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    Clinical Trial Results:
    Efficacy of AM-111 in Patients with Acute Sensorineural Hearing Loss: A Multi-Centre, Double-Blind, Randomised, Placebo-Controlled, Dose-Escalation Phase II Study

    Summary
    EudraCT number
    		 2008-000132-40
    Trial protocol
    		 DE   CZ  
    Global end of trial date
    17 Jul 2012

    Results information
    Results version number
    		 v1(current)
    This version publication date
    06 Aug 2016
    First version publication date
    06 Aug 2016
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    AM-111-CL-08-01
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 -
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    Auris Medical AG
    Sponsor organisation address
    Falknerstr. 4, Basel, Switzerland, 4001
    Public contact
    Thomas Meyer, Auris Medical AG, +41 61 201 13 50, ear@aurismedical.com
    Scientific contact
    Thomas Meyer, Auris Medical AG, +41 61 201 13 50, ear@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
    18 Jun 2013
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    17 Jul 2012
    Global end of trial reached?
    Yes
    Global end of trial date
    17 Jul 2012
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    The primary objective of the study was the evaluation of the therapeutic benefit of a single intratympanic (i.t.) AM-111 injection in comparison to placebo in the treatment of acute sensorineural hearing loss (ASNHL).
    Protection of trial subjects
    This Clinical Trial was conducted in accordance with the study protocol, the International Conference on Harmonisation (ICH) harmonized tripartite guideline on Good Clinical Practices (GCP) (E6), as well as the ethical principles outlined in the Declaration of Helsinki dated 1989, respectively in their most current version.
    Background therapy
    		 Reserve therapy option: Subjects whose pure tone average (PTA) recovered on average less than 10 dB from baseline to Day7 were given the option to receive a 5-day course of prednisolone by way of oral administration (2 x 50 mg daily).
    Evidence for comparator
    		 -
    Actual start date of recruitment
    05 Feb 2009
    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
    Germany: 41
    Country: Number of subjects enrolled
    Poland: 143
    Country: Number of subjects enrolled
    Czech Republic: 26
    Worldwide total number of subjects
    210
    EEA total number of subjects
    210
    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)
    210
    From 65 to 84 years
    0
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 Twenty-five European sites (academic tertiary referral centers and private ENT practices) from 3 EU countries participated in the study. A total of 210 patients were screened. Of these, all 210 patients were randomised.

    Pre-assignment
    Screening details
    		 Main inclusion criteria were: Age 18 - 60 years; unilateral ISSNHL or uni-or bilateral AAT; hearing loss at least 30 dB; onset not more than 48h before. All 210 screened patients have been randomised.

    Period 1
    Period 1 title
    Whole study period (overall period)
    Is this the baseline period?
    		 Yes
    Allocation method
    Randomised - controlled
    Blinding used
    		 Double blind
    Roles blinded
    		 Subject, Investigator

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 AM-111 0.4 mg/mL
    Arm description
    		 Study drug (gel formulation) was administered on Day 0 by intratympanic injection under local anesthesia of the tympanic membrane. Patients came back for 3 further follow-up visits on Days 3, 7, 30, and 90. Glass vials containing 0.7 mL of the gel formulation were provided for each treatment visit of which 0.25 mL were used for treatment.
    Arm type
    		 Experimental

    Investigational medicinal product name
    JNK inhibitor (D-JNKI-1)
    Investigational medicinal product code
    AM-111
    Other name
    Pharmaceutical forms
    Gel for injection
    Routes of administration
    Intratympanic use
    Dosage and administration details
    Single intratympanic application of AM-111 0.4 mg/mL (0.25 mL). In case of bilateral AAT, only the worse affected ear was treated.

