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 (the 4-week [28 Days] Interval From Week 9 Through Week 12) - FAS-1 Population | 3 months | In the Full Analysis Set (FAS)-1 population, the number of DVDs at Week 12 (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. The Baseline visit occurred at the end of lead-in. No intervention was administered during lead-in. |
| The Number of DVD at Week 12 (the 4-week [28 Days] Interval From Week 9 Through Week 12) - FAS-2 Population | 3 months | The number of DVDs at Week 12 (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. The Baseline visit occurred at the end of lead-in. No intervention was administered during lead-in. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| 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 (Week12 \[Month 3\]). Week 12 = 12 weeks after dosing at the Baseline visit. The Baseline visit occurred at the end of lead-in. No intervention was administered during lead-in. |
| 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 (\<=10 dB) to impairment (\>10 dB) when measure at 500 Hz. Week 12 = 12 weeks after dosing at the Baseline visit. The Baseline visit occurred at the end of lead-in. No intervention was administered during lead-in. |
| Effect of Vertigo on Daily Activities - Number of Days Sick at Home or Bedridden at Week 12 (Month 3): FAS-1 | 3 months | Week 12 = 12 weeks after dosing at the Baseline visit. The Baseline visit occurred at the end of lead-in. No intervention was administered during lead-in. 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. = bedridden |
| Audiometry - Shift in Air-Bone Gap at 2000 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 2000 Hz. Week 12 (Month 3) = 12 weeks after dosing at the Baseline visit. The Baseline visit occurred at the end of lead-in. No intervention was administered during lead-in. |
| Audiometry - Shift in Air-Bone Gap at 1000 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 1000 Hz. Week 12 (Month 3) = 12 weeks after dosing at the Baseline visit. The Baseline visit occurred at the end of lead-in. No intervention was administered during lead-in. |
| Effect of Vertigo on Daily Activities - Number of Days Sick at Home or Bedridden at Week 12 (Month 3): FAS-2 | 3 months | Week 12 = 12 weeks after dosing at the Baseline visit. The Baseline visit occurred at the end of lead-in. No intervention was administered during lead-in. 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. = bedridden |
Countries
United States
Participant flow
Recruitment details
176 subjects were randomized and 174 subjects received study drug. The most common reason for screen failure was insufficient number of definitive vertigo days in the 28-day lead-in period. The first subject enrolled March 21, 2016, and the last subject completed September 15, 2017. A total of 49 centers in Europe (Belgium, France, Germany, Italy, Poland, United Kingdom) enrolled subjects.
Pre-assignment details
This study was terminated early based on results of study 104-201506, a US Phase 3 study that indicated no statistically significant difference in the primary endpoint of reduction in definitive vertigo days (DVD) for OTO-104 vs placebo nor for any of the secondary endpoints. Decision was made to terminate all ongoing studies on August 31, 2017, including this study. At the time of termination, 112/176 randomized subjects completed the study out to Week 12 (Month 3).
