Phase 3 Clinical Trial: D-methionine to Reduce Noise-Induced Hearing Loss (NIHL)

Study Overview
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Brief Summary
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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
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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).

Official Title
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Phase 3 Clinical Trial: D-methionine to Reduce Noise-Induced Hearing Loss (NIHL)

Conditions
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Noise-induced Hearing Loss

Intervention / Treatment
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* Drug: D-methionine
* Drug: Placebo


Participation Criteria
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Eligibility Criteria
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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.

Ages Eligible for Study
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Minimum Age: 21 Years
Maximum Age: 45 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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Accepts Healthy Volunteers

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Prevention
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Placebo Comparator: Placebo<br>Placebo contains sorbitol, orange flavor and purified water; is flavor and color matched to D-Met. | Drug: Placebo<br>* Placebo contains sorbitol, orange flavor and purified water; is flavor and color matched to D-Met.<br>|
| Experimental: D-methionine, oral liquid suspension<br>D-methionine liquid suspension also contains sorbitol, orange flavor and purified water Intervention: Drug: D-methionine, oral liquid suspension. | Drug: D-methionine<br>* D-methionine, oral liquid suspension<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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. | Change from baseline to day 29-36 after initial administration of study drug (Day 15-22 after cessation of weapons training). | 
| 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. | Change from baseline to day 29-36 after initial administration of study drug (Day 15-22 after cessation of weapons training). | 
| 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. | Change from baseline to day 29-36 after initial administration of study drug (Day 15-22 after cessation of weapons training). | 
| 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. | Change from baseline to day 29-36 after initial administration of study drug (Day 15-22 after cessation of weapons training). | 
| 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. | Change from baseline to day 29-36 after initial administration of study drug (Day 15-22 after cessation of weapons training). | 
| 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. | Change from baseline to day 29-36 after initial administration of study drug (Day 15-22 after cessation of weapons training). | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| 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. | Change from baseline to day 29-36 after initial administration of study drug (Day 15-22 after cessation of weapons training). | 
| 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. | Change from baseline to day 29-36 after initial administration of study drug (Day 15-22 after cessation of weapons training). | 
| 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. | Change from baseline to day 29-36 after initial administration of study drug (Day 15-22 after cessation of weapons training). | 
| 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) | Change from baseline to day 29-36 after initial administration of study drug (Day 15-22 after cessation of weapons training). |