Tinnitus, Subjective
Conditions
Keywords
tinnitus, intratympanic injection, gacyclidine
Brief summary
The purpose of this study is to evaluate the safety, tolerability, plasma pharmacokinetics (PK), and exploratory efficacy of OTO-313 administered as an intratympanic injection for the treatment of subjective tinnitus.
Interventions
DRUGOTO-313
single intratympanic injection of gacyclidine
DRUGPlacebo
single intratympanic injection of placebo
Sponsors
Otonomy, Inc.
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
TRIPLE (Subject, Investigator, Outcomes Assessor)
Intervention model description
Randomized, double-blind, placebo-controlled, multicenter
Eligibility
Sex/Gender
ALL
Age
18 Years to 75 Years
Healthy volunteers
No
Inclusion criteria
* Subject has subjective unilateral tinnitus and is consistently aware of their tinnitus throughout much of the waking day. * Subject is able to use the electronic diary to complete their daily tinnitus ratings * Subject's tinnitus is likely of cochlear origin, e.g., associated with sensorineural hearing loss; acute hearing loss from noise trauma, barotrauma, or traumatic cochlear injury (acute acoustic trauma, blast trauma, middle ear surgery, inner ear barotrauma); age-related hearing loss; resolved otitis media; ototoxic drug exposure. * Subject is willing to comply with the protocol and attend all study visits.
Exclusion criteria
* Subject has pulsatile tinnitus, tinnitus resulting from traumatic head or neck injury, or tinnitus resulting from a tumor or stroke. * Subject is pregnant or lactating. * Subject has other clinically significant illness, medical condition or medical history at Screening or Baseline (Day 1) that, in the Investigator's opinion, would likely reduce the safety of study participation or compliance with study procedures.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Audiometry - Pure Tone Average Done Over 1000, 2000 and 4000 Hertz (HZ) | Up to end of study (Part A - Day 29 [4 weeks after dosing]), (Part B - Day 57 [8 weeks after dosing]) | Mean Change from Baseline to End of Study (baseline to Day 29 \[4 weeks after dosing\](Part A) or baseline to Day 57 \[8 weeks after dosing\] (Part B)). in Pure Tone Average Hearing Thresholds; a negative change indicates improvement. |
| Otoscopic Examination - Presence of Perforation in the Treated Ear at the End of Study Visit (Day 29 [4 Weeks After Dosing] (Part A) or Day 57 [8 Weeks After Dosing] (Part B)). | Up to end of study (Part A - Day 29 [4 weeks after the injection], Part B - Day 57 [8 weeks after the injection]) | Ear examinations were done at every visit. One of the important safety endpoints was an observation of a perforation in the ear drum that did not heal properly after the injection. |
Other
| Measure | Time frame | Description |
|---|---|---|
| Change From Baseline in Tinnitus Functional Index (TFI) | Up to the End of Study Visit (Part A - Day 29 [4 weeks after the injection]), (Part B - Day 57 [8 weeks after injection]) | Validated, 25-item questionnaire; index score from 0 to 100; a negative change indicates improvement. The 25 items of the TFI represent 8 subscales covering multiple domains of tinnitus severity: 1) Intrusive, 2) Sense of Control, 3) Cognitive, 4) Sleep, 5) Auditory, 6) Relaxation, 7) Quality of Life, and 8) Emotional. Subjects answer each TFI question by rating their experience over the past week. Each subscale has 3 questions with a response ranging from 0 (best response) to 10 (worst response) in regard to the impact of tinnitus in these different aspects of the subject's life. The highest raw score would be 250 and the lowest would be 0. The raw score is then divided by the total number of valid answers and that in turn is multiplied by 10 to give an overall score range from 0-100, with 0 representing no impact of tinnitus on their daily life and 100 representing complete impact of tinnitus on their daily life. |
| Patient Global Impression of Change (PGIC) | Measured at the end of study visit (Part A - Day 29 [4 weeks after injection]), (Part B - Day 57 [8 weeks after injection]). | Change in overall tinnitus status as perceived by the subject; this was a subject-reported outcome that evaluated the change in overall global tinnitus status as perceived by the subject. The subject was asked: Since the beginning of the clinical study, how would you rate your tinnitus?. The beginning of the clinical study in this context was the time prior to investigational product administration. The 7 response categories (and point scores) for the PGIC are: * Very much improved = 3 * Much improved = 2 * Minimally improved = 1 * Unchanged = 0 * Minimally worse = -1 * Much worse = -2 * Very much worse = -3 |
Countries
United States
Participant flow
Recruitment details
For Part A, a total of 8 subjects registered for this study at a single site and signed an informed consent. Subject needed to have subjective unilateral or bilateral tinnitus (ringing or noise in the ear when there was no external cause) and be consistently aware of their tinnitus throughout much of the waking day.
