Evaluating the Efficacy and Tolerability of Targeted Transcranial Magnetic Stimulation in Youth
Phase: NA
Conditions: Depression
Sponsor: Stanford University

Evaluating the Efficacy and Tolerability of Targeted 
Transcranial Magnetic Stimulation in Youth 
NCT03845504 
October 27, 2020 
1. 
PURPOSE OF THE STUDY 
a. 
Brief Summary 
To evaluate the antidepressant effects of daily active iTBS in adolescents and young 
adults with moderate to severe depressive symptoms. 
b. 
Objectives 
The investigators hope to learn if iTBS is an effective treatment for depressive symptoms 
in adolescents. This is important knowledge as many adolescents are intolerant to 
medications or do not want to receive medications for the treatment of depression. 
c. 
Rationale for Research in Humans 
Human subjects must be used since the efficacy of the iTBS procedure is being tested in 
adolescent humans. 
2. 
STUDY PROCEDURES 
a. 
Procedures 
Screening 
 
Subjects will undergo medical, psychological and neuropsychological assessments to 
assure compliance with all inclusion and exclusion criteria. Eligible subjects will receive 
active iTBS. 
 
TMS Treatment 
 
All treatments and motor threshold determinations will be completed by physicians or 
other health care providers who have been trained to the process based on the 
MagVenture User Manual and certified by the department. All processes are consistent 
with the clinical use of the MagVenture MagPro rTMS research system. 
 
iTBS sessions will occur approximately 2 days after the baseline session with week daily 
sessions delivered to left DLPFC over 6 weeks. We will start with the currently FDA 
approved iTBS protocol for adults. Stimulation will be administered using the 
MagVenture MagPro rTMS Research System at currently FDA approved parameters: 
80% of the active motor threshold, 20 cycles of 10 bursts of 3 pulses at 50Hz delivered in 
2 second trains with an 8 second inter-train interval. The stimulation will be applied for 

October 27, 2020 
 
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3 min delivering a total of 1800 pulses/session. These stimulation sessions will occur 
daily (week days) for 6 weeks. Resulting in a total of 30 sessions. Motor Threshold (MT) 
Determination: MT Location and MT Level - The motor threshold location will be 
determined by visual confirmation of the location on the motor cortex that controls the 
abductor pollicis brevis (APB) muscle of the thumb. The resting MT level is the 
minimum power to produce a stimulation response 50% of the time. 
 
Prophylactic use of acetaminophen or ibuprofen will be allowed for subjects reporting 
sensations at or near the stimulation site which are uncomfortable or painful. During the 
first week of treatment only, in the event that the subject cannot tolerate the treatment at 
these dose parameters, dose intensity may be titrated downward to 110% of the motor 
threshold, with all other dose parameters remaining the same. 
 
Heart Rate Variability (HRV) 
 
Participants will have their HRV measured before they receive any stimulation, at the end 
of each stimulation week and at the end of the six week treatment course. HRV will be 
measured using ECG electrodes attached to the wrists and an r-wave trigger device 
(neuroConn, Ilmenau, Germany). HRV will be measured when viewing videos depicting 
negative emotions (e.g. anger, fear) and when viewing neutral stimuli. 
 
Structural/Functional Brain MRI 
 
Structural MRI comparisons will be acquired for subjects at the Cognitive Neuroscience 
Institute (CNI) on the Stanford campus. A consistent MRI technician at each study site 
will be requested for each of the study scans. Each subject will have a baseline scan and a 
post- treatment scan. 
 
First-level models: We will use a canonical hemodynamic response function (HRF) 
convolved event-related model with temporal and dispersion derivatives to model the 
blood oxygen level dependent (BOLD) in the context of a generalized linear model. 
Temporal and dispersion derivatives will be treated as regressors of no interest. A region 
of interest (ROI) analysis will be performed using our established methods, to identify 
BOLD- dependent signal change in the dorsolateral prefrontal cortex, subgenual 
cingulate, and default mode network nodes (right, left). Beta values for each ROI will be 
extracted for each subject for regression analyses. 
 
