Investigation of the NMDA Antagonist Ketamine as a Treatment for Tinnitus
Phase: PHASE2
Conditions: Tinnitus
Sponsor: New York State Psychiatric Institute

Cover page: 
 
Title: Investigation of the NMDA Antagonist Ketamine as a Treatment for Tinnitus 
NCT03336398 
IRB approval date: March 4, 2025 

  
 
 
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Click or tap here to enter text. 
 
Lay Summary of Proposed Research 
This section is intended to provide a basic overview of the study including a description of its purpose, study procedures, 
and subject population.  The summary should provide a concise overview of the study for non-scientific and scientific 
members of the IRB.  Please avoid medical or technical terminology.  In general, the abstract of a grant does not provide 
a suitable lay summary. 
Tinnitus, or ringing in the ears, is a very common problem that often accompanies hearing loss. It affects up to 1 in 10 
adults, and about 30% of people who experience chronic tinnitus find it very distressing. In these patients, symptoms of 
depression and anxiety often accompany tinnitus and there are no approved treatments. Clinical trials are ongoing to 
test a glutamate NMDA receptor antagonist (called esketamine), which is injected into the inner ear. However, the 
preliminary results with this medication show that it only works for tinnitus that results from acute injury. It does not 
treat tinnitus resulting from progressive hearing loss. 
Research in humans and animals suggest that the neurotransmitters glutamate and GABA are important in the 
development and maintenance of tinnitus. This data shows that overactivation of the NMDA receptor and a decrease in 
GABA signaling in the brain play a crucial role. Studies from our institution show that ketamine, which an antagonist at 
the NMDA receptor, increases GABA levels in the brain in subjects with depression.  Thus, in this experiment, we will test 
the effect of ketamine on tinnitus since it blocks the NMDA glutamate receptor and increase GABA levels.  
 
Background, Significance, and Rationale 
In this section, provide a brief summary of the status quo of the relevant work field and how the proposed study will 
advance knowledge. Specifically, identify the gaps in knowledge that your project is intended to fill. If no gaps exist that 
are obviously and directly related to your project, explain how your proposed research will contribute to the overall 
understanding of your field. Describe potential impacts of your project within your field of study and in a broader context. 
Provide a critical evaluation of existing knowledge. The literature review does not have to be exhaustive.  
Tinnitus has a prevalence of approximately 1 in 10 adults in the United States (Bhatt, 2016). Among those with tinnitus, 
36% had nearly constant symptoms and almost 30% of those report that their tinnitus as a big or a very big problem.  
Currently there are few effective treatments for tinnitus, and no approved medications. Cognitive behavioral and 
retraining therapy provide some relief, but many patients fail to respond (Bhatt, 2016). 
Animal research and human studies indicate that maladaptive plasticity plays a role in tinnitus, which involves 
glutamatergic signaling largely at the NMDA and AMPA receptors. Additionally, GABA signaling has been shown to be 
impaired in tinnitus. Rodent models show a diminished sensitivity to GABA signaling (Llano et al., 2012) and human 

  
 
 
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magnetic resonance spectroscopy (MRS) studies show decreased GABA levels in the auditory cortex (Sedley et al., 2015). 
Ketamine is a non-competitive NMDA receptor antagonist that has also been shown to activate AMPA receptors (Zanos 
et al., 2016), and modulates ongoing plasticity. Additionally, ketamine activates a subpopulation of cortical GABAergic 
interneurons and projection neurons and increases GABA levels in the human brain, measured with MRS (Rodriguez et 
al., 2015, Milak et al., 2016). Ketamine is FDA approved as an anesthetic, and recent work has demonstrated its efficacy 
in treating refractory depression and chronic pain. Importantly, these demonstrate that low dose ketamine, at doses 
lower than those required for anesthesia, are effective in lifting depressed mood and improving the sensation of chronic 
pain (Radvansky et al., 2015). 
For many, tinnitus has an important affective component to it, with distress and co-morbid symptoms of depression and 
anxiety (Guitton 2012, Pattyn et al., 2016). The onset and severity of tinnitus can correlate with stressful events (Guitton 
2012, Pattyn et al., 2016), and it has been posited that stress lowers the threshold of perception, and unmasks tinnitus 
(Guitton, 2012).  Tinnitus then triggers more anxiety and depressed mood, which in turn reinforces the symptoms 
(Guitton, 2012, Pattyn et al., 2016). An advantage of ketamine may be its effect on depression and anxiety, in addition to 
tinnitus, to interrupt this cycle.  
Our goal is to perform a proof-of-concept preliminary study of ketamine in tinnitus associated with sensori-neural 
hearing loss. MRS imaging will be used to assess ketamine-induced changes in GABA in the auditory cortex.  
 
