Pharmaceutical Interventions for Noise-Induced Hearing Loss-Acute Exposure Treatment
Phase: PHASE2
Conditions: Hearing Loss, Noise-Induced
Sponsor: Washington University School of Medicine

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Pharmaceutical Interventions for Noise-Induced Hearing Loss–Acute Exposure Treatment 
(PINIHL-AET) 
 
 
 
The University of Akron 
School of Speech Language Pathology and Audiology 
Polsky Building 
225 South Main Street 
Akron OH 44325-3001 
 
Protocol#: PINIHL-UA  
Version #: 7.0 
  Version Date: 23 MARCH 2022 
 
 
 
 
ClinicalTrials.gov #: 
 
NCT04774250 
IND: 
 
147812 
 
 
 
 
 
 
 
 
CONFIDENTIAL 
The information contained in this document is regarded as confidential and, except to the extent necessary to 
obtain informed consent, may not be disclosed to another party unless law or regulations require such 
disclosure.  Persons to whom the information is disclosed must be informed that the information is 
confidential and may not be further disclosed by them 
 
 
 

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Signature Page: 
 
Clinical Study Protocol No. PINIHL-UA v7.0 
 
 
Title: Pharmaceutical Interventions for Noise-Induced Hearing Loss–Acute Exposure Treatment 
(PINIHL-AET) 
 
 
I have read this protocol and agree to conduct this study in accordance with all stipulations of the 
protocol. 
 
 
 
 
 
Kristine Sonstrom Malowski, AuD PhD 
_____________________________       03/23/2022  
Principal Investigator Name:  
 
Signature 
 
 
 
 
Date 
(Printed) 
 

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Pharmaceutical Interventions for Noise-Induced Hearing Loss–Acute Exposure Treatment 
(PINIHL-AET) 
 
Protocol Revision History 
 
Version Date 
Revision Summary 
19 January 2021 
Initial Approval Version 
14 February 2021 
Addition of Drs. Craig Buchman and 
Thomas Rench as sub-investigators. 
19 February 2021 
 
Addition of baseline and follow-up blood 
draws that includes an electrolyte panel, 
BUN, Cr, ALT, and AST; serum pregnancy 
test at baseline 
 
Addition of effective birth control 
instruction  
10 June 2021 
 
Addition of NIOSH red flag guideline (an 
increase in hearing threshold level of 15 dB 
or more at any frequency (2, 3, 4, 6 kHz) in 
either ear for permanent threshold shift as a 
secondary endpoint. 
 
Change in sample size 
 
Removal of saliva collection and inclusion 
of blood draw for DNA analysis. 
 
Inclusion criteria corrected. 
 
Addition of primary and secondary efficacy 
measures to study design (section 4.0) 
 
Added detail and updated modifications to 
tests within scheduled assessments (section 
5.1) and follow-up assessments (5.5) 
 
Updated cognitive test section to reflect 
specific measures being used (5.0) 
 
Clarified wording for evaluability section 
(section 6.0) 
 
Removed NEQ and HHIA Questionnaires 
from appendix and assessment (5.0) section 
 
Added 1-Minute Noise Screen Questionnaire 
to appendix and assessment section (5.0) 
 
Corrected timing of evaluation for post-dose 
drug related adverse events from 2 weeks to 
30 days (6.0) 
 
Delineated and updated study calendar to 
reflect each visit for when assessments and 
questionnaires are administered (9.0) 
 
Clarified which assessments would be 
administered at what visit in each of the 
assessment sections (screening, baseline and 
follow-up visits) (5.0) 

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 
Removed PI and Sub-Investigator 
information (cover page) 
 
List protocol version as a separate line 
(cover page) 
 
Name change of form “Audiologic and 
Medical History” to “Case History”. 
 
Clarification of when clinical ear exam will 
be performed (5.0, 9.0) 
 
Statistical Considerations section updated to 
match SAP (12.0) 
21 October 2021 
 
Inclusion of stratification table for noise 
exposure (5.2) 
 
Randomization language updated (4.0) 
09 November 2021 
 
Clarification of language for secondary 
outcomes analysis criteria 
21 January 2022 
 
Addition of section “Blood collection, 
transportation, and storage” 
23 March 2022 
 
Addition of audiometry language in 
situations of an absence of a threshold. 
 
 
 

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TABLE OF CONTENTS 
 
1.0 
BACKGROUND AND SIGNIFICANCE .............................................................................................. 6 
1.1 
Noise-induced hearing loss (NIHL) ............................................................................................... 6 
1.2 
NIHL and its Pathogenesis ............................................................................................................. 6 
1.3 
Molecular Pathways Underlying NIHL ........................................................................................ 7 
1.4 
NIHL and Pharmacogenetics ......................................................................................................... 8 
1.5 
NIHL in Police Officers .................................................................................................................. 10 
2.0 
STUDY OBJECTIVES ........................................................................................................................ 12 
2.1 
Primary Objective ........................................................................................................................... 12 
2.2 
Secondary Objectives .................................................................................................................... 12 
3.0 
ELIGIBILITY CRITERIA ..................................................................................................................... 12 
3.1a 
Screening Inclusion criteria......................................................................................................... 12 
3.1b 
Enrollment Inclusion Criteria ..................................................................................................... 13 
3.2 
Exclusion Criteria .......................................................................................................................... 13 
3.3 
Inclusion of Women and Minorities ........................................................................................... 13 
4.0 
STUDY DESIGN .................................................................................................................................. 14 
5.0 
SCHEDULED ASSESSMENTS ........................................................................................................ 15 
5.1 
Screening (Visit 1) and Baseline (Visit 2) Assessments ........................................................ 15 
5.2 
Randomization ................................................................................................................................ 17 
5.3 
Testing on the Range (Visit 3) ..................................................................................................... 18 
5.4 
Follow-Up Assessments (Visits 3, 4 and 5) .............................................................................. 18 
5.5 
Blood collection, transportation, and storage ......................................................................... 19 
6.0 
EVALUABILITY.................................................................................................................................... 20 
7.0 
PHARMACEUTICAL INFORMATION .............................................................................................. 20 
7.1 
Zonisamide (ZONEGRAN®) .......................................................................................................... 20 
7.1 
Placebo.............................................................................................................................................. 21 
8.0 
REGULATORY AND REPORTING REQUIREMENTS .................................................................. 22 
8.1 
Sponsor-Investigator Reporting Requirements ....................................................................... 22 
8.2 
Secondary Site Reporting Requirements .................................................................................. 24 
8.3 
Exceptions to Expedited Reporting ............................................................................................ 24 
9.0 
STUDY CALENDAR ............................................................................................................................ 25 
10.0 
DATA SUBMISSION SCHEDULE.................................................................................................... 25 
11.0 
DATA AND SAFETY MONITORING ................................................................................................ 25 
11.1 
Adverse Event Collection in the Case Report Forms ............................................................. 26 
12.0 
STATISTICAL CONSIDERATIONS .................................................................................................. 26 
12.1 
Data analysis .................................................................................................................................. 27 
12.2 
Efficacy analysis ............................................................................................................................. 27 
12.2.1 Analysis of primary outcome variable ....................................................................................... 27 
12.2.2 Analysis for secondary outcome measures. ............................................................................. 29 
12.3 
Sample size estimation ................................................................................................................. 31 
12.4 
Interim analysis .............................................................................................................................. 32 
12.5 
Pharmacogenetic analysis plan .................................................................................................. 33 
13.0 
REFERENCES ..................................................................................................................................... 35 
APPENDIX A: Definitions for Adverse Event Reporting ......................................................................... 46 
APPENDIX B: Reporting Timelines ............................................................................................................. 48 
APPENDIX C: Washington University Unanticipated Problem Reporting Cover Sheet .................. 50 
APPENDIX D: Questionnaire 1: Case History Form ............................................................................... 51 
APPENDIX E: Questionnaire 2: Life Exposure to Noise and Solvents (LENS-Q) ............................. 54 
APPENDIX F: Questionnaire 3: Tinnitus Functional Index (TFI) ........................................................ 74 
APPENDIX G: Questionnaire 4: LENS-Q Adapted Survey for Stratification (High vs. Low Noise 
Exposure Group Stratification) ................................................................................................................... 76 
APPENDIX H: Questionnaire 5: 1-Minute Noise Screen (30-day post follow-up visit) ................... 79 
 
 

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1.0 
BACKGROUND AND SIGNIFICANCE 
 
1.1 
Noise-induced hearing loss (NIHL) 
 
Noise-induced hearing loss (NIHL) is a serious problem. When a service member 
leaves the military, hearing loss can impact his or her quality of life and 
employability (Pfannenstiel, 2014). Service members are vulnerable to two types 
of NIHL: occupational NIHL due to continuous or intermittent noise exposure and 
acoustic trauma due to a sudden burst of sound. Because no form of hearing 
protection offers complete protection against noise of that intensity, repeated firing 
of weapons even with ear protection devices can subsequently lead to occupational 
NIHL (Chen and Brueck, 2011). Almost every member of the armed forces will be 
exposed to hazardous noise at some point in his or her career (McIlwain et al., 2008; 
Kirchner et al., 2012; Yankaskas, 2013), highlighting the urgent need for 
pharmaceutical intervention. Despite positive outcomes in preclinical studies, to 
date, no drugs have been approved by the U.S. Food and Drug Administration 
(FDA) for use in the amelioration of NIHL (Le Prell and Bao, 2012; Mukherjea et 
al., 2015). 
 
1.2 
NIHL and its Pathogenesis 
 
After noise exposure, two phases of hearing loss can be measured. The first is a 
temporary threshold shift (TTS), which is greatest immediately after noise 
exposure, and gradually lessens within the first 24 hours. The second phase is a 
permanent threshold shift (PTS), which is measured two to three weeks after noise 
exposure (for recent review, Ryan et al., 2016; Liberman, 2016). These changes are 
typically monitored using behavioral pure-tone thresholds, distortion product 
otoacoustic emissions (DPOAE), or the auditory brainstem response (ABR) to 
generate an audiogram (a plot of threshold as a function of test frequency). The 
noise-induced damage is dependent on the noise pattern, intensity, and duration, 
with longer and louder noises being more hazardous than shorter or quieter sound 
exposures (Wang et al., 2002; Harding and Bohne, 2007; Chen et al., 2015). In 
addition, NIHL susceptibility differs markedly among individuals, resulting from 
the interaction of genetic and environmental factors (Clifford et al., 2016; Groth et 
al., 2016; Lavinsky et al., 2016). For example, in animals, the C57BL/6J mouse 
strain is more susceptible to noise than other mouse strains (Davis et al., 2001). In 
humans, individuals with specific single nucleotide polymorphisms (SNPs) in 
genes for certain antioxidant enzymes may be more susceptible to NIHL (Lin et al., 
2009) and a recent study developed a genetic risk score for the likelihood of NIHL 
based on genetic markers (Zhang et al., 2019). Over 100 loci associated with 
syndromic and non-syndromic hearing loss provide excellent biomarkers for PGx 
studies and are easily surveyed in genetic screening protocols (e.g. Pawelczyk et 
al., 2009; Konings et al., 2009; Grondin et al., 2015). Furthermore, known genetic 
variation is associated with the metabolism of anti-epileptic drugs including 
zonisamide (Saruwatari et al., 2010) and could be used to predict patient 
populations that are both responsive and non-responsive to drug treatments.  

