Tinnitus
Conditions
Brief summary
The purpose of this research study is to test the safety and effectiveness of the study drug, AM-101. AM-101 is tested for the treatment of tinnitus that started as the result of an injury to the inner ear or due to middle ear inflammation (otitis media). Subjects with tinnitus can take part in the study, if their tinnitus started within the last 3 months.
Detailed description
This phase III study is assessing the drug's safety and is aiming to demonstrate efficacy of repeated intratymanic AM-101 injections in the treatment of acute peripheral tinnitus (up to 3 months from onset).
Interventions
DRUGAM-101
AM-101 gel for intratympanic injection
DRUGPlacebo
Placebo gel for intratympanic injection
Sponsors
Auris Medical, Inc.
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
Eligibility
Sex/Gender
ALL
Age
18 Years to 75 Years
Healthy volunteers
No
Inclusion criteria
1. Persistent subjective peripheral tinnitus (unilateral or bilateral) following traumatic cochlear injury (acute acoustic trauma, blast trauma, middle ear surgery, inner ear barotrauma, tympanic membrane trauma) or otitis media with onset no longer than 3 months prior to randomization 2. Age ≥ 18 years and ≤ 75 years (≥ 14 years and ≤ 75 years at selected sites); 3. Negative pregnancy test (woman of childbearing potential); 4. Willing and able to use adequate hearing protection, respectively to refrain from engaging in activities or work involving loud noise exposure where sufficient hearing protection is not possible or ensured; 5. Willing and able to protect ear canal and middle ear from water exposure as long as tympanic membrane is not fully closed. Other protocol-defined inclusion criteria may apply.
Exclusion criteria
1. Fluctuating tinnitus; 2. Intermittent tinnitus; 3. Tinnitus resulting from traumatic head or neck injury; 4. Presence of chronic tinnitus; 5. Meniere's Disease, history of endolymphatic hydrops, or history of fluctuating hearing loss; 6. History of repeated idiopathic sudden sensorineural hearing loss or history of acoustic neuroma; 7. Ongoing acute or chronic otitis media or otitis externa; 8. Other treatment of tinnitus for the study duration; 9. Known hypersensitivity, allergy or intolerance to the study medication or any history of severe, abnormal drug reaction; 10. Women who are breast-feeding, pregnant or who are planning to become pregnant during the study; 11. Women of childbearing potential who are unwilling or unable to practice contraception, such as hormonal contraceptives, double barrier, sexual abstinence or intercourse with a partner who has been vasectomised for at least three months; 12. Concurrent participation in another clinical study or participation in another clinical study within 30 days prior to randomization. Other protocol-defined
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Efficacy: Change in Patient-reported Tinnitus Loudness Questionnaire (TLQ) Improvement From Baseline to Follow up Visit 3 (FUV3) | Screening (D-14) versus final follow-up (D83) | Starting at the screening visit (SV), each subject recorded the following numerical rating scales (NRS) throughout the entire study duration: \- Tinnitus loudness at its loudest within the last 24 hours (Tinnitus Loudness Questionnaire \[TLQ\] NRSLoudest). Subjects were asked On a scale from 0 to 10, where 0 represents no tinnitus and 10 represents extremely loud tinnitus, what one number best describes your tinnitus at its loudest in the last 24 hours (including right now)? TLQ NRSLoudest was collected from SV (D-14) to the evening before FUV3 (D83). The ratings were to be recorded every day before going to sleep on an electronic device. As Baseline the10 ratings of the screening period before the first treatment were averaged. For the FUV3 endpoint, the ratings of the 7 days before FUV3 were averaged. |
| Co-Primary Efficacy: Improvement in Tinnitus Functional Index (TFI) Total Score From Baseline to FUV3 | D0 (=TV1) versus Day 84 (=FUV3) | The TFI was recorded on an electronic device (electronic patient reported outcome) at Treatment Visit 1 (TV1), before randomization, and at Follow up Visit 1 (FUV1), FUV2 and FUV3. The TFI is a patient reported outcome questionnaire and contains 25 questions. It includes eight subscales: Intrusive, Sense of Control, Cognitive, Sleep, Auditory, Relaxation, Quality of Life, and Emotional. Each question is to be rated on a NRS between 0 and 10 (or 0 to 100%), with a recall period of over the past week. The TFI total score is considered as valid if there are evaluable answers for at least 19 of the 25 items (76% of items) (Meikle et al. 2012). The repondent's overall TFI score is within a 0-100 range. For the subscales the range is the same. A lower value represents an improvement for all scales. Please refer to the following publicly available link for more information: http://download.lww.com/wolterskluwer\_vitalstream\_com/PermaLink/EANDH/A/EANDH\_2011\_09\_27\_HENRY\_200593\_SDC15.pdf |
| Safety: Frequency of Subjects With Deterioration of Hearing at Follow up Visit 2 (FUV2) | Day 35 | Occurence of deterioration of hearing (Air and Bone conduction) in the treated ear at FUV2. Deterioration is defined as a deterioration of hearing threshold of at least 15 dB from Baseline at the average of 2 contiguous frequencies. |
Countries
United States
Participant flow
Recruitment details
A total of 86 sites were initiated in Canada, the United States, the Czech Republic, Israel, Turkey and Republic of South Korea. In total, 69 sites screened each at least 1 subject and 64 sites randomized subjects for treatment.
