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    Clinical Trial Results:
    Efficacy and Safety of AM-111 in the Treatment of Acute Inner Ear Hearing Loss (HEALOS)

    Summary
    EudraCT number
    		 2013-002077-21
    Trial protocol
    		 BG   HU   ES   DE   CZ  
    Global end of trial date
    28 Sep 2017

    Results information
    Results version number
    		 v1(current)
    This version publication date
    15 Oct 2020
    First version publication date
    15 Oct 2020
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    AM-111-CL-13-01
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 -
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    Auris Medical AG
    Sponsor organisation address
    Dornacherstrasse 210, Basel, Switzerland, 4053
    Public contact
    Thomas Meyer, Auris Medical AG, +41 61 201 13 50, hear@aurismedical.com
    Scientific contact
    Thomas Meyer, Auris Medical AG, +41 61 201 13 50, hear@aurismedical.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
    13 Mar 2018
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    28 Sep 2017
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    Confirmation of the efficacy of AM-111 in the recovery of severe to profound idiopathic sudden sensorineural hearing loss (ISSNHL).
    Protection of trial subjects
    The trial was performed in compliance with International Conference on Harmonisation Good Clinical Practice (ICH GCP) Guidelines, and in accordance with the current version of the Declaration of Helsinki.
    Background therapy
    		 Optional reserve therapy - In case of insufficient hearing recovery at Day 7, the option of a treatment course of oral corticosteroids was offered as reserve therapy to subjects, unless medically contraindicated.
    Evidence for comparator
    		 -
    Actual start date of recruitment
    13 Nov 2015
    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
    Thailand: 47
    Country: Number of subjects enrolled
    Turkey: 5
    Country: Number of subjects enrolled
    Poland: 30
    Country: Number of subjects enrolled
    Bulgaria: 41
    Country: Number of subjects enrolled
    Czech Republic: 19
    Country: Number of subjects enrolled
    Germany: 19
    Country: Number of subjects enrolled
    Hungary: 8
    Country: Number of subjects enrolled
    Russian Federation: 47
    Country: Number of subjects enrolled
    Serbia: 21
    Country: Number of subjects enrolled
    Taiwan: 19
    Worldwide total number of subjects
    256
    EEA total number of subjects
    117
    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)
    251
    From 65 to 84 years
    5
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 Due to the acute nature of the disease and the short time window for treatment, potential subjects were recruited in emergency units and by ENT professionals.

    Pre-assignment
    Screening details
    		 A total of 258 subjects have been screeened. After 2 screening failurs, 256 subjects were randomized into the study.

    Period 1
    Period 1 title
    Whole study (overall period)
    Is this the baseline period?
    		 Yes
    Allocation method
    Randomised - controlled
    Blinding used
    		 Double blind
    Roles blinded
    		 Subject, Investigator, Monitor, Data analyst
    Blinding implementation details
    The Investigators and subjects were blinded regarding the dose administered during the study. This applied also to the trial personnel at the Sponsor and the clinical research organization (CRO) except for designated unblinded staff at the CRO. The gel formulation was of the same appearance for AM-111 0.4 and 0.8 mg/mL and placebo, with no differences apparent to Investigator or subject during or following injection. None of the Investigators were aware of the randomization schedule.

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Placebo
    Arm description
    		 -
    Arm type
    		 Placebo

    Investigational medicinal product name
    Placebo gel
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Gel for injection
    Routes of administration
    Intratympanic use
    Dosage and administration details
    Injection of 0.25 mL study drug (AM-111 0.4 mg/mL or 0.8 mg/mL or placebo) into the eligible ear at the treatment visit.

    Arm title
    		 AM-111 0.4 mg/mL
    Arm description
    		 -
    Arm type
    		 Experimental

    Investigational medicinal product name
    AM-111
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Gel for injection
    Routes of administration
    Intratympanic use
    Dosage and administration details
    Injection of 0.25 mL study drug (AM-111 0.4 mg/mL or 0.8 mg/mL or placebo) into the eligible ear at the treatment visit.

