A Randomized, Sham-Controlled Trial Evaluating the Safety and Effectiveness of NeuroStar® Transcranial Magnetic Stimulation (TMS) Therapy in Depressed Adolescents
Phase: NA
Conditions: Major Depressive Disorder
Sponsor: Neuronetics

Protocol 44-02219-000 
 
NeuroStar® TMS Adolescent MDD RCT 
Page 1 of 61  
 
 
 
                          Revision C,  31 Aug 2015 
 
CONFIDENTIAL 
 
44-02219-000 A Randomized, Sham-Controlled Trial Evaluating the Safety and Effectiveness of 
NeuroStar Transcranial Magnetic Stimulation (TMS) Therapy in Depressed Adolescents 
 
 
 
Regulatory Sponsor: 
Neuronetics, Inc 
3222 Phoenixville Pike 
Malvern, PA 19355 
Principal Investigator: 
 
 
 
 
 
Dr. Paul E. Croarkin 
Assistant Professor of Psychiatry 
Child and Adolescent Psychiatry 
Mayo Clinic 
200 First Street SW 
Rochester, MN 55905 
 
Study Product: 
NeuroStar TMS Therapy® System using NeuroStar XPLOR® 
research configuration 
 
 
 
Rev A:  June 8, 2015 
Rev B:  June 19, 2015 
Rev C: August 31, 2015 
 
NCT02586688

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Protocol 44-02219-000 
 
NeuroStar® TMS Adolescent MDD RCT 
Page 4 of 61  
 
 
 
                          Revision C,  31 Aug 2015 
 
CONFIDENTIAL 
APPENDIX A. PHASE I SCHEDULE OF EVENTS ........................................................................................ 53 
APPENDIX B. PHASE II SCHEDULE OF EVENTS ....................................................................................... 55 
APPENDIX C. PHASE III SCHEDULE OF EVENTS ...................................................................................... 56 
APPENDIX D. ........................................................................................................................................... 57 
 CONCOMITANT MEDICATION LIST ........................................................................................................ 57 
 
 
 

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Protocol 44-02219-000 
 
NeuroStar® TMS Adolescent MDD RCT 
Page 6 of 61  
 
 
 
                          Revision C,  31 Aug 2015 
 
CONFIDENTIAL 
2 Medical Monitor Signature 
I have read and approve this protocol. This study will be conducted according to all stipulations of the 
protocol, including all statements regarding confidentiality.  
 
 
Medical Monitor’s Signature 
 
Date of Signature  
(DD Mmm YYYY) 
 
  
 
  
Mark A. Demitrack, MD 
  
Medical Monitor’s Name (print) 
  
 
  
 
 
 

Protocol 44-02219-000 
 
NeuroStar® TMS Adolescent MDD RCT 
Page 7 of 61  
 
 
 
                          Revision C,  31 Aug 2015 
 
CONFIDENTIAL 
3 Investigator Agreement 
I have read this protocol and agree that it contains all necessary details for conducting the study as 
described. 
I will conduct this investigation in accordance with the agreement, the investigational plan, Part 812 and 
other applicable FDA regulations, and any conditions of approval imposed by the Institutional Review 
Board (IRB) and FDA. 
I will provide a copy of my current curriculum vitae. 
I will provide a summary of my relevant clinical experience (including dates, location, extent and type of 
experience) for the conduct of this trial. 
By signing this document, I attest to the fact that I have not been involved in an investigation or other 
research that was terminated, or if so, I will provide an explanation of the circumstances that led to 
termination. 
I will maintain all confidentiality. 
I will supervise all testing of the device involving human subjects. 
I will ensure that all study personnel are appropriately trained and that they have access to all relevant 
documents related to the investigations, as furnished by the sponsor. 
I will discuss all relevant study-related information with study personnel to ensure that they are fully 
informed about the device and the studies. 
I will assure that all requirements of informed consent are met for subjects participating in these studies.  
I understand that this study may be terminated or enrollment suspended at any time by the sponsor, with 
or without cause, or by me if it becomes necessary to protect the best interests of the study subjects. 
 
 
Investigator’s Signature 
 
Date of Signature  
(DD Mmm YYYY) 
 
  
Investigator’s Name (print) 
  
 
 
 
 

Protocol 44-02219-000 
 
NeuroStar® TMS Adolescent MDD RCT 
Page 8 of 61  
 
 
 
                          Revision C,  31 Aug 2015 
 
CONFIDENTIAL 
4 Institutional Review Board (IRB) 
The name, address, and phone number of the IRB used by each site participating in this study is identified 
below. 
 
IRB: 
 
 
 
Address: 
 
 
 
 
 
 
 
Phone No.: 
 
 
 
 
IRB: 
 
 
 
Address: 
 
 
 
 
 
 
 
Phone No.: 
 
 
 
 
IRB: 
 
 
 
Address: 
 
 
 
 
 
 
 
Phone No.: 
 
 
 
 
 

Protocol 44-02219-000 
 
NeuroStar® TMS Adolescent MDD RCT 
Page 9 of 61  
 
 
 
                          Revision C,  31 Aug 2015 
 
CONFIDENTIAL 
5 Disclosure Statement 
This protocol contains information that is confidential and proprietary to the sponsor. It is being provided 
to you for the sole purpose of evaluating and/or conducting a clinical trial for the sponsor. You may 
disclose the contents of this document only to study personnel under your supervision, IRBs, or duly 
authorized representatives of the U.S. FDA or other regulatory authority for this purpose under the 
condition that they maintain confidentiality.  
The contents of this protocol may not be used in any other device trial, disclosed to any other person or 
entity, and/or published without the prior written permission of the sponsor. The foregoing shall not apply 
to disclosure required by any regulations; however, you will give prompt notice to the sponsor of any 
such disclosure. 
Any information that may be added to this protocol is also confidential and proprietary to the sponsor and 
must be kept in confidence in the same manner as the contents of this protocol. 

Protocol 44-02219-000 
 
NeuroStar® TMS Adolescent MDD RCT 
Page 10 of 61  
 
 
 
                          Revision C,  31 Aug 2015 
 
CONFIDENTIAL 
6 List of Abbreviations 
1H-MRS 
Proton Magnetic Resonance Spectroscopy 
3T 
3 Tesla 
AC 
Anterior Cingulate 
AE 
Adverse Event/Adverse Experience 
AMI 
Autobiographical Memory Interview 
APB 
Abductor Pollicis Brevis 
ATHF 
Antidepressant Treatment History Form 
ATR 
Antidepressant Treatment Record 
CDRS-R 
Childhood Depression Rating Scale – Revised 
CFR 
Code of Federal Regulations 
CGI-S 
Clinical Global Impression – Severity of Illness 
CRF 
Case Report Form 
CSF 
Cerebrospinal Fluid 
C-SSRS 
Columbia – Suicide Severity Rating Scale 
DSMB 
Data and Safety Monitoring Board 
DSM-5 
Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition 
eCRF 
Electronic Case Report Form 
ECT 
Electroconvulsive Therapy 
EDC 
Electronic Data Capture 
EMR 
Electronic Medical Record 
FDA 
Food and Drug Administration 
GCP 
Good Clinical Practice 
HAMD 
Hamilton Depression Rating Scale 
HIPAA 
Health Insurance Portability and Accountability Act 
Hz 
Hertz 
IDE 
Investigational Device Exemption 
IRB 
Institutional Review Board 
ITT 
Intention-to-Treat 
L-DLPFC 
Left Dorsolateral Prefrontal Cortex 
MADRS 
Montgomery Asberg Depression Rating Scale 
M.I.N.I. 
Mini International Neuropsychiatric Interview 
M.I.N.I. KID 
Mini International Neuropsychiatric Interview for Children and Adolescents 
MDD 
Major Depressive Disorder 
MRI 
Magnetic Resonance Imaging 
MRS 
Magnetic Resonance Spectroscopy 
NIH 
National Institutes of Health 
PHI 
Protected Health Information 
PI 
Principal Investigator 
QIDS-A17-SR 
Quick Inventory of Depressive Symptoms – Adolescent Version – Self Report 
TMS 
Transcranial Magnetic Stimulation 
SAE 
Serious Adverse Event/Serious Adverse Experience 
SOP 
Standard Operating Procedure 
SSRI 
Selective Serotonin Reuptake Inhibitor 
TASS 
Transcranial Magnetic Stimulation Adult Safety Screen 
TEEQ 
Treatment Expectations and Experience Questionnaire 
YMRS 
Young Mania Rating Scale 

Protocol 44-02219-000 
 
NeuroStar® TMS Adolescent MDD RCT 
Page 11 of 61  
 
 
 
                          Revision C,  31 Aug 2015 
 
CONFIDENTIAL 
7 Study Summary 
 
Title 
A Randomized, Sham-Controlled Trial of the Safety and Effectiveness of 
NeuroStar Transcranial Magnetic Stimulation (TMS) Therapy in Depressed 
Adolescents 
Running Title 
NeuroStar® TMS Adolescent MDD RCT 
Protocol Number 
 44-02219-000  
Methodology 
Randomized, sham-controlled, triple-blinded; crossover open-label acute 
treatment and post treatment follow up. (Investigator Blinded to criteria for 
eligibility to entry into crossover study phase) 
Overall Study 
Duration 
42 months  
Subject Participation 
Duration 
Screening to Randomization:  1 week 
 
Phase I (Randomized, Blinded): 6 weeks (Active TMS vs. Sham)  
 
Phase II (Non-Randomized, Open-label): 6 weeks of open-label acute treatment 
(for Phase I subjects who did not receive protocol-defined clinical benefit). 
(Note:  The definition of protocol defined clinical benefit is concealed from 
study staff.) 
 