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Finally, methodologies are currently under development to predict genotypic 
variation based on audiographic profiles that could in practice be integrated with 
genetic data (https://audiogene.eng.uiowa.edu/) facilitating the statistical analysis 
of drug efficacy in clinical trials. 
 
NIHL is caused by sensorineural damage, primarily to the sensory hair cells and 
primary auditory neurons of the cochlea (Liberman, 2017). Outer hair cells (OHCs) 
are particularly sensitive to noise. When OHCs are damaged, hearing thresholds 
increase due to a loss in amplification of the cochlear signal. Recently, Kujawa and 
Liberman (2006, 2009) have expanded on these classic findings with the 
observation that certain noise exposures at “benign” levels to rodents can result in 
only TTS, but no PTS. Nevertheless, the animals show selective synaptic loss 
between inner hair cells (IHCs) and spiral ganglion neurons (SGNs) with high 
thresholds, ultimately accelerating hearing loss over time. Because this cochlear 
synaptopathy does not change the hearing threshold immediately, the term “hidden 
hearing loss” has been used to label the hidden synaptopathic injury, and this term 
has also been used to describe corresponding functional deficits that are assumed 
to be hidden behind the normal hearing threshold. 
 
Clinically, difficulties with understanding speech in noise have long been observed 
in older adults with normal audiometric thresholds (e.g. Frisina and Frisina, 1997). 
Loss of fidelity in the encoding of suprathreshold signals may provide one 
explanation for this deficit (Sergeyenko et al., 2013; Tremblay et al., 2015). Thus, 
there is the potential for profound functional consequences after a so-called benign 
noise exposure that led to only TTS. Of particular concern for military personnel 
with the potential for repeat exposure (Davis, 2016; Bramhall et al., 2017), further 
studies have found that benign noise exposures resulting in only TTS can also 
contribute to PTS after repeated exposure (Wang and Ren, 2012), underpinning the 
importance of developing pharmaceutical interventions to prevent noise-induced 
cochlear synaptopathy for military service members. 
 
1.3 
Molecular Pathways Underlying NIHL 
 
Although mechanical destruction and decreased blood flow contribute to NIHL 
(Quirk et al., 1991; Mulroy et al., 1998), several key molecular mechanisms such 
as signaling mediated by an ATP receptor have been identified to contribute to TTS 
(for recent review, see Kurabi et al., 2017). Common mechanisms underlying both 
TTS and PTS have also been identified. One is the increase of mitochondrial free 
radical formation such as reactive oxygen species (ROS) due to noise-induced 
intense metabolic activity in the cochlea (e.g., Yamane et al., 1995; Ohlemiller et 
al., 1999; Ohinata et al., 2000; Henderson et al., 2006; Campbell et al., 2007; Darrat 
et al., 2007). Thus, it is not surprising that attempts to prevent NIHL with 
antioxidant agents have become the focus of much research in this field (Seidman 
et al., 1993; Hight et al., 2003; McFadden et al., 2005; Yamashita et al., 2005; for 
review, see Le Prell and Lobarinas, 2015). However, most of these interventions 
have been only partially effective or ineffective in preventing NIHL (Lynch and 

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Kil, 2005; Campbell et al., 2007; Kopke et al., 2007; Le Prell et al., 2007). The 
largely disappointing outcomes may be due to a narrow therapeutic window. As 
ROS signaling is also important for normal cellular function (for recent review, 
Sbodio et al., 2018), high doses of antioxidants may have less therapeutic benefit 
(for example, Kil et al., 2017). Recently, new signaling pathways underlying NIHL 
have been identified, including deregulation of calcium homeostasis (Guitton et al., 
2004; Zine and Van De Water, 2004; Chen et al., 2012; Han et al., 2015; Chen et 
al., 2015). Deregulation of calcium signaling may contribute to development of 
both TTS and PTS. In addition, calcium signaling is upstream of many other 
cellular survival signaling pathways. For example, it can control ROS signaling by 
regulating the release of ROS from the mitochondrion (Estergerg et al., 2013, 
2014). Calcium homeostasis in the cochlea can be regulated by several types of 
calcium channels, which include voltage-gated calcium channels (VGCCs) 
(Rodrigues Contreraz and Yamoah, 2001; Adamson et al., 2002; Fuchs, 2002; 
Schnee and Ricci, 2003). VGCCs can be divided into two groups: high-voltage-
activated calcium channels and low-voltage-activated calcium channels (Igelmund 
et al., 1996; Lacinova et al., 2000; Perez-Reyes, 2003; Yunker and McEnery, 2003). 
The family of low-voltage-activated, or T-type, calcium channels (Cav3) is 
composed of three members (Cav3.1, Cav3.2, and Cav3.3) based on their respective 
main pore-forming alpha subunits: α 1G, α 1H, and α1I (Perez-Reyes, 2003; 
Yunker and McEnery, 2003). Our studies on drug repurposing have shown that a 
family of antiepileptic drugs blocking T-type calcium channels can prevent and 
treat NIHL (Shen et al., 2007; Bao et al., 2013). We have also determined the 
expression pattern of these calcium channels in the cochlea. All subtypes are 
present in SGNs, and α 1G and α 1I are expressed in the hair cells and supporting 
cells (Shen et al., 2007). Thus, it is not surprising that an antiepileptic drug (AED), 
zonisamide (ZNS), which blocks T-type calcium channels, has both prophylactic 
and therapeutic functions against NIHL (Bao et al., 2013). In addition, 
epidemiological studies show that ZNS is well-tolerated even for long-term 
treatment (Hashimoto et al., 1994; Leppik, 2006, White et al., 2010). These findings 
have led us to this project, which is the repurposing ZNS against NIHL for military 
service members. 
 
1.4 
NIHL and Pharmacogenetics 
 
Preliminary results. Pharmacogenetics (PGx) is the study of how a person’s genetic 
makeup determines his or her response to a therapeutic intervention. It offers the 
promise of utilizing genetic fingerprints to predict an individual’s responses to 
drugs in terms of safety, efficacy, and pharmacokinetics. It can revolutionize the 
practice of medicine by individualizing treatment through the use of novel 
diagnostic tools.  
 
Here, we provide three types of data from our PGx study of age-related hearing 
loss. They are highly pertinent because the same approaches will be applied to this 
project. First, we describe our recent clinical findings on the delay of ARHL in 
human subjects taking calcium channel blockers (CCBs). Second, we present our 

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preliminary human genetic studies of ARHL in the same population based on the 
continuous extreme phenotypes (CEP) and sequence kernel association test 
(SKAT) approaches. Third, we present 
an estimate of patient populations using 
the CEP-SKAT method. 
 
Delay of ARHL in patients taking 
CCBs. In our preliminary study, a total 
of 35 white female patients have 
completed their first visit, with 26 of 
them using amlodipine (74%) for more 
than one year. We compared this CCB 
group with two control cohorts, also of white females: control 1 group (Con 1) from 
the 
Rochester, 
NY, 
area 
(447 
participants) and control 2 group (Con 2) 
from the St. Louis, MO, area (55 
participants) (Fig. 1).  
 
Since ARHL starts at higher frequencies 
in the cochlea, we divided audiograms into three pure tone averages (PTA): 
averages of 0.25, 0.5, and 1 kHz (PTAL); averages of 2 and 4 kHz (PTAH24); and 
averages of 2, 4, and 8 kHz (PTAH248). The means for the CCB group were: PTAL 
(15.1 dB HL), PTAH24 (20.7 dB HL), and PTAH248 (24.0 dB HL), and the means 
for the control 1 group were: PTAL (20.1 dB HL), PTAH24 (30.7 dB HL), and 
PTAH248 (35.2 dB HL). 
Since there were no data 
for 8 kHz for the control 2 
group, the means for this 
group were PTAL (20.7, 
dB HL) and PTAH24 
(29.3 dB HL). The two-
tailed unequal variance t-
test showed a significant 
difference between the 
CCB and the control 1 
group for PTAL (p = 
0.00067), PTAH24 (p = 
0.00001), and PTAH248 
(p = 0.00021), and a 
significant 
difference 
between the CCB and 
control 2 groups for PTAL (p = 0.02777) and PTAH24 (p = 0.00959). To correct 
for possible influences from both age and the three cohort sites, we used 
multivariate regression models with the Bonferroni correction method (Table 1, 2 
and 3 for PTAL, PTAH24 and PTAH248, respectively). No significant difference 
was observed for PTAL between the CCB and control 1 or 2 groups (Table 1), or 
Fig. 1. CCB protection against ARHL. 
Participants taking CCBs show better hearing 
thresholds than participants taking no CCBs 
even at low frequency regions (0.25 to 1 kHz). 

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PTAH24 (Table 2) between the CCB and control 2 group. However, statistically 
significant differences were found for both PTAH24 and PTAH248 between the 
CCB and control 1 group (Table 2 and 3). These data indicate CCB had beneficial 
effects against peripheral ARHL.  
 
The goal of this study is to increase the sensitivity of our clinical trial by identifying 
subgroups sensitive to NIHL prevention or treatment by ZNS. The expected high 
variability in individual responses to ZNS against NIHL is dependent on known 
factors such as age, sex, and previous hearing loss history, all of which are 
considered in the health survey during the initial screening process. However, 
unknown genetic variations in the participants can contribute to additional variable 
responses to ZNS against NIHL. PGx is the ideal approach to address this issue. 
Based on our preliminary studies, even with the sample size limitation, extreme 
ZNS protection phenotypes could still be identified, and sampling these individuals 
can enrich the presence of associated genetic variants. However, the 
dichotomization procedure used for most extreme phenotype sampling can reduce 
the analysis power due to a loss of sample size. The CEP-SKAT method can be 
used to avoid this issue by using continuous phenotypes in the analysis of extreme 
phenotype samples (Li et al., 2011; Barnett et al., 2012). Therefore, we will use this 
CEP-SKAT method to analyze our samples.  
 
Pharmacogenetic testing will be performed by the Washington University School 
of Medicine Genome Technology Access Center. 
 
