A Pilot Study of iTBS in Bipolar I Depression
Phase: NA
Conditions: Bipolar Depression, Bipolar I Disorder
Sponsor: Johns Hopkins University

 
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A Pilot Study of iTBS in Bipolar I Depression  
Principal Investigator: 
Peter Zandi, PhD 
Johns Hopkins University School of Medicine 
Department of Psychiatry & Behavioral Sciences 
Tel: (410) 614-1923 
Email: pzandi1@jhu.edu 
 
Site-PI: 
 
 
Jorge Almeida, MD PhD 
University of Texas at Austin 
Department of Psychiatry & Behavioral Sciences 
Tel: (512) 495-5338 
Email: jorge.almeida@austin.utexas.edu 
 
Co-Investigators:   
Irving Reti, MD 
Johns Hopkins University School of Medicine 
Department of Psychiatry & Behavioral Sciences 
Tel: (410) 955-1484 
Email: imreti@jhmi.edu 
 
Kevin Li, MD 
Johns Hopkins University School of Medicine 
Department of Psychiatry & Behavioral Sciences 
Tel: (443) 475-0671 
Email: kevinli@jhmi.edu 
 
 
Protocol Application Number: IRB00327675 
 
ClinicalTrials.gov: NCT05375214 
 
Protocol Version Date: 01 May 2023 
 
Version Number: 1.8 
 

 
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Tool Revision History 
Version Number: 1.2 
Version Date: 03 May 2022 
Summary of Revisions Made: Made reliance IRB pre-screen revisions (see 4.3, 13.1, and 13.2) 
Version Number: 1.3 
Version Date: 09 May 2022 
Summary of Revisions Made: Made minor revisions to wording of inclusion criteria and 
recruitment procedures. Also fixed grammatical and spelling errors  
Version Number: 1.4 
Version Date: 07 Jul 2022 
Summary of Revisions Made: Minor revisions to treatment details (see 5.1) and methods for 
assessing adverse events related to suicide assessments (see 7.1) 
Version Number: 1.5 
Version Date: 31 Aug 2022 
Summary of Revisions Made:  Removal of some self-report instruments (see 6.2) that will be 
given to patients. Description of instruments (see 6.3) has been updated accordingly. 
Version Number: 1.6 
Version Date: 11 Jan 2023 
Summary of Revisions Made: Updated adverse event reporting procedures (see 7.3) to include 
reporting to TMS device manufacturer. Changed age range in inclusion criteria (see 4.1) and 
added pre-consent screening instrument (see 4.3)
Version Number: 1.7 
Version Date: 23 Mar 2023 
Summary of Revisions Made: Made various updates to timing and inclusion of certain study 
evaluations to better capture patient symptom change (see 6.2). Changed definition of 
immediate follow up throughout entire protocol (changed from 3-5 days to up to 5 days). Made 
consistent/clarified instruments that assess suicidality (see 7.1). Updated age in study synopsis 
to be consistent with inclusion/exclusion criteria 
Version Number: 1.8 
Version Date: 19 Apr 2023 
Summary of Revisions Made: Updated schedule of screening visit to all participant’s to be on a 
sufficient medication or medication dose as required by inclusion criteria 4 and 5 (see 6.1, 6.2). 
Participant reimbursement method is further specified  (see 3).

 
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TABLE OF CONTENTS 
Page 
A Pilot Study of iTBS in Bipolar I Depression .............................................................. 1 
Tool Revision History ............................................................................................................... 2 
TABLE OF CONTENTS ..................................................................................................... 3 
STUDY SYNOPSIS ............................................................................................................ 5 
ABSTRACT ........................................................................................................................ 6 
1. STUDY OBJECTIVES ................................................................................................... 7 
1.1 
Primary Objective ......................................................................................................... 7 
2. BACKGROUND AND RATIONALE .............................................................................. 8 
2.1 
Background on Condition, Disease, or Other Primary Study Focus .................... 8 
2.2 
Study Rationale ............................................................................................................ 8 
3. STUDY DESIGN ........................................................................................................... 10 
4. SELECTION AND ENROLLMENT OF PARTICIPANTS ........................................... 11 
4.1 
Inclusion Criteria ......................................................................................................... 11 
4.2 
Exclusion Criteria ....................................................................................................... 11 
4.3 
Study Enrollment Procedures................................................................................... 12 
5. STUDY INTERVENTIONS ........................................................................................... 14 
5.1 
Interventions, Administration, and Duration ........................................................... 14 
6. STUDY PROCEDURES ............................................................................................... 17 
6.1 
Schedule of Evaluations ................................................................................................ 17 
6.2 
Descriptions of Evaluations ...................................................................................... 18 
6.3 
Description of Study Measures ................................................................................ 21 
7. SAFETY ASSESSMENTS ........................................................................................... 23 
7.1 
Methods for Assessing Adverse Events ................................................................. 24 
7.2 
Management of Adverse Events .............................................................................. 25 
7.3 
Reporting Procedures ................................................................................................ 25 
7.4 
Follow up for Adverse Events................................................................................... 26 

 
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8. INTERVENTION DISCONTINUATION ....................................................................... 27 
9. STATISTICAL CONSIDERATIONS ............................................................................ 28 
9.1 
General Design Considerations ............................................................................... 28 
9.2 
Early Stopping Rules ................................................................................................. 28 
9.3 
Outcomes .................................................................................................................... 28 
9.3.1 
Primary Outcome .................................................................................................. 28 
9.3.2 
Secondary Outcomes ............................................................................................ 28 
9.4 
Data Analyses ............................................................................................................. 29 
10. DATA COLLECTION AND QUALITY ASSURANCE .............................................. 30 
10.1 
Data Collection ........................................................................................................... 30 
10.2 
Data Management ...................................................................................................... 30 
10.3 
Quality Assurance ...................................................................................................... 30 
10.3.1 
Training ................................................................................................................. 30 
10.3.2 
Protocol Deviations ............................................................................................... 30 
10.3.3 
Monitoring ............................................................................................................ 30 
11. PARTICIPANT RIGHTS AND CONFIDENTIALITY ................................................. 31 
11.1 
Institutional Review Board (IRB) Review ................................................................ 31 
11.2 
Informed Consent Forms .......................................................................................... 31 
11.3 
Participant Confidentiality ......................................................................................... 31 
13. Outline of JHU Roles and Responsibilities........................................................... 32 
13.1 
Coordinating Center ................................................................................................... 32 
13.2 
Single IRB .................................................................................................................... 32 
14. REFERENCES ........................................................................................................... 33 
 
