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    Clinical Trial Results:
    A prospective, randomized, double blind, placebo-controlled, multicenter, Phase 3 efficacy and safety study of OTO-104 given as a single intratympanic injection in subjects with unilateral Meniere’s disease.

    Summary
    EudraCT number
    2018-001464-35
    Trial protocol
    GB   ES   BE   IT  
    Global end of trial date
    22 Dec 2020

    Results information
    Results version number
    v1(current)
    This version publication date
    15 Dec 2022
    First version publication date
    15 Dec 2022
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    104-201811
    Additional study identifiers
    ISRCTN number
    -
    US NCT number
    NCT03664674
    WHO universal trial number (UTN)
    -
    Sponsors
    Sponsor organisation name
    Otonomy, Inc.
    Sponsor organisation address
    4796 Executive Drive, San Diego, United States, 92121
    Public contact
    Medical Information, Otonomy, Inc., 1 6193232200,
    Scientific contact
    Medical Information, Otonomy, Inc., 1 844-686-4636, medinfo@otonomy.com
    Paediatric regulatory details
    Is trial part of an agreed paediatric investigation plan (PIP)
    No
    Does article 45 of REGULATION (EC) No 1901/2006 apply to this trial?
    No
    Does article 46 of REGULATION (EC) No 1901/2006 apply to this trial?
    No
    Results analysis stage
    Analysis stage
    Final
    Date of interim/final analysis
    25 Feb 2021
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    22 Dec 2020
    Global end of trial reached?
    Yes
    Global end of trial date
    22 Dec 2020
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    To investigate the efficacy of OTO-104 in subjects with Meniere’s disease, as measured by the number of definitive vertigo days (DVD) at Week 12 (the 4-week interval from Week 9 through Week 12).
    Protection of trial subjects
    The study was conducted in accordance with current Good Clinical Practice (GCP). This study was undertaken only after a designated Independent Ethics Committee (IEC) had fully approved the protocol and the sponsor had received a copy of the approval. Written informed consent was obtained from each subject prior to the performance of any study-specific procedures according to local requirements after the nature of the study had been fully explained. Each subject was informed that they were free not to participate in the study and that they could withdraw consent to participate at any time. Subjects who chose to participate signed an informed consent document. Lastly, to decrease pain from the injection procedure, the tympanic membrane was anesthetized with a topical lidocaine/prilocaine cream.
    Background therapy
    Subjects were allowed to continue symptomatic relief medications for Ménière's disease symptoms, prescription drugs, herbal products, vitamins, minerals, and over-the-counter medications they were on when they started in the trial. They were requested to maintain the same regimen throughout the study.
    Evidence for comparator
    The study used a placebo control, which the sponsor believed was the most direct way to measure the effect of the investigational product. In addition, the following points support use of a placebo control: • There is no drug product injected in the ear that is approved for the treatment of Ménière's disease. While ear injections of steroid solutions are used in clinical practice, there is need for research to find out if they work. • Betahistine has been approved by certain health authorities and is commonly used to treat Ménière's disease. It may have been an active control to compare its effect versus OTO-104 however, a review of previous trials conducted with betahistine concluded that there is “insufficient evidence to say whether betahistine has any effect on Ménière's disease.” In addition, a more recent trial concluded that in the “randomised, placebo-controlled study described, the effects of two different doses of betahistine could not be distinguished from a patient reported effect caused by placebo intervention.” Therefore, its value as an active control is unknown. • Notwithstanding, subjects were recommended to continue taking medications they were taking before the study started. This could have included betahistine, diuretics (water pills), and/or a low salt diet (in other words, their standard of care). • The option of a sham injection of air or the patient not receiving any injection as a control was also considered. However, there was concern that this could accidentally “unblind” the patient (the patient would know they did not receive anything) if they could not tell if there was material in their ear. This could make it difficult to properly evaluate their vertigo, which could affect the study results.
    Actual start date of recruitment
    01 Oct 2018
    Long term follow-up planned
    No
    Independent data monitoring committee (IDMC) involvement?
    No
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    Poland: 60
    Country: Number of subjects enrolled
    Spain: 4
    Country: Number of subjects enrolled
    United Kingdom: 16
    Country: Number of subjects enrolled
    Belgium: 9
    Country: Number of subjects enrolled
    Germany: 15
    Country: Number of subjects enrolled
    Italy: 12
    Country: Number of subjects enrolled
    United States: 21
    Country: Number of subjects enrolled
    Turkey: 11
    Worldwide total number of subjects
    148
    EEA total number of subjects
    100
    Number of subjects enrolled per age group
    In utero
    0
    Preterm newborn - gestational age < 37 wk
    0
    Newborns (0-27 days)
    0
    Infants and toddlers (28 days-23 months)
    0
    Children (2-11 years)
    0
    Adolescents (12-17 years)
    0
    Adults (18-64 years)
    108
    From 65 to 84 years
    40
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    Overall, 66 investigators were approved in Belgium, Germany, Italy, Poland, Spain, Turkey, United States, and United Kingdom) to conduct this study. Forty-two investigators enrolled subjects. First subject was randomized 14 December 2018; Last subject was randomized 29 September 2020.

