Hearing Loss, Noise-Induced
Conditions
Brief summary
The purpose of this study is to assess the safety and efficacy of zonisamide (ZNS) for the treatment of noise-induced hearing loss in adults.
Detailed description
This is a randomized, double-blind, and placebo-controlled study is to test whether zonisamide (ZNS) can treat noise-induced hearing loss in police officers on the range following training and certifications sessions. Participants who meet the eligibility requirements will be randomized to receive either ZNS 100 milligrams (mg) or placebo. 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. After being informed about the study expectations and potential risks, all individuals providing written informed consent will undergo screening to determine eligibility for study entry.
Interventions
ZONEGRAN® is commercially available for oral administration as capsules containing 100 mg of Zonisamide.
DRUGPlacebo
The placebo will contain microcrystalline cellulose which is the predominant filler in the generic capsule.
Sponsors
Washington University School of Medicine
United States Department of Defense
University of Texas
Gateway Biotechnology, Inc.
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
PREVENTION
Masking
TRIPLE (Subject, Investigator, Outcomes Assessor)
Masking description
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 drug packets and will seal the envelopes, and the programmer not involved with the study who will produce the random treatment assignments and print the labels will know the order of treatments for any subject. An independent medical professional who is not part of the study team will complete the de-identification of the study drug, and a procedure and documentation log will be in place for quality assurance purposes. The ZNS and placebo capsules will look, taste, and smell the same.
Intervention model description
Randomized, double-blind, and placebo-controlled
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
Yes
Inclusion criteria
Screening Inclusion Criteria: * Police officers who are scheduled for firearm training and/or certification on the range. * At least 18 years of age. * 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. * Ability to understand and willingness to sign an IRB approved written informed consent document. Enrollment Inclusion Criteria: * Observed audiometric TTS ≥ 10 dB HL at 2, 3, 4 and/or 6 kHz * Observed air-bone gap \< 10 dB HL at .5, 1, 2 and 4 kHz, with normal tympanometry
Exclusion criteria
* History of known sulfa allergy or hypersensitivity to carbonic anhydrase inhibitors. * History of moderate-to-severe kidney or liver disease. * Acute viral, bacterial, fungal or parasitic infection. * History of seizures. * Currently pregnant or breast-feeding. * Any current or history of otologic disorder. * History of ototoxic drug use. * Current use of strong/moderate 3A4 inhibitor/inducer and grapefruit juice. * For secondary outcomes,
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Proportion of Officers With Permanent Threshold Shift (PTS) | 30 days (+/- 3 days) after training | 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. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Distortion Product Otoacoustic Emissions (DPOAE) | baseline (before shooting), 30 days (+/-3 days) after training | DPOAE amplitudes are measured to determine threshold shifts. A change is noted in DPOAE amplitude at any frequency that is significantly greater than the stability of each measurement (i.e., 95% confidence interval of each measurement do not overlap). |
| Ultra-high Frequency Audiometry | baseline (before shooting), within 5-10 minutes after shooting and 30 days (+/-3 days) after training | Number of participants that experience a change in ultra-high frequencies greater than 5 dB; to measure for both temporary and permanent high frequency audiometric changes. A significant change is defined for any frequency that is greater than 5 dB HL from baseline thresholds. |
| Electrocochleography (ECochG) AP Amplitude | baseline (before shooting) and 30 days (+/-3 days) after training | To measure for changes in ECochG AP amplitude between baseline (before training) visit and 30-days after training visits. |
| Change in Words In Noise (WIN) Test Signal-to-Noise Ratio Threshold | baseline (before shooting) and 30 days (+/-3 days) after training | 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 WIN score 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. Reported information is the change in score between baseline testing and testing 30 days after training. This measure assesses the change in signal-to-noise ratio (SNR) threshold, reported in decibels SNR (dB SNR), at which a participant correctly identifies 50% of the words presented in background noise. |
| Electrocochleography (ECochG) Latency | baseline (before shooting) and 30 days (+/-3 days) after training | To measure for changes in ECochG latency between baseline (before training) visit and 30-days after training visits. |
| Electrocochleography (ECochG) Width | baseline (before shooting) and 30 days (+/-3 days) after training | To measure for changes in ECochG width between baseline (before training) visit and 30-days after training visits. |
| Determine PGx Link Between Noise Induced Hearing Loss (NIHL) and Zonisamide (ZNS) | Baseline prior to training | Exploratory analysis to determine a pharmacogenetic link between noise induced hearing loss (NIHL) and zonisamide (ZNS) treatment effect. |
Countries
United States
Contacts
PRINCIPAL_INVESTIGATORCraig A Buchman, MD, FACS
Washington University School of Medicine
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Zonisamide For subjects randomized to zonisamide, the package will contain one zonisamide capsule (100 mg PO).