Specific Aims and Hypotheses 
Concisely state the objectives of the study and the hypothesis or primary research question(s) being examined.  There 
should be one hypothesis for every major study procedure or intervention.  For pilot studies, it is important not to 
overstate the study's objectives.  If there are no study hypotheses, describe broad study goals/aims. 
Specific Aim 1: To test the effect of ketamine in subjects with tinnitus. We will use a randomized, cross-over design in 40 
subjects. Each subject will receive ketamine (0.5 mg/kg IV) versus placebo. Subjects will serve as their own controls and 
the sessions will be performed in a controlled laboratory environment with experienced personnel. We will use the dose 
of ketamine that has been shown to be effective in depression and anxiety disorders (0.5 mg/kg), administered 
intravenously, to allow the delivery to be paced and carefully controlled.  The outcome measures will include measures 
of tinnitus burden, depression and anxiety.  
Specific Aim 2: To investigate changes in GABA in the auditory cortex before and after ketamine administration. An MRS 
imaging study has shown a decrease in GABA levels in the right auditory cortex in tinnitus subjects (Sedley et al., 2015). 
Our group has shown that ketamine (0.5 mg/kg IV) increases cortical GABA, measured with MRS, in subjects with 
obsessive compulsive disorder and depression (Rodriguez et al., 2015, Milak et al., 2016). Thus, our hypothesis is that 
ketamine will increase GABA levels in the auditory cortex, in subjects suffering with tinnitus. We will investigate the 
correlation between the change in GABA with symptom improvement.  

  
 
 
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Description of Subject Population 
In this section, you are to describe each subject population of the study.  The demographics of the population should 
reflect the gender and ethnic distribution of each population being studied.  Enter each subject population’s sample size, 
Gender, Racial, and Ethnic breakdown, and finally, describe each subject population. 
 Example: 
Sample subject population: 
Subject Population 
Number of completers 
required to accomplish 
study aims 
Projected number of 
subjects who will be 
enrolled to obtain required 
number of completers 
Age range of subject 
population 
Participants with tinnitus  
30 
60 
21-60 
Suicide Risk Management Plan 
This section will include all information regarding the Suicide Risk Management Plan.   
  Any participant reporting suicidal ideation or behavior to any member of the research team will be evaluated. If the 
patient is an active suicide risk, 911 will be called and/or the participant will be escorted to the Emergency Department. 
If the participants is not an active risk, they will be provided with referrals for outpatient treatment. If the participant 
has outpatient treatment in place, their clinician will be notified.  
Recruitment Procedures 
This section will include all information regarding your study’s recruitment process/procedures.   
Describe settings where recruitment will occur.  Subjects will be recruited through advertisements or word of mouth 
How and by whom will subjects be approached and/or recruited?  As above 
Clinical Trials: 
Please provide the NCT Registration Number for your Clinical Trial.  NCT03336398  
 
YOU MUST REGISTER AT ClinicalTrials.gov IMMEDIATELY UPON RECEIPT OF IRB APPROVAL AND PRIOR TO 
ENROLLMENT OF THE FIRST SUBJECT.  YOU WILL BE PROVIDED WITH A NCT REGISTRATION NUMBER ON 
REGISTRATION.  PLEASE REVISE THIS SECTION OF THE PROTOCOL SUMMARY FORM TO INCLUDE THE NCT NUMBER 
AND RE-SUBMIT AS AN AMENDMENT TO THE IRB. 

  
 
 
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Concurrent Research Studies 
In this section, please identify if subjects in this study participate in or will be recruited from other studies.   
Describe where subjects are recruited from.   
N/A 
Describe the recruitment source for (Must provide IRB Number, PI and Title).   
N/A 
Inclusion/Exclusion Criteria 
This section details your study sample(s) and addresses the requirement for risk minimization. 
You may choose to divide your sample by population (healthy controls vs. patient population) or by procedure (subjects 
who will have an MRI vs. those who will not) and then define different sets of criteria for each. 
For each sample, create or insert a table to describe detailed criteria for study inclusion and exclusion and the method 
you will use to ascertain each criterion. The method of ascertainment may describe tests, scales and instruments.  When 
relevant, indicate the level of training of the person who will make the assessment (e.g. clinical interview by a 
psychiatrist). 
Inclusion/Exclusion Criteria need to be numbered and listed in outline form (see Table template below). 
   Participants with tinnitus  
CRITERION                                                          
METHOD OF ASCERTAINMENT                
Inclusion: 
 
1. Subjects aged 21-60 
Self-report 
2. Tinnitus associated with at least mild 
sensori-neural hearing loss of at least 6 
months duration 
Medical History 
3. Score on the Tinnitus Handicap Inventory 
(THI) of at least moderate symptoms  
Tinnitus Handicap Inventory (THI) 
Exclusion: 
 
1. DSM-V psychiatric disorders other than 
mild-moderate depression and anxiety, 
including substance use disorder 
Psychiatric Interview. 