 
 

 
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STUDY SYNOPSIS  
Title 
A Pilot Study of iTBS in Bipolar I Depression 
Source of Funding 
Baszucki Brain Research Fund 
Study Population 
Participants aged 18+ years old with a diagnosis of 
bipolar I disorder, current episode depressed 
Study Design 
A multisite, open label pilot study to investigate the 
efficacy and safety of a novel accelerated 
intermittent theta-burst stimulation (iTBS) protocol 
while assessing for changes in neuroimaging 
biomarkers associated with treatment response 
Primary Objectives To examine the use of accelerated iTBS to treat 
symptoms of treatment resistant depression in 
bipolar I disorder and assess changes in 
neuroimaging biomarkers that may predict treatment 
response.  
Number of Sites 
2 
Total number of 
Participants 
10 (5 at each site) 
Study Duration 
1 year 
 
 
 

 
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ABSTRACT  
Intermittent theta-burst stimulation (iTBS) is a patterned form of repetitive transcranial 
magnetic stimulation (rTMS), an effective, neuromodulatory treatment for refractory 
depression. Accelerated rTMS paradigms have become of increasing clinical interest to 
address the potential limiting factors of dose response variability and the burden that 
standard rTMS treatment poses due to the requirement of weeks of treatment at great 
financial expense. Even with reduced treatment time in iTBS compared with standard 
rTMS, there remains a barrier in requiring weeks or months of daily treatment sessions 
for desired response. A recent study carried out by members of our collaborative study 
team assessed the safety, tolerability and efficacy of an accelerated iTBS protocol and 
found a 90% antidepressant response in individuals with treatment resistant depression 
(TRD), in only 5 days (Cole et al., 2020, 2022) This proposed pilot study intends to use 
this novel accelerated iTBS approach for TRD in bipolar disorder, while assessing 
changes in neuroimaging biomarkers that are associated with treatment response. It will 
provide feasibility data to lead to development of a larger, multisite, adequately powered 
study of this treatment approach and factors associated with treatment response 
through collaborations within nodes of the National Network of Depression Centers 
(NNDC), a consortium of academic centers of excellence providing care for participants 
with mood disorders. 
 
 

 
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1. STUDY OBJECTIVES 
1.1 
Primary Objective 
To examine the use of accelerated iTBS to treat symptoms of treatment resistant 
depression in bipolar I disorder and assess changes in neuroimaging biomarkers that 
may predict treatment response: 
 
Primary Outcome Measure: Change in Montgomery-Asberg Depression Rating Scale 
(MADRS) score. 
 
Secondary Outcome Measure: Changes in MRI derived functional connectivity of the 
subcallosal cingulate to the DLPFC and within the default mode network. 
 
 

 
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2. BACKGROUND AND RATIONALE 
2.1 
Background on Condition, Disease, or Other Primary Study Focus 
Bipolar disorder is a chronic and burdensome illness that affects up to 5% of adults 
(Merikangas et al., 2011) and is associated with direct and indirect costs of care 
exceeding $200 billion annually in the US (Cloutier et al., 2018). Individuals with bipolar 
disorder spend considerably more time ill with depression than with mania or hypomania 
symptoms (Miller et al., 2014), such that depression accounts for the majority of the time 
spent unwell.  Bipolar disorder is associated with high rates of morbidity and mortality and 
is an important contributor to long-term dysfunction due to psychosocial impairment, loss 
of work productivity and high rates of substance abuse (McIntyre & Calabrese, 2019). 
Compared to the general population, individuals with bipolar disorder are at greater risk 
to attempt and complete suicide, especially among individuals experiencing longer 
periods of depression than mania (Baldessarini et al., 2006). First line treatments for 
depression are limited in bipolar disorder, and treatment resistance can be up to two times 
higher when compared to unipolar depression (Tondo et al., 2014).  
2.2 
Study Rationale 
Repetitive transcranial magnetic stimulation (rTMS) is a safe, neuromodulatory clinical 
intervention used to treat depression. When stimuli are applied to the left dorsolateral 
prefrontal cortex (LDLPFC), rTMS has been shown to be safe and effective in treating 
individuals with both unipolar and bipolar depression (Kazemi et al., 2018; Rachid et al., 
2017). Accelerated rTMS paradigms have recently been explored to determine the safety, 
tolerability, and efficacy of delivering multiple sessions over fewer days, to achieve similar 
outcomes compared with a standard series of rTMS (Sonmez et al., 2019). Reducing 
treatment time is important not only to reduce individuals’ suffering and resource strain, 
but also to address accelerating antidepressant response in more severely depressed 
individuals who are at greater risk for suicide. Intermittent theta burst stimulation (iTBS) 
is a form of patterned rTMS, recently deemed “non-inferior” to standard rTMS in the 
treatment of unipolar major depressive disorder (Blumberger et al., 2018; Chung et al., 
2015). Even with a significant benefit in reduced treatment time in iTBS compared with 
the standard rTMS treatment time of 4-6 weeks, time constraints, transportation, and the 
financial resources to attend daily sessions over weeks of time remain cumbersome 
limitations (Bakker et al., 2015). Moreover, as individuals with bipolar disorder tend to 
have more treatment resistance and spend more time in a depressed state with higher 
risk for suicide the value of non-invase treatment options is emphasized.  
 
A recent study carried out by members of our collaborative study team developed an 
accelerated iTBS treatment paradigm called Stanford Accelerated Intelligent 
Neuromodulation Therapy (SAINT). SAINT utilized prior evidence to further enhance the 

 
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propensity of antidepressant response to iTBS by modifying parameters in pulse spacing, 
dosage and treatment target location (Cazzoli et al., 2009, 2012; Fox et al., 2012; 
Gamboa et al., 2010; Noh et al., 2012). Applied in a sample of individuals with unipolar 
(n=20) and bipolar (n=5) treatment resistant depression (TRD), the use of an accelerated 
iTBS paradigm yielded approximately 90% response and remission rates in depressive 
symptoms, in both unipolar and bipolar TRD participants (Cole et al., 2020). Of the 5 
bipolar TRD participants, all met depression remission criteria within 5 days of treatment, 
with no hypomania/mania conversion observed during treatment or at follow-up. More 
recently, SAINT demonstrated evidence of efficacy over sham stimulation in RCT for 
treatment-resistance depression (Cole et al., 2022). The current study aims to further 
evaluate the use of an adapted accelerated iTBS protocol for bipolar TRD and 
neuroimaging biomarkers of treatment response.  It will leverage the resources of the 
National Network of Depression Centers (NNDC), a consortium of academic centers of 
excellence caring for participants with depression and bipolar disorder, to conduct the 
pilot study. 
 
