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

• Sponsor: Southern Illinois University (Other)
• Overall Status: Terminated
• CT.gov ID: NCT02903355
• Collaborator: (none)
• Enrollment: 351
• Location: 1
• Arms: 2
• Duration (Months): 51
• Patients Per Site Per Month: 6.9

Study Details

Study Description

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.

Condition or Disease	Intervention/Treatment	Phase
Noise-induced Hearing Loss	Drug: D-methionine; Drug: Placebo	Phase 3

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).

Study Design

• Study Type: Interventional
• Actual Enrollment: 351 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
• Primary Purpose: Prevention
• Official Title: Phase 3 Clinical Trial: D-methionine to Reduce Noise-Induced Hearing Loss (NIHL)
• Study Start Date: Sep 1, 2013
• Actual Primary Completion Date: Dec 1, 2017
• Actual Study Completion Date: Dec 1, 2017

Arms and Interventions

Arm	Intervention/Treatment
Placebo Comparator: Placebo Placebo contains sorbitol, orange flavor and purified water; is flavor and color matched to D-Met.	Drug: Placebo; Placebo contains sorbitol, orange flavor and purified water; is flavor and color matched to D-Met.
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.	Drug: D-methionine; D-methionine, oral liquid suspension

Outcome Measures

Primary Outcome Measures

1. 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.

2. 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.

3. 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.

4. 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.

5. 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.

6. 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.

Secondary Outcome Measures

1. 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.

2. 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.

3. 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.

4. 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)

Eligibility Criteria

Criteria

• Ages Eligible for Study: 21 Years to 45 Years
• Sexes Eligible for Study: All
• Accepts 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.

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Moncrief Army Community Hospital	Fort Jackson	South Carolina	United States	29207

Sponsors and Collaborators

• Southern Illinois University

Investigators

• Principal Investigator: Kathleen Campbell, PhD, MetArmor, Inc.
• Study Director: CPT William Grimes, MD, United States Department of Defense, US Army Ft. Jackson, South Carolina

Study Documents (Full-Text)

• Study Protocol and Statistical Analysis Plan - Mar 23, 2016

More Information

Publications

None provided.

• Responsible Party: Southern Illinois University
• ClinicalTrials.gov Identifier: NCT02903355
• Other Study ID Numbers: 01345474; NCT01345474
• First Posted: Sep 16, 2016
• Last Update Posted: Jun 28, 2022
• Last Verified: Jun 1, 2022

• Individual Participant Data (IPD) Sharing Statement: No
• Plan to Share IPD: No
• Additional relevant MeSH terms: Hearing Loss; Deafness; Hearing Loss, Noise-Induced

Study Results

Participant Flow

Arm/Group Title	Placebo	D-methionine, Oral Liquid Suspension
Arm/Group Description	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.	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
Period Title: Overall Study
STARTED	186	165
COMPLETED	142	124
NOT COMPLETED	44	41

Baseline Characteristics

Arm/Group Title	Placebo	D-methionine, Oral Liquid Suspension	Total
Arm/Group Description	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.	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	Total of all reporting groups
Overall Participants	142	124	266
Age (Count of Participants)
<=18 years	0 0%	0 0%	0 0%
Between 18 and 65 years	142 100%	124 100%	266 100%
>=65 years	0 0%	0 0%	0 0%
Age (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	30.34 (4.01)	31.01 (4.35)	30.65 (4.18)
Sex: Female, Male (Count of Participants)
Female	34 23.9%	27 21.8%	61 22.9%
Male	108 76.1%	97 78.2%	205 77.1%
Race/Ethnicity, Customized (Count of Participants)
American Indian or Alaska Native	1 0.7%	0 0%	1 0.4%
Hispanic	32 22.5%	29 23.4%	61 22.9%
Asian or Native Hawaiian or Pacific Islander	4 2.8%	4 3.2%	8 3%
Black or African American	18 12.7%	17 13.7%	35 13.2%
White	84 59.2%	73 58.9%	157 59%
More than on race	1 0.7%	0 0%	1 0.4%
Unknown or not Reported	2 1.4%	1 0.8%	3 1.1%
Region of Enrollment (participants) [Number]
United States	142 100%	124 100%	266 100%

Outcome Measures

1. Primary Outcome

Title	ASHA Shift Ear (Left)
Description	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).

Outcome Measure Data

Analysis Population Description

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/Group Title	Placebo	D-methionine, Oral Liquid Suspension
Arm/Group Description	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.	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
Measure Participants	137	121
Count of Participants [Participants]	12 8.5%	9 7.3%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Placebo, D-methionine, Oral Liquid Suspension
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	.4385
	Comments
	Method	Fisher Exact
	Comments

2. Primary Outcome

Title	ASHA Shift Ear (Right)
Description	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).

Outcome Measure Data

Analysis Population Description

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/Group Title	Placebo	D-methionine, Oral Liquid Suspension
Arm/Group Description	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.	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
Measure Participants	139	120
Count of Participants [Participants]	12 8.5%	10 8.1%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Placebo, D-methionine, Oral Liquid Suspension
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	.5562
	Comments
	Method	Fisher Exact
	Comments

3. Primary Outcome

Title	ASHA Shift Ear (Either)
Description	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).

