Noise-induced Hearing Loss
Conditions
Brief summary
This prospective study is a randomized, double-blind, placebo-controlled Phase 3 clinical trial of oral D-methionine (D-met) to reduce noise-induced hearing loss (NIHL) and tinnitus. The goal of the study is to develop a safe, oral pharmacological agent to augment physical hearing protectors for noise exposures that exceed the protective capabilities of ear plugs and/or muffs. The study population is a cohort of Drill Sergeant (DS) instructor trainees during and 22 days after their 11 day weapons training. The primary objective of this study is to determine the efficacy of D-met in preventing NIHL or reducing tinnitus secondary to a minimum of 500 rounds of M-16 weapons training occurring over an 11 day period.
Detailed description
Hearing loss can render a soldier less able to detect and identify the enemy, less able to understand commands, particularly in background noise typical on the battlefield, and may permanently reduce quality of life. In some cases, hearing loss may preclude redeployment or result in less optimal job assignment. Currently, no FDA approved pharmacological prevention exists for noise-induced hearing loss (NIHL). We have documented in animal studies that administration of D-methionine (D-met) can reduce or prevent NIHL. We now need to determine if it has similar efficacy in humans. Although we have not yet tested D-met on protection from noise-induced tinnitus in animals, this clinical trial would provide us the opportunity to also test for protection from noise induced tinnitus simultaneously. Objective Hypotheses: Primary Hypothesis: Administration of oral D-methionine prior to, during and 4 days post-weapons training will reduce or prevent permanent noise-induced hearing loss. Secondary Hypothesis: Administration of oral D-methionine prior to, during and 4 days post-weapons training will reduce or prevent noise-induced tinnitus. Specific Aims: To determine whether administering oral D-met can prevent permanent NIHL after weapons training. This aim will be addressed by comparing the results of D-met versus placebo administration starting 3 days prior to, during the 11 day period of weapons training (Monday-Friday for first week, Monday-Thursday for second week), and 4 days after for a total of 18 days. Pure tone hearing thresholds will be assessed before and 22 days after completion of weapons training (ie; 18 days after the last day of study drug/placebo administration). To determine whether administering oral D-met can prevent tinnitus after weapons training. This aim will be addressed by comparing the results of D-met versus placebo administration starting 3 days prior to, during the 11 day period of weapons training (Monday-Friday for first week, Monday-Thursday for second week), and 4 days after for a total of 18 days. Tinnitus questionnaires will be assessed before and 22 days after completion of weapons training (ie; 18 days after the last day of study drug/placebo administration). To monitor for any potential side effects of D-met in human subjects. This aim will be accomplished by subject query on each day study drug is dispensed (twice daily) and at final study visit, routing of any adverse event reports to study medical personnel, statisticians and to the Food and Drug Administration (FDA).
Interventions
DRUGD-methionine
D-methionine, oral liquid suspension
DRUGPlacebo
Placebo contains sorbitol, orange flavor and purified water; is flavor and color matched to D-Met.
Sponsors
Southern Illinois University
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
PREVENTION
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
Eligibility
Sex/Gender
ALL
Age
21 Years to 45 Years
Healthy volunteers
Yes
Inclusion criteria
Male or female 21 to 45 years of age Negative pregnancy test at enrollment and prior to taking study drug Willing to use an effective method of birth control during the study (Both male and female participants should avoid pregnancy during study) Pure tone air conduction threshold average at 0.5, 1 and 2 kHz of no greater than 40 dB HL bilaterally with no air bone gaps greater than 10 dB and normal otoscopy and tympanometry screens Willing to refrain from using supplements containing or derived from protein while participating in this study Ability to comply with all study requirements
Exclusion criteria
History of allergic or idiosyncratic reaction to methionine, amino acid mixtures, nutritional supplements, egg white, or other proteins or food additives Vegetarian (Individual excludes meat and fish from their diet) History of chronic balance disorders Abnormal otoscopic findings, otologic surgery, autoimmune inner ear disease, significant air-bone gaps, abnormal tympanograms or other indication of middle-ear abnormality, history of fluctuant hearing or asymmetric hearing worse than 25 dB at any frequency in either ear, perilymphatic fistula, tumor of the auditory system, or other CNS disorder that is likely to affect hearing Treatment with intravenous (IV) antibiotics within the past 6 months Any surgical or medical condition which might significantly alter the absorption, distribution, metabolism, or excretion of any drug Treatment for alcohol or substance abuse within past 6 months Women of childbearing age who are not using effective contraceptive methods and who may become pregnant during the course of the study Women who are pregnant or breastfeeding. National Guardsmen History of psychotic schizophrenia Exposure within the previous 6 months to systemic ototoxic substances including aminoglycosides or vancomycin Body weight exceeding 225 pounds Renal impairment measured as eGFR \< 50 on screening creatinine clearance blood draw.