 
Details regarding neuroimaging: 
 
The subjects will undergo an MRI scan of the brain that will require about 1 hour in the 
MRI scanner. A structural MRI scan, fMRI scan will be done using a 3T system at 
Stanford facilities. 
 
During the scan, subjects will lie on the table in the magnet for approximately 30 minutes 
while the images are acquired. Subjects will wear earplugs to reduce the noise of the 
scanner. The standard of care regarding incidental findings that will be communicated to 

October 27, 2020 
 
Page 3 of 14 
patient is as follows: The investigators for this project are not trained to perform 
radiological diagnosis, and the scans performed in this study are not optimized to find 
abnormalities. The investigators and Stanford are not responsible for failure to find 
existing abnormalities in your MRI scans. However, on occasion the investigator may 
notice a finding on a MRI scan that seems abnormal. When this occurs, a radiologist will 
be consulted as to whether the finding merits further investigation, in which case the 
principal investigator of the research study being conducted will contact the participant's 
primary care physician and inform them of the finding. The decision as to whether to 
proceed with further examination or treatment lies solely with the participant and his/her 
physician. The investigators, the consulting radiologist, and Stanford are not responsible 
for any examination or treatment that you undertake based upon these findings. Because 
the images collected in this study do not comprise a proper clinical MRI series, these 
images will not be made available for diagnostic purposes. In the event that a potential 
abnormality on the MRI images is detected by the researchers, the magnet manager, is to 
be notified immediately to report the potential issue. Films of images are not be provided 
to the researcher or volunteer scan subject as the images were obtained using a research 
MRI scan protocol and not from a clinically- ordered MRI scan protocol prescribed by a 
radiologist at Stanford. 
b. 
Procedures to Minimize Risks 
Outcome Assessments 
 
Trained physicians and raters will administer all diagnostic assessments and clinical 
interviews determining study eligibility during screening. All study staff will be trained 
on study procedures. 
 
Outcome screening will occur after both the Informed Assent/Consent Document and the 
HIPAA Authorization are signed. Baseline assessments will occur prior to the first iTBS 
treatment session. 
 
The following outcome assessments will be completed: HAMD/MADRS structured 
interview, CDRS-R, CGI-S, and QIDS-A17-SR. 
 
Safety Assessments 
 
A physical and complete medical and psychiatric history will be obtained at the screening 
visit. Subjects will be evaluated clinically for adverse events at each visit. SAEs will be 
recorded as they occur and reported to the IRB within one business day of notification. 
 
The YMRS will be completed if the interval assessment of spontaneous adverse events 
indicates the potential occurrence of symptoms of mania or hypomania. 
c. 
Use of Deception in the Study 
No deception will be used. 

October 27, 2020 
 
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d. 
Use of Audio and Video Recordings 
No audio or video recording to be used. 
e. 
Alternative Procedures or Courses of Treatment 
Other treatments are available for the treatment of depression, including Psychotherapy 
or medications (tricyclic, SSRI, SNRI, antidepressants). 
f. 
Will it be possible to continue the more (most) appropriate therapy for the 
participant(s) after the conclusion of the study? 
When youth become adults, they can receive iTBS through TMS outpatient clinics 
throughout the peninsula. 
g. 
Study Endpoint 
The end of the study is defined as “the last visit of the last patient undergoing the study.” 
The end of study definition is for the entire study. The study is expected to start in spring 
2019 and to be completed by the end of 2020. The study may be terminated if the study 
procedures are not being performed according to GCP, or if recruitment is slow. 
3. 
BACKGROUND  
a. 
Past Experimental and/or Clinical Findings 
rTMS Therapy System Mechanism of Action 
 
The MagVenture TMS Therapy® System is a computerized electromechanical 
instrument that produces and delivers brief duration, rapidly alternating (pulsed) 
magnetic fields to induce electrical currents in localized regions of the cerebral cortex. 
Since TMS therapy produces a time varying magnetic field, its intended effect derives 
fundamentally from Faraday’s Law, which asserts that a time-varying magnetic field 
produces an electrical current in an adjacent conductive substance. During TMS, the 
conductive substance of interest is the brain, in particular the region of the cortex that lies 
beneath the treatment coil. 
 
