Reversing Synchronized Brain Circuits With Targeted Auditory-Somatosensory Stimulation to Treat Phantom Percepts- Stage 2
Phase: NA
Conditions: Tinnitus
Sponsor: University of Michigan

[Type here] 
 
Title: REVERSING SYNCHRONIZED BRAIN CIRCUITS WITH TARGETED AUDITORY-
SOMATOSENSORY STIMULATION TO TREAT PHANTOM PERCEPTS – STAGE 2 
Brief title: Targeted auditory-somatosensory tinnitus treatment 
Protocol Number: HUM00143675 
National Clinical Trial (NCT) Identified Number:  NCT03621735 
Principal Investigator: Susan Shore, PhD 
Sponsor: National Institutes of Health (NIMH) 
Funded by:  NIMH RF1MH114244 
 
Version Number:  v.1.12 
16 February 2022 
 
 
Summary of Changes from Previous Version: 
Affected 
Section 
Summary of Revisions Made 
Rationale 
1.2 
Updated both schemas in Section 1.2 of 
the protocol 
-  The schema on page 6 shows the 
End of Study visit occurring prior to 
the washout, but this visit happens 
after the washout, as shown in 
Section 1.3.  
-  The schema on page 7, in the Visit 
15-28 Time Point section, states the 
final washout is 4 weeks, but it is 
actually 6 weeks, as shown in Section 
1.3 and confirmed by the study 
team.  
1.1 
Added an exclusion criterion 
- Added “pulsating” because this 
type of tinnitus is not what the 

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device has been tested on with the 
animals. 
8.1 
Deleted “within 30 days.” 
- Give subjects more flexibility for 
when is best to begin the study with 
their schedule or if they need to wait 
on an MRI.  
6.1.2 
Added “Completion of Arm 1 and Arm 
2 do not necessarily have to be 
consecutive, and we will allow for 12 
weeks in between in order to provide 
more flexibility for subjects.” 
- Give subjects flexibility to remain in 
study, if they have to miss a chunk of 
time due to a family emergency, job, 
etc.  
8.1 
Added section under Specific 
Procedures: Otologic examination and 
medical case history regarding mental 
health identification 
-noting that if mental health issues 
are identified during screening 
process, subjects will be referred 
back to their PCP for further 
evaluation and/or follow-up. 
7.3 
Added sentence defining missed visits 
and protocol deviation 
-Clarifying that one missed visit per 
6-week time period does not qualify 
a protocol deviation. 
5.5 
Added section detailing remote 
consenting 
-allows subjects to consent remotely 
to reduce unnecessary in-person 
visits 
5.1 
Expanding hearing criteria 
-slightly expanding 
inclusion/exclusion hearing criteria 
to include more subjects in the study 
 
Expanding consenting number from 
300 to 400 
-allows more subjects to be 
consented to reach goal for active 
subjects 

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Expanding randomized subjects from 
50 to up to 100 
-some subjects that were enrolled 
during pandemic shutdown were not 
able to participate completely and 
have incomplete data, allows us to 
reach goal of 50 subjects with 
complete data 
7.1, 8.2 
Clarifying exclusion criteria 
Clarifying exclusion criteria with TFI 
and TT 
8.2 
Adding online locations for consenting 
and medical screening, and 2nd floor of 
Med Sci I for medical screening, and Dr. 
Stucken for referrals as needed 
Allows to meet online and prevent 
excessive in person appointments, 
allow Dr. Stucken to refer as needed 
8.2 
Updating adverse event reporting to 
match IRBMED 
Updating adverse event reporting 
timeline from 7 days to 14 days to 
match IRBMED 

  
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Table of Contents 
STATEMENT OF COMPLIANCE ................................................................................................................ 1 
1 
PROTOCOL SUMMARY ................................................................................................................ 1 
1.1 
Synopsis ......................................................................................................................... 1 
1.2 
Schema .......................................................................................................................... 5 
1.3 
Schedule of Activities (SoA) ................................................................................................ 8 
2 
INTRODUCTION ......................................................................................................................... 8 
2.1 
Study Rationale ................................................................................................................ 8 
2.2 
Background ..................................................................................................................... 8 
2.3 
Risk/Benefit Assessment .................................................................................................. 10 
2.3.1 
Known Potential Risks ..................................................................................... 10 
2.3.2 
Known Potential Benefits ................................................................................ 11 
2.3.3 
Assessment of Potential Risks and Benefits ......................................................... 11 
3 
OBJECTIVES AND ENDPOINTS .................................................................................................... 11 
4 
STUDY DESIGN ........................................................................................................................ 14 
4.1 
Overall Design ............................................................................................................... 14 
4.2 
Scientific Rationale for Study Design .................................................................................. 15 
4.3 
Justification for Dose ....................................................................................................... 15 
4.4 
End of Study Definition .................................................................................................... 15 
5 
STUDY POPULATION ................................................................................................................ 15 
5.1 
Inclusion Criteria ............................................................................................................ 15 
5.2 
Exclusion Criteria ............................................................................................................ 16 
5.3 
Lifestyle Considerations ................................................................................................... 17 
5.4 
Screen Failures............................................................................................................... 17 
5.5 
Strategies for Recruitment and Retention ........................................................................... 17 
6 
STUDY INTERVENTION .............................................................................................................. 18 
6.1 
Study Intervention(s) Administration ................................................................................. 18 
6.1.1 
Study Intervention Description ......................................................................... 18 
6.1.2 
Dosing and Administration............................................................................... 22 
6.2 
Preparation/Handling/Storage/Accountability ..................................................................... 22 
6.2.1 
Acquisition and accountability .......................................................................... 22 
6.2.2 
Formulation, Appearance, Packaging, and Labeling .............................................. 22 
6.2.3 
Product Storage and Stability ........................................................................... 23 
6.2.4 
Preparation .................................................................................................. 23 
6.3 
Measures to Minimize Bias: Randomization and Blinding ....................................................... 24 
6.4 
Study Intervention Compliance ......................................................................................... 24 
6.5 
Concomitant Therapy ...................................................................................................... 24 
6.5.1 
Rescue Medicine ............................................................................................ 24 
7 
STUDY INTERVENTION DISCONTINUATION AND PARTICIPANT DISCONTINUATION/WITHDRAWAL .......... 25 

  
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7.1 
Discontinuation of Study Intervention ................................................................................ 25 
7.2 
Participant Discontinuation/Withdrawal from the Study ........................................................ 25 
7.3 
Lost to Follow-Up ........................................................................................................... 26 
8 
STUDY ASSESSMENTS AND PROCEDURES ..................................................................................... 26 
8.1 
Efficacy Assessments ....................................................................................................... 26 
8.2 
Safety and Other Assessments .......................................................................................... 28 
8.3 
Adverse Events and Serious Adverse Events ........................................................................ 30 
8.3.1 
Definition of Adverse Events (AE) ...................................................................... 30 
8.3.2 
Definition of Serious Adverse Events (SAE) .......................................................... 31 
8.3.3 
Classification of an Adverse Event ..................................................................... 31 
8.3.4 
Time Period and Frequency for Event Assessment and Follow-Up ........................... 32 
8.3.5 
Adverse Event Reporting ................................................................................. 33 
8.3.6 
Serious Adverse Event Reporting ...................................................................... 33 
8.3.7 
Reporting Events to Participants ....................................................................... 34 
8.3.8 
Events of Special Interest ................................................................................ 34 
8.3.9 
Reporting of Pregnancy ................................................................................... 34 
8.4 
Unanticipated Problems .................................................................................................. 34 
8.4.1 
Definition of Unanticipated Problems (UP).......................................................... 34 
8.4.2 
Unanticipated Problem Reporting ..................................................................... 34 
8.4.3 
Reporting Unanticipated Problems to Participants ............................................... 35 
9 
STATISTICAL CONSIDERATIONS .................................................................................................. 35 
9.1 
Statistical Hypotheses ..................................................................................................... 35 
9.2 
Sample Size Determination .............................................................................................. 36 
9.3 
Populations for Analyses .................................................................................................. 36 
9.4 
Statistical Analyses ......................................................................................................... 37 
9.4.1 
General Approach ............................................. Error! Bookmark not defined. 
9.4.2 
Analysis of the Primary Efficacy Endpoint(s) ........................................................ 37 
9.4.3 
Analysis of the Secondary Endpoint(s) ................................................................ 37 
9.4.4 
Safety Analyses.............................................................................................. 38 
9.4.5 
Baseline Descriptive Statistics........................................................................... 38 
9.4.6 
Planned Interim Analyses ................................................................................ 38 
9.4.7 
Sub-Group Analyses ....................................................................................... 38 
9.4.8 
Tabulation of Individual participant Data ............................................................ 38 
9.4.9 
Exploratory Analyses ...................................................................................... 38 
10 
SUPPORTING DOCUMENTATION AND OPERATIONAL CONSIDERATIONS ............................................ 38 
10.1 
Regulatory, Ethical, and Study Oversight Considerations ........................................................ 38 
10.1.1 
Informed Consent Process ............................................................................... 38 
10.1.2 
Study Discontinuation and Closure .................................................................... 39 
10.1.3 
Confidentiality and Privacy .............................................................................. 39 

  
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10.1.4 
Future Use of Stored Specimens and Data .......................................................... 40 
10.1.5 
Key Roles and Study Governance ...................................................................... 40 
10.1.6 
Safety Oversight ............................................................................................ 41 
10.1.7 
Clinical Monitoring ......................................................................................... 41 
10.1.8 
Quality Assurance and Quality Control ............................................................... 41 
10.1.9 
Data Handling and Record Keeping .................................................................... 41 
10.1.10 
Protocol Deviations ........................................................................................ 42 
10.1.11 
Publication and Data Sharing Policy ................................................................... 42 
10.1.12 
Conflict of Interest Policy ................................................................................. 43 
10.2 
Additional Considerations ................................................................................................ 43 
10.3 
Abbreviations ................................................................................................................ 44 
10.4 
Protocol Amendment History ........................................................................................... 45 
11 
REFERENCES ........................................................................................................................... 47 
 

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STATEMENT OF COMPLIANCE 
 
The Principal Investigator will assure that no deviation from, or changes to the protocol 
will take place without prior agreement from the funding agency and documented 
approval from the Institutional Review Board (IRB), except where necessary to eliminate 
an immediate hazard(s) to the trial participants.  
 
The protocol, informed consent form(s), recruitment materials, and all participant 
materials will be submitted to the IRB for review and approval.  Approval of both the 
protocol and the consent form must be obtained before any participant is enrolled.  Any 
amendment to the protocol will require review and approval by the IRB before the 
changes are implemented to the study.  All changes to the consent form will be IRB 
approved; a determination will be made regarding whether a new consent needs to be 
obtained from participants who provided consent, using a previously approved consent 
form. 
1 
 
PROTOCOL SUMMARY 
1.1 SYNOPSIS  
Title: 
REVERSING SYNCHRONIZED BRAIN CIRCUITS WITH TARGETED 
AUDITORY-SOMATOSENSORY STIMULATION TO TREAT 
PHANTOM PERCEPTS – STAGE 2 
Study Description: 
This study will assess the effectiveness of a bimodal auditory-
somatosensory stimulation protocol in reducing the tinnitus 
loudness and life-impact in adults with tinnitus. 
Objectives: 
 
 
Primary Objective:  to reduce tinnitus loudness and life impact. 
 
Secondary Objectives: to alter the tinnitus spectrum minimum 
masking level 
Endpoints: 
 
Primary Endpoints:  
1) Tinnitus Loudness: (TinnTester Interactive Software)  
2) Tinnitus Functional Index (TFI) questionnaire 
3) Tinnitus Handicap Inventory (THI)  
 

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Secondary Endpoints:  
1)Tinnitus bandwidth/spectrum (TinnTester Interactive Software)  
2) Tinnitus Hearing Survey (THS) 
3) Minimum Masking Levels (MML) 
 
 
  
Study Population: 
Inclusion and Exclusion Criteria 
Inclusion: 400 male or female, adult (18 years of age and 
older) subjects will be consented with a goal of including up to 100 
subjects in the study. 
1. Must be 18 years of age or older.  
2. A score of >17 points on the Tinnitus Functional Index, as 
measured at the screening visit. 
3. Must report constant, subjective, preferably unilateral 
tinnitus without any active external or middle ear 
pathology.   
4. No greater than a moderate hearing loss at the tinnitus 
frequencies (≤55 dB HL) and no greater than a moderate 
hearing loss (≤50 dB HL) from 125 – 6000 Hz.   
5. Must be able to modulate their tinnitus with a somatic 
maneuver 
6. Preferably onset of tinnitus less than one year ago, but 
present for at least 6 months.  Tinnitus should be 
bothersome. 
7. Absence of retrocochlear pathology/ VIIIth nerve lesion  

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8. No participation in a tinnitus treatment regimen within 
the past six months or participation in the UM stage 1 
clinical trial. 
9. Resides within 100 miles of the study site. 
 