Zonisamide 100Mg Cap: ZONEGRAN® is commercially available for oral administration as capsules containing 100 mg of Zonisamide. | 1 |
| Placebo For the subjects randomized to placebo, the package will contain one placebo capsule that looks, smells, and taste the same as zonisamide capsule.
Placebo: The placebo will contain microcrystalline cellulose which is the predominant filler in the generic capsule. | 2 |
| Total | 3 |
Baseline characteristics
| Characteristic | Placebo | Zonisamide | Total |
|---|---|---|---|
| Age, Categorical <=18 years | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical >=65 years | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical Between 18 and 65 years | 2 Participants | 1 Participants | 3 Participants |
| Age, Continuous | 37 years STANDARD_DEVIATION 6 | 44 years STANDARD_DEVIATION 0 | 39 years STANDARD_DEVIATION 5.9 |
| Ethnicity (NIH/OMB) Hispanic or Latino | 0 Participants | 0 Participants | 0 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 2 Participants | 1 Participants | 3 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Black or African American | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) White | 2 Participants | 1 Participants | 3 Participants |
| Region of Enrollment United States | 2 participants | 1 participants | 3 participants |
| Sex: Female, Male Female | 0 Participants | 0 Participants | 0 Participants |
| Sex: Female, Male Male | 2 Participants | 1 Participants | 3 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 0 / 1 | 0 / 2 |
| other Total, other adverse events | 0 / 1 | 0 / 2 |
| serious Total, serious adverse events | 0 / 1 | 0 / 2 |
Outcome results
Primary
Proportion of Officers With Permanent Threshold Shift (PTS)
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.
Time frame: 30 days (+/- 3 days) after training
Population: The study was prematurely terminated. Due to the very low number of subjects in each study group there was no statistical analysis performed; no statistical test, p-value, or parameter estimation can be reported.
| Arm | Measure | Category | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Zonisamide | Proportion of Officers With Permanent Threshold Shift (PTS) | PTS-positive participants | 0 Participants |
| Zonisamide | Proportion of Officers With Permanent Threshold Shift (PTS) | PTS-negative participants | 1 Participants |
| Placebo | Proportion of Officers With Permanent Threshold Shift (PTS) | PTS-positive participants | 1 Participants |
| Placebo | Proportion of Officers With Permanent Threshold Shift (PTS) | PTS-negative participants | 1 Participants |
Secondary
Change in Words In Noise (WIN) Test Signal-to-Noise Ratio Threshold
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 WIN score 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. Reported information is the change in score between baseline testing and testing 30 days after training. This measure assesses the change in signal-to-noise ratio (SNR) threshold, reported in decibels SNR (dB SNR), at which a participant correctly identifies 50% of the words presented in background noise.
Time frame: baseline (before shooting) and 30 days (+/-3 days) after training
Population: The study was prematurely terminated. Due to the very low number of subjects in each study group there was no statistical analysis performed; no statistical test, p-value, or parameter estimation can be reported.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Zonisamide | Change in Words In Noise (WIN) Test Signal-to-Noise Ratio Threshold | -0.267 dB SNR | Standard Deviation 0 |
| Placebo | Change in Words In Noise (WIN) Test Signal-to-Noise Ratio Threshold | 1.933 dB SNR | Standard Deviation 0.66 |
Secondary
Distortion Product Otoacoustic Emissions (DPOAE)
DPOAE amplitudes are measured to determine threshold shifts. A change is noted in DPOAE amplitude at any frequency that is significantly greater than the stability of each measurement (i.e., 95% confidence interval of each measurement do not overlap).