The electric current induced in this region of the cortex travels in a path orthogonal to the 
direction of the alternating magnetic field with the point of maximum field strength and 
greatest current located directly beneath the center of the coil, which is the TMS system 
component that rests against the patient’s head and transmits magnetic pulses to the 
patient’s brain. The induced current is tangential to the scalp at the cortical surface, and 
diminishes in magnitude with increasing depth. 
 
In the targeted area of the motor cortex, where field strength achieves the stimulation 
threshold, it is postulated that neuronal depolarization occurs. The peak magnetic field 
strength achieved with each pulse in the cortex is approximately 0.5 Tesla. 
 
Although the mechanism of action is unknown, it is hypothesized that TMS causes direct 
neuronal depolarization in brain regions immediately adjacent to the magnetic coil, and 

October 27, 2020 
 
Page 5 of 14 
also results in changes in functional activity in areas of the brain that are synaptically 
connected to the brain regions experiencing direct neuronal depolarization. It is thought 
that these actions may cause various physiologic changes in the brain which are 
associated with the symptomatic relief of depression in patients. 
 
Efficacy and Safety of TMS in Major Depression in Adult Patients 
 
The efficacy and safety of TMS in adult patients with major depressive disorder (MDD) 
who failed to receive satisfactory improvement from prior antidepressant medication was 
established in two randomized controlled trials (O’Reardon2007; Janicak 2008; George 
2010; Li et al., 2012). Clinical efficacy outcomes of the use of TMS in adult patients with 
major depression in real world clinical practice was demonstrated in a multisite 
naturalistic study in 42 US centers under conditions of general clinical use (Carpenter, 
2012; Janicak2013). 
 
A randomized controlled trial funded by the National Institute of Mental Health, 
evaluated the safety and efficacy of TMS using a clinical trial version of the NeuroStar 
TMS Therapy System in adult patients (N=197, 4 sites) with moderate to severe major 
depressive disorder and who failed to benefit from 1 through 4 adequate antidepressant 
medication trials, as defined using the Antidepressant Treatment History Form (ATHF), 
or who could not tolerate 3 or more antidepressant medications (George 2010). The study 
evaluated 197 outpatients across 4 sites, ages 21-70 years, most with a recurrent course of 
major depression (~97%), with the maximum duration of the current episode of 
depression of ≤3 years. Patients had received a median of 1.6 total prior antidepressant 
medications at an adequate dose and duration in the current episode or a median of 4 
treatment attempts at any dose and duration. The primary outcome measure was 
remission using the HAMD24 (HAMD24 total score ≤3 or 2 consecutive HAMD24 total 
scores <10) through 6 weeks of acute treatment. A statistically significant benefit of 
active TMS as compared to sham treatment for the HAMD24 remission outcome (Active 
TMS: 13.4% vs Sham TMS: 5.0%, P=0. 0173) was observed in the ITT study population 
(N=197). An adjusted odds ratio of achieving remission with active TMS was 4.05 (95% 
confidence interval (CI), 1.28- 12.83) as compared to sham TMS. The baseline to 
endpoint change score outcome using the HAMD24 also favored active TMS compared 
to sham treatment (-2.11, 95% CI: -4.30, 0.08; P=0.0588). Baseline to endpoint outcomes 
for patients treated with active TMS were statistically significant as compared to sham 
treatment as measured using the MADRS (P=0.0136), CGI-S (P=0.0181) and the patient-
rated IDS-SR (P=0.0008). For the categorical endpoints, higher rates of remission were 
observed for patients receiving active TMS as compared to sham treatment as measured 
using the MADRS (P=0.0170) and the patient-rated IDS-SR (P=0.1199), and for 
response (50% improvement from baseline) for all three measures (HAMD24, P=0.0104; 
MADRS, P=0.0063; IDS-SR, P=0.0145). Standardized effect size estimates for the 
continuous outcome endpoints range from 0.43 to 0.67, indicating a moderate to large 
effect size in this patient population. 
 