Exclusion: 
1. Anyone not meeting the above inclusion criteria, and in 
addition: 
2. Diagnosis of Meniere’s disease 
3. Dianosis of Semicircular Canal Dehiscence 
4. Unilateral or bilateral cochlear implant recipients 
5. Diagnosis of acoustic neuroma 
6. Reports their tinnitus is pulsating 
7. Evidence of retrocochlear disease 
8. Patients with any indwelling electronic stimulation 
devices 
9. Current or previous use of any acoustic hearing aid or 
over the counter personal sound amplification product 
(PSAP) in the last 6 months 
10. Current or former use of any of the following 
medications within the past 6 months: high dose aspirin 
(>325mg/day), high dose NSAIDs (ibuprofen, Motrin, 
Celebrex) (>800mg/day), narcotics (any opioids), lithium, 
clonazepam, oxazepam, cholinergic medications (anti-
dementia medications), anti-depressant medications 
(serotonin specific reuptake inhibitors; SSRIs, tri-cyclic 
anti-depressants; TCAs); anti-seizure/convulsant 
medications (Depakote), anti-psychotic medications 

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(Haldol, Seroquel), Ototoxic medications, other 
chemotherapy agents, benzodiazepines, and central 
nervous system stimulants. 
11. Current diagnoses of any of the following: obsessive 
compulsive disorder (OCD), schizophrenia, bipolar 
disorder, extreme generalized anxiety disorder, 
drug/alcohol dependence. 
12. Pregnant or nursing. 
Participant’s eligibility will be assessed at an initial examination 
conducted by an otologist and audiologist consisting of otoscopy, 
audiometry, tinnitus modulation checklist, case history 
questionnaire, and the Tinnitus Functional Index (TFI) questionnaire. 
 
Phase: 
 
Phase I/II 
Description of 
Sites/Facilities 
Enrolling Participants: 
. 
One site – University of Michigan Kresge Hearing Research Institute   
Description of Study 
Intervention: 
 
Bimodal auditory-somatosensory (electrical) stimulation will be 
delivered to subjects using specially-fabricated programmable 
devices by In2being inc.  that adhere to FDA regulations for De-novo 
devices with non-significant risk (as per pre-submission feedback 
from FDA).  The devices will be programmed in the lab by our staff, 
and the somatosensory and auditory stimuli will be limited by 
hardware to safe and comfortable levels for the subjects.  
The auditory stimulus, presented through a calibrated earphone, 
will simulate the tinnitus as estimated above at the tinnitus 
frequency or frequencies. The intensity of the auditory stimulus will 
be based on the presentation levels in the previous clinical trial that 
were found to be effective (originally based on preclinical data). The 
auditory stimulus level will be based on subjects’ individual hearing 
and tinnitus profile, and will be restricted to their comfort range. 
The durations and timing of the auditory and somatosensory 
(electrical) stimulation will use preclinical study determined stimulus 

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timing and durations of stimulation (Marks et al, 2018, STM). The 
intensity of the electrical stimulation will be adjusted to be just 
below that which elicits mild muscle contractions. Somatosensory 
stimulation will be delivered by standard electrode pads positioned 
on the cheek overlying the trigeminal ganglion, the juncture of the 
temporomandibular joint or on the neck at overlying cervical nerves, 
c1 or c2, determined by the manner in which the subject can 
modulate the tinnitus.  If the modulation alters tinnitus loudness or 
pitch, the position that causes reduction will be the position of 
choice. Subjects will be able to feel a slight tingling with the onset of 
the electrical stimulation, which usually fades away after a few 
minutes. 
To mitigate potential placebo effects, subjects will receive both a 
sham treatment and an active treatment.  The subjects will be 
blinded to which treatment they are receiving.  Subjects will be told 
that they may receive different treatment protocols, some of which 
are expected to be ineffective. While subjects will be informed that 
they will receive both the active and the sham treatment, they will 
not be told which treatment they are receiving.  As the sham 
treatment is using the same device as the active treatment, there 
will be no additional risks to the subject.   
Treatment durations: Daily, 30- 60 minutes. Devices will 
programmed to take home for 30-60 minutes per day for 6 weeks 
for each arm of the study (treatment and sham).  
Study Duration: 
4 years 
Participant Duration: 
10 months 
 
 
 
 
 
 
 
 
 
 
 
 
 
1.2 SCHEMA 

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12 weeks 
6 weeks 
6 weeks 
6 weeks 
6 weeks 
Total N=400  Obtain informed consent. Screen potential participants by inclusion and 
exclusion criteria; obtain history, document. 
Randomization 
Baseline 
Sham 
Sham 
Treatment 
Treatment 
End of Study 
Follow Up 
Washout 
Washout 

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Prior to  
Enrollment 
 
 
 
 
 
 
 
 
 
 
Visit 1-2 
Time Point  
 
 
 
Home use 
Time Point  
 
 
Visits 3-14 
Weekly  
 
 
 
Visit 15-28 
Time Point 
 
 
 
 
Visit 29 
Time Point 
 
 
 
 
Perform baseline assessments. 
Audiogram, ENT exam; tinnitus loudness, spectrum, TFI TH questionnaires to be see 
Section 1.3, Schedule of Activities> 
Train on device use, take home device.  
At end of washout (6 weeks), then groups switch treatment (treatment to sham or sham 
to treatment) for another 6 weeks with weekly assessments, followed by final washout of 
6 weeks.  
Follow-up assessments of study endpoints weekly for 6 weeks treatment and 6 weeks 
washout (refer to Section 1.3, Schedule of Activities) 
Final Assessments 
Section 1.3, Schedule of Activities 
And 12 week Follow-Up 
Arm 2 
N=25 
Arm 1 
N=25 
Daily (morning) 30-60 min for 6 weeks 
Randomize 

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1.3 SCHEDULE OF ACTIVITIES (SOA) 
 
 
 
 
2 
 
INTRODUCTION 
 
2.1 STUDY RATIONALE  
Fifty million people in the United States suffer from tinnitus. Tinnitus is the number one service-
connected disability for returning veterans from Iraq and Afghanistan. Tinnitus is most often 
the result of extreme noise exposure from either a single impulse noise or the accumulation of 
noise exposure; head and neck injury is the second leading complaint. In fact, lumbosacral or 
cervical strain account for 23% of service-connected disabilities for Iraq and Afghanistan 
veterans as of July 2009. In addition to factors that cause hearing loss, such as noise over-
exposure, tinnitus can occur as a result of temporal-mandibular joint disorder, or somatic 
insults, including lumbosacral or cervical strain. Tinnitus is on the rise in young people under 
the age of 20 because of the increased use of high-volume personal music players.  
The majority of tinnitus patients can modify their tinnitus by manipulating regions of the head 
and neck, such as in jaw clenching while many can attribute their tinnitus onset to a somatic 
insult in the head and neck region (Levine, 1999a, Levine, 1999b, Abel and Levine, 2004). 
Somatic manipulations of the head and neck can modulate or induce a tinnitus percept, even in 
people who do not have tinnitus. Some examples of this include clenching of the jaw or neck 
muscles. These maneuvers can modulate the tinnitus percept in up to 80% of subjects while 
light cutaneous pressure over the right scapula can induce a clicking tinnitus percept. Thus, 
while tinnitus has long been considered an exclusive disorder of the auditory system, 
accumulating evidence suggests that it is an expression of neural plasticity encompassing 
reactions of multisensory neurons to changes in the neural signaling environment due to 
changes in auditory input. 
 
2.2 BACKGROUND  
The connections of these somatosensory neurons to the first auditory brainstem nucleus, the 
cochlear nucleus (CN), suggests that tinnitus may be triggered by an alteration of firing rates in 

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CN neurons by abnormal activity in somatosensory neurons innervating the head and neck, 
especially after noise damage (Shore et al., 2008) as well as head and neck trauma. Indeed, 
increased spontaneous and sound-driven firing rates in the dorsal cochlear nucleus (DCN) have 
been shown to be physiological correlates of tinnitus (Brozoski et al., 2002, Shore et al., 2008, 
Dehmel et al., 2012b). Our work over the past several years has provided strong support for 
somatosensory neurons from the head and neck region being involved in the generation and 
maintenance of tinnitus (Zeng et al., 2009, Dehmel et al., 2012b, Zeng et al., 2012).  
Preclinical work in our lab has shown that tinnitus is generated by neurons in a brainstem 
station, the dorsal cochlear nucleus.  Here, principle neurons become hyperactive after tinnitus 
induction in an animal model.  One important mechanism that regulates neuronal firing 
properties is spike-timing-dependent plasticity (STDP), the up- or down-regulation of synaptic 
strength based on the order and timing of pre- and post-synaptic activity. Spike-timing-
dependent plasticity has been shown in the parallel fiber portion of the dorsal CN (DCN) circuit 
in vitro (Tzounopoulos et al., 2004) and has been confirmed in vivo in our laboratory by 
demonstrating stimulus-timing dependent synaptic plasticity. Stimulus timing dependent 
plasticity (StDP) is the macroscopic correlate of STDP and has been shown to be a mechanism 
underlying persistent or lasting bimodal integration (Koehler and Shore, 2013a). This finding 
could have important, far-reaching implications for treating tinnitus, such as auditory-
somatosensory training and with surface or deep brain stimulation, both of which would be 
more effective if operating through synaptic plasticity. 
 
Thus, here we utilize STDP to instigate long term suppression in DCN neurons. Our studies have 
shown that particular sequences and intervals between somatosensory and auditory stimuli 
produce either enhancement or suppression (Koehler and Shore, 2013b). In our previous 
studies in animals we replicated this result using trans-cutaneous stimulation (Martel et al., 
2014). The tonal quality of tinnitus suggests that hyperactive neurons are located in tonotopic 
regions similar to the tinnitus frequency. Thus, in order to treat tinnitus, hyperactive neurons in 
CN regions tonotopically similar to the tinnitus frequency should be suppressed. This should 
reduce or eliminate the phantom perception of sound. To ensure that this suppression is long-
term, STDP based suppression in those neurons will be accomplished by combining frequency-
specific auditory stimuli (i.e. close to the tinnitus frequency) with somatosensory stimuli with 
precise timing intervals. For more complex tinnitus, more complex auditory stimuli will be used 
to suppress firing rates across multiple regions. Somatosensory stimulation is achieved by 
placing electrodes on various skin sites in the head and neck region, which contain the neurons 
that send their axons to the CN. 
The degree of hyperactivity and tinnitus can be modulated though auditory-somatosensory 
(bimodal) stimulation with specially-timed intervals that cause long term depression in the 

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tinnitus-initiating neurons, and thereby reduce tinnitus in the animal model.  Remarkably the 
same stimulus protocol can reduce tinnitus loudness and life impact in human adults, as 
demonstrated in the stage 1 clinical trial which was completed last year (Marks, Martel et al. 
2018).  This stage 2 trial will replicate the previous trial but using more subjects, adding 
outcome measures, and increasing treatment and washout period durations. 
 