 

 
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3. STUDY DESIGN 
In order to establish feasibility of study design and approach, we will conduct an open 
label pilot trial of treatment using accelerated iTBS over the left dorsolateral prefrontal 
cortex (LDLPFC) (up to five days, up to 10x/day) using the MagVenture MagPro X100 
rTMS System. Participants will have individualized treatment targets that will be 
produced from structural and functional MRI scans using the software services of 
Magnus Medical. We will enroll a total of 10 outpatient participants at two participating 
NNDC centers, the Johns Hopkins University and University of Texas at Austin. The 
participants will be diagnosed with bipolar I disorder, currently depressed, as 
determined by a SCID-5 assessment at screening [Day -5/-14].  Participants will be 
asked to remain on their psychotropic medications for stabilization throughout the 
screening, baseline, active study and follow-up phases of the study. During active study, 
changes in medication dosages may be made based on clinical judgment as outlined 
below. Participants will be required to have an established psychiatrist in order to 
facilitate ongoing care after the trial. 
 
The expected overall study duration is one year. Each patient will have up to 9 total 
visits over the course of one month. One visit for consent and screening. One visit for 
baseline clinical and self-report assessments, MRI scan, and neurocognitive tests. Five 
consecutive day visits (or less per symptom remission as outlined above via MADRS 
</=10) of 10 hours each for treatment. Two visits for follow-up. One immediately (up to 5 
days) after last day of treatment for clinical and self-report assessments, MRI scan, and 
neurocognitive tests. And another visit 1-month post-treatment visit for clinical and self-
report assessments. All costs for the clinical assessments, MRI scans and TMS 
treatment related to the conduct of the study will be covered by the study at no expense 
to the patient. Participants will receive $500 compensation upon completion of last 
follow up appointment. This study will offer participants a choice to receive 
payment/reimbursement through the JHU Greenphire ClinCard Program. The standard 
Greenphire information sheet will be used to explain the use of Greenphire to 
participants. 
 
 
 
 

 
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4. SELECTION AND ENROLLMENT OF PARTICIPANTS  
4.1 
Inclusion Criteria 
 
1. 18+ years of age 
2. Bipolar I disorder diagnosis as defined by The Diagnostic and Statistical Manual 
of Mental Disorders, Fifth Edition (DSM-5) 
3. Currently experiencing a Major Depressive Episode with Montgomery-Asberg 
Depression Rating Scale (MADRS) >/= 20 at screening [Day -5/-14] and baseline 
[Day 0] 
4. On a stable and adequate dose of an anti-manic agent (Lithium with a level of at 
least 0.6, Depakote with a level of at least 50, or a therapeutic dose of 
carbamazepine, oxcarbazepine, or a neuroleptic for treatment of mania per 
clinician judgment) without dose changes for at least 6 weeks prior to the active 
study time period. Final assessment of appropriateness of participant’s 
pharmacologic regimen is subject to study team clinician judgment. 
5. Having failed a therapeutic trial of a first line bipolar depression antidepressant 
(as specified by the Antidepressant Treatment History Form and updated with 
new medications approved by the FDA for treatment of bipolar depression) in this 
current episode. This includes a minimum 4 week trial of one of the following 
medications (minimum dosage): lithium 900mg daily (or blood level >= 0.6 
mEq/L), carbamazepine 400mg daily (or blood level >= 0.8 mEq/L), lamotrigine 
200mg daily, asenapine 20mg daily, lurasidone 20mg daily, olanzapine 10mg 
daily, quetiapine 300mg daily, or lumateperone 42mg daily. Final determination 
of a failed adequate therapeutic trial is subject to study team clinician judgement. 
6. Established outpatient psychiatrist 
4.2 
Exclusion Criteria 
 
1. Female that is pregnant or breastfeeding, or of childbearing potential but not 
using medically acceptable birth control during study 
2. Current mixed episode assessed by clinician judgment as defined by DSM-5 
criteria 
3. Current active substance use disorder (as defined by DSM-5) with exception of 
nicotine and caffeine. Participants may be subject to urine drug screen base on 
study team clinician judgment. 

 
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4. Participation in any clinical trial with an investigational drug or device within the 
last 3 month or concurrent to study participation 
5. History of epilepsy, shrapnel or metal in the head or skull, cardiovascular 
disease/event, OCD, or autism spectrum disorder 
6. Clinically defined major neurological disorder; including, but not limited to, 
seizure disorder and history of loss of consciousness due to head injury for 
greater than 10 minutes, or documented evidence of brain injury 
7. Active suicidal risk based on investigator’s clinical judgment 
8. Clinically significant unstable medical condition 
9. Other condition judged by investigator that could prevent the participant from 
completion of the study (such as but not limited to, significant physical disability 
(e.g., hearing/visual deficits) to perform a neutral memory task and/or 
neuropsychological test battery) 
10. Ferromagnetic metal implant or another contraindication to imaging in a 3 Tesla 
MRI 
11. ECT treatment in the past 3 months 
12. Minimum of 6 months since last manic or hypomanic episode as defined by 
DSM-5 criteria 
4.3 
Study Enrollment Procedures  
At Johns Hopkins University, participants will be recruited through clinics affiliated with 
the Johns Hopkins Mood Disorders Center in the Department of Psychiatry and 
Behavioral Sciences, or they may be referred to the study by other Johns Hopkins and 
community physicians. Clinicians will consider potential patients who meet 
inclusion/exclusion criteria and discuss the study with them. Then, the clinician or patient 
may contact the study team to schedule a meeting to undergo the consent and formal 
screening process. Once a study team member has been contacted, they may send 
potential participants a pre-consent screener via REDCap survey. This screener focuses 
on basic questions to establish whether the individual may be eligible to participate in the 
study.  A copy of the screener is included with this application.  The screener will explain 
why we are asking these questions and will inform the individual that their responses are 
completely voluntary.  The screener will also inform the individual that any information we 
collect on them will be permanently removed if they decide not to participate in the study 
or are not eligible to participate.  
 

 
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At University of Texas at Austin, participants will be recruited through the UT Health Austin 
Bipolar Disorder Center. UT Austin and community physicians may also refer patients 
who may be eligible to participate in this study.  
 
At both sites, the consenting and clinical screening assessment will be preformed in-
person in a private office setting, or virtually by secure audio/video platform as works best 
for the individual and current COVID environment. Only after the consenting process will 
patient medical records be reviewed as provided by patient or patient’s mental health 
provider. 
 