Efficacy of TMS for the treatment of adolescent depression, for all TMS devices 
including the NeuroStar TMS Therapy® System, has been reported in two pilot clinical 
studies and in multiple case reports (Walter 2001; Bloch 2008; Wall 2011). These open-

October 27, 2020 
 
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label studies describe the treatment of 24 patients, ages 10-18. The 2011 Wall et al. open-
label trial is the only study that used the NeuroStar TMS Therapy System. This study 
reported on the treatment of 7 antidepressant-resistant adolescents and demonstrated a 
robust response rate noted by 5 of 7 subjects achieving remission of depression,as rated 
using the Childhood Depression Rating Scale – Revised (CDRS-R). Furthermore, CDRS-
R mean depression severity scores were significant by treatment 20 as compared to 
baseline with similar efficacy demonstrated using the patient reported Quick Inventory of 
Depressive Symptoms – Adolescent Version (QIDS-A17- SR). Placebo effects in open-
label trials of adolescents are a well- known phenomenon. However, adolescents 
demonstrate enduring mood improvement for at least 6 months following their final acute 
treatment (session 30). Furthermore, 7 of 8 subjects completed the entire treatment 
course, with 1 patient exiting the study after only 5 minutes of treatment due to scalp 
discomfort and a perceived lack of improvement. 
 
iTBS has been shown to be more effective at inducing antidepressant responses in adults 
than traditional rTMS. 3 minutes of iTBS induce equivalent antidepressant responses as 
37 minutes of traditional rTMS stimulation (Blumberger et al., 2015) and lower 
stimulation intensities are required to induce antidepressant responses (Wu, Shahana, 
Huddleston, Lewis, & Gilbert, 2012). 
 
The shorter stimulation times and the lower stimulation intensities required for iTBS in 
comparison to traditional rTMS make iTBS potentially advantageous method for 
adolescents with MDD. Traditional rTMS has been shown to be effective at reducing 
depressive symptoms in adolescents (Carpenter et al., 2012) but iTBS has not been 
trialled in adolescents with MDD. Initial trials investigating the safety of iTBS in 
adolescents have identified iTBS as minimal risk (Hong et al., 2015; Wu et al., 2012). 
 
It is clear that the dorsolateral prefrontal cortex is heavily implicated in the 
pathophysiology of depression. The left DLPFC is hypoactive in depressed patients and 
is associated with negative emotional judgment (Grimm et al., 2008). Additionally, the 
DLPFC is a component of the cognitive control network (CCN) and the modulation of 
this node appears to modulate the CCN. At least four groups have performed iTBS to the 
DLPFC in adults and have seen antidepressant effects (Chung et al., 2015; Desmyter et 
al., 2016; Duprat et al., 2016). 
 
Safety of TMS in adolescent depression: 
 
rTMS and iTBS have been well tolerated in pediatric populations, with reports of mild 
adverse events that bear only minimal risk to children. Risk from stimulation protocols 
(e.g. high frequency TMS and theta-burst) in children has been deemed to be similar to 
that in adults. 
b. 
Findings from Past Animal Experiments 
N/A 

October 27, 2020 
 
Page 7 of 14 
4. 
RADIOISOTOPES OR RADIATION MACHINES 
N/A 
5. 
DEVICES USED IN THE STUDY 
a. 
Investigational Devices (Including Commercial Devices Used Off-Label) 
Investigational Device 1 
Name: 
TMS Magnet (MagVenture) 
Description: 
Transcranial Magnetic Stimulation 
Significant Risk? (Y/N) 
No 
Rationale for Non-Significant Risk 
Device within FDA specified parameters (iTBS). 
 