2.3 RISK/BENEFIT ASSESSMENT   
 
2.3.1 KNOWN POTENTIAL RISKS  
The known or expected risks are: 
Audiometric testing and tinnitus matching is performed routinely in audiology centers with no 
associated risks.   
The device was custom manufactured for this study. It generates sound and somatosensory 
stimulation. There are software and hardware limiters in place to ensure the device never 
outputs any unsafe somatosensory or sound stimulation.  We will also make individualized 
adjustments in the lab to ensure both the sound and somatosensory stimulation are also at 
comfortable levels for you. Because of the limits in place, you will be unable to make unsafe 
adjustments to the sound and somatosensory stimulation.  This study is to test the 
effectiveness of the device. 
All research has the potential risk of confidentiality breach. The investigators conducting the 
research have put the following mechanisms in place to protect confidentiality: all test results 
are de-identified. Information is also stored in password protected encrypted files or locked in a 
cabinet accessible only by the investigators.  
Based on the study protocol and stimuli used, it is not anticipated that subjects would 
experience different or more adverse risks when tested in the treatment vs. sham arms of the 
study. The sham treatment will consist of stimuli for which there is evidence from animal 
studies to suggest that it will not cause improvement or worsening of their tinnitus and will 
have no other side effects.  
As with any research study, there may be additional risks that are unknown or unexpected. 
While unlikely, it is possible that tinnitus may become louder or more noticeable during the 
trial. 
 
 

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2.3.2 KNOWN POTENTIAL BENEFITS  
There may be no benefit to participants as a results of using the device. Alternatively, subjects 
may experience a decrease in tinnitus loudness or may be less bothered by their tinnitus after 
participating in the treatment arm of the study.   
 
2.3.3 ASSESSMENT OF POTENTIAL RISKS AND BENEFITS  
The study proposes to use a completely non-invasive device in order to alleviate symptoms of a 
condition (i.e., tinnitus) that affects millions of people worldwide.  There is currently no 
consistent, effective treatment for tinnitus. An initial phase of this study (double-blinded 
crossover) demonstrated that when undergoing the active treatment, on average, participants 
(N=20) experienced a statistically significant reduction in their tinnitus loudness.  Additionally, 
they reported their tinnitus to be less bothersome. Therefore, the benefits far outweigh the 
risks.  
 
The funding institution has deemed this clinical trial as “greater than minimal risk” because it 
does include a placebo arm.  Please refer to further documentation from the program officer 
(email) indicating this risk level following determination of NIMH.  
 
 
3 
OBJECTIVES AND ENDPOINTS 
 
3.1 PRIMARY MEASURES 
1) Tinnitus loudness:  Measurements by the TinnTester software (McMaster 
University, supplied by Dr. Larry Roberts) are completed by interactive computer 
administered in a soundproof booth. To assess loudness in this procedure, subjects 
adjust the level of each of 11 sounds differing in center frequency to match the level 
of their tinnitus. This gives a measure of loudness in sound pressure level (SPL) for 
each subject (loudness matching method). The subjects then rate each sound for the 
similarity of its frequency to the frequency of their tinnitus. This gives the tinnitus 
frequency spectrum for each subject. Data are recorded automatically by the 
software. This software package has been used extensively by the tinnitus research 
community and is published (Roberts et al, 2008). The TinnTester sounds will be 
delivered by the devices through calibrated earphones. The devices have hardware 
limits on the sound pressure levels so that they are presented at safe levels (lower 
than 60 dB SL (above threshold). 

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2) Tinnitus Functional Index (TFI): The 25 item version of the TFI determines severity 
of tinnitus on a 100 point numeric scale (scores above 17 indicate the patient’s 
tinnitus is a problem) based on patients’ responses to 25 questions regarding the 
impact their tinnitus has on their emotional, social, and mental well-being. A 
thirteen-point reduction in score is considered clinically significant, indicating a 
noticeable improvement in tinnitus. This version has recently been validated for the 
test-retest reliability and internal consistency in New Zealand and the UK. 
3) Tinnitus Handicap Inventory (THI): A 25 item questionnaire which assesses 
subjective impacts of tinnitus related to quality of life on a 100 point numeric scale. 
Scores 17 points or higher are considered bothersome tinnitus.  We are including this 
measure as several other studies use it so it is a point of comparison. 
3.2 SECONDARY MEASURES 
 
1) Tinnitus bandwidth/spectrum: Near its start the TinnTester software asks 
subjects to indicate which of three sounds best resembles their tinnitus; 5 kHz 
pure tone (“tonal” tinnitus), a narrow band noise centered at 5 kHz (±5% of 
CF, BPN5 masker, “ringing” tinnitus), or a wider band of noise centered at 5 
kHz (±15% of CF, BPN15 masker, “hissing” tinnitus). We will relate treatment 
outcomes to tinnitus bandwidth by these measurements. We will also be able 
to determine whether the treatment alters bandwidth. 
2) Minimum Masking Level (MML): Subjects adjust the level of the 5 kHz 
BPN15 sound until they can no longer hear their tinnitus. MML may prove 
sensitive to the bimodal treatment procedure. MML should be reduced, if 
tinnitus assessed by loudness matching is also reduced. However, even when 
tinnitus loudness is reduced, there are subjects for whom tinnitus cannot be 
masked. 
3) Tinnitus Hearing Survey: A brief nine question survey which determines 
self-perceived handicap due to tinnitus, hearing loss, and hyperacusis. This 
questionnaire differs from the two primary questionnaires in that it qualifies 
any perceived handicap due to hearing loss and/or sound sensitivity 
(hyperacusis).  
 

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OBJECTIVES 
ENDPOINTS 
JUSTIFICATION FOR 
ENDPOINTS 
Primary 
 
 
1) Objective Tinnitus loudness 
(TinnTester)  
 
 
 
 
 
 
 
2) Tinnitus Functional Index 
 
 
 
 
 
 
3) Tinnitus Handicap Index 
 
 
 
1) End of 1st arm 
2) End of first washout 
3) End of 2nd arm 
4) End of second washout 
 
 
 
 
1) End of 1st arm 
2) End of first washout 
3) End of 2nd arm 
4) End of second washout 
 
 
 
1) End of 1st arm 
2) End of first washout 
3) End of 2nd arm 
4) End of second washout 
 
To determine how 
use of device affects 
objective tinnitus 
loudness before and 
after the treatment 
and sham arms of 
the study. 
 
To determine how 
use of device affects 
the tinnitus and 
quality of life before 
and after the 
treatment and sham 
arms of the study 
 
To determine how 
use of device affects 
the  tinnitus and 
quality of life before 
and after the 
treatment and sham 
arms of the study 
Secondary 
 
 
1) Tinnitus bandwidth/spectrum 
(TinnTester) 
 
 
 
 
 
 
 
 
2) Minimum Masking Level 
(MML) 
 
1) End of 1st arm 
2) End of first washout 
3) End of 2nd arm 
4) End of second washout 
 
 
 
 
 
 
1) End of 1st arm 
2) End of first washout 
3) End of 2nd arm 
To determine how 
use of the device may 
or may not change 
the perceived 
frequency (spectra) 
of tinnitus following 
the treatment or 
sham arms. 
 
 
To determine if the 
MML for a 5kHz tone 

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OBJECTIVES 
ENDPOINTS 
JUSTIFICATION FOR 
ENDPOINTS 
 
 
 
 
3) Tinnitus Hearing Survey 
4) End of second washout 
 
 
 
1) End of 1st arm 
2) End of first washout 
3) End of 2nd arm 
4) End of second washout 
 
is reduced in the 
active treatment arm 
 
 
 
To determine if the 
active treatment has 
an effect or 
interaction with 
perceived handicap 
due to hearing loss 
and sound level 
tolerance 
 
 
 
4 
STUDY DESIGN  
 
4.1 OVERALL DESIGN 
 
Aims/Hypotheses: 
Note: Aim 1 of the grant is to be performed in ANIMAL subjects only. However, Aim 2 of the 
grant is to be carried out in human subjects and therefore the design of Aim 2 is somewhat 
dependent on the results of Aim 1.  For information purposes only, both are described below: 
Specific Aim 1: Determine precise parameters/dosages for modulating multisensory plasticity 
in fusiform cells (FCs) and cartwheel cells (CWCs) in normal and pathological (tinnitus) 
circuitry in guinea pigs. Hypothesis 1: Presenting bimodal AN-SS stimuli with optimal 
parameters to guinea pigs with tinnitus will reverse pathological StDP in FCs and CWCs. 
Specific Aim 2: Test parameters/dosages determined in Specific Aim 1, for modulation of 
multisensory plasticity in human subjects with changes in tinnitus severity as the outcome 
measure. Hypothesis 2: AN-SS stimuli with optimal dosage/parameters (based on the results of 
Specific Aim 1), will effectively modulate DCN circuitry to reduce tinnitus in humans. 
Experiment 2a: Using a double-blind cross-over model, we will use a bimodal AN-SS paradigm 
with optimal stimulus parameters based on the results of Specific Aim 1 to assess changes in 
subjects’ tinnitus perception. Modulations in tinnitus perception will be assessed using 
objective loudness matching and subjective measures (standard questionnaires) in response to 
active and sham bimodal stimuli. Neural circuitry changes will be assessed by examining 
changes in the severity of subjects’ tinnitus. It is anticipated that chosen bimodal intervals and 
durations of treatment (dose) will reduce the abnormal percepts. Experiment 2b: Subjects will 

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be monitored during a washout period for a return to baseline to determine durability of effect. 
To assess dose-response of the bimodal modulation, the length of bimodal stimulation 
treatment will be varied and effects and duration of effect on tinnitus will be assessed as above 
Phase:  Phase I/II 
Type of design:  Double-blinded, cross-over design.  There will be two treatment arms 
(treatment and sham).  All subjects will participate in both arms of the study. This is a single-site 
study.  Total duration of the study for each subject will be 36 weeks.    
 
 
 
4.2 SCIENTIFIC RATIONALE FOR STUDY DESIGN 
Previous studies examining efficacy of various tinnitus treatments have shown a strong placebo 
effect (Dobie 1999).  Therefore, is important to include a placebo arm in order to truly evaluate 
the efficacy of the device and treatment.  It is also important that both the subject and the 
administrator (all study team members) are also blinded to the enrollment and assignment of 
the subjects for the same reasons.  The placebo stimulus is an auditory stimulus which is benign 
and shown in the first trial to have no effect (Marks et al, Science Translational Medicine, 
January, 2018, HUM00088432).  
 
4.3 JUSTIFICATION FOR DOSE 
The justification for dosage is based on Aim 1 of the project (preclinical experiments) as stated 
above.   
 
 
 
4.4 END OF STUDY DEFINITION 
A participant is considered to have completed the study if he or she has completed all phases of 
the study including the last visit or the last scheduled procedure shown in the Schedule of 
Activities (SoA), Section 1.3. 
 
5 
STUDY POPULATION 
 
5.1 INCLUSION CRITERIA 
 
In order to be eligible to participate in this study, an individual must meet all of the following 
criteria: 
 
1. Must be 18 years of age or older.  

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2. A score of >17 points on the Tinnitus Functional Index, as measured at the 
screening visit. 
3. Must report constant, subjective, preferably unilateral tinnitus without any 
active external or middle ear pathology.   
4. No greater than a moderate hearing loss at the tinnitus frequencies (≤55 dB 
HL) and no greater than moderate hearing loss (≤50 dB HL) from 125 – 6000 
Hz .   
5. Must be able to modulate their tinnitus with a somatic maneuver 
6. Preferably onset of tinnitus less than one year ago, but for at least 6 months.  
Tinnitus should be bothersome. 
7. Absence of retrocochlear pathology/ VIIIth nerve lesion  
8. No participation in a tinnitus treatment regimen within the past six months 
and no participation in Stage 1 trial. 
9. Resides within 100 miles of study site. 
 
5.2 EXCLUSION CRITERIA 
An individual who meets any of the following criteria will be excluded from participation in this 
study: 
1. Anyone not meeting the above inclusion criteria, and in addition: 
2. Diagnosis of Meniere’s disease 
3. Diagnosis of Semicircular Canal Dehiscence.  
4. Unilateral or bilateral cochlear implant recipients 
5. Diagnosis of acoustic neuroma 
6. Evidence of retrocochlear disease 
7. Patients with any indwelling electronic stimulation devices 
8. Current of previous use of any acoustic hearing aid or over-the-counter 
personal sound amplification product (PSAP) in the last 6 months. 
9. Current or former use of any of the following medications within the past 6 
months: high dose aspirin (>325mg/day), high dose NSAIDs (ibuprofen, 
Motrin, Celebrex) (>800mg/day), narcotics (any opioids), lithium, 
clonazepam, oxazepam, cholinergic medications (anti-dementia 
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inhibitors; SSRIs, tri-cyclic anti-depressants; TCAs); anti seizure/convulsant 
medications (Depakote), anti-psychotic medications (Haldol, Seroquel), 
Ototoxic medications, other chemotherapy agents, central nervous system 
stimulants, and benzodiazepines. 
10. Current diagnoses of any of the following: obsessive compulsive disorder 
(OCD), schizophrenia, bipolar disorder, extreme generalized anxiety disorder, 
drug/alcohol dependence. 
11. Pregnant or Nursing. 
5.3 LIFESTYLE CONSIDERATIONS 
 
During this study, participants are asked to: 
• Refrain from participation in any other tinnitus treatment 
• Report any changes in health status  
• Report any changes in prescribed or over-the-counter medications 
 
 
5.4 SCREEN FAILURES 
Screen failures are defined as participants who consent to participate in the clinical trial but are 
not subsequently randomly assigned to the study intervention or entered in the study. A 
minimal set of screen failure information is required to ensure transparent reporting of screen 
failure participants, to meet the Consolidated Standards of Reporting Trials (CONSORT) 
publishing requirements and to respond to queries from regulatory authorities. Minimal 
information includes demography, screen failure details, eligibility criteria, and any serious 
adverse event (SAE). 
 