Pre-assignment details
Part A and Part B were conducted as 2 separate studies under a single protocol.
Participants by arm
| Arm | Count |
|---|---|
| Part A OTO-313 Subjects received 0.11 mg OTO-313 via an injection through the eardrum of a 0.2 mL medium chain triglycerides solution. | 6 |
| Part A Placebo Subjects received an injection through the eardrum of a 0.2 mL medium chain triglycerides solution. | 2 |
| Part B OTO-313 Subjects received 0.32 mg OTO-313 via an injection through the eardrum of a 0.2 mL medium chain triglycerides solution. | 15 |
| Part B Placebo Subjects received an injection through the eardrum of a 0.2 mL medium chain triglycerides solution. | 16 |
| Total | 39 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 | FG003 |
|---|---|---|---|---|---|
| Overall Study | Lost to Follow-up | 0 | 0 | 0 | 1 |
| Overall Study | Withdrawal by Subject | 0 | 0 | 2 | 1 |
Baseline characteristics
| Characteristic | Part A OTO-313 | Part A Placebo | Part B OTO-313 | Part B Placebo | Total |
|---|---|---|---|---|---|
| Age, Categorical <=18 years | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical >=65 years | 3 Participants | 0 Participants | 6 Participants | 4 Participants | 13 Participants |
| Age, Categorical Between 18 and 65 years | 3 Participants | 2 Participants | 9 Participants | 12 Participants | 26 Participants |
| Age, Continuous | 64.0 years | 57.0 years | 58.0 years | 55.0 years | 57.5 years |
| Months Since Initial Onset of Tinnitus | 95.8 Months STANDARD_DEVIATION 87.09 | 49.0 Months STANDARD_DEVIATION 16.42 | 4.5 Months STANDARD_DEVIATION 1.96 | 4.20 Months STANDARD_DEVIATION 1.62 | 38.38 Months STANDARD_DEVIATION 37.84 |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 0 Participants | 0 Participants | 0 Participants | 1 Participants | 1 Participants |
| Race (NIH/OMB) Black or African American | 0 Participants | 0 Participants | 0 Participants | 1 Participants | 1 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 1 Participants | 0 Participants | 1 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) White | 6 Participants | 2 Participants | 14 Participants | 14 Participants | 36 Participants |
| Region of Enrollment United States | 6 participants | 2 participants | 15 participants | 16 participants | 39 participants |
| Sex: Female, Male Female | 3 Participants | 0 Participants | 7 Participants | 7 Participants | 17 Participants |
| Sex: Female, Male Male | 3 Participants | 2 Participants | 8 Participants | 9 Participants | 22 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk | EG003 affected / at risk |
|---|---|---|---|---|
| deaths Total, all-cause mortality | 0 / 6 | 0 / 2 | 0 / 17 | 0 / 18 |
| other Total, other adverse events | 2 / 6 | 1 / 2 | 5 / 17 | 8 / 18 |
| serious Total, serious adverse events | 0 / 6 | 0 / 2 | 1 / 17 | 0 / 18 |
Outcome results
Primary
Audiometry - Pure Tone Average Done Over 1000, 2000 and 4000 Hertz (HZ)
Mean Change from Baseline to End of Study (baseline to Day 29 \[4 weeks after dosing\](Part A) or baseline to Day 57 \[8 weeks after dosing\] (Part B)). in Pure Tone Average Hearing Thresholds; a negative change indicates improvement.