Taper (End of Phase I or Phase II):  After acute treatment is completed (prior to 
exit of study at end of phase or prior to entry into Phase III), subject will receive 
3 weeks of taper treatments (week 1:3, week 2:2, week 3:1 
 
Phase III (Long term follow up): 6 month follow up with retreatment course for 
symptom re-emergence (for Phase I and II subjects who received protocol-
defined clinical benefit) 
Objectives 
Primary:   
To evaluate the antidepressant effects of daily, active TMS (when compared with 
sham treatment) in adolescents meeting criteria for Major Depressive Disorder, 
single or recurrent episode (Phase I).   
 
Secondary:   
To evaluate the acute and long term safety of TMS treatment in adolescent MDD 
subjects. 
 
To evaluate the durability of benefit of TMS treatment over the course of 6 
months in subjects who received clinical benefit from acute treatment course(s) 
(Phase III). 
 
To evaluate the benefit of daily, active, open-label TMS in Phase I subjects who 
did not receive  protocol-defined clinical benefit; as new acute treatment (sham 
to active) or as extended treatment course (blinded active to open label active) 
(Phase II) 
 

Protocol 44-02219-000 
 
NeuroStar® TMS Adolescent MDD RCT 
Page 12 of 61  
 
 
 
                          Revision C,  31 Aug 2015 
 
CONFIDENTIAL 
Structural MRI (conducted at specific sites only):   To utilize standard 
morphometric measures to determine structural changes in the brain associated 
with TMS treatment. 
Number of Subjects 
Phase I: Total of 100 enrolled (50 Active/50 Sham) across sites 
 
Phase II: Subjects from phase I who did not receive protocol-defined clinical 
benefit from acute treatment will be offered open-label treatment (estimated to 
be 42 subjects) 
 
Phase III: Subject who did meet protocol-defined clinical benefit after acute 
treatment in Phase I or Phase II will be followed for 6 months post taper 
(estimated to be 37 subjects) 
 
Structural MRI subset: Approximately 25% of subjects of the Phase I population.  
 
 
Diagnosis and Main 
Inclusion Criteria 
• 
Male or female outpatients, age 12-21, meeting DSM-5 diagnosis of Major 
Depressive Disorder, single or recurrent course of illness, of moderate or 
greater symptom severity  
• 
CGI-S score ≥ 4 
• 
HAMD24, item 1 ≥ 2 and total score at least 20 at screening 
• 
At the end of the baseline visit, subject must have a HAMD24 score of ≥ 18 
and change in score may not be ≥ 25% decrease from that seen at the 
screening visit 
• 
Duration of current episode of depression ≥ 4 weeks and ≤ 3 years 
• 
Resistance to antidepressant treatment in a discrete illness episode defined 
by the Antidepressant Treatment Record (ATR): 
- 
Resistance to treatment defined by ATR level 1 through 4 in current 
episode.  If insufficient number of trials in the current episode, then 
must also have failed  ≥1 and ≤ 4 trials in a previous episode 
- 
Subjects who have been unable to complete an  antidepressant trial of 
adequate dose and duration due to intolerance to antidepressant 
therapy may be included if they have demonstrated intolerance to ≥ 4 
antidepressant medications within one discrete illness episode 
(current or a previous episode as defined above) 
• 
For any subject currently receiving antidepressant medication, the clinician 
must determine that insufficient benefit is being received from this treatment 
and it is clinically appropriate to discontinue the existing antidepressant. 
Exclusion Criteria 
• 
Subjects associated directly with this study or indirectly by a parent or 
sibling being affiliated with the study. 
• 
Subjects diagnosed by the investigator with one or more of the following 
conditions (current, unless otherwise stated):  depression secondary to a 
general medical condition or substance-induced; seasonal pattern of 
depression; history of substance abuse or dependence within the past year 
(except nicotine or caffeine); any psychotic disorder (lifetime), including 
schizoaffective disorder, or major depression with psychotic features in this 
or previous episodes; amnestic disorder, mental retardation, bipolar disorder; 
eating disorder (lifetime); obsessive compulsive disorder (lifetime); or 

Protocol 44-02219-000 
 
NeuroStar® TMS Adolescent MDD RCT 
Page 13 of 61  
 
 
 
                          Revision C,  31 Aug 2015 
 
CONFIDENTIAL 
posttraumatic stress disorder (lifetime) 
• 
Any psychiatric disorder, which in the judgement of the Investigator may 
hinder the subject in completing the procedures required by the study 
protocol. 
• 
Subject with a clinically defined neurological disorder or insult including, 
but not limited to any condition likely increase the risk of seizure; such as,  
space occupying brain lesion; any history or family history of epilepsy; 
history of cerebrovascular accident; transient ischemic attack within two 
years; cerebral aneurysm; dementia; brain surgery or history of stroke.  
• 
Increased risk of seizure for any reason, including prior diagnosis of 
increased intracranial pressure or history of significant head trauma with loss 
of consciousness for ≥ 5 minutes. 
• 
A true positive response to any question on the TASS 
• 
Inability to locate and quantify a motor threshold as defined in the protocol 
• 
History of treatment with ECT or TMS Therapy for any disorder 
• 
Use of any investigational drug within 4 weeks of the baseline visit 
• 
Use of any excluded medication(s) listed on the Concomitant Medication 
List (Appendix D) within 1 week of the baseline visit 
• 
Significant acute suicide risk, defined as follows:  Suicide attempt within the 
previous 6 months that required medical treatment or ≥ 2 attempts in the past 
12 months, or has a clear cut plan for suicide and states that he/she cannot 
guarantee that he/she will inform a family member or call his/her psychiatrist 
or the investigator if the impulse to implement the plan becomes substantial 
during the study; or, in the investigator’s opinion, is likely to attempt suicide 
within the next 6 months. 
• 
Conductive, ferromagnetic, or other magnetic-sensitive metals implanted in 
the subject’s head within 30 cm of the treatment coil excluding the mouth 
that cannot safely be removed. Examples include cochlear implants, 
implanted electrodes/stimulators, aneurysm clips or coils, stents, bullet 
fragments, jewelry and hair barrettes.  
• 
Active or inactive implants (including device leads), including deep brain 
stimulators, cochlear implants, and vagus nerve stimulators.  
• 
Cardiac pacemakers, implanted medication pumps, intracardiac lines, or 
acute, unstable cardiac disease 
• 
Known or suspected pregnancy 
• 
If sexually active female, not on an approved method of birth control. 
• 
Unstable psychotherapy (therapy must be for at least 3 months prior to entry 
into the study, with no anticipation of change in the frequency or treatment 
focus of the therapeutic sessions over the duration of the study) 
• 
Positive urine drug screen (a positive screen at screening may be repeated 
once prior to randomization upon approval from the Sponsor) 
• 
Clinically significant laboratory abnormality or medical condition, in the 
opinion of the Investigator would hinder the subject in completing the 
procedures required by the study. 
Study Device 
NeuroStar TMS Therapy® System using NeuroStar XPLOR® research 
configuration 

Protocol 44-02219-000 
 
NeuroStar® TMS Adolescent MDD RCT 
Page 14 of 61  
 
 
 
                          Revision C,  31 Aug 2015 
 
CONFIDENTIAL 
Duration of Exposure 
Phase I (Randomized, Blinded): 
For subjects randomized to the active treatment, stimulation will occur at a 
maximum of 120% magnetic field intensity relative to the subject’s resting 
motor threshold (MT), at 10 pulses per second (10 Hz) for 4 seconds, with an 
intertrain interval of 26 seconds.  Repositioning of coil, per NeuroStar User 
Manual, and prophylactic use of acetaminophen or ibuprofen will be allowed for 
subjects reporting sensations at or near the stimulation site which are 
uncomfortable.  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.  Treatment sessions will last for 37.5 minutes 
(75 trains) to provide a total of 3,000 pulses per treatment session.  A maximum 
total of 36 treatments will be completed within 9 weeks of Phase I (including the 
6 treatments administered during the 3 week taper phase).  If the subject meets 
criteria (blinded to Site personnel) to enter Phase II, they will not complete the 3 
week taper phase, resulting in a maximum total of 30 treatments. 
 
Phase II (Non-Randomized, Open-label): 
Subjects who do not achieve ;protocol-defined clinical benefit to treatment in 
Phase I will be offered the opportunity to undergo acute TMS treatment using 
the known-active therapy coil in Phase II.  A maximum total of 36 treatments 
will be completed within 9 weeks of Phase II (including the 6 treatments 
administered during the 3 week taper phase).   
 
Therefore, subjects who are randomized to active treatment during Phase I and 
subsequently enroll into Phase II will receive up to a total of 66 active treatments 
using stated study parameters within the 15 week combined timeframe 
(including one taper phase).  
 
Subjects who are randomized to sham treatment during Phase I and subsequently 
enroll in Phase II will receive up to a total of 36 active treatments using stated 
study parameters within the 15 week combined timeframe (including one taper 
phase). 
 
Phase III (Long Term Follow up):  
Subjects who achieve protocol-defined clinical benefit from treatment in Phase I 
or Phase II will be followed for 6 months after treatment. 
 