 

 
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5. STUDY INTERVENTIONS  
5.1 
Interventions, Administration, and Duration  
 
Device Rationale: 
In our study, iTBS will be delivered using the Magnus Transcranial Magnetic 
Neuromodulation System (MNS). MNS consists of the MagVenture MagPro X100 rTMS 
Stimulator System (Magventure A/S, Denmark) equipped with a MagVenture Cool-B65 
coil. A Localite neuronavigation system (Localite GmbH, Sankt Augustin, Germany) will 
be used to position the TMS coil over the individualized stimulation target at each 
session. MagVenture has a 40+ history in the development of safe and reliable TMS 
stimulators which have widespread clinical and research use. We will follow the dosing 
that was used successfully in the prior SAINT study carried out by members of our 
collaborative study team. This is the same equipment that has been used for all 
published SAINT clinical trials to date. 
 
Traditional 10Hz TMS treatment is on label for the MagVenture MagPro X100 device we 
are using. Theta burst with an X100 is FDA cleared for treatment of MDD (K173620). 
No TMS is FDA cleared yet for treating bipolar depression. So, we are using a TMS 
machine that is FDA-cleared for treating MDD, but for a non-FDA-cleared indication, 
bipolar depression. 
 
Theta burst stimulation (iTBS) is minimal risk because the risk of seizure is very low 
(only reported once in literature) and there is no other risk other than minimal scalp 
irritation. We are using iTBS with “off label” stimulation parameters which have a lower 
risk profile than the on label approved parameters. Specifically, these parameters 
include: 1) 1800 pulses of iTBS (600 was in clearance, but only 1800 has been shown 
to work in a blinded RCT), 2) 10 session per day instead of 1, 3) 90,000 overall pulses 
instead of 18,000 total, 4) 5 days instead of 36, 5) 90% depth adjusted intensity instead 
of 120% non-depth adjusted, and neuronavigated targeting. The increased dose and 
dose density increases the risk, the lower stimulation intensity, fewer days, and 
navigated targeting all reduce risk.  
 
Treatment Details: 
Motor threshold: Using single pulse TMS, the scalp position of lowest motor threshold 
for the left first dorsal interosseous or abductor pollicis brevis muscles will be 
determined. Resting motor threshold (MT) will be defined by the lowest power setting 
producing a visible muscle contraction in ≥5 of 10 trials.  
 

 
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rTMS system and treatment: For this study, we will be using the the MagVenture 
MagPro X100 rTMS Stimulator System (Magventure A/S, Denmark) equipped with a 
double-sided MagVenture Cool-B65 coil. A Localite neuronavigation system (Localite 
GmbH, Sankt Augustin, Germany) will be used to position the TMS coil over the 
individualized stimulation target at each session. All participants will receive stimulation 
using iTBS over the LDLPFC (1800 pulses per session). The individualized treatment 
targets will be produced from structural and functional MRI scans using the software 
services of Magnus Medical. The targeting approach will be the same as that used in 
prior publications (Cole et al., 2020, 2022; Williams et al., 2018).  
 
Stimulation intensity will be standardized at 90% of left RMT, adjusted to skull to cortex 
distance. No further adjustments are needed based on other patient characteristics or 
conditions. For safety, stimulation will never be delivered above 120% rMT. Sessions 
will be delivered using the MagVenture MagPro X100 stimulator, with triple-pulse 50-Hz 
bursts given every 200ms (at 5 Hz). 
 
The iTBS protocol will consist of a 2s train of bursts given every 10 s for a total of 570s 
(1800 pulses) over the LDLPFC. 
 
If treatment emergent mania occurs (defined as an increase of 2 or more points in at 
least 2 YMRS items or clinician judgment), we will discontinue treatment and adjust anti-
manic medication and, if necessary, add on other pharmacologic measures 
(neuroleptics, benzodiazepines) as clinically indicated with the intent to treat until 
remission is achieved.  
 
Neuroimaging Biomarkers: 
We will perform structural and resting state functional connectivity MRI with a 3T system 
prior to active study phase and immediately after active study phase (up to 5 days 
following final iTBS stimulation). The MRI scans will require about 1 hour in the MRI 
scanner. During the scan, participants will lie on the table in the magnet while the 
images are acquired. Instructions may be given through an auditory system. Subjects 
will wear earplugs and may be fitted for a bite bar to help them to keep their head still 
during the scans; for studies that enroll older adults, a bite bar will not be used so as to 
accommodate participants with dentures. These procedures have been used previously 
in younger and older adults alike, and do not cause undue distress in subjects.  
 
At Baseline and 1 week, our MRI scans will include: 
-Anatomical (T1) - 5min 
-Resting state fMRI  - 24 min 
-Resting state ASL - 7 min 

 
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-Diffusion-weighted imaging (DWI) - DWI acquisition will take approximately 4 min along 
90 non-collinear directions with a b-value=2400s/mm2. 
TOTAL scan time: ~40min 
 
Biomarker measures: 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. 
Separate regressors (convolved with the HRF) will be created for stimulus events in 
each paradigm. 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. 
 
 

 
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6. STUDY PROCEDURES 
6.1 
Schedule of Evaluations 
Assessment 
Screening 
(Day -50 to 
Day -5) 
Baseline 
(Day 0) 
Active 
Study 
(Day 1) 
Active 
Study 
(Day 2) 
Active 
Study 
(Day 3) 
Active 
Study 
(Day 4) 
Active 
Study 
(Day 5) 
Follow up: 
Immediate 
(Day 8 to 
Day 10) 
Follow up: 
1-month 
(Day 30 to 
Day 40) 
Informed Consent   
X 
 
 
 
 
 
 
 
 
Medical History/Records 
X 
 
 
 
 
 
 
 
 
MRI Safety Form 
X 
 
 
 
 
 
 
 
 
Structured Clinical Interview 
X 
 
 
 
 
 
 
 
 
Clinician Administered Scales 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Self-Rated Scales 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Biometric Data 
 
X 
X 
X 
X 
X 
X 
X 
X 
MRI 
 
X 
 
 
 
 
 
X 
 
Neurocognitive Measures 
 
X 
 
 
 
 
 
X 
 
Study Treatment 
 
 
X 
X 
X 
X 
X 
 
 
Continue Medications 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Monitor for Adverse Events  
 
 
X 
X 
X 
X 
X 
 
 
 

 
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6.2 
Descriptions of Evaluations  
 
Screening [Day -5/-50]: 
We will recruit participants from our clinics with a treatment history verifying they meet 
inclusion/exclusion criteria (see below in Section 5).  We will obtain informed consent 
from the participant and a trained rater will administer a SCID (Structured Clinical 
Interview for DSM-5) to confirm the diagnosis of bipolar I disorder. Participants will be 
staged using a modified Maudsley staging method tailored for bipolar depression to 
determine the severity of treatment resistance. The consenting and clinical screening 
assessment will be preformed in-person, or virtually by secure audio/video platform as 
works best for the individual and current COVID environment. We will also gather the 
participants’ medical records and review all information to screen for inclusion and 
exclusion criteria, MRI safety, TMS safety, medical and psychiatric history, a pregnancy 
test, and current medications. 
 