    Arm title
    		 AM-111 2.0 mg/mL
    Arm description
    		 Study drug (gel formulation) was administered on Day 0 by intratympanic injection under local anesthesia of the tympanic membrane. Patients came back for 3 further follow-up visits on Days 3, 7, 30, and 90. Glass vials containing 0.7 mL of the gel formulation were provided for each treatment visit of which 0.25 mL were used for treatment.
    Arm type
    		 Experimental

    Investigational medicinal product name
    JNK inhibitor (D-JNKI-1)
    Investigational medicinal product code
    AM-111
    Other name
    Pharmaceutical forms
    Gel for injection
    Routes of administration
    Intratympanic use
    Dosage and administration details
    Single intratympanic application of AM-111 2.0 mg/mL (0.25 mL). In case of bilateral AAT, only the worse affected ear was treated.

    Arm title
    		 Placebo pooled
    Arm description
    		 The study consisted of 2 dose cohorts each randomised individually against placebo in a 2:1 ratio. In the results presentation the 2 placebo groups from the 2 cohorts were pooled and are presented as 1 pooled placebo group. Study drug (gel formulation) was administered on Day 0 by intratympanic injection under local anesthesia of the tympanic membrane. Patients came back for 3 further follow-up visits on Days 3, 7, 30, and 90. Glass vials containing 0.7 mL of the gel formulation were provided for each treatment visit of which 0.25 mL were used for treatment.
    Arm type
    		 Placebo

    Investigational medicinal product name
    Placebo
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Gel for injection
    Routes of administration
    Intratympanic use
    Dosage and administration details
    0.25 mL of gel without active were injected. In case of bilateral AAT, only the worse affected ear was treated.

    Number of subjects in period 1
    		AM-111 0.4 mg/mL AM-111 2.0 mg/mL Placebo pooled
    Started
    68
    70
    72
    Completed
    61
    62
    66
    Not completed
    7
    8
    6
         Refused/Unable to attend visit(s)
    5
    2
    3
         Consent withdrawn by subject
    -
    5
    1
         Reason unknown
    2
    1
    -
         Change of Residence
    -
    -
    1
         Lost to follow-up
    -
    -
    1

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    AM-111 0.4 mg/mL
    Reporting group description
    		 Study drug (gel formulation) was administered on Day 0 by intratympanic injection under local anesthesia of the tympanic membrane. Patients came back for 3 further follow-up visits on Days 3, 7, 30, and 90. Glass vials containing 0.7 mL of the gel formulation were provided for each treatment visit of which 0.25 mL were used for treatment.

    Reporting group title
    AM-111 2.0 mg/mL
    Reporting group description
    		 Study drug (gel formulation) was administered on Day 0 by intratympanic injection under local anesthesia of the tympanic membrane. Patients came back for 3 further follow-up visits on Days 3, 7, 30, and 90. Glass vials containing 0.7 mL of the gel formulation were provided for each treatment visit of which 0.25 mL were used for treatment.

    Reporting group title
    Placebo pooled
    Reporting group description
    		 The study consisted of 2 dose cohorts each randomised individually against placebo in a 2:1 ratio. In the results presentation the 2 placebo groups from the 2 cohorts were pooled and are presented as 1 pooled placebo group. Study drug (gel formulation) was administered on Day 0 by intratympanic injection under local anesthesia of the tympanic membrane. Patients came back for 3 further follow-up visits on Days 3, 7, 30, and 90. Glass vials containing 0.7 mL of the gel formulation were provided for each treatment visit of which 0.25 mL were used for treatment.

    Reporting group values
    		 AM-111 0.4 mg/mL AM-111 2.0 mg/mL Placebo pooled Total
    Number of subjects
    		 68 70 72 210
    Age categorical
    Units: Subjects
        In utero
    		 0 0 0 0
        Preterm newborn infants (gestational age < 37 wks)
    		 0 0 0 0
        Newborns (0-27 days)
    		 0 0 0 0
        Infants and toddlers (28 days-23 months)
    		 0 0 0 0
        Children (2-11 years)
    		 0 0 0 0
        Adolescents (12-17 years)
    		 0 0 0 0
        Adults (18-64 years)
    		 68 70 72 210
        From 65-84 years
    		 0 0 0 0
        85 years and over
    		 0 0 0 0
    Age continuous
    Units: years
        arithmetic mean (standard deviation)
    		 41.1 ± 10.9 43.9 ± 10.9 41.7 ± 11.8 -
    Gender categorical
    Units: Subjects
        Female
    		 24 30 28 82
        Male
    		 44 40 44 128