  
 
 
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2. History of recreational ketamine use, 
recreational PCP use, or an adverse reaction 
to ketamine 
Medical/Psychiatric Evaluation 
3. Currently taking psychotropic medication 
(e.g. antipsychotics, tricyclic antidepressants, 
monoamine oxidase inhibitors, or 
benzodiazepines).  
Medical/Psychiatric Evaluation 
4. Presence or positive history of significant 
medical or neurological illness, including high 
blood pressure, cardiac illness, abnormality 
on EKG, head injury 
Medical/Psychiatric Evaluation, Physical Exam, 
EKG 
5. Pregnancy, abortion, or lack of effective 
birth control during 15 days before the scan 
Medical Assessment, pregnancy test 
6. Metal implants, pacemaker, other metal 
(e.g. shrapnel or surgical prostheses) or 
paramagnetic objects contained within the 
body which may present a risk to the subject 
or interfere with the MR scan. 
Medicinal patch that cannot be removed for 
the scan. 
Medical/Psychiatric Evaluation, Physical Exam 
(NYSPI) 
 
Consent Procedures 
Explain, in this section, the procedures for obtaining consent from study participants. 
If the eligibility screening for this study is conducted under a different IRB protocol, enter the NYSPI IRB# Screening is 
conducted under this protocol only. 
 
Waiver of Consent / Authorization 
The following sections are to be completed for the appropriate waiver/alteration of consent.   
Waiver of Consent for use of Protected Health Information (PHI) 
What records do you wish to review?   

  
 
 
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What information are you seeking access to?    
Describe your plan to protect identifiers from improper use and disclosure.   
 
Describe your plan to destroy the identifiers as soon as possible, consistent with the conduct of the research, or 
provide a health or research justification for retaining the identifiers or explain how retention is required by law.  
 
 
Explain why the research could not be practicably carried out without the information (for which you are 
requesting access).   
 
Explain why the research cannot be practicably carried out without the waiver.    
 
Explain how/if subjects will be provided with additional pertinent information after participation.   
 
 
Justification for Waiver or Alteration of Consent 
Waiver of consent is requested for the following.   
 
Explain why your research cannot be practicably carried out without the waiver or alteration.    
Describe whether and how subjects will be provided with additional pertinent information after participation.    
 
Waiver of Documentation of Consent 
Would the consent form signature be the only link between the subject’s identity and the research data?  
 
Is breach of confidentiality the main study risk?   
 
Is consent for this research procedure ordinarily not required outside of the research context?  Explain.    
 
Describe the study component(s) for which waiver of documentation is requested.   
 
 
Waiver of Parental Consent 
Explain why parental/guardian consent is not a reasonable requirement to protect the minor participants in this 
study.    
 
If parental consent is waived, describe a mechanism that will be substituted to provide appropriate protections 
for the subjects.   
 

  
 
 
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Independent Assessment of Capacity 
This section is designated for those studies that have been identified where subjects May Lack capacity to consent.   
Describe the Methods/procedures for capacity assessment.   
N/A 
If your study involves subjects who DO LACK capacity to consent, please justify.    
 
Procedures for surrogate consent.   
 
 
Study Procedures 
Provide a clear, concise narrative of study procedures with special attention to the subjects' involvement.  Detail the 
overall study timeline and location of study procedures, list all interventions, assessments and interviews, estimate the 
duration of each procedure, provide dosing schedules, identify study personnel involved in each procedure, and provide 
credentials for relevant personnel.  If treatment is provided, specify the minimum credentials for providing that 
treatment. For complicated study designs, we strongly encourage attaching tables, flow-charts, and study algorithms. 
Screening:  Screening will occur in two steps. The first will be a virtual visit and the second will be in person. Subjects will 
be provided with the screening CF prior to the virtual visit, either an electronic (via encrypted email) or paper (via 
standard mail) version. Screening consent and can be signed by a trained research assistant/study coordinator (Alex 
Grassetti) or a study physician.  Participants may provide verbal (not written) consent for the screening process in order 
to minimize in-person contact and travel.  If verbal consent is to be obtained, study personnel will ensure that the 
participant has an electronic (via encrypted email) or paper (via traditional mail) copy of the consent form and has had 
sufficient time to read it through and form questions.   Study personnel will discuss the document, the study, and any 
other questions the participant might have. The consent process will include discussion of the technology HIPAA-
compliant platforms to be used. 
The screening visit will include: 1) a collection of blood samples (about 15 cc) for routine medical tests and a pregnancy 
test (females of childbearing potential); 2) a urine sample for urine analysis and toxicological screen; 3) an EKG; 4) a 
diagnostic interview 5) a physical exam.  
Screening will also include the following scales: The Tinnitus Functional Index (TFI): The TFI is a widely used and reliable 
self-administered test to determine the degree of functional impairment in tinnitus patients (Meikle et al, 2012). 2) The 
Tinnitus Handicap Inventory (THI), a widely used and reliable self-administered test to determine the degree of distress 
in tinnitus patients (Newman et al., 1996). The THI consists of 25 questions that cover three domains: functional, 
emotional, and catastrophic; 3) Visual Analogue Scale (VAS), a straight line of 10 mm with no numbers other than 0 (no 
tinnitus) to 100 (maximal experience of tinnitus). The subject marks their level of tinnitus (loudness and annoyance) on 
the line, and the outcome is measured in millimeters; 4) The Beck Depression Inventory (BDI), a 21 question multiple 
choice inventory used to asses depressed mood, including irritability, physical symptoms of depressed mood, and 