Time frame: Up to end of study (Part A - Day 29 [4 weeks after dosing]), (Part B - Day 57 [8 weeks after dosing])
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Part A OTO-313 | Audiometry - Pure Tone Average Done Over 1000, 2000 and 4000 Hertz (HZ) | -0.3 decibels | Standard Deviation 2.66 |
| Part A Placebo | Audiometry - Pure Tone Average Done Over 1000, 2000 and 4000 Hertz (HZ) | 0.71 decibels | Standard Deviation 2.5 |
| Part B OTO-313 | Audiometry - Pure Tone Average Done Over 1000, 2000 and 4000 Hertz (HZ) | -0.8 decibels | Standard Deviation 6.44 |
| Part B Placebo | Audiometry - Pure Tone Average Done Over 1000, 2000 and 4000 Hertz (HZ) | 0.3 decibels | Standard Deviation 6.95 |
Primary
Otoscopic Examination - Presence of Perforation in the Treated Ear at the End of Study Visit (Day 29 [4 Weeks After Dosing] (Part A) or Day 57 [8 Weeks After Dosing] (Part B)).
Ear examinations were done at every visit. One of the important safety endpoints was an observation of a perforation in the ear drum that did not heal properly after the injection.
Time frame: Up to end of study (Part A - Day 29 [4 weeks after the injection], Part B - Day 57 [8 weeks after the injection])
| Arm | Measure | Category | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Part A OTO-313 | Otoscopic Examination - Presence of Perforation in the Treated Ear at the End of Study Visit (Day 29 [4 Weeks After Dosing] (Part A) or Day 57 [8 Weeks After Dosing] (Part B)). | Perforation present: >50% tympanic membrane | 0 Participants |
| Part A OTO-313 | Otoscopic Examination - Presence of Perforation in the Treated Ear at the End of Study Visit (Day 29 [4 Weeks After Dosing] (Part A) or Day 57 [8 Weeks After Dosing] (Part B)). | Perforation present: ≤25% tympanic membrane | 0 Participants |
| Part A OTO-313 | Otoscopic Examination - Presence of Perforation in the Treated Ear at the End of Study Visit (Day 29 [4 Weeks After Dosing] (Part A) or Day 57 [8 Weeks After Dosing] (Part B)). | Perforation not present | 6 Participants |
| Part A OTO-313 | Otoscopic Examination - Presence of Perforation in the Treated Ear at the End of Study Visit (Day 29 [4 Weeks After Dosing] (Part A) or Day 57 [8 Weeks After Dosing] (Part B)). | Perforation present: >25% and ≤50% tympanic membrane | 0 Participants |
| Part A OTO-313 | Otoscopic Examination - Presence of Perforation in the Treated Ear at the End of Study Visit (Day 29 [4 Weeks After Dosing] (Part A) or Day 57 [8 Weeks After Dosing] (Part B)). | Perforation present: pinhole size | 0 Participants |
| Part A Placebo | Otoscopic Examination - Presence of Perforation in the Treated Ear at the End of Study Visit (Day 29 [4 Weeks After Dosing] (Part A) or Day 57 [8 Weeks After Dosing] (Part B)). | Perforation present: >25% and ≤50% tympanic membrane | 0 Participants |
| Part A Placebo | Otoscopic Examination - Presence of Perforation in the Treated Ear at the End of Study Visit (Day 29 [4 Weeks After Dosing] (Part A) or Day 57 [8 Weeks After Dosing] (Part B)). | Perforation present: >50% tympanic membrane | 0 Participants |
| Part A Placebo | Otoscopic Examination - Presence of Perforation in the Treated Ear at the End of Study Visit (Day 29 [4 Weeks After Dosing] (Part A) or Day 57 [8 Weeks After Dosing] (Part B)). | Perforation not present | 2 Participants |
| Part A Placebo | Otoscopic Examination - Presence of Perforation in the Treated Ear at the End of Study Visit (Day 29 [4 Weeks After Dosing] (Part A) or Day 57 [8 Weeks After Dosing] (Part B)). | Perforation present: ≤25% tympanic membrane | 0 Participants |