Participants by arm
| Arm | Count |
|---|---|
| OTO-104 (Full Analysis Set -1) 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). | 86 |
| Placebo (Full Analysis Set - 1) 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 least1 post baseline daily diary entry). | 88 |
| Total | 174 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Other - Not Specified | 2 | 0 |
| Overall Study | Study Terminated by Sponsor | 31 | 29 |
| Overall Study | Subject Randomized, but Did not Receive Drug | 2 | 0 |
Baseline characteristics
| Characteristic | OTO-104 (Full Analysis Set -1) | Total | Placebo (Full Analysis Set - 1) |
|---|---|---|---|
| Age, Categorical <=18 years | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical >=65 years | 14 Participants | 27 Participants | 13 Participants |
| Age, Categorical Between 18 and 65 years | 72 Participants | 147 Participants | 75 Participants |
| Age, Continuous | 53.0 years | 53.0 years | 53.0 years |
| Ethnicity (NIH/OMB) Hispanic or Latino | 0 Participants | 1 Participants | 1 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 77 Participants | 152 Participants | 75 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 9 Participants | 21 Participants | 12 Participants |
| Previous IT Steroid Injection | 5 Participants | 12 Participants | 7 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 82 Participants | 164 Participants | 82 Participants |
| Race (NIH/OMB) Asian | 1 Participants | 2 Participants | 1 Participants |
| Race (NIH/OMB) Black or African American | 0 Participants | 0 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 | 3 Participants | 8 Participants | 5 Participants |
| Race (NIH/OMB) White | 0 Participants | 0 Participants | 0 Participants |
| Region of Enrollment Belgium | 3 participants | 8 participants | 5 participants |
| Region of Enrollment France | 4 participants | 9 participants | 5 participants |
| Region of Enrollment Germany | 13 participants | 28 participants | 15 participants |
| Region of Enrollment Italy | 12 participants | 18 participants | 6 participants |
| Region of Enrollment Poland | 28 participants | 62 participants | 34 participants |
| Region of Enrollment United Kingdom | 26 participants | 49 participants | 23 participants |
| Sex: Female, Male Female | 44 Participants | 92 Participants | 48 Participants |
| Sex: Female, Male Male | 42 Participants | 82 Participants | 40 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 0 / 86 | 0 / 88 |
| other Total, other adverse events | 52 / 86 | 29 / 88 |
| serious Total, serious adverse events | 2 / 86 | 0 / 88 |
Outcome results
Primary
The Number of DVD at Week 12 (the 4-week [28 Days] Interval From Week 9 Through Week 12) - FAS-1 Population
In the Full Analysis Set (FAS)-1 population, the number of DVDs at Week 12 (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. The Baseline visit occurred at the end of lead-in. No intervention was administered during lead-in.
Time frame: 3 months
Population: A subject is included in the analysis if they 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 one post-baseline daily diary entry. The model and corresponding method of estimation adjusted for overdispersion and addressed missing 4-week intervals under the assumption of Missing at Random (MAR).
| Arm | Measure | Value (MEAN) |
|---|---|---|
| OTO-104 (Full Analysis Set -1) | The Number of DVD at Week 12 (the 4-week [28 Days] Interval From Week 9 Through Week 12) - FAS-1 Population | 2.336 Definitive Vertigo Day |
| Placebo (Full Analysis Set - 1) | The Number of DVD at Week 12 (the 4-week [28 Days] Interval From Week 9 Through Week 12) - FAS-1 Population | 3.549 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: =0.02995% CI: [0.453, 0.957]Regression, Linear
Primary
The Number of DVD at Week 12 (the 4-week [28 Days] Interval From Week 9 Through Week 12) - FAS-2 Population
The number of DVDs at Week 12 (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. The Baseline visit occurred at the end of lead-in. No intervention was administered during lead-in.
Time frame: 3 months
Population: The FAS - 2 includes all subjects from FAS-1 who were randomized 12 weeks prior to the study termination decision date of August 31, 2017 (i.e., subjects that had the opportunity to complete 12 weeks of daily diary entries in the study at the time of study termination).
| Arm | Measure | Value (MEAN) |
|---|---|---|
| OTO-104 (Full Analysis Set -1) | The Number of DVD at Week 12 (the 4-week [28 Days] Interval From Week 9 Through Week 12) - FAS-2 Population | 2.044 Definitive Vertigo Day |
| Placebo (Full Analysis Set - 1) | The Number of DVD at Week 12 (the 4-week [28 Days] Interval From Week 9 Through Week 12) - FAS-2 Population | 3.467 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: =0.01495% CI: [0.388, 0.896]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. Week 12 (Month 3) = 12 weeks after dosing at the Baseline visit. The Baseline visit occurred at the end of lead-in. No intervention was administered during lead-in.