b. 
IDE-Exempt Devices 
N/A 
 
6. 
DRUGS, BIOLOGICS, REAGENTS, OR CHEMICALS USED IN THE STUDY 
N/A 
7. 
DISINFECTION PROCEDURES FOR MEDICAL EQUIPMENT USED ON BOTH HUMANS AND 
ANIMALS 
N/A 
 
8. 
PARTICIPANT POPULATION 
a. 
Planned Enrollment 
A total of 30 subjects are expected to enroll at Stanford. All subjects will have single or 
recurrent depression of moderate or greater symptom severity. 
b. 
Age, Gender, and Ethnic Background 
Male and Female Outpatients between the ages of 12-21 yo of any ethnic background 
will be recruited. 
c. 
Vulnerable Populations 
All of the subjects enrolled into this trial are adolescents per the FDA definition. The 
TMS treatment is being investigated for efficacy and safety in the adolescent population 
that experiences major depression. TMS is currently FDA approved for the treatment of 
MDD in adults. 
d. 
Rationale for Exclusion of Certain Populations 
Women, minorities, non-English speaking individuals, or children are included in 
enrollment. 

October 27, 2020 
 
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e. 
Stanford Populations 
Stanford laboratory personnel, employees, and/or students will not be specifically sought, 
they will also not be excluded from participation. 
f. 
Healthy Volunteers 
No healthy volunteers. 
g. 
Recruitment Details 
We anticipate a majority of the recruitment will also come from the outpatient child 
psychiatry clinic. 
 
Several resources will be utilized for recruitment of potential subjects including: 
from within the clinical and referral practices of the clinical study site 
• 
referrals from other care providers within the treatment communities 
• 
radio advertisements 
• 
invitation letters sent to parents of potentially eligible subjects 
• 
print advertisements, including but not limited to brochures, flyers, Craig’s List, 
and listings in research classifieds 
• 
trial listing with ClinicalTrials.gov 
• 
trial listing on university and clinical study site website 
• 
social media 
 
We will also begin utilizing the Stanford Research Registry (protocol 25422) to recruit 30 
study participants. The research registry is a list of individuals who have consented to be 
contacted by researchers at Stanford and at present includes over 1,000 volunteers. 
h. 
Eligibility Criteria 
i. 
Inclusion Criteria 
1) Ages 12-21 years of age; 
2) with at least moderate to severe depressive symptoms confirmed by the 
Children’s Depression Rating Scale-Revised (CDRS-R>40); 
3) able to commit to protocol schedule and provide Informed consent by a legal 
guardian and assent by a youth participant; 
4) have had at least one prior antidepressant treatment failure with adequate dose 
and duration. 
5) Display low heart rate variability (HRV) at baseline 
ii. 
Exclusion Criteria 
1) No prior neurological diagnosis (neurodevelopmental disorders, 
strokes/traumatic brain injuries, brain tumor, epilepsy); 
• 
Antecedent seizures 
• 
Any condition likely to be associated with increased intracranial pressure 
• 
Space occupying brain lesion 
• 
of cerebrovascular accident 

October 27, 2020 
 
Page 9 of 14 
• 
Transient ischemic attack within 2 years 
• 
Cerebral aneurysm 
• 
Dementia 
• 
Brain surgery 
• 
Head trauma with loss of consciousness for >5 minutes 
• 
History of stroke 
• 
History and/or family history of epilepsy 
2) No contraindications for TMS or MRI e.g. have any implanted metal; 
3) Unstable medical conditions 
 