    Arm title
    		 AM-111 0.8 mg/mL
    Arm description
    		 -
    Arm type
    		 Experimental

    Investigational medicinal product name
    AM-111
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Gel for injection
    Routes of administration
    Intratympanic use
    Dosage and administration details
    Injection of 0.25 mL study drug (AM-111 0.4 mg/mL or 0.8 mg/mL or placebo) into the eligible ear at the treatment visit.

    Number of subjects in period 1
    		Placebo AM-111 0.4 mg/mL AM-111 0.8 mg/mL
    Started
    85
    85
    86
    Completed
    81
    81
    83
    Not completed
    4
    4
    3
         Consent withdrawn by subject
    4
    4
    1
         Physician decision
    -
    -
    1
         Protocol deviation
    -
    -
    1

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Placebo
    Reporting group description
    		 -

    Reporting group title
    AM-111 0.4 mg/mL
    Reporting group description
    		 -

    Reporting group title
    AM-111 0.8 mg/mL
    Reporting group description
    		 -

    Reporting group values
    		 Placebo AM-111 0.4 mg/mL AM-111 0.8 mg/mL Total
    Number of subjects
    		 85 85 86 256
    Age categorical
    Units: Subjects
        Adults (18-64 years)
    		 83 83 85 251
        From 65-84 years
    		 2 2 1 5
    Age continuous
    Units: years
        arithmetic mean (standard deviation)
    		 45.5 ± 12.1 45.8 ± 13.1 48.0 ± 10.9 -
    Gender categorical
    Units: Subjects
        Female
    		 39 41 42 122
        Male
    		 46 44 44 134

    End points

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    End points reporting groups
    Reporting group title
    Placebo
    Reporting group description
    		 -

    Reporting group title
    AM-111 0.4 mg/mL
    Reporting group description
    		 -

    Reporting group title
    AM-111 0.8 mg/mL
    Reporting group description
    		 -

    Primary: Efficacy: Improvement of PTA for all subjects

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    End point title
    		 Efficacy: Improvement of PTA for all subjects
    End point description
    Pure tone average (PTA) - average across the 3 most affected contiguous air conduction audiometric pure tone frequencies. Pure tone audiometry measures were performed by certified audiologists or adequately trained site staff and conducted in a sound attenuated booth/room, using standard earphones or earphone inserts. Hearing thresholds were determined by pure tone audiometry in both ears at 0.25, 0.5, 1, 2, 3, 4, 6, and 8 kHz (air conduction) in accordance with ISO standard 8253-1 and any other relevant standards.
    End point type
    Primary
    End point timeframe
    From Baseline to follow-up visit 3 (FUV3) (Day 28)
    End point values
    		 Placebo AM-111 0.4 mg/mL AM-111 0.8 mg/mL
    Number of subjects analysed
    79
    77
    84
    Units: Frequency
        least squares mean (standard error)
    33.78 ± 2.709
    38.44 ± 2.753
    36.63 ± 2.614
    Statistical analysis title
    		 PTA difference between Placebo and AM-111 0.4mg/mL
    Comparison groups
    Placebo v AM-111 0.4 mg/mL
    Number of subjects included in analysis
    156
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.2263
    Method
    		 ANCOVA
    Parameter type
    		 Difference
    Confidence interval
         level
    		 96%
         sides
    2-sided
         lower limit
    		 -3.28
         upper limit
    		 12.6
    Statistical analysis title
    		 PTA difference between Placebo and AM-111 0.8mg/mL
    Statistical analysis description
    Superiority testing of Placebo vs. AM-111 0.8 mg/mL was not the primary efficacy endpoint
    Comparison groups
    Placebo v AM-111 0.8 mg/mL
    Number of subjects included in analysis
    163
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.448
    Method
    		 ANCOVA
    Parameter type
    		 Difference
    Confidence interval
         level
    		 99%
         sides
    2-sided
         lower limit
    		 -6.89
         upper limit
    		 12.59