If a subject experiences re-emergence of depressive symptoms, an acute TMS 
retreatment course will be initiated.  The TMS retreatment course will continue 
up to 6 weeks until symptom score is at or below Phase III entry score.  Each 
successful retreatment is followed by a 3 week taper.  Subjects could receive 
retreatment on more than one occasion; therefore, any subject could receive up 
to 72 treatments in Phase III over 6 months, in addition to Phase I and II 
exposure. 
Reference Therapy 
Subjects in Phase I who are randomized to sham treatments will have schedules, 
systematic assessments, and treatment approaches that are identical to subjects 
randomized to active treatments.  Subjects, treaters, and clinical raters will not 
know whether the treatment is active or sham in nature (triple-blinded).  The 
sham coil is identical in its appearance to the active coil.  Furthermore, the sham 

Protocol 44-02219-000 
 
NeuroStar® TMS Adolescent MDD RCT 
Page 15 of 61  
 
 
 
                          Revision C,  31 Aug 2015 
 
CONFIDENTIAL 
coil operates with an acoustically matched profile that renders the auditory 
experience of the treatments virtually indistinguishable to subjects or 
researchers.  The sham coil also creates a mild percussive sensation that may be 
felt by the subject and further assists in simulating the active condition.  The 
blinded randomization of patients in the Phase I acute phase to the active or 
sham condition will remain blinded for the duration of all study phases including 
Phases II and III.  
Concomitant Therapy 
Permitted: Zaleplon, zolpidem, or zopiclone (1 dose nightly) as needed for 
treatment emergent insomnia or lorazepam (up to 2 mg daily) for treatment 
emergent anxiety, may be administered for up to 14 doses during Phase I and an 
additional 14 doses during Phase II.  For Phase III, these medications may be 
administered for up to 10 days, on ≤5 occasions. The use of alternative hypnotics 
or anxiolytic compounds requires prior approval from the Sponsor.  Hormonal 
contraceptives are allowed if the subject has been on a stable dose for at least 3 
months. The use of alternative hypnotics or anxiolytic compounds requires prior 
approval from the Sponsor.  Short-term treatments for headaches, allergies, 
colds, or flu-like symptoms require prior approval from the Sponsor. 
 
Prohibited: Any medication administered for the treatment of any psychiatric or 
neurologic disorder or any other known CNS-active drugs, including herbal, 
over-the-counter, and homeopathic medications, MAOIs, other antidepressants, 
antipsychotics, stimulants and mood stabilizers. 
Statistical 
Methodology 
Statistical analysis plan for Primary objective and secondary objectives :  
• 
Primary efficacy outcome, HAMD24, will be examined in a frequentist 
analysis (i.e., meta-analysis) combining the data obtained in this study 
with data borrowed from two prior randomized controlled trials 
conducted in adults tested using the same procedures outlines in this 
protocol (O’Reardon, et al., 2007; George, et al., 2010). 
• 
The model for this analysis will include the following terms: treatment 
(active vs. sham), baseline score (continuous), medication resistance 
level as determined using the Antidepressant Treatment Record (ATR), 
(ATR=1 ‘Lo’ vs. ATR=2-4 ‘Hi’), and Study (adolescent study, and adult 
studies O’Reardon, et al, 2007 and George, et al, 2010) as fixed effects, 
and, interaction terms for “study-by-treatment” and “ATHF medication 
resistance level-by-treatment”.  A random effect of “site nested within 
study” will also be included to assess any potential site effects. 
• 
In the absence of a statistically significant interaction between Study and 
Treatment on the primary efficacy outcome variable at a pre-specified 
alpha level = 0.10, the continuity of efficacy across the age range 12 to 
70 will be established, and the main effect for treatment is statistically 
significant at the alpha level = 0.05. 
• 
A sample size of 50 patients per treatment condition in the adolescent 
study and an alpha level of 0.10 to test the Study by Treatment 
interaction, will detect a statistically significant Study by Treatment 
interaction if the mean treatment group difference, in favor of active, is 
greater than the upper bound of 5.5 points or less than the lower bound 
of -0.8 points.  In the absence of a statistically significant interaction 
between Study and Treatment, the lower bound of the observed 
treatment group difference must be greater than 1.7 in favor of the active 

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Protocol 44-02219-000 
 
NeuroStar® TMS Adolescent MDD RCT 
Page 17 of 61  
 
 
 
                          Revision C,  31 Aug 2015 
 
CONFIDENTIAL 
A company-independent, 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.  Study 101 evaluated the safety and efficacy of NeuroStar TMS Therapy in 301 adult 
outpatients across 23 sites with moderate to severe major depressive disorder and who failed to benefit 
from 1 through 4 prior antidepressant medication trials administered at an adequate dose and duration, 
and verified using the ATHF (O’Reardon2007; Janicak, 2008). The patient population was similar to 
patients enrolled in the independent NIMH-funded trial.  Outcome on the primary efficacy endpoint 
(MADRS change from baseline at 4 weeks) favored NeuroStar TMS Therapy (P=0.057) over sham 
treatment for the ATHF 1 through 4 population. A subgroup analysis of the overall study population 
demonstrated that the device was safe and effective for patients who had failed to achieve satisfactory 
improvement from one prior antidepressant medication (N=164 patients, P=0.0006, MADRS, primary 
efficacy endpoint) in the current episode. 
 
Study 19-50001 was a multisite naturalistic study in 42 US centers that evaluated the acute efficacy and 
12-month durability of NeuroStar TMS Therapy under conditions of general clinical use (Carpenter, 
2012; Janicak, 2013; Dunner 2014).  This study enrolled adult patients (N=307) with MDD who failed to 
benefit from any number of antidepressant medications administered at an adequate dose and duration 
(mean of 2.5, range 0-14) in the current episode. 
 
There was a statistically significant improvement from baseline in CGI-S total score (CGI-S, −1.9 ± 1.4, 
P < .0001, primary efficacy outcome) at end of acute treatment. A similar pattern and magnitude of 
clinical improvement was observed in the two patient self-reported outcome measures, the PHQ-9 (−8.7 ± 
7.2, P <0.0001) and the IDS-SR (−18.3 ± 14.9, P<0.0001). Categorical response and remission rates were 
consistent in clinical magnitude on all three outcome measures i.e., CGI-S (58.0% response; 37.1% 
remission), PHQ-9 (56.4% response; 28.7% remission), and IDS-SR (41.5% response; 26.5% remission). 
 

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Protocol 44-02219-000 
 
NeuroStar® TMS Adolescent MDD RCT 
Page 21 of 61  
 
 
 
                          Revision C,  31 Aug 2015 
 
CONFIDENTIAL 
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 TMS 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. All sites will be required to 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 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. 
 
All personnel involved in the administration of TMS in this study will be required to participate 
in individual site initiation visits and/or complete other sponsor training requirements and be able 
to demonstrate understanding of these issues to sponsor study personnel prior to initiation of 
subject enrollment at that site. 
 
If a seizure occurs during the active treatment phase of the study, that subject will be discontinued 
from the study. 
Mood considerations 
There is a risk that the TMS treatment may not be effective for some subjects and that their depression 
may worsen.  Concerns for theoretical mood destabilization, including induction of mania or worsening of 
suicidality, will be carefully considered throughout the course of treatment (at every treatment visit); and 
subjects, their families, and investigators may elect to discontinue the treatment protocol and withdraw 
from the study at any point.  Furthermore, safety considerations consistent with current standard of care in 
child and adolescent psychiatric practice will be employed including contacting the primary mental health 
care provider, referral to on-call child and adolescent psychiatric services, referral to the emergency room, 
and/or hospitalization if necessary.  
 
Several studies in the adult population and limited studies in the adolescent population have so far 
demonstrated the feasibility of TMS to treat depression without any indicators of exacerbation of 
depression or suicidality (Loo 2006; Janicak 2008; George 2010; Wall 2011).  However, pediatric use of 
antidepressant pharmacotherapy has corresponded with warnings about increases in suicidal ideation and 

Protocol 44-02219-000 
 
NeuroStar® TMS Adolescent MDD RCT 
Page 22 of 61  
 
 
 
                          Revision C,  31 Aug 2015 
 
CONFIDENTIAL 
behavior in youths and young adults.  No compelling data are available to indicate whether the net result 
of treatment of depressed youths with these compounds is an overall increase or an overall decrease in the 
hazard of completed suicide; there is limited and inconclusive evidence in either direction (Rapaport 
2006; Gibbons 2007; Libby 2007; Cheung 2008; Maalouf 2010). 
 
Exacerbation of depression that results in hospitalization or increased suicidality, or any emergent 
symptoms that are deemed clinically significant by the treating physician, will be considered a Serious 
Adverse Event (SAE), regardless of relatedness to TMS treatment. 
 
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 each site’s consent/assent document.  Furthermore, 
during the active treatment phases of the protocol, subjects will have assessments weekly where 
changes of psychological symptoms will be queried (see Appendix A-C for schedules of events).  
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.  See Section 17 for SAE handling.  Subject would 
then be referred for clinical follow-up outside of the study. 
 
Other potential side effects of TMS that may be experienced during treatment 
In the adult controlled registration studies using the NeuroStar TMS Therapy® System, the adverse event 
verbatim terms were collected at each clinical visit and subsequently coded using the current version of 
the Medical Dictionary for Regulatory Activities (MedDRA) and reported by MedDRA preferred terms.  
The most commonly occurring adverse events in the randomized controlled trial described in O’Reardon, 
et al (2007) are shown in Table 1, for those events occurring with an incidence of 5% or greater in the 
active TMS treatment group and twice the rate for the sham TMS treatment group.  Headache occurred 
equally in subjects in both treatment groups.  Similar rates of adverse events were reported in the 
controlled trial using the NeuroStar TMS Therapy System described in George, et al., 2010.  Post market 
surveillance has been consistent with these events reported, with no additional types of events reported for 
adolescent subjects. 
 
