Flag of the European Union EU Clinical Trials Register Help

Clinical trials

The European Union Clinical Trials Register   allows you to search for protocol and results information on:
  • interventional clinical trials that were approved in the European Union (EU)/European Economic Area (EEA) under the Clinical Trials Directive 2001/20/EC
  • clinical trials conducted outside the EU/EEA that are linked to European paediatric-medicine development

  • EU/EEA interventional clinical trials approved under or transitioned to the Clinical Trial Regulation 536/2014 are publicly accessible through the
    Clinical Trials Information System (CTIS).


    The EU Clinical Trials Register currently displays   43973   clinical trials with a EudraCT protocol, of which   7311   are clinical trials conducted with subjects less than 18 years old.   The register also displays information on   18700   older paediatric trials (in scope of Article 45 of the Paediatric Regulation (EC) No 1901/2006).

    Phase 1 trials conducted solely on adults and that are not part of an agreed paediatric investigation plan (PIP) are not publicly available (see Frequently Asked Questions ).  
     
    Examples: Cancer AND drug name. Pneumonia AND sponsor name.
    How to search [pdf]
    Search Tips: Under advanced search you can use filters for Country, Age Group, Gender, Trial Phase, Trial Status, Date Range, Rare Diseases and Orphan Designation. For these items you should use the filters and not add them to your search terms in the text field.
    Advanced Search: Search tools
     

    < Back to search results

    Download PDF

    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 Ménière's disease.

    Summary
    EudraCT number
    2015-004496-71
    Trial protocol
    GB   BE   DE   IT  
    Global end of trial date
    31 Aug 2017

    Results information
    Results version number
    v1(current)
    This version publication date
    13 Dec 2021
    First version publication date
    13 Dec 2021
    Other versions

    Trial information

    Close Top of page
    Trial identification
    Sponsor protocol code
    104-201508
    Additional study identifiers
    ISRCTN number
    -
    US NCT number
    NCT02717442
    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 Center, Otonomy Inc., medinfo@otonomy.com
    Scientific contact
    Otonomy Medical Information Center, Otonomy Inc., 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
    29 Mar 2019
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    31 Aug 2017
    Global end of trial reached?
    Yes
    Global end of trial date
    31 Aug 2017
    Was the trial ended prematurely?
    Yes
    General information about the trial
    Main objective of the trial
    To confirm the efficacy of OTO-104 in subjects with Ménière'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 contained a placebo control, which the sponsor believed is the most direct way to measure the effect of this investigational product. In addition, the following considerations would also lead to the conclusion that a placebo control is appropriate: • There is no drug product administered intratympanically that is approved for the treatment of Ménière's disease. While intratympanic steroid solutions are used in clinical practice, there is need for additional clinical research to support their effectiveness. In addition, the intratympanic administration of gentamicin acts through an ototoxic effect and its use is typically restricted in Ménière's disease patients with residual hearing. • Betahistine is approved and widely used for Ménière's disease, although a Cochrane Review concludes that there is “insufficient evidence to say whether betahistine has any effect on Ménière's disease”. In addition, a recent article in The BMJ 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 are recommended to continue on medications they are on prior to the study start, which may include betahistine, diuretics, and/or a low salt diet (i.e., their standard of care). The requirement is simply that they must have the requisite number of definitive vertigo days in order to be randomized. • The option of a sham injection (i.e., air) was also considered. However, there was concern that this could inadvertently “unblind” the subject if there were no perception of material in the ear.
    Actual start date of recruitment
    21 Mar 2016
    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: 62
    Country: Number of subjects enrolled
    United Kingdom: 49
    Country: Number of subjects enrolled
    Belgium: 8
    Country: Number of subjects enrolled
    France: 9
    Country: Number of subjects enrolled
    Germany: 28
    Country: Number of subjects enrolled
    Italy: 18
    Worldwide total number of subjects
    174
    EEA total number of subjects
    174
    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)
    144
    From 65 to 84 years
    30
    85 years and over
    0

    Subject disposition

    Close Top of page
    Recruitment
    Recruitment details
    Overall, 57 investigators were approved in Europe (Belgium, France, Germany, Italy, Poland, United Kingdom) were approved to conduct this study. Forty-nine investigators enrolled subjects. First subject was randomized 21 March 2016; Last subject was randomized 22 August 2017.