    Primary: Safety: Occurence of clinically relevant hearing deterioration

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    End point title
    		 Safety: Occurence of clinically relevant hearing deterioration
    End point description
    Occurence of clinically relevant hearing deterioration (increase in air conduction hearing threshold > 10 dB at the average of any 2 contiguous test frequencies) in the treated ear from baseline to FUV3 (Day 28).
    End point type
    Primary
    End point timeframe
    From Baseline to Follow-up Visit 3 (FUV3) (Day 28)
    End point values
    		 Placebo AM-111 0.4 mg/mL AM-111 0.8 mg/mL
    Number of subjects analysed
    76
    74
    83
    Units: Number subjects
    5
    4
    2
    Statistical analysis title
    		 Difference between Placebo and AM-111 0.4 mg/mL
    Comparison groups
    Placebo v AM-111 0.4 mg/mL
    Number of subjects included in analysis
    150
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 1
    Method
    		 Fisher exact
    Confidence interval
    Statistical analysis title
    		 Difference between Placebo and AM-111 0.8 mg/mL
    Comparison groups
    Placebo v AM-111 0.8 mg/mL
    Number of subjects included in analysis
    159
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.2603
    Method
    		 Fisher exact
    Confidence interval

    Post-hoc: Efficacy: Improvement of PTA for profound hearing loss subjects

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    End point title
    		 Efficacy: Improvement of PTA for profound hearing loss subjects
    End point description
    PTA: Pure tone average determined by air conduction audiometry. Profound hearing loss: The post-hoc analyses were based on a commonly used classification of hearing loss severity, which separates severe from profound hearing loss at the level of 90 dB. Profound hearing loss is present when the hearing loss is equal or above 90 dB. Those subjects perceive loud sounds mainly as vibrations.
    End point type
    Post-hoc
    End point timeframe
    From Baseline (Day 0) to Follow-up Visit 3 (FUV3) (Day 28)
    End point values
    		 Placebo AM-111 0.4 mg/mL AM-111 0.8 mg/mL
    Number of subjects analysed
    34
    35
    30
    Units: Frequency
        arithmetic mean (standard error)
    26.78 ± 4.706
    42.71 ± 4.645
    37.34 ± 5.008
    Statistical analysis title
    		 PTA difference between Placebo and AM-111 0.4mg/mL
    Statistical analysis description
    Post-hoc analysis with subjects that experienced a profound hearing loss.
    Comparison groups
    AM-111 0.4 mg/mL v Placebo
    Number of subjects included in analysis
    69
    Analysis specification
    Post-hoc
    Analysis type
    		 superiority
    P-value
    		 = 0.0176
    Method
    		 ANCOVA
    Parameter type
    		 Difference
    Confidence interval
         level
    		 96%
         sides
    2-sided
         lower limit
    		 2.2
         upper limit
    		 29.66
    Statistical analysis title
    		 PTA difference between Placebo and AM-111 0.8mg/mL
    Comparison groups
    Placebo v AM-111 0.8 mg/mL
    Number of subjects included in analysis
    64
    Analysis specification
    Post-hoc
    Analysis type
    		 superiority
    P-value
    		 = 0.126
    Method
    		 ANCOVA
    Parameter type
    		 Difference
    Confidence interval
         level
    		 99%
         sides
    2-sided
         lower limit
    		 -7.43
         upper limit
    		 28.54

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    The AE reporting for this study began at the time of signature of informed consent and ended at the last follow-up visit (FUV4).
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    20.1
    Reporting groups
    Reporting group title
    Placebo
    Reporting group description
    		 2% threshold applies for subjects affected by non-serious adverse events

    Reporting group title
    AM-111 0.4 mg/mL
    Reporting group description
    		 2% threshold applies for subjects affected by non-serious adverse events

    Reporting group title
    AM-111 0.8 mg/mL
    Reporting group description
    		 2% threshold applies for subjects affected by non-serious adverse events