  
 
 
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distress; 5) Profile of Mood States (POMS), is a questionnaire used to assess mood states, and includes scales that 
investigate depression/dejection, tension/anxiety, fatigue/inertia, confusion/bewilderment. 6) The Beck Anxiety 
Inventory (BAI), a 21-item self-report measure of anxiety. The scales will be obtained at screening, at the beginning and 
end of the ketamine/placebo sessions, and daily for 10 days after the sessions.  As much as the screening procedures as 
possible will be acquired remotely via a HIPAA compliant method.  The questionnaires will be completed via Qualtrics 
(remotely) prior to the in-person visit.  
MRI scans and ketamine infusion:  
The research team will review the imaging facility safety guidelines with the participant and answer any questions they 
may have.  While at the imaging facility participants will be required to wear a mask not containing metal (KN-95) and 
gloves.  The participant will be met in the lobby of the imaging facility by a single member of the research team, also 
wearing an MRI compatible mask and gloves, at this time their temperature will be checked to ensure they do not have 
a fever.  Participants with normal temperatures will be escorted down to the scanner.  The participant and the research 
team will wear metal-free masks throughout the interaction, from first physical contact between researcher and staff in 
the lobby to seeing the subject off in the lobby after the scan.  If the researcher deems it appropriate, the participant 
may shift their mask to their chin while in the scanner. 
Prior to ketamine or placebo administration, the subjects will be positioned in the MRI scanner. The MRS scans will be 
obtained with 0.5 mg/kg IV of ketamine hydrochloride in saline or saline alone, administered over 40 minutes. The MRS 
data frames will be acquired (as follows: one pre-ketamine, and 5 following the 40-minute ketamine infusion. Each scan 
session is up to 2 hours in time. A study physician (Drs. Martinez or Wai) will be present during the ketamine and 
placebo infusions. The two scan sessions will occur on different days, separated by at least 14 days. 
Vital signs will be constantly monitored prior to, during, and after the ketamine infusion until the end of the MRS scan. 
Blood pressure and heart rate will be monitored and recorded at baseline and at 5-minute intervals and throughout the 
ketamine infusion. After that, vital signs will be acquired every 10 minutes until at least 90 minutes have passed since 
the beginning of infusion. The ketamine will be stopped for systolic BP increases to > 180 mm Hg and remains > 180 mm 
Hg for more than 5 minutes, or diastolic BP increases to > 110 mm Hg and remains > 110 mm Hg for more than 5 
minutes. Subjects will be asked to stay until: 1) at least 1 hour after the end of the MRS scan has passed, 2) there are 
two measurements at least 15 minutes apart that are within 10 mmHg of the baseline systolic and diastolic blood 
pressure; 3) the acute subjective effects of ketamine have subsided. They will be assessed by a study physician prior to 
being discharged home. Transportation home will be provided for using a car service.  
Briefly, a high-speed localizer imaging series will be obtained, followed by a volumetric T1-weighted spoiled gradient 
recalled echo scan. Brain spectra containing GABA and Glutamate/Glutamine (Glx) resonances will be acquired of the 
auditory cortex using the volume-selective PRESS J-editing difference method. Data will be acquired from a voxel 
oriented parallel to and placed superiorly abutting the Sylvian fissure and centered on Heschl’s sulcus, encompassing 
most of Heschl’s gyrus, including the primary auditory cortex, the planum temporale, the superior temporal sulcus, 

  
 
 
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planum polare, and small portions of the insula and middle temporal gyrus adjacent to these auditory regions. The GABA 
and Glx peak areas will be quantified as ratios relative to the area of the unsuppressed voxel tissue water.   
Statistical Plan and Data Analysis:  
Specific Aim 1: To test the effect of ketamine in subjects with chronic tinnitus induced by hearing loss. The 
primary clinical outcome measures will be the severity of tinnitus, which will be fitted with a mixed linear 
effects model, with each outcome modeled as a function of infusion type (active ketamine vs placebo), 
infusion order (ketamine first vs placebo first), baseline scores, and post-infusion time (day after infusion, vs 
week after infusion). The test of the hypothesis will be the main effect of infusion type, and for descriptive 
purposes the difference in post-infusion scores (and 95% confidence limits) between active ketamine and 
placebo will be calculated from the model. 
 
Specific Aim 2: To investigate changes in GABA in the auditory cortex in tinnitus subjects, before and after 
ketamine administration. 
The GABA/W values will be fitted using a mixed linear effects model, with infusion type (ketamine vs placebo), 
infusion order (ketamine first vs placebo first), and MRS data frame, as fixed effects, and subject and scan 
(nested within subject) as random effects. When the overall F test reaches significance (p < 0.05, 2-tailed) a 
post hoc analyses will be conducted to identify the potential effects of ketamine at each of the 6 MRS 
acquisitions.  Analysis across the six 13-min acquisitions will give a more detailed picture of which time points 
are driving the trend. The effect of ketamine of Glx/W will be included as an exploratory analysis.   
 