Outcome Measure Data

Analysis Population Description

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/Group Title	Placebo	D-methionine, Oral Liquid Suspension
Arm/Group Description	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.	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
Measure Participants	135	117
Count of Participants [Participants]	21 14.8%	18 14.5%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Placebo, D-methionine, Oral Liquid Suspension
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	.5441
	Comments
	Method	Fisher Exact
	Comments

4. Primary Outcome

Title	ASHA Shift Ear (Both)
Description	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).

Outcome Measure Data

Analysis Population Description

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/Group Title	Placebo	D-methionine, Oral Liquid Suspension
Arm/Group Description	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.	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
Measure Participants	135	117
Count of Participants [Participants]	3 2.1%	1 0.8%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Placebo, D-methionine, Oral Liquid Suspension
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	.3666
	Comments
	Method	Fisher Exact
	Comments

5. Primary Outcome

Title	ASHA Shift Ear (Trigger Hand)
Description	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).

Outcome Measure Data

Analysis Population Description

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/Group Title	Placebo	D-methionine, Oral Liquid Suspension
Arm/Group Description	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.	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
Measure Participants	139	120
Count of Participants [Participants]	11 7.7%	8 6.5%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Placebo, D-methionine, Oral Liquid Suspension
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	.4446
	Comments
	Method	Fisher Exact
	Comments

6. Primary Outcome

Title	ASHA Shift Ear (Non-Trigger Hand)
Description	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).

Outcome Measure Data

Analysis Population Description

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/Group Title	Placebo	D-methionine, Oral Liquid Suspension
Arm/Group Description	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.	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
Measure Participants	137	121
Count of Participants [Participants]	13 9.2%	11 8.9%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Placebo, D-methionine, Oral Liquid Suspension
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	.5431
	Comments
	Method	Fisher Exact
	Comments

7. Secondary Outcome

Title	DOEHRSHC Shift
Description	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).

Outcome Measure Data

Analysis Population Description

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/Group Title	Placebo	D-methionine, Oral Liquid Suspension
Arm/Group Description	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.	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
Measure Participants	142	123
Count of Participants [Participants]	2 1.4%	2 1.6%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Placebo, D-methionine, Oral Liquid Suspension
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	.7409
	Comments
	Method	Fisher Exact
	Comments

8. Secondary Outcome

Title	EWS STS Shift
Description	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).

Outcome Measure Data

Analysis Population Description

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/Group Title	Placebo	D-methionine, Oral Liquid Suspension
Arm/Group Description	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.	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
Measure Participants	142	123
Count of Participants [Participants]	11 7.7%	5 4%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Placebo, D-methionine, Oral Liquid Suspension
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	.1597
	Comments
	Method	Fisher Exact
	Comments

9. Secondary Outcome

Title	Total THI Score Change
Description	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).

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Placebo	D-methionine, Oral Liquid Suspension
Arm/Group Description	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.	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
Measure Participants	142	124
Mean (Standard Deviation) [units on a scale]	.169 (5.3022)	-.1452 (3.2876)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Placebo, D-methionine, Oral Liquid Suspension
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	.2784
	Comments
	Method	t-test, 1 sided
	Comments

10. Secondary Outcome

Title	Significant Change in Tinnitus
Description	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).

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Placebo	D-methionine, Oral Liquid Suspension
Arm/Group Description	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.	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
Measure Participants	142	124
Count of Participants [Participants]	4 2.8%	1 0.8%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Placebo, D-methionine, Oral Liquid Suspension
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	.2303
	Comments
	Method	Fisher Exact
	Comments

Adverse Events

Time Frame	Adverse events monitored from first dose to day 36.
Adverse Event Reporting Description	The at-risk numbers presented are for those subjects that took at least one dose (D-Met or placebo). If they did not take a dose, even if they started the study, they were not considered at risk for an adverse event.
Arm/Group Title	Placebo		D-methionine, Oral Liquid Suspension
Arm/Group Description	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.		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
All Cause Mortality
	Placebo		D-methionine, Oral Liquid Suspension
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/159 (0%)		0/157 (0%)
Serious Adverse Events
	Placebo		D-methionine, Oral Liquid Suspension
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/159 (0%)		0/157 (0%)
Other (Not Including Serious) Adverse Events
	Placebo		D-methionine, Oral Liquid Suspension
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	93/159 (58.5%)		120/157 (76.4%)
Gastrointestinal disorders
Abdominal Pain/Cramps	6/159 (3.8%)		9/157 (5.7%)
Diarrhea	12/159 (7.5%)		18/157 (11.5%)
Nausea/ Vomiting	10/159 (6.3%)		27/157 (17.2%)
Nervous system disorders
Headache	9/159 (5.7%)		9/157 (5.7%)
Product Issues
Body Odor	3/159 (1.9%)		35/157 (22.3%)
Flatulence	56/159 (35.2%)		52/157 (33.1%)
Urine Odor	7/159 (4.4%)		66/157 (42%)

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

Principal Investigators are NOT employed by the organization sponsoring the study.

There is NOT an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.