Individuals who do not meet the criteria for participation in this trial (screen failure) because of 
a recent participation on another tinnitus treatment regimen may be rescreened once the 
observed period of time as passed as stated in the protocol. Rescreened participants should be 
assigned the same participant number as for the initial screening. 
 
5.5 STRATEGIES FOR RECRUITMENT AND RETENTION 
General procedures: 
Study team members will recruit patients from patient populations seen in the otology and 
audiology clinics at UMHS, as well as those who have contacted Dr. Shore or other study team 
members to report having tinnitus.  Once they have contacted a study team member, they will 
receive an automatic reply which will be sent using the Mail Chimp email automation platform.  
Please see additional documentation for Mail Chimp platform security information (Attachment 
A) and an email script (Attachment B) that will be sent to potential participants.  Within the 
email script, potential participants will be directed to the clinical study website which will 
appear on the umhealthresearch.org website.  Participants will be asked to create an account 

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and log in, and then they will have the ability to contact the study team through the website if 
they are interested in participating. Please see Attachment C for content that will be posted on 
umhealthresearch.org.  Once a potential participant has contacted the study team using the 
umhealthresearch.org website, he/she will be contacted by a member of the study team via 
phone, email, or secure messaging via the umhealthresearch.org website in order to confirm 
that they meet the inclusion and exclusion criteria. Please see additional documentation for 
phone and/or email script (Attachment D). Once such information is confirmed, they will be 
scheduled for an initial visit to the lab at which time consenting and candidacy evaluations will 
be performed. 
 
Subjects may also sign the informed consent through the SignNow application. Subjects will 
meet with a staff member through HIPAA compliant Zoom videocall platform where the staff 
member will review the informed consent with the subject and answer any questions the 
subject may have prior to signing the document. 
 
The patient will have the opportunity to ask questions at all times throughout the recruitment 
process. All questions or concerns will be addressed by a study team member. Through 
purposeful sampling, we will attempt to include a diverse set of respondents based on ethnic, 
socioeconomic, and educational backgrounds.    
 
Target study sample size: We will enroll 400 subjects in order to assign up to 100 subjects to 2 
treatment arms. We anticipate testing 34 subjects per year in order to meet this recruitment 
goal. There is one recruiting site (University of Michigan).  
 
Subjects will be provided compensation for parking at each visit.  
 
6 
STUDY INTERVENTION 
 
6.1 STUDY INTERVENTION(S) ADMINISTRATION 
 
6.1.1 STUDY INTERVENTION DESCRIPTION 
Describe the study intervention(s) and control product. Product information can usually be 
obtained from the: 
• The investigational devices for providing the stimulation protocols have been designed 
by members of the Shore Lab and fabricated by In2being, LLC.  The device provides 
acoustic and electrical stimulation at levels deemed safe by OSHA, ISO and ANSI.         
• The device is labeled “for investigational use only” 
• Final labeling for a marketed device will be obtained after FDA final review after 
completion of the trial. In2being, LLC will incorporate any changes to the labeling that 
are suggested. 
•  A pre-submission has been reviewed already by the FDA and they were in agreement 
that this device would be de novo, non-significant risk.  
 

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In addition: 
• FDA and the IRB consider our device class 2 de novo, thus we do not require an IDE to 
run the clinical trial, stage 2. 
• The study intervention is not yet commercially available. Since the stage 1 clinical trial 
that has been completed, we are hiring In2being to upgrade the devices so that the next 
generation is FDA compliant. 
• If conducting a study with a device, the following information should be included: 
o Device size(s): Less than 3”/2”/7” 
o Device model(s): Gen 2 
o Description of each component:  
 CPU 
 SD card for data storage 
 power supply 
 rechargeable lithium ion batteries 
 electrical stimulator 
 sound stimulator 
 earphones 
 stimulating pads   
o Device settings and programming:  
 See Figure 1 for all device tunable parameters 
 Auditory SPL below 95 dB SLP 
 Current less than 3 mA (see Figure 1) 
 Misapplication of electrodes is detected by the device as shown by red 
light.   
 Device has only two settings (on/off), limiting subject errors. 
o Duration of stimulation (30-60 min/day). 
o Once per day 
o Current levels with known potentiometer values and Maximum SPL are shown in 
Fig. 2 
• Figure 1: Device Tunable Parameters. Each indicated parameter is regulated by the 
device. Current level, audio intensity and frequency content are altered on an 
individualized basis for the treatment; all other parameters remain fixed. 
•  

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•  
 
0
20
40
60
80
100
120
140
160
180
200
-1.5
-1
-0.5
0
0.5
1
1.5
Figure of Protocol Trial
Time of Single Trial (ms)
Stimulus Amplitude
 
 
Audio Signal
Electrical Signal
Audio Duration
Audio Onset
Audio Intensity
Trial Duration and Number of Repetitions
Electrical Intensity
Pulse Count
Pulse Duration
Pulse Interval
Frequency Content
Onset 
Delay

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• Figure 2. Calibration Data. Stimuli are calibrated prior to device use. A) Each device 
features an internal self-calibration for the electrical stimulator. This check is run every 
trial to ensure appropriate treatment stimulation. This feature also checks for open and 
short circuits, which indicate improper electrode placement. For a given potentiometer 
value (x-axis), the device output current (right y-axis) and regulated voltage (left y-axis) 
are shown. B) Device ear phones are matched to a device and calibrated using a 
standard microphone. Dashed line shows earphone output without limiter installed, 
solid with limiter. 
•  
•  
•  
 
0 
200 
400
600
800 
1000
1200
Potentiometer Value (index)
0 
0.5
1 
1.5
2 
2.5
3 
3.5
0 
0.5
1 
2 
2.5
3 
Current (mA)
Device electrical stimulation values 
1.5 
Voltage (V) 
0 
2 
4 
6 
8
10 
12 
14
16
Freq (kHz) 
75 
80 
85 
90 
95 
100 
105 
110 
115 
120 
Intensity (dB SPL) 
  
Earphone Calibration 
without limiter 
with limiter 

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6.1.2 DOSING AND ADMINISTRATION 
Each subject will have their tinnitus spectrum assessed with the Tinn Tester protocol (L. Roberts 
et al, 2008).  This spectrum is digitized and programmed into the device as the signal to be 
delivered to the subject.  The amplitude is limited to 95 dB SPL and is delivered together with 
an electrical stimulus delivered a short time after the auditory stimulus (as determined by the 
preclinical studies).  This stimulus is presented by the device when the subject turns on the 
device.  The device limits the time of presentation to 30-60 min per day. 
 
This protocol is presented once a day for 30-60 minutes for 6 weeks.  After that there is a 
washout period of 6 weeks in which no device is used.  Subjects are tested once a week to 
assess the primary and secondary outcomes and when baseline is achieved.  The second arm of 
the study begins for another 6 weeks.  A second washout of 6 weeks occurs, end of study visit, 
and 12 weeks of follow up, after which the subject participation is ended. Completion of Arm 1 
and Arm 2 do not necessarily have to be consecutive, and we will allow for 12 weeks in 
between in order to provide more flexibility for subjects. The dose will not change over the 
course of the study.  Maximum duration of enrollment is 36 weeks.   
 
The subjects will be trained on how to use the devices and place the earphones and electrode 
pads.  Once they have been effectively trained, subjects will take the devices home to use for 
the 30-60 min/day periods.  Once a week the primary and secondary outcomes will be tested 
along with any review or questions that the subjects need to be answered. Subjects are asked 
to use the device at the same time every day but If subjects miss a treatment they are 
instructed to use it at another time rather than miss that treatment.  
 
  
6.2 PREPARATION/HANDLING/STORAGE/ACCOUNTABILITY 
 
6.2.1 ACQUISITION AND ACCOUNTABILITY 
In2being will provide a unique identifier for each device.  The study team members will 
program the devices based on individuals’ audiograms and tinnitus spectra and will show the 
subjects how to use the devices to implement the treatments.  Devices will be returned to 
study team members following subject participation.  Devices will be reprogrammed for 
subsequent subjects.    
 
6.2.2 FORMULATION, APPEARANCE, PACKAGING, AND LABELING 
See Figure 3. 
Figure 3. Generation 1 Device Pictures. Generation 2 devices, to be tested in this study, will not 
be larger than the current designs, and will feature upgrades to ensure FDA approval. 
Device dimensions: less than 2” x 5 “ x 8” 

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6.2.3 PRODUCT STORAGE AND STABILITY 
Kept at room temperature when not in use. Subjects will be supplied with sufficient electrode 
pads and gel and earphone tips to ensure use of new pads and closed acoustic system with 
each treatment. 
 
6.2.4 PREPARATION 
Subjects are required to gently wipe area for electrode contact (neck skin or face skin) with 
alcohol-based wipes prior to electrode placement. 
 
 
 
 

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6.3 MEASURES TO MINIMIZE BIAS: RANDOMIZATION AND BLINDING 
Subjects are randomly assigned to group 1 (active first, then sham) or group 2 (sham first, then 
active) using Matlab’s randsample command with a predetermined, fixed, secret seed value. 
Randsample generates random numbers using the Mersenne twister algorithm. We will enroll 
subjects in a 1:1 ratio to create a balanced study design. To ensure blinding, group assignment 
is generated in silico and assignment programmed into each device, without the intervention of 
a study member. This parameter is not made accessible to study members without password 
authorization.  Devices are encrypted to prevent study team members or subjects from 
accessing device data in an unauthorized manner. 
As the randomization list is generated algorithmically, the code can be reproduced with 
knowledge of the secret seed value. Unblinding may occur at the end of the study or in the case 
of an SAE related to the study (worsening of tinnitus, worsening of hearing threshold). Study 
investigators that do not have contact with subjects may unblind. Intentional and unintentional 
unblinding must be reported to the principle investigator.  
Imperfect blinding could arise from the presence of the electrical stimulation present during 
active treatment. To avoid unblinding, subjects will be told that they may or may not feel 
electrical stimulation during both phases of the study. The previous study suggested that 
subjects tend to acclimate to the presence or lack of electrical stimulation during a day’s 
treatment. Subjects will be discouraged from divulging whether they can feel the electrical 
stimulus.  
No investigators are allowed to remain unblinded for the duration of the study.  All analyses 
that could require unblinding (SAEs, worsening of a subject’s tinnitus/hearing) will be identified 
by software, and the investigators notified by automated communication methods. 
 
6.4 STUDY INTERVENTION COMPLIANCE 
The devices are electronic monitoring compliant – successful daily use is registered, also detects 
and records open circuits or failures.  Primary and secondary outcomes are measured weekly 
and recorded by study team members electronically on secure databases. 
 