    Pre-assignment
    Screening details
    A total of 317 subjects registered for this study and signed informed consent. Of these, 149 subjects were randomized and 148 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.

    Period 1
    Period 1 title
    Baseline
    Is this the baseline period?
    Yes
    Allocation method
    Randomised - controlled
    Blinding used
    Double blind [1]
    Roles blinded
    Subject, Monitor, Data analyst, Assessor
    Blinding implementation details
    A treatment syringe (OTO-104 or placebo) was pre-loaded by an unblinded person. Each syringe was prepared to prevent visualization of syringe contents by all other study staff through the use of a syringe overlabel. Any interaction with subjects with regard to the collection, review or discussion of study assessments, with the exception of otoscopic exams, was done by the study coordinator, audiologist or someone other than the person who prepared the syringe and the physician who administered.

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    OTO-104
    Arm description
    Dexamethasone suspension in an aqueous solution containing poloxamer 407. Poloxamer 407 has thermosensitive properties such that it is a liquid at room temperature and will gel when exposed to body temperature when injected into the middle ear.
    Arm type
    Experimental

    Investigational medicinal product name
    OTO-104
    Investigational medicinal product code
    Other name
    Dexamethasone
    Pharmaceutical forms
    Powder and solution for suspension for injection
    Routes of administration
    Intratympanic use
    Dosage and administration details
    OTO-104 12 mg was administered as a single, 0.2 mL intratympanic injection of 60 mg/mL OTO-104. The OTO-104 final product suspension for dosing was prepared from 2 separate components: 16% poloxamer 407 solution (1 vial needed) and OTO-104 Active (1 vial needed). An appropriate volume of 16% poloxamer solution was withdrawn and delivered into the OTO 104 Active vial to achieve a visually homogeneous suspension of a target drug concentration of 60 mg/mL.

    Arm title
    Placebo
    Arm description
    The placebo was an aqueous solution of poloxamer 407.
    Arm type
    Placebo

    Investigational medicinal product name
    Placebo
    Investigational medicinal product code
    Other name
    Poloxamer 407 solution
    Pharmaceutical forms
    Solution for injection
    Routes of administration
    Intratympanic use
    Dosage and administration details
    Placebo was administered as a single, 0.2 mL intratympanic injection.

    Notes
    [1] - The roles blinded appear to be inconsistent with a double blind trial.
    Justification: Since the OTO-104 and placebo looked different (OTO-104 is a white suspension and placebo is clear), the investigator who administered the injection was unblinded. However, the other staff remained blinded since care was taken in preparation of the dosing syringe and examination of the ear post-injection. A blinding plan was created for each site prior to the first dose administration.
    Number of subjects in period 1
    OTO-104 Placebo
    Started
    73
    75
    Completed
    73
    75
    Period 2
    Period 2 title
    Follow-Up (Week 12)
    Is this the baseline period?
    No
    Allocation method
    Randomised - controlled
    Blinding used
    Double blind [2]
    Roles blinded
    Subject, Monitor, Data analyst, Assessor
    Blinding implementation details
    Any interaction with subjects with regard to the collection, review or discussion of study assessments, with the exception of otoscopic exams, was done by the study coordinator, audiologist or someone other than the person who prepared the syringe and the physician who administered the injection. As the injection was give at the Baseline visit, no further IMP was administered.