Criteria for Early Discontinuation 
Define criteria that will be used to exit or drop subjects from the study and operationalize.  Indicate the time points when 
such criteria will be applied, and describe the rating instruments, parameters, and thresholds that will lead to a decision 
to terminate a subject's participation and the role of the person who will make these determinations. Studies which 
include a medication taper and discontinuation may be asked to include an independent medical monitor (an MD not on 
the study team) who will aid the study team in determining whether study discontinuation is needed.   In addition, 
explain procedures for managing subjects who are withdrawn from the protocol. 
For treatment studies: To minimize risks to subjects, operationalized drop-out criteria should be defined so that subjects 
who worsen, or in some cases, fail to improve, are removed from the study and offered standard care.  The threshold for 
drop-out should consider the level of risk associated with non-improvement for the specific disorder, the availability of 
alternatives, and the typical required duration of treatment.  For example, emergence of suicidal intent, or psychosis, 
should prompt immediate clinical evaluation and withdrawal from the study. 
Subjects will be withdrawn from the study if 

  
 
 
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1. They request it for any reason. 
2. Systolic BP increases to > 180 mm Hg and remains > 180 mm Hg for more than 5 minutes, or diastolic BP increases to 
> 110 mm Hg and remains > 110 mm Hg for more than 5 minutes. 
3. Negative subject response to ketamine, such as dysphoria, anxiety, paranoia, or any adverse event. 
4. Subjects experience a worsening of depressive symptoms or an BDI > 31 and/or the participant is found to be at risk 
of suicide by the study clinician. 
 
5. The PI judges that it is medically unwise to continue in the study, for example if the subjects are unable to comply 
with the study procedures and rules. 
Blood and other Biological Samples 
Describe how the sample will be used and indicate, when relevant, the amount of the sample.  The IRB wants to know 
that the sample is sufficient for the purposes of the study, but that sampling is limited to what is minimally necessary.   
If you’ve indicated that you intend to store a sample for future use, indicate where the sample will be stored, how long 
the sample will be stored, and to what purposes the sample will eventually be put.  Check the IRB website at 
https://irb.nyspi.org/investigators/guidance/genetic-research   for specific guidance and additional information about 
future use of DNA samples. 
Blood samples totaling 15 mL will be obtained at screening. 
 
Research Related Delay to Treatment 
Research involving participants who are in need of treatment invariably involves delay to care, and this delay is 
associated with risk.  Scheduling of procedures must be carefully organized to minimize delay.  Other delay must involve 
only that minimally necessary to accomplish the aims of the research while respecting subject well- being and safety. 
Describe the delay, by virtue of research participation in this study, before a participant can receive treatment of known 
efficacy or standard care routinely offered in the community. 
There is no delay to care in this study.   
Clinical Treatment Alternatives 
Describe what other treatment or assessment options are available to subjects who do not participate in research. 
Alternative treatments are cognitive behavioral and retraining therapy. Subjects will be made aware that these 
alternatives exist. 
 

  
 
 
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Risks/Discomforts/Inconveniences 
"Risk" is a broad term used to convey the potential for harm, burden, and inconvenience related to research 
participation.  Use this section to provide a comprehensive description of foreseeable physical, psychological, social, 
interpersonal, and economic risks introduced by the research.  Include the source of the information.  Consider both the 
probability and magnitude of harm and its impact.  Describe the foreseeable harms associated with the research 
(untoward effects of a medication) and those related to delay to individualized treatment.  Include data from the 
literature, and local data, if available, on risk rates and subject experiences with research procedures. Describe 
procedures in place to minimize risk. In general, please create a numbered list of risks/categories of risk, and in general 
put the list in the order of significance or level of risk, the most significant risks should be listed first.  
Risks include: 
1) Ketamine infusion.  
Ketamine is an FDA-approved dissociative anesthetic. Ketamine exposure at the subanesthetic dose to be used in this 
study can be associated with a moderate dissociative state, which is well tolerated in the majority of cases. There is 
extensive clinical experience with ketamine used at anesthetic doses and no long-term detrimental effects of ketamine 
exposure have been reported. It is possible that ketamine administration will increase the risk of psychosis, even in 
normal subjects. Ketamine is a street drug of abuse, and thus poses the risk that exposure during this study may 
predispose subjects to subsequent abuse of this drug. For this reason, a history of any past or present problems with 
substance use will be obtained on screening; history of substance or alcohol dependence or diagnosis of abuse in the 
prior year will be exclusionary.  
An increase in vital signs can also occur with the infusion of ketamine. Subjects will be closely monitored for changes in 
blood pressure or heart rate, and the infusion will be stopped if needed. As described above, the ketamine will be 
stopped for systolic BP increases to > 180 mm Hg and remains > 180 mm Hg for more than 5 minutes, or diastolic BP 
increases to > 110 mm Hg and remains > 110 mm Hg for more than 5 minutes. After the scan, the monitoring of subjects 
will continue and blood pressure will be obtained until there are two measurements at least 15 minutes apart that are 
within 10 mmHg of the baseline diastolic blood pressure. After the subject is transferred back to the examination room, 
the blood pressure and heart rate will be obtained manually by the research assistant or nurse.  
Ketamine administration has the potential to produce agitation or hyperarousal. If needed, this will be treated with 
intravenous diazepam and the study terminated. The risks of exposing healthy subjects to a drug of abuse potential will 
be minimized by explaining this risk to prospective subjects, and by excluding from the study any subjects with 
documented or suspected prior substance or alcohol history of dependence or abuse as outlined in the 
inclusion/exclusion criteria.  
2) MRI scanning: It may be uncomfortable to lie motionless in the scanner (MRI) and it may cause some subjects to feel 
anxious. While there have been no reports of any long-term effects caused by magnets of the same or even higher 
strength, the long-term effects of being placed in a magnet of this strength (3 Tesla) are unknown. The MRI scanner uses 

