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    Clinical Trial Results:
    A 6-month, prospective, randomized, multicenter, placebo-controlled safety study of OTO-104 given at 3-month intervals by intratympanic injection in subjects with unilateral Meniere's disease, followed by a 6-month open-label extension

    Summary
    EudraCT number
    2014-001337-86
    Trial protocol
    GB  
    Global end of trial date
    19 May 2016

    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

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    Trial identification
    Sponsor protocol code
    104-201403
    Additional study identifiers
    ISRCTN number
    -
    US NCT number
    NCT02265393
    WHO universal trial number (UTN)
    -
    Sponsors
    Sponsor organisation name
    Otonomy Inc
    Sponsor organisation address
    4796 Executive Drive, San Diego, United States, CA 92121
    Public contact
    Otonomy Medical Information, Otonomy Inc., medinfo@otonomy.com
    Scientific contact
    Otonomy Medical Information, 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
    21 Dec 2016
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    19 May 2016
    Global end of trial reached?
    Yes
    Global end of trial date
    19 May 2016
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    The objective of the first part of the study was to evaluate the safety of 2 intratympanic doses of 12 mg OTO-104, compared with placebo, given at 3-month intervals in subjects with unilateral Meniere’s disease. The objective of the second part of the study was to continue to assess the safety of 2 intratympanic injections of 12 mg OTO-104 at 3 month intervals in an open-label phase.
    Protection of trial subjects
    Subjects in this study were to receive up to 4 intratympanic injections spaced 3 months apart. Prior to each injection, a numbing cream (containing lidocaine and prilocaine) was applied to the subject's tympanic membrane to manage pain/discomfort associated with the injection. One of the primary concerns identified prior to the study was the potential for tympanic membrane perforation because of the injection procedure itself as well as any other risks associated with the study. To that end, a data safety monitoring board was organized, had their first meeting prior to the 1st subject's 3rd injection and then quarterly thereafter to review the study progress and the evolving safety data. The DSMB could be convened as needed, which it was when there was a serious adverse event that occurred during a subject's second injection. At each meeting, the DSMB was charged with evaluating safety data to determine whether the study should continue and concluded each time that the study could continue.
    Background therapy
    Subjects maintained their current standard-of-care treatment for Meniere’s disease while on study, including but not limited to, low-salt diet, diuretic, and/or betahistine.
    Evidence for comparator
    This was a safety study so there was no comparator.
    Actual start date of recruitment
    01 Jul 2014
    Long term follow-up planned
    No
    Independent data monitoring committee (IDMC) involvement?
    Yes
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    United Kingdom: 128
    Worldwide total number of subjects
    128
    EEA total number of subjects
    128
    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)
    106
    From 65 to 84 years
    22
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    Sixteen centers in the United Kingdom screened 144 subjects, with 128 randomized (103 to OTO-104; 25 subjects to placebo). In the second phase of the study all subjects received OTO-104 (n = 123; there were 5 discontinuations prior to the beginning of the second phase [Month 6].

    Pre-assignment
    Screening details
    Subjects enrolled in the study were required to have unilateral Meniere’s disease as outlined by the American Academy of Otolaryngology – Head and Neck Surgery (AAO-HNS) Committee on Hearing and Equilibrium in 1995 (Committee on Hearing and Equilibrium, 1995). A total of 144 subjects were screened to enroll 128 subjects.

    Period 1
    Period 1 title
    overall study (overall period)
    Is this the baseline period?
    Yes
    Allocation method
    Randomised - controlled
    Blinding used
    Double blind [1]
    Roles blinded
    Subject, Monitor, Data analyst, Carer, Assessor
    Blinding implementation details
    Study site personnel, who were blinded to treatment assignment, provided the information (unique number) contained in the central randomization system notification to the unblinded qualified medical professional (QMP) responsible for preparing the syringe containing study drug. The QMP prepared the syringe from the contents of the study drug. The QMP prepared the syringe from the contents of the study drug package corresponding to the randomization system unique number.

