Meniere's Disease
Conditions
Keywords
Meniere's Disease, Vertigo
Brief summary
The purpose of this study is to evaluate the effectiveness of OTO-104 for the treatment of Meniere's disease.
Interventions
DRUGOTO-104
Single intratympanic injection of 12 mg OTO-104
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)
Eligibility
Sex/Gender
ALL
Age
18 Years to 85 Years
Healthy volunteers
No
Inclusion criteria
includes, but is not limited to: * Subject has a diagnosis of unilateral Meniere's disease by 1995 American Academy of Otolaryngology - Head and Neck Surgery (AAOHNS) criteria and reports active vertigo for the 2 months prior to the study lead-in period. * Subject has experienced active vertigo during the lead-in period. * Subject has documented asymmetric sensorineural hearing loss. * Subject agrees to maintain their current treatments for Meniere's disease while on-study.
Exclusion criteria
includes, but is not limited to: * Subject is pregnant or lactating. * Subject has a history of immunodeficiency disease. * Subject has a history of previous endolymphatic sac surgery. * Subject has a history of previous use of intratympanic (IT) gentamicin in the affected ear. * Subject has a history of tympanostomy tubes with evidence of perforation or lack of closure. * Subject has experienced an adverse reaction to IT injection of steroids. * Subject has used an investigational drug or device in the 3 months prior to screening. * Subject has previously been randomized to a trial of OTO-104.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| The Number of DVD at Week 12 (Defined as the 4-week [28 Days] Interval From Week 9 Through Week 12). | Week 12 (3 months) | The number of DVDs at Week 12 (defined as the 4-week \[28 days\] interval from Week 9 through Week 12) was compared between OTO-104 and placebo. Week 12 = 12 weeks after dosing at the Baseline visit. Baseline occurred at the end of lead-in and no intervention was administered during lead-in. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Effect of Vertigo on Daily Activities - Number of Days Sick at Home or Bedridden at Week 12 (Month 3) | 3 months | Questionnaire - subjects were instructed to record the effect on their daily activities of their total vertigo experienced that day using a 5-point scoring system: 0 = normal activity 1. = slight limitation 2. = moderate limitation 3. = sick at home 4. = bed ridden |
| Otoscopic Examination - Tympanic Membrane Perforation at Week 12 (Month 3) | 3 months | Otoscopic examinations were conducted at each visit. It was considered important to understand if the tympanic perforation that resulted from the IT injection at the Baseline visit persisted at the end of study visit (Week 12 \[Month 3\]). |
| Audiometry - Shift in Air-Bone Gap at 500 Hz From Baseline to Week 12 (Month 3) | 3 months | The number of subjects with a change in air-bone gap from Baseline to Week 12 (Month 3) from no impairment at baseline (\<= 10 dB) to impairment at Month 3 (\>10 dB) when measured at 500 Hz. |
| Audiometry - Shift in Air-Bone Gap at 1000 Hz From Baseline to Week 12 (Month 3) | Week 12 (Month 3) | The number of subjects with a change in air-bone gap from Baseline to Week 12 (Month 3) from no impairment at baseline (\<= 10 dB) to impairment at Month 3 (\>10 dB) when measured at 1000 Hz. |
| Audiometry - Shift in Air-Bone Gap at 2000 Hz From Baseline to Week 12 (Month 3) | Week 12 (Month 3) | The number of subjects with a change in air-bone gap from Baseline to Week 12 (Month 3) from no impairment at baseline (\<= 10 dB) to impairment at Month 3 (\>10 dB) when measured at 2000 Hz. |
Countries
United States
Participant flow
Recruitment details
166 subjects were randomized and 165 subjects received study drug. The most common reason for screen failure was that there was not a sufficient number of definitive vertigo days in the 28-day lead-in period. The first subject enrolled on October 27, 2015, and the last subject completed the study on July 18, 2017. A total of 47 centers in the US enrolled subjects.