 

Protocol 44-02219-000 
 
NeuroStar® TMS Adolescent MDD RCT 
Page 23 of 61  
 
 
 
                          Revision C,  31 Aug 2015 
 
CONFIDENTIAL 
Table 1.  Adverse Events with an Incidence in Active TMS at a Rate of > 5% and at Least 
2x Sham in the Safety Exposure Study Population  
Body System  
- 
Preferred Term 
Active TMS 
(N=165) 
N (%) 
Sham TMS 
(N=158) 
N (%) 
Eye disorders 
- 
 Eye pain 
10 (6.1) 
3 (1.9) 
Gastrointestinal disorders 
- 
 Toothache 
12 (7.3) 
1 (0.6) 
General disorders and site administration conditions 
- 
 Application site discomfort 
- 
 Application site pain 
- 
 Facial pain 
18 (10.9) 
59 (35.8) 
11 (6.7) 
2 (1.3) 
6 (3.8) 
5 (3.2) 
Musculoskeletal and connective tissue disorders 
- 
 Muscle twitching 
34 (20.6) 
5 (3.2) 
Skin and subcutaneous tissue disorders 
- 
 Pain of skin 
14 (8.5) 
1 (0.6) 
 
There is the potential risk of alteration in auditory threshold.  As a result of the rapid changes in the 
magnetic field during TMS administration, the coil produces an audible, high-energy clicking sound, 
which may be associated with temporary increases in auditory threshold.  During previous studies with 
the NeuroStar TMS Therapy® System (O’Reardon 2007; George 2010; Carpenter 2012), all subjects were 
required to use hearing protection at a protection rating of ≥30 db.  No change in hearing was found with 
air conduction threshold testing in the two randomized clinical studies (Janicak 2008 and George 2010) 
when this method of ear protection was used.  As a safety precaution, auditory assessments will be 
conducted during this study per the schedule of events 
Treatment plan for other side effects of TMS experienced during treatment: 
Repositioning of coil, consistent with the guidelines in the NeuroStar User Manual, 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, in the event that the participant cannot tolerate the treatment at the stipulated 
study dose parameters, dose intensity may be titrated downward to 110% of the motor threshold, 
with all other dose parameters remaining the same. 
Treatment plan for other potential side effects experienced following treatment: 
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 TMS.  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. 
 
**Treatment with the Neurostar TMS Therapy System may involve other risks that are not known 
at the present time.  The long-term effects of TMS are not known.** 
 

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Protocol 44-02219-000 
 
NeuroStar® TMS Adolescent MDD RCT 
Page 27 of 61  
 
 
 
                          Revision C,  31 Aug 2015 
 
CONFIDENTIAL 
 
Vital signs including height, weight, blood pressure and heart rate will be collected at the baseline visit 
and at week 6. 
 
Laboratory determination will be measured at screening and include: Blood chemistry, hematology, urine 
drug screen, and urine pregnancy for female subjects. 
 
Subjects will be evaluated clinically for adverse events at each visit.  Serious adverse events (SAEs) will 
be recorded as they occur and reported to Neuronetics by the study site within one business day of 
notification. 
 
Cognitive function assessments will be conducted at the baseline visit and at week 6.  The following tests 
from the NIH Toolbox Cognition Battery are used for this study: 
 
• 
Education 
• 
Handedness 
• 
Attention 
o Flanker Inhibitory Control and Attention Test 
• 
Episodic Memory 
o Picture Sequence Memory Test 
o Auditory Verbal Learning Test (Rey) 
• 
Executive Function 
o Dimensional Change Card Sort Test 
o Flanker Inhibitory Control and Attention Test 
• 
Language 
o Picture Vocabulary Test 
o Oral Reading Recognition Test 
• 
Processing Speed 
o Pattern Comparison Processing Speed Test 
• 
Memory 
o List Sorting Working Memory Test 
 
The C-SSRS will be completed weekly during TMS treatment to assess worsening of illness and 
suicidality.  The YMRS will be completed at baseline and will be repeated based on reported change in 
symptoms. 
 
Air conduction thresholds will be assessed for both left and right ears at the baseline visit and at week 6. 
Phase II 
See Appendix B for schedule of events.  The schedule of efficacy and safety measures for Phase II will be 
identical to that of Phase I.  
Phase III 
See Appendix C for schedule of events. 
 
Outcome measures for Follow up Phase III, including HAMD/MADRS structured interview, QIDS-A17-
SR, CDRS-R, and CGI-S, will be assessed per schedule of events.  
 

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Protocol 44-02219-000 
 
NeuroStar® TMS Adolescent MDD RCT 
Page 30 of 61  
 
 
 
                          Revision C,  31 Aug 2015 
 
CONFIDENTIAL 
Contraindication to TMS  
Conductive, ferromagnetic, or other magnetic-sensitive metals implanted 
in the subject’s head within 30 cm of the treatment coil excluding the 
mouth that cannot safely be removed. Examples include cochlear 
implants, implanted electrodes/stimulators, aneurysm clips or coils, 
stents, bullet fragments, jewelry and hair barrettes.  
Active or inactive implants (including device leads), including deep 
brain stimulators, cochlear implants, and vagus nerve stimulators.  
Physician evaluation and review of 
medical record  
Cardiac pacemakers, implanted medication pumps, intracardiac lines 
Physician evaluation and review of 
medical record 
A true positive response to any question on the TASS questionnaire  
Physician evaluation 
History of neurological disorder or insult including but not limited to the 
following that may increase risk of seizure: 
• 
Antecedent seizures 
• 
Any condition likely to be associated with increased intracranial 
pressure 
• 
Space occupying brain lesion 
• 
History of cerebrovascular accident 
• 
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 
Physician evaluation and review of 
medical record 
Unstable medical conditions, including:  
• 
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. 
Physician evaluation; medical 
history 
Clinically significant laboratory abnormality, in the opinion of the 
Investigator 
Physician review of screening 
laboratory tests 
Individuals diagnosed with the following conditions (current unless 
otherwise stated): 
• 
Depression secondary to a general medical condition, or 
substance induced: 
• 
Seasonal pattern of depression as defined by DSM-5 
• 
Any psychotic disorder (lifetime), including history of 
schizophrenia, schizoaffective disorder, other psychosis, 
psychotic features in this or previous episodes, amnestic 
M.I.N.I. or M.I.N.I. KID (age <18) 
to confirm DSM-5 criteria 
 
Physician Examination and 
conference with family 
member/guardian to confirm 
findings (age <18 or legal 
requirements of the state) 

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Protocol 44-02219-000 
 
NeuroStar® TMS Adolescent MDD RCT 
Page 38 of 61  
 
 
 
                          Revision C,  31 Aug 2015 
 
CONFIDENTIAL 
Prohibited Concomitant Therapy 
Any medication administered for the treatment of any psychiatric or neurologic disorder or any other 
known CNS active drugs, including herbal, over-the-counter, and homeopathic medications, MAOIs, 
other antidepressants, antipsychotics, stimulants and mood stabilizers are prohibited during this study 
(See Appendix D, Concomitant Medication Exclusion List).  Use of Zaleplon, zolpidem, zopiclone or 
lorazepam for more than the permitted days (see above) or beginning a new regimen of hormonal 
contraception may lead to excluding the subject from the study.

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Protocol 44-02219-000 
 
NeuroStar® TMS Adolescent MDD RCT 
Page 41 of 61  
 
 
 
                          Revision C,  31 Aug 2015 
 
CONFIDENTIAL 
Poorly recruiting sites, defined as those with fewer than 2 randomization blocks, will be pooled into one 
or more pseudo-sites for purposes of analysis.  To ensure that nearly all sites will be of adequate size we 
will adopt a strict closure policy for sites that do not show early signs of enrollment success.  With 16 
sites, the average number of subjects per site is approximately 18, so there may be a few sites with fewer 
than 2 randomization blocks.   A site that has not randomized at least 2 subjects in the first quarter of their 
enrollment may be closed.  Then if as many as 2 sites are closed, and one poorly performing site eludes 
closure, there will be no more than one pseudo-site comprising a total of no more than 2 subjects from the 
closed site and approximately 11 from the poorly performing site, or no more than 13 subjects in all (i.e. 
<5% of the total sample). 
 
As noted elsewhere in this protocol, the sites will remain blinded to which efficacy measure has been 
declared as the primary outcome and to the point of efficacy declaration in order to improve the study’s 
signal detection ability. Point of declaration and the primary outcome measure will be documented in the 
study master file prior to unblinding of the dataset. The null hypothesis will be tested in an analysis of 
covariance of the LV, using baseline score, and ATR medication resistance level as fixed effect 
covariates, adjusting for site differences using a random effect.  As discussed elsewhere, the ATR 
medication resistance levels will group subjects categorically by number of medications which have 
shown an adequate degree of resistance for that subject.  These resistance levels will be grouped into two 
categories in statistical model, 0-1 in the current episode or 2-4 in the current episode, unless the final 
distribution of ATR scores in the study population suggests another allocation would be more statistically 
appropriate.  All tests are two-sided, at the 5% level. The primary outcome should be available and 
meaningful for nearly all subjects, so the main analysis will be by strict intention-to-treat as defined 
above. An analysis of observed cases only will be performed as a secondary outcome measure.  A site by 
treatment interaction analysis will be done as a secondary analysis to see if there is significant 
heterogeneity in the effect of TMS across sites.  In particular, we will examine site-specific treatment 
effects (with confidence intervals) to test for evidence of true reversal of effect. 
 
Secondary outcomes include other continuous measures, and within-subject dichotomous variables as 
outlined in the efficacy variables described elsewhere in this protocol. The treatment effect null 
hypothesis will be tested by logistic regression on treatment group assignment with adjustment for site 
and ATR medication resistance level. In addition, the longitudinal symptom scores will be analyzed with 
a general linear model adjusting for baseline scores and ATR medication resistance level, using a 
saturated means model for time since baseline, with treatment effect parameterized by a linear effect in 
time. The correlation of scores within individuals over time will be handled by allowing a within-subjects 
residual covariance matrix selected by exploration of the sample semi-variogram, as described by Diggle, 
Liang and Zeger. If this exploration reveals that a mixed model approach will fit the covariance structure 
better, random effects will be included in the model.  As in the main analysis, site by treatment 
interactions will be tested. 
 