1.5 
NIHL in Police Officers 
 
Both continuous and impulse-induced NIHL are sensorineural in nature. Unlike 
other injuries, sensorineural hearing loss will continue to progress with age 
(Kujawa and Liberman, 2006, 2009; Fausti et al., 2009). The incidence of hearing 
loss disability can increase four-fold after an average of only 4 years of active 
service among individuals with mild and moderate hearing loss prior to joining to 
the military (Gubata et al., 2013), suggesting NIHL from repeated noise exposure 
can cause more auditory damage in military service members with prior hearing 
loss. Similarly, police offices are repeatedly exposed to both continuous and 
impulse noises. A large population study of police officers (a total of 1880 subjects 
with 887 police officers) found that police officers were 1.4 times more likely to 
have a selective NIHL at 4 KHz than civil servants (Lesage et al., 2009). A 
subsequent study of 543 police officers found that of the officers identified with 
hearing loss, 93% presented with mild NIHL (26-40 dBA), 3.5% with moderate 
NIHL (41-60 dBA), and 3.5% with severe NIHL (61-80 dBA).  Further analyses 
indicated a strong association of NIHL with age, duration of service and rank (Win 
et al., 2015).  Several researchers have found NIHL across police populations.  
Lesage and colleagues (2009) found NIHL in 28% of police officers investigated, 
Shrestha and colleagues (2011) found NIHL in 66.4% of police personnel studied, 
and Gupta and colleagues (2015) found 22% of a police population presented with 
NIHL.  Furthermore, tinnitus has been reported by several police officers across 

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studies (Singh & Mehta, 1999; Shrestha et al., 2011; Win et al., 2015; Thirugnanam 
et al., 2017). Based on this evidence, police officers are an ideal population for this 
project. 
 
Hearing studies on police officers were performed by the current researchers in 
Northeast Ohio from 2017-2018 (Sonstrom Malowski & Steiger, 2020).  Hearing 
assessments were performed on 30 police officers, ranging from 35-61 years of age. 
40% of these individuals served in the military, 26% of these individuals were part 
of the SWAT team, and 10% of the population served for both the military and the 
SWAT team at some point of their career.  Results indicated that 73% of the officers 
presented with some degree of permanent hearing loss.  Specifically, 70% of the 
population presented with evidence of NIHL, as characterized by a sensorineural 
hearing loss with the greatest amount of loss at 4-6 kHz, seen as a notch or dip on 
the audiogram (McBride & Williams, 2001).  Initial signs of NIHL may present as 
a distinct notch from 3-6 kHz even in the presence of “normal hearing,” where 
thresholds fall at or above 25 dB HL, another observation observed from this study.  
Furthermore, evidence of NIHL was observed from absent otoacoustic emission 
recordings and absent high-frequency audiometric thresholds in the presence of 
normal audiometric results from .25-8 kHz.  An increased sensitivity of OAEs in 
comparison to audiometric thresholds has been found whereby low-level OAEs 
indicate an increased risk of future hearing loss by as much as nine-fold (Marshall 
et al., 2009).   
 
Hidden hearing loss was further investigated in a small sample of police officers in 
Rootstown, OH. Audiometric hearing thresholds were obtained from six graduate 
students and three campus police officers by using the Interacoustics® AD629 
Diagnostic audiometer. Sennheiser HDA 200 headphones were used to obtain pure-
tone air-conduction thresholds at 0.25, 0.5, 1, 3, 4, 6, 8, 10, 12, 14, and 16 kHz. For 
each test frequency, thresholds were assessed in 2 dB steps using ascending and 
descending runs in a modified Hughson-Westlake procedure (ANSI, 2009). The 
initial stimulus level for the ascending track was below the subject’s audible 
threshold, whereas the initial stimulus level for the descending track was above the 
subject’s behavioral threshold. Interestingly, two control subjects showed an 
increase of hearing thresholds only at 16 kHz, all three police officers showed an 
increase of hearing thresholds above 12.5 kHz, a sign of noise-induced hidden 
hearing loss (Liberman et al., 2016). In addition, all these three right-handed police 
officers have a notch at 6 kHz on their left ears. Asymmetric hearing losses were 
consistently observed across the officers tested.  Thus, hidden hearing loss may be 
highly present for police officers.  
 
One major obstacle to test drug candidates against NIHL is a lack of robust hearing 
loss (even as TTS) to testing possible drug protective effects (Le Prell et al., 2011). 
At the same time, a high percentage of police officers show permanent hearing loss 
after several years of service as seen with 70% of the officers tested in our 
preliminary studies.  To further examine this paradox observation, we carried out a 
longitudinal study of police officers on our campus. One case, a female without 

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prior hearing loss, right-handed, demonstrated this phenomenon. Her audiogram 
performed in October 2017 was normal up to 12 kHz for both ears. However, a 
mild hearing loss was observed in her left ear at 6 kHz, and there are no obvious 
differences before and after one-hour shooting certification with 146 gun firing with 
M&P Shield and M&P 15 (about 156 dB SPL), which suggested a good hearing 
protection from her ear muffs, which offer a 34 dB SNR (Noise Reduction Rating) 
for noise cancelling. The only sign of noise-induced damage is a slight decrease of 
DPOAE amplitude near 3 kHz 5 minutes after the shooting. Thus, the repeated 
noise exposure during their service may contribute to a high incident of permanent 
hearing loss although the noise-induced damages are hard to detect immediately 
following each noise exposure.  
 
The overarching goal of this study is to test whether ZNS can treat TTS and PTS in 
police officers on the range following training and certifications sessions.  
Participants will be randomized to receive either active treatment (ZNS) or placebo. 
 
2.0 
STUDY OBJECTIVES 
 
2.1 
Primary Objective 
 
To determine if ZNS is more effective than placebo in preventing permanent 
threshold shift (PTS) in police officers identified with temporary threshold shift 
(TTS) following shooting range noise exposure.   
 
2.2 
Secondary Objectives 
 
To determine if ZNS is more effective than placebo in the prevention of additional 
auditory dysfunction in police officers following shooting range noise exposure as 
measured by ultra-high frequency audiometry, distortion product otoacoustic 
emissions (DPOAE), electrocochleography (EcochG) and words-in-noise (WIN) 
scores, and to determine a PGx link between NIHL and ZNS treatment effect. 
 
3.0 
ELIGIBILITY CRITERIA 
 
3.1a 
Screening Inclusion criteria 
 
1. Police officers who are scheduled for firearm training and/or certification 
on the range. 
 
2. At least 18 years of age. 
 
3. Air conduction thresholds are to be no worse than 25 dB HL from 0.5 kHz 
to 3 kHz, no worse than 30 dB HL at 4 kHz, and no worse than 45 dB HL 
at 6 and 8 kHz prior to shooting range exposure.  
 

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4. Observed air-bone gap < 10 dB HL at .5, 1, 2 and 4 kHz, with normal 
tympanometry. 
 
5. Ability to understand and willingness to sign an IRB approved written 
informed consent document. 
 
3.1b 
Enrollment Inclusion Criteria 
 
1. Observed audiometric TTS ≥ 10 dB HL at 2, 3, 4 and/or 6 kHz 
 
3.2 
Exclusion Criteria 
 
1. History of known sulfa allergy or hypersensitivity to carbonic anhydrase 
inhibitors. 
 
2. History of moderate-to-severe kidney or liver disease. 
 
3. Acute viral, bacterial, fungal or parasitic infection. 
 
4. History of seizures. 
 
5. Currently pregnant or breast-feeding. 
 
6. Any current or history of otologic disorder. 
 
7. History of ototoxic drug use. 
 
8. Current use of strong/moderate 3A4 inhibitor/inducer and grapefruit juice. 
 
Note:  For secondary outcomes analysis only, exclusion criteria is as 
 
follows:  
a) DPOAE data will be used as a secondary outcome measure of TTS, 
and participants will be excluded if their DPOAE is absent at more 
than 4/10 frequencies. Criteria for a present response is any response 
that is > 5 dB SPL above the noise floor and replicable within ±5 dB 
SPL. 
b) ECochG: Participants will be excluded if the ECochG/ABR wave I 
response is absent. 
c) WIN test: Participants with WIN scores greater than moderate 
difficulty or 14.9 dB SNR will be excluded. 
 
 
Participants will not be excluded from the study for not meeting secondary  
 
 
outcome criteria. 
 
3.3 
Inclusion of Women and Minorities 
 

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Both men and women and members of all races and ethnic groups are eligible for 
this trial. 
 
4.0 
STUDY DESIGN  
 
A randomized, double-blind, and placebo-controlled clinical trial has been designed.  
 
Study participants will be recruited from the Akron Police Department, Summit 
County Police Department, and other local surrounding police departments. Police 
officers will be offered participation if they are training for firearm certification as part 
of their standard occupational requirements. These are officers that would be 
recommended and/or required to complete these trainings/certifications despite this 
investigation and this investigation will have no influence on audiologic 
recommendations.   
 
The primary efficacy endpoint will be the proportion of PTS-positive subjects defined 
as the ratio of PTS-positive subjects to total number of subjects within each study 
arm/group. Subjects defined as PTS-positive will demonstrate an increase in threshold 
that is ≥10 dB HL at any frequency from 2-6 kHz post-shooting as compared to 
baseline audiogram.  
 
The secondary efficacy outcome measures will be: (1) the proportion of PTS-positive 
subjects as defined above, but the definition of PTS will also include the NIOSH red 
flag guideline for permanent threshold shift: an increase in hearing threshold level of 
15 dB or more at any frequency (2, 3, 4, 6 kHz). (2) The rate of temporary cochlear 
change as measured by a DPOAE amplitude shift at any frequency that is significantly 
greater than the stability of each measurement (i.e., 95% confidence interval of each 
measurement do not overlap). The rate of DPOAE shift is the ratio of DPOAE shift-
positive subjects to total subjects within each arm. 
 
Interested police officers will be consented and enrolled in the study.  They will then 
undergo screening for TTS following shooting range noise exposure.  Those officers 
identified with TTS will be randomized via an interactive randomization tool (IRT) 
and assigned to a study group.  Once assigned the subject will be provided a kit that 
will contain either ZNS (100 mg PO) or a placebo. The ZNS and placebo capsules will 
look, taste, and smell the same. Participants will be instructed to take zonisamide 
without food. We will recommend that capsules be swallowed whole per the current 
approved labeling. Those without TTS will be finished with their study commitment.   
 
The study will be “masked” or “blinded” in the sense that all the study participants 
and the study team members will be blinded to the assignment in the study groups. 
Only the pharmacist who will prepare the study drug kits and the unblinded statistician 
will have access to the kit assignments. The Medical Monitor will be contacted. A 
copy of the randomization list with study ID assignments will be saved in a limited 
access folder on a secure network server at Pharm-Olam. The Medical Monitor will 

15 | P a g e  
 
be contacted in emergent medical cases when knowing the treatments assignment is 
mandatory for clinical care of the study subject. 
 
5.0 
SCHEDULED ASSESSMENTS 
 
5.1 
Screening (Visit 1) and Baseline (Visit 2) Assessments 
 
The screening assessment (Visit 1) will occur within 3 months of the first training 
session.  The baseline assessment (Visit 2) will occur within one week of the first 
training following commencement of the study.  These assessments will include the 
following tests or procedures: 
 
1. Documentation of demographic information, including gender, age, 
allergies, and current medications (screening visit 1). 
 
2. Clinical examination of the ears (screening and baseline visit 1 and 2). 
 
3. Documentation of key clinical data such as confirmation of thresholds being 
< 25 dB HL  up to 4 kHz, ≤ 30 dB HL at 4 kHz, and ≤ 45 dB HL at 6 and 8 
kHz, and the absence of any ear disorder (screening visit 1).  
 
