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

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).

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.