Subjective Tinnitus
Conditions
Keywords
intratympanic injection, IT injection, gacyclidine, tinnitus
Brief summary
The purpose of this study is to determine the efficacy of OTO-313 in subjects with unilateral tinnitus and to determine the safety and tolerability of OTO-313 in subjects with unilateral tinnitus.
Interventions
DRUGOTO-313
Single intratympanic injection
DRUGPlacebo
Single intratympanic injection
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 early-onset subjective unilateral tinnitus that is persistent (consistently aware of their tinnitus throughout much of the waking day). * Subject is able to use the 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, temporomandibular joint disease (TMJ) associated with tinnitus perception, tinnitus resulting from traumatic head or neck injury, or tinnitus resulting from a tumor or stroke. * Subject is pregnant, lactating, or undergoing fertility treatment. * Subject has other clinically significant illness, medical condition or medical history at Screening or Baseline 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 |
|---|---|---|
| Percentage of Tinnitus Functional Index (TFI) Responders at Weeks 4 and at Week 8 | Week 4 and Week 8 (both had to meet criterion for the subject to be considered a responder) | The TFI is a validated, 25-item questionnaire; index score from 0 to 100; higher scores indicate a greater problem with tinnitus. A responder is considered as any subject with at least a 13-point improvement from Baseline on the (TFI). This responder analysis required both Week 4 and Week 8 to have a 13-point improvement from Baseline. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Change From Baseline in Daily Tinnitus Loudness at Week 8 | The average is calculated for the Baseline and for each study week. Reported here is the change from Baseline to Week 8. | Numerical rating scale (NRS) from 0 (No Tinnitus) to 10 (Extremely Loud Tinnitus) collected every day. Post-baseline weekly NRS scores will be calculated as the average score of all recorded diary entries within each study week. |
| Change From Baseline in Daily Tinnitus Annoyance at Week 8 | The average is calculated for the Baseline and for each study week. Reported here is the change from Baseline to Week 8 | Numerical rating scale from 0 (Not Annoying) to 10 (Extremely Annoying) collected every day. Post-baseline weekly NRS scores will be calculated as the average score of all recorded diary entries within each study week. |
| Patient Global Impression of Change at Week 8 | Week 8 reported here | Change in overall tinnitus status as perceived by the subject as assessed at the Week 8 visit. Subjects were asked, Since the beginning of the clinical study, how would you rate your tinnitus? and had the choice to answer from very much worse (-3) to very much improved (3). The mean change from baseline at Week 8 is reported here. |
Other
| Measure | Time frame | Description |
|---|---|---|
| Otoscopic Examinations - Presence of Perforation in the Treated Ear at Week 16 (Final Visit) | After dosing (Baseline) up to end of study (16 Weeks) | Ear examinations were done at every visit. One of the important safety endpoints is an observation of a perforation in the ear drum that did not heal properly after the injection. Reported here are the Week 16 (final visit) results. |
Countries
Germany, Poland, United Kingdom, United States
Participant flow
Recruitment details
Overall, 56 clinical centers were approved in Germany, Poland, United States, and United Kingdom to conduct this study. Thirty-six centers enrolled subjects. First subject was randomized 04 May 2021; Last subject was randomized 21 February 2022.
Pre-assignment details
All subjects registered for this study signed an informed consent and entered a lead-in period. Following Lead-in, 153 subjects were randomized (=Full Analysis Set) and 151 subjects received study drug (=Safety Analysis Set). The most common reason for not being randomized was too low a score on the Tinnitus Functional Index (TFI)..
Participants by arm
| Arm | Count |
|---|---|
| OTO-313 OTO-313: Single intratympanic injection | 77 |
| Placebo Placebo: Single intratympanic injection | 76 |
| Total | 153 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Follow-up and Efficacy Analysis | Lost to Follow-up | 2 | 1 |
| Follow-up and Efficacy Analysis | Withdrawal by Subject | 5 | 3 |
Baseline characteristics
| Characteristic | Total | OTO-313 | Placebo |
|---|---|---|---|
| Age, Continuous | 51.6 years STANDARD_DEVIATION 14.01 | 52.4 years STANDARD_DEVIATION 12.75 | 50.8 years STANDARD_DEVIATION 15.22 |
| Duration of Tinnitus ≥2 to ≤6 months | 66 Participants | 33 Participants | 33 Participants |
| Duration of Tinnitus >6 to ≤12 months | 87 Participants | 44 Participants | 43 Participants |
| Ethnicity (NIH/OMB) Hispanic or Latino | 15 Participants | 8 Participants | 7 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 135 Participants | 67 Participants | 68 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 3 Participants | 2 Participants | 1 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 1 Participants | 0 Participants | 1 Participants |
| Race (NIH/OMB) Asian | 1 Participants | 1 Participants | 0 Participants |
| Race (NIH/OMB) Black or African American | 11 Participants | 6 Participants | 5 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 5 Participants | 3 Participants | 2 Participants |
| Race (NIH/OMB) White | 135 Participants | 67 Participants | 68 Participants |
| Region of Enrollment Germany | 13 participants | 6 participants | 7 participants |
| Region of Enrollment Poland | 25 participants | 13 participants | 12 participants |
| Region of Enrollment United Kingdom | 1 participants | 1 participants | 0 participants |
| Region of Enrollment United States | 114 participants | 57 participants | 57 participants |
| Sex: Female, Male Female | 79 Participants | 41 Participants | 38 Participants |
| Sex: Female, Male Male | 74 Participants | 36 Participants | 38 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 0 / 77 | 0 / 76 |
| other Total, other adverse events | 23 / 77 | 24 / 76 |
| serious Total, serious adverse events | 2 / 77 | 0 / 76 |
Outcome results
Primary
Percentage of Tinnitus Functional Index (TFI) Responders at Weeks 4 and at Week 8
The TFI is a validated, 25-item questionnaire; index score from 0 to 100; higher scores indicate a greater problem with tinnitus. A responder is considered as any subject with at least a 13-point improvement from Baseline on the (TFI). This responder analysis required both Week 4 and Week 8 to have a 13-point improvement from Baseline.
