Trial Outcomes & Findings for Phase 3 Clinical Trial: D-methionine to Reduce Noise-Induced Hearing Loss (NIHL) (NCT NCT02903355)

NCT ID: NCT02903355

Last Updated: 2022-06-28

Results Overview

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.

• Recruitment status: TERMINATED
• Study phase: PHASE3
• Target enrollment: 351 participants
• Primary outcome timeframe: Change from baseline to day 29-36 after initial administration of study drug (Day 15-22 after cessation of weapons training).
• Results posted on: 2022-06-28

Participant Flow

Participant milestones

Measure	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.	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
Overall Study STARTED	186	165
Overall Study COMPLETED	142	124
Overall Study NOT COMPLETED	44	41

Reasons for withdrawal

Withdrawal data not reported

Baseline Characteristics

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

Baseline characteristics by cohort

Measure	Placebo n=142 Participants 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, Oral Liquid Suspension n=124 Participants 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 n=266 Participants Total of all reporting groups
Age, Categorical <=18 years	0 Participants n=5 Participants	0 Participants n=7 Participants	0 Participants n=5 Participants
Age, Categorical Between 18 and 65 years	142 Participants n=5 Participants	124 Participants n=7 Participants	266 Participants n=5 Participants
Age, Categorical >=65 years	0 Participants n=5 Participants	0 Participants n=7 Participants	0 Participants n=5 Participants
Age, Continuous	30.34 years STANDARD_DEVIATION 4.01 • n=5 Participants	31.01 years STANDARD_DEVIATION 4.35 • n=7 Participants	30.65 years STANDARD_DEVIATION 4.18 • n=5 Participants
Sex: Female, Male Female	34 Participants n=5 Participants	27 Participants n=7 Participants	61 Participants n=5 Participants
Sex: Female, Male Male	108 Participants n=5 Participants	97 Participants n=7 Participants	205 Participants n=5 Participants
Race/Ethnicity, Customized American Indian or Alaska Native	1 Participants n=5 Participants	0 Participants n=7 Participants	1 Participants n=5 Participants
Race/Ethnicity, Customized Hispanic	32 Participants n=5 Participants	29 Participants n=7 Participants	61 Participants n=5 Participants
Race/Ethnicity, Customized Asian or Native Hawaiian or Pacific Islander	4 Participants n=5 Participants	4 Participants n=7 Participants	8 Participants n=5 Participants
Race/Ethnicity, Customized Black or African American	18 Participants n=5 Participants	17 Participants n=7 Participants	35 Participants n=5 Participants
Race/Ethnicity, Customized White	84 Participants n=5 Participants	73 Participants n=7 Participants	157 Participants n=5 Participants
Race/Ethnicity, Customized More than on race	1 Participants n=5 Participants	0 Participants n=7 Participants	1 Participants n=5 Participants
Race/Ethnicity, Customized Unknown or not Reported	2 Participants n=5 Participants	1 Participants n=7 Participants	3 Participants n=5 Participants
Region of Enrollment United States	142 participants n=5 Participants	124 participants n=7 Participants	266 participants n=5 Participants

PRIMARY outcome

Timeframe: 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.

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.

Outcome measures

Measure	Placebo n=137 Participants 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, Oral Liquid Suspension n=121 Participants 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
ASHA Shift Ear (Left)	12 Participants	9 Participants

PRIMARY outcome

Timeframe: 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.

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.

Outcome measures

Measure	Placebo n=139 Participants 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, Oral Liquid Suspension n=120 Participants 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
ASHA Shift Ear (Right)	12 Participants	10 Participants

PRIMARY outcome

Timeframe: 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.

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.

Outcome measures

Measure	Placebo n=135 Participants 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, Oral Liquid Suspension n=117 Participants 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
ASHA Shift Ear (Either)	21 Participants	18 Participants

PRIMARY outcome

Timeframe: 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.

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.

Outcome measures

Measure	Placebo n=135 Participants 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, Oral Liquid Suspension n=117 Participants 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
ASHA Shift Ear (Both)	3 Participants	1 Participants

PRIMARY outcome

Timeframe: 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.

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.

Outcome measures

Measure	Placebo n=139 Participants 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, Oral Liquid Suspension n=120 Participants 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
ASHA Shift Ear (Trigger Hand)	11 Participants	8 Participants

PRIMARY outcome

Timeframe: 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.

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.

Outcome measures

Measure	Placebo n=137 Participants 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, Oral Liquid Suspension n=121 Participants 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
ASHA Shift Ear (Non-Trigger Hand)	13 Participants	11 Participants

SECONDARY outcome

Timeframe: 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.

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.

Outcome measures

Measure	Placebo n=142 Participants 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, Oral Liquid Suspension n=123 Participants 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
DOEHRSHC Shift	2 Participants	2 Participants

SECONDARY outcome

Timeframe: 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.

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.

Outcome measures

Measure	Placebo n=142 Participants 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, Oral Liquid Suspension n=123 Participants 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
EWS STS Shift	11 Participants	5 Participants

SECONDARY outcome

Timeframe: 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.

Outcome measures

Measure	Placebo n=142 Participants 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, Oral Liquid Suspension n=124 Participants 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 THI Score Change	.169 units on a scale Standard Deviation 5.3022	-.1452 units on a scale Standard Deviation 3.2876

SECONDARY outcome

Timeframe: 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)

Outcome measures

Measure	Placebo n=142 Participants 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, Oral Liquid Suspension n=124 Participants 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
Significant Change in Tinnitus	4 Participants	1 Participants

Adverse Events

Placebo

Serious events: 0 serious events

Other events: 93 other events

Deaths: 0 deaths

D-methionine, Oral Liquid Suspension

Serious events: 0 serious events

Other events: 120 other events

Deaths: 0 deaths

Serious adverse events

Adverse event data not reported

Other adverse events

Measure	Placebo n=159 participants at risk 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, Oral Liquid Suspension n=157 participants at risk 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
Gastrointestinal disorders Abdominal Pain/Cramps	3.8% 6/159 • Adverse events monitored from first dose to day 36. 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.	5.7% 9/157 • Adverse events monitored from first dose to day 36. 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.
Product Issues Body Odor	1.9% 3/159 • Adverse events monitored from first dose to day 36. 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.	22.3% 35/157 • Adverse events monitored from first dose to day 36. 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.
Gastrointestinal disorders Diarrhea	7.5% 12/159 • Adverse events monitored from first dose to day 36. 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.	11.5% 18/157 • Adverse events monitored from first dose to day 36. 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.
Product Issues Flatulence	35.2% 56/159 • Adverse events monitored from first dose to day 36. 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.	33.1% 52/157 • Adverse events monitored from first dose to day 36. 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.
Nervous system disorders Headache	5.7% 9/159 • Adverse events monitored from first dose to day 36. 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.	5.7% 9/157 • Adverse events monitored from first dose to day 36. 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.
Gastrointestinal disorders Nausea/ Vomiting	6.3% 10/159 • Adverse events monitored from first dose to day 36. 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.	17.2% 27/157 • Adverse events monitored from first dose to day 36. 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.
Product Issues Urine Odor	4.4% 7/159 • Adverse events monitored from first dose to day 36. 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.	42.0% 66/157 • Adverse events monitored from first dose to day 36. 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.

Additional Information

Gary Fifer, MSHI

Southern Illinois University School of Medicine

Phone: 217-545-7823

Email: gfifer@siumed.edu

Results disclosure agreements

• Principal investigator is a sponsor employee
• Publication restrictions are in place