    End points

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    End points reporting groups
    Reporting group title
    AM-111 0.4 mg/mL
    Reporting group description
    		 Study drug (gel formulation) was administered on Day 0 by intratympanic injection under local anesthesia of the tympanic membrane. Patients came back for 3 further follow-up visits on Days 3, 7, 30, and 90. Glass vials containing 0.7 mL of the gel formulation were provided for each treatment visit of which 0.25 mL were used for treatment.

    Reporting group title
    AM-111 2.0 mg/mL
    Reporting group description
    		 Study drug (gel formulation) was administered on Day 0 by intratympanic injection under local anesthesia of the tympanic membrane. Patients came back for 3 further follow-up visits on Days 3, 7, 30, and 90. Glass vials containing 0.7 mL of the gel formulation were provided for each treatment visit of which 0.25 mL were used for treatment.

    Reporting group title
    Placebo pooled
    Reporting group description
    		 The study consisted of 2 dose cohorts each randomised individually against placebo in a 2:1 ratio. In the results presentation the 2 placebo groups from the 2 cohorts were pooled and are presented as 1 pooled placebo group. Study drug (gel formulation) was administered on Day 0 by intratympanic injection under local anesthesia of the tympanic membrane. Patients came back for 3 further follow-up visits on Days 3, 7, 30, and 90. Glass vials containing 0.7 mL of the gel formulation were provided for each treatment visit of which 0.25 mL were used for treatment.

    Primary: Absolute improvement of pure tone average (PTA)

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    End point title
    		 Absolute improvement of pure tone average (PTA)
    End point description
    The absolute improvement of PTA given in dB between Day 0 and Day 7 based on the average of the three most affected contiguous frequencies.
    End point type
    Primary
    End point timeframe
    Day 0 to Day 7.
    End point values
    		 AM-111 0.4 mg/mL AM-111 2.0 mg/mL Placebo pooled
    Number of subjects analysed
    62
    64
    71
    Units: dB
        arithmetic mean (standard deviation)
    28.1 ± 17.7
    27.7 ± 15.6
    24 ± 16
    Statistical analysis title
    		 Absolute Change in PTA (dB) from baseline to Day 7
    Statistical analysis description
    Global comparison with analysis set "valid for efficacy" was used.
    Comparison groups
    Placebo pooled v AM-111 2.0 mg/mL
    Number of subjects included in analysis
    135
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.611
    Method
    		 ANCOVA
    Parameter type
    		 Mean difference (final values)
    Confidence interval
    Statistical analysis title
    		 Absolute Change in PTA (dB) from baseline to Day 7
    Statistical analysis description
    Global comparison with analysis set "valid for efficacy" was used.
    Comparison groups
    AM-111 0.4 mg/mL v Placebo pooled
    Number of subjects included in analysis
    133
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.203
    Method
    		 ANCOVA
    Parameter type
    		 Mean difference (final values)
    Confidence interval

    Primary: Co-primary: Relative Change in PTA (%)

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    End point title
    		 Co-primary: Relative Change in PTA (%)
    End point description
    Relative changes from baseline in (%)
    End point type
    Primary
    End point timeframe
    Day 0 to Day 7
    End point values
    		 AM-111 0.4 mg/mL AM-111 2.0 mg/mL Placebo pooled
    Number of subjects analysed
    62
    64
    71
    Units: percentage
        arithmetic mean (standard deviation)
    61.1 ± 37.5
    49.6 ± 44.5
    57.6 ± 40.3
    Statistical analysis title
    		 Relative Change Placebo pooled vs AM-111 2.0 mg/mL
    Statistical analysis description
    Valid for efficacy analysis set was used.
    Comparison groups
    AM-111 2.0 mg/mL v Placebo pooled
    Number of subjects included in analysis
    135
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.12
    Method
    		 ANCOVA
    Confidence interval
    Statistical analysis title
    		 Relative Change Placebo pooled vs AM-111 0.4 mg/mL
    Statistical analysis description
    Valid for efficacy analysis set was used.
    Comparison groups
    AM-111 0.4 mg/mL v Placebo pooled
    Number of subjects included in analysis
    133
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.5
    Method
    		 ANCOVA
    Confidence interval