In addition to testing the hypothesis noted above in the study alone, a meta-analysis will be used to 
establish evidence of efficacy.  Specifically, in addition to the evidence to be obtained in this study 
protocol, there are already two large, randomized, multisite sham-controlled studies of the use of the 
NeuroStar TMS Therapy® System in adult patients (ages 18-70 years of age) with major depressive 
disorder.  These data are statistically important to consider in the interpretation of the data to be collected 
in the adolescent study population using the NeuroStar® TMS device.  Therefore, a frequentist analysis 
will be used to demonstrate the effectiveness of the NeuroStar TMS Therapy System across ages 12-70 by  
borrowing data from the two adult studies to be used in a meta-analysis with the adolescent study data.  
This approach effectively allows meaningful computational use of the preponderamce of  adult study 
evidence with the adolescent study datato permit a “sample-sparing” adolescent study design.  This 
approach is clinically justified by the substantial evidence of safety and effectiveness already shown in 
the adult patient population, the biological and clinical continuity of the disease state from adolescence to 

Protocol 44-02219-000 
 
NeuroStar® TMS Adolescent MDD RCT 
Page 42 of 61  
 
 
 
                          Revision C,  31 Aug 2015 
 
CONFIDENTIAL 
adulthood, the shared mechanism of action of transcranial magnetic stimulation across age groups, and 
because of the significant unmet need in treatment options available for adolescent patients with major 
depressive disorder. 
 
Details of the statistical approach to be used in the meta-analysis are contained in the blinded statistical 
plan associated with this study protocol.  The meta-analysis will include data from all three studies.  The 
model for this analysis will include the following terms: treatment (active vs. sham), baseline score 
(continuous), medication resistance level as determined using the Antidepressant Treatment Record 
(ATR), (ATR=1 ‘Lo’ vs. ATR=2-4 ‘Hi’), and Study (adolescent study (IDE G120121), and the two adult 
studies combined (O’Reardon, et al, 2007 and George, et al, 2010) as fixed effects, and, interaction terms 
for “study-by-treatment” and “ATR medication resistance level-by-treatment”.  A random effect of “site 
nested within study” will also be included to assess any potential site effects. 
 
Based on this meta-analysis, there are 3 essential criteria to declare success and conclude that the 
evidence rejects the null hypothesis of no difference between active TMS and sham TMS in adolescent 
patients with treatment resistant major depressive disorder.  These criteria are: 
 
 
1) The main effect of treatment on the primary efficacy variable of mean change from baseline on 
the HAMD24 in the adolescent/adult studies meta-analysis will be statistically significant, and 
fall below the specified alpha level of 0.05, 
2) There will be no statistically significant evidence of interaction between Study and Treatment on 
the primary efficacy outcome variable at the pre-specified alpha level > 0.10, 
3) The study-specific treatment effect observed for the primary efficacy outcome variable in the 
adolescent study as a stand-alone analysis will reside between the ranges of 1.7 points to 5.5 
points on the HAMD24, and to meet the maximum Type I error rate of 15%.  
 
 
The criteria above are clinically justified based on the results using the HAMD24 outcome measure in 
the prior adult studies which ranges from 1.7 to 2.5 (O’Reardon, et al, 2007; George, et al, 2010).  The 
maximum Type I error rate of 15% for the adolescent data alone is justified given the large dataset 
available in adults (N=491) and that adult and adolescent populations should respond similarly to TMS 
Therapy.  Simulations using data from the adult studies and N=100 adolescents, shows that with a type I 
error rate of 5%, the observed HAMD24 mean difference between active and sham treatment would 
need to be 2.67, which would require a result greater than what it would need to achieve had it been 
considered alone.  For this reason, the 15% type I error rate for the adolescent data is justified.  
 
 
If the criteria described above for pooling the adolescent study with the adult studies are not satisfied, the 
adolescent study must stand alone.  If the results of the analysis of the adolescent study shows a 
statistically significant treatment group difference in favor of the active treatment at a pre-specified alpha 
level = 0.05, then this study alone will be sufficient to establish efficacy in the adolescent population. 
 
A listing of the efficacy outcome measures and their intended sequence of testing in priority order are 
listed here. Note that the point of declaration of efficacy for the primary outcome measure is concealed 
from the Investigator and hence, is not specifically noted in this listing. All tests are to be performed on 
the intent to treat sample unless specifically noted.  Please refer to the Schedule of Events for a listing of 
study timing for collection of primary and secondary outcome measures. 
 

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Protocol 44-02219-000 
 
NeuroStar® TMS Adolescent MDD RCT 
Page 44 of 61  
 
 
 
                          Revision C,  31 Aug 2015 
 
CONFIDENTIAL 
 
• 
Any clinically significant worsening of a pre-existing condition; 
• 
An AE occurring from overdose (i.e., a dose higher than that described in the protocol) of a 
Neuronetics device, whether accidental or intentional; 
• 
An AE occurring from abuse (e.g., use for non-clinical reasons) of a Neuronetics device; 
• 
An AE that has been associated with the discontinuation of the use of a Neuronetics device; a 
preexisting condition is a clinical condition (including a condition being treated) that is diagnosed 
before an informed consent form is signed and is documented as part of the subject’s medical history. 
 
The questions concerning whether the condition existed before the start of the active phase of the study 
and whether it has increased in severity and/or frequency will be used to determine whether an event is a 
treatment-emergent AE (TEAE). An AE is considered to be treatment emergent if (1) it was not present 
when the active phase of the study began and is not a chronic condition that is part of the subject’s 
medical history, or (2) it was present at the start of the active phase of the study or as part of the subject’s 
medical history, but the severity or frequency increased during the active phase. 
 
The treatment phase of the study begins at the time of the first administration of a TMS treatment (active 
or sham).  A serious adverse event (SAE) is defined by Neuronetics as an AE that: 
 
• 
Results in death: 
• 
Is life threatening (see below) 
• 
Requires inpatient hospitalization or prolongation of an existing hospitalization  
• 
Results in a substantial disruption of a person's ability to conduct normal life functions, i.e., the 
adverse event resulted in a significant, persistent or permanent change, impairment, damage or 
disruption in the patient's body function/structure, physical activities and/or quality of life 
• 
Necessitates medical or surgical intervention to preclude such impairment  
• 
Results in a congenital anomaly or birth defect 
 
Additionally, important medical events that may not result in death, be life-threatening, or require 
hospitalization, may be considered SAEs, based upon appropriate medical judgment. 
 
Life threatening refers to immediate risk of death as the event occurred or use or continued use of the 
device or other medical product might have resulted in the death per the reporter. A life-threatening event 
does not include an event that, had it occurred in a more severe form, might have caused death, but as it 
actually occurred, did not create an immediate risk of death.  
 
Hospitalization is to be considered only as an admission. Hospitalization or prolongation of a 
hospitalization constitutes an AE to be classified as serious. 
 
Note that hospitalizations planned before the start of the study, for a preexisting condition that has not 
worsened, do not constitute an SAE (e.g., elective hospitalization for a total knee replacement due to a 
preexisting condition of osteoarthritis of the knee that has not worsened during the study). 
 
An adverse event of special interest is a device-specific adverse event designated by Neuronetics for 
transmission in the same time frame as an SAE, even if it does not meet serious reporting criteria.  For 
this protocol, seizure should be reported as an adverse event of special interest. 
 
If there is any doubt whether the information constitutes an SAE, the information should be treated as an 
SAE for the purpose of this study. 

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Protocol 44-02219-000 
 
NeuroStar® TMS Adolescent MDD RCT 
Page 51 of 61  
 
 
 
                          Revision C,  31 Aug 2015 
 
CONFIDENTIAL 
20 References 
 
American Academy of Child and Adolescent Psychiatry. (2001) Practice parameter for the assessment 
and treatment of children and adolescents with suicidal behavior. American Academy of Child and 
Adolescent Psychiatry. J Am Acad Child Adolesc Psychiatry.40(7 Suppl):24S-51S 
Bloch, Y., et al., (2008)Repetitive transcranial magnetic stimulation in the treatment of depression in 
adolescents: An open-label study. Journal of ECT. 24(2): 156-159 
Brent, D., et al., (2008) Switching to another SSRI or to venlafaxine with or without cognitive behavioral 
therapy for adolescents with SSRI-resistant depression: The TORDIA randomized controlled trial. JAMA 
- Journal of the American Medical Association. 299(8): 901-913. 
Carpenter L.L. et al.(2012). Transcranial magnetic stimulation (TMS) for major depression: a multisite, 
naturalistic, observational study of acute  treatment outcomes in clinical practice. Depress Anxiety. 
29(7):587-96.  
Cheung, A., et al., (2008) Pediatric prescribing practices and the FDA Black-box warning on 
antidepressants. Journal of developmental and behavioral pediatrics : JDBP. 29(3): p. 213-5. 
Craig, A.D.,(2010). The sentient self. Brain structure & function. 214(5-6): 563-77 
Croarkin, P.E., et al. (2010). The emerging role for repetitive transcranial magnetic stimulation in 
optimizing the treatment of adolescent depression. Journal of ECT. 26(4): 323-329. 
Dunner D.L., et al (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. J Clin Psychiatry. 75(12):1394-401.  
George, M.S., et al.(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. 
Gibbons, R.D., et al., (2007) Early evidence on the effects of regulators' suicidality warnings on SSRI 
prescriptions and suicide in children and adolescents. The American journal of psychiatry. 164(9): 1356-
63. 
Janicak PG, et al. (2008). Transcranial magnetic stimulation in the treatment of major depressive disorder: 
a comprehensive summary of safety experience from acute exposure, extended exposure, and during 
reintroduction treatment. J Clin Psychiatry.69(2):222-32. 
Janicak PG, et al. (2013). Transcranial magnetic stimulation (TMS) for major depression: a multisite, 
naturalistic, observational study of quality of life outcome measures in clinical practice. CNS Spectr. 
18(6):322-32.  
Libby, A.M., et al., (2007) Decline in treatment of pediatric depression after FDA advisory on risk of 
suicidality with SSRIs. The American journal of psychiatry. 164(6): 884-91. 
Loo, C., T. McFarquhar, and G. Walter, (2006). Transcranial magnetic stimulation in adolescent 
depression. Australas Psychiatry. 14(1): 81-5. 