6.5 CONCOMITANT THERAPY 
NA 
 
6.5.1 RESCUE MEDICINE 
NA 
 

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7 
STUDY INTERVENTION DISCONTINUATION AND PARTICIPANT 
DISCONTINUATION/WITHDRAWAL 
 
7.1 DISCONTINUATION OF STUDY INTERVENTION 
This study uses a non-invasive device.  We will use strictly calibrated instruments to ensure that 
both acoustic and electrical stimulation are being delivered at safe levels for each subject. 
However, specific stopping rules will be identified for each subject to ensure patient safety.  For 
each subject, data for the TFI, THI, and TinnTester will be examined on a weekly basis (following 
weekly testing for each subject) for tinnitus assessments.  Additionally, audiometric criteria will 
be assessed at least every 6 weeks (please see schedule of events) to monitor hearing status.  
Audiometric criteria will be evaluated during the interim if a subject reports concern for a 
change in hearing ability.  This metric will be monitored by the ISM.  If tinnitus is found to 
statistically, significantly increase according to aggregated mean baseline, then the subject will 
not continue in the study regardless of which arm (active or sham) in which the subject is 
enrolled.  Furthermore, if the subject subjectively reports increase in tinnitus or worsening of 
hearing, without a significant change in any of the subjective or objective measures, and he/she 
wishes to discontinue participation in the study then he/she will withdraw from the study. 
 
A subject’s participation in the study will be discontinued following both 1) an increase of 16 or 
more points in TFI, and 2) an average increase of 12 dB in TinnTester compared to baseline, for 
two consecutive weekly measures. Both measures are our primary outcome measures.  Using 
both criteria for determining discontinuation is critical as the tinntester measures tinnitus 
loudness, which reflects the circuitry changes identified in our preclincal studies.  TFI is also 
important for the human study as it gauges the subject’s subjective response to their 
tinnitus.  However, TFI can also reflect outside life stressors unrelated to the treatment and 
could result in a subject's discontinuation for reasons unrelated to the treatment. 
 
7.2 PARTICIPANT DISCONTINUATION/WITHDRAWAL FROM THE STUDY 
• Pregnancy 
• Significant study intervention non-compliance  
• If any clinical adverse event (AE), laboratory abnormality, or other medical condition or 
situation occurs such that continued participation in the study would not be in the best 
interest of the participant 
• If the participant meets an exclusion criterion (either newly developed or not previously 
recognized) that precludes further study participation 
• Participant becomes unable to participate in the study on a weekly basis.  
The reason for participant discontinuation or withdrawal from the study will be recorded on the 
Case Report Form (CRF). Subjects who sign the informed consent form and are randomized but 
do not receive the study intervention may be replaced.  Subjects who sign the informed 
consent form, and are randomized and receive the study intervention, and subsequently 
withdraw, or are withdrawn or discontinued from the study, will be replaced. 

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7.3 LOST TO FOLLOW-UP 
 
A participant will become ineligible to continue in the study if he/she misses more than one 
visit for each of the following 6-week time periods: Arm 1 treatment, Arm 1 washout, Arm 2 
treatment, Arm 2 washout. It is not considered a protocol deviation if a subject misses only one 
visit in any 6-week time period.  A participant will be considered lost to follow-up if he or she 
fails to return for 2 consecutive scheduled visits and is unable to be contacted by the study site 
staff. 
 
The following actions must be taken if a participant fails to return to the clinic for a required 
study visit: 
• The site will attempt to contact the participant and reschedule the missed visit within 1 
week and counsel the participant on the importance of maintaining the assigned visit 
schedule and ascertain if the participant wishes to and/or should continue in the study. 
• Before a participant is deemed lost to follow-up, the investigator or designee will make 
every effort to regain contact with the participant (where possible, 3 telephone calls, 
emails or portal messages). 
• Should the participant continue to be unreachable, he or she will be considered to have 
withdrawn from the study with a primary reason of lost to follow-up. If participant 
refuses to return device, the Office of General Council and/or the UM Police department 
will be notified of device theft, pursuant to Mich. Comp. § 750.356(3), § 750.356a(1), 
“Felony Theft in Michigan”. 
 
8 
STUDY ASSESSMENTS AND PROCEDURES 
8.1 EFFICACY ASSESSMENTS  
 
Study Procedures: 
 
General overview: All subjects will complete consenting and then a candidacy evaluation to 
determine if they meet study criteria.  Once they meet criteria, they will be scheduled for a 
baseline re-assessment.  Following the baseline assessment, they will be randomly assigned to a 
study arm (treatment or sham) and then training on how to use the device before taking it 
home.  They will take home the device on the same day they complete the baseline 
assessment.  Follow up assessments will take place weekly, and assessments completed at the 
weekly session are noted below. Additionally, some measures will only be completed at the 
beginning or end of the active treatment or sham conditions and following washout of active or 
sham treatment.  
 
Specific procedures: 

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1. Audiologic case history:  
a. Will be administered to each enrolled subject at the initial appointment in the 
study (candidacy evaluation) following completion of the consent form.  This 
questionnaire includes basic information regarding the patient’s audiologic and 
medical history. This will be administered by the study team audiologist or other 
trained technician. This is not repeated at any other point in the study unless the 
patient reports a change in audiologic history.  
2.  Otologic examination and medical case history: 
a. Will be administered to each enrolled subject at the initial appointment in the 
study (candidacy evaluation) following completion of the consent form.  This 
questionnaire includes basic information regarding the patient’s otologic and 
medical history. This will be administered by a physician/otologist on the study 
team. This is not repeated at any other point in the study unless the patient 
reports a change in otologic or medical history. 
b. If an otologic examination warrants further medical evaluation or intervention 
(standard of care) then an appropriate recommendation will be made by a 
physician study team member.  If a subject is required to seek further medical 
evaluation, he/she will not be able to participate in the trial until he/she has 
been properly evaluated and has provided test results or a letter from a 
physician indicating as such.  These costs are not covered by the study.  
c. If mental health issues are identified during the screening process, the screening 
physician will refer the subject back to their primary care physician for further 
evaluation and/or follow-up. 
3. Tinnitus modulation checklist 
a. Will be administered to each enrolled subject at the initial appointment in the 
study (candidacy evaluation) following completion of the consent form.  This 
questionnaire involves a study team member asking the subject to perform a 
series of movements and then requiring that the subject subjectively report if a 
given movement caused a change in tinnitus.  Only subjects who are able to 
modulate their tinnitus with one of the somatic maneuvers will be eligible to 
participate in the study. This will be assessed at the candidacy evaluation, and 
then according to the Schedule of Events (Section 1.3).  
4.  Audiometric assessment: 
a.  A basic audiometric assessment will be performed at the initial appointment in 
the study (candidacy evaluation) following completion of the consent form and 
then according to the Schedule of Events (Section 1.3).  The basic audiometric 
assessment follows standard clinic procedures in both ears.  This includes a 
behavioral audiogram using air-conduction (250-8000 Hz) and bone conduction 
(250-4000 Hz) stimuli presented through calibrated headphones or bone 
conduction transducer, respectively.  Speech detection thresholds will also be 
assessed to determine reliability. This data will be assessed to determine if a 
subject meets eligibility criteria for hearing loss.  It will also be reassessed bi-
weekly to determine if hearing thresholds worsen during each treatment arm as 
outlined in the stopping criteria.  

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5. TinnTester: 
a. Objective tinnitus loudness (TinnTester): This assessment is described in Section 
3 of this document.  It will be assessed at the baseline evaluation, and then 
according to the Schedule of Events (Section 1.3). 
b. Objective tinnitus bandwidth (TinnTester): This assessment is described in 
Section 3 of this document.  It will be assessed at the baseline evaluation, and 
then according to the Schedule of Events (Section 1.3). 
c. Sound tolerance level (TinnTester): This assessment is described in Section 3 of 
this document.  It will be assessed at the baseline evaluation, and then according 
to the Schedule of Events (Section 1.3). 
 
 
 
6. Minimum Masking Level: 
a. This assessment is described in Section 3 of this document.  It will be assessed at 
the baseline evaluation, and then according to the Schedule of Events (Section 
1.3). 
7.  Tinnitus Function Index (TFI) 
a. This assessment is described in Section 3 of this document.  It will be assessed at 
the candidacy evaluation, and then according to the Schedule of Events (Section 
1.3). 
8. Tinnitus Handicap Inventory (THI) 
a. This assessment is described in Section 3 of this document.  It will be assessed at 
the baseline evaluation, and then according to the Schedule of Events (Section 
1.3). 
9. Tinnitus Hearing Survey (THS): 
a. This assessment is described in Section 3 of this document.  It will be assessed at 
the baseline evaluation and then according to the Schedule of Events (Section 
1.3) 
 
8.2 SAFETY AND OTHER ASSESSMENTS 
 
Subject participation will entail weekly visits to the lab for detailed assessments. The weekly 
visits to the lab will ensure that subjects are using the devices correctly and safely. The weekly 
visits also allow us to monitor changes in the tinnitus percept in response to device use or 
washout from the treatment. The regular assessments also provide us with the opportunity to 
detect any adverse events as soon as possible, should any occur.  
 
Currently, there is no standard treatment for tinnitus that has been shown to be broadly 
effective at treating tinnitus, so participation in the study will not interfere with standard 
clinical intervention. Subjects will be informed during the consenting process that there are 
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referred to their primary care physician for referrals should they elect to pursue that form of 
treatment.  
 
Regular assessments will also allow for swift intervention should a subject experience an 
adverse event or worsening of symptoms. We will stop the study should 10% of subjects show a 
persistent worsening in their symptoms. A subject’s participation in the study will be 
discontinued following both 1) an increase of 16 or more points in TFI, and 2) an average 
increase of 12 dB in TinnTester compared to baseline, for two consecutive weekly measures. 
Both measures are our primary outcome measures.  Using both criteria for determining 
discontinuation is critical as the tinntester measures tinnitus loudness, which reflects the 
circuitry changes identified in our preclincal studies.  TFI is also important for the human study 
as it gauges the subject’s subjective response to their tinnitus.  However, TFI can also reflect 
outside life stressors unrelated to the treatment and could result in a subject's discontinuation 
for reasons unrelated to the treatment. A subject’s participation can also be discontinued even 
if the criteria above is not met, but the subject feels their tinnitus is worse.  
 
This study does not require and will not use a Data Safety Monitoring Board (DSMB) because it 
is not a multi-site study.  However, because it is a double-blinded, cross-over study we will 
implement and an Independent Safety Monitor (ISM) for data monitoring purposes.  The ISM 
will be clinical research monitor of the Michigan Institute for Clinical & Health Research (MICHR) 
who can provide independent monitoring of the human data. The ISM will be responsible for 
overseeing and monitoring the enrollment data, safety data and data integrity.  The ISM will be 
unblinded to the intervention assignment for each subject.  The ISM will be independent of the 
investigation.  He/she will not be a collaborator, co-author, supervisor, mentor/mentee, 
research lab member, or member of the institutional department within the last three years. 
He/she will not have any professional or financial conflict of interest.  
 
The PI (Susan Shore, PhD) will comply with the NIMH Reportable Events policy. The intervention 
will continue for each subject so long as adverse events do not occur for that individual.  The 
ISM will monitor data and review safety data.  If adverse events related to the study (definitely 
related, probably related, or potentially related) do occur, they will be reported to the IRB 
within 14 days and will be reported to the PI immediately.  All other adverse events will be 
reported annually at the time of IRB renewal.  This study uses a non-invasive device.  We will 
use strictly calibrated instruments to ensure that both acoustic and electrical stimulation are 
being delivered at safe levels for each subject. However, specific stopping rules will be 
identified for each subject to ensure patient safety.  For each subject, data for the TFI, THI, 
TinnTester, and audiologic examinations will be examined on a weekly basis (following weekly 
testing for each subject) for tinnitus assessments to determine if either measures indicate a 
statistically significant increase in tinnitus or decrease in hearing (in reference to the 
individual’s baseline measure).  This metric will be monitored by the ISM.  If tinnitus is found to 
increase or hearing loss worsen, then the subject will not continue in the study regardless of 
which arm (active or sham) in which the subject is enrolled.  Furthermore, if the subject 
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any of the subjective or objective measures, and he/she wishes to discontinue participation in 
the study then he/she will withdraw from the study.  
 
