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

• tinnitus scales [ Time Frame: 22 days after cessation of weapons training ] [ Designated as safety issue: No ]
  Tinnitus questionnaire report of change from baseline in scores for both loudness and annoyance
• tympanic membrane function [ Time Frame: 22 days after cessation of weapons training ] [ Designated as safety issue: No ]
  tympanometry measurement report of change from baseline

This prospective study is a randomized, double-blind, placebo-controlled Phase 3 clinical trial of oral 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.

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:

1. 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).
2. 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).
3. 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).

• Drug: D-methionine, oral liquid suspension
  Two daily doses of up to 100mg/kg/day of D-met for 18 days
  Other Name: D-Met
• Other: Placebo Comparator
  Equal volume placebo.

• Placebo Comparator: Placebo
  Placebo contains sorbitol, orange flavor and purified water; is flavor and color matched to D-Met.
  Intervention: Other: Placebo Comparator
• Experimental: D-methionine, oral liquid suspension
  D-methionine liquid suspension also contains sorbitol, orange flavor and purified water
  Intervention: Drug: D-methionine, oral liquid suspension

• Campbell KC, Meech RP, Klemens JJ, Gerberi MT, Dyrstad SS, Larsen DL, Mitchell DL, El-Azizi M, Verhulst SJ, Hughes LF. Prevention of noise- and drug-induced hearing loss with D-methionine. Hear Res. 2007 Apr;226(1-2):92-103. Epub 2007 Jan 16.
• Kopke RD, Coleman JK, Liu J, Campbell KC, Riffenburgh RH. Candidate's thesis: enhancing intrinsic cochlear stress defenses to reduce noise-induced hearing loss. Laryngoscope. 2002 Sep;112(9):1515-32.
• Campbell K, Claussen A, Meech R, Verhulst S, Fox D, Hughes L. D-methionine (D-met) significantly rescues noise-induced hearing loss: timing studies. Hear Res. 2011 Dec;282(1-2):138-44. Epub 2011 Sep 6.

Inclusion Criteria:

• Negative pregnancy test confirmed by urine dipstick at enrollment and prior to taking first study drug dose
• Willing to use an effective method of birth control during the study (Female participants should avoid pregnancy and male participants should avoid fathering children during study). Subject should either abstain from sexual relations or practice a method of birth control while taking part in the study. Except for surgical removal of the uterus, birth control methods such as condoms, a diaphragm or cervical cap, birth control pills, IUD, or sperm killing products are not totally effective in preventing pregnancy. Male study participants should refrain from fathering babies while enrolled in this study.
• Pure tone air conduction threshold average (PTA) at .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
• Ability to comply with all study requirements

Exclusion Criteria:

• History of allergic reaction to methionine, amino acid mixtures, nutritional supplements, egg white, or other proteins or food additives
• Vegetarian (individual who excludes both meat and fish from their diet)
• History of 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 asymmetry in hearing worse than 25 dB at any test frequency, or central nervous system disorder that is likely to affect hearing
• Exposure in the previous 6 months to systemic ototoxic substances including aminoglycoside antibiotics, or chemotherapy with carboplatin, cisplatin, vincristine, vinblastine or difluoromethylornithine
• Any surgical or medical condition which might significantly alter the absorption, distribution, metabolism, or excretion of any drug
• Recent history of drug or alcohol abuse
• 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
• Army Reservists or National Guardsmen