Protocol 44-02219-000 
 
NeuroStar® TMS Adolescent MDD RCT 
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                          Revision C,  31 Aug 2015 
 
CONFIDENTIAL 
Maalouf, F.T. and D.A. Brent, (2010), Pharmacotherapy and psychotherapy of pediatric depression. 
Expert opinion on pharmacotherapy. 11(13): 2129-40. 
March, J.S., et al. (2007) The Treatment for Adolescents with Depression Study (TADS): Long-term 
effectiveness and safety outcomes. Archives of General Psychiatry. 64(10): 1132-1144. 
March, J.S., (2004)Fluoxetine, cognitive-behavioral therapy, and their combination for adolescents with 
depression: Treatment for Adolescents with Depression Study (TADS) randomized controlled trial. 
Journal of the American Medical Association. 292(7): 807-820. 
O'Reardon, J.P., et al., (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. 
Rappaport, N., et al., (2006) Treating pediatric depression in primary care: coping with the patients' blue 
mood and the FDA's black box. The Journal of pediatrics. 148(5):567-8 
Rossi S, et al. (2009) Safety of TMS Consensus Group. Safety, ethical considerations, and application 
guidelines for the use of transcranial magnetic stimulation in clinical practice and research. 
ClinNeurophysiol. 120(12):2008-39. 
Walkup, J.T., (2010) Treatment of depressed adolescents. American Journal of Psychiatry. 167(7): p. 734-
737. 
Wall, C.A., et al.(2011) Adjunctive use of repetitive transcranial magnetic stimulation in depressed 
adolescents: A prospective, open pilot study. Journal of Clinical Psychiatry. 72(9): 1263-1269. 
Walter, G., et al., (2001) Transcranial magnetic stimulation in young persons: a review of known cases. 
Journal of child and adolescent psychopharmacology. 11(1): 69-75. 
Wassermann, E.M., et al (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. 108(1): 1-
16. 
 

Protocol 44-02219-000 
 
NeuroStar® TMS Adolescent MDD RCT 
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                          Revision C,  31 Aug 2015 
 
CONFIDENTIAL 
Appendix A. Phase I Schedule of Events 
Phase 
1-Week  
Prestudy 
6-Week  
Acute Treatment 
3-Week  
Post-Treatment Taperm 
Week 
Wk –2 to -1a 
(Screening) 
Wk 0a 
(Baseline) 
Wk 1b 
Wk 2b 
Wk 3b 
Wk 4b 
Wk 5 b 
Wk 
6b,c/ET 
Wk 1 
Wk 2 
Wk 3 
Day(s) 
-7a 
0a 
1-5 
8-12 
15-19 
22-26 
29-35 
36-42 
43-49 
50-56 
57-63 
Informed Consent/Assent/HIPAA 
X 
 
 
 
 
 
 
 
 
 
 
Psychiatric/Medical History/TASS 
X 
 
 
 
 
 
 
 
 
 
 
Antidepressant Treatment Record 
(ATR) 
X 
 
 
 
 
 
 
 
 
 
 
M.I.N.I. / M.I.N.I. KID 
X 
 
 
 
 
 
 
 
 
 
 
Pre/Post-TEEQ-Pd 
 
X 
 
 
 
 
 
X 
 
 
 
Pre/Post-TEEQ-A 
 
X 
 
 
 
 
 
X 
 
 
 
Efficacy Assessmentse 
 
 
 
 
 
 
 
 
 
 
 
HAMD24/MADRSf 
X 
X 
 
 
 
Xd 
 
Xc,e 
 
 
Xe 
CDRS-R 
X 
X 
 
 
 
Xd 
 
Xc,e 
 
 
Xe 
CGI-S 
X 
X 
 
 
 
Xd 
 
Xc,e 
 
 
Xe 
QIDS-A17-SR 
X 
X 
 
 
 
Xd 
 
Xc,e 
 
 
Xe 
Neuropsychological Assessmentse 
 
 
 
 
 
 
 
 
 
 
 
NIH Toolbox Cognition Battery  
 
X 
 
 
 
 
 
 
Xc,e 
 
 
 
Safety Assessments 
 
 
 
 
 
 
 
 
 
 
 
Physical examination 
X 
 
 
 
 
 
 
 
 
 
 
Vital Signs 
 
X 
 
 
 
 
 
Xc 
 
 
 
YMRSe 
 
X 
 
 
 
 
 
 
 
 
 
C-SSRSe 
X 
X 
Xe 
Xe 
Xe 
Xe 
Xe 
Xc,e 
Xe 
Xe 
Xe 
Laboratory determinationsg 
X 
 
 
 
 
 
 
 
 
 
 
Urine drug screen 
X 
 
 
 
 
 
 
 
 
 
 
Pregnancy testh 
X 
 
 
 
 
 
 
 
 
 
 
Structural MRIi 
X 
 
 
 
 
 
 
X 
 
 
 
Audiometry assessment 
 
X 
 
 
 
 
 
Xc 
 
 
 
Adverse Eventsj 
X ---------------------------------------------------------------------------------------------------------------------------------------------------X 
Prior/Concomitant Treatmentk 
X ---------------------------------------------------------------------------------------------------------------------------------------------------X 
Motor Threshold Determinationl 
Xl 
 
 
 
 
 
 
 
 
 
 
TMS Treatment Sessionb 
(daily × 5 weekdays/week) 
 
 
X---Xb 
X---Xb 
X---Xb 
X---Xb 
X---Xb 
X---Xb 
 
 
 
Post-Treatment Taper TMS 
Session(s)m 
(3X/Wk1, 2X/Wk 2, 1X/Wk 3) 
 
 
 
 
 
 
 
 
X 
X 
X 
a. A minimum of 7 days may elapse between the screening and baseline visits; a maximum of 5 days may elapse between the baseline visit and the first treatment day of Week 1.  
All baseline assessments must be completed and laboratory results received before 1st TMS treatment. 
b. The first visit during each week of treatment should occur on a Monday, with daily treatment sessions occurring on Monday through Friday of each week. 
c. Subjects who prematurely discontinue should complete all Week 6 procedures within 2 days after their last TMS treatment session. 
d. If subject <18 yrs of age or the legal age requirement of the state 
e. Efficacy,  neuropsychological and safety assessments to be performed after last TMS treatment session on last day of the treatment week when assessments are required. Y-
MRS to be completed if symptom indicating mania occurs.  If positive, a M.I.N.I./M.I.N.I. KID must be repeated to determine if subject meets full DSM-5 criteria for mania or 
hypomania.  If positive, subject to be discontinued from the study and followed clinically. 
f. Subject must have been off of any antidepressants for at least one week. 
g. Laboratory determinations to include standard hematology, and blood chemistry. 
h. If subject is female of childbearing potential, a urine pregnancy test will be performed in the office at screening. 
i. Performed on a subset of subjects at participating sites, 
j. Adverse events occurring prior to randomization will be recorded as part of each patient’s medical history. Those AEs occurring following the first TMS treatment session 
through 30 days after last study visit will be collected. 

Protocol 44-02219-000 
 
NeuroStar® TMS Adolescent MDD RCT 
Page 54 of 61  
 
 
 
                          Revision C,  31 Aug 2015 
 
CONFIDENTIAL 
k. Medication treatment for emergent insomnia and emergent anxiety is permitted (refer to protocol for usage allowance).  Refer to Appendix D for the Concomitant Medication List. 
l. In addition to the indicated day, Motor Threshold Determination (MT) may be repeated at any time during the course of the active TMS treatment sessions based on clinical 
assessment of the supervising physician.  Justification for the additional MT must be documented and pre-approved by the Sponsor when possible.   
m. Taper occurs only if exiting the study or transitioning directly to Phase III.  
 

Protocol 44-02219-000 
 
NeuroStar® TMS Adolescent MDD RCT 
Page 55 of 61  
 
 
 
                          Revision C,  31 Aug 2015 
 
CONFIDENTIAL 
Appendix B. Phase II Schedule of Events 
Phase 
6-Week  
Open Label Acute Treatment 
3-Week  
Post-Treatment Taper i  
Week 
Wk 1b 
Wk 2b 
Wk 3b 
Wk 4b 
Wk 5b 
Wk 6b,c/ET 
Wk 1 
Wk 2 
Wk 3 
Day(s) 
1-5 
8-12 
15-19 
22-26 
29-35 
36-42 
43-49 
50-56 
57-63 
Informed Consent/Assent 
X a 
 
 
 
 
 
 
 
 
Efficacy Assessmentsd 
 
 
 
 
 
 
 
 
 
HAMD24/MADRS 
 
 
 
Xd 
 
Xc,d 
 
 
X 
CDRS-R 
 
 
 
Xd 
 
Xc,d 
 
 
X 
CGI-S 
 
 
 
Xd 
 
Xc,d 
 
 
X 
QIDS-A17-SR 
 
 
 
Xd 
 
Xc,d 
 
 
X 
Neuropsychological Assessmentsd 
 
 
 
 
 
 
 
 
 
NIH Toolbox Cognition Battery 
 
 
 
 
 
Xc,d 
 
 
 
Safety Assessments 
 
 
 
 
 
 
 
 
 
Vital Signs 
 
 
 
 
 
Xc 
 
 
 
C-SSRSd 
Xd 
Xd 
Xd 
Xd 
Xd 
Xc,d 
Xd 
Xd 
Xc,d 
YMRSd 
 
 
 
 
 
Xc,d 
 
 
 
Structural MRIe 
 
 
 
 
 
X 
 
 
 
Audiometry assessment 
 
 
 
 
 
Xc 
 
 
 
Adverse Eventsf 
X ------------------------------------------------------------------------------------------------------------X 
Concomitant Treatmentg 
X ------------------------------------------------------------------------------------------------------------X 
Motor Threshold Determination 
Xh 
 