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    OTO-104
    Arm description
    OTO-104 (Dexamethasone suspension in a poloxamer 407 solution for intratympanic injection)
    Arm type
    Experimental

    Investigational medicinal product name
    Dexamethasone suspension in a poloxamer 407 solution
    Investigational medicinal product code
    OTO-104
    Other name
    Pharmaceutical forms
    Solution for injection
    Routes of administration
    Intratympanic use
    Dosage and administration details
    The OTO-104 final product suspension for dosing was prepared by an unblinded qualified medical professional from 2 separate components, OTO-104 Diluent (1 vial) and OTO-104 Active (1 vial). An appropriate volume of OTO-104 Diluent was withdrawn and delivered into the OTO-104 Active vial to achieve a visually homogeneous suspension with a target drug concentration of 60 mg/mL. The subject is placed in a recumbent position with the treated ear upwards. The tympanic membrane is anesthetized by either covering the external surface of the posterior-inferior quadrant with topical lidocaine/prilocaine cream ([EMLA] cream) until the tympanic membrane is numb. The needle is inserted through the tympanic membrane with the bevel facing in an inferoposterior direction to a depth of approximately 2-3 mm just inferior to the round window niche, and with firm but gentle pressure, 0.2 mL is injected.

    Arm title
    Placebo
    Arm description
    Poloxamer 407 solution
    Arm type
    Placebo

    Investigational medicinal product name
    Poloxamer 407
    Investigational medicinal product code
    P407
    Other name
    Pharmaceutical forms
    Solution for injection
    Routes of administration
    Intratympanic use
    Dosage and administration details
    Placebo (P407; OTO-104 Diluent) 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
    103
    25
    Completed
    97
    24
    Not completed
    6
    1
         Physician decision
    1
    -
         Consent withdrawn by subject
    4
    -
         Lost to follow-up
    1
    -
         subject refused IP
    -
    1

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    OTO-104
    Reporting group description
    OTO-104 (Dexamethasone suspension in a poloxamer 407 solution for intratympanic injection)

    Reporting group title
    Placebo
    Reporting group description
    Poloxamer 407 solution

    Reporting group values
    OTO-104 Placebo Total
    Number of subjects
    103 25 128
    Age categorical
    Units: Subjects
        Adults (18-64 years)
    84 22 106
        From 65-84 years
    19 3 22
        85 years and over
    0 0 0
    Age continuous
    The age if the subject when they signed the consent form.
    Units: years
        median (full range (min-max))
    54 (21 to 78) 55 (31 to 75) -
    Gender categorical
    The gender as collected at Screening.
    Units: Subjects
        Female
    54 16 70
        Male
    49 9 58
    Subject analysis sets

    Subject analysis set title
    Safety
    Subject analysis set type
    Safety analysis
    Subject analysis set description
    All subjects who received at least one IT dose

    Subject analysis sets values
    Safety
    Number of subjects
    128
    Age categorical
    Units: Subjects
        Adults (18-64 years)
    106
        From 65-84 years
    22
        85 years and over
    0
    Age continuous
    The age if the subject when they signed the consent form.
    Units: years
        median (full range (min-max))
    54.5 (21 to 78)
    Gender categorical
    The gender as collected at Screening.
    Units: Subjects
        Female
    70
        Male
    58

    End points

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    End points reporting groups
    Reporting group title
    OTO-104
    Reporting group description
    OTO-104 (Dexamethasone suspension in a poloxamer 407 solution for intratympanic injection)

    Reporting group title
    Placebo
    Reporting group description
    Poloxamer 407 solution

    Subject analysis set title
    Safety
    Subject analysis set type
    Safety analysis
    Subject analysis set description
    All subjects who received at least one IT dose

    Primary: Audiometry - Shift in Pure Tone Average

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    End point title
    Audiometry - Shift in Pure Tone Average [1]
    End point description
    Change from Baseline in Pure Tone Average (PTA) calculated as the mean of air conduction thresholds at 500, 1000, and 2000 Hz.
    End point type
    Primary
    End point timeframe
    Up to 1 year
    Notes
    [1] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: The primary endpoints for this study were safety in nature and as such, no additional statistics were performed other than summary statistics.
    End point values
    OTO-104 Placebo
    Number of subjects analysed
    93 [2]
    24 [3]
    Units: Pure Tone Average
        arithmetic mean (standard deviation)
    -0.2 ± 15.07
    -1.5 ± 14.66
    Notes
    [2] - Subjects with PTA measurements at Baseline and Month 12
    [3] - Subjects with PTA measurements at Baseline and Month 12
    No statistical analyses for this end point

