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Negative Efficacy Results from the recently completed Phase 3 study 104-201506
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The purpose of this study is to evaluate the effectiveness of OTO-104 for the treatment of Meniere's disease.
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| Label | Type | Description | Intervention Names |
|---|---|---|---|
| OTO-104 | Experimental | 12 mg dexamethasone |
|
| Placebo | Placebo Comparator |
|
| Name | Type | Description | Arm Group Labels | Other Names |
|---|---|---|---|---|
| OTO-104 | Drug | Single intratympanic injection of 12 mg OTO-104 |
| |
| Measure | Description | Time Frame |
|---|---|---|
| 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. | 3 months |
| 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. | 3 months |
| Measure | Description | Time Frame |
|---|---|---|
| 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
|
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Inclusion Criteria includes, but is not limited to:
Exclusion Criteria includes, but is not limited to:
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| Name | Affiliation | Role |
|---|---|---|
| Kathie Bishop, PhD | Otonomy, Inc. | Study Chair |
| Facility | Status | City | State | ZIP | Country | Contacts |
|---|---|---|---|---|---|---|
| Many sites in Europe. Refer to the contact info listed below. | San Diego | California | 92121 | United States |
| PubMed Identifier | Type | Citation | Retractions |
|---|---|---|---|
| 37185596 | Derived | Phillips J, Mikulec AA, Robinson JM, Skarinsky D, Anderson JJ. Efficacy of Intratympanic OTO-104 for the Treatment of Meniere's Disease: The Outcome of Three Randomized, Double-Blind, Placebo-Controlled Studies. Otol Neurotol. 2023 Jul 1;44(6):584-592. doi: 10.1097/MAO.0000000000003886. Epub 2023 Apr 22. |
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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).
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.
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| ID | Title | Description |
|---|---|---|
| FG000 | OTO-104 | 12 mg dexamethasone OTO-104: Single intratympanic injection of 12 mg OTO-104 |
| FG001 | Placebo | Placebo: Single intratympanic injection of placebo |
| Title | Milestones | Reasons Not Completed | |||||||||||||||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Overall Study |
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| ID | Title | Description |
|---|---|---|
| BG000 | 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). |
| Units | Counts |
|---|---|
| Participants |
|
| Title | Description | Population Description | Parameter Type | Dispersion Type | Unit of Measure | Calculate Percentage | Denominator Units Selected | Denominators | Classes |
|---|---|---|---|---|---|---|---|---|---|
| Age, Categorical | Count of Participants |
| Type | Title | Description | Population Description | Reporting Status | Anticipated Posting Date | Parameter Type | Dispersion Type | Unit of Measure | Calculate Percentage | Time Frame | Units Analyzed | Denominator Units Selected | Arm/Group Information | Denominators | Classes | Analyses | ||
|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|---|
| 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. | 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). | Posted | Mean | 95% Confidence Interval | Definitive Vertigo Day | 3 months |
|
Reported or observed during or after dosing with the study drug at the Baseline visit up until the Week 12 (3 Months) end of study visit. The Baseline visit occurred at the end of lead-in. No intervention was administered during lead-in, which is why adverse events were collected starting at the Baseline visit during dosing up until the final visit.