  
 
 
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a large magnet to take pictures of the brain and is not associated with any known medical risks, except for persons who 
have a heart pacemaker, or have metal in their body (e.g. shrapnel or surgical prostheses) which may be affected by the 
magnet. Subjects will be asked to notify us if this is the case. There is also the risk of burns from medicinal patches 
during the MRI; therefore, subjects will be asked to remove any patches prior to the scanning session. Also, although 
there are no known risks associated with pregnancy, we will not scan someone who is pregnant. Therefore, for women 
of childbearing years, pregnancy testing will be conducted the day of the MRI. Some people have reported sensations 
during the MRI scan such as “tingling” or “twitching” (or, very rarely a painful sensation), which are caused by changes in 
the magnetic field that can stimulate nerves in your body. Occasionally, some people experience nervousness or 
claustrophobic feelings due to the scanner’s small space. Despite these sensations, in our experience, no one has had 
sensations from the scanning that did not stop as soon as the scanning stopped.  
3) Intra-venous catheters. There is a small risk of infection and bleeding associated with intravenous catheters. The risk 
of this will be minimized by using proper techniques.  
Methods to Protect Confidentiality 
Describe the data management plan and the methods you will employ to protect subject privacy and the confidentiality 
of research data.  The section should detail how information will be collected, recorded, coded, stored, transmitted, and 
as applicable, shared with other investigators so as to minimize risks related to breach of confidentiality.  Confirm that 
identifiers are removed, to the extent possible, from research data, and explain if there are links between subject identity 
and research data, or if the data are anonymous.  Also, indicate where the data are stored, who is responsible for data 
safekeeping, and who has access to subject identity and codes, if any, which cross-link research data and subject identity.  
Confirm that identifiable data are not collected, stored, or transmitted by mail, fax, on removable drives, laptops, or via 
the internet without proper protections, e.g. encryption. 
Confidentiality will be strictly maintained. Medical charts, standard questionnaires, records, rating scales, and any other 
recorded information will be kept in a locked file in an office or in the record room of the New York State Psychiatric 
Institute. Records may be reviewed by state or federal regulatory agencies and their personnel. Research records, like 
other medical and clinical records, will be kept confidential to the extent permitted by law. There are legal advocacy 
organizations that have the authority under state law to access otherwise confidential subject records, though they 
cannot disclose this information without the subject’s consent. Confidentiality is further supported by the use of unique 
ID numbers in coding some records. Data entered into a computer and/or submitted electronically will contain 
numerical IDs and, in some cases, initials, and will be password-protected. No identifiers (name, address, phone number, 
etc.) will be used that could allow direct linking of database information to individual participants. Where temporary 
linking of information with identifiers is necessary, such identifiers will be temporarily attached to the questionnaire, 
and will immediately be removed after information has been encoded. No identifying information will be used in 
publications. Only the research team and institutional personnel will have access to such materials.  
 

  
 
 
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References 
Please limit references, preferably no more than twenty. 
 Bhatt, J. M., H. W. Lin and N. Bhattacharyya (2016). "Prevalence, Severity, Exposures, and Treatment Patterns of 
Tinnitus in the United States." JAMA Otolaryngol Head Neck Surg 142(10): 959-965. 
 
Guitton, M. J. (2012). "Tinnitus: pathology of synaptic plasticity at the cellular and system levels." Front Syst 
Neurosci 6: 12. 
 
Llano, D. A., J. Turner and D. M. Caspary (2012). "Diminished cortical inhibition in an aging mouse model of chronic 
tinnitus." J Neurosci 32(46): 16141-16148. 
 
Meikle, M. B., B. J. Stewart, S. E. Griest and J. A. Henry (2008). "Tinnitus outcomes assessment." Trends Amplif 
12(3): 223-235. 
 