Pre-assignment details
A total of 478 subjects were screened, 343 subjects were randomized, and 336 subjects were treated. 7 subjects were randomized (3 to AM-101 and 4 to placebo) but not treated; these subjects were excluded from the analysis sets. The majority (92%) of subjects completed the study.
Participants by arm
| Arm | Count |
|---|---|
| AM-101 0.87 mg/mL Gel Three intratympanic administration of AM-101 0.87 mg/mL gel within 5 days (D0-D4) | 204 |
| Placebo Gel Three intratympanic administration of placebo gel within 5 days (D0-D4). | 139 |
| Total | 343 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Adverse Event | 1 | 1 |
| Overall Study | Lost to Follow-up | 5 | 1 |
| Overall Study | Protocol Violation | 1 | 0 |
| Overall Study | Randomization error | 1 | 2 |
| Overall Study | Withdrawal by Subject | 9 | 6 |
Baseline characteristics
| Characteristic | AM-101 0.87 mg/mL Gel | Placebo Gel | Total |
|---|---|---|---|
| Age, Categorical <=18 years | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical >=65 years | 16 Participants | 14 Participants | 30 Participants |
| Age, Categorical Between 18 and 65 years | 188 Participants | 125 Participants | 313 Participants |
| Age, Continuous | 43.4 years STANDARD_DEVIATION 14.6 | 44.2 years STANDARD_DEVIATION 15.2 | 43.7 years STANDARD_DEVIATION 14.8 |
| Region of Enrollment Canada | 20 participants | 14 participants | 34 participants |
| Region of Enrollment Czechia | 38 participants | 26 participants | 64 participants |
| Region of Enrollment Israel | 2 participants | 1 participants | 3 participants |
| Region of Enrollment South Korea | 15 participants | 12 participants | 27 participants |
| Region of Enrollment Turkey | 7 participants | 4 participants | 11 participants |
| Region of Enrollment United States | 122 participants | 82 participants | 204 participants |
| Sex: Female, Male Female | 43 Participants | 37 Participants | 80 Participants |
| Sex: Female, Male Male | 161 Participants | 102 Participants | 263 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 0 / 201 | 0 / 135 |
| other Total, other adverse events | 63 / 201 | 38 / 135 |
| serious Total, serious adverse events | 5 / 201 | 1 / 135 |
Outcome results
Primary
Co-Primary Efficacy: Improvement in Tinnitus Functional Index (TFI) Total Score From Baseline to FUV3
The TFI was recorded on an electronic device (electronic patient reported outcome) at Treatment Visit 1 (TV1), before randomization, and at Follow up Visit 1 (FUV1), FUV2 and FUV3. The TFI is a patient reported outcome questionnaire and contains 25 questions. It includes eight subscales: Intrusive, Sense of Control, Cognitive, Sleep, Auditory, Relaxation, Quality of Life, and Emotional. Each question is to be rated on a NRS between 0 and 10 (or 0 to 100%), with a recall period of over the past week. The TFI total score is considered as valid if there are evaluable answers for at least 19 of the 25 items (76% of items) (Meikle et al. 2012). The repondent's overall TFI score is within a 0-100 range. For the subscales the range is the same. A lower value represents an improvement for all scales. Please refer to the following publicly available link for more information: http://download.lww.com/wolterskluwer\_vitalstream\_com/PermaLink/EANDH/A/EANDH\_2011\_09\_27\_HENRY\_200593\_SDC15.pdf
Time frame: D0 (=TV1) versus Day 84 (=FUV3)
Population: Valid for Efficacy dataset includes all subjects treated with at least one i.t. injection (AM-101 or placebo), a valid TLQ NRSLoudest or TFI rating at baseline and at least one valid post-baseline rating.~Ten subjects had neither TLQ nor TFI baseline plus additional 25 subjects had no baseline for the TFI resulting in 301 evaluable subjects.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) |
|---|---|---|
| AM-101 0.87 mg/mL Gel | Co-Primary Efficacy: Improvement in Tinnitus Functional Index (TFI) Total Score From Baseline to FUV3 | 10.4 units on a scale |
| Placebo Gel | Co-Primary Efficacy: Improvement in Tinnitus Functional Index (TFI) Total Score From Baseline to FUV3 | 9.6 units on a scale |
p-value: 0.6395% CI: [-4, 2.4]Mixed Models Analysis
Primary
Efficacy: Change in Patient-reported Tinnitus Loudness Questionnaire (TLQ) Improvement From Baseline to Follow up Visit 3 (FUV3)
Starting at the screening visit (SV), each subject recorded the following numerical rating scales (NRS) throughout the entire study duration: \- Tinnitus loudness at its loudest within the last 24 hours (Tinnitus Loudness Questionnaire \[TLQ\] NRSLoudest). Subjects were asked On a scale from 0 to 10, where 0 represents no tinnitus and 10 represents extremely loud tinnitus, what one number best describes your tinnitus at its loudest in the last 24 hours (including right now)? TLQ NRSLoudest was collected from SV (D-14) to the evening before FUV3 (D83). The ratings were to be recorded every day before going to sleep on an electronic device. As Baseline the10 ratings of the screening period before the first treatment were averaged. For the FUV3 endpoint, the ratings of the 7 days before FUV3 were averaged.