Time frame: baseline (before shooting), 30 days (+/-3 days) after training
Population: Each participant's left and right ears were analyzed for threshold shifts at 30 days (+/- 3 days) after training.
| Arm | Measure | Category | Value (COUNT_OF_UNITS) |
|---|---|---|---|
| Zonisamide | Distortion Product Otoacoustic Emissions (DPOAE) | No Shift | 1 ears |
| Zonisamide | Distortion Product Otoacoustic Emissions (DPOAE) | Shift | 1 ears |
| Zonisamide | Distortion Product Otoacoustic Emissions (DPOAE) | Excluded | 0 ears |
| Placebo | Distortion Product Otoacoustic Emissions (DPOAE) | Excluded | 1 ears |
| Placebo | Distortion Product Otoacoustic Emissions (DPOAE) | No Shift | 0 ears |
| Placebo | Distortion Product Otoacoustic Emissions (DPOAE) | Shift | 3 ears |
Secondary
Electrocochleography (ECochG) AP Amplitude
To measure for changes in ECochG AP amplitude between baseline (before training) visit and 30-days after training visits.
Time frame: baseline (before shooting) and 30 days (+/-3 days) after training
Population: The study was prematurely terminated. Due to the very low number of subjects in each study group there was no statistical analysis performed; no statistical test, p-value, or parameter estimation can be reported.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Zonisamide | Electrocochleography (ECochG) AP Amplitude | 0.035 millivolts (mV) | Standard Deviation 0 |
| Placebo | Electrocochleography (ECochG) AP Amplitude | 0.1025 millivolts (mV) | Standard Deviation 0.159 |
Secondary
Electrocochleography (ECochG) Latency
To measure for changes in ECochG latency between baseline (before training) visit and 30-days after training visits.
Time frame: baseline (before shooting) and 30 days (+/-3 days) after training
Population: The study was prematurely terminated. Due to the very low number of subjects in each study group there was no statistical analysis performed; no statistical test, p-value, or parameter estimation can be reported.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Zonisamide | Electrocochleography (ECochG) Latency | 0.105 milliseconds (ms) | Standard Deviation 0 |
| Placebo | Electrocochleography (ECochG) Latency | -0.053 milliseconds (ms) | Standard Deviation 0.046 |
Secondary
Electrocochleography (ECochG) Width
To measure for changes in ECochG width between baseline (before training) visit and 30-days after training visits.
Time frame: baseline (before shooting) and 30 days (+/-3 days) after training
Population: The study was prematurely terminated. Due to the very low number of subjects in each study group there was no statistical analysis performed; no statistical test, p-value, or parameter estimation can be reported.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Zonisamide | Electrocochleography (ECochG) Width | 0.295 milliseconds (ms) | Standard Deviation 0 |
| Placebo | Electrocochleography (ECochG) Width | 0.030 milliseconds (ms) | Standard Deviation 0.028 |
Secondary
Ultra-high Frequency Audiometry
Number of participants that experience a change in ultra-high frequencies greater than 5 dB; to measure for both temporary and permanent high frequency audiometric changes. A significant change is defined for any frequency that is greater than 5 dB HL from baseline thresholds.
Time frame: baseline (before shooting), within 5-10 minutes after shooting and 30 days (+/-3 days) after training
Population: The study was prematurely terminated. Due to the very low number of subjects in each study group there was no statistical analysis performed; no statistical test, p-value, or parameter estimation can be reported.
| Arm | Measure | Category | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Zonisamide | Ultra-high Frequency Audiometry | Experienced a change in ultra-high frequencies greater than 5 dB | 1 Participants |
| Zonisamide | Ultra-high Frequency Audiometry | Did not experience a change in ultra-high frequencies greater than 5 dB | 0 Participants |
| Placebo | Ultra-high Frequency Audiometry | Experienced a change in ultra-high frequencies greater than 5 dB | 2 Participants |
| Placebo | Ultra-high Frequency Audiometry | Did not experience a change in ultra-high frequencies greater than 5 dB | 0 Participants |