    Primary: Meniere's Symptom Questionnaire

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    End point title
    Meniere's Symptom Questionnaire [4]
    End point description
    Change in Meniere's disease Questionnaire values; each category can be scored from 1 = none to 5 = extremely severe; a negative change = improvement.
    End point type
    Primary
    End point timeframe
    Up to 1 Year
    Notes
    [4] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: The primary endpoints for this study were safety in nature and as such, no additional statistics were performed other than summary statistics.
    End point values
    OTO-104 Placebo
    Number of subjects analysed
    97 [5]
    25 [6]
    Units: Score at Month 12
    median (full range (min-max))
        Vertigo
    1.0 (1 to 5)
    1.0 (1 to 4)
        Tinnitus
    3.0 (1 to 5)
    3.0 (1 to 4)
        Ear Fullness
    2.0 (1 to 5)
    2.0 (1 to 4)
        Hearing Difficulty
    3.0 (1 to 5)
    3.0 (2 to 4)
    Notes
    [5] - Subjects with a questionnaire at Month 12
    [6] - Subjects with a questionnaire at Month 12
    No statistical analyses for this end point

    Primary: Tympanic Membrane Perforation

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    End point title
    Tympanic Membrane Perforation [7]
    End point description
    Perforations were rated as "Present" or "Not Present"; if a subject did not receive an otoscopy, then the perforation is listed as "Missing".
    End point type
    Primary
    End point timeframe
    Up to 12 months; otoscopy examinations were performed at 3, 6, 9, 12 months in the ear that received the injection(s) at Baseline, Month 3, Month 6, and Month 9, respectively.
    Notes
    [7] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: The primary endpoints for this study were safety in nature and as such, no additional statistics were performed other than summary statistics.
    End point values
    OTO-104 Placebo
    Number of subjects analysed
    103 [8]
    25 [9]
    Units: ears
        Present
    2
    0
        Not Present
    94
    25
        Missing
    7
    0
    Notes
    [8] - OTO-104 subjects who had an Otoscopy at Baseline and last visit (up to Month 12).
    [9] - Placebo subjects who had an Otoscopy at Baseline and last visit (up to Month 12).
    No statistical analyses for this end point

    Secondary: Tympanometry - Shift from Type A at Baseline

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    End point title
    Tympanometry - Shift from Type A at Baseline
    End point description
    Tympanometry assessments are used to assess the mobility and compliance of the tympanic membrane, pressure and volume in the middle ear, and function of the tympanic membrane, ossicles and eustachian tube. Type A is considered normal and the results presented here are for the percentage of treated ears that change from normal (Type A) at Baseline to another category.
    End point type
    Secondary
    End point timeframe
    Up to 1 Year
    End point values
    OTO-104 Placebo Safety
    Number of subjects analysed
    92 [10]
    22 [11]
    109 [12]
    Units: Subject
        Number with shift from Type A at Baseline
    2
    1
    4
    Notes
    [10] - Subjects randomized to OTO-104 with a tympanometry at Baseline and one at Month 6 after 2 injections
    [11] - Subjects randomized to Placebo with a tympanometry at Baseline and one at Month 9 after 2 injections
    [12] - Subjects with a tympanometry at Baseline and one at Month 12 after 4 injections
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    Adverse events recorded at 6 months
    Assessment type
    Non-systematic
    Dictionary used for adverse event reporting
    Dictionary name
    MedDRA
    Dictionary version
    19.0
    Reporting groups
    Reporting group title
    OTO-104
    Reporting group description
    Dexamethasone suspension in a poloxamer 407 solution for intratympanic injection

    Reporting group title
    Placebo
    Reporting group description
    Poloxamer 407 solution