Time frame: Screening (D-14) versus final follow-up (D83)
Population: Valid for Efficacy dataset includes all subjects treated with at least one i.t. injection (AM-101 or placebo), a valid TLQ NRSLoudest or TFI rating at baseline and at least one valid post-baseline rating.~Ten subjects had neither TLQ nor TFI baseline and 2 subjects had no valid rating for the TLQ resulting in 324 evaluable subjects.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) |
|---|---|---|
| AM-101 0.87 mg/mL Gel | Efficacy: Change in Patient-reported Tinnitus Loudness Questionnaire (TLQ) Improvement From Baseline to Follow up Visit 3 (FUV3) | 0.80 units on a scale |
| Placebo Gel | Efficacy: Change in Patient-reported Tinnitus Loudness Questionnaire (TLQ) Improvement From Baseline to Follow up Visit 3 (FUV3) | 0.63 units on a scale |
p-value: 0.3295% CI: [-0.51, 0.17]Mixed Models Analysis
Primary
Safety: Frequency of Subjects With Deterioration of Hearing at Follow up Visit 2 (FUV2)
Occurence of deterioration of hearing (Air and Bone conduction) in the treated ear at FUV2. Deterioration is defined as a deterioration of hearing threshold of at least 15 dB from Baseline at the average of 2 contiguous frequencies.
Time frame: Day 35
Population: Valid for Safety dataset was used. Of the 336 valid for safety subjects, 323 could be evaluated for this endpoint.
| Arm | Measure | Group | Category | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|---|
| AM-101 0.87 mg/mL Gel | Safety: Frequency of Subjects With Deterioration of Hearing at Follow up Visit 2 (FUV2) | Air conduction | Subjects with hearing deterioration | 12 Participants |
| AM-101 0.87 mg/mL Gel | Safety: Frequency of Subjects With Deterioration of Hearing at Follow up Visit 2 (FUV2) | Air conduction | Subjects without hearing deterioration | 181 Participants |
| AM-101 0.87 mg/mL Gel | Safety: Frequency of Subjects With Deterioration of Hearing at Follow up Visit 2 (FUV2) | Bone conduction | Subjects with hearing deterioration | 3 Participants |
| AM-101 0.87 mg/mL Gel | Safety: Frequency of Subjects With Deterioration of Hearing at Follow up Visit 2 (FUV2) | Bone conduction | Subjects without hearing deterioration | 190 Participants |
| Placebo Gel | Safety: Frequency of Subjects With Deterioration of Hearing at Follow up Visit 2 (FUV2) | Bone conduction | Subjects without hearing deterioration | 126 Participants |
| Placebo Gel | Safety: Frequency of Subjects With Deterioration of Hearing at Follow up Visit 2 (FUV2) | Air conduction | Subjects with hearing deterioration | 9 Participants |
| Placebo Gel | Safety: Frequency of Subjects With Deterioration of Hearing at Follow up Visit 2 (FUV2) | Bone conduction | Subjects with hearing deterioration | 4 Participants |
| Placebo Gel | Safety: Frequency of Subjects With Deterioration of Hearing at Follow up Visit 2 (FUV2) | Air conduction | Subjects without hearing deterioration | 121 Participants |
Comparison: Analysis for air conductionp-value: 0.821Fisher Exact
Comparison: Analysis for bone conductionp-value: 1Fisher Exact