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    Clinical Trial Results:
    A phase I/II multiple ascending dose open-label safety and efficacy study of the Notch Inhibitor LY3056480 in patients with mild to moderate sensorineural hearing loss.

    Summary
    EudraCT number
    		 2016-004544-10
    Trial protocol
    		 GB   GR   DE  
    Global end of trial date
    07 Oct 2020

    Results information
    Results version number
    		 v1(current)
    This version publication date
    31 Mar 2022
    First version publication date
    31 Mar 2022
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    AUT-001
    Additional study identifiers
    ISRCTN number
    		 ISRCTN59733689
    US NCT number
    		 -
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    Audion Therapeutics BV
    Sponsor organisation address
    Hogeweg 54, Amsterdam, Netherlands, 1098CE
    Public contact
    Clinical Trial Information, Audion Therapeutics, 0031 o6 46767255, rjrutten@audiontherapeutics.com
    Scientific contact
    Clinical Trial Information, Audion Therapeutics, 0031 06 46767255, rjrutten@audiontherapeutics.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
    16 Jul 2021
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    07 Oct 2020
    Global end of trial reached?
    Yes
    Global end of trial date
    07 Oct 2020
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    The main objectives of this trial (Part B) are: 1. Main objective is to establish the efficacy of local treatment with LY3056480 in terms of hearing at 12 weeks; 2. To establish the efficacy of local treatment with LY3056480 in terms of hearing at 6 weeks; 3. To assess the safety and tolerance of local treatment with LY3056480
    Protection of trial subjects
    Informed consent, insurance
    Background therapy
    		 NA
    Evidence for comparator
    		 NA
    Actual start date of recruitment
    08 Nov 2017
    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: 39
    Country: Number of subjects enrolled
    Germany: 12
    Country: Number of subjects enrolled
    Greece: 8
    Worldwide total number of subjects
    59
    EEA total number of subjects
    20
    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)
    44
    From 65 to 84 years
    15
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 From January 24 to October 17, 2018, 15 Phase I trial patients were enrolled at the UK site. From January 30 to August 5, 2019, 44 Phase IIa patients were enrolled in the UK (N=24), Germany (N=12) and Greece (N=8).

    Pre-assignment
    Screening details
    		 In phase I 27 patients were screened, N = 12 were not enrolled (Eligibility criteria = 8, Sponsor decision = 2, Withdrew consent = 3). In phase IIa 55 patients were screened, N = 11 were not enrolled (Eligibility criteria = 8, Withdrew consent = 3).

    Period 1
    Period 1 title
    Study duration (overall period)
    Is this the baseline period?
    		 Yes
    Allocation method
    Not applicable
    Blinding used
    		 Not blinded
    Blinding implementation details
    NA

    Arms
    Arm title
    		 LY3056480
    Arm description
    		 In phase I three injections of LY3056480 were administered trans-tympanically into one ear. The patients were treated in ascending dose cohorts of 25µg, 125µg, 200µg and 250µg applied in a volume of 500 µl (sterile diluent). In phase IIa patients received three injections of 250µg of LY3056480 applied in 500 µL.
    Arm type
    		 Experimental

    Investigational medicinal product name
    LY3056480
    Investigational medicinal product code
    LY3056480
    Other name
    Pharmaceutical forms
    Solution for injection
    Routes of administration
    Transdermal use
    Dosage and administration details
    Three injections of LY3056480 were administered trans-tympanically into one ear. The patients were treated with 25µg, 125µg, 200µg and 250µg applied in a volume of 500 µl (sterile diluent).