    Primary: Co-primary: Fequency complete recovery

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    End point title
    		 Co-primary: Fequency complete recovery
    End point description
    Subjects with complete recovery were counted.
    End point type
    Primary
    End point timeframe
    Day 0 to Day 7
    End point values
    		 AM-111 0.4 mg/mL AM-111 2.0 mg/mL Placebo pooled
    Number of subjects analysed
    62
    64
    71
    Units: subjects
        Complete recovery
    27
    24
    33
        without complete recovery
    35
    40
    38
    Statistical analysis title
    		 Complete recovery rate
    Statistical analysis description
    Valid for Efficacy analysis set was used.
    Comparison groups
    AM-111 2.0 mg/mL v Placebo pooled
    Number of subjects included in analysis
    135
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.3
    Method
    		 Regression, Logistic
    Confidence interval
    Statistical analysis title
    		 Complete recovery rate
    Statistical analysis description
    Valid for Efficacy analysis set was used.
    Comparison groups
    Placebo pooled v AM-111 0.4 mg/mL
    Number of subjects included in analysis
    133
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.55
    Method
    		 Regression, Logistic
    Confidence interval

    Primary: Safety: Frequency of patients with clinically significant hearing loss in the treated ear

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    End point title
    		 Safety: Frequency of patients with clinically significant hearing loss in the treated ear
    End point description
    The primary safety endpoint was defined as the number of subjects with clinically significant hearing loss, defined as deterioration of hearing thresholds of ≥10 dB at the average of any 3 contiguous test frequencies, in the treated ear from baseline to Day 7. Analysis performed on Valid for Safety group.
    End point type
    Primary
    End point timeframe
    Day 0 to Day 7
    End point values
    		 AM-111 0.4 mg/mL AM-111 2.0 mg/mL Placebo pooled
    Number of subjects analysed
    62 [1]
    68
    67
    Units: number patients
    4
    5
    5
    Notes
    [1] - number of patients with significant clinically hearing loss is shown, same for all reporting groups
    Statistical analysis title
    		 Comparison - frequency of significant hearing Loss
    Statistical analysis description
    Comparison of subjects with clinically significant hearing loss in the treated ear. Only within-cohort data were used. Valid for Safety data set is used.
    Comparison groups
    Placebo pooled v AM-111 2.0 mg/mL
    Number of subjects included in analysis
    135
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 1
    Method
    		 Fisher exact
    Confidence interval
    Statistical analysis title
    		 Comparison - frequency of significant hearing Loss
    Statistical analysis description
    Comparison of subjects with clinically significant hearing loss in the treated ear. Only within-cohort data were used. Valid for Safety data set is used.
    Comparison groups
    Placebo pooled v AM-111 0.4 mg/mL
    Number of subjects included in analysis
    129
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.69
    Method
    		 Fisher exact
    Confidence interval

    Other pre-specified: Improvement in Speech Discrimination Score (SDS) (all)

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    End point title
    		 Improvement in Speech Discrimination Score (SDS) (all)
    End point description
    Average improvement in SDS between baseline and Day 7. Words were presented at 80 dB stimulus level.
    End point type
    Other pre-specified
    End point timeframe
    Day 0 to Day 7
    End point values
    		 AM-111 0.4 mg/mL AM-111 2.0 mg/mL Placebo pooled
    Number of subjects analysed
    62
    64
    69
    Units: percent of correctly discriminated words
        arithmetic mean (standard deviation)
    18.8 ± 29.6
    12.5 ± 23.4
    8 ± 20.7
    Statistical analysis title
    		 Absolute Change in SDS at 80 dB
    Comparison groups
    Placebo pooled v AM-111 2.0 mg/mL
    Number of subjects included in analysis
    133
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.15
    Method
    		 ANCOVA
    Confidence interval
    Statistical analysis title
    		 Absolute Change in SDS at 80 dB
    Comparison groups
    Placebo pooled v AM-111 0.4 mg/mL
    Number of subjects included in analysis
    131
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.028
    Method
    		 ANCOVA
    Confidence interval