    Pre-assignment
    Screening details
    A total of 360 subjects registered for this study and signed informed consent. Of these, 176 subjects were randomized and 174 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, Carer, 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
    0.2 mL of a 6% suspension of dexamethasone in poloxamer 407 aqueous solution
    Arm type
    Experimental

    Investigational medicinal product name
    OTO-104
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Suspension for injection
    Routes of administration
    Intratympanic use
    Dosage and administration details
    Subjects are administered the single intratympanic injection at baseline.

    Arm title
    Placebo
    Arm description
    0.2 mL poloxamer 407 aqueous solution
    Arm type
    Placebo

    Investigational medicinal product name
    placebo
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for injection
    Routes of administration
    Intratympanic use
    Dosage and administration details
    Subjects are administered a single intratympanic injection at baseline.

    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
    86
    88
    Completed
    86
    88
    Period 2
    Period 2 title
    Follow-up
    Is this the baseline period?
    No
    Allocation method
    Randomised - controlled
    Blinding used
    Double blind [2]
    Roles blinded
    Subject, Monitor, Carer, Assessor
    Blinding implementation details
    This period is comprised of all post-Baseline clinic visits. Because treatment was administered one time at the Baseline visit, the only blinding detail that is relevant is that only the unblinded staff member can perform the otoscopic examination. Any interaction with subjects with regard to the collection, review or discussion of study assessments, was done by someone other than the unblinded person who prepared the syringe and the investigator who administered the dose at the Baseline visit

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    OTO-104
    Arm description
    0.2 mL of a 6% suspension of dexamethasone in poloxamer 407 aqueous solution
    Arm type
    Experimental

    Investigational medicinal product name
    OTO-104
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Suspension for injection
    Routes of administration
    Intratympanic use
    Dosage and administration details
    There is no drug administered during the follow-up period. Subjects efficacy and safety are attributed to the single dose administered at baseline.

    Arm title
    Placebo
    Arm description
    0.2 mL poloxamer 407 aqueous solution
    Arm type
    Placebo

    Investigational medicinal product name
    placebo
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for solution for injection
    Routes of administration
    Intratympanic use
    Dosage and administration details
    There is no drug administered during the follow-up period. Subjects efficacy and safety are attributed to the single dose administered at baseline.

    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
    86
    88
    Completed
    53
    59
    Not completed
    34
    29
         Reason for discontinuation not stated
    4
    -
         Study terminated by Sponsor
    30
    29
    Joined
    1
    0
         Subject randomized but not treated
    1
    -

    Baseline characteristics

    Close Top of page
    Baseline characteristics reporting groups
    Reporting group title
    OTO-104
    Reporting group description
    0.2 mL of a 6% suspension of dexamethasone in poloxamer 407 aqueous solution

    Reporting group title
    Placebo
    Reporting group description
    0.2 mL poloxamer 407 aqueous solution

    Reporting group values
    OTO-104 Placebo Total
    Number of subjects
    86 88 174
    Age categorical
    Units: Subjects
        Adults (18-64 years)
    72 72 144
        From 65-84 years
    14 16 30
    Age continuous
    Age in years
    Units: years
        arithmetic mean (standard deviation)
    51.8 ± 12.13 52.6 ± 13.24 -
    Gender categorical
    Units: Subjects
        Female
    44 48 92
        Male
    42 40 82
    Race
    Units: Subjects
        White
    82 82 164
        Black or African American
    0 0 0
        Asian
    1 1 2
        Not Applicable
    3 5 8
    Subject analysis sets

    Subject analysis set title
    Safety Analysis Set
    Subject analysis set type
    Safety analysis
    Subject analysis set description
    All randomized subjects that received study drug (OTO-104 or placebo)

    Subject analysis set title
    Full Analysis Set-1
    Subject analysis set type
    Full analysis
    Subject analysis set description
    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.