The study protocol and treatment device includes transmission of both acoustic and electric 
(transdermal) stimulation.  For both stimulation types, stimuli are strictly controlled as to not 
cause harm or discomfort for the subject. For acoustic stimulation, the intensity is set at 30 dB 
SL (as determined by the subject’s pure tone average), with each sound presented for 10 ms 
with 2 ms linear rise and fall times. This intensity level is expected to be within a comfortable 
listening range for each subject (based on clinical experience and previous research trial data).  
For the electric stimulation, the electrodes are positioned on the cheek overlying the trigeminal 
ganglion, the juncture of the temporomandibular joint or on the neck at overlying cervical 
nerves, C1 or C2, depending on which region modulates the tinnitus (based on the modulation 
maneuver checklist. Electrical stimulation levels are just below the threshold of muscular 
contraction (1-3 mA) as in the animal studies, limited by subject’s comfort. This level of electric 
stimulation is typically one that initially results in a small, comfortable tinging at the stimulation 
site upon initial activation.  However, based on our previous research trial subjects often report 
that electric stimulation cannot be detected within a few minutes of initial stimulation.  This 
low level of electrical stimulation causes no harm to the subject.  The sham protocol uses the 
same electrical and acoustic levels but the bimodal interval is wider than that used to induce 
STDP (>100 ms). Based on work in the animal, we expect that using wider bimodal intervals will 
cause no harm to the subject.  
The subject will be consented by one of the study team members at the initial candidacy 
appointment.  Consenting will take place in the Human lab on the 2nd floor of Med. Sci. I. at the 
University of Michigan, or online via HIPAA approved Zoom videoconferencing application.  
Patients will be seated in a comfortable chair in a semi-private room and be allowed to ask 
questions regarding the study.  Tinnitus assessments will take place in a private, double-walled 
sound booth.  Fitting of the device will take place in a semi-private laboratory room.  Medical 
evaluations will be completed by Dr. Basura or Dr. Stucken in a private examination room at the 
Otology Clinic at the University of Michigan, in the Human Lab on the 2nd floor of Med. Sci. I, or 
online via HIPAA approved Zoom videoconferencing application.  Any incidental findings will be 
reported to the subject and Dr. Basura or Dr. Stucken will make the appropriate medical 
referrals if necessary. 
 
We will keep all subject information secure.  All data will be collected and tracked 
electronically.  Data will be stored, using a secure data network system supported by the 
Michigan Institute for Clinical and Health Research (MICHR).  Subjects will communicate with 
research team members by phone or a secure web portal. Data will be coded, password 
protected and encrypted.   
 
 
8.3 ADVERSE EVENTS AND SERIOUS ADVERSE EVENTS 
 
8.3.1 DEFINITION OF ADVERSE EVENTS (AE) 

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Adverse event means any untoward medical occurrence associated with the use of an 
intervention in humans, whether or not considered intervention-related (21 CFR 312.32 (a)). 
 
 
8.3.2 DEFINITION OF SERIOUS ADVERSE EVENTS (SAE)  
 
An adverse event (AE) or suspected adverse reaction is considered "serious" if, in the view of 
either the investigator or sponsor, it results in any of the following outcomes: death, a life-
threatening adverse event, inpatient hospitalization or prolongation of existing hospitalization, 
a persistent or significant incapacity or substantial disruption of the ability to conduct normal 
life functions, or a congenital anomaly/birth defect. Important medical events that may not 
result in death, be life-threatening, or require hospitalization may be considered serious when, 
based upon appropriate medical judgment, they may jeopardize the participant and may 
require medical or surgical intervention to prevent one of the outcomes listed in this definition.  
 
8.3.3 CLASSIFICATION OF AN ADVERSE EVENT 
 
8.3.3.1 SEVERITY OF EVENT 
 
• Mild – Events require minimal or no treatment and do not interfere with the 
participant’s daily activities.  
• Moderate – Events result in a low level of inconvenience or concern with the 
therapeutic measures. Moderate events may cause some interference with functioning. 
• Severe – Events interrupt a participant’s usual daily activity and may require systemic 
drug therapy or other treatment. Severe events are usually potentially life-threatening 
or incapacitating.  Of note, the term “severe” does not necessarily equate to “serious”.] 
 
 
8.3.3.2 RELATIONSHIP TO STUDY INTERVENTION 
 
All adverse events (AEs) must have their relationship to study intervention assessed by the 
clinician who examines and evaluates the participant based on temporal relationship and 
his/her clinical judgment. The degree of certainty about causality will be graded using the 
categories below. In a clinical trial, the study product must always be suspect.  
 
• Related – The AE is known to occur with the study intervention, there is a reasonable 
possibility that the study intervention caused the AE, or there is a temporal relationship 
between the study intervention and event. Reasonable possibility means that there is 
evidence to suggest a causal relationship between the study intervention and the AE. 
• Not Related – There is not a reasonable possibility that the administration of the study 
intervention caused the event, there is no temporal relationship between the study 
intervention and event onset, or an alternate etiology has been established. 

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OR 
 
• Definitely Related – There is clear evidence to suggest a causal relationship, and other 
possible contributing factors can be ruled out. The clinical event, including an abnormal 
laboratory test result, occurs in a plausible time relationship to study intervention 
administration and cannot be explained by concurrent disease or other drugs or 
chemicals. The response to withdrawal of the study intervention (dechallenge) should 
be clinically plausible. The event must be pharmacologically or phenomenologically 
definitive, with use of a satisfactory rechallenge procedure if necessary. 
• Probably Related – There is evidence to suggest a causal relationship, and the influence 
of other factors is unlikely. The clinical event, including an abnormal laboratory test 
result, occurs within a reasonable time after administration of the study intervention, is 
unlikely to be attributed to concurrent disease or other drugs or chemicals, and follows 
a clinically reasonable response on withdrawal (dechallenge). Rechallenge information is 
not required to fulfill this definition. 
• Potentially Related – There is some evidence to suggest a causal relationship (e.g., the 
event occurred within a reasonable time after administration of the trial medication). 
However, other factors may have contributed to the event (e.g., the participant’s clinical 
condition, other concomitant events). Although an AE may rate only as “possibly 
related” soon after discovery, it can be flagged as requiring more information and later 
be upgraded to “probably related” or “definitely related”, as appropriate. 
• Unlikely to be related – A clinical event, including an abnormal laboratory test result, 
whose temporal relationship to study intervention administration makes a causal 
relationship improbable (e.g., the event did not occur within a reasonable time after 
administration of the study intervention) and in which other drugs or chemicals or 
underlying disease provides plausible explanations (e.g., the participant’s clinical 
condition, other concomitant treatments). 
• Not Related – The AE is completely independent of study intervention administration, 
and/or evidence exists that the event is definitely related to another etiology. There 
must be an alternative, definitive etiology documented by the clinician. 
 
 
8.3.3.3 EXPECTEDNESS  
 
The PI and ISM will be responsible for determining whether an adverse event (AE) is expected 
or unexpected.  An AE will be considered unexpected if the nature, severity, or frequency of the 
event is not consistent with the risk information previously described for the study 
intervention. 
 
8.3.4 TIME PERIOD AND FREQUENCY FOR EVENT ASSESSMENT AND FOLLOW-UP 
 

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The occurrence of an adverse event (AE) or serious adverse event (SAE) may come to the 
attention of study personnel during study visits and interviews of a study participant presenting 
for medical care, or upon review by a study monitor. 
 
All AEs including local and systemic reactions not meeting the criteria for SAEs will be captured 
on the appropriate case report form (CRF). Information to be collected includes event 
description, time of onset, clinician’s assessment of severity, relationship to study product 
(assessed only by those with the training and authority to make a diagnosis), and time of 
resolution/stabilization of the event. All AEs occurring while on study must be documented 
appropriately regardless of relationship. All AEs will be followed to adequate resolution. 
 
Any medical condition that is present at the time that the participant is screened will be 
considered as baseline and not reported as an AE. However, if the study participant’s condition 
deteriorates at any time during the study, it will be recorded as an AE.  
 
Changes in the severity of an AE will be documented to allow an assessment of the duration of 
the event at each level of severity to be performed. AEs characterized as intermittent require 
documentation of onset and duration of each episode. 
 
The PI and ISM will record all reportable events with start dates occurring any time after 
informed consent is obtained until 7 (for non-serious AEs) or 30 days (for SAEs) after the last 
day of study participation.  At each study visit, the investigator will inquire about the 
occurrence of AE/SAEs since the last visit.  Events will be followed for outcome information 
until resolution or stabilization. 
 
 
8.3.5 ADVERSE EVENT REPORTING  
The PI (Susan Shore, PhD) will comply with the NIMH Reportable Events policy. The intervention 
will continue for each subject so long as adverse events do not occur for that individual.  The 
ISM will monitor data and review safety data.  If adverse events related to the study (definitely 
related, probably related, or potentially related) do occur, they will be reported to the IRB 
within 7 days and will be reported to the PI immediately.  All other adverse events will be 
reported annually at the time of IRB renewal. 
 
8.3.6 SERIOUS ADVERSE EVENT REPORTING  
 
The study investigator shall complete an Unanticipated Adverse Device Effect Form and submit 
to the study sponsor and to the reviewing Institutional Review Board (IRB) as soon as possible, 
but in no event later than 10 working days after the investigator first learns of the effect.  The 
study sponsor is responsible for conducting an evaluation of an unanticipated adverse device 
effect and shall report the results of such evaluation to the Food and Drug Administration (FDA) 
and to all reviewing IRBs and participating investigators within 10 working days after the 

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sponsor first receives notice of the effect. Thereafter, the sponsor shall submit such additional 
reports concerning the effect as FDA requests. 
 
8.3.7 REPORTING EVENTS TO PARTICIPANTS  
N/A 
 
8.3.8 EVENTS OF SPECIAL INTEREST  
N/A 
8.3.9 REPORTING OF PREGNANCY  
N/A 
 
 
8.4 UNANTICIPATED PROBLEMS 
 
8.4.1 DEFINITION OF UNANTICIPATED PROBLEMS (UP) 
 
The Office for Human Research Protections (OHRP) considers unanticipated problems involving 
risks to participants or others to include, in general, any incident, experience, or outcome that 
meets all of the following criteria: 
 
• Unexpected in terms of nature, severity, or frequency given (a) the research procedures 
that are described in the protocol-related documents, such as the Institutional Review 
Board (IRB)-approved research protocol and informed consent document; and (b) the 
characteristics of the participant population being studied; 
• Related or possibly related to participation in the research (“possibly related” means 
there is a reasonable possibility that the incident, experience, or outcome may have 
been caused by the procedures involved in the research); and 
• Suggests that the research places participants or others at a greater risk of harm 
(including physical, psychological, economic, or social harm) than was previously known 
or recognized. 
 
This definition could include an unanticipated adverse device effect, any serious adverse effect 
on health or safety or any life-threatening problem or death caused by, or associated with, a 
device, if that effect, problem, or death was not previously identified in nature, severity, or 
degree of incidence in the investigational plan or application (including a supplementary plan or 
application), or any other unanticipated serious problem associated with a device that relates 
to the rights, safety, or welfare of subjects (21 CFR 812.3(s)). 
 
 
8.4.2  UNANTICIPATED PROBLEM REPORTING  

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The investigator will report unanticipated problems (UPs) to the reviewing Institutional Review 
Board (IRB) and to the Data Coordinating Center (DCC)/lead principal investigator (PI). The UP 
report will include the following information: 
 
• Protocol identifying information: protocol title and number, PI’s name, and the IRB 
project number; 
• A detailed description of the event, incident, experience, or outcome;  
• An explanation of the basis for determining that the event, incident, experience, or 
outcome represents an UP;  
• A description of any changes to the protocol or other corrective actions that have been 
taken or are proposed in response to the UP. 
 
To satisfy the requirement for prompt reporting, UPs will be reported using the following 
timeline:   
 
• UPs that are serious adverse events (SAEs) will be reported to the IRB and to the 
DCC/study sponsor within 10 days of the investigator becoming aware of the event.  
• Any other UP will be reported to the IRB and to the DCC/study sponsor within 10 days of 
the investigator becoming aware of the problem.  
• All UPs should be reported to appropriate institutional officials (as required by an 
institution’s written reporting procedures), the supporting agency head (or designee), 
and the Office for Human Research Protections (OHRP) within 10 days of the IRB’s 
receipt of the report of the problem from the investigator. 
 
 
 
8.4.3 REPORTING UNANTICIPATED PROBLEMS TO PARTICIPANTS  
N/A 
 
9 
STATISTICAL CONSIDERATIONS  
 
9.1 STATISTICAL HYPOTHESES 
The data will be collected throughout the course of the study by blinded test administrators. A 
General Linear/Logistic Mixed (GLLM) effects analytic model was developed in consultation 
with UM statistics department prior to our preliminary trial. GLLM is considered ideal when 
analyzing repeated measures as it treats time as a continuous variable and can account for 
missing data. This framework can readily adapt to subgroupings present in the data. GLLM 
analysis includes random and fixed effects. In this study, treatment order (active first vs sham 
first), treatment condition (active, active washout, sham, sham washout), baseline loudness, 
baseline TFI, and interaction of treatment and treatment order are treated as fixed while 
intercept is treated as a random effect. All metrics are computed relative to baseline for each 
subject. 
 