 
 
 
 
 
 
 
TMS Treatment Sessiona 
(daily × 5 weekdays/week) 
X---Xb 
X---Xb 
X---Xb 
X---Xb 
X---Xb 
X---Xb 
 
 
 
Post-Treatment Taper TMS Session(s)i 
(3X/Wk1, 2X/Wk 2, 1X/Wk 3) 
 
 
 
 
 
 
X 
X 
X 
a. 
An Informed Consent/Assent for this study must be signed prior to initiating any study-related procedures. 
b. 
The first visit during each week of treatment should occur on a Monday, with daily treatment sessions occurring on Monday through Friday of each week. 
c. 
Subjects who prematurely discontinue should complete all Week 6 procedures within 2 days after their last TMS treatment session. 
d. 
Efficacy, neuropsychological and safety assessments to be performed after last TMS treatment session on last day of the treatment week when assessments are 
required.  YMRS to be completed if symptom indicating mania occurs.  If positive, a M.I.N.I./M.I.N.I.-KID must be repeated to determine if subject meets full DSM-5 
criteria for mania or hypomania.  If positive, subject to be discontinued from the study and followed clinically. 
e. 
Performed on a subset of subjects at participating sites 
f. 
Adverse events occurring prior to randomization will be recorded as part of each subject’s medical history. Those AEs occurring following the first TMS treatment 
session through 30 days after last study visit will be collected. 
g. 
Medication treatment for emergent insomnia and emergent anxiety is permitted (refer to protocol for usage allowance).  Refer to Appendix D for 
the Concomitant Medication List. 
h. 
Motor Threshold Determination (MT) is to be performed prior to the administration of the first active TMS treatment session.  In addition, MT may 
be repeated at any time during the course of the active TMS treatment sessions based on clinical assessment of the supervising physician.  
Justification for the additional MT must be documented and pre-approved by the Sponsor when possible. 
i. 
Taper occurs at end of acute treatment and prior to entry into Phase III.. 
,

Protocol 44-02219-000 
 
NeuroStar® TMS Adolescent MDD RCT 
Page 56 of 61  
 
 
 
                          Revision C,  31 Aug 2015 
 
CONFIDENTIAL 
Appendix C. Phase III Schedule of Events 
Phase 
6-Month  
Long-term follow up 
Timepoint 
Month 1 
Month 2 
Month 3 
Month 4 
Month 5 
Month 6/ETb 
Day(s) 
Taper-30 
Day 60 
Day 90 
Day 120 
Day 150 
Day 180 
Informed Consent/Assent 
Xa 
 
 
 
 
 
Efficacy Assessmentsc,h 
 
 
 
 
 
 
HAMD24/MADRS 
 
 
X 
 
 
X 
CDRS-R 
 
 
X 
 
 
X 
CGI-S 
X 
X 
X 
X 
X 
X 
QIDS-A17-SR 
X 
X 
X 
X 
X 
X 
Neuropsychological Assessments 
 
 
 
 
 
 
NIH Toolbox Cognition Battery 
 
 
 
 
 
X 
Safety Assessments 
 
 
 
 
 
 
Vital Signs 
 
 
 
 
 
X 
YMRSd 
 
 
 
 
 
 
C-SSRSe 
 
 
 
 
 
 
Structural MRIf 
 
 
 
 
 
X 
Audiometry Assessmentg 
 
 
 
 
 
X 
Adverse Eventsh,i 
X ------------------------------------------------------------------------------------------------------------------X 
Concomitant Treatmenth,j 
X ------------------------------------------------------------------------------------------------------------------X 
Motor Threshold Determinationk 
 
 
 
 
 
 
TMS Retreatment,c, ,e,l 
(5x/week for 6 weeks) 
See protocol text for description of 
retreatment parameters 
 
 
 
 
 
 
a. 
An Informed Consent/Assent for this study must be signed prior to initiating any study-related procedures. 
b. 
Subjects who prematurely discontinue should complete all Month 6 procedures within 2 days after their last TMS treatment session. 
c. 
TMS retreatments should begin on a Monday, with daily treatment sessions occurring on Monday through Friday of each week.  All efficacy and 
safety assessments must be completed prior to the start of retreatment.  Efficacy assessments must be completed every other week during each 
TMS retreatment with the assessment beings conducted after the last treatment for the two week block.  TMS treatment to stop when the CGI-S 
value returns to the Phase III entry score or a full 6 weeks of TMS treatment has been completed.  A 3 week taper should follow each retreatment 
session. TMS retreatment can occur multiple times if symptom re-emergence occurs. 
d. 
Y-MRS to be completed if symptom indicating mania occurs.  If positive, a M.I.N.I./M.I.N.I. KID must be repeated to determine if subject meets full 
DSM-5 criteria for mania or hypomania.  If positive, subject to be discontinued from the study and followed clinically.  
e. 
C-SSRS to be performed after last TMS retreatment session on last day of the retreatment week.  
f. 
Performed on a subset of subjects at participating sites. 
g. 
Audiometry assessments must be performed immediately prior to the start of the TMS retreatment and at the completion of the retreatment course.   
h. 
Efficacy assessments to be performed the end of each month for monthly visits.  Subjects will be called to assess safety and well-being between 
visits at approximately 2 weeks post previous months visit. 
i. 
Those AEs occurring following informed consent signature through 30 days after the last study visit will be collected. 
j. 
Medication treatment for emergent insomnia and emergent anxiety is permitted (refer to protocol for usage allowance).  
k. 
A Motor Threshold Determination (MT) is to be performed prior to the administration of the first TMS treatment in each treatment course.  In 
addition, motor threshold may be repeated at any time during the course of the active TMS treatment sessions based on clinical assessment of the 
supervising physician.  
l. 
TMS retreatment is to occur if the CGI-S increases by 1 from the score at entry into Phase III and is confirmed one week later. 
 
 
 

Protocol 44-02219-000 
 
NeuroStar® TMS Adolescent MDD RCT 
Page 57 of 61  
 
 
 
                          Revision C,  31 Aug 2015 
 
CONFIDENTIAL 
Appendix D. Concomitant Medication List 
   
CONCOMITANT MEDICATION LIST 
 
This list should not be considered exhaustive. In general, drugs that are categorized into one of the 
drug categories listed in the table below should be treated similarly.  Contact Neuronetics if questions 
arise. 
 
CLASS:  
    Drug 
PRN 
Chronic 
ANTIASTHMA DRUGS 
 
 
 
 
Theo-Dur (theophylline)  
N 
N 
 
Bronchodilators 
 
 
 
 
Alupent (metaproterenol), Proventil (albuterol), Ventolin (albuterol) 
Y 
Y 
 
Steroids  
 
 
 
 
Inhaled (Beclovent [beclomethasone], Azmacort [triamcinolone], 
Vanceril [beclomethasone]) 
Y 
Y 
 
 
Oral 
C 
N 
 
Leukotriene antagonists 
 
 
 
 
Accolate (zafirlukast), Zyflo (zileuton), Singulair (monoleukast)  
N 
Y 
 
 
 
 
 
ANTICOAGULANTS 
 
 
 
 
Coumadin (warfarin) 
N 
Y  
(w/ stable 
protime) 
 
 
 
 
 
ANTICHOLINGERGICS 
 
 
 
 
Cogentin (benztropine), Artane (trihexyphenidyl), etc. 
N 
N 
 
 
Phenylpropanolamine (PPA) and pseudoephedrine 
N 
N 
 
 
 
 
 
ANTIHISTAMINE and DECONGESTANTS 
 
 
 
Sedating 
 
 
 
 
Anticholinergic (Benadryl [diphenhydramine], chlorpheniramine, 
brompheniramine, Atarax [hydroxyzine]) (not for psychiatric indications) 
N 
N 
 
Non-sedating 
 
 
 
 
Allegra (fexofenadine), Claritin (loratadine), Zyrtec (cetirizine) 
Y 
Y 
 
 
Hismanal (astemizole) 
N 
N 
 
 
 
 
 
ANTI-INFECTIVE AGENTS 
 
 
 
Antibacterial antibiotics (Penicillin, sulfa, etc.) 
Y 
Y 
 
Antifungal agents (ketoconazole, fluconazole, etc.) 
 
 
 
 
Topical creams and ointments 
Y 
Y 
 
 
Oral antifungals (single-dose for vaginitis OK)  
Y 
N 
 
Antiviral agents 
 
 
 
 
Zovirax (acyclovir), Famvir (famcyclovir), Valtrex (valacyclovir) 
Y 
Y 
 
 
Antiretroviral drugs (e.g. AZT, protease inhibitors) 
N 
N 
 
 
 
 
 
ANTI-NEOPLASTIC AGENTS  
N 
N 
 
 
 
 
 
SKELETAL MUSCLE RELAXANTS 
 
 
 
 
Lioresal (baclofen), Flexeril (cyclobenzaprine), Parafon Forte 
N 
N 

Protocol 44-02219-000 
 
NeuroStar® TMS Adolescent MDD RCT 
Page 58 of 61  
 
 
 
                          Revision C,  31 Aug 2015 
 
CONFIDENTIAL 
CLASS:  
    Drug 
PRN 
Chronic 
(chlorzoxazone), Robaxin (methocarbamol), Soma (carisoprodol) 
ANALGESICS AND ANTIPYRETICS 
 
 
 
 
Nonsteroidal anti-inflammatory agents (aspirin, ibuprofen, naproxen)  
Y 
Y 
 
 
Opiate Agonists / Partial Agonists (including Ultram [tramadol])  
N 
N 
 
 
Miscellaneous analgesics & antipyretics (acetaminophen, paracetamol)  
Y 
Y 
 
CARDIOVASCULAR DRUGS (All drugs in this category must be stable for at least 3 months) 
CARDIAC DRUGS 
 
 
 