    Subject analysis sets values
    Safety Analysis Set Full Analysis Set-1
    Number of subjects
    174
    174
    Age categorical
    Units: Subjects
        Adults (18-64 years)
    144
    144
        From 65-84 years
    30
    30
    Age continuous
    Age in years
    Units: years
        arithmetic mean (standard deviation)
    52.2 ± 12.67
    52.2 ± 12.67
    Gender categorical
    Units: Subjects
        Female
    92
    92
        Male
    82
    82
    Race
    Units: Subjects
        White
    164
    164
        Black or African American
    0
    0
        Asian
    2
    2
        Not Applicable
    8
    8

    End points

    Close Top of page
    End points reporting groups
    Reporting group title
    OTO-104
    Reporting group description
    0.2 mL of a 6% suspension of dexamethasone in poloxamer 407 aqueous solution

    Reporting group title
    Placebo
    Reporting group description
    0.2 mL poloxamer 407 aqueous solution
    Reporting group title
    OTO-104
    Reporting group description
    0.2 mL of a 6% suspension of dexamethasone in poloxamer 407 aqueous solution

    Reporting group title
    Placebo
    Reporting group description
    0.2 mL poloxamer 407 aqueous solution

    Subject analysis set title
    Safety Analysis Set
    Subject analysis set type
    Safety analysis
    Subject analysis set description
    All randomized subjects that received study drug (OTO-104 or placebo)

    Subject analysis set title
    Full Analysis Set-1
    Subject analysis set type
    Full analysis
    Subject analysis set description
    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.

    Primary: Definitive Vertigo Day

    Close Top of page
    End point title
    Definitive Vertigo Day
    End point description
    A Definitive Vertigo Day (DVD) was defined as a day where the subject recorded at least 1 vertigo episode lasting at least 20 minutes corresponding to a Vertigo Severity Score of 2 or more. If multiple episodes occurred on a given day, subjects were instructed to record the Vertigo Severity Score for the worst episode experienced during the day.
    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
    86
    88
    Units: Day
        arithmetic mean (confidence interval 95%)
    2.336 (1.747 to 3.125)
    3.549 (2.763 to 4.560)
    Statistical analysis title
    Generalized Poisson Linear Mixed Model
    Statistical analysis description
    The model included fixed effects for randomized treatment group (OTO 104 vs placebo), sex (male vs female), study week (4, 8, 12), a treatment group by study week interaction, and the count of lead-in period DVD standardized to 28 days as a covariate. Study week was modeled as a categorical variable. The model also included a random intercept to account for the longitudinal design; an offset for the log of the number of daily diary entries recorded for each 4-week post-baseline period was added
    Comparison groups
    OTO-104 v Placebo
    Number of subjects included in analysis
    174
    Analysis specification
    Pre-specified
    Analysis type
    superiority [1]
    P-value
    = 0.029
    Method
    Poisson
    Confidence interval
    Notes
    [1] - The count of DVD at each 4-week study period standardized to 28 days was summarized using descriptive statistics. In addition, the count of DVD at each 4-week study period was summarized (not standardized to 28 days) descriptively. The ratio of the adjusted means from the model comparing OTO-104 to placebo at Week 12, the corresponding 95% CI, and p-value was presented.