Meikle M. B., Henry J. A., Griest S. E., Stewart B. J., Abrams H. B., McArdle R, Myers P. J., Newman C. W., Sandridge S., 
Turk D. C., Folmer R. L., Frederick E. J., House J. W., Jacobson G. P., Kinney S. E., Martin W. H., Nagler S. M., Reich G. E., 
Searchfield G., Sweetow R, Vernon J. A. The tinnitus functional index: development of a new clinical measure for 
chronic, intrusive tinnitus. Ear Hear. 2012 Mar-Apr;33(2):153-76. doi: 10.1097/AUD.0b013e31822f67c0. Erratum 
in: Ear Hear. 2012 May;33(3):443.  
 
Milak, M. S., C. J. Proper, S. T. Mulhern, A. L. Parter, L. S. Kegeles, R. T. Ogden, X. Mao, C. I. Rodriguez, M. A. Oquendo, 
R. F. Suckow, T. B. Cooper, J. G. Keilp, D. C. Shungu and J. J. Mann (2016). "A pilot in vivo proton magnetic resonance 
spectroscopy study of amino acid neurotransmitter response to ketamine treatment of major depressive disorder." 
Mol Psychiatry 21(3): 320-327. 
 
Newman, C. W., G. P. Jacobson and J. B. Spitzer (1996). "Development of the Tinnitus Handicap Inventory." Arch 
Otolaryngol Head Neck Surg 122(2): 143-148. 
 
Pattyn, T., F. Van Den Eede, S. Vanneste, L. Cassiers, D. J. Veltman, P. Van De Heyning and B. C. Sabbe (2016). 
"Tinnitus and anxiety disorders: A review." Hear Res 333: 255-265. 
 
Radvansky, B. M., S. Puri, A. N. Sifonios, J. D. Eloy and V. Le (2015). "Ketamine-A Narrative Review of Its Uses in 
Medicine." Am J Ther. 
 
Rodriguez, C. I., L. S. Kegeles, A. Levinson, R. T. Ogden, X. Mao, M. S. Milak, D. Vermes, S. Xie, L. Hunter, P. Flood, H. 
Moore, D. C. Shungu and H. B. Simpson (2015). "In vivo effects of ketamine on glutamate-glutamine and gamma-
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Zarate, Jr. and T. D. Gould (2016). "NMDAR inhibition-independent antidepressant actions of ketamine 
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Quality Assurance Monitoring Plan 
Protocol #_______7432________ 
Title:___ Investigation of the NMDA Antagonist Ketamine as a Treatment for Tinnitus 
This is the Quality Assurance (QA) Monitoring Plan for the above-referenced protocol.   
 
__Diana Martinez and Alex Grassetti___ will be the QA Monitors for the internal monitoring for this study.  The Monitor 
will be instructed to carry out the specific monitoring activities outlined below.  Section A will describe the monitoring 
schedule and reporting and Section B will describe the data that will be reviewed on an ongoing basis. 
 
A. 
GENERAL MONITORING SCHEDULE AND REPORTING 
 
1. 
PRE-STUDY MEETING (ACAR meeting) 
Following development of a protocol-specific QA monitoring plan for this study and prior to initiation of such study, the 
Monitor/Research Coordinator, Principal Investigator(s) and research personnel will meet to review the study goals and 
study protocol requirements, including the following: 
 
a. Good Clinical Practice (GCP) requirements; 
b. Proper delegation of authority; 
c. Informed consent procedures and documentation; 
d. Reporting requirements to the IRB; 
e. Procedures for enrolling subjects, including inclusion/exclusion criteria; 
f. Study treatment procedures; 

  
 
 
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g. Management and reporting of adverse events (AEs), serious adverse events (SAEs), unanticipated problems 
(UPs), deviations and violations; 
h. Timely completion of Case Report Forms (CRFs) and appropriate source documentation; 
i. 
Regulatory documentation; 
j. 
Reporting requirements to the Sponsor, including timely submission of information for annual reports; 
k. Investigational product dispensing, administration and documentation. 
 
2. 
SCHEDULED MONITORING VISITS 
QA monitoring will be scheduled to take place: 
a. Every 6 months during study data collection.  
b. After the last subject has completed his/her participation in the study. 
 
With approval from the IRB, the schedule may be reviewed and adjusted, depending on the following factors: 
a. Rate of enrollment; 
b. Prior history of protocol deviations or non-compliance with GCP; 
c. Volume of data and documentation corrections required; 
d. Outcomes of prior monitoring visits. 
 
3. 
DOCUMENTATION OF FINDINGS 
At the end of each QA review, the Monitor/Research Coordinator will meet with the site PI and research personnel to 
review and correct any findings from the visit and discuss how to prevent similar occurrences.  Within approximately 1 
week of each monitoring visit, a written monitoring report with the findings and required corrective actions will be 
issued to the PI and IRB Research Compliance Monitor.  The PI will be required to correct any deficiencies that do not 
pose immediate harm to research subjects within a month of receipt of the report.  At the next monitoring visit, the 
Monitor/Research Coordinator will confirm that the deficiencies have been addressed. 
 

