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    Clinical Trial Results:
    Efficacy of AM-101 in Patients with Acute Inner Ear Tinnitus: A Multi-Centre, Double-Blind, Randomised, Placebo-Controlled, Multiple Dose, Group Comparison Phase II Study

    Summary
    EudraCT number
    		 2008-005178-10
    Trial protocol
    		 DE   BE   NL  
    Global end of trial date
    10 May 2011

    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-101-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
    11 Jan 2012
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    10 May 2011
    Global end of trial reached?
    Yes
    Global end of trial date
    10 May 2011
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    The primary objective of the trial was the evaluation of the therapeutic benefit of 3 repeated dose intratympanic AM-101 injections in comparison to placebo in the treatment of acute inner ear tinnitus (onset within 3 months) following acute acoustic trauma (AAT), sudden deafness (idiopathic sudden sensorineural hearing loss, ISSNHL) or acute otitis media (OM).
    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, or in their most current version.
    Background therapy
    		 N/A
    Evidence for comparator
    		 N/A
    Actual start date of recruitment
    31 Mar 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: 123
    Country: Number of subjects enrolled
    Belgium: 66
    Country: Number of subjects enrolled
    Netherlands: 3
    Country: Number of subjects enrolled
    Poland: 56
    Worldwide total number of subjects
    248
    EEA total number of subjects
    248
    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)
    1
    Adults (18-64 years)
    247
    From 65 to 84 years
    0
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 Twenty-eight European sites (academic tertiary referral centers and private ENT practices) participated in the study. A total of 284 patients were screened. Of these, 248 were randomised.

    Pre-assignment
    Screening details
    		 Main inclusion criteria were: Persistent tinnitus following AAT, sudden deafness or acute OM, with onset less than 3 months ago (ie, acute tinnitus); medical report of tinnitus provoking incident; age from 18 - 65 years. Screening assessments were performed on Day 0.

    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, Monitor, Data analyst, Investigator
    Blinding implementation details
    The Sponsor, Investigators as well as the subjects were blinded regarding the treatment administered during the study. In particular, the gel formulation was of the same appearance for AM-101 and Placebo. The gel (either AM-101 or Placebo) revealed no differences during or following injection, neither to the Investigator, nor to the subject. The packaging was identical for all AM-101 doses and placebo. Subjects were randomized to one of the three treatment arms (low dose, high dose or placebo).

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 AM-101 low dose
    Arm description
    		 Study drug (gel formulation) was administered on Days 0, 1, and 2 by intratympanic injection under local anesthesia of the tympanic membrane. Patients came back for 3 further follow-up visits on Days 7, 30, and 90. The study drug was provided in glass vials containing 0.7 mL of the gel formulation. One vial per patient per treatment visit was used to extract 0.25 mL for the intratympanic application.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Esketamine hydrochloride gel
    Investigational medicinal product code
    AM-101
    Other name
    Pharmaceutical forms
    Gel for injection
    Routes of administration
    Intratympanic use
    Dosage and administration details
    0.25 ml of Esketamine HCl gel at a concentration of 0.27 mg/mL were injected. Only worse affected ear treated in case of bilateral tinnitus.

    Arm title
    		 AM-101 high dose
    Arm description
    		 see above at AM-101 low dose
    Arm type
    		 Experimental

    Investigational medicinal product name
    Esketamine hydrochloride gel
    Investigational medicinal product code
    AM-101
    Other name
    Pharmaceutical forms
    Gel for injection
    Routes of administration
    Intratympanic use
    Dosage and administration details
    0.25 ml of Esketamine HCl gel at a concentration of 0.81 mg/mL were injected. Only worse affected ear treated in case of bilateral tinnitus.

    Arm title
    		 Placebo
    Arm description
    		 see above at AM-101 low dose
    Arm type
    		 Placebo

    Investigational medicinal product name
    Placebo gel
    Investigational medicinal product code
    Placebo
    Other name
    Pharmaceutical forms
    Gel for injection
    Routes of administration
    Intratympanic use
    Dosage and administration details
    0.25 mL of Placebo (not containing Esketamine HCl) were injected. Only worse affected ear treated in case of bilateral tinnitus.