    Adverse events

    Close Top of page
    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
    18.1
    Reporting groups
    Reporting group title
    OTO-104
    Reporting group description
    0.2 mL of a 6% suspension of dexamethasone on poloxamer 407 aqueous solution

    Reporting group title
    Placebo
    Reporting group description
    0.2 mL poloxamer 407 aqueous solution

    Serious adverse events
    OTO-104 Placebo
    Total subjects affected by serious adverse events
         subjects affected / exposed
    2 / 86 (2.33%)
    0 / 88 (0.00%)
         number of deaths (all causes)
    0
    0
         number of deaths resulting from adverse events
    0
    0
    Injury, poisoning and procedural complications
    Head injury
    Additional description: The subject was admitted to the hospital 2 days after collapsing and hitting his head;. the cause of collapse was unknown; no symptoms to suggest the collapse was related to inner ear disorder; considered not related to study drug; subject completed
         subjects affected / exposed
    1 / 86 (1.16%)
    0 / 88 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hepatobiliary disorders
    Cholecystitis
    Additional description: Subject had 2 hospitalisations during the study due to symptoms of cholecystitis. After the second hospitalization, the subject was placed on a waiting list for an elective cholecystectomy. The event was not considered related to study drug.
         subjects affected / exposed
    1 / 86 (1.16%)
    0 / 88 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    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
    41 / 86 (47.67%)
    20 / 88 (22.73%)
    Nervous system disorders
    Headache
         subjects affected / exposed
    9 / 86 (10.47%)
    4 / 88 (4.55%)
         occurrences all number
    9
    4
    Dizziness
         subjects affected / exposed
    7 / 86 (8.14%)
    2 / 88 (2.27%)
         occurrences all number
    7
    2
    Ear and labyrinth disorders
    Meniere's disease
         subjects affected / exposed
    5 / 86 (5.81%)
    1 / 88 (1.14%)
         occurrences all number
    5
    1
    Tinnitus
         subjects affected / exposed
    4 / 86 (4.65%)
    2 / 88 (2.27%)
         occurrences all number
    4
    2
    Vertigo
         subjects affected / exposed
    3 / 86 (3.49%)
    2 / 88 (2.27%)
         occurrences all number
    3
    2
    Ear discomfort
         subjects affected / exposed
    2 / 86 (2.33%)
    2 / 88 (2.27%)
         occurrences all number
    2
    2
    Ear pain
         subjects affected / exposed
    3 / 86 (3.49%)
    3 / 88 (3.41%)
         occurrences all number
    3
    3
    Gastrointestinal disorders
    Nausea
         subjects affected / exposed
    3 / 86 (3.49%)
    2 / 88 (2.27%)
         occurrences all number
    3
    2
    Psychiatric disorders
    Suicidal ideation
         subjects affected / exposed
    3 / 86 (3.49%)
    1 / 88 (1.14%)
         occurrences all number
    3
    1
    Infections and infestations
    Nasopharyngitis
         subjects affected / exposed
    2 / 86 (2.33%)
    3 / 88 (3.41%)
         occurrences all number
    2
    3

    More information

    Close Top of page

    Substantial protocol amendments (globally)

    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    15 Oct 2015
    Added EudraCT Number and modified storage condition of the drug to be refrigerated as opposed to frozen.
    13 Jan 2016
    - Additional exclusion criteria to hypersensitivity to dexamethasone or any of the OTO-104 excipients. - Modified Section 1.1, Study Rationale to include rationale for dose selection. - Modified statement regarding contacting the medical monitor if an unblinding has occurred. - Changed pharmacovigilance vendor, and therefore contacts were updated.

    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
    For support, Contact us.
    The status and protocol content of GB trials is no longer updated since 1 January 2021. For the UK, as of 31 January 2021, EU Law applies only to the territory of Northern Ireland (NI) to the extent foreseen in the Protocol on Ireland/NI. Legal notice
    As of 31 January 2023, all EU/EEA initial clinical trial applications must be submitted through CTIS . Updated EudraCT trials information and information on PIP/Art 46 trials conducted exclusively in third countries continues to be submitted through EudraCT and published on this website.

    European Medicines Agency © 1995-2024 | Domenico Scarlattilaan 6, 1083 HS Amsterdam, The Netherlands
    EMA HMA