4. Blood draw for laboratory testing that include a serum pregnancy test*, 
electrolyte panel, BUN, Cr, ALT, and AST and DNA analysis will be 
collected (baseline visit 2). 
*Women capable of becoming pregnant will be asked to have a pregnancy 
test before beginning this study. Women capable of becoming pregnant will 
be instructed to use effective birth control methods and not to become 
pregnant while participating in this study as there may be unknown risks to 
the unborn child.  There may be long-term effects of the treatment being 
studied that could increase the risk of harm to an unborn child.  The study 
team must be notified if the birth control method fails while on the study 
and/or if the participant becomes pregnant while participating in this 
research study. 
 
5. Audiogram, ECochG, DPOAE, and WIN testing to document baseline 
 
measurements (baseline visit 2).  
 
Audiometry: The audiogram will be performed to look for TTS and PTS. 
Earphones will be placed over the participant’s ears and a series of tones at 
a soft volume will be played at varying frequencies. The participant 
indicates that they hear the tones by pressing a button. Thresholds will be 
measured from .025-16 kHz. If there is an absence of a threshold at the 
limits of the equipment, the threshold will be reported as equipment limits 
(in dB HL) + 10 dB HL. As with the DPOAE, all equipment and procedures 
are based on a clinically approved protocol.  Each ear will be tested 
separately. 

16 | P a g e  
 
 
Electrocochleography (ECochG): An ECochG is an electrophysiological 
measurement of the cochlea in response to sound. It is a clinically-approved 
auditory evoked potential that is used to evaluate the status of both the 
cochlea and the auditory nerve fiber. This measurement is obtained by 
inserting a soft gold-foiled earphone into the participant’s ear. This 
earphone serves to deliver a series of clicks, as well as an electrode to 
measure the electrophysiological response of the cochlea to the sound. The 
electrode montage is completed with a ground electrode on the forehead at 
midline and a gold-foil electrode in the contralateral ear to serve as the 
inverting electrode. The impedance between electrodes will be < 3 kΩ for 
all participants. The click stimuli at 90 dB nHL used for the study will be 
repeated 2000 times so that the recording signal can be averaged with 
artifact rejection. The measurement will be repeated three times.  Testing 
time will take 45 minutes to 1 hour. 
 
Distortion Product Otoacoustic Emissions (DPOAE): DPOAEs are a 
measure of outer hair cell function and will be used as an indicator of 
changes in cochlear health and possible PTS in the early period following 
noise exposure. A soft earphone will be inserted into the participant’s ear 
and a series of tones at a comfortable volume will be played at varying 
frequencies. No participation is required of the participant as DPOAE are 
an objective assessment of cochlear health. The measurement system 
(Interacoustics Titan DPOAE440) will record the level of the emissions 
evoked by two primary tones, f1 and f2 (f2/f1 = 1.22) at levels 65 and 55 
dB SPL respectively. The f2 primary tone will be swept from 1- 6 kHz, and 
will be repeated at least five times per session in order to calculate the 
stability of the emission at each session. All data will be identified and 
stored on a password protected computer. DPOAE recording will take about 
20 minutes to complete. 
 
Words in Noise Test (WIN): Earphones will be placed over the 
participant’s ears and the WIN test will presented to each ear separately. 
The WIN test battery consists of 35 words that are presented in a 
background noise (speech babble) with varying degrees of signal-to-noise 
ratios (SNR) from 24 dB HL to 0 dB HL. The babble is set at 80 dB SPL, 
and the target word levels decrease from 104 dB SPL to 80 dB SPL.  The 
SNR at 24 dB HL is the easiest, with words presented at 24 dB above the 
noise background, whereas the SNR of 0 dB is the most difficult with target 
words being presented at the same level as the background noise (Wilson 
and Burks, 2005; Wilson and Watts, 2012). The WIN will be repeated three 
times in order to assess test-retest reliability. The total number of words 
correctly identified will be used to calculate a dB HL S/N threshold by the 
Spearman-Karber equation at the mean of 50% correct points.  All of speech 
testing will take 10-15 minutes to complete. 
 

17 | P a g e  
 
6. Baseline sound measurements will be obtained at the start of each test 
session, including the peak ambient noise level and the average noise level 
(screening and baseline visit 1 and 2).   
 
7. Completion of participant questionnaires, including (screening visit 1): 
a. Case history form 
b. Life Exposure to Noise and Solvents (LENS-Q) (Full) 
c. Life Exposure to Noise and Solvents (LENS-Q) (Adapted) 
d. Tinnitus Functional Index (TFI) 
 
8. Completion of baseline cognitive assessments, including (baseline visit 2): 
a. Digit-symbol substitution test: Measures processing speed 
b. List learning task/RBANS: Measures memory function. 
c. Verbal fluency test (word finding task): Measures working memory, 
speech/language.  
d. Stroop test: Measures executive functioning (vigilance, attention, 
inhibition). 
 
All data will be identified and stored on a password protected computer. 
 
5.2 
Randomization  
 
Following identification of TTS, eligible participants will be randomized via an 
interactive randomization tool (IRT) in a balanced fashion into one of two study 
groups: ZNS (100 mg PO) or placebo.  Randomization will be based on a 
randomization list generated from the study statistician using a computer algorithm 
written in SAS using randomly selected blocks of sizes 2.  Within each block of 2, 
there will be 1 subject assigned to each study group. To balance noise-exposure 
history across study arms we will employ stratified randomization. The subjects 
will be stratified based on noise exposure survey responses (see table below), and 
will then be randomized to study groups. The random assignment of subjects to the 
different study groups will be associated with consecutively assigned study 
identification numbers (Study ID) which will be unique for each study participant. 
The stratified randomization kit list will be provided to Advanced Rx who will 
package and label the drug for shipment to the pharmacist for each participant. Each 
bottle will be labeled with the kit number, study ID, and instructions on how to take 
the medication. The bottle will not contain any information of the treatment 
allocation.  
 
 ZNS (100 mg PO) group 
 
 Placebo PO group 
 
Name 
Description 
1: High Noise 
Screening: 
   LENS-Q Adapted for Police Officer 
– 

18 | P a g e  
 
Name 
Description 
1A Or 2A Or 3A =   
a.Daily, Or 
b.Less than 
daily/more than 
weekly, Or 
c.Weekly, Or 
d.Less than 
weekly/more than 
monthly Or 
e.Monthly 
OR 
1C Or 2C Or 4C >= 5 Years 
 
2: Low Noise 
Screening: 
   LENS-Q Adapted for Police Officer 
– 
1A AND 2A AND 3A =   
f.Less than 
monthly/more than 
yearly, 
g.Yearly, 
h.Less than yearly Or 
i.Never 
OR 
1C AND 2C AND 4C < 5 
Years 
 
 
5.3 
Testing on the Range (Visit 3) 
 
1. Duration of each shooting session and number of rounds fired by each 
participating officer will be documented. 
 
2. Handedness will be documented. 
 
3. Weapon type(s), including caliber and ammunition, used for each participating 
police officer will be documented. 
 
4. Hearing protection device(s) including type, make, model and noise reduction 
rating (NRR) used by each participating police officer will be documented.   
 
5.4 
Follow-Up Assessments (Visits 3, 4 and 5) 
 
 
The follow-up assessments will occur after training and include the following 
tests or procedures: 

19 | P a g e  
 
 
1. Audiogram and DPOAEs to measure for TTS and auditory changes, as soon 
as possible after the training session.  The exact time of testing following 
training operations will be documented. A clinical ear exam will be completed 
prior to the audiogram and DPOAEs. (follow-up visit 3 and 5).  
 
2. Baseline environmental/ambient sound measurements will be recorded at 
the start of each test session, including the peak ambient noise level and the 
average noise level (follow-up visit 3 and 5). 
 
3. Collection of blood for laboratory testing to include an electrolyte panel, 
BUN, Cr, ALT, and AST. This will occur within 12-24 hours following 
drug intake (follow-up visit 4). 
 
4. Cognitive assessments within 24 hours following drug intake, including 
(follow-up visit 4): 
a. Digit-symbol substitution test (processing speed) 
b. Verbal fluency (working memory, speech/language)  
c. Stroop (Executive function, inhibition) 
d. List Learning task/RBANS (memory) 
 
Additionally, after each officer is asked about potential study-related side 
effects for safety monitoring, they will be asked a question regarding their 
feeling of safety on the job, i.e. they will be asked “if they feel safe partaking 
in required responsibilities associated with their job at this time or not?” 
 
5. Completion of LENS-Q 1-minute noise screening for noise exposure 
questionnaire (follow-up visit 5). 
 
6. Audiogram, ECochG, DPOAE, and WIN testing 30 days (+/- 3 days) after 
each training session to assess for PTS and auditory changes, only if TTS is 
observed from #1 (visit 5).  
  
7. Documentation of adverse events at all follow-up visits (5-30 minutes post, 
within 24 hours and at 30 day visit) (follow-up visit 3, 4 and 5).   
 
Follow-up assessments will be planned at the stated time points; actual follow up 
times may vary due to patient logistics and compliance. 
 
5.5 
Blood collection, transportation, and storage 
 
 
Blood samples will be collected from each participant during the baseline visit and 
the post-training visit within 24 hours.  A phlebotomost will draw blood into a red-
top tube (EDTA or citrate).  Samples will be labeled with a study identification 
number.  Samples to be used for safety labs will be sent to the lab by the 
phlebomtomist. PGx samples will be stored in a 2-8oC degree refrigerator or a -

20 | P a g e  
 
20oC degree freezer at Akron.  Samples will then be transported for extraction and 
stored in a -80oC freezer at Gateway Biotechnology’s lab. 
 
 
6.0 
EVALUABILITY 
 
All participants are evaluable for the primary outcome – the proportion of patients who are 
PTS positive as defined by the ratio of the number of participants with > 10 dB increase in 
PTS to the total number of participants tested 30 days (+/- 3 days) post-shooting – provided 
they have had the assigned study dose and undergone post study assessments. 
 
Participants who receive the study medication are evaluable for toxicity related to the drug.  
Participants are evaluated from the time of dose administration through 30 days post dose 
for drug related adverse events. 
   
 
The participant will be withdrawn from the study if: 
 Participant withdraws consent 
 Investigator removes the participant from study 
 The Sponsor decides to close the study 
 
7.0 
PHARMACEUTICAL INFORMATION 
 
7.1 
Zonisamide (ZONEGRAN®) 
 
7.1.1 Zonisamide Description 
 
 
 
 
 
Molecular formula: C8H8N2O3S 
 
Molecular weight: 212.23 
 
 
7.1.2 Clinical Pharmacology 
 
The precise mechanism(s) by which ZNS exerts its antiseizure effect is 
unknown.  ZNS may produce these effects through action at sodium and 
calcium channels. In vitro pharmacological studies suggest that ZNS blocks 
sodium channels and reduces voltage-dependent, transient inward currents (T-
type Ca2+ currents), consequently stabilizing neuronal membranes and 
suppressing neuronal hypersynchronization.  Additional information can be 
found in the package insert. 
 