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| ASHA Shift Ear (Non-Trigger Hand) | Change from baseline to day 29-36 after initial administration of study drug (Day 15-22 after cessation of weapons training). | An increase of at least 20 dB at any one frequency, An increase of at least 10 dB at any two consecutive frequencies, or Loss of response at 3 consecutive frequencies where responses were obtained at baseline. |
| ASHA Shift Ear (Right) | Change from baseline to day 29-36 after initial administration of study drug (Day 15-22 after cessation of weapons training). | An increase of at least 20 dB at any one frequency, An increase of at least 10 dB at any two consecutive frequencies, or Loss of response at 3 consecutive frequencies where responses were obtained at baseline. |
| ASHA Shift Ear (Either) | Change from baseline to day 29-36 after initial administration of study drug (Day 15-22 after cessation of weapons training). | An increase of at least 20 dB at any one frequency, An increase of at least 10 dB at any two consecutive frequencies, or Loss of response at 3 consecutive frequencies where responses were obtained at baseline. |
| ASHA Shift Ear (Both) | Change from baseline to day 29-36 after initial administration of study drug (Day 15-22 after cessation of weapons training). | An increase of at least 20 dB at any one frequency, An increase of at least 10 dB at any two consecutive frequencies, or Loss of response at 3 consecutive frequencies where responses were obtained at baseline. |
| ASHA Shift Ear (Trigger Hand) | Change from baseline to day 29-36 after initial administration of study drug (Day 15-22 after cessation of weapons training). | An increase of at least 20 dB at any one frequency, An increase of at least 10 dB at any two consecutive frequencies, or Loss of response at 3 consecutive frequencies where responses were obtained at baseline. |
| ASHA Shift Ear (Left) | Change from baseline to day 29-36 after initial administration of study drug (Day 15-22 after cessation of weapons training). | An increase of at least 20 dB at any one frequency, An increase of at least 10 dB at any two consecutive frequencies, or Loss of response at 3 consecutive frequencies where responses were obtained at baseline. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| EWS STS Shift | Change from baseline to day 29-36 after initial administration of study drug (Day 15-22 after cessation of weapons training). | Greater than or equal to 15 dB change (deficit) in any of the following frequencies in either ear (1k or 2k or 3k or 4k). This is a binary outcome measure based on meeting this definition. |
| Total THI Score Change | Change from baseline to day 29-36 after initial administration of study drug (Day 15-22 after cessation of weapons training). | Tinnitus Handicap Inventory. Tinnitus handicap inventory designed to evaluate the difficulties experienced as a result of hearing loss. Score ranges from 0 to 100 with 0 indicating no handicap, and 100 indicating catastrophic handicap. The THI score was to compare pre and post treatment effects of hearing loss. |
| Significant Change in Tinnitus | Change from baseline to day 29-36 after initial administration of study drug (Day 15-22 after cessation of weapons training). | An increase of at least 5 points in the Tinnitus Handicap Inventory (THI), AND an increase in one severity grade category (Categories listed below). Tinnitus handicap inventory is designed to evaluate the difficulties experienced as a result of hearing loss. Score ranges from 0 to 100, with 0 indicating no handicap, and 100 indicating catastrophic handicap. The THI score was to compare pre and post treatment effects of hearing loss. 0-16: Slight or no handicap (Grade 1) 18-36: Mild handicap (Grade 2) 38-56: Moderate handicap (Grade 3) 58-76: Severe handicap (Grade 4) 78-100: Catastrophic handicap (Grade 5) |
| DOEHRSHC Shift | Change from baseline to day 29-36 after initial administration of study drug (Day 15-22 after cessation of weapons training). | Greater than or equal to 10 dB change for the average of 2k, 3k, and 4k in either ear. This is a binary outcome measure based on meeting this definition. |
Countries
United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Placebo Placebo contains sorbitol, orange flavor and purified water; is flavor and color matched to D-Met.
Placebo: Placebo contains sorbitol, orange flavor and purified water; is flavor and color matched to D-Met. | 142 |
| D-methionine, Oral Liquid Suspension D-methionine liquid suspension also contains sorbitol, orange flavor and purified water Intervention: Drug: D-methionine, oral liquid suspension.