| Part A Placebo | Otoscopic Examination - Presence of Perforation in the Treated Ear at the End of Study Visit (Day 29 [4 Weeks After Dosing] (Part A) or Day 57 [8 Weeks After Dosing] (Part B)). | Perforation present: pinhole size | 0 Participants |
| Part B OTO-313 | Otoscopic Examination - Presence of Perforation in the Treated Ear at the End of Study Visit (Day 29 [4 Weeks After Dosing] (Part A) or Day 57 [8 Weeks After Dosing] (Part B)). | Perforation present: >25% and ≤50% tympanic membrane | 0 Participants |
| Part B OTO-313 | Otoscopic Examination - Presence of Perforation in the Treated Ear at the End of Study Visit (Day 29 [4 Weeks After Dosing] (Part A) or Day 57 [8 Weeks After Dosing] (Part B)). | Perforation present: pinhole size | 0 Participants |
| Part B OTO-313 | Otoscopic Examination - Presence of Perforation in the Treated Ear at the End of Study Visit (Day 29 [4 Weeks After Dosing] (Part A) or Day 57 [8 Weeks After Dosing] (Part B)). | Perforation present: ≤25% tympanic membrane | 0 Participants |
| Part B OTO-313 | Otoscopic Examination - Presence of Perforation in the Treated Ear at the End of Study Visit (Day 29 [4 Weeks After Dosing] (Part A) or Day 57 [8 Weeks After Dosing] (Part B)). | Perforation present: >50% tympanic membrane | 0 Participants |
| Part B OTO-313 | Otoscopic Examination - Presence of Perforation in the Treated Ear at the End of Study Visit (Day 29 [4 Weeks After Dosing] (Part A) or Day 57 [8 Weeks After Dosing] (Part B)). | Perforation not present | 14 Participants |
| Part B Placebo | Otoscopic Examination - Presence of Perforation in the Treated Ear at the End of Study Visit (Day 29 [4 Weeks After Dosing] (Part A) or Day 57 [8 Weeks After Dosing] (Part B)). | Perforation present: >50% tympanic membrane | 0 Participants |
| Part B Placebo | Otoscopic Examination - Presence of Perforation in the Treated Ear at the End of Study Visit (Day 29 [4 Weeks After Dosing] (Part A) or Day 57 [8 Weeks After Dosing] (Part B)). | Perforation present: ≤25% tympanic membrane | 0 Participants |
| Part B Placebo | Otoscopic Examination - Presence of Perforation in the Treated Ear at the End of Study Visit (Day 29 [4 Weeks After Dosing] (Part A) or Day 57 [8 Weeks After Dosing] (Part B)). | Perforation present: pinhole size | 0 Participants |
| Part B Placebo | Otoscopic Examination - Presence of Perforation in the Treated Ear at the End of Study Visit (Day 29 [4 Weeks After Dosing] (Part A) or Day 57 [8 Weeks After Dosing] (Part B)). | Perforation present: >25% and ≤50% tympanic membrane | 0 Participants |
| Part B Placebo | Otoscopic Examination - Presence of Perforation in the Treated Ear at the End of Study Visit (Day 29 [4 Weeks After Dosing] (Part A) or Day 57 [8 Weeks After Dosing] (Part B)). | Perforation not present | 15 Participants |
Other Pre-specified
Change From Baseline in Tinnitus Functional Index (TFI)
Validated, 25-item questionnaire; index score from 0 to 100; a negative change indicates improvement. The 25 items of the TFI represent 8 subscales covering multiple domains of tinnitus severity: 1) Intrusive, 2) Sense of Control, 3) Cognitive, 4) Sleep, 5) Auditory, 6) Relaxation, 7) Quality of Life, and 8) Emotional. Subjects answer each TFI question by rating their experience over the past week. Each subscale has 3 questions with a response ranging from 0 (best response) to 10 (worst response) in regard to the impact of tinnitus in these different aspects of the subject's life. The highest raw score would be 250 and the lowest would be 0. The raw score is then divided by the total number of valid answers and that in turn is multiplied by 10 to give an overall score range from 0-100, with 0 representing no impact of tinnitus on their daily life and 100 representing complete impact of tinnitus on their daily life.