• 
Hematological or infectious (e.g., human immunodeficiency virus-HIV) 
disorders. 
• 
History of autoimmune, endocrine, viral, or vascular disorder 
• 
Unstable cardiac disease, uncontrolled hypertension, or sleep apnea 
• 
Current anticoagulant, immune suppressive, and/or chemotherapy or those 
who have received any of these therapies within 3 months before enrollment 
in the study. 
4) Acute suicide risk as defined by the investigator 
5) Pregnancy, suspected pregnancy or not on birth control if sexually active; 
6) Inability to locate and quantify a motor threshold; and 
7) Any factor that the PI determines to be reason for exclusion. 
i. 
Screening Procedures 
Following the informed consent process, enrolled subjects will begin the study eligibility 
screening process. Verification of inclusion and exclusion will be completed by the study 
physician to ensure that the subject is eligible for the study and that it is safe for them to 
participate. 
j. 
Participation in Multiple Protocols 
The consent form clearly asks patients if they are participating in any other research 
studies. The PI and/or research coordinator will also ask the patient. If patients are 
currently participating in another protocol, the PI will determine if it is appropriate to 
continue the participation. 
k. 
Payments to Participants 
Participants will be paid $50.00 per MRI scan. 
l. 
Costs to Participants 
All procedures are covered by the study. There may be additional costs incurred for the 
personal time it will take for participants to come to study appointments. 
m. 
Planned Duration of the Study 
The estimated duration of the entire study is two years. Screening a participant may take 
4-6 hours, and active participation would involve daily iTBS treatments for 6 weeks. 
Analyses of participant data may take up to 2-3 years. 

October 27, 2020 
 
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9. 
RISKS 
a. 
Potential Risks 
i. 
Investigational devices 
Anticipated Risks 
 
Seizures 
 
Repetitive transcranial magnetic stimulation is generally regarded as safe and without any 
serious or lasting adverse effects (Wasserman 1998; Rossi 2009). Inadvertent induction 
of a seizure is the most medically significant potential safety concern. However, there is 
no known risk of seizure for the above-stated brain stimulation parameters. The motor 
threshold is reflective of stimulation output necessary to cause neuronal depolarization. 
Since its first use in 2005, only one case of TBS has resulted in seizure, which occurred 
for stimulation at >100% resting MT (120% of aMT) and this was continuous TBS not 
iTBS. This proposed protocol involves iTBS delivered at 80% motor threshold. Finally, 
the proposed stimulation parameters mirror those used in Stanford IRB-approved iTBS 
protocols (Protocol Director Williams N; ID 33797, ID 38138), which have received a 
“minimal risk” designation. 
Studies evaluating the safety of iTBS in adolescents have shown it to be minimal risk 
(Hong et al., 2015; Wu et al., 2012). 
 
Safety Monitoring for Potential Seizure Risk 
 
Safety monitoring for the potential risk of seizure is addressed in several ways in this 
protocol. All subjects will be assessed during the screening phase for neurologic disease, 
concurrent medication use, or other clinical factors that may contribute to the risk of 
seizure. The Transcranial Magnetic Stimulation Adult Safety Screen (TASS) will be used 
as a screening tool to assure rigorous review of these clinical factors. Stimulation 
parameters have been selected to optimize the likelihood of clinical efficacy, while 
maintaining a safety level within the guidelines consistent with the 1998 NINDS 
workshop recommendations (Wasserman 1998). 
All clinical personnel involved in the motor threshold determinations and the iTBS 
treatment sessions will be familiar with the ISTS Consensus Statement on Managing the 
Risks of Repetitive Transcranial Magnetic Stimulation, with specific attention to the 
requirements of medical supervision and first-responder capability in the event of a 
seizure as outlined in that document. Specifically, all personnel will be familiar with the 
procedures for subject screening for risk factors prior to treatment, individual risks and 
potential benefits for specific subjects, appropriate discussion of the risks and potential 
benefits of study participation as outlined in the informed consent document, the 
stimulation parameters to be used in this study, monitoring subjects for the potential 
development of seizures by continuous visual inspection during the course of each 
treatment session (especially the more subtle signs and symptoms of frontal lobe 
seizures), and first responder management in the event of a seizure. We will have 
immediate (i.e., within minutes) availability of more sophisticated medical support, 
including access to an emergency room, in the event that a seizure is not a self-limited 

October 27, 2020 
 
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event, access to antiepileptic medications, and to life support equipment including 
oxygen, suction, blood pressure monitoring and cardiopulmonary (CPR) equipment. 
 