D-methionine: D-methionine, oral liquid suspension | 124 |
| Total | 266 |
Baseline characteristics
| Characteristic | D-methionine, Oral Liquid Suspension | Placebo | 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 | 124 Participants | 142 Participants | 266 Participants |
| Age, Continuous | 31.01 years STANDARD_DEVIATION 4.35 | 30.34 years STANDARD_DEVIATION 4.01 | 30.65 years STANDARD_DEVIATION 4.18 |
| Race/Ethnicity, Customized American Indian or Alaska Native | 0 Participants | 1 Participants | 1 Participants |
| Race/Ethnicity, Customized Asian or Native Hawaiian or Pacific Islander | 4 Participants | 4 Participants | 8 Participants |
| Race/Ethnicity, Customized Black or African American | 17 Participants | 18 Participants | 35 Participants |
| Race/Ethnicity, Customized Hispanic | 29 Participants | 32 Participants | 61 Participants |
| Race/Ethnicity, Customized More than on race | 0 Participants | 1 Participants | 1 Participants |
| Race/Ethnicity, Customized Unknown or not Reported | 1 Participants | 2 Participants | 3 Participants |
| Race/Ethnicity, Customized White | 73 Participants | 84 Participants | 157 Participants |
| Region of Enrollment United States | 124 participants | 142 participants | 266 participants |
| Sex: Female, Male Female | 27 Participants | 34 Participants | 61 Participants |
| Sex: Female, Male Male | 97 Participants | 108 Participants | 205 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 0 / 159 | 0 / 157 |
| other Total, other adverse events | 93 / 159 | 120 / 157 |
| serious Total, serious adverse events | 0 / 159 | 0 / 157 |
Outcome results
Primary
ASHA Shift Ear (Both)
An increase of at least 20 dB at any one frequency, An increase of at least 10 dB at any two consecutive frequencies, or Loss of response at 3 consecutive frequencies where responses were obtained at baseline.
Time frame: Change from baseline to day 29-36 after initial administration of study drug (Day 15-22 after cessation of weapons training).
Population: 7 and 7 participants in the placebo and D-methionine arms, respectively, failed a final tympanogram screen in either ear to rule out middle ear pathology as a cause of the hearing loss and were excluded from the analysis for this outcome.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Placebo | ASHA Shift Ear (Both) | 3 Participants |
| D-methionine, Oral Liquid Suspension | ASHA Shift Ear (Both) | 1 Participants |
p-value: 0.3666Fisher Exact
Primary
ASHA Shift Ear (Either)
An increase of at least 20 dB at any one frequency, An increase of at least 10 dB at any two consecutive frequencies, or Loss of response at 3 consecutive frequencies where responses were obtained at baseline.
Time frame: Change from baseline to day 29-36 after initial administration of study drug (Day 15-22 after cessation of weapons training).
Population: 7 and 7 participants in the placebo and D-methionine arms, respectively, failed a final tympanogram screen in either ear to rule out middle ear pathology as a cause of the hearing loss and were excluded from the analysis for this outcome.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Placebo | ASHA Shift Ear (Either) | 21 Participants |
| D-methionine, Oral Liquid Suspension | ASHA Shift Ear (Either) | 18 Participants |
p-value: 0.5441Fisher Exact
Primary
ASHA Shift Ear (Left)
An increase of at least 20 dB at any one frequency, An increase of at least 10 dB at any two consecutive frequencies, or Loss of response at 3 consecutive frequencies where responses were obtained at baseline.
Time frame: Change from baseline to day 29-36 after initial administration of study drug (Day 15-22 after cessation of weapons training).
Population: 5 and 3 participants in the placebo and D-methionine arms, respectively, failed a final tympanogram screen in the left ear to rule out middle ear pathology as a cause of the hearing loss and were excluded from the analysis for this outcome.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Placebo | ASHA Shift Ear (Left) | 12 Participants |
| D-methionine, Oral Liquid Suspension | ASHA Shift Ear (Left) | 9 Participants |
p-value: 0.4385Fisher Exact
Primary
ASHA Shift Ear (Non-Trigger Hand)
An increase of at least 20 dB at any one frequency, An increase of at least 10 dB at any two consecutive frequencies, or Loss of response at 3 consecutive frequencies where responses were obtained at baseline.
Time frame: Change from baseline to day 29-36 after initial administration of study drug (Day 15-22 after cessation of weapons training).
Population: 5 and 3 participants in the placebo and D-methionine arms, respectively, failed a final tympanogram screen in the non-trigger hand ear to rule out middle ear pathology as a cause of the hearing loss and were excluded from the analysis for this outcome.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Placebo | ASHA Shift Ear (Non-Trigger Hand) | 13 Participants |
| D-methionine, Oral Liquid Suspension | ASHA Shift Ear (Non-Trigger Hand) | 11 Participants |
p-value: 0.5431Fisher Exact
Primary
ASHA Shift Ear (Right)
An increase of at least 20 dB at any one frequency, An increase of at least 10 dB at any two consecutive frequencies, or Loss of response at 3 consecutive frequencies where responses were obtained at baseline.