Time frame: Up to the End of Study Visit (Part A - Day 29 [4 weeks after the injection]), (Part B - Day 57 [8 weeks after injection])
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Part A OTO-313 | Change From Baseline in Tinnitus Functional Index (TFI) | -4.2 score on a scale | Standard Deviation 10.68 |
| Part A Placebo | Change From Baseline in Tinnitus Functional Index (TFI) | 4.0 score on a scale | Standard Deviation 0 |
| Part B OTO-313 | Change From Baseline in Tinnitus Functional Index (TFI) | -12.9 score on a scale | Standard Deviation 25.21 |
| Part B Placebo | Change From Baseline in Tinnitus Functional Index (TFI) | -4.3 score on a scale | Standard Deviation 18.18 |
Other Pre-specified
Patient Global Impression of Change (PGIC)
Change in overall tinnitus status as perceived by the subject; this was a subject-reported outcome that evaluated the change in overall global tinnitus status as perceived by the subject. The subject was asked: Since the beginning of the clinical study, how would you rate your tinnitus?. The beginning of the clinical study in this context was the time prior to investigational product administration. The 7 response categories (and point scores) for the PGIC are: * Very much improved = 3 * Much improved = 2 * Minimally improved = 1 * Unchanged = 0 * Minimally worse = -1 * Much worse = -2 * Very much worse = -3
Time frame: Measured at the end of study visit (Part A - Day 29 [4 weeks after injection]), (Part B - Day 57 [8 weeks after injection]).
| Arm | Measure | Category | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Part A OTO-313 | Patient Global Impression of Change (PGIC) | Very much improved | 0 Participants |
| Part A OTO-313 | Patient Global Impression of Change (PGIC) | Much worse | 0 Participants |
| Part A OTO-313 | Patient Global Impression of Change (PGIC) | Minimally worse | 1 Participants |
| Part A OTO-313 | Patient Global Impression of Change (PGIC) | Much improved | 0 Participants |
| Part A OTO-313 | Patient Global Impression of Change (PGIC) | Very much worse | 1 Participants |
| Part A OTO-313 | Patient Global Impression of Change (PGIC) | Minimally improved | 1 Participants |
| Part A OTO-313 | Patient Global Impression of Change (PGIC) | Unchanged | 3 Participants |
| Part A Placebo | Patient Global Impression of Change (PGIC) | Much worse | 0 Participants |
| Part A Placebo | Patient Global Impression of Change (PGIC) | Unchanged | 2 Participants |
| Part A Placebo | Patient Global Impression of Change (PGIC) | Minimally improved | 0 Participants |
| Part A Placebo | Patient Global Impression of Change (PGIC) | Minimally worse | 0 Participants |
| Part A Placebo | Patient Global Impression of Change (PGIC) | Very much worse | 0 Participants |
| Part A Placebo | Patient Global Impression of Change (PGIC) | Much improved | 0 Participants |
| Part A Placebo | Patient Global Impression of Change (PGIC) | Very much improved | 0 Participants |
| Part B OTO-313 | Patient Global Impression of Change (PGIC) | Unchanged | 5 Participants |
| Part B OTO-313 | Patient Global Impression of Change (PGIC) | Very much improved | 3 Participants |
| Part B OTO-313 | Patient Global Impression of Change (PGIC) | Much improved | 1 Participants |
| Part B OTO-313 | Patient Global Impression of Change (PGIC) | Minimally improved | 2 Participants |
| Part B OTO-313 | Patient Global Impression of Change (PGIC) | Minimally worse | 3 Participants |
| Part B OTO-313 | Patient Global Impression of Change (PGIC) | Much worse | 0 Participants |
| Part B OTO-313 | Patient Global Impression of Change (PGIC) | Very much worse | 1 Participants |
| Part B Placebo | Patient Global Impression of Change (PGIC) | Minimally improved | 3 Participants |
| Part B Placebo | Patient Global Impression of Change (PGIC) | Very much worse | 0 Participants |
| Part B Placebo | Patient Global Impression of Change (PGIC) | Much worse | 2 Participants |
| Part B Placebo | Patient Global Impression of Change (PGIC) | Much improved | 1 Participants |
| Part B Placebo | Patient Global Impression of Change (PGIC) | Very much improved | 0 Participants |
| Part B Placebo | Patient Global Impression of Change (PGIC) | Minimally worse | 0 Participants |
| Part B Placebo | Patient Global Impression of Change (PGIC) | Unchanged | 10 Participants |