    Number of subjects in period 1
    		LY3056480
    Started
    59
    Completed
    42
    Not completed
    17
         Consent withdrawn by subject
    17

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Study duration (overall period)
    Reporting group description
    		 all subjects enrolled

    Reporting group values
    		 Study duration (overall period) Total
    Number of subjects
    		 59 59
    Age categorical
    Age in years
    Units: Subjects
        In utero
    		 0 0
        Preterm newborn infants (gestational age < 37 wks)
    		 0 0
        Newborns (0-27 days)
    		 0 0
        Infants and toddlers (28 days-23 months)
    		 0 0
        Children (2-11 years)
    		 0 0
        Adolescents (12-17 years)
    		 0 0
        Adults (18-64 years)
    		 44 44
        From 65-84 years
    		 15 15
        85 years and over
    		 0 0
        Adult
    		 0 0
        elderly
    		 0 0
    Age continuous
    Units: years
        median (full range (min-max))
    		 59 (22 to 79) -
    Gender categorical
    Gender (male or female)
    Units: Subjects
        Female
    		 22 22
        Male
    		 37 37

    End points

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    End points reporting groups
    Reporting group title
    LY3056480
    Reporting group description
    		 In phase I three injections of LY3056480 were administered trans-tympanically into one ear. The patients were treated in ascending dose cohorts of 25µg, 125µg, 200µg and 250µg applied in a volume of 500 µl (sterile diluent). In phase IIa patients received three injections of 250µg of LY3056480 applied in 500 µL.

    Subject analysis set title
    Part B
    Subject analysis set type
    		 Modified intention-to-treat
    Subject analysis set description
    analysis partB

    Subject analysis set title
    week12
    Subject analysis set type
    		 Modified intention-to-treat
    Subject analysis set description
    week 12

    Primary: PTA

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    End point title
    		 PTA
    End point description
    End point type
    Primary
    End point timeframe
    3 months
    End point values
    		 LY3056480 Part B
    Number of subjects analysed
    43
    43
    Units: decibel
        number (confidence interval 95%)
    0.44 (-2.01 to 1.13)
    0.44 (-2.01 to 1.13)
    Statistical analysis title
    		 Mixed-effect model
    Statistical analysis description
    For Phase IIa we set a recruitment target of 40 patients, based on 87% power to detect a 10 dB(HL) change (standard deviation 20 dB(HL)) corresponding to an effect size of 0.5024. We performed exploratory analyses for all efficacy points of Phase IIa and subgroup analyses per trial site. A three-level linear mixed-effect model was used to account for repeated measures and the multilevel structure of the pure-tone audiometry and speech-in-noise data.
    Comparison groups
    LY3056480 v Part B
    Number of subjects included in analysis
    86
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 > 0.05
    Method
    		 Mixed models analysis
    Parameter type
    		 Mean difference (final values)
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -
         upper limit
    		 -
    Variability estimate
    Standard deviation

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    From informed consent until month 12
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    21.1
    Reporting groups
    Reporting group title
    LY3056480
    Reporting group description
    		 all patients who have received at least 1 dose of LY3056480

    Serious adverse events
    		 LY3056480
    Total subjects affected by serious adverse events
         subjects affected / exposed
    2 / 59 (3.39%)
         number of deaths (all causes)
    0
         number of deaths resulting from adverse events
    0
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Bladder tumor
         subjects affected / exposed
    1 / 59 (1.69%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    General disorders and administration site conditions
    broken shoulder
         subjects affected / exposed
    1 / 59 (1.69%)
         occurrences causally related to treatment / all
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    		 LY3056480
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    57 / 59 (96.61%)
    Ear and labyrinth disorders
    Injection site pain
    Additional description: 49 of the 59 participants experienced injection site pain, 83%
         subjects affected / exposed
    49 / 59 (83.05%)
         occurrences all number
    49
    Tinnitus
    Additional description: 27 of the 59 participants experiened transient tinnitus (46%)
         subjects affected / exposed
    27 / 59 (45.76%)
         occurrences all number
    27

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    01 Jun 2017
    see protocol
    17 Jul 2017
    see protocol
    20 Mar 2018
    see protocol
    04 Dec 2018
    see protocol

    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.

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