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    Clinical Trial Results:
    A 6-MONTH, MULTICENTER, PHASE 3, OPEN-LABEL EXTENSION SAFETY STUDY OF OTO-104 GIVEN AT 3-MONTH INTERVALS BY INTRATYMPANIC INJECTION IN SUBJECTS WITH UNILATERAL MENIERE’S DISEASE

    Summary
    EudraCT number
    		 2016-000766-29
    Trial protocol
    		 GB   BE   DE   IT  
    Global end of trial date
    05 Sep 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

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    Trial identification
    Sponsor protocol code
    104-201610
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT02768662
    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., medinfo@otonomy.com
    Scientific contact
    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
    08 Jun 2018
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    05 Sep 2017
    Global end of trial reached?
    Yes
    Global end of trial date
    05 Sep 2017
    Was the trial ended prematurely?
    Yes
    General information about the trial
    Main objective of the trial
    The objective is to assess the safety of repeat intratympanic injections of 12 mg OTO-104 at 3-month intervals in an open-label study in subjects with unilateral Meniere’s disease.
    Protection of trial subjects
    Not Applicable
    Background therapy
    		 Subjects were permitted to continue medications for relief of symptoms related to Meniere’s disease during the course of the study. Intermittent use of vestibular suppressants and anti-emetics was allowed as symptomatic relief medications. Subjects were allowed to take betahistine as well.
    Evidence for comparator
    		 Not Applicable - no comparator
    Actual start date of recruitment
    20 Jul 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
    United Kingdom: 83
    Country: Number of subjects enrolled
    Poland: 23
    Country: Number of subjects enrolled
    Belgium: 6
    Country: Number of subjects enrolled
    France: 4
    Country: Number of subjects enrolled
    Germany: 17
    Country: Number of subjects enrolled
    Italy: 9
    Worldwide total number of subjects
    142
    EEA total number of subjects
    59
    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)
    123
    From 65 to 84 years
    19
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 This was a 6-month, multicenter, Phase 3, open-label extension safety study in subjects with unilateral Meniere’s disease that had previously completed the Phase 2 (104-201403) or Phase 3 (104-201508) studies.

    Pre-assignment
    Screening details
    		 Subjects that completed one of the prior studies were asked if they wanted to participate in this study and if so, they signed an informed consent.

    Period 1
    Period 1 title
    Treatment (overall period)
    Is this the baseline period?
    		 Yes
    Allocation method
    Not applicable
    Blinding used
    		 Not blinded
    Blinding implementation details
    This was an open-label study and therefore, no blinding was required.

    Arms
    Arm title
    		 OTO-104
    Arm description
    		 dexamethasone suspension in a solution of poloxamer 407
    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
    The tympanic membrane was anesthetized by covering the external surface of the inferior-posterior quadrant with topical lidocaine or lidocaine/prilocaine cream. 200 microliters of a 6% w/v suspension of dexamethasone (12 mg) was administered via intratympanic injection by inserting the needle into the inferior-posterior quadrant of the tympanic membrane at the level of the round window.

    Number of subjects in period 1
    		OTO-104
    Started
    142
    Completed
    90
    Not completed
    52
         Consent withdrawn by subject
    4
         Subject received saccotomy
    1
         Adverse event, non-fatal
    1
         Missing reason for discontinuation
    1
         Study terminated by sponsor
    43
         Lost to follow-up
    2

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Treatment
    Reporting group description
    		 All subjects that received at least one intratympanic injection of OTO-104.

    Reporting group values
    		 Treatment Total
    Number of subjects
    		 142 142
    Age categorical
    Units: Subjects
        Adults (18-64 years)
    		 123 123
        From 65-84 years
    		 19 19
    Gender categorical
    Units: Subjects
        Female
    		 77 77
        Male
    		 65 65
    Subject analysis sets

    Subject analysis set title
    Safety
    Subject analysis set type
    		 Safety analysis
    Subject analysis set description
    The safety analysis set included all subjects who received at least one dose of study drug.

    Subject analysis sets values
    		 Safety
    Number of subjects
    142
    Age categorical
    Units: Subjects
        Adults (18-64 years)
    123
        From 65-84 years
    19
    Age continuous
    Units:
        
    ±
    Gender categorical
    Units: Subjects
        Female
    77
        Male
    65

    End points

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    End points reporting groups
    Reporting group title
    OTO-104
    Reporting group description
    		 dexamethasone suspension in a solution of poloxamer 407

    Subject analysis set title
    Safety
    Subject analysis set type
    		 Safety analysis
    Subject analysis set description
    The safety analysis set included all subjects who received at least one dose of study drug.