Time frame: Change from baseline to day 29-36 after initial administration of study drug (Day 15-22 after cessation of weapons training).
Population: 3 and 4 participants in the placebo and D-methionine arms, respectively, failed a final tympanogram screen in the right ear to rule out middle ear pathology as a cause of the hearing loss and were excluded from the analysis for this outcome.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Placebo | ASHA Shift Ear (Right) | 12 Participants |
| D-methionine, Oral Liquid Suspension | ASHA Shift Ear (Right) | 10 Participants |
p-value: 0.5562Fisher Exact
Primary
ASHA Shift Ear (Trigger Hand)
An increase of at least 20 dB at any one frequency, An increase of at least 10 dB at any two consecutive frequencies, or Loss of response at 3 consecutive frequencies where responses were obtained at baseline.
Time frame: Change from baseline to day 29-36 after initial administration of study drug (Day 15-22 after cessation of weapons training).
Population: 3 and 4 participants in the placebo and D-methionine arms, respectively, failed a final tympanogram screen in the trigger hand ear to rule out middle ear pathology as a cause of the hearing loss and were excluded from the analysis for this outcome.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Placebo | ASHA Shift Ear (Trigger Hand) | 11 Participants |
| D-methionine, Oral Liquid Suspension | ASHA Shift Ear (Trigger Hand) | 8 Participants |
p-value: 0.4446Fisher Exact
Secondary
DOEHRSHC Shift
Greater than or equal to 10 dB change for the average of 2k, 3k, and 4k in either ear. This is a binary outcome measure based on meeting this definition.
Time frame: Change from baseline to day 29-36 after initial administration of study drug (Day 15-22 after cessation of weapons training).
Population: 0 and 1 participants in the placebo and D-methionine arms, respectively, failed a final tympanogram screen in both ears to rule out middle ear pathology as a cause of the hearing loss and were excluded from the analysis for this outcome.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Placebo | DOEHRSHC Shift | 2 Participants |
| D-methionine, Oral Liquid Suspension | DOEHRSHC Shift | 2 Participants |
p-value: 0.7409Fisher Exact
Secondary
EWS STS Shift
Greater than or equal to 15 dB change (deficit) in any of the following frequencies in either ear (1k or 2k or 3k or 4k). This is a binary outcome measure based on meeting this definition.
Time frame: Change from baseline to day 29-36 after initial administration of study drug (Day 15-22 after cessation of weapons training).
Population: 0 and 1 participants in the placebo and D-methionine arms, respectively, failed a final tympanogram screen in both ears to rule out middle ear pathology as a cause of the hearing loss and were excluded from the analysis for this outcome.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Placebo | EWS STS Shift | 11 Participants |
| D-methionine, Oral Liquid Suspension | EWS STS Shift | 5 Participants |
p-value: 0.1597Fisher Exact
Secondary
Significant Change in Tinnitus
An increase of at least 5 points in the Tinnitus Handicap Inventory (THI), AND an increase in one severity grade category (Categories listed below). Tinnitus handicap inventory is designed to evaluate the difficulties experienced as a result of hearing loss. Score ranges from 0 to 100, with 0 indicating no handicap, and 100 indicating catastrophic handicap. The THI score was to compare pre and post treatment effects of hearing loss. 0-16: Slight or no handicap (Grade 1) 18-36: Mild handicap (Grade 2) 38-56: Moderate handicap (Grade 3) 58-76: Severe handicap (Grade 4) 78-100: Catastrophic handicap (Grade 5)
Time frame: Change from baseline to day 29-36 after initial administration of study drug (Day 15-22 after cessation of weapons training).
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Placebo | Significant Change in Tinnitus | 4 Participants |
| D-methionine, Oral Liquid Suspension | Significant Change in Tinnitus | 1 Participants |
p-value: 0.2303Fisher Exact
Secondary
Total THI Score Change
Tinnitus Handicap Inventory. Tinnitus handicap inventory designed to evaluate the difficulties experienced as a result of hearing loss. Score ranges from 0 to 100 with 0 indicating no handicap, and 100 indicating catastrophic handicap. The THI score was to compare pre and post treatment effects of hearing loss.
Time frame: Change from baseline to day 29-36 after initial administration of study drug (Day 15-22 after cessation of weapons training).
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Placebo | Total THI Score Change | .169 units on a scale | Standard Deviation 5.3022 |
| D-methionine, Oral Liquid Suspension | Total THI Score Change | -.1452 units on a scale | Standard Deviation 3.2876 |
p-value: 0.2784t-test, 1 sided