As stated above, for all subjects who may experience a seizure during the study, the 
Investigator will provide a letter documenting that the seizure was experimentally 
produced. 
 
If a seizure occurs during the study, that subject will be discontinued from the study. 
ii. 
Investigational drugs 
N/A 
iii. 
Commercially available drugs, biologics, reagents or chemicals 
N/A 
iv. 
Procedures 
Structural/Functional Head MRI 
 
As this study only involves MR scans, the risk is assessed as minimal. No contrast 
material or exposure to ionizing radiation will occur for the conduct of this protocol. 
 
To minimize any potential risks from the scans, the physician will ensure that the subject 
does not meet any contradictions for an MRI. Subjects who are uncomfortable in 
enclosed places (claustrophobic) may experience some discomfort. The MRI staff will be 
in contact with subjects at all times throughout the scanning process, and if necessary the 
scan can be stopped at any time. The total scanning time will be approximately 60 
minutes per scanning session. 
 
Participants may have tattoos or piercings that are magnetic. Because of the 
electromagnetic pulse, these might feel warm or hot during the treatment. 
v. 
Radioisotopes/radiation-producing machines 
N/A 
vi. 
Physical well-being 
The risks to physical well being include those listed above for study intervention (iTBS) 
and MRI. 
vii. 
Psychological well-being 
While completing the self report assessments and the clinical assessments, patients may 
become upset or frustration may occur. 
 
Participants may not experience an improvement in mood or their mood may worsen over 
the course of the study. 
 
Patients may find the study visits to be inconvenient. 

October 27, 2020 
 
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viii. 
Economic well-being 
The cost of patient's time for attending the study visits may be an economic difficulty. 
ix. 
Social well-being 
No risk to social well-being is anticipated. 
x. 
Overall evaluation of risk 
Medium 
b. 
International Research Risk Procedures 
N/A 
c. 
Procedures to Minimize Risk 
Management plan for treatment-emergent mania, exacerbation of depression, and/or 
suicidality 
 
During the consent process, subjects and families will be educated about the possibility of 
significant changes in mood, suicidal thinking, and/or behaviors during the treatment. 
These changes could include emergence of mania, worsening of depression, and/or 
suicidal thinking and behaviors. Both the subject and parent(s) will be told to initiate 
contact with their study doctor, if they experience any significant mood or behavior 
changes including suicidal ideation. Principal Investigator contact information is included 
in the consent/assent document. Furthermore, during the protocol, subjects will have 
assessments weekly where changes of psychological symptoms will be queried. Ongoing 
monitoring for worsening of depression and emergence of suicidal ideation and/or 
behaviors will be evaluated using the HAMD, C-SSRS, and CGI-S. 
 
Suspected treatment-induced mania will be evaluated using the Young Mania Rating 
Scale (YMRS). A YMRS score of ≥ 20 will prompt administration of the 
M.I.N.I./M.I.N.I. KID to determine whether or not the subject meets the Diagnostic and 
Statistical Manual of Mental Disorders, Fifth Edition (DSM-5) criteria for mania. A 
YMRS score of 20 or greater will be considered an adverse event (AE) and will be 
monitored using the YMRS; the emergence of DSM-5 verified mania will be treated as a 
serious adverse event (SAE) and will also be monitored using the YMRS. 
 
Exacerbation of depression, suicidality or induction of mania would constitute an SAE 
and the subject would be discontinued from the study. Subject would then be referred for 
clinical follow-up outside of the study. 
 
Treatment plan for other side effects of iTBS experienced during treatment: 
Repositioning of coil and prophylactic use of acetaminophen or ibuprofen will be allowed 
for subjects reporting sensations at or near the stimulation site which are uncomfortable 
or painful. During the first week of treatment only. 
 