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MICHR has provided templates, tools, and general guidance in support of activities conducted 
by the study team to facilitate study and data management, and will continue to do so. The 
University of Michigan’s Department of Statistics Consulting for Statistics, Computing and 
Analytics Research (CSCAR) has provided individualized support and training to our team on 
management, collection, and analysis of data for phase 1 (which is identical to the second 
except in terms of subject numbers and treatment duration). Staff are available for continued 
support in the use of technical software, and advanced computing in research. 
 
• Primary Efficacy Endpoint(s):  
 
1) Objective Tinnitus Loudness 
2) Tinnitus Functional Index 
3) Tinnitus Handicap Index 
 
• Secondary Efficacy Endpoint(s): 
1) Tinnitus bandwidth/spectrum 
2) Minimum masking level 
3) Tinnitus Hearing Survey 
 
 
9.2 SAMPLE SIZE DETERMINATION 
To compute statistical power, we utilized a linear model of our prior trial data, where change 
from baseline in both TFI and loudness is a linear function of the time in study, with a constant 
term reflecting enrollment in study. Time in study was extended out to six weeks. Data sample 
independence was achieved by normalizing each subject by their own baseline. With these 
parameters, alpha = 0.05 and beta = 0.8, we simulated new data sets with samples ranging 
from 5 to 50. Model slopes were tested for significant differences using analysis of covariance. 
Each new model was simulated 50 times, and the total number of significant models counted. 
The first sample size where the computed power was greater than 0.8 was determined. 14 
subjects are required per arm to achieve a power of 0.8 for the loudness test, and 17 subjects 
are required per arm for the TFI. Thus, this study design requires a total subject count of 34. 
We propose a minimum sample size of 50 to account for subject variability and compliance. 
 
9.3 POPULATIONS FOR ANALYSES 
 
All subject’s data will be analyzed in one cohort. We will perform both per-protocol and 
intention-to-treat analyses. While intention-to-treat analysis is ideal, our protocol may require 
subjects to adhere to a strict schedule in order to fully realize the benefit of the treatment. 
Our pilot study had excellent compliance rates, but a longer and larger study provides more 
opportunity for non-compliant subjects. Should sensitivity analysis between the intention-to-
treat and per-protocol analyses attain significance, differences between compliant and non-
compliant subjects will be further explored in an effort more fully understand who best can 
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a last observation carried forward approach. Sensitivity analysis to outliers will also be 
performed. If results differ significantly between with and without outliers, outliers will be 
further investigated to determine what factors impact the likelihood of a subject responding or 
being resistant to the treatment protocol. 
 
9.4 STATISTICAL ANALYSES 
 
Data will be analyzed as means with standard deviations. All hypothesis-testing derived 
analyses will utilize an alpha of 0.05, beta of 0.8, and utilize two-tailed tests.  
 
9.4.1 ANALYSIS OF THE PRIMARY EFFICACY ENDPOINT(S) 
 
For all endpoints (Tinnitus loudness, TFI and THI), the following approach will be utilized. All 
measures are ordinal, repeated measures. Final analysis will occur after unblinding. 
 
Tinnitus loudness is measured by having subjects match the loudness and likeness of their 
tinnitus to one of 11 sounds with different center frequencies. Absolute differences are 
averaged relative to baseline to determine loudness. TFI and THI are questionnaires to be 
completed at each weekly visit. Both are measured on an interval scale. See section 3.1 for 
more details 
 
A General Linear/Logistic Mixed (GLLM) effects analytic model will be used. GLLM is considered 
ideal when analyzing repeated measures as it treats time as a continuous variable and can 
account for missing data. This framework can readily adapt to subgroupings present in the data. 
GLLM analysis includes random and fixed effects. In this study, treatment order (active first vs 
sham first), treatment condition (active, active washout, sham, sham washout), baseline 
loudness, baseline TFI, and interaction of treatment and treatment order are treated as fixed 
while intercept is treated as a random effect. 
 
Adjustments for Type I error over the set of endpoints is unnecessary as the measures are not 
directly related. 
 
 
9.4.2 ANALYSIS OF THE SECONDARY ENDPOINT(S) 
 
The following analytical framework will be applied to 2ndary measures (see section 3.2 for 
more details). Analyses are not dependent on primary-measures. All measures are ordinal, 
repeated measures. Data will be analyzed using repeated-measures ANOVA, and shown as 
mean+/-SEM. Normality will be assessed using Kolmogorov-Smirnoff tests, and non-parametric 
tests used for non-normally distributed data. To assess how the secondary measures might co 
vary with the primary measures, we will use principal component analysis or linear fixed effects 
models. 
 

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Non-compliant and missing data points will be excluded from analysis. 
 
9.4.3 SAFETY ANALYSES 
All AEs will be classified recorded and reported as noted in the Sections above. 
 
. 
9.4.4 BASELINE DESCRIPTIVE STATISTICS 
 
See statistical tests above.  All analyzed metrics are computed for each subject’s baseline.   
 
9.4.5 PLANNED INTERIM ANALYSES  
N/A 
 
9.4.6 SUB-GROUP ANALYSES 
N/A 
 
9.4.7 TABULATION OF INDIVIDUAL PARTICIPANT DATA 
State whether individual participant data will be listed by measure and time point. 
 
Individual data will be listed by time point. 
 
9.4.8 EXPLORATORY ANALYSES 
To be determined. 
 
10 SUPPORTING DOCUMENTATION AND OPERATIONAL CONSIDERATIONS 
 
10.1 REGULATORY, ETHICAL, AND STUDY OVERSIGHT CONSIDERATIONS 
 
 
10.1.1 INFORMED CONSENT PROCESS 
 
10.1.1.1 
CONSENT/ASSENT AND OTHER INFORMATIONAL DOCUMENTS PROVIDED 
TO PARTICIPANTS 
Consent forms describing in detail the study intervention, study procedures, and risks are given 
to the participant and written documentation of informed consent is required prior to starting 
intervention/administering study intervention.   
 
10.1.1.2 
CONSENT PROCEDURES AND DOCUMENTATION 
Informed consent is a process that is initiated prior to the individual’s agreeing to participate in 
the study and continues throughout the individual’s study participation. Consent forms will be 
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the document. The investigator will explain the research study to the participant and answer 
any questions that may arise. A verbal explanation will be provided in terms suited to the 
participant’s comprehension of the purposes, procedures, and potential risks of the study and 
of their rights as research participants.  Participants will have the opportunity to carefully 
review the written consent form and ask questions prior to signing. The participants should 
have the opportunity to discuss the study with their family or surrogates or think about it prior 
to agreeing to participate. The participant will sign the informed consent document prior to any 
procedures being done specifically for the study. Participants must be informed that 
participation is voluntary and that they may withdraw from the study at any time, without 
prejudice. A copy of the informed consent document will be given to the participants for their 
records. The informed consent process will be conducted and documented in the source 
document (including the date), and the form signed, before the participant undergoes any 
study-specific procedures. The rights and welfare of the participants will be protected by 
emphasizing to them that the quality of their medical care will not be adversely affected if they 
decline to participate in this study. 
 
 
10.1.2 STUDY DISCONTINUATION AND CLOSURE 
 This study may be temporarily suspended or prematurely terminated if there is sufficient 
reasonable cause.  Written notification, documenting the reason for study suspension or 
termination, will be provided by the suspending or terminating party to investigator, and 
funding agency.  If the study is prematurely terminated or suspended, the Principal Investigator 
(PI) will promptly inform study participants, the Institutional Review Board (IRB), and sponsor 
and will provide the reason(s) for the termination or suspension.  Study participants will be 
contacted, as applicable, and be informed of changes to study visit schedule. 
  
Circumstances that may warrant termination or suspension include, but are not limited to: 
• Determination of unexpected, significant, or unacceptable risk to participants 
• Demonstration of efficacy that would warrant stopping    
• Insufficient compliance to protocol requirements 
• Data that are not sufficiently complete and/or evaluable 
• Determination that the primary endpoint has been met 
• Determination of futility 
 
Study may resume once concerns about safety, protocol compliance, and data quality are 
addressed, and satisfy the sponsor, IRB and/or Food and Drug Administration (FDA). 
 
10.1.3 CONFIDENTIALITY AND PRIVACY  
 
Participant confidentiality and privacy is strictly held in trust by the participating investigators, 
their staff, and the sponsor(s) and their interventions. This confidentiality is extended to cover 
testing of biological samples and genetic tests in addition to the clinical information relating to 
participants. Therefore, the study protocol, documentation, data, and all other information 

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generated will be held in strict confidence. No information concerning the study or the data will 
be released to any unauthorized third party without prior written approval of the sponsor.  
 
All research activities will be conducted in as private a setting as possible. 
 
The ISM other authorized representatives of the sponsor, representatives of the Institutional 
Review Board (IRB), regulatory agencies or pharmaceutical company supplying study product 
may inspect all documents and records required to be maintained by the investigator, including 
but not limited to, medical records (office, clinic, or hospital) and pharmacy records for the 
participants in this study. The clinical study site will permit access to such records. 
 
The study participant’s contact information will be securely stored at each clinical site for 
internal use during the study. At the end of the study, all records will continue to be kept in a 
secure location for as long a period as dictated by the reviewing IRB, Institutional policies, or 
sponsor requirements. 
 
Study participant research data, which is for purposes of statistical analysis and scientific 
reporting, will be transmitted to and stored with MICHR’s REDCap Service  
(https://www.michr.umich.edu/redcap-access). This will not include the participant’s contact 
or identifying information. Rather, individual participants and their research data will be 
identified by a unique study identification number. The study data entry and study 
management systems used by clinical sites and by MICHR’s REDCap Service research staff will 
be secured and password protected. At the end of the study, all study databases will be de-
identified and archived at the NIMH database. 
 
10.1.4 FUTURE USE OF STORED SPECIMENS AND DATA  
 
Data collected for this study will be analyzed and stored with MICHR’s REDCap Service. After 
the study is completed, the de-identified, archived data will be transmitted to and stored at the 
NIMH data repository for use by other researchers including those outside of the study. 
Permission to transmit data to the NIMH data repository will be included in the informed 
consent.  
 
10.1.5 KEY ROLES AND STUDY GOVERNANCE 
Provide the name and contact information of the Principal Investigator and the Independent 
Safety Monitor. 
Principal Investigator 
Independent Safety Monitor 
Susan Shore, PhD 
MICHR 
University of Michigan  
University of Michigan  
1150 W. Medical Center Drive, 
Ann Arbor MI 48109 
1600 Huron Parkway Bldg 400 
Ann Arbor, MI 48105 

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734-647-2116 
734-998-7474 
sushore@umich.edu 
UM-MICHR@umich.edu 
 
 
 
 
10.1.6 SAFETY OVERSIGHT 
Safety oversight will be under the direction of the PI and the ISM.  
The ISM is independent from the study conduct and free of conflict of interest, or measures 
should be in place to minimize perceived conflict of interest.  The ISM and PI will meet at least 
semiannually to assess safety and efficacy data on each arm of the study. The ISM will operate 
under the rules of an approved charter that will be written and reviewed at the organizational 
meeting of the ISM. At this time, each data element that the ISM needs to assess will be clearly 
defined. The ISM will provide its input to NIMH. 
 
10.1.7 CLINICAL MONITORING 
N/A 
 
10.1.8 QUALITY ASSURANCE AND QUALITY CONTROL 
N/A 
 
10.1.9 DATA HANDLING AND RECORD KEEPING  
 
10.1.9.1 
DATA COLLECTION AND MANAGEMENT RESPONSIBILITIES  
 
Data collection is the responsibility of the clinical trial staff at the site under the supervision of 
the site investigator. The investigator is responsible for ensuring the accuracy, completeness, 
legibility, and timeliness of the data reported. 
 