7.1.3 Supplier 
 
 
 
 
ZNS will be supplied through Advanced Rx (Washington, PA).  
 
7.1.4 Dosage Form and Preparation 
 

21 | P a g e  
 
ZONEGRAN® is commercially available for oral administration as 
capsules containing 25mg, 50 mg, or 100 mg of ZNS. 
 
Each 100 mg capsule contains the labeled amount of ZNS plus the following 
inactive ingredients: microcrystalline cellulose, hydrogenated vegetable oil, 
gelatin, and titanium dioxide.  
 
7.1.5 Storage and Stability 
 
Store at 25◦C (77◦F), excursions permitted to 15–30◦C (59–86◦F), in a dry 
place and protected from light. 
 
7.1.6 Administration 
 
Participants will receive one time dose of oral ZNS or matching placebo. 
Participants will be instructed to take study drug without food. We will 
recommend that capsules be swallowed whole per the current approved 
labeling. 
 
7.1.7 Side Effects 
 
Potential side effects from the administration of ZNS: 
 Somnolence 
 Anorexia 
 Dizziness 
 Ataxia 
 Agitation/irritability 
 Difficulty with memory and/or concentration   
 
ZNS may rarely cause serious side effects, including: 
 Serious skin rash that can cause death. 
 Serious allergic reactions that may affect different parts of the 
body. 
 Less sweating and increase in body temperature (fever). 
 Suicidal thoughts or actions in some people. 
 Increased level of acid in blood (metabolic acidosis). 
 Problems with concentration, attention, memory, thinking, speech, 
or language. 
 Blood cell changes such as reduced red and white blood cell 
counts. 
 
7.1 
Placebo 
 
The placebo will contain microcrystalline cellulose which is the predominant 
filler in the generic capsule.  
 

22 | P a g e  
 
 
8.0 
REGULATORY AND REPORTING REQUIREMENTS 
 
The entities providing oversight of safety and compliance with the protocol require 
reporting as outline below.  Please refer to Appendix A for definitions and Appendix B for 
a grid of reporting timelines. 
 
Adverse events will be tracked for the Akron site post dose within 30 minutes, 24 hours, 
and at 30 days.  All adverse events must be recorded on the AE tracking case report form 
(CRF). AEs related to study medication only will be tracked. 
 
Reporting requirements for Washington University study team may be found in Section 8.1.  
Reporting requirements for secondary site study teams participating in Washington 
University-coordinated research may be found in Section 8.2. 
 
In the event of a Serious Adverse Event determined by the PI to necessitate the breaking 
of the blind, the intervention assignment will be revealed by the independent programmer 
to the medical staff doctor caring for the patient. In the event the statistician is unable to 
be reached in a time needed, to assure the safety of the subject, the blind can be broken by 
Sara Kukuljan, RN and information will be shared with the medical staff assuming care 
for the research subject. 
 
 
8.1 
Sponsor-Investigator Reporting Requirements 
 
8.1.1 Reporting to the Human Research Protection Office (HRPO) 
at Washington University 
 
Reporting will be conducted in accordance with Washington University 
IRB Policies. 
 
Pre-approval of all protocol exceptions must be obtained prior to 
implementing the change. 
 
8.1.2 Reporting to the FDA 
 
The conduct of the study will comply with all FDA safety reporting 
requirements.  It is the responsibility of the Washington University principal 
investigator to report to the FDA as follows: 
 
 Report any unexpected fatal or life-threatening suspected adverse 
reaction (refer to Appendix A for definitions) no later than 7 
calendar days after initial receipt of the information.   
 Report a suspected adverse reaction that is both serious and 
unexpected (SUSAR, refer to Appendix A) no later than 15 
calendar days after it is determined that the information qualifies 

23 | P a g e  
 
for reporting.  Report an adverse event (refer to Appendix A) as a 
suspected adverse reaction only if there is evidence to suggest a 
causal relationship between the drug and the adverse event, such as: 
o A single occurrence of an event that is uncommon and known 
to be strongly associated with drug exposure 
o One or more occurrences of an event that is not commonly 
associated with drug exposure but is otherwise uncommon in 
the population exposed to the drug 
o An aggregate analysis of specific events observed in a clinical 
trial that indicates those events occur more frequently in the 
drug treatment group than in a concurrent or historical control 
group 
 Report any findings from epidemiological studies, pooled analysis 
of multiple studies, or clinical studies that suggest a significant risk 
in humans exposed to the drug no later than 15 calendar days after 
it is determined that the information qualifies for reporting. 
 Report any findings from animal or in vitro testing that suggest 
significant risk in humans exposed to the drug no later than 15 
calendar days after it is determined that the information qualifies 
for reporting.  
 Report any clinically important increase in the rate of a serious 
suspected adverse reaction of that listed in the protocol or IB within 
15 calendar days after it is determined that the information qualifies 
for reporting. 
 
Submit each report as an IND safety report in a narrative format or on FDA 
Form 3500A or in an electronic format that FDA can process, review, and 
archive.   
 
Each notification to FDA must bear prominent identification of its contents 
(“IND Safety Report”) and must be transmitted to the review division in the 
Center for Drug Evaluation and Research (CDER) or in the Center for 
Biologics Evaluation and Research (CBER) that has responsibility for 
review of the IND.  Relevant follow-up information to an IND safety report 
must be submitted as soon as the information is available and must be 
identified as such (“Follow-up IND Safety Report”). 
 
 
 
 
8.1.3 Reporting to Secondary Sites 
 
The Washington University Sponsor-Investigator will notify the research 
team at the secondary site of all unanticipated problems involving risks to 
participants or others that have occurred at other sites within 10 working 
days of the occurrence of the event or notification of the Sponsor-
Investigator of the event.  This includes events that take place both at 
Washington University and at other site, if applicable. 

24 | P a g e  
 
 
 
8.2 
Secondary Site Reporting Requirements  
 
The research team at each secondary site is required to promptly notify the 
Washington University Sponsor-Investigator of all serious adverse events (refer to 
Appendix A, Section D) within 1 working day of the occurrence of the event or 
notification of the secondary site’s PI of the event.  This notification may take place 
via email if there is not yet enough information for a formal written report (using 
FDA Form 3500a (MedWatch) and Washington University’s cover sheet 
(Appendix C).  A formal written report must be sent to the Washington University 
Sponsor-Investigator and designee within 4 calendar days (for fatal or life-
threatening suspected adverse reactions) or 11 calendar days (for serious 
unexpected suspected adverse reactions) of the occurrence of the event or 
notification of the secondary site’s PI of the event. 
 
The research team at the secondary site is responsible for following its site’s 
guidelines for reporting applicable events to its site’s IRB according to its own 
institutional guidelines.  The research team at Washington University is responsible 
for reporting all applicable events to the FDA as needed. 
 
Washington University pre-approval of all protocol exceptions must be obtained 
prior to implementing the change.  Local IRB approval must be obtained as per local 
guidelines.  Washington University IRB approval is not required for protocol 
exceptions occurring at secondary sites. 
 
8.3 
Exceptions to Expedited Reporting  
 
Events that do not require expedited reporting as described in Section 1.1 include: 
 planned hospitalizations 
 hospitalizations < 24 hours 
 respite care 
 events related to disease progression 
 
Events that do not require expedited reporting must still be captured in the EDC. 
 
 
 
 

25 | P a g e  
 
9.0 
STUDY CALENDAR 
 
 
VISIT 1 
Screening 
Assessment 
VISIT 2 
Baseline 
Assessment 
Post-training 
 
 
 
 
VISIT 3 
Within 
5-30 Minutes 
VISIT 4 
Within 24 
Hours 
VISIT 5 
30 days (+/- 
3 days)*** 
Informed Consent 
X 
 
 
 
 
Demographic Info 
X 
 
 
 
 
Current Meds 
X 
 
 
 
 
Questionnaires 
X 
 
 
 
X 
Cognitive Assessment 
 
X 
 
X 
 
Clinical ear exam 
X 
X 
X 
 
X 
Audiogram 
X 
X 
X 
 
X 
ECochG 
 
X 
 
 
X 
DPOAE 
 
X 
X 
 
X 
WIN 
 
X 
 
 
X 
Sound Measurements 
X 
X 
X 
 
 
Randomization 
 
 
X* 
 
 
Oral Dose* ZNS or 
Placebo 
 
 
X* 
 
 
Blood draw** 
 
X 
 
X 
 
AE Assessment 
 
 
X 
X 
X 
* Dispensed after training if TTS is identified on audiogram 5-30 minutes after shooting.   
** Blood draw: Electrolyte panel, BUN, Cr, ALT, and AST; DNA analysis and serum 
pregnancy test at baseline 
*** If TTS is seen from pure tones after each training session 
 
10.0 
DATA SUBMISSION SCHEDULE 
 
Case report forms with appropriate source documentation will be completed according to 
the schedule listed in this section. 
 
Case Report Form 
Submission Schedule 
Original Consent Form 
Prior to study activities 
Eligibility Form 
At time of consent; Prior to firearm training 
Firearm Training Form 
Time of firearm training 
Adverse Event Form 
Continuous 
 
11.0 
DATA AND SAFETY MONITORING 
 
In compliance with the Washington University Institutional Data and Safety Monitoring 
Plan, an independent Data and Safety Monitoring Board (DSMB) will be specifically 
convened for this trial to review toxicity data.  A DSMB will consist of no fewer than 3 
members including 2 clinical investigators and a biostatistician.  Individuals invited to serve 

26 | P a g e  
 
on the DSMB will disclose any potential conflicts of interest to the trial principal 
investigator and/or appropriate university officials, in accordance with institution policies.  
Potential conflicts that develop during a trial or a member’s tenure on a DSMB must also 
be disclosed.  
 
The DSM report for the DSMB will be prepared by the study team with assistance from the 
study statistician, will be reviewed by the DSMB, and will be submitted to the PI.  The 
DSMB must meet at least every six months beginning six months after enrollment of the 
first participant at the secondary site, no more than one month prior to the due date of the 
DSM report to the PI.  This report will include: 
 
 HRPO protocol number, protocol title, Principal Investigator name, data coordinator 
name, regulatory coordinator name, and statistician 
 Date of initial HRPO approval, date of most recent consent HRPO 
approval/revision, date of HRPO expiration, date of most recent QA audit, study 
status, and phase of study 
 History of study including summary of substantive amendments; summary of 
accrual suspensions including start/stop dates and reason; and summary of protocol 
exceptions, error, or breach of confidentiality including start/stop dates and reason 
 Study-wide target accrual and study-wide actual accrual  
 Protocol activation date at each participating site 
 Average rate of accrual observed in year 1, year 2, and subsequent years at each 
participating site 
 Expected accrual end date, accrual by site, and accrual by cohort 
 Objectives of protocol with supporting data and list the number of participants who 
have met each objective 
 Measures of efficacy  
 Early stopping rules with supporting data and list the number of participants who 
have met the early stopping rules 
 Power analysis and/or interim analysis (if described in the protocol) 
 Summary of toxicities  
 Abstract submissions/publications 
 Summary of any recent literature that may affect the safety or ethics of the study 
 
 
The study principal investigator and coordinator will monitor for serious toxicities on an 
ongoing basis. Once the principal investigator or coordinator becomes aware of an adverse 
event, the AE will be reported to the HRPO according to institutional guidelines (please 
refer to Section 1.0). 
 