Pre-assignment details
In addition to meeting all screening visit inclusion criteria, potential subjects had to experience and record at least 4 and a maximum of 22 definitive vertigo day (DVD) during the 4 week lead-in period. In addition, the subject needed to complete at least 22 of 28 diary entries during the 4-week lead-in period. A DVD was defined each day the subject recorded a vertigo episode lasting at least 20 minutes corresponding to a vertigo score of 2 or more.
Participants by arm
| Arm | Count |
|---|---|
| OTO-104 (Full Analysis Set) Subjects that were randomized to OTO-104, received study drug, had a baseline definitive vertigo measurement (i.e., at least 1 baseline daily diary entry) for the 4-week lead-in period and at least one 4-week definitive vertigo measurement post-baseline (i.e., at least 1 post baseline daily diary entry). | 83 |
| Placebo (Full Analysis Set) Subjects that were randomized to placebo, received study drug, had a baseline definitive vertigo measurement (i.e., at least 1 baseline daily diary entry) for the 4-week lead-in period and at least one 4-week definitive vertigo measurement post-baseline (i.e., at least 1 post baseline daily diary entry). | 82 |
| Total | 165 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Did not receive study drug | 0 | 1 |
| Overall Study | Lack of Efficacy | 1 | 0 |
| Overall Study | Withdrawal by Subject | 2 | 2 |
Baseline characteristics
| Characteristic | Total | OTO-104 (Full Analysis Set) | Placebo (Full Analysis Set) |
|---|---|---|---|
| Age, Categorical <=18 years | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical >=65 years | 39 Participants | 18 Participants | 21 Participants |
| Age, Categorical Between 18 and 65 years | 126 Participants | 65 Participants | 61 Participants |
| Age, Continuous | 55.7 years | 54.0 years | 58.0 years |
| Ethnicity (NIH/OMB) Hispanic or Latino | 15 Participants | 8 Participants | 7 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 148 Participants | 73 Participants | 75 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 2 Participants | 2 Participants | 0 Participants |
| Previous IT Steroid Injection | 50 Participants | 20 Participants | 30 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 1 Participants | 0 Participants | 1 Participants |
| Race (NIH/OMB) Asian | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Black or African American | 8 Participants | 8 Participants | 0 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 | 2 Participants | 1 Participants | 1 Participants |
| Race (NIH/OMB) White | 154 Participants | 74 Participants | 80 Participants |
| Region of Enrollment United States | 165 participants | 83 participants | 82 participants |
| Sex: Female, Male Female | 94 Participants | 48 Participants | 46 Participants |
| Sex: Female, Male Male | 71 Participants | 35 Participants | 36 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 0 / 82 | 0 / 83 |
| other Total, other adverse events | 34 / 82 | 30 / 83 |
| serious Total, serious adverse events | 2 / 82 | 2 / 83 |
Outcome results
Primary
The Number of DVD at Week 12 (Defined as the 4-week [28 Days] Interval From Week 9 Through Week 12).
The number of DVDs at Week 12 (defined as the 4-week \[28 days\] interval from Week 9 through Week 12) was compared between OTO-104 and placebo. Week 12 = 12 weeks after dosing at the Baseline visit. Baseline occurred at the end of lead-in and no intervention was administered during lead-in.
Time frame: Week 12 (3 months)
Population: The full analysis set subjects who were randomized, received study drug, had a baseline definitive vertigo measurement for the 4-week lead-in period and at least one 4-week definitive vertigo measurement post-baseline, i.e., at least 1 post-baseline daily diary entry.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) |
|---|---|---|
| OTO-104 (Full Analysis Set) | The Number of DVD at Week 12 (Defined as the 4-week [28 Days] Interval From Week 9 Through Week 12). | 2.191 Definitive Vertigo Day |
| Placebo (Full Analysis Set) | The Number of DVD at Week 12 (Defined as the 4-week [28 Days] Interval From Week 9 Through Week 12). | 2.415 Definitive Vertigo Day |
Comparison: The primary efficacy endpoint was compared between OTO-104 and placebo at the 2-tailed 0.05 alpha level using a generalized Poisson linear mixed model. The model included fixed effects for randomized treatment group, sex, study week, a treatment group by study week interaction, and the count of lead-in period DVD standardized to 28 days as a covariate.p-value: 0.62395% CI: [0.615, 1.339]Regression, Linear
Secondary
Audiometry - Shift in Air-Bone Gap at 1000 Hz From Baseline to Week 12 (Month 3)
The number of subjects with a change in air-bone gap from Baseline to Week 12 (Month 3) from no impairment at baseline (\<= 10 dB) to impairment at Month 3 (\>10 dB) when measured at 1000 Hz.