    Number of subjects in period 1
    		AM-101 low dose AM-101 high dose Placebo
    Started
    78
    84
    86
    Completed
    74
    75
    83
    Not completed
    4
    9
    3
         Consent withdrawn by subject
    1
    4
    1
         Significant medical condition
    -
    -
    1
         Other
    -
    1
    -
         Lost to follow-up
    3
    4
    1

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    AM-101 low dose
    Reporting group description
    		 Study drug (gel formulation) was administered on Days 0, 1, and 2 by intratympanic injection under local anesthesia of the tympanic membrane. Patients came back for 3 further follow-up visits on Days 7, 30, and 90. The study drug was provided in glass vials containing 0.7 mL of the gel formulation. One vial per patient per treatment visit was used to extract 0.25 mL for the intratympanic application.

    Reporting group title
    AM-101 high dose
    Reporting group description
    		 see above at AM-101 low dose

    Reporting group title
    Placebo
    Reporting group description
    		 see above at AM-101 low dose

    Reporting group values
    		 AM-101 low dose AM-101 high dose Placebo Total
    Number of subjects
    		 78 84 86 248
    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 1 0 1
        Adults (18-64 years)
    		 78 83 86 247
        From 65-84 years
    		 0 0 0 0
        85 years and over
    		 0 0 0 0
    Age continuous
    Units: years
        arithmetic mean (standard deviation)
    		 39 ( 12.5 ) 38.2 ( 11.3 ) 39.4 ( 12.2 ) -
    Gender categorical
    Units: Subjects
        Female
    		 21 23 31 75
        Male
    		 57 61 55 173

    End points

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    End points reporting groups
    Reporting group title
    AM-101 low dose
    Reporting group description
    		 Study drug (gel formulation) was administered on Days 0, 1, and 2 by intratympanic injection under local anesthesia of the tympanic membrane. Patients came back for 3 further follow-up visits on Days 7, 30, and 90. The study drug was provided in glass vials containing 0.7 mL of the gel formulation. One vial per patient per treatment visit was used to extract 0.25 mL for the intratympanic application.

    Reporting group title
    AM-101 high dose
    Reporting group description
    		 see above at AM-101 low dose

    Reporting group title
    Placebo
    Reporting group description
    		 see above at AM-101 low dose

    Primary: Efficacy: Differences between treatment groups in the change of MML from baseline to Day 90

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    End point title
    		 Efficacy: Differences between treatment groups in the change of MML from baseline to Day 90
    End point description
    The Minimum Masking Level was determined with a pulsed standard speech audiometry broadband masking noise and using the descending method of limits with bracketing at 5 dB resolution. Analysis performed on valid for efficacy analysis set.
    End point type
    Primary
    End point timeframe
    Baseline to Day 90
    End point values
    		 AM-101 low dose AM-101 high dose Placebo
    Number of subjects analysed
    72
    64
    76
    Units: dB
        arithmetic mean (standard deviation)
    7.76 ( 11.4 )
    7.65 ( 14.3 )
    9.19 ( 15.1 )
    Statistical analysis title
    		 Global comparison
    Statistical analysis description
    For continuous efficacy end points, analysis of covariance (ANCOVA) models were used including treatment group as fixed class effect, and the baseline values (Day 0) of the respective end point as covariate.
    Comparison groups
    AM-101 low dose v AM-101 high dose v Placebo
    Number of subjects included in analysis
    212
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.9919
    Method
    		 ANCOVA
    Confidence interval

    Primary: Efficacy - Co-Primary: Improvement of the score of the tinnitus loudness question (TLQ)