11.1 
Adverse Event Collection in the Case Report Forms 
 
All adverse events that occur beginning with start of treatment must be captured in the AE 
Form.   
 
12.0 
STATISTICAL CONSIDERATIONS 

27 | P a g e  
 
 
12.1 
Data analysis 
 
Data will be analyzed using an intention to treat principle with patients analyzed in 
the groups they were randomized to. The primary outcome measure for assessing 
effectiveness of ZNS (100 mg PO) will be the proportion of officers experiencing 
PTS 30 days (+/- 3 days) after training in the ZNS group as compared to proportion 
of officers experiencing PTS in the placebo group (Group 2). The secondary 
outcome measures are key audiological and clinical assessments of hearing loss.  
OAE shift will be a secondary outcome measure and an early indicator of TTS and 
PTS. 
 
Standard descriptive statistics will be used to describe distribution of demographic, 
clinical and audiometric characteristics as well as outcome measures for each study 
group. For continuous level characteristics Q-Q plots and Shapiro-Wilk test will be 
used to test assumption of normality. For normally distributed data mean and 
standard deviation will be used as descriptive stats of continuous level variables, 
and if the assumption of normality is violated we will report median and range for 
description of variables. Frequency and relative frequency will be used for 
description of categorical level variables.  
 
12.2 
Efficacy analysis 
 
12.2.1 Analysis of primary outcome variable 
 
Efficacy analysis at the end of the study 
 
The primary outcome measure for assessing effectiveness of ZNS (100 mg 
PO) post-shooting compared to the placebo group will be the proportion of 
officers with TTS defined as PTS positive 30 days (+/- 3 days) after 
shooting range exposure. 
  
Audiogram will be performed to look for PTS. Officers for whom the 
difference at any frequency from 2-6 kHz in hearing thresholds (30 days 
(+/- 3 days) post-shooting - Baseline) is ≥10 dB HL will be defined as PTS 
positive. Primary analysis and sensitivity analyses will be carried out on the 
primary endpoint. 
 
Primary analysis. 
 
Frequency and relative frequency will be used to describe the distribution 
of the primary outcome measure in each study group. To assess efficacy, 
Fisher’s exact test will be used to compare the proportion of officers with 
PTS positive in ZNS group with the proportion of officers with PTS positive 
in the placebo group.  
 

28 | P a g e  
 
To provide an estimate of treatment effect a supportive logistic regression 
analysis will be done with covariates: age, pre-existing hearing loss 
dichotomized to normal to minimal hearing loss and slight to mild loss, 
noise exposure history dichotomized to high risk and low risk, average post-
shooting  
 
Sensitivity analysis of the primary endpoint 
 
The potential impact of missing primary endpoint data will be explored in 
sensitivity analyses using multiple imputation.  Two sensitivity analyses 
performed: 
 
Sensitivity 1: MI analysis under the missing not at random assumption 
(MNAR) 
Sensitivity 2: Logistic regression tipping point analysis under the 
assumption of data missing at random. 
 
 
Sensitivity 1. 
Proc MI procedure in SAS will be used to impute missing data for study 
treatment groups using the distribution implied by the non-missing officer 
data within the placebo group. The SAS code to impute data for Sensitivity 
analysis 1 under the MNAR assumption will be of the form: 
 
PROC MI DATA=X SEED=<value> NIMPUTE=10  OUT=MI_OUT1 NOPRINT; 
CLASS  GROUP; 
VAR AGE PTA LSurg………; 
FCS LOGISTIC(PTS);  
RUN; 
 
Post imputation each of the imputed 10 datasets will be analyzed using the 
same approach as for the primary outcome measure. The estimates of the 
analysis of the 10 imputed datasets will be then combined following 
Rubin’s rules using PROC MIANALYZE procedure in SAS which will be 
of the form:  
 
PROC MIANALYZE PARMS=GMPARMS COVB=GMCOVB PARMINFO=GMPINFO WCOV 
BCOV 
    TCOV; / *dataset "gmparms" contains the estimates and 
associated standard errors for the mean parameters from each of 
the M=10 imputed data sets. 
dataset "gmcovb" contains the asymptotic covariance matrics 
dataset "gmpinfo" contains parameter info*/ 
 
    MODELEFFECTS INTERCEPT AGE PTA LSurg………; 
RUN; 
Sensitivity 2. 
 
Multiple imputation will be used to impute data in each of the study groups. 
A progressive penalty of 𝛿𝑖= 𝑘𝑖× log⁡(𝑂𝑅) will be added to imputed 

29 | P a g e  
 
values in ZNS arm where (i) 𝑂𝑅 is the Odds ratio estimate for ZNS as 
compared to Placebo from the primary logistic regression analysis and (ii)  
𝑘𝑖= 1, 0.95, 0.90,… 0.05, 0, 1.05, 1.10,… thus k ranges from 1 (equivalent 
to MI approach based on MAR) to 0 (or higher), until the conclusion of the 
primary analysis is overturned (i.e., p<0.05 is lost at, this value of 𝑘𝑖 being 
the ‘tipping point’). Rubin’s method will be used to combine the primary 
endpoint treatment effects across imputations for each value, 𝑘𝑖, of the 
penalty.  Forest plots will be used to graphically display the penalty value 
that results in loss of statistical significance.  
 
SAS code sample for Sensitivity analysis is provided below: 
 
**Step 1: Generate 10  datasets by imputing the missing data**; 
 
PROC MI DATA=X SEED=<value> NIMPUTE=10  OUT=MI_OUT1 NOPRINT; 
CLASS  GROUP; 
VAR AGE PTA LSurg………; 
FCS LOGISTIC(PTS);  
RUN; 
 
**Step 2: Generate 10 complete datasets from the 10 monotonized 
datasetsin Step 1 for missing values in the drug arm,  
subtract DELTA derived above from their imputed data.**; 
proc mi data=YYY NIMPUTE=1 SEED=<value> OUT=YYY_shift; 
by group; 
class group; 
var AGE PTA LSurg………; 
monotone method=logistic; 
mnar adjust(PTS / shift=DELTA adjustobs=(group=’1’)); 
run; 
 
**Step 3: Apply the primary MMRM to the 10 complete datasets in 
Step 2**; 
proc genmod data=YYY_shift descending; 
by _imputation_; 
class group; 
model PTS = group AGE PTA LSurg………; 
ods output GEEModPEst=gmparms; 
run; 
 
 
 
 
**Step 4: Obtain the pooled inference from 10 sets of estimates 
from Step 3**; 
 
PROC MIANALYZE PARMS=GMPARMS COVB=GMCOVB PARMINFO=GMPINFO WCOV 
BCOV 
    TCOV;  
    MODELEFFECTS group; 
RUN; 
 
 
12.2.2 Analysis for secondary outcome measures. 
 

30 | P a g e  
 
The focus of the study is to determine efficacy of ZNS for treatment of acute 
hearing loss based on the testing of the hypothesis for the primary outcome. 
In addition, we will also conduct analysis to evaluate other important 
audiologic measures. The secondary outcome measures are key 
audiological and clinical assessments of hearing loss, and include: 
Audiometric TTS, DPOAEs, Ultra-high frequency audiometry, ECochG, 
and WIN testing 30 days (+/- 3 days) after shooting, and are measured as 
continuous level variables.  We do not plan any adjustment of alpha error 
for multiple comparisons.  
 
Analysis of variance (ANCOVA) will be used for comparison of outcome 
measures between each of the ZNS groups and placebo study group after 
controlling for baseline value, age, pre-op hearing   dichotomized to: normal 
to minimal hearing loss and slight to mild loss, noise exposure history 
dichotomized to: high risk and low risk, average post-shooting TTS. 
 
Statistical analyses will be conducted using the SAS software (SAS Institute Inc., 
Cary, N.C., USA). 
 
Measurements will include (1) the average audiogram threshold shift between 3 
and 6 kHz (sensitive region for NIHL) and 10 and 16 kHz (markers for hidden 
hearing loss), (2) DPOAE amplitudes, (3) ECochG changes (AP amplitude and 
latency, AP width), and (4) WIN scores.  
 
Missing Data 
 
Every attempt will be made to ensure data completeness. We do not anticipate much 
loss to follow-up because of the relatively short time follow-up interval. 
Conservatively, we would estimate that fewer than 5% of subjects will drop 
out/withdraw of the study.  The participant will be withdrawn from the study 
follow-up and procedures if the participant withdraws consent, or the sponsor 
decides to close the study. 
 
If any, the loss of data would almost certainly be due to the fact that the subjects 
refused to complete or did not show up for the assessment of PTS 30 days (+/- 3 
days) after the baseline assessment on shooting day. If the subjects reschedule the 
follow-up appointment for a later date for any reason, and if this delay is within 30 
days of the scheduled date, the data will be considered valid and used in the efficacy 
analysis. Any measure outside this time window of +30 days will be defined and 
considered missing data. 
 
Missing PTS at 30 days will be imputed using SAS PROC MI procedure within 
each treatment group using the distribution implied by the non-missing data for the 
specific treatment group.  
 

31 | P a g e  
 
The SAS code below using MICE via the Fully Conditional Specification (FCS) 
statement will be used to impute the missing data under the missing at random 
(MAR) assumption.  
 
PROC MI DATA=X SEED=<value> NIMPUTE=10  OUT=MI_OUT1 NOPRINT; 
CLASS  GROUP; 
VAR AGE PTA LSurg………; 
FCS LOGISTIC(PTS);  
RUN; 
 
The estimates of the analysis of the 10 imputed datasets will be then combined 
following Rubin’s rules using PROC MIANALYZE procedure in SAS which will 
be of the form:  
 
PROC MIANALYZE PARMS=GMPARMS COVB=GMCOVB PARMINFO=GMPINFO WCOV BCOV 
    TCOV; / *dataset "gmparms" contains the estimates and associated 
standard errors for the mean parameters from each of the M=10 imputed 
data sets. 
dataset "gmcovb" contains the asymptotic covariance matrics 
dataset "gmpinfo" contains parameter info*/ 
 
    MODELEFFECTS group; 
RUN; 
 
 
12.3 
Sample size estimation 
 
Sample size estimation for primary outcome measure. 
 