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    OTO-104
    Arm description
    Dexamethasone suspension in an aqueous solution containing poloxamer 407. Poloxamer 407 has thermosensitive properties such that it is a liquid at room temperature and will gel when exposed to body temperature when injected into the middle ear.
    Arm type
    Experimental

    Investigational medicinal product name
    OTO-104
    Investigational medicinal product code
    Other name
    Dexamethasone
    Pharmaceutical forms
    Powder and solution for suspension for injection
    Routes of administration
    Intratympanic use
    Dosage and administration details
    OTO-104 12 mg was administered as a single, 0.2 mL intratympanic injection of 60 mg/mL OTO-104. The OTO-104 final product suspension for dosing was prepared from 2 separate components: 16% poloxamer 407 solution (1 vial needed) and OTO-104 Active (1 vial needed). An appropriate volume of 16% poloxamer solution was withdrawn and delivered into the OTO 104 Active vial to achieve a visually homogeneous suspension of a target drug concentration of 60 mg/mL.

    Arm title
    Placebo
    Arm description
    The placebo was an aqueous solution of poloxamer 407.
    Arm type
    Placebo

    Investigational medicinal product name
    Placebo
    Investigational medicinal product code
    Other name
    Poloxamer 407 solution
    Pharmaceutical forms
    Solution for injection
    Routes of administration
    Intratympanic use
    Dosage and administration details
    Placebo was administered as a single, 0.2 mL intratympanic injection.

    Notes
    [2] - The roles blinded appear to be inconsistent with a double blind trial.
    Justification: Since the OTO-104 and placebo looked different (OTO-104 is a white suspension and placebo is clear), the investigator who administered the injection was unblinded. However, the other staff remained blinded since care was taken in preparation of the dosing syringe and examination of the ear post-injection. A blinding plan was created for each site prior to the first dose administration.
    Number of subjects in period 2
    OTO-104 Placebo
    Started
    73
    75
    Completed
    70
    73
    Not completed
    3
    2
         Consent withdrawn by subject
    2
    -
         Physician decision
    -
    1
         Adverse event, non-fatal
    1
    1

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    OTO-104
    Reporting group description
    Dexamethasone suspension in an aqueous solution containing poloxamer 407. Poloxamer 407 has thermosensitive properties such that it is a liquid at room temperature and will gel when exposed to body temperature when injected into the middle ear.

    Reporting group title
    Placebo
    Reporting group description
    The placebo was an aqueous solution of poloxamer 407.

    Reporting group values
    OTO-104 Placebo Total
    Number of subjects
    73 75 148
    Age categorical
    Units: Subjects
        Adults (18-64 years)
    51 57 108
        From 65-84 years
    22 18 40
        85 years and over
    0 0 0
    Age continuous
    Inclusion age for this study was 18 to 85 years, inclusive.
    Units: years
        median (full range (min-max))
    57.0 (27 to 75) 57.0 (26 to 83) -
    Gender categorical
    Both males and females were allowed in this study.
    Units: Subjects
        Female
    44 44 88
        Male
    29 31 60
    Duration of Meniere's Disease
    The length of time since diagnosis
    Units: Subjects
        <=5 years
    61 53 114
        6-10 years
    9 13 22
        11-15 years
    0 4 4
        >15 years
    3 5 8
    Subject analysis sets

    Subject analysis set title
    Intent to Treat Analysis Set
    Subject analysis set type
    Intention-to-treat
    Subject analysis set description
    The intent to treat analysis set included all randomized subjects all who receive study drug. Subjects were included in the treatment group to which they were randomized regardless of the actual study drug received.

    Subject analysis set title
    Safety Analysis Set
    Subject analysis set type
    Safety analysis
    Subject analysis set description
    The safety population included all subjects who received study drug. Note: The safety analysis set populations were displayed by the treatment the subject received.

    Subject analysis sets values
    Intent to Treat Analysis Set Safety Analysis Set
    Number of subjects
    148
    148
    Age categorical
    Units: Subjects
        Adults (18-64 years)
    108
    108
        From 65-84 years
    40
    40
        85 years and over
    0
    0
    Age continuous
    Inclusion age for this study was 18 to 85 years, inclusive.
    Units: years
        median (full range (min-max))
    57.0 (26 to 83)
    57.0 (26 to 83)
    Gender categorical
    Both males and females were allowed in this study.
    Units: Subjects
        Female
    86
    88
        Male
    58
    60
    Duration of Meniere's Disease
    The length of time since diagnosis
    Units: Subjects
        <=5 years
    111
    114
        6-10 years
    21
    22
        11-15 years
    4
    4
        >15 years
    8
    8

    End points

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    End points reporting groups
    Reporting group title
    OTO-104
    Reporting group description
    Dexamethasone suspension in an aqueous solution containing poloxamer 407. Poloxamer 407 has thermosensitive properties such that it is a liquid at room temperature and will gel when exposed to body temperature when injected into the middle ear.