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    End point title
    		 Efficacy - Co-Primary: Improvement of the score of the tinnitus loudness question (TLQ)
    End point description
    For determining tinnitus loudness, subjects were presented the question: ‘‘Describe the loudness of your tinnitus right now using a scale from 0-100’’. The scale was anchored at the extremes 0 = no tinnitus heard, respectively not annoying at all, and 100 = very loud, respectively very annoying. TLQ at Day 90 was defined as co-primary endpoint. Analysis performed on valid for efficacy data set.
    End point type
    Primary
    End point timeframe
    Day 0 to Day 90.
    End point values
    		 AM-101 low dose AM-101 high dose Placebo
    Number of subjects analysed
    71
    64
    75
    Units: 0 - 100 numerical rating scale
        arithmetic mean (standard deviation)
    16.1 ( 21.6 )
    22.2 ( 28.6 )
    15.9 ( 21.6 )
    Statistical analysis title
    		 Delta TLQ - Placebo vs AM-101 high dose
    Comparison groups
    Placebo v AM-101 high dose
    Number of subjects included in analysis
    139
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.089
    Method
    		 ANCOVA
    Confidence interval
    Statistical analysis title
    		 Delta TLQ - Placebo vs AM-101 low dose
    Comparison groups
    Placebo v AM-101 low dose
    Number of subjects included in analysis
    146
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.59
    Method
    		 ANCOVA
    Confidence interval

    Primary: Efficacy - Co-Primary: Improvement of the score of the tinnitus annoyance question (TAQ)

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    End point title
    		 Efficacy - Co-Primary: Improvement of the score of the tinnitus annoyance question (TAQ)
    End point description
    For determining tinnitus annoyance, patients was presented the question: ‘‘Describe the annoyance of your tinnitus today using a scale from 0-100’’. The scale was anchored at the extremes 0 = no tinnitus heard, respectively not annoying at all, and 100 = very loud, respectively very annoying. TLQ at Day 90 was defined as co-primary endpoint. Analysis performed on valid for efficacy data set.
    End point type
    Primary
    End point timeframe
    Day 0 to Day 90
    End point values
    		 AM-101 low dose AM-101 high dose Placebo
    Number of subjects analysed
    71
    64
    75
    Units: 0 - 100 numerical rating scale
        arithmetic mean (standard deviation)
    17.2 ( 20.7 )
    22.3 ( 28.9 )
    19.4 ( 21.8 )
    Statistical analysis title
    		 Delta TAQ - Placebo vs AM-101 low dose
    Comparison groups
    Placebo v AM-101 low dose
    Number of subjects included in analysis
    146
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.94
    Method
    		 ANCOVA
    Confidence interval
    Statistical analysis title
    		 Delta TAQ - Placebo vs AM-101 high dose
    Comparison groups
    AM-101 high dose v Placebo
    Number of subjects included in analysis
    139
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.53
    Method
    		 ANCOVA
    Confidence interval

    Primary: Safety: Incidence of change in hearing threshold ≥ 15 dB from Baseline

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    End point title
    		 Safety: Incidence of change in hearing threshold ≥ 15 dB from Baseline
    End point description
    The primary safety endpoint was the number and percent of study subjects with a (clinically relevant) change in hearing threshold ≥15 dB from Day 0 to Day 30 in any 2 contiguous test frequencies in the treated ear (only deteriorations were considered). The frequency of patients meeting the primary safety end point was compared by treatment group with the Fisher exact test. For analysis valid for safety analysis set was used (n = 248).
    End point type
    Primary
    End point timeframe
    Day 0 to Day 30.
    End point values
    		 AM-101 low dose AM-101 high dose Placebo
    Number of subjects analysed
    74
    74
    86
    Units: number subjects
    4
    3
    2
    Statistical analysis title
    		 Difference Placebo - AM-101 low dose
    Comparison groups
    Placebo v AM-101 low dose
    Number of subjects included in analysis
    160
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.42
    Method
    		 Fisher exact
    Confidence interval
    Statistical analysis title
    		 Difference Placebo - AM-101 high dose
    Comparison groups
    AM-101 high dose v Placebo
    Number of subjects included in analysis
    160
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.66
    Method
    		 Fisher exact
    Confidence interval