 
Calcium Channel Blockers  for coronary disease or angina (see also 
"Antihypertensives") (Calan [verapamil], Cardizem [diltiazem], Norvasc 
[amlodipine], Procardia [nifedipine])  
N 
Y 
 
Antiarrhythmics 
 
 
 
 
Cordarone (amiodarone), lidocaine (note: local anesthesia injection OK), 
Mexitil (mexiletine), Norpace (disopyramide), Procan (procainamide), 
quinidine, Tambocor (flecainide) 
N 
N 
 
 
Digoxin (blood levels must be monitored)  
N 
Y 
 
 
 
 
 
ANTI-HYPERTENSIVE AGENTS  (All anti-hypertensives must be stable dose x 1 month) 
 
 
ACE Inhibitors (Vasotec, Capoten, Zestril) 
N 
Y 
 
 
Angiotensin receptor blockers (Cozaar)  
N 
Y 
 
 
Calcium Channel Blockers 
N 
Y 
 
 
Diuretics  
Y 
Y 
 
 
Phentolamine  
N 
N 
Beta-Adrenergic Blockers (see also Anti-Migraine) 
 
 
 
 
Low lipid solubility/CNS penetration (Corgard [nadolol], Tenormin 
[atenolol]) 
Y 
Y 
 
 
High lipid solubility/CNS penetration (Inderal [propranolol], Lopressor 
[metaprotereno]), (low lipid solubility preferred) 
Y 
Y 
 
Peripherally-acting alpha adrenergic agents 
 
 
 
 
Cardura (doxazosin), Hytrin (terazosin), Minipress (prazosin)  
Y 
Y 
 
Centrally-acting alpha adrenergic agents 
 
 
 
 
Aldomet (methyldopa), Catapres (clonidine)  
N 
N 
 
All others (quanethidine, reserpine, etc.)  
N 
N 
 
 
 
 
 
ANTILIPEMIC AGENTS 
 
 
 
 
Niacin (no slow-release preparations), Lipitor (atorvastatin), Lopid 
(gemfibrozil), Mevacor (lovastatin), Zocor (simvastatin) 
N 
Y 
 
 
 
 
 
VASODILATING AGENTS 
 
 
 
 
Hydralazine  
N 
Y 
 
 
minoxidil (topical OK) 
N 
C 
 
 
 
 
 
ANTI-CONVULSANTS 
N 
N 
 
 

Protocol 44-02219-000 
 
NeuroStar® TMS Adolescent MDD RCT 
Page 59 of 61  
 
 
 
                          Revision C,  31 Aug 2015 
 
CONFIDENTIAL 
CLASS:  
    Drug 
PRN 
Chronic 
PSYCHOTHERAPEUTIC AGENTS 
 
 
 
 
Antidementia drugs (donepezil, etc.), Antidepressants, Antipsychotics 
(Thorazine, Prolixin, etc.), Miscellaneous Psychotherapeutic Agents 
N 
N 
 
Anxiolytics (per protocol) 
Y 
N 
 
Stimulants 
N 
 
 
Sedatives and Hypnotics 
 
 
 
 
Barbiturates, Benzodiazepines (except those allowed per the protocol), 
Other hypnotic agents 
N 
N 
 
 
Ambien (zolpidem; per protocol), chloral hydrate (per protocol), Sonata 
(zaleplon; per protocol), Lunesta (eszopiclone; per protocol), Rozerem 
(ramelteon; per protocol) 
Y 
N 
 
 
 
 
 
ANTIMANIC AGENTS 
 
 
 
 
Anticonvulsants, lithium 
N 
N 
 
 
 
 
 
HORMONES & SYNTHETIC SUBSTITUTES 
 
 
 
 
Corticosteroids (methylprednisolone, prednisone)  
Y 
C 
 
 
Mineralocorticoids (Florinef [fludrocortisone]) 
N 
C 
 
 
Topical steroids (creams, ointments, eyedrops)  
Y 
Y 
 
 
pregnenolone 
N 
N 
 
Androgens 
N 
N 
 
 
DHEA, testosterone, danazol  
N 
N 
 
Contraceptives  
 
 
 
 
Hormonal (dose must be stable for at least 3 months): Oral, Vaginal 
Ring, Patch, Injections, Norplant (levonorgestrel)  
N 
Y 
 
 
Intrauterine device 
Y 
Y 
 
 
Latex condom, diaphragm and or cervical cap with spermicide 
Y 
Y 
 
Estrogen replacement (postmenopausal, stable dose for ≥3 months)  
N 
Y 
 
Thyroid (stable dose for ≥3 months and thyroid function tests within normal 
limits.  Clinical significance to be determined by the physician) 
N 
Y 
 
 
 
 
 
ANTIDIABETIC AGENTS 
 
 
 
 
Oral hypoglycemic agents 
N 
Y 
 
 
Insulin’s 
Y 
Y 
 
 
 
DERMATOLOGIC AGENTS 
 
 
 
 
Topical steroid preparations, Rogaine (topical minoxidil), Miscellaneous 
creams, ointments, etc. 
Y 
Y 
 
 
 
 
 
VITAMINS  
Y 
Y 
 
 
 
OVER-THE-COUNTER SUPPLEMENTS 
 
 
 
 
chromium picolinate, DHEA, melatonin, pregnenolone, St. John’s Wort 
N 
N 
 
 
 
 
 
 
 
 

Protocol 44-02219-000 
 
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Page 60 of 61  
 
 
 
                          Revision C,  31 Aug 2015 
 
CONFIDENTIAL 
CLASS:  
    Drug 
PRN 
Chronic 
GASTROINTESTINAL DRUGS 
 
 
 
 
Cisapride (propulsid)  
Y 
Y 
 
Antiemetics 
 
 
 
 
Over-the-counter (e.g., Emetrol [dextrose], Coke syrup) 
Y 
Y 
 
 
Phenothiazines & related drugs (Compazine [prochloroperazine], 
Phenergan [promethazine], Reglan [metoclopramide], Tigan 
[trimethobenzamide]), Anzemet (dolasetron), Kytril (granisetron), Zofran 
(ondansetron) 
C 
N 
 
 
Marinol (dronabinol), 
N 
N 
 
Antacids 
 
 
 
 
AlternaGel (aluminum hydroxide), Amphojel (aluminum hydroxide), 
Basaljel (aluminum carbonate), Bicitra (sodium citrate), Maalox (calcium 
carbonate), MagOX (magnesium oxide), Mylanta (magnesium 
hydroxide), Tums (calcium carbonate), UroMag (magnesium oxide) 
Y 
Y 
 
Antidiarrhea agents  
 
 
 
 
Arco-Lase (trizyme), Furoxone (furazolidone), Motofen (difenoxin), 
Sandostatin (octreotide acetate) 
N 
N 
 
 
Imodium (loperamide), Lomotil (diphenoxylate), Pepto-Bismol (bismuth 
subsalicylate) 
Y 
N 
 
Cathartics & Laxatives  
 
 
 
 
Colace (docusate), enemas, Metamucil, Perdiem, Senokot, Soflax, 
Unifibre 
Y 
Y 
 
 
Dialose (docusate) 
Y 
Y 
 
Antisecretory agents 
 
 
 
H2 Blockers 
N 
N 
 
 
Axid (nizatidine), Pepcid (famotidine), Zantac (ranitidine)  
Y 
Y 
 
Proton pump inhibitors 
 
 
 
 
Prevacid (lansoprazole), Prilosec (omeprazole) 
Y 
Y 
 
Miscellaneous gastrointestinal drugs 
 
 
 
 
Carafate (sucralfate) 
Y 
Y 
 
 
Reglan (metoclopramide)  
N 
N 
 
 
Levsin (L-hyoscyamine sulfate) 
Y 
Y 
 
 
 
 
 
ANTI-MIGRAINE  
 
 
 
 
DHE 45 (dihydroergotamine), Imitrex (sumatriptan), methysergide, 
Midrin (isometheptene mucate), Zomig (zolmitriptan) 
N 
C 
 
 
Fiorinal (butalbital, ASA, caffeine), Cafergot (ergotamine) 
Y 
C 
 
 
Nonsteroidal anti-inflammatory drugs (ibuprofen, naproxen, Toradol, 
etc.) 
Y 
Y 
 
Beta-blocking drugs 
 
 
 
 
Corgard (nadolol), Tenormin (atenolol), Other beta-blockers (e.g., 
Inderal [propranolol]) 
Y 
Y 
 
 
 
 
 
SKIN & MUCOUS MEMBRANE AGENTS  
Y 
Y 
 
 
 
 
 
 
 

Protocol 44-02219-000 
 
NeuroStar® TMS Adolescent MDD RCT 
Page 61 of 61  
 
 
 
                          Revision C,  31 Aug 2015 
 
CONFIDENTIAL 
CLASS:  
    Drug 
PRN 
Chronic 
MISCELLANEOUS DRUGS 
 
 
 
 Acutane, All over-the-counter diet pills,  Ionamin (phentermine resin), 
Lioresal (baclofen), Wellbutrin (bupropion), Zyban (bupropion) 
N 
N 
 
 Allopurinol, colchicine 
Y 
Y 
 
 Fosamax (alendronate) 
N 
Y 
 
 Gold compounds, hydroxychloroquine, and methotrexate for severe 
arthritis 
N 
C 
 
 Smoking cessation aids (Nicorrette, nicotine patches) 
C 
C 
 
 Chantix (varenicline) 
N 
N 
 
 
 
 
 
ENDNOTES 
 
 
N = Never to be used in this study. 
Y = Can be used in this study for either PRN or Chronic use as indicated in the table. 
C = Call for Sponsor approval.  Approval for these medications is generally granted if the patient is 
otherwise acceptable, including stable medical condition, no undue risk, no other "marginal" 
considerations in the medical history or concomitant medications. Or may be used during the long-term 
maintenance phase with certain restrictions.