    Primary: Tympanic Membrane Perforation

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    End point title
    		 Tympanic Membrane Perforation [1]
    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 6 months; otoscopy examinations were performed at 3 and 6 months in the ear that received the injection(s).
    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 endpoint for this study was safety in nature and as such, no additional statistics were performed other than summary statistics.
    End point values
    		 OTO-104
    Number of subjects analysed
    142
    Units: ears
        Present
    0
        Not Present
    92
        Missing
    50
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    From Day 1 to end of study, which could have been up to Month 6.
    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
    		 dexamethasone suspension in a solution of poloxamer 407

    Serious adverse events
    		 OTO-104
    Total subjects affected by serious adverse events
         subjects affected / exposed
    4 / 142 (2.82%)
         number of deaths (all causes)
    0
         number of deaths resulting from adverse events
    0
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Invasive ductal breast carcinoma
    Additional description: Subject was diagnosed with invasive ductal breast carcinoma on Day 85. The event was considered not related to study drug was ongoing at the date of last contact.
         subjects affected / exposed
    1 / 142 (0.70%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Pancreatic carcinoma
    Additional description: Subject as diagnosed with pancreatic carcinoma on Day 54. Treatment included surgery, which was planned, not yet performed at the date of last contact. The event was considered not related to study drug.
         subjects affected / exposed
    1 / 142 (0.70%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Blood and lymphatic system disorders
    Anaemia
    Additional description: Subject had anemia on Day 1. The subject was hospitalized and received blood transfusions from Day 22 to Day 27, when the event was considered resolved and the subject was discharged.
         subjects affected / exposed
    1 / 142 (0.70%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Gastrointestinal disorders
    Abdominal pain upper
    Additional description: Subject had 3 Serious adverse events: abdominal pain upper, constipation, and helicobacter infection on Day 34. Treatment included lansoprazole, clarithromycin, metronidazole, and Laxido sachets. The event resolved 4 days later.
         subjects affected / exposed
    1 / 142 (0.70%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Constipation
    Additional description: Subject had 3 Serious adverse events: abdominal pain upper, constipation, and helicobacter infection on Day 34. Treatment included lansoprazole, clarithromycin, metronidazole, and Laxido sachets. The event resolved 4 days later.
         subjects affected / exposed
    1 / 142 (0.70%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Helicobacter infection
    Additional description: Subject had 3 Serious adverse events: abdominal pain upper, constipation, and helicobacter infection on Day 34. Treatment included lansoprazole, clarithromycin, metronidazole, and Laxido sachets. The event resolved 4 days later.
         subjects affected / exposed
    1 / 142 (0.70%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 2%
    Non-serious adverse events
    		 OTO-104
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    37 / 142 (26.06%)
    Injury, poisoning and procedural complications
    Procedural dizziness
         subjects affected / exposed
    3 / 142 (2.11%)
         occurrences all number
    3
    Nervous system disorders
    Headache
         subjects affected / exposed
    4 / 142 (2.82%)
         occurrences all number
    4
    Dizziness
         subjects affected / exposed
    3 / 142 (2.11%)
         occurrences all number
    3
    General disorders and administration site conditions
    Injection site discomfort
         subjects affected / exposed
    3 / 142 (2.11%)
         occurrences all number
    3
    Ear and labyrinth disorders
    Tinnitus
         subjects affected / exposed
    5 / 142 (3.52%)
         occurrences all number
    5
    Vertigo
         subjects affected / exposed
    4 / 142 (2.82%)
         occurrences all number
    4
    Meniere's disease
         subjects affected / exposed
    3 / 142 (2.11%)
         occurrences all number
    3
    Gastrointestinal disorders
    Nausea
         subjects affected / exposed
    3 / 142 (2.11%)
         occurrences all number
    3
    Musculoskeletal and connective tissue disorders
    Arthralgia
         subjects affected / exposed
    3 / 142 (2.11%)
         occurrences all number
    3
    Infections and infestations
    Nasopharyngitis
         subjects affected / exposed
    3 / 142 (2.11%)
         occurrences all number
    3
    Urinary tract infection
         subjects affected / exposed
    3 / 142 (2.11%)
         occurrences all number
    3

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    26 Apr 2016
    - Added EudraCT number to title page - Removed telephone as a method to report SAEs. - Added safety fax number as a back-up contact method for reporting SAEs.

    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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    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.

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