Calculation of sample size for this study is based on a balanced design and a one-
sided significance level of 0.025. We estimate that among officers identified as 
being at high risk for permanent hearing loss due to having TTS, the proportion of 
PTS positive officers 30 days (+/- 3 days) after shooting will be 50%. This is the 
proportion of PTS positive we expect to observe in the placebo group. Thus, for the 
primary outcome, we estimated that 66 subjects per group will provide us with 
80.5% power to detect a 50% reduction in the proportion of PTS positive officers 
(from 50% to 25%) at the 1-sided alpha level of 0.025 and with 84% power to detect 
a 50% reduction in the proportion of PTS positive officers (from 50% to 25%) at 
the one-sided alpha level of 0.025. Our one-sided hypothesis is supported by animal 
studies, and lack of any evidence of hearing loss as a side effect of ZNS in human 
studies. A total of 132 subjects will be enrolled. 
 
Using a number needed to treat estimate for the assumed proportion of officers with 
PTS positive in each study group, the absolute risk reduction of 25% tells us that 
we will need to treat 4 officers with TTS with ZNS to protect 1 from PTS.  We do 
not expect to have any missing data in this short-term study, so no plan for missing 
data analysis is included. 
 
Sample size for secondary outcome measures. 
 

32 | P a g e  
 
Blioskas et al. reported that 280 out of 344 (81%) military cadets had TTS. Thus, 
for TTS as secondary outcome measure, the estimated sample size of 63 subjects 
in each arm will provide us with 96.1% power to detect a 40% reduction in the 
proportion of subjects experiencing TTS (from 80% to 48%) at the 1-sided alpha 
level of 0.0235.   
 
 
12.4 
Interim analysis 
 
A sponsor blinded interim analysis focused on the primary endpoint after 33% of 
the officers have completed participation in the study (22 in each group).  The 
independent programmer will prepare the dataset using a pre-prepared SAS code 
and will freeze them for the interim analysis. To ensure the double blinding of the 
study the subjects will not be presented in the assigned groups. The blinded 
statistician will estimate the overall proportion of PTS positive subjects in each 
group.  
 
With 33% information, the trial would be stopped for futility if the interim z-value 
<= 0.5233 (p=0.60 2-sided) corresponding to a conditional power less than 10%. 
This design would provide 79.4% overall power (i.e. the probability of passing 
futility and reaching p<0.025 for the comparison in the final analysis would be 
79.4%). 
 
 
Based on interim analysis the following actions may be taken: 
 Stop the trial for futility 
 Continue the trial as planned. 
 
 
Early stopping rule related to serious adverse events: In the event of a serious 
adverse event, DSMB will evaluate the association of the serious adverse events 
with the study arm, break the blind if needed, and if found to be associated with 
treatment, DSMB will consider the study for revision or stopping.  
 
Serious feasibility or design difficulties. If one year after the start of the trial, <50% 
of the planned accrual goals are met, DSM and study team will discuss difficulties 
in recruitment. Amount of remuneration will be revised, if needed. If there are not 
enough officers meeting inclusion/exclusion criteria, then the criteria will be 
revised without impacting study objectives. If there are recruitment difficulties, the 
DSM will discuss with the PI and research team what are the main reasons for these 
difficulties and will identify ways to deal with them.  For example, if there are not 
enough police officers identified with a TTS ≥ 10dB, then the study inclusion 
criteria will be revised to include members of the Bomb squad.  In order to preserve 
the balanced design and group representation, a stratified randomization strategy 
will be employed.  If there are difficulties in recruitment related to length of 

33 | P a g e  
 
audiometric testing pre- and post-shooting, then the DSM and research team will 
discuss using OAE testing. 
For this study, we have approximately 800 officers from Akron and Summit 
County, not including additional local police departments from which to screen and 
recruit, understanding a large percentage of the population may already present 
with significant NIHL, thus, may not meet the eligibility criteria.  In a previous 
study by the investigators, 62-85% of police officers presented with evidence of 
NIHL (62.5% of canine police handlers and 85.7% of non-canine police handlers), 
therefore, we need a significantly larger sample size to recruit subjects that meet 
our eligibility criteria. We estimate that each year we will have at least 60 officers 
screened within 1 hour of shooting each year.  If the rate of TTS after 1 hour of 
shooting is that of the study from Blioskas et al, we estimate that 48 officers will 
qualify to undergo randomization each year. If 70% of them consent to be 
randomized there will be 34 officers enrolled and completing the trial each year. 
Based on these estimates, we will be able to meet our accrual goals and complete 
the study with a sample size of 132 officers in approximately 4 years.   
 
12.5 
Pharmacogenetic analysis plan 
  
This analysis will be performed at the end of the trial by Gateway Biotechnology. 
To identify genetic variants with ZNS protection against hearing loss, we will first 
use univariate logistic regression analyses to identify potential confounding 
variables: sex, age, Z-scores of drug concentration, Z-scores of noise intensity and 
duration, and Z-scores of hearing functions measured immediately following range 
shooting. Single-marker allelic association analyses will be conducted on the two 
imputed data sets in PLINK v1.07. The data will be analyzed with a logistic 
regression model on the additive continuous dosage of minor alleles from 0 to 2 to 
account for uncertainty of imputation. We will combine association results in the 
two cohorts by performing a genome-wide inverse-variance weighting meta-
analysis using PLINK v1.07, and assuming a fixed-effect model. Functional 
annotation of top-associated markers will be performed with R package NCBI2R 
1.4.6 (http://CRAN.Rproject. org/package=NCBI2R), and key regional association 
plots of meta-analyzed results will be generated. To confirm whether these variants 
are specific to ZNS response, we will apply CEP SKAT to analyze genetic 
associations based on Z-scores of audiogram average threshold shifts and DPOAE 
amplitudes. All genetic variants, including both common and rare variants, will be 
included in this association study. Age, gender, drug concentration, and noise 
duration and intensity will be adjusted for the analysis. The analysis will also be 
performed using hearing data collected two to four weeks after range shooting. The 
only differences will be a) using the Z scores of ECochG AP amplitude, latency, 
and width as well as WIN score, and b) using average audiogram threshold shifts 
and DPOAE amplitudes at 30 days (+/- 3 days) post-treatment. To control for 
confounding effects, these models will be adjusted for age, gender, drug 
concentration, and noise duration and intensity. Finally, the control and ZNS-
treated comparisons will be performed using post-hoc comparisons with a 
Bonferroni adjustment for multiple comparisons of any ZNS versus none. 

34 | P a g e  
 
Statistical analyses will be performed using the CEP-SKAT method in R language, 
and the statistical software SAS version 9.4 for Windows will be used for additional 
analysis. 
 
 

35 | P a g e  
 
13.0 
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APPENDIX A: Definitions for Adverse Event Reporting 
 
A. Adverse Events (AEs) 
 
As defined in 21 CFR 312.32: 
 
Definition: any untoward medical occurrence associated with the use of a drug in humans, 
whether or not considered drug-related. 
 
Grading: the descriptions and grading scales that should be used are those provided by the 
Department of Health and Human Services’ Office for Human Research Protections (OHRP).  
A copy of this guidance can be found on OHRP’s website: 
http://www.hhs.gov/ohrp/policy/advevntguid.html 
 
Attribution (relatedness), Expectedness, and Seriousness: the definitions for the terms 
listed that should be used are those provided by the Department of Health and Human Services’ 
Office for Human Research Protections (OHRP).  A copy of this guidance can be found on 
OHRP’s website: 
http://www.hhs.gov/ohrp/policy/advevntguid.html 
 
B. Suspected Adverse Reaction (SAR) 
 
As defined in 21 CFR 312.32: 
 
Definition: any adverse event for which there is a reasonable possibility that the drug caused 
the adverse event.  “Reasonable possibility” means there is evidence to suggest a causal 
relationship between the drug and the adverse event.  “Suspected adverse reaction” implies a 
lesser degree of certainty about causality than adverse reaction, which means any adverse event 
caused by a drug. 
 
C. Life-Threatening Adverse Event / Life Threatening Suspected Adverse Reaction  
 
As defined in 21 CFR 312.32: 
 
Definition: any adverse drug event or suspected adverse reaction is considered “life-
threatening” if, in the view of the investigator, its occurrence places the patient at immediate 
risk of death. It does not include an adverse event or suspected adverse reaction that, had it 
occurred in a more severe form, might have caused death. 
 
D.  Serious Adverse Event (SAE) or Serious Suspected Adverse Reaction 
 
As defined in 21 CFR 312.32: 
 
Definition:  an adverse event or suspected adverse reaction is considered “serious” if, in the 
view of the investigator, it results in any of the following outcomes: 
o Death 

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o A life-threatening adverse event 
o Inpatient hospitalization or prolongation of existing hospitalization 
o A persistent or significant incapacity or substantial disruption of the ability to conduct 
normal life functions 
o A congenital anomaly/birth defect 
o Any other important medical event that does not fit the criteria above but, based upon 
appropriate medical judgment, may jeopardize the subject and may require medical or 
surgical intervention to prevent one of the outcomes listed above 
 
E. Protocol Exceptions 
 
Definition: A planned change in the conduct of the research for one participant. 
 
F. Deviation 
 
Definition: Any alteration or modification to the IRB-approved research without prospective 
IRB approval.  The term “research” encompasses all IRB-approved materials and documents 
including the detailed protocol, IRB application, consent form, recruitment materials, 
questionnaires/data collection forms, and any other information relating to the research study. 
 
A minor or administrative deviation is one that does not have the potential to negatively impact 
the rights, safety, or welfare of participants or others or the scientific validity of the study. 
 
A major deviation is one that does have the potential to negatively impact the rights, safety, or 
welfare of participants or others or the scientific validity of the study. 
 

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APPENDIX B: Reporting Timelines 
 
Event 
HRPO 
FDA 
Serious AND unexpected suspected adverse 
reaction 
 
Report no later than 15 calendar days after it is 
determined that the information qualifies for reporting 
Unexpected fatal or life-threatening 
suspected adverse reaction 
 
Report no later than 7 calendar days after initial 
receipt of the information 
Unanticipated problem involving risk to 
participants or others 
Report within 10 working days.  If the event results in 
the death of a participant enrolled at WU/BJH/SLCH, 
report within 1 working day. 
 
Major deviation 
Report within 10 working days.  If the event results in 
the death of a participant enrolled at WU/BJH/SLCH, 
report within 1 working day. 
 
A series of minor deviations that are being 
reported as a continuing noncompliance 
Report within 10 working days.   
 
Protocol exception 
Approval must be obtained prior to implementing the 
change 
 
Clinically important increase in the rate of a 
serious suspected adverse reaction of that list 
in the protocol or IB 
 
Report no later than 15 calendar days after it is 
determined that the information qualifies for reporting 
Complaints 
If the complaint reveals an unanticipated problem 
involving risks to participants or others OR 
noncompliance, report within 10 working days.  If the 
event results in the death of a participant enrolled at 
WU/BJH/SLCH, report within 1 working day.  
Otherwise, report at the time of continuing review. 
 
Breach of confidentiality 
Within 10 working days. 
 
Incarceration 
If withdrawing the participant poses a safety issue, 
report within 10 working days.   
 
If withdrawing the participant does not represent a 
safety issue and the patient will be withdrawn, report at 
continuing review. 
 