All source documents should be completed in a neat, legible manner to ensure accurate 
interpretation of data.  All data will be captured by custom developed software from the Shore 
Lab, a 21 CFR Par 11-compliant system, and automatically saved on the previously identified 
encrypted servers. Data include audiograms, TFI, THI, use/compliance monitoring, etc. All data 
will be centrally collected, stored on an ongoing basis. 
 
Hardcopies of the study visit worksheets will be provided for use as source document 
worksheets for recording data for each participant enrolled in the study.  Data recorded in the 
electronic case report form (eCRF) derived from source documents should be consistent with 
the data recorded on the source documents. Source code, documentation, user manuals and 
monitoring analyses will be made available on completion of system. Data collected by devices 
will be encrypted locally on each device, and accessible only to study investigators with 
appropriate passwords. 
 

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Clinical data (including adverse events (AEs), concomitant medications, and expected adverse 
reactions data) and clinical laboratory data will be entered into MICHR REDCap, a 21 CFR Part 
11-compliant data capture system provided by the MICHR REDCap Service. The data system 
includes password protection and internal quality checks, such as automatic range checks, to 
identify data that appear inconsistent, incomplete, or inaccurate. Clinical data will be entered 
directly from the source documents. 
 
All data will be captured by custom developed software and automatically saved on the 
previously identified encrypted servers. Data include audiograms, TFI, THI, use/compliance 
monitoring, etc. All data will be centrally collected, stored on an ongoing basis. 
 
Source code, documentation, user manuals and monitoring analyses will be made available on 
completion. 
 
Data collected by devices will be encrypted locally on each device, and accessible only to study 
investigators with appropriate passwords. 
 
 
 
10.1.9.2 
STUDY RECORDS RETENTION  
 
All records and information collected as part of participation in this study will be kept for 7 
years from the date the study is completed.   
 
10.1.10 
PROTOCOL DEVIATIONS  
The investigator is responsible for complying with the protocol and all appropriate regulations 
and guidelines governing global clinical research.  Additionally, he/she is responsible for 
ensuring that all participating staff members are adequately trained and competent to perform 
his/her assigned tasks. 
 
Modifications to the study protocol will not be implemented by either the sponsor or the 
investigator without agreement by both parties.  However, the investigator may implement a 
deviation form, or a change of, the protocol to eliminate an immediate hazard(s) to the trial 
subjects without prior IRB/sponsor approval/favorable opinion.  As soon as possible, the 
implemented deviation or change, the reasons for it and if appropriate the proposed protocol 
amendment should be submitted to the IRB/sponsor. 
 
Deviations from the protocol must be recorded and reported (per local IRBMED guidelines) by 
the investigator. The circumstances, action taken and impact of major deviations on the trial 
must be communicated by the Principal Investigator to the designated ISM.    
 
10.1.11 
PUBLICATION AND DATA SHARING POLICY 

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This study will be conducted in accordance with the following publication and data sharing 
policies and regulations: 
 
National Institutes of Health (NIH) Public Access Policy, which ensures that the public has access 
to the published results of NIH funded research. It requires scientists to submit final peer-
reviewed journal manuscripts that arise from NIH funds to the digital archive PubMed Central 
upon acceptance for publication. 
 
This study will comply with the NIH Data Sharing Policy and Policy on the Dissemination of NIH-
Funded Clinical Trial Information and the Clinical Trials Registration and Results Information 
Submission rule. As such, this trial will be registered at ClinicalTrials.gov, and results 
information from this trial will be submitted to ClinicalTrials.gov. In addition, every attempt will 
be made to publish results in peer-reviewed journals.  In addition, in accordance with the 
funding source, data will be shared on the NIMH Data Archive. 
 
 
10.1.12 
CONFLICT OF INTEREST POLICY 
 
The independence of this study from any actual or perceived influence, such as by the 
pharmaceutical industry, is critical.  Therefore, any actual conflict of interest of persons who 
have a role in the design, conduct, analysis, publication, or any aspect of this trial will be 
disclosed and managed. Furthermore, persons who have a perceived conflict of interest will be 
required to have such conflicts managed in a way that is appropriate to their participation in 
the design and conduct of this trial.  The study leadership in conjunction with the <specify NIH 
Institute or Center (IC)> has established policies and procedures for all study group members to 
disclose all conflicts of interest and will establish a mechanism for the management of all 
reported dualities of interest. 
 
Susan Shore and David Martel are inventors on U.S. patent no. 3A9242067 “Personalized 
auditory-somatosensory stimulation to treat tinnitus.” We have disclosed this conflict to the 
UMMS Conflict of Interest Board (MEDCOI) and will seek their review of decisions pertaining to 
the actual or perceived conflicts. 
 
10.2 ADDITIONAL CONSIDERATIONS 
N/A 
 
 
 

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10.3 ABBREVIATIONS 
 
AE 
Adverse Event 
ANOVA 
Analysis of Variance 
ANSI 
American National Standards Institute 
CN 
Cochlear Nucleus 
CONSORT Consolidated Standards of Reporting Trials 
CPU 
Central Processing Unit 
CRF 
Case Report Form 
CSCAR 
Consulting for Statistics, Computing and Analytics Research 
DCC 
Data Coordinating Center 
DCN 
Dorsal Cochlear Nucleus 
DSMB 
Data Safety Monitoring Board 
eCRF 
Electronic Case Report Forms 
FDA 
Food and Drug Administration 
GLMM 
Generalized Linear Mixed Modeling 
IHS 
Intelligent Hearing Systems 
IRB 
Institutional Review Board 
ISM 
Independent Safety Monitor 
ISO 
International Organization for Standardization 
MICHR 
Michigan Institute for Clinical & Health Research 
MML 
Minimum Masking Level 
NIH  
National Institutes of Health 
NIMH 
NIH National Institute of Mental Health 
OSHA 
Occupational Safety and Health Administration 
PI 
Principal Investigator 
SAE 
Serious Adverse Event 
SOA 
Schedule of Activities 
STDP 
Spike Timing Dependent Plasticity  
StDP 
Stimulus Timing Dependent Plasticity 
TFI 
Tinnitus Functional Index 
THI 
Tinnitus Hearing Survey 
THS 
Tinnitus Hearing Survey 
UP 
Unanticipated Problem 
 
 
 

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10.4 PROTOCOL AMENDMENT HISTORY 
The table below is intended to capture changes of IRB-approved versions of the protocol, 
including a description of the change and rationale. A Summary of Changes table for the current 
amendment is located in the Protocol Title Page.  
 
Version 
Date 
Description of Change  
Brief Rationale 
1.2 
11/6/2018 
Amending inclusion criteria to 
include a subject “must have no 
greater than a mild hearing loss 
125-6000 Hz”.  
This is so we are able to have 
similar hearing profiles from 
Stage 1 of the clinical trial. 
1.3 
12/3/2018 
Remove TinnTester from the 
screening appointment. 
The TinnTester is not needed 
to determine eligibility. 
1.3 
12/3/2018 
Complete the tinnitus modulation 
checklist throughout the study, 
specifically on Day 42, 91, 133, 
and 175. 
To evaluate the effect of the 
device on the somatosensory 
system.  
1.3 
12/3/2018 
Remove Auditory Brainstem 
Response (ABR) from study.  
Not completing this measure 
because it is not a primary 
objective for study aim.  
1.3 
12/3/2018 
Remove Residual Inhibition (RI) 
from study.  
Not completing this measure 
because it is not a primary 
objective for study aim.  
1.4 
1/29/2019 
On page 40, deleted “Medical” 
and inserted “Independent 
Study”. 
The monitor is not a medical 
monitor.  
1.5  
3/29/2019 
On page 4, added “central 
nervous system stimulants” and 
“benzodiazepines” to the 
medication exclusion criteria. 
These drugs may be causing, 
contributing to, and 
influencing one’s tinnitus.  
1.5 
3/29/2019 
On page 2, 7, and 18, changed 
“100” people consented to “200” 
people consented. 
We need to expand this 
number in order to reach 50 
people enrolled in the study.  
1.6 
1/27/2020 
On page 10, added sentence 
stating that though unlikely, it is 
possible that tinnitus may 
become louder or more 
noticeably during the trial. 
This was added to reflect 
occurrences in the trial and 
changes on the consent 
form. 
1.6 
1/27/2020 
On pages 2, 7, and 18, updated 
the total number of participants 
from N=200 to N=300 
To allow more screenings in 
order to reach goal of 50 
subjects actively enrolled. 
1.11 
4/14/21 
On pages 2, 7, and 18, updated the 
total number of participants from 
N=300 to N=400 
To allow more screenings in 
order to reach goal of 50 
subjects with complete data 

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1.11 
4/14/21 
On pages 2, 18, changed 50 
randomized subjects to up to 100 
randomized subjects 
To allow more subjects to 
reach goal of 50 subjects 
with complete data 
7.1, 8.2 
6/22/2021 
Pg 24, 29, Clarifying exclusion 
criteria 
Clarifying exclusion criteria 
with TFI and TT 
8.2 
6/22/2021 
Pg 29, added online location for 
consenting and medical 
screenings, added 2nd floor of 
Med Sci I for medical screenings, 
added Dr. Stucken for medical 
referrals as needed 
To prevent excessive in 
person appointments and 
allow Dr. Stucken to refer as 
needed 
8.2 
2/16/2022 
Pg 29, changed adverse event 
reporting time from 7 days to 14 
days to match IRBMED 
Changing adverse event 
reporting time to match 
IRBMED 
 
 

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11 REFERENCES  
Dobie, R. A. (1999). "A review of randomized clinical trials in tinnitus." Laryngoscope 109(8): 
1202-1211. 
 
OBJECTIVES: Review reports of randomized clinical trials (RCTs) in tinnitus to identify 
well-established treatments, promising developments, and opportunities for 
improvement in this area of clinical research. STUDY DESIGN: Literature review of RCTs 
(1964-1998) identified by MEDLINE and OLD MEDLINE searches and personal files. 
METHODS: Studies were compared with the RCT criteria of Guyatt et al. for quality of 
design, performance, and analysis; "positive" results were critically examined for 
potential clinical relevance. RESULTS: Sixty-nine RCTs evaluated tocainide and related 
drugs, carbamazepine, benzodiazepines, tricyclic antidepressants, 16 miscellaneous 
drugs, psychotherapy, electrical/magnetic stimulation, acupuncture, masking, 
biofeedback, hypnosis, and miscellaneous other nondrug treatments. No treatment can 
yet be considered well established in terms of providing replicable long-term reduction 
of tinnitus impact, in excess of placebo effects. CONCLUSIONS: Nonspecific support and 
counseling are probably helpful, as are tricyclic antidepressants in severe cases. 
Benzodiazepines, newer antidepressants, and electrical stimulation deserve further 
study. Future tinnitus therapeutic research should emphasize adequate sample size, 
open trials before RCTs, careful choice of outcome measures, and long-term follow-up. 
 
Marks, K. L., et al. (2018). "Auditory-somatosensory bimodal stimulation desynchronizes brain 
circuitry to reduce tinnitus in guinea pigs and humans." Sci Transl Med 10(422). 
 
The dorsal cochlear nucleus is the first site of multisensory convergence in mammalian 
auditory pathways. Principal output neurons, the fusiform cells, integrate auditory nerve 
inputs from the cochlea with somatosensory inputs from the head and neck. In previous 
work, we developed a guinea pig model of tinnitus induced by noise exposure and 
showed that the fusiform cells in these animals exhibited increased spontaneous activity 
and cross-unit synchrony, which are physiological correlates of tinnitus. We delivered 
repeated bimodal auditory-somatosensory stimulation to the dorsal cochlear nucleus of 
guinea pigs with tinnitus, choosing a stimulus interval known to induce long-term 
depression (LTD). Twenty minutes per day of LTD-inducing bimodal (but not unimodal) 
stimulation reduced physiological and behavioral evidence of tinnitus in the guinea pigs 
after 25 days. Next, we applied the same bimodal treatment to 20 human subjects with 
tinnitus using a double-blinded, sham-controlled, crossover study. Twenty-eight days of 
LTD-inducing bimodal stimulation reduced tinnitus loudness and intrusiveness. 
Unimodal auditory stimulation did not deliver either benefit. Bimodal auditory-
somatosensory stimulation that induces LTD in the dorsal cochlear nucleus may hold 
promise for suppressing chronic tinnitus, which reduces quality of life for millions of 
tinnitus sufferers worldwide. 

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