Treatment plan for other potential side effects experienced following treatment: 

October 27, 2020 
 
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Subjects reporting headaches during or following study treatment will be encouraged to 
take acetaminophen or ibuprofen prior to the daily treatment. To reduce the risk of 
temporary or permanent hearing loss due to noise emitted from the stimulator, subjects 
will wear protective ear plugs during treatment. All subjects will be monitored, and 
appropriate treatment will be recommended including the possibility of stopping iTBS. 
Any other potential side effects will be managed symptomatically with treatment(s) 
deemed appropriate by the study site Principal Investigator. All symptomatic 
interventions will be recorded in the subject’s case file and, if applicable, adverse event 
CRF. 
d. 
Study Conclusion 
Subjects may withdraw voluntarily from the study at any time. They may be withdrawn 
from the study by the Investigator if a subject: 
• 
experiences a seizure, 
• 
experiences a DSM-5-confirmed treatment-induced mania, 
• 
is non-compliant with study procedures 
 
The Investigator may also withdraw a subject if he/she believes that for safety reasons it 
is in the best interest of the subject to be withdrawn. 
 
Discontinuation information [e.g., date and the reason(s) for discontinuation] must be 
recorded in the subject’s CRF (i.e., Study Completion Form). Subjects who discontinue 
prematurely should complete the final assessments within 2 days following their last 
iTBS treatment session. 
 
Subjects withdrawn from the study due to an AE will be followed up for 30 days or until 
resolution. 
e. 
Data Safety Monitoring Plan (DSMC) 
i. 
Data and/or events subject to review 
The IRB has oversight for the overall safety of the study. Safety monitoring will 
include careful assessment and appropriate reporting of adverse events as noted 
above, as well as the construction and implementation of a data and safety-
monitoring plan. Medical monitoring will include a regular assessment of the number 
and type of serious adverse events. 
ii. 
Person(s) responsible for Data and Safety Monitoring 
The protocol director will be responsible for data and safety monitoring for this pilot 
study. 
iii. 
Safety Reporting 
Any SAE, regardless of causal relationship, will be reported immediately to the IRB 
(within one business day). Compliance with this time requirement is essential so that 
the IRB may comply with its regulatory obligations. 
 

October 27, 2020 
 
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Follow-up information relating to an SAE must be reported to the IRB after the 
information is received by the Investigator by faxing a completed serious adverse 
event form to the fax telephone number listed in Section 1.2 of this protocol and 
confirming by telephone that the fax was received. The subject should be observed 
and monitored carefully until the condition resolves or stabilizes or its cause is 
identified. 
iv. 
Specific triggers or stopping rules 
Specific occasions when study treatment may be stopped are explained Section 8.4 in 
the discussion of Anticipated Risks. 
Because of the anticipated low level of adverse events of iTBS, the PD will be 
charged with reviewing adverse events at least every six months. Serious adverse 
events will be reviewed on a monthly basis, unless a more urgent review is requested. 
v. 
DSMB Reporting 
The outcome of the review will be disseminated to the investigators as appropriate. 
vi. 
Will a board, committee, or safety monitor be responsible for study monitoring?  
Yes 
f. 
Risks to Special Populations 
iTBS may be a beneficial treatment for adolescents that have not responded well to medication. 
The risks of iTBS are less great than alternative approaches such as ECT. 
All parents or LAR will sign consent for adolescents bw 12-17 yo inclusive. All adolescents bw 
12-17yo will also sign assent. These consent and assent procedures are applicable for both the 
parent and the MRI portion of the study. 
10. 
BENEFITS 
It is possible that depression symptoms will improve while receiving the study 
iTBS. 
 
The study may also benefit other people with MDD by furthering our understanding of the 
antidepressant effectiveness and safety of iTBS in adolescents and young adults. 
11. 
PRIVACY AND CONFIDENTIALITY 
All participant information and specimens are handled in compliance with the Health Insurance 
Portability and Accountability Act (HIPAA) and privacy policies of Stanford University, Stanford 
Health Care, and Stanford Children’s Health.