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| ID | Title | Description | Deaths (Affected) | Deaths (At Risk) | Serious Events (Affected) | Serious Events (At Risk) | Other Events (Affected) | Other Events (At Risk) |
|---|---|---|---|---|---|---|---|---|
| EG000 | OTO-104 (Safety Analysis Set) | All subjects who receivedOTO-104. Subjects were included in this treatment group according to the actual treatment received regardless of their randomized assignment. |
| Term | Organ System | Source Vocabulary | Assessment Type | Notes | Statistical Information |
|---|---|---|---|---|---|
| Head Injury | Injury, poisoning and procedural complications | MedDRA (18.1) | Non-systematic Assessment |
| Term | Organ System | Source Vocabulary | Assessment Type | Notes | Statistical Information |
|---|---|---|---|---|---|
| Headache | Nervous system disorders | MedDRA (18.1) | Non-systematic Assessment |
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| Title | Organization | Phone | Extension | |
|---|---|---|---|---|
| Otonomy Medical Information Center | Otonomy, Inc. | 1-844-686-4636 | medinfo@otonomy.com |
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| Type | Includes Protocol | Includes SAP | Includes ICF | Document Label | Document Date | Document Uploaded Date | Document File Name |
|---|---|---|---|---|---|---|---|
| Prot_SAP | Yes | Yes | No | Study Protocol and Statistical Analysis Plan | Jan 13, 2016 | Sep 27, 2022 | Prot_SAP_000.pdf |
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| ID | Term |
|---|---|
| D008575 | Meniere Disease |
| D014717 | Vertigo |
| ID | Term |
|---|---|
| D018159 | Endolymphatic Hydrops |
| D007759 | Labyrinth Diseases |
| D004427 | Ear Diseases |
| D010038 | Otorhinolaryngologic Diseases |
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| Placebo |
| Drug |
Single intratympanic injection of placebo |
|
| 3 months |
| 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
| 3 months |
| 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. | 3 months |
| 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. | 3 Months |
| 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. | 3 months |
| 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. | 3 months |
| Other - Not Specified |
|
| BG001 |
| 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). |
| BG002 | Total | Total of all reporting groups |
| Participants |
|
| Age, Continuous | Median | Full Range | years |
|
| Sex: Female, Male | Count of Participants | Participants |
|
| Ethnicity (NIH/OMB) | Count of Participants | Participants |
|
| Race (NIH/OMB) | Count of Participants | Participants |
|
| Region of Enrollment | Number | participants |
|
| Previous IT Steroid Injection | Count of Participants | Participants |
|
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). |
| OG001 | 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 least 1 post baseline daily diary entry). |
|
|
|
| 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. | 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). | Posted | Mean | 95% Confidence Interval | Definitive Vertigo Day | 3 months |
|
|
|
|
| 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
| 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). | Posted | Mean | Standard Deviation | days | 3 months |
|
|
|
| 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
| Posted | Mean | Standard Deviation | days | 3 months |
|
|
|
| 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. | Only subjects that had a Month 3 otoscopic examination are included in assessment of this emdpoint. | Posted | Count of Participants | Participants | 3 months |
|
|
|
| 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. | 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. | Posted | Count of Participants | Participants | 3 Months |
|
|
|
| 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. | 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. | Posted | Count of Participants | Participants | 3 months |
|
|
|
| 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. | 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. | Posted | Count of Participants | Participants | 3 months |
|
|
|
| 0 |
| 86 |
| 2 |
| 86 |
| 52 |
| 86 |
| EG001 | Placebo (Safety Analysis Set) | All subjects who received Placebo. Subjects were included in this treatment group according to the actual treatment received regardless of their randomized assignment. | 0 | 88 | 0 | 88 | 29 | 88 |
| Cholecystitis | Hepatobiliary disorders | MedDRA (18.1) | Non-systematic Assessment |
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| Dizziness | Nervous system disorders | MedDRA (18.1) | Non-systematic Assessment |
|
| Dysgeusia | Nervous system disorders | MedDRA (18.1) | Non-systematic Assessment |
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| Hypoesthesia | Nervous system disorders | MedDRA (18.1) | Non-systematic Assessment |
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| Meniere's Disease | Ear and labyrinth disorders | MedDRA (18.1) | Non-systematic Assessment |
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| Tinnitus | Ear and labyrinth disorders | MedDRA (18.1) | Non-systematic Assessment |
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| Ear Pain | Ear and labyrinth disorders | MedDRA (18.1) | Non-systematic Assessment |
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| Vertigo | Ear and labyrinth disorders | MedDRA (18.1) | Non-systematic Assessment |
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| Ear Discomfort | Ear and labyrinth disorders | MedDRA (18.1) | Non-systematic Assessment |
|
| Nasopharyngitis | Infections and infestations | MedDRA (18.1) | Non-systematic Assessment |
|
| Upper Respiratory Tract Infection | Infections and infestations | MedDRA (18.1) | Non-systematic Assessment |
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| Nausea | Gastrointestinal disorders | MedDRA (18.1) | Non-systematic Assessment |
|
| Erythema | Skin and subcutaneous tissue disorders | MedDRA (18.1) | Non-systematic Assessment |
|
| Injection Site Pain | General disorders | MedDRA (18.1) | Non-systematic Assessment |
|
| Suicidal Ideation | Psychiatric disorders | MedDRA (18.1) | Non-systematic Assessment |
|
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| D015837 |
| Vestibular Diseases |
| D009461 | Neurologic Manifestations |
| D009422 | Nervous System Diseases |
| D012816 | Signs and Symptoms |
| D013568 | Pathological Conditions, Signs and Symptoms |