    Serious adverse events
    OTO-104 Placebo
    Total subjects affected by serious adverse events
         subjects affected / exposed
    3 / 103 (2.91%)
    2 / 25 (8.00%)
         number of deaths (all causes)
    0
    0
         number of deaths resulting from adverse events
    0
    0
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Bowel Cancer
    Additional description: Moderate and not related.
    alternative assessment type: Systematic
         subjects affected / exposed
    1 / 103 (0.97%)
    0 / 25 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Injury, poisoning and procedural complications
    Laceration
    Additional description: Laceration to right hand ring finger. Severe and not related.
    alternative assessment type: Systematic
         subjects affected / exposed
    0 / 103 (0.00%)
    1 / 25 (4.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Nervous system disorders
    Dizziness
    Additional description: Severe and related.
    alternative assessment type: Systematic
         subjects affected / exposed
    1 / 103 (0.97%)
    0 / 25 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Ear and labyrinth disorders
    Hearing Loss
    Additional description: Unilateral Deafness. Severe, definitely related.
    alternative assessment type: Systematic
         subjects affected / exposed
    1 / 103 (0.97%)
    0 / 25 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastrointestinal disorders
    Vomiting
    Additional description: Severe and definitely related.
    alternative assessment type: Systematic
         subjects affected / exposed
    1 / 103 (0.97%)
    0 / 25 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hepatobiliary disorders
    Cholecystitis
    Additional description: Severe. Not related.
    alternative assessment type: Systematic
         subjects affected / exposed
    1 / 103 (0.97%)
    0 / 25 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Musculoskeletal and connective tissue disorders
    Back Pain
    Additional description: Moderate and not related.
    alternative assessment type: Systematic
         subjects affected / exposed
    0 / 103 (0.00%)
    1 / 25 (4.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    OTO-104 Placebo
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    56 / 103 (54.37%)
    5 / 25 (20.00%)
    Nervous system disorders
    Migraine
         subjects affected / exposed
    6 / 103 (5.83%)
    0 / 25 (0.00%)
         occurrences all number
    6
    0
    Ear and labyrinth disorders
    Vertigo
         subjects affected / exposed
    15 / 103 (14.56%)
    2 / 25 (8.00%)
         occurrences all number
    15
    2
    Dizziness
         subjects affected / exposed
    10 / 103 (9.71%)
    1 / 25 (4.00%)
         occurrences all number
    10
    1
    Meniere's disease
         subjects affected / exposed
    13 / 103 (12.62%)
    0 / 25 (0.00%)
         occurrences all number
    13
    0
    Tinnitus
         subjects affected / exposed
    4 / 103 (3.88%)
    2 / 25 (8.00%)
         occurrences all number
    4
    2
    Ear pain
         subjects affected / exposed
    8 / 103 (7.77%)
    1 / 25 (4.00%)
         occurrences all number
    8
    1

    More information

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    Substantial protocol amendments (globally)

    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    03 Jun 2014
    Corrected the Visit Number for the Meniere’s symptom questionnaire from Visit 1 to Visit 2 (Synopsis, Page 11). Modified the unblinding procedure to clarify that the physician administering the study drug is unblinded at the time of injection as well as accessing the study drug preparation records if the physician administering the study drug is not available or does not recollect the treatment administered (Section 5.3, Blinding, Page 19). Replace “violation” with “deviation” (Section 7.1, Proscribed Therapy During the Study Period, pg. 20; Section 7.2, Symptomatic Relief Medications, pg. 20; Section 11.4, Subject Demographics, Baseline Disease Status, and Disposition, pg. 30 Modified the number and description of the responses to the Meniere’s Symptom Questionnaire (Section 8.2.6, Meniere’s Symptom Questionnaire, pg. 24).
    02 Oct 2015
    Updated Medical Monitor contact to include Otonomy Drug Safety contact (Section 9.3, Contacting Sponsor Regarding Safety, page 28) Included the following additional text in bold per DSMB recommendation after SAE: “Using the tuberculin syringe pre-loaded with OTO-104 or placebo and equipped with a 26 gauge or 25 gauge needle, insert the needle through the tympanic membrane with the bevel facing in an inferoposterior direction to a depth of approximately 2-3 mm just inferior to the round window niche, and with firm but gentle pressure, inject 0.2 mL, taking care not to insert the needle further than necessary (Section 6.1, Study Drug Administration, page 19) Time and Events Table/Study Flow Chart to include the C-SSRS assessment for Visits 4-6 and included a footnote (Table 1, pg. 13-14) . Included the C-SSRS guidance (Section 8.2.7 C-SSRS Assessment, pg. 26) Section changed for Safety stopping rules with the addition of C-SSRS (Changed from Section 8.2.7 to 8.2.8, page 26) Included C-SSRS in the Safety Evaluation section (Section 11.7, page 35)Included C-SSRS guidance (Sections 11.7.6, 11.7.6.1, 11.7.6.2) DSMB section referenced the incorrect section for the safety stopping rules: "Should any untoward safety issue be observed, or any of the stopping rules outlined in Section 8.2.8 be invoked, the DSMB will schedule an immediate meeting to review the relevant safety data" (Section 8.2.8, page 40).

    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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