At the clinical screening assessment, a trained rater will also collect the following 
assessments:   
1. MADRS (Montgomery-Asberg Depression Rating Scale)  
2. YMRS (Young Mania Rating Scale)   
3. CGI-BP (Clinical Global Impression – Bipolar Disorder) 
4. ATHF current and lifetime (Antidepressant Treatment History Form) – ATHF 
reviews patient antidepressant trials to assess whether patients have had “failed, 
adequate trials” of various classes of antidepressants. 
5. TASS (Transcranial Magnetic Simulation Adult Safety Screen) – a screening 
form that evaluates prior adverse reaction to TMS and various seizure risk 
factors and relative contraindications 
 
Participants will also complete the following:  
1. AS-18 (Affective Self Rating Scale) 
2. PANAS (Positive and Negative Affect Schedule) 
3. digiBP (Digital Self-Report Survey of Mood for Bipolar Disorder) 
4. MADRS-S (Montgomery-Asberg Depression Rating Scale – Self Rated)  
5. C-SSRS (Columbia Suicide Severity Rating Scale) 
 
Baseline [Day 0]: 
Baseline visits will be separate from screening visits to confirm stability of symptoms. 
Participants will have an MRI scan in the morning (see Neuroimaging Biomarker section 
below for more details). 
 

 
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Baseline clinical measures will include:  
1. MADRS   
2. YMRS  
3. CGI-BP 
 
Baseline self-report measures will include:  
1. AS-18 
2. PANAS  
3. digiBP  
4. MADRS-S   
5. C-SSRS 
 
Cognitive measures collected using Cambridge Neuropsychological Test Automated 
Battery (CANTAB) software on a tablet. Neurocognitive Measures will include: 
1. Rapid Visual Information Processing (7 min): sensitive tool for assessment of 
sustained attention 
2. Delayed Matching to Sample (7 min): test of attention and recognition. 
3. One Touch Stocking of Cambridge (10 min): test of executive function, planning 
and working memory based upon “Tower of Hanoi”. 
4. Stop Signal Task (20 min): test of impulse control and response inhibition. 
5. Cambridge Gambling Task (18 min): test of decision making and risk-taking 
behavior outside a learning context. 
6. Emotional Bias Task (Happy-Sad) (4 min): detects perceptual bias in facial 
emotion perception. 
7. Emotional Recognition Task (6 min): measures the ability to identify six basic 
emotions from facial expressions 
8. Multi-Tasking Test (8 min): assesses ability to manage conflicting information 
and ignore task-irrelevant information 
 
Biometric data will be recorded daily by a wearable device that captures biometric data 
provided by Magnus Medical. This device will be worn daily from baseline through 
follow-up. Biometric data measures include: 
1. Heart Rate Variability  
2. Actigraphy  
3. Body Temperature  
4. Sweat Chloride  
 
Active Study [Day 1-5]: 
TMS sessions will be scheduled in a 5-day sequence, resulting in a total of up to 50 
sessions. Prior to each daily treatment series, participants will be asked a short series of 

 
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questions assessing medication compliance and substance use, amount and quality of 
sleep, and any other changes in mood since their last treatment session. We will 
monitor any medication changes throughout the course of the entire study. Participants 
will receive up to 10 daily stimulations with active iTBS over the left dorsolateral 
prefrontal cortex (LDLPFC) (1800 pulses). In the event of depression treatment 
remission (i.e. MADRS </=10), treatment emergent mania occurring (defined as an 
increase of 2 or more points in at least 2 YMRS items), or clinician judgment, LDLPFC 
treatment will be discontinued and emergent symptoms will be treated by increasing the 
dose of the participant’s anti-manic agent and other pharmacologic measures if 
necessary as assessed by the onsite clinician. 
 
If participants do not experience a significant increase in manic/hypomanic symptoms 
(>/=2 item increase of 2 or more points on the YMRS scale), LDLPFC treatment will 
continue until MADRS </=10 or the end of the 5-day treatment series is reached. 
 
Each session will be separated by a 50-minute break. This separation between 
stimulation sessions decreases the risk of associated TMS side effects (e.g. irritation 
from the device, headache).  The modified PANAS (items 3, 9, 11, 17, 18, 19) will be 
administered between every stimulation session to assess for any potential shift 
towards (hypo)mania. If a significant increase (>/=2 item increase of 2 or more points) is 
observed, the YMRS will be administered. 
 
Active study clinical measures collected at beginning and end of each treatment day 
(unless where noted) will include:  
1. YMRS (AM and PM) 
2. MADRS (AM, PM, and as clinically indicated) 
3. Daily Check-In Form (AM only) 
 
Active study self-report measures collected at end of each treatment day will include:  
1. AS-18 
2. digiBP  
3. MADRS-S   
 
The goal will be to treat participants to remission over the course of 5 days or earlier 
(when patient achieves remission of symptoms per MADRS </=10). 
 
Follow-up [Day 8-40]: 
Due to COVID-19 or related considerations, we will perform follow-up assessments via 
a secure audio/video platform in cases where we cannot conduct in-person 
assessments or per participant preference. 

 
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For participants completing treatment prior to the 5-day period, immediate post-
treatment evaluation is defined as up to 5 days after the last day of treatment and 1-
month post-treatment evaluation is defined as 25-35 days after the last day of 
treatment. 
 
Participants will have the same clinical and neurocognitive assessments that were 
completed during the baseline time-period at the immediate post-treatment and 1-month 
post-treatment mark. In addition, we will also administer the CGI-BP at these 2 time 
points. 
 
Participants will complete the following self-report assessments at these two follow-up 
time points as long as they meet responder/remission criteria:  
1. AS-18 
2. PANAS  
3. digiBP  
4. MADRS-S   
5. C-SSRS 
 
If participants do not remit but respond (>/=50% decrease on the MADRS from 
baseline) to treatment by the end of the acute, 5-day treatment series, they may be 
referred to a TMS clinic or further treatment per their outpatient psychiatrist. 
 