  
 
 
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The report will include, but will not be limited to, the following: 
a. A list of records reviewed (i.e., subject charts and medical records); 
b. The number of CRFs reviewed by research subject identification number and visit date; 
c. Whether there was any failure to report AEs, SAEs or UPs; 
d. General adherence to the protocol; 
 
B. 
 MONITORING SPECIFICS 
 
Unless otherwise specified below, ____30___ percent of subject files will be reviewed to obtain the required QA 
information.  
 
 
1. 
INFORMED CONSENT PROCESS  
a. Review the Informed Consent Process Checklist for 100% of the subjects; 
b. Verify that the correct version of IRB-approved consent form was used; 
c. Verify that each consent form was signed and dated; 
d. Verify, by comparing the date of the consent form to the subject’s medical record or other source, that the 
consent was signed prior to any research procedure having been performed. 
 
 
 
2. 
ELIGIBILITY CRITERIA 
a. Review the Eligibility Checklists for 100% of the subjects; 
b. Compare the protocol inclusion/exclusion criteria against each subject’s medical record or other source 
documentation, to determine whether the subject was eligible for inclusion in the study; 
c. Confirm that the Eligibility Checklist was signed and dated by the PI prior to any research procedures having 
been performed. 
 

  
 
 
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3. 
ENROLLMENT AND SCREENING OF SUBJECTS   
a. Compare the number of subjects enrolled to the limit approved by the IRB; 
b. Check subject screening and enrollment logs. 
 
4. 
STUDY PROCEDURES 
a. Verify that subject visits have taken place as required by the protocol; 
b. Verify that all tests have been completed as required by the protocol; 
c. Verify if any visit was out of allowable time parameters (out of window) by looking at subject visit schedules; 
d. Verify any deviations by comparing the protocol with source documentation and/or subject CRFs. 
 
5. 
IRB REQUIREMENTS 
a. Confirm that all protocol procedures were approved by the IRB; 
b. Review all IRB modifications, exception requests and renewals and confirm that they have been 
added to the regulatory binder; 
c. Confirm that protocol deviations were approved by the PI and IRB (if necessary) unless there was a 
need to eliminate an immediate hazard to a subject. 
 
6. 
REPORTING   
a. Verify that all protocol violations, unanticipated problems and serious adverse events were reported to 
the IRB on a timely basis; 
b. Verify that all safety concerns, including serious unexpected suspected adverse reactions (SUSARs) that 
are required by FDA regulations to be reported to the FDA have been reported on a timely basis (note 
no IND required). 
 
7. 
CASE REPORT FORMS AND SUBJECT RECORDS 

  
 
 
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a. Verify that the PIs or his/her authorized designee has appropriately completed, signed and dated 
CRFs; 
b. Verify that source documentation was used to complete CRFs; 
c. Review data and source documents in terms of their organization, condition, completeness and 
legibility;   
d. Verify that the data required by the protocol are reported accurately on the CRFs and are consistent 
with the source data/documents; 
e. Verify that any dose or therapy modifications are properly documented; 
f. Verify that AEs, SAEs, concomitant medications and underlying illnesses are reported accurately on 
the CRFs, in accordance with the protocol; 
g. Verify that CRFs reflect all visits that subjects fail to make and all tests or examinations that are not 
performed; 
h. Verify that subject withdrawals and subjects lost to follow-up are reported and explained on CRFs; 
i. 
 Ensure that appropriate corrections, additions or deletions are made, dated, explained (if 
necessary), and initialed by the PI or his/her/their authorized designee;  
 
8. 
TRAINING OF INVESTIGATORS AND RESEARCH PERSONNEL 
Verify that all required institutional and protocol specific training has been completed prior to study initiation, including 
training with respect to obtaining informed consent.  Verify that new study team members have been properly trained 
and added to the Delegation of Authority Log and Training Log. 
 
9. 
DELEGATION OF AUTHORITY 
a. Establish the identity of all research personnel involved in the study; 
b. Verify that all such personnel are listed on the Delegation of Authority Log; 
c. Review study protocol to establish which responsibilities have been delegated; 

  
 
 
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d. Verify that the Delegation of Authority Log accurately reflects the delegated responsibilities, that all 
personnel listed have signed the log and that the training completed for specific responsibilities is 
also noted in the Training Log. 
 
10. 
INVESTIGATIONAL PRODUCT MANAGEMENT * 
a. Not applicable, this FDA has deemed that no IND is needed 
 
11. 
REGULATORY BINDER 
Confirm that the following essential documents are included in the Regulatory Binder in accordance with the Regulatory 
Binder Checklist: 
a. All IRB versions of the protocol and informed consent  
b. SAE reports 
c. Study specific Manual of Procedures 
d. Sample Case Report Forms (CRFs) 
e. Protocol deviations 
f. FCOI disclosures for all key personnel 
g. Site monitoring log and reports 
h. Delegation of authority log 
i. 
Enrollment log  
j. 
Sponsor correspondence 
k. IRB correspondence