 
 
 

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Event 
HRPO 
FDA 
Adverse event or SAE that does not require 
expedited reporting 
If they do not meet the definition of an unanticipated 
problem involving risks to participants or others, report 
summary information at the time of continuing review 
The most current toxicity table from the DSM report 
is provided to the FDA with the IND’s annual report. 
Minor deviation 
Report summary information at the time of continuing 
review. 
 
Complaints 
If the complaint reveals an unanticipated problem 
involving risks to participants or others OR 
noncompliance, report within 10 working days.  If the 
event results in the death of a participant enrolled at 
WU/BJH/SLCH, report within 1 working day.  
Otherwise, report at the time of continuing review. 
 
Incarceration 
If withdrawing the participant poses a safety issue, 
report within 10 working days.   
 
If withdrawing the participant does not represent a 
safety issue and the patient will be withdrawn, report at 
continuing review. 
 
 
Event 
WU (Coordinating Center) 
Local IRB 
FDA 
Serious AND unexpected suspected 
adverse reaction 
Report no later than 11 calendar days after it is 
determined that the information qualifies for 
reporting. 
Report all applicable 
events to local IRB 
according to local 
institutional 
guidelines. 
The research team at Washington 
University is responsible for reporting all 
applicable events to the FDA as needed. 
Unexpected fatal or life-threatening 
suspected adverse reaction 
Report no later than 4 calendar days after initial 
receipt of the information. 
Unanticipated problem involving 
risk to participants or others 
Report no later than 4 calendar days after initial 
receipt of the information. 
Adverse event or SAE that does not 
require expedited reporting 
As per routine data entry expectations 
Protocol exception 
Approval must be obtained prior to implementing the 
change. 
 
 
 

 
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APPENDIX C: Washington University Unanticipated Problem Reporting Cover Sheet 
 
SAE COVER SHEET- Secondary Site Assessment 
 
Washington University HRPO#:  
Sponsor-Investigator:  
Subject Initials:   
Subject ID:  
Treating MD:  
Treating Site:  
EVENT TERM:  
Admission Date:  
EVENT GRADE: 
Date of site’s first notification: 
 
Treating MD Event Assessment:  
 
 
Is this event possibly, probably, or definitely related study treatment? 
 
 yes  
 
 no 
 
If yes, please list which drug (if more than one)______________________________ 
 
       
Explain ______________________________________________________________________ 
 
______________________________________________________________________________ 
 
 
 
_________________________           ___________________________      _________________  
Physician’s Name 
 
 
Physician’s Signature 
 
Date 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

 
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APPENDIX D: Questionnaire 1: Case History Form 
 
Medical / Hearing History Questionnaire 
 
Name: _______________________________________ 
Date of Birth: _________________________________ 
Gender: ______________________________________ 
Length of time as a police officer: __________________ 
Handedness: _________________________________ Shoot with: __________________ 
How often do you shoot for certification, annually (occupational)? __________________ 
Communication radio location: _______________________________________________ 
 
Do you have an existing hearing problem? 
Yes       No       Unknown 
If you have a hearing problem, has it been: 
Gradual       Lifelong       Sudden 
Have you ever had your hearing tested? 
Yes       No 
If yes, when? __________________ 
Have you recently experienced pain in either ear? 
Yes       No       Left       Right       
Both 
Have you recently experienced drainage from your 
ear? 
Yes       No       Left       Right       
Both 
Have you recently experienced ear fullness of 
discomfort? 
Yes       No       Left       Right       
Both 
Have you recently experienced dizziness? 
Yes       No       Left       Right       
Both 
Do you experience tinnitus (ringing) in your ears? 
Yes       No       Left       Right       
Both 
Center 
If yes, how often? 
Rarely (few times a year) 
Several times a year 
Several times a month 
Several times a week 
Daily 
Have you ever been to an ear specialist? 
Yes       No 
Have you ever had ear surgery? 
Yes       No 
Do you have frequent ear infections? 
Yes       No 
Do you have sinus problems? 
Yes       No 
Do you have allergies? 
Yes       No 
Do you currently use prescription or over-the-
counter drugs? 
Yes       No 
 

 
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Have you ever had kidney disease? 
Yes       No 
Have you ever had meningitis? 
Yes       No 
Do you have diabetes? 
Yes       No 
Do you have high blood pressure? 
Yes       No 
Do you experience headaches? 
Yes       No 
Have you experienced head trauma? 
Yes      No 
Do you have facial numbness? 
Yes      No 
Do you shoot recreationally (i.e. hunting)? 
Yes       No 
If yes, how often do you shoot recreationally? 
Rarely (few times a year) 
Several times a year 
Several times a month 
Several times a week 
Daily 
Is hearing protection used when you shoot 
recreationally? 
Never (0% of time) 
Minimally (~25% of time or less) 
Moderately (~50% of time) 
Often (~75% of time) 
Always (100% of time) 
Do you participate in loud activities (music, 
concerts, motorcycle)? 
Yes       No 
What types of activities? 
_____________________________ 
_____________________________ 
_____________________________ 
If yes, how often do you participate in these 
activities? 
Rarely (few times a year) 
Several times a year 
Several times a month 
Several times a week 
Daily 
Is hearing protection used when you participate in 
these activities? 
Never (0% of time) 
Minimally (~25% of time or less) 
Moderately (~50% of time) 
Often (~75% of time) 
Always (100% of time) 
Do you operate chain or power tools? 
Yes       No 
If yes, how often do you operate chain and/or 
power tools? 
Rarely (few times a year) 
Several times a year 
Several times a month 
Several times a week 
Daily 
Is hearing protection used when you operate 
chain/power tools? 
Never (0% of time) 
Minimally (~25% of time or less) 

 
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Moderately (~50% of time) 
Often (~75% of time) 
Always (100% of time) 
Does any of your immediate family have a hearing 
loss? 
Yes       No  
Do you, or have you previously worn hearing 
aids? 
Yes       No 
Please rate your hearing 
Very Good       Good       Average    
Poor       Very Poor        
 
PATIENT MEDICATION LIST 
MEDICATION 
NAME 
DOSAGE / 
STRENGTH 
FREQUENCY 
(How often) 
ROUTE 
(Oral, 
injection, 
spray) 
REASON 
FOR USE 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
ALLERGY INFORMATION 
ALLERGIC TO 
REACTION 
 
 
 
 
 
 
 
 
 
 
 
Please add or elaborate on any additional comments regarding your medical and hearing health that was 
not addressed: 
 
 
 
 
 
 
 
 
 
 
 
 

 
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APPENDIX E: Questionnaire 2: Life Exposure to Noise and Solvents (LENS-Q) 
 

 
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APPENDIX F: Questionnaire 3: Tinnitus Functional Index (TFI) 
 
 

 
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APPENDIX G: Questionnaire 4: LENS-Q Adapted Survey for Stratification (High vs. Low Noise 
Exposure Group Stratification) 
 
LENS-Q Adapted for Police Officer Study: By virtue of working in a career with required firearm use, all 
participants are automatically categorized as high noise.  The point of this modified survey is to stratify participants 
into relatively higher and relatively lower exposure groups. 
Noise Exposure History Interview Questions  
1.  
In your role as a police officer: 
A. How often does your police officer job cause you to be exposed to loud noise(s) where you have to shout to 
be heard? (For example, loud equipment or trucks, loud ship or jet engines, exposure from the rifle range, 
sirens, K-9 noise, loud crowds, loud music (e.g. concert/band events), loud noise from construction sites)  
a. Daily 
b. Less than daily/more than weekly 
c. Weekly 
d. Less than weekly/more than monthly 
e. Monthly 
f. Less than monthly/more than yearly 
g. Yearly 
h. Less than yearly 
i. 
Never 
 
B. How likely are you to be wearing hearing protection when this occurs (circle one)? 
 
Never          Rarely          Sometimes          Usually          Always 
 
C. How many years have you worked in a police officer job? _________________ 
 
2.  
Have you served in the military? If yes: 
A. How often did your military service cause you to be exposed to loud noise(s) where you had to shout to be 
heard? (For example, loud equipment or trucks, loud ship or jet engines, loud aircraft)  
a. Daily 
b. Less than daily/more than weekly 
c. Weekly 
d. Less than weekly/more than monthly 
e. Monthly 
f. Less than monthly/more than yearly 
g. Yearly 
h. Less than yearly 
i. 
Never 
 
B. How likely were you to be wearing hearing protection when this occurred (circle one)? 

 
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Never          Rarely          Sometimes          Usually          Always 
 
C. How many years did you serve in the military? _________________ 
 
3. 
In either your police officer position, your military service, or your recreational activities:  
 
A. How often have you been exposed to sudden intense noise? (For example, shooting range, target practice, 
hunting, explosions, cannon fire, gun shot, music (e.g. drums), etc.)  
a. Daily 
b. Less than daily/more than weekly 
c. Weekly 
d. Less than weekly/more than monthly 
e. Monthly 
f. Less than monthly/more than yearly 
g. Yearly 
h. Less than yearly 
i. 
Never 
 
B. Were you wearing hearing protection when this occurred (circle one)?  
 
Never          Rarely          Sometimes          Usually          Always 
 
4.  
A. How often did or do non-police officer/non-military jobs or recreational activities cause you to be exposed 
to loud noise(s) where you would have to shout to be heard?  
a. Daily 
b. Less than daily/more than weekly 
c. Weekly 
d. Less than weekly/more than monthly 
e. Monthly 
f. Less than monthly/more than yearly 
g. Yearly 
h. Less than yearly 
i. 
Never 
 
B. Were you wearing hearing protection when this occurred?  
 
Never          Rarely          Sometimes          Usually          Always 
 
C. How many years did you work in a non-police officer/non-military job where you had to shout to be heard? 
____________________________________ 
 

 
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Noise Exposure Group Assignment Based on Interview Questions  
 
Participants with a response to 1.A., 2.A., or 3.A. of monthly or more frequent exposure are assigned to the 
higher noise group. Participants with less than monthly exposure are assigned to the lower noise group. 
 
Participants with a response to 1.C., 2.C, or 4.C. of 5 years or more are assigned to the Higher Noise group. 
 
 
 
 
 

 
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APPENDIX H: Questionnaire 5: 1-Minute Noise Screen (30-day post follow-up visit) 
 
 
1-Minute Noise Screen 
 
     ID Number: ______________________________________       Date: _____________________ 
 
 
DURING THE PAST 30 DAYS,  
 
1. How often were you around or did you shoot firearms such as rifles, pistols, shotguns, 
etc.?  
 Never      Less than weekly      Weekly      More than weekly      Daily 
 
2. How often were you exposed to loud sounds while working on a paid job? By loud 
sounds, we mean sounds so loud that you had to shout or speak in a raised voice to be 
heard at arm’s length.  
 
 Never      Less than weekly      Weekly      More than weekly      Daily 
 
3.  How often were you exposed to any other types of loud sounds, such as power tools, 
lawn equipment, or loud music? By loud sounds, we mean sounds so loud that you had 
to shout or speak in a raised voice to be heard at arm’s length.  
 
 Never      Less than weekly      Weekly      More than weekly      Daily 
 
 
 
 
Noise exposure score: __________