6.3 
Description of Study Measures  
a. Montgomery-Asberg Depression Scale-Clinician Rated (MADRS): The MADRS is a 
ten-item clinician rated questionnaire. Total scores can range from 0 to 60, with 
higher scores indicating greater severity of depression (0-6 normal range, 7-19 mild 
depression, 20-34 moderate depression, >34 severe depression). We will utilize this 
assessment to determine participant’s level of depression and consequent eligibility 
for the trial. We will then subsequent utilize the MADRS daily and at follow up as our 
primary outcome measure.  
 
b. Young Mania Rating Scale (YMRS): The YMRS is an 11-item clinician-administered 
scale used to measure symptoms of mania. Each item is scored from 0-4 with scores 
of 4 indicating the presence of more severe mania. This scale will be used to monitor 
symptoms of mania through each day of iTBS treatment. 
 
c. Clinical Global Impression Scale - Bipolar Disorder (CGI-BP): The CGI-BP is a 3-item 
clinician rated scale to provide a global rating of severity of manic and depressive 

 
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episodes and the degree of change from the immediately preceding phase and from 
the worst phase of illness. Each item is rated from 1 to 7 (0 = not assessed and 7 = 
very much worse or severely ill). The CGI-BP will be administered at screening, 
baseline and visit follow ups for a more global assessment of patient’s illness and 
symptoms.  
 
d. Affective Self Rating Scale (AS-18): The AS-18 is a 18 item self-rating scale that 
assess depressive, manic, and mixed affective states. Each symptom is rated from 0 
“none” to 4 “very severe”. The AS-18 will be filled out at every study encounter: 
screening, baseline, active study, and follow up. 
 
e. Positive and Negative Affect Schedule (PANAS): The PANAS is a 20-item self report 
scale that consists of different words that describe different positive and negative 
feelings and emotions. Every item is rated from 1 “very slightly or not at all” to 5 
“extremely”. The PANAS will be filled out screening, baseline, and follow up 
encounters. A modified PANAS (items 3, 9, 11, 17, 18, 19) will be administered 
between every stimulation session to assess for any potential shift towards 
(hypo)mania 
 
f. Digital Self-Report Survey of Mood for Bipolar Disorder (digiBP): The digiBP is a 6-
item digital survey for measuring mood in bipolar disorder. It has three depressive 
items (depressed mood, fidgeting, fatigue), two manic items (increased energy, rapid 
speech), and one mixed item (irritability); and recovers two scores (m and d) to 
measure manic and depressive severity. The digiBP will be filled out at every study 
encounter: screening, baseline, active study, and follow up.  
 
g. Montgomery-Asberg Depression Scale-Self Report (MADRS-S): The MADRS-S is the 
self-report version of the original ten-item clinician rated questionnaire (MADRS). The 
MADRS-S comprises 9 items rated on a 0-3 point scale which are summed to 
calculate a total score. This score is then doubled for comparison with the clinician 
version of the MADRS. The MADRS-S will be filled out at every study encounter: 
screening, baseline, active study, and follow up.  
 
h. Columbia Suicide Severity Rating Scale (C-SSRS): The C-SSRS is questionnaire 
used for suicide assessment. The C‐SSRS measures four constructs: the severity of 
ideation, the intensity of ideation, behavior and lethality. It includes “stem questions,” 
which if endorsed, prompt additional follow‐up questions to obtain more information. 
We will utilize this along with clinical assessment to monitor for participant’s suicide 
risk. The C-SSRS will be filled out at screening, baseline and follow up. 
 

 
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7. SAFETY ASSESSMENTS  
 
Risk Assessment: 
TMS: Extensive published data show that this accelerated theta-burst rTMS protocol in 
prefrontal cortex is safe and very well tolerated (Sonmez et al., 2019). The most 
common side effects were mild headache, fatigue, and some discomfort at the 
stimulation site.  
 
No seizures were observed in any of the above studies. However, very rarely, TMS can 
induce seizures (17 reported cases to date among tens of thousands of participants 
treated with rTMS, but few to none if proper safety and enrollment procedures are 
followed), with a seizure risk at approximately 1:30,000 sessions for traditional high 
frequency rTMS (Rossi et al., 2009). To minimize the chances of this adverse event, 
participants with seizure history will be excluded. The FDA has considered studies of 
standard TMS to be nonsignificant risk (not requiring an IDE). 
 
Another potential immediate risk is that of induction of mania. Although there have been 
no such cases of mania induced by TBS, there have been at least 13 cases of rTMS-
induced mania reported from fixed-frequency rTMS in participants with depression (Xia 
et al., 2008). The rTMS-induced mania rate reported by Xia et al was 0.84% as 
compared to 0.73% for sham, which were not significantly different from each other.  
 
Another potential risk is mild pain at the site of stimulation, which occurs during 
stimulation only, and which wanes with each session. There is also a risk of 
psychological distress related to this pain, should it occur, though discomfort associated 
with rTMS is typically mild, and not distressing when participants are reassured it is not 
dangerous. For participants that continue to experience discomfort with TMS, pre- 
treatment with acetaminophen, ibuprofen, and/or lidocaine will be allowed as warranted. 
Participants and treaters will wear earplugs during all treatment sessions. In between 
sessions, participants will be placed in a relaxing environment to maximize 
psychological well-being. 
 
MRI: Common MRI risks include claustrophobia, localized twitching (not painful) 
sensation during MRI, and tinnitus after MRI. There are some contraindications that 
may prevent a participant from having a scan; however, all participants will be screened 
prior to scanning to evaluate these risk factors. Due to the strength of the magnetic field, 
contraindications include participants with heart pacemakers, metallic foreign bodies in 
their eye, and brain aneurysm clips, as the magnetic field may dislodge the metal 
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Confidentiality: A risk of all clinical studies is that they collect personal information that 
may be seen by individuals not associated with the study. This could lead to 
psychological, social, and cultural risks.  However, we will use best practice procedures 
to minimize the potential for breaches of confidentiality. To protect participants’ 
confidentiality, a numerical system will be used as unique identifiers, and identifying 
information will not be stored with the data. Electronic data will be collected via 
REDCap, a HIPAA compliant electronic data capture system, maintained in a protected 
environment in the SAFE Desktop Environment at Johns Hopkins. Secured information 
linking participant’s ID with protected health information will be separated from the 
unidentified data. All treatment interactions will occur in a closed-door room with 
specified study personnel. We will have private rooms available for all participant 
interviews and follow-up interactions. All video meetings will be conducted using the 
PHI-safe Zoom video meeting interface or comparable platform. 
 
