E., Nahas, Z., ... & 
Demitrack, M. A. (2007). Efficacy and safety of transcranial magnetic stimulation in the acute treatment of 
major depression: a multisite randomized controlled trial. Biological psychiatry, 62(11), 1208-1216. 
2  Carpenter, L. L., Janicak, P. G., Aaronson, S. T., Boyadjis, T., Brock, D. G., Cook, I. A., ... & Demitrack, 
M. A. (2012). Transcranial magnetic stimulation (TMS) for major depression: a multisite, naturalistic, 
observational study of acute treatment outcomes in clinical practice. Depression and anxiety, 29(7), 587-
596. 
3  Janicak, P. G., Nahas, Z., Lisanby, S. H., Solvason, H. B., Sampson, S. M., McDonald, W. M., ... & 
O’Reardon, J. P. (2010). Durability of clinical benefit with transcranial magnetic stimulation (TMS) in the 
treatment of pharmacoresistant major depression: assessment of relapse during a 6-month, multisite, 
open-label study. Brain stimulation, 3(4), 187-199. 
4 George, M. S., Lisanby, S. H., Avery, D., McDonald, W. M., Durkalski, V., Pavlicova, M., ... & 
Holtzheimer, P. E. (2010). Daily left prefrontal transcranial magnetic stimulation therapy for major 
depressive disorder: a sham-controlled randomized trial. Archives of general psychiatry, 67(5), 507-516. 
5 Perera, T., George, M. S., Grammer, G., Janicak, P. G., Pascual-Leone, A., & Wirecki, T. S. (2016). 
The clinical TMS society consensus review and treatment recommendations for TMS therapy for major 
depressive disorder. Brain stimulation, 9(3), 336-346. 
6 Wassermann, E. M. (1998). Risk and safety of repetitive transcranial magnetic stimulation: report and 
suggested guidelines from the International Workshop on the Safety of Repetitive Transcranial Magnetic 
Stimulation, June 5–7, 1996. Electroencephalography and Clinical Neurophysiology/Evoked Potentials 
Section, 108(1), 1-16. 
7 Janicak, P. G., Dunner, D. L., Aaronson, S. T., Carpenter, L. L., Boyadjis, T. A., Brock, D. G., ... & 
Demitrack, M. A. (2013). Transcranial magnetic stimulation (TMS) for major depression: a multisite, 
naturalistic, observational study of quality of life outcome measures in clinical practice. CNS 
spectrums, 18(6), 322-332. 
XIV. References/Appendices 
XIII. Multiple Sites 

Page 11 of 11 
8 Mantovani, A., Pavlicova, M., Avery, D., Nahas, Z., McDonald, W. M., Wajdik, C. D., ... & Lisanby, S. H. 
(2012). LONG‐TERM EFFICACY OF REPEATED DAILY PREFRONTAL TRANSCRANIAL MAGNETIC 
STIMULATION (TMS) IN TREATMNT‐RESISTANT DEPRESSION. Depression and anxiety, 29(10), 883-
890. 
9 Blumberger, D. M., Vila-Rodriguez, F., Thorpe, K. E., Feffer, K., Noda, Y., Giacobbe, P., ... & Downar, J. 
(2018). Effectiveness of theta burst versus high-frequency repetitive transcranial magnetic stimulation in 
patients with depression (THREE-D): a randomised non-inferiority trial. The Lancet, 391(10131), 1683-
1692. 
10 Philip, N. S., Dunner, D. L., Dowd, S. M., Aaronson, S. T., Brock, D. G., Carpenter, L. L., ... & George, 
M. S. (2016). Can medication free, treatment-resistant, depressed patients who initially respond to TMS 
be maintained off medications? A prospective, 12-month multisite randomized pilot study. Brain 
stimulation, 9(2), 251-257. 
11 Dunner, D. L., Aaronson, S. T., Sackeim, H. A., Janicak, P. G., Carpenter, L. L., Boyadjis, T., ... & 
Lanocha, K. (2014). A multisite, naturalistic, observational study of transcranial magnetic stimulation for 
patients with pharmacoresistant major depressive disorder: durability of benefit over a 1-year follow-up 
period. The Journal of clinical psychiatry, 75(12), 1394-1401. 
12 Fitzgerald, P. B., Grace, N., Hoy, K. E., Bailey, M., & Daskalakis, Z. J. (2013). An open label trial of 
clustered maintenance rTMS for patients with refractory depression. Brain stimulation, 6(3), 292-297.