    Reporting group title
    Placebo
    Reporting group description
    The placebo was an aqueous solution of poloxamer 407.
    Reporting group title
    OTO-104
    Reporting group description
    Dexamethasone suspension in an aqueous solution containing poloxamer 407. Poloxamer 407 has thermosensitive properties such that it is a liquid at room temperature and will gel when exposed to body temperature when injected into the middle ear.

    Reporting group title
    Placebo
    Reporting group description
    The placebo was an aqueous solution of poloxamer 407.

    Subject analysis set title
    Intent to Treat Analysis Set
    Subject analysis set type
    Intention-to-treat
    Subject analysis set description
    The intent to treat analysis set included all randomized subjects all who receive study drug. Subjects were included in the treatment group to which they were randomized regardless of the actual study drug received.

    Subject analysis set title
    Safety Analysis Set
    Subject analysis set type
    Safety analysis
    Subject analysis set description
    The safety population included all subjects who received study drug. Note: The safety analysis set populations were displayed by the treatment the subject received.

    Primary: 28-Day Average DVD at Week 12 (month 3)

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    End point title
    28-Day Average DVD at Week 12 (month 3)
    End point description
    End point type
    Primary
    End point timeframe
    Month 3 - defined as the 4 week interval from Week 9 and Week 12.
    End point values
    OTO-104 Placebo
    Number of subjects analysed
    73
    75
    Units: Days
        least squares mean (confidence interval 95%)
    2.869 (2.109 to 3.903)
    3.577 (2.641 to 4.844)
    Statistical analysis title
    Analysis of DVD Count at Week 12
    Statistical analysis description
    The count of definitive vertigo days for Week 12 was determined during the 4-week period between Weeks 9 and 12. A definitive vertigo day was any day the subject recorded a vertigo episode lasting at least 20 minutes and corresponding to a Vertigo Severity Score of 2 or more. Negative binomial model including coefficients for randomized treatment, sex, and lead-in period definitive vertigo days standardized to 28 days as a covariate.
    Comparison groups
    OTO-104 v Placebo
    Number of subjects included in analysis
    148
    Analysis specification
    Pre-specified
    Analysis type
    superiority [1]
    P-value
    = 0.312 [2]
    Method
    Generalized Linear Model – Neg Binomial
    Parameter type
    Mean difference (final values)
    Point estimate
    -0.221
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -0.648
         upper limit
    0.207
    Variability estimate
    Standard error of the mean
    Dispersion value
    0.218
    Notes
    [1] - Generalized Linear Model – Negative Binomial Regression Model with count data by subject transformed using the log-link function.
    [2] - The parameter estimate and confidence interval results back-transform to the ratio of adjusted mean definitive vertigo days (OTO-104/Placebo) to be 0.802 (0.523, 1.230).

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    Adverse events were recorded as observed or reported during or after dosing up to the final visit (Day 84).
    Assessment type
    Non-systematic
    Dictionary used for adverse event reporting
    Dictionary name
    MedDRA
    Dictionary version
    23.0
    Reporting groups
    Reporting group title
    OTO-104
    Reporting group description
    Dexamethasone suspension in an aqueous solution containing poloxamer 407. Poloxamer 407 has thermosensitive properties such that it is a liquid at room temperature and will gel when exposed to body temperature when injected into the middle ear.

    Reporting group title
    Placebo
    Reporting group description
    The placebo was an aqueous solution of poloxamer 407.