    Post-hoc: Efficacy: Improvement of the score of the tinnitus loudness question (TLQ) from baseline to Day 90 (subset AAT and OM)

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    End point title
    		 Efficacy: Improvement of the score of the tinnitus loudness question (TLQ) from baseline to Day 90 (subset AAT and OM)
    End point description
    This was a post-hoc secondary analysis of the efficacy measures. The subgroup comprises all subjects with acute acoustic trauma (AAT) and otitis media (OM) as tinnitus onset factors. In this subgroup with known tinnitus etiology related to cochlear glutamate excitotoxicity, the ANCOVA demonstrated superiority of the high dose with respect to placebo for the change in TLQ.
    End point type
    Post-hoc
    End point timeframe
    Day 0 to Day 90.
    End point values
    		 AM-101 low dose AM-101 high dose Placebo
    Number of subjects analysed
    37
    34
    34
    Units: 0 – 100 numerical rating scale
        arithmetic mean (standard deviation)
    13.4 ( 20.4 )
    24.4 ( 30.02 )
    9.7 ( 18.5 )
    Statistical analysis title
    		 Delta TLQ - Placebo vs AM-101 low dose
    Statistical analysis description
    Analysis was performed on valid for efficacy data set.
    Comparison groups
    Placebo v AM-101 low dose
    Number of subjects included in analysis
    71
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.0926
    Method
    		 ANCOVA
    Confidence interval
    Statistical analysis title
    		 Delta TLQ - Placebo vs AM-101 high dose
    Statistical analysis description
    Analysis was performed on valid for efficacy data set.
    Comparison groups
    AM-101 high dose v Placebo
    Number of subjects included in analysis
    68
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.0033
    Method
    		 ANCOVA
    Confidence interval

    Post-hoc: Efficacy: Improvement of the score of the sleep impact questions from baseline to Day 90 (subset AAT and OM)

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    End point title
    		 Efficacy: Improvement of the score of the sleep impact questions from baseline to Day 90 (subset AAT and OM)
    End point description
    The subgroup comprises all subjects with acute acoustic trauma (AAT) and otitis media (OM) as Tinnitus onset factors. In this subgroup with known tinnitus etiology related to cochlear glutamate excitotoxicity, the ANCOVA demonstrated superiority of both dose groups with respect to placebo for the change in Sleep impact.
    End point type
    Post-hoc
    End point timeframe
    D0 to D90.
    End point values
    		 AM-101 low dose AM-101 high dose Placebo
    Number of subjects analysed
    27
    30
    32
    Units: 0 – 100 numerical rating scale
        arithmetic mean (standard deviation)
    0.4 ( 2.27 )
    0.69 ( 3.3 )
    -0.58 ( 2.4 )
    Statistical analysis title
    		 Delta Sleep Impact - Placebo vs AM-101 low dose
    Statistical analysis description
    Analysis was performed on valid for efficacy data set.
    Comparison groups
    AM-101 low dose v Placebo
    Number of subjects included in analysis
    59
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.037
    Method
    		 ANCOVA
    Confidence interval
    Statistical analysis title
    		 Delta Sleep Impact - Placebo vs AM-101 high dose
    Statistical analysis description
    Analysis was performed on valid for efficacy data set.
    Comparison groups
    Placebo v AM-101 high dose
    Number of subjects included in analysis
    62
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.02
    Method
    		 ANCOVA
    Confidence interval

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    At all Treatment Visits and Follow-Up Visits.
    Adverse event reporting additional description
    Assessed by investigator at all visits. The occurrence of a treatment emergent adverse event in the same subject more than once was counted only once in non-serious adverse events.
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    14.0
    Reporting groups
    Reporting group title
    AM-101 low dose
    Reporting group description
    		 -

    Reporting group title
    AM-101 high dose
    Reporting group description
    		 -

    Reporting group title
    Placebo
    Reporting group description
    		 -