    Post-hoc: Subgroup analysis: Absolute improvement of pure tone average (PTA) - severe to profound hearing loss

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    End point title
    		 Subgroup analysis: Absolute improvement of pure tone average (PTA) - severe to profound hearing loss
    End point description
    Due to unexpected high spontaneous recovery in mild to moderate hearing loss cases, an additional analysis on the subgroup with severe to profound hearing loss was performed.
    End point type
    Post-hoc
    End point timeframe
    Day 0 - Day 7
    End point values
    		 AM-111 0.4 mg/mL AM-111 2.0 mg/mL Placebo pooled
    Number of subjects analysed
    29
    33
    30
    Units: dB
        arithmetic mean (standard deviation)
    28.6 ± 22.6
    24.6 ± 20.7
    17.2 ± 18.3
    Statistical analysis title
    		 Absolute Change in PTA in profound to severe HL
    Statistical analysis description
    Subgroup analysis in patients with profound to severe hearing loss on Valid for Efficacy analysis set.
    Comparison groups
    Placebo pooled v AM-111 0.4 mg/mL
    Number of subjects included in analysis
    59
    Analysis specification
    Post-hoc
    Analysis type
    		 superiority
    P-value
    		 = 0.017
    Method
    		 ANCOVA
    Confidence interval
    Statistical analysis title
    		 Absolute Change in PTA in profound to severe HL
    Statistical analysis description
    Subgroup analysis in patients with profound to severe hearing loss on Valid for Efficacy analysis set.
    Comparison groups
    AM-111 2.0 mg/mL v Placebo pooled
    Number of subjects included in analysis
    63
    Analysis specification
    Post-hoc
    Analysis type
    		 superiority
    P-value
    		 = 0.32
    Method
    		 ANCOVA
    Confidence interval

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    From baseline to end of study at all visits.
    Adverse event reporting additional description
    The occurrence of a treatment emergent adverse event in the same subject more than once was counted only once for non-serious adverse events.
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    15.1
    Reporting groups
    Reporting group title
    AM-111 0.4 mg/mL
    Reporting group description
    		 -

    Reporting group title
    AM-111 2.0 mg/mL
    Reporting group description
    		 -

    Reporting group title
    Placebo pooled
    Reporting group description
    		 -