Long-range Risks: No long-range risks associated with TBS or routine MRI have been 
reported, and none are anticipated for this study. 
 
Potential Benefits: 
Participants may have reduction and/or remission of depressive symptoms allowing for 
improved quality of life, engagement, and functioning. This translates to other 
downstream benefits such as increased societal/economic productivity. Further, this 
study may give a way for participants to receive rTMS treatment who otherwise would 
be ineligible given that rTMS treatment is not covered by many insurance carriers. 
Demonstration of SAINT efficacy may lead to larger real-world clinical trials for both 
bipolar I disorder but also perhaps other psychiatric conditions.   
7.1 
Methods for Assessing Adverse Events 
Seizure: A physician will be available at all times during treatment to evaluate any 
participant experiencing a suspected seizure.  
 
Mania: The rTMS parameters used in this study are the least risky because the intervals 
of stimulation have been shown to be appropriate for theta burst stimulation in the motor 
system with no adverse outcomes. Moreover, participants' symptoms will be monitored 
carefully by both members of the research team and clinical staff. The YMRS will be 
administered daily to check for mania symptoms. If the participant displays an increased 
YMRS score (>/=2 points) on 2 questions, stimulation will be stopped and patient will be 
treated for emergent symptoms via increase of their anti-manic agent and other 
pharmacologic measures as indicated per clinician assessment.  
 

 
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If any of the research team or clinical staff believe that the participant may be showing 
signs of hypomania/mania, the YMRS will be administered by trained personnel 
immediately, the researchers will not wait until the daily assessments are conducted. 
Further, independently, the modified PANAS (items 3, 9, 11, 17, 18, 19) may be 
administered between every stimulation session to assess for any potential shift 
towards (hypo)mania. If a significant increase (>/=2 item increase of 2 or more points) is 
observed, the YMRS will be administered. 
 
Suicide: Monitoring participants depressive symptoms will allow the identification of 
individuals at risk of suicide and therefore the risk of this occurring can be minimized. At 
screening, baseline, and follow up the C-SSRS will be administered to directly assess 
suicidal risk. During active study days suicide risk will be screened via the MADRS 
which has a question to assess suicidal thoughts. Evaluation of the suicidal risk 
assessments will be made by the research team immediately upon collection of these 
insturments to determine if any follow-up is needed as described in section 7.2.  
7.2 
Management of Adverse Events  
Seizure: In the unlikely occurrence of a suspected seizure, participation will be 
discontinued and the participants will be provided with a referral to outpatient care. Any 
seizure that theoretically could occur would likely be self-limited and lead to no residual 
neurological impairment. Seizures induced by rTMS are rare, brief and don’t result in 
sequelae, with no events of status epilepticus ever being reported (Rossi et al., 2009).  
 
Mania: In the event of emergent mania symptoms (defined as an increase of 2 or more 
points in at least 2 YMRS items), or clinician judgment, treatment will be discontinued and 
emergent symptoms will be treated by increasing the dose of the participant’s anti-manic 
agent and other pharmacologic measures if necessary as assessed by the onsite 
clinician.  
 
Suicide: If any study personnel believe a participant is at suicide risk, the site PI will be 
notified immediately and an emergency consultation between them, clinical staff, and the 
participant will be had. If the study team considers it necessary, the patient will be referred 
for emergency psychiatric treatment. 
7.3 
Reporting Procedures 
All adverse events occurring in this study will be reported to both local and Central IRBs 
according to each institutions’ IRB policies. Central IRB shall promptly notify the Principal 
Investigators (PI) of the study as designated on the IRB protocol submission of all IRB 
decisions and shall make available to the PIs all applicable study related documents 

 
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including but not limited to approved protocols, consent forms, surveys, and decision 
letters.  
All adverse events will also be reported to Magnus Medical, who manufacture the TMS 
device intended for use in this study, via their safety email address 
(safety@magnusmed.com).  
7.4 
Follow up for Adverse Events 
All adverse events will be followed through until the event(s) have resolved, no further 
action is required, or participant has been transferred to an appropriate level of clinical 
care. The study team will communicate with the participants’ pre-study care team to 
coordinate care. 
 
 

 
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8. INTERVENTION DISCONTINUATION  
 
Participants are free to withdraw from the study at any time for any reason. Study 
doctors are to discontinue participants from the study if participants: 
• Request early discontinuation or withdraw consent. 
• Experience a serious or intolerable adverse event that prevents the participant 
from continuing. 
• In the Investigator’s opinion, is experiencing a clinically significant deterioration. 
• Conduct a protocol violation, including lack of compliance. 
• Are “lost to follow-up” as defined as no response from participant after daily 
attempts to contact over the planned five day treatment course. 
• Encounter other conditions (such as administrative issues or pregnancy). 
 
If a participant discontinues from the study at any time at their own request or at the 
study clinician’s discretion, the reason(s) for discontinuation are to be recorded by the 
study. 
 
Participants are to continue care with their pre-study care team. If participants do not 
remit but respond (>/=50% decrease on the MADRS from baseline) to treatment by the 
end of the acute, 5-day treatment series, they may be referred to a TMS clinic. If 
participants are withdrawn from the study for reasons related to the treatment (typically 
adverse event within 30 days of last treatment), they will be followed until the event(s) 
have resolved or no further action is required. The study team will communicate with the 
participants’ pre-study care team to coordinate care.  
 
 

 
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9. STATISTICAL CONSIDERATIONS  
9.1 
General Design Considerations 
This is an open label pilot study. The study will not include blinding given that this is a 
single group assignment to treatment. Study will not include a placebo or non-treatment 
group as this is a feasibility pilot study. 
 