    Serious adverse events
    OTO-104 Placebo
    Total subjects affected by serious adverse events
         subjects affected / exposed
    2 / 73 (2.74%)
    2 / 75 (2.67%)
         number of deaths (all causes)
    0
    0
         number of deaths resulting from adverse events
    0
    0
    Ear and labyrinth disorders
    Vertigo
         subjects affected / exposed
    0 / 73 (0.00%)
    1 / 75 (1.33%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Meniere's disease
         subjects affected / exposed
    0 / 73 (0.00%)
    1 / 75 (1.33%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Reproductive system and breast disorders
    Uterine haemorrhage
         subjects affected / exposed
    1 / 73 (1.37%)
    0 / 75 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Infections and infestations
    COVID-19
         subjects affected / exposed
    1 / 73 (1.37%)
    0 / 75 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 2%
    Non-serious adverse events
    OTO-104 Placebo
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    26 / 73 (35.62%)
    27 / 75 (36.00%)
    Injury, poisoning and procedural complications
    Limb injury
         subjects affected / exposed
    2 / 73 (2.74%)
    0 / 75 (0.00%)
         occurrences all number
    2
    0
    Fall
         subjects affected / exposed
    1 / 73 (1.37%)
    2 / 75 (2.67%)
         occurrences all number
    1
    2
    Nervous system disorders
    Headache
         subjects affected / exposed
    2 / 73 (2.74%)
    0 / 75 (0.00%)
         occurrences all number
    2
    0
    Ear and labyrinth disorders
    Meniere's disease
         subjects affected / exposed
    6 / 73 (8.22%)
    6 / 75 (8.00%)
         occurrences all number
    6
    6
    Tinnitus
         subjects affected / exposed
    5 / 73 (6.85%)
    0 / 75 (0.00%)
         occurrences all number
    5
    0
    Vertigo
         subjects affected / exposed
    4 / 73 (5.48%)
    7 / 75 (9.33%)
         occurrences all number
    4
    7
    Ear discomfort
         subjects affected / exposed
    2 / 73 (2.74%)
    2 / 75 (2.67%)
         occurrences all number
    2
    2
    Ear pain
         subjects affected / exposed
    1 / 73 (1.37%)
    4 / 75 (5.33%)
         occurrences all number
    1
    4
    Tympanic membrane disorder
         subjects affected / exposed
    0 / 73 (0.00%)
    2 / 75 (2.67%)
         occurrences all number
    0
    2
    Infections and infestations
    Upper respiratory tract infection
         subjects affected / exposed
    2 / 73 (2.74%)
    2 / 75 (2.67%)
         occurrences all number
    2
    2
    Nasopharyngitis
         subjects affected / exposed
    1 / 73 (1.37%)
    2 / 75 (2.67%)
         occurrences all number
    1
    2

    More information

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    Substantial protocol amendments (globally)

    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    16 Aug 2019
    Version 2.0 implemented the following substantive changes: • Clarified that subjects should continue to record their daily vertigo experience until Day 84 even if Visit 5 was performed early (out of window) • Increased the number of study sites from approximately 50 to 60 • Increased upper age limit from 75 to 85 • Clarified that unblinding could be done through the study randomization system • Clarified the topical lidocaine included lidocaine spray and that other related anesthetics may have been used • Clarified that tympanometry did not need to be performed if the examiner decided that there was a contraindication to performing the procedure, such as tympanic perforation • Corrected the protocol to indicate that at Screening audiograms should also have been conducted at 250 and 3000 Hz • Clarified that medical staff who perform the otoscopic examinations did not need to be physicians, but should have been medical personnel who were experienced in performing otoscopic examinations • Removed the Completer analysis set to be consistent with the draft statistical analysis plan
    30 Jul 2020
    Version 3.0 implemented the following substantive changes: • Updated number of enrolled subjects from 160 to approximately 142 subjects • Revised sample size calculation based on Negative Binomial model at Week 12 (replacing the generalized Poisson model) • Analysis sets definitions revised and reflected primary analysis at Week 12 (the 4-week [28 day] interval from Week 9 to Week 12) and clarified when the ITT analysis set would be used. • For subgroup analyses, added age categories at the higher end • For subgroup analyses, added betahistine use as a subgroup • Updated the primary efficacy endpoint to the 28-day average DVD at Week 12 (rather than number of DVD at Week 12) • Added 2 new secondary endpoints (75% and 50% reduction from baseline in DVD) and refined the definition of previously named secondary endpoints • Added 1 new exploratory endpoint and refined the definition of previously named secondary endpoints • Described gate-keeping procedure to control the Type I error

    Interruptions (globally)

    Were there any global interruptions to the trial? No

    Limitations and caveats

    Limitations of the trial such as small numbers of subjects analysed or technical problems leading to unreliable data.
    None reported
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