    Serious adverse events
    		 Placebo AM-111 0.4 mg/mL AM-111 0.8 mg/mL
    Total subjects affected by serious adverse events
         subjects affected / exposed
    3 / 85 (3.53%)
    2 / 85 (2.35%)
    2 / 86 (2.33%)
         number of deaths (all causes)
    0
    0
    0
         number of deaths resulting from adverse events
    0
    0
    0
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Fibroadenoma of breast
         subjects affected / exposed
    0 / 85 (0.00%)
    1 / 85 (1.18%)
    0 / 86 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Surgical and medical procedures
    Acoustic neuroma removal
         subjects affected / exposed
    0 / 85 (0.00%)
    0 / 85 (0.00%)
    1 / 86 (1.16%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Cardiac disorders
    Cardiac failure congestive
         subjects affected / exposed
    0 / 85 (0.00%)
    0 / 85 (0.00%)
    1 / 86 (1.16%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Blood and lymphatic system disorders
    Polycythaemia
         subjects affected / exposed
    1 / 85 (1.18%)
    0 / 85 (0.00%)
    0 / 86 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Gastrointestinal disorders
    Vomiting
         subjects affected / exposed
    0 / 85 (0.00%)
    1 / 85 (1.18%)
    0 / 86 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Skin and subcutaneous tissue disorders
    Rash
         subjects affected / exposed
    1 / 85 (1.18%)
    0 / 85 (0.00%)
    0 / 86 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Metabolism and nutrition disorders
    Diabetes mellitus inadequate control
         subjects affected / exposed
    1 / 85 (1.18%)
    0 / 85 (0.00%)
    0 / 86 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 2%
    Non-serious adverse events
    		 Placebo AM-111 0.4 mg/mL AM-111 0.8 mg/mL
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    29 / 85 (34.12%)
    24 / 85 (28.24%)
    22 / 86 (25.58%)
    Investigations
    Blood pressure increased
         subjects affected / exposed
    1 / 85 (1.18%)
    2 / 85 (2.35%)
    0 / 86 (0.00%)
         occurrences all number
    1
    2
    0
    Nervous system disorders
    Headache
         subjects affected / exposed
    5 / 85 (5.88%)
    2 / 85 (2.35%)
    5 / 86 (5.81%)
         occurrences all number
    5
    2
    7
    Dizziness
         subjects affected / exposed
    1 / 85 (1.18%)
    3 / 85 (3.53%)
    4 / 86 (4.65%)
         occurrences all number
    1
    3
    6
    General disorders and administration site conditions
    Pyrexia
         subjects affected / exposed
    2 / 85 (2.35%)
    0 / 85 (0.00%)
    1 / 86 (1.16%)
         occurrences all number
    2
    0
    1
    Ear and labyrinth disorders
    Vertigo
         subjects affected / exposed
    4 / 85 (4.71%)
    2 / 85 (2.35%)
    5 / 86 (5.81%)
         occurrences all number
    4
    3
    5
    Ear pain
         subjects affected / exposed
    2 / 85 (2.35%)
    3 / 85 (3.53%)
    1 / 86 (1.16%)
         occurrences all number
    2
    3
    1
    Tinnitus
         subjects affected / exposed
    4 / 85 (4.71%)
    1 / 85 (1.18%)
    0 / 86 (0.00%)
         occurrences all number
    4
    1
    0
    Vertigo positional
         subjects affected / exposed
    1 / 85 (1.18%)
    3 / 85 (3.53%)
    1 / 86 (1.16%)
         occurrences all number
    1
    3
    1
    Ear discomfort
         subjects affected / exposed
    2 / 85 (2.35%)
    1 / 85 (1.18%)
    0 / 86 (0.00%)
         occurrences all number
    2
    1
    0
    Gastrointestinal disorders
    Vomiting
         subjects affected / exposed
    1 / 85 (1.18%)
    2 / 85 (2.35%)
    1 / 86 (1.16%)
         occurrences all number
    1
    2
    1
    Nausea
         subjects affected / exposed
    2 / 85 (2.35%)
    0 / 85 (0.00%)
    0 / 86 (0.00%)
         occurrences all number
    2
    0
    0
    Skin and subcutaneous tissue disorders
    Rash
         subjects affected / exposed
    2 / 85 (2.35%)
    0 / 85 (0.00%)
    0 / 86 (0.00%)
         occurrences all number
    2
    0
    0
    Infections and infestations
    Nasopharyngitis
         subjects affected / exposed
    2 / 85 (2.35%)
    5 / 85 (5.88%)
    1 / 86 (1.16%)
         occurrences all number
    2
    5
    1
    Rhinitis
         subjects affected / exposed
    0 / 85 (0.00%)
    0 / 85 (0.00%)
    3 / 86 (3.49%)
         occurrences all number
    0
    0
    3

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? No

    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

    Online references
    http://www.ncbi.nlm.nih.gov/pubmed/31083077
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