The sample size for this pilot study was selected to allow for a sufficient evaluation of 
the feasibility of carrying out the protocol across multiple NNDC centers given the 
available resources and provide preliminary data to motivate further study of this 
treatment approach. 
9.2 
Early Stopping Rules 
The study will be terminated if: 
 
Three or more participants reach hypomania as defined by a score of greater than 10 
on the YMRS scale without resolution (YMRS <10) within 24 hours with pharmacologic 
measures as outlined above. 
9.3 
Outcomes  
9.3.1 Primary Outcome   
The primary outcome measures for this study will be change in MADRS scores. The 
MADRS is a clinical assessment tool used to rate a patient's level of depression and is 
the standard scale used for depression research studies. The YMRS will be used as a 
second primary outcome measure to assess any changes in symptoms of mania over 
the course of treatment. The YMRS is a clinical assessment tool used to assess the 
presence and severity of manic symptoms. The primary outcome measures will be 
assessed as the change between baseline and immediate (up to 5 days after last day of 
treatment) post-treatment assessment. 
9.3.2 Secondary Outcomes   
Secondary outcome measures will include changes in MRI derived functional 
connectivity of the subcallosal cingulate to the DLPFC and within the default mode 
network. Secondary outcome measures will be assessed as the change between 
baseline and 1-month post-treatment assessment. Exploratory endpoints include 
biometrics related to sympathetic nervous system activity - Heart Rate, Sweat Chloride, 
Body Temperature, and Actigraphy. 

 
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9.4 
Data Analyses  
The primary outcome measures will be analyzed using generalized linear mixed models 
to test if there are significant changes in scores over follow-up.  Based on previous 
work, we will use a compound symmetry or autoregressive covariance structure (based 
on distribution of residuals) and robust estimation of coefficients to handle violations of 
model assumptions. Random effects will be included to account for repeated measures 
on the same participants, and fixed effects of time will be evaluated controlling for fixed 
effects of age, sex and number of days to reach treatment remission.  All post hoc 
pairwise comparisons will be Bonferroni corrected. Exploratory endpoints related to 
biometrics will be analyzed in similar fashion.  
 
For assessment of the secondary outcome measures of change in functional 
connectivity, we will employ a resting-state seed-based functional connectivity approach 
to assess connectivity between the subcallosal cingulate connectivity to the DLPFC and 
within the default mode network. For each participant, the correlation coefficients 
between average blood oxygen level-dependent (BOLD) time series of the seed-region 
and the BOLD time series of each grey matter voxel within the DLPFC or default mode 
network will be calculated.  The correlation coefficient will be converted to normally 
distributed z scores by the application of Fisher’s r to z transformation. The resulting 
connectivity maps will be analyzed with repeated measures ANOVA to compare pre-
iTBS vs post-iTBS connectivity measures as a within-subject variable, and sex and site 
as a between-subject covariate. 
 
 

 
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10. DATA COLLECTION AND QUALITY ASSURANCE 
10.1 Data Collection 
Data collection is the responsibility of the clinical study staff at the site under the 
supervision of the site investigator. Clinical study staff will oversee the collection and 
organization of study data, and the investigator will ensure the accuracy, completeness, 
legibility, and timeliness of the data reported. The study will not include blinding given 
that this is a single group assignment to treatment.  
10.2 Data Management  
Study data will be collected and managed with REDCap, a secure online data capture 
system, maintained at the Johns Hopkins University site, which will serve as the Data 
Coordinating Center for the study. Participant information will be coded in REDCap with 
an anonymous study ID assigned by the REDCap system. Personally identifiable 
information will not be kept in the REDCap database. Local sites will be responsible for 
maintaining personally identifiable information and link to the anonymous study ID for 
the participants recruited at their sites. The clinician and patient rated assessments will 
be built into the REDCap database. We note that all assessments described above are 
well validated and widely used measures. Copies of each of the assessments are 
included as attachments.    
10.3 Quality Assurance  
 
10.3.1 Training 
Clinical study staff will undergo or have already undergone training requisite for 
administration of TMS as well as study clinical measures by  
 
10.3.2 Protocol Deviations 
Unanticipated problems or study deviations will be reported to the IRB within 10 days of 
the PI becoming aware of such problems or deviations in accordance with the IRB 
policy on prompt reporting. 
 
10.3.3 Monitoring 
Study team will meet to discuss potential participants after screening and record review 
to ensure they meet inclusion/exclusion criteria and are appropriate for this study. Study 
team will have monthly meetings to review and ensure protocol compliance as 
participant’s are enrolled and undergo active study treatment.    
 

 
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11. PARTICIPANT RIGHTS AND CONFIDENTIALITY  
11.1 Institutional Review Board (IRB) Review  
This protocol and the informed consent document and any subsequent modifications 
will be reviewed and approved by the IRB responsible for oversight of the study. The 
consent form should be separate from the protocol document.  
11.2 Informed Consent Forms 
A signed consent form will be obtained from each participant. The consent form will 
describe the purpose of the study, the procedures to be followed, and the risks and 
benefits of participation. A copy will be given to each participant or legal guardian and 
this fact will be documented in the participant’s record.  
The initial ICF, any subsequent revised written ICF and any written information provided 
to the subject must be approved by Central IRB prior to use. The ICF will adhere to 
Central IRB requirements, applicable laws and regulations. 
11.3 Participant Confidentiality  
Any data, specimens, forms, reports, video recordings, and other records that leave the 
site will be identified only by a participant identification number (Participant ID, PID) to 
maintain confidentiality. All records will be kept on secure servers. All computer entry 
and networking programs will be done using PIDs only. Information will not be released 
without written permission of the participant, except as necessary for monitoring by IRB.  
 
 

 
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13. Outline of JHU Roles and Responsibilities  
13.1 Coordinating Center  
JHU will serve as the Coordinating Center for this study. PI has contact information for 
all sites. Each participating center has on file an active FWA with OHRP. Any protocol 
updates will be sent to each participating site PI with comments regarding changes. All 
protocol events and deviations will first be simultaneously reported to both site PI and 
lead PI. Apart from this, monthly meetings will be held to discuss protocol events and 
deviations to ensure appropriate reporting to the JHM IRB. All data will be stored on 
JHU REDCap and SAFE Desktop. PI will ensure data collection after each participant.  
13.2 Single IRB  
Johns Hopkins Medicine is serving as the single IRB for this study. It is the preference 
of Johns Hopkins Medicine IRB to use the SMART IRB reliance agreement as the basis 
of reliance. The SMART IRB master reliance agreement was created in 2016 to 
harmonize and streamline the IRB review process for multisite studies. It enables 
reliance on a study-by-study basis, clearly defines roles and responsibilities of relying 
institutions and reviewing IRBs, and eliminates the need to sign reliance agreements for 
each study [e.g., a non-SMART IRB agreement]. 900+ institutions have already signed 
onto this agreement and are actively using it as the basis of reliance for multisite 
projects. Sites that will rely on JHM IRB are still responsible for conducting a local 
context review prior to the start of research at their site and for following any local and 
institutionally required policies as it applies to research at their site [e.g., reporting of 
unanticipated problems]. 
 
 

 
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