Time frame: Week 12 (Month 3)
Population: Subjects that had no impairment at the Baseline visit (air-bone gap \<=10 dB
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| OTO-104 (Full Analysis Set) | Audiometry - Shift in Air-Bone Gap at 1000 Hz From Baseline to Week 12 (Month 3) | 3 Participants |
| Placebo (Full Analysis Set) | Audiometry - Shift in Air-Bone Gap at 1000 Hz From Baseline to Week 12 (Month 3) | 3 Participants |
Secondary
Audiometry - Shift in Air-Bone Gap at 2000 Hz From Baseline to Week 12 (Month 3)
The number of subjects with a change in air-bone gap from Baseline to Week 12 (Month 3) from no impairment at baseline (\<= 10 dB) to impairment at Month 3 (\>10 dB) when measured at 2000 Hz.
Time frame: Week 12 (Month 3)
Population: Subjects that had no impairment at the Baseline visit (air-bone gap \<=10 dB)
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| OTO-104 (Full Analysis Set) | Audiometry - Shift in Air-Bone Gap at 2000 Hz From Baseline to Week 12 (Month 3) | 4 Participants |
| Placebo (Full Analysis Set) | Audiometry - Shift in Air-Bone Gap at 2000 Hz From Baseline to Week 12 (Month 3) | 1 Participants |
Secondary
Audiometry - Shift in Air-Bone Gap at 500 Hz From Baseline to Week 12 (Month 3)
The number of subjects with a change in air-bone gap from Baseline to Week 12 (Month 3) from no impairment at baseline (\<= 10 dB) to impairment at Month 3 (\>10 dB) when measured at 500 Hz.
Time frame: 3 months
Population: Subjects that had no impairment at the Baseline visit (air-bone gap \<=10 dB)
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| OTO-104 (Full Analysis Set) | Audiometry - Shift in Air-Bone Gap at 500 Hz From Baseline to Week 12 (Month 3) | 2 Participants |
| Placebo (Full Analysis Set) | Audiometry - Shift in Air-Bone Gap at 500 Hz From Baseline to Week 12 (Month 3) | 7 Participants |
Secondary
Effect of Vertigo on Daily Activities - Number of Days Sick at Home or Bedridden at Week 12 (Month 3)
Questionnaire - subjects were instructed to record the effect on their daily activities of their total vertigo experienced that day using a 5-point scoring system: 0 = normal activity 1. = slight limitation 2. = moderate limitation 3. = sick at home 4. = bed ridden
Time frame: 3 months
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| OTO-104 (Full Analysis Set) | Effect of Vertigo on Daily Activities - Number of Days Sick at Home or Bedridden at Week 12 (Month 3) | 1.287 days | Standard Deviation 2.8797 |
| Placebo (Full Analysis Set) | Effect of Vertigo on Daily Activities - Number of Days Sick at Home or Bedridden at Week 12 (Month 3) | 1.058 days | Standard Deviation 2.077 |
Secondary
Otoscopic Examination - Tympanic Membrane Perforation at Week 12 (Month 3)
Otoscopic examinations were conducted at each visit. It was considered important to understand if the tympanic perforation that resulted from the IT injection at the Baseline visit persisted at the end of study visit (Week 12 \[Month 3\]).
Time frame: 3 months
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| OTO-104 (Full Analysis Set) | Otoscopic Examination - Tympanic Membrane Perforation at Week 12 (Month 3) | 4 participants |
| Placebo (Full Analysis Set) | Otoscopic Examination - Tympanic Membrane Perforation at Week 12 (Month 3) | 0 participants |