    Serious adverse events
    		 AM-111 0.4 mg/mL AM-111 2.0 mg/mL Placebo pooled
    Total subjects affected by serious adverse events
         subjects affected / exposed
    4 / 68 (5.88%)
    3 / 70 (4.29%)
    2 / 72 (2.78%)
         number of deaths (all causes)
    0
    0
    0
         number of deaths resulting from adverse events
    0
    0
    0
    Nervous system disorders
    Neurosurgery
         subjects affected / exposed
    0 / 68 (0.00%)
    1 / 70 (1.43%)
    0 / 72 (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
    Ear and labyrinth disorders
    Deafness neurosensory
         subjects affected / exposed
    3 / 68 (4.41%)
    1 / 70 (1.43%)
    2 / 72 (2.78%)
         occurrences causally related to treatment / all
    0 / 3
    1 / 1
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Reproductive system and breast disorders
    Abortion spontaneous
         subjects affected / exposed
    0 / 68 (0.00%)
    1 / 70 (1.43%)
    0 / 72 (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
    Musculoskeletal and connective tissue disorders
    Intervertebral disc disorder
         subjects affected / exposed
    1 / 68 (1.47%)
    0 / 70 (0.00%)
    0 / 72 (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
    		 AM-111 0.4 mg/mL AM-111 2.0 mg/mL Placebo pooled
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    25 / 68 (36.76%)
    27 / 70 (38.57%)
    27 / 72 (37.50%)
    Injury, poisoning and procedural complications
    Incision site complications
         subjects affected / exposed
    2 / 68 (2.94%)
    2 / 70 (2.86%)
    3 / 72 (4.17%)
         occurrences all number
    2
    2
    3
    Vascular disorders
    Hypertension
         subjects affected / exposed
    2 / 68 (2.94%)
    0 / 70 (0.00%)
    2 / 72 (2.78%)
         occurrences all number
    2
    0
    2
    Nervous system disorders
    Headache
         subjects affected / exposed
    0 / 68 (0.00%)
    0 / 70 (0.00%)
    2 / 72 (2.78%)
         occurrences all number
    0
    0
    2
    Ear and labyrinth disorders
    Hearing impaired
         subjects affected / exposed
    15 / 68 (22.06%)
    15 / 70 (21.43%)
    14 / 72 (19.44%)
         occurrences all number
    15
    15
    14
    Tinnitus
         subjects affected / exposed
    7 / 68 (10.29%)
    7 / 70 (10.00%)
    6 / 72 (8.33%)
         occurrences all number
    7
    7
    6
    Ear Pain
         subjects affected / exposed
    1 / 68 (1.47%)
    2 / 70 (2.86%)
    1 / 72 (1.39%)
         occurrences all number
    1
    2
    1
    Ear Discomfort
         subjects affected / exposed
    2 / 68 (2.94%)
    0 / 70 (0.00%)
    1 / 72 (1.39%)
         occurrences all number
    2
    0
    1
    Vertigo
         subjects affected / exposed
    0 / 68 (0.00%)
    1 / 70 (1.43%)
    2 / 72 (2.78%)
         occurrences all number
    0
    1
    2
    Gastrointestinal disorders
    Nausea
         subjects affected / exposed
    0 / 68 (0.00%)
    2 / 70 (2.86%)
    0 / 72 (0.00%)
         occurrences all number
    0
    2
    0
    Musculoskeletal and connective tissue disorders
    Back pain
         subjects affected / exposed
    0 / 68 (0.00%)
    2 / 70 (2.86%)
    0 / 72 (0.00%)
         occurrences all number
    0
    2
    0
    Infections and infestations
    Rhinitis
         subjects affected / exposed
    2 / 68 (2.94%)
    1 / 70 (1.43%)
    1 / 72 (1.39%)
         occurrences all number
    2
    1
    1
    Influenza
         subjects affected / exposed
    0 / 68 (0.00%)
    2 / 70 (2.86%)
    1 / 72 (1.39%)
         occurrences all number
    0
    2
    1

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    11 May 2009
    Modification of inclusion criteria: - Average hearing loss of at least 30 dB in the 3 most affected contiguous frequencies instead of ≥ 30 dB at each of the 3 frequencies. - Option to determine the hearing loss against the age and gender adjusted ISO tables and no longer only against the contralateral ear or against a pre-existing audiogram. - Inclusion of bilateral hearing loss resulting from noise trauma. Modification of exclusion criteria: - Requirement of pre-existing audiogram to document history of asymmetric hearing before ASNHL dropped.
    03 Nov 2010
    - Change of concentration for second cohort from 6.0 to 0.4 mg/mL; correspondingly waiver of safety and tolerability review prior to start of second cohort (no patient was dosed with 6.0 mg/mL). - Requirement for ABR measurements prior to study inclusion added to help diagnose retrocochlear lesions. - Clarification of conditions for prednisolone reserve therapy. - Comprehensive revision of the statistics section, including: Definition of statistical analysis sets; Imputation of missing values; Endpoint model; Test hypotheses; Adjustment for multiple testing of efficacy endpoints.

    Interruptions (globally)
    Were there any global interruptions to the trial? Yes
    Date
    Interruption
    Restart date
    30 Oct 2009
    Observation of an impurity in stability testing. Batches were replaced.
    02 Dec 2009

    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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