Time frame: 3 months
Population: Subjects that had no impairment at the baseline visit (air-bone gap \<=10 dB) and had an audiogram collected at the Week 12 (Month 3) visit.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| OTO-104 (Full Analysis Set -1) | Audiometry - Shift in Air-Bone Gap at 1000 Hz From Baseline to Week 12 (Month 3) | 11 Participants |
| Placebo (Full Analysis Set - 1) | 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. Week 12 (Month 3) = 12 weeks after dosing at the Baseline visit. The Baseline visit occurred at the end of lead-in. No intervention was administered during lead-in.
Time frame: 3 months
Population: Subjects that had no impairment at the baseline visit (air-bone gap \<=10 dB) and had an audiogram collected at the Week 12 (Month 3) visit.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| OTO-104 (Full Analysis Set -1) | Audiometry - Shift in Air-Bone Gap at 2000 Hz From Baseline to Week 12 (Month 3) | 0 Participants |
| Placebo (Full Analysis Set - 1) | Audiometry - Shift in Air-Bone Gap at 2000 Hz From Baseline to Week 12 (Month 3) | 4 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 (\<=10 dB) to impairment (\>10 dB) when measure at 500 Hz. Week 12 = 12 weeks after dosing at the Baseline visit. The Baseline visit occurred at the end of lead-in. No intervention was administered during lead-in.
Time frame: 3 Months
Population: Subjects that had no impairment at the baseline visit (air-bone gap \<=10 dB) and had an audiogram collected at the Week 12 (Month 3) visit.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| OTO-104 (Full Analysis Set -1) | Audiometry - Shift in Air-Bone Gap at 500 Hz From Baseline to Week 12 (Month 3) | 8 Participants |
| Placebo (Full Analysis Set - 1) | 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): FAS-1
Week 12 = 12 weeks after dosing at the Baseline visit. The Baseline visit occurred at the end of lead-in. No intervention was administered during lead-in. 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. = bedridden
Time frame: 3 months
Population: A subject is included in the analysis if they 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 one post-baseline daily diary entry. The model and corresponding method of estimation adjusted for overdispersion and addressed missing 4-week intervals under the assumption of Missing at Random (MAR).
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| OTO-104 (Full Analysis Set -1) | Effect of Vertigo on Daily Activities - Number of Days Sick at Home or Bedridden at Week 12 (Month 3): FAS-1 | 1.2 days | Standard Deviation 2.32 |
| Placebo (Full Analysis Set - 1) | Effect of Vertigo on Daily Activities - Number of Days Sick at Home or Bedridden at Week 12 (Month 3): FAS-1 | 2.3 days | Standard Deviation 4.58 |
Secondary
Effect of Vertigo on Daily Activities - Number of Days Sick at Home or Bedridden at Week 12 (Month 3): FAS-2
Week 12 = 12 weeks after dosing at the Baseline visit. The Baseline visit occurred at the end of lead-in. No intervention was administered during lead-in. 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. = bedridden
Time frame: 3 months
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| OTO-104 (Full Analysis Set -1) | Effect of Vertigo on Daily Activities - Number of Days Sick at Home or Bedridden at Week 12 (Month 3): FAS-2 | 1.2 days | Standard Deviation 2.18 |
| Placebo (Full Analysis Set - 1) | Effect of Vertigo on Daily Activities - Number of Days Sick at Home or Bedridden at Week 12 (Month 3): FAS-2 | 2.2 days | Standard Deviation 4.68 |
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 (Week12 \[Month 3\]). Week 12 = 12 weeks after dosing at the Baseline visit. The Baseline visit occurred at the end of lead-in. No intervention was administered during lead-in.
Time frame: 3 months
Population: Only subjects that had a Month 3 otoscopic examination are included in assessment of this emdpoint.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| OTO-104 (Full Analysis Set -1) | Otoscopic Examination - Tympanic Membrane Perforation at Week 12 (Month 3) | 1 Participants |
| Placebo (Full Analysis Set - 1) | Otoscopic Examination - Tympanic Membrane Perforation at Week 12 (Month 3) | 0 Participants |