Time frame: Week 4 and Week 8 (both had to meet criterion for the subject to be considered a responder)
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| OTO-313 Full Analysis Set | Percentage of Tinnitus Functional Index (TFI) Responders at Weeks 4 and at Week 8 | 20 Participants |
| Placebo Full Analysis Set | Percentage of Tinnitus Functional Index (TFI) Responders at Weeks 4 and at Week 8 | 27 Participants |
Comparison: The percentage of responders will be compared between the two groups using the Mantel Haenszel test controlling for category of duration of tinnitus and category of baseline TFI overall score. The primary efficacy analysis will be conducted for the comparison of OTO-313 and placebo, using a 2-sided test and an alpha level of 5%. The 95% confidence intervals (CI) around the common risk difference will also be provided.p-value: =0.38595% CI: [-26, 5]Mantel Haenszel
Secondary
Change From Baseline in Daily Tinnitus Annoyance at Week 8
Numerical rating scale from 0 (Not Annoying) to 10 (Extremely Annoying) collected every day. Post-baseline weekly NRS scores will be calculated as the average score of all recorded diary entries within each study week.
Time frame: The average is calculated for the Baseline and for each study week. Reported here is the change from Baseline to Week 8
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| OTO-313 Full Analysis Set | Change From Baseline in Daily Tinnitus Annoyance at Week 8 | -0.73 units on a scale | Standard Deviation 1.91 |
| Placebo Full Analysis Set | Change From Baseline in Daily Tinnitus Annoyance at Week 8 | -1.11 units on a scale | Standard Deviation 1.804 |
Secondary
Change From Baseline in Daily Tinnitus Loudness at Week 8
Numerical rating scale (NRS) from 0 (No Tinnitus) to 10 (Extremely Loud Tinnitus) collected every day. Post-baseline weekly NRS scores will be calculated as the average score of all recorded diary entries within each study week.
Time frame: The average is calculated for the Baseline and for each study week. Reported here is the change from Baseline to Week 8.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| OTO-313 Full Analysis Set | Change From Baseline in Daily Tinnitus Loudness at Week 8 | -0.67 units on a scale | Standard Deviation 1.767 |
| Placebo Full Analysis Set | Change From Baseline in Daily Tinnitus Loudness at Week 8 | -0.90 units on a scale | Standard Deviation 1.557 |
Secondary
Patient Global Impression of Change at Week 8
Change in overall tinnitus status as perceived by the subject as assessed at the Week 8 visit. Subjects were asked, Since the beginning of the clinical study, how would you rate your tinnitus? and had the choice to answer from very much worse (-3) to very much improved (3). The mean change from baseline at Week 8 is reported here.
Time frame: Week 8 reported here
| Arm | Measure | Value (LEAST_SQUARES_MEAN) | Dispersion |
|---|---|---|---|
| OTO-313 Full Analysis Set | Patient Global Impression of Change at Week 8 | 0.32 score on a scale | Standard Error 0.139 |
| Placebo Full Analysis Set | Patient Global Impression of Change at Week 8 | 0.36 score on a scale | Standard Error 0.138 |
Other Pre-specified
Otoscopic Examinations - Presence of Perforation in the Treated Ear at Week 16 (Final Visit)
Ear examinations were done at every visit. One of the important safety endpoints is an observation of a perforation in the ear drum that did not heal properly after the injection. Reported here are the Week 16 (final visit) results.
Time frame: After dosing (Baseline) up to end of study (16 Weeks)
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| OTO-313 Full Analysis Set | Otoscopic Examinations - Presence of Perforation in the Treated Ear at Week 16 (Final Visit) | 0 Participants |
| Placebo Full Analysis Set | Otoscopic Examinations - Presence of Perforation in the Treated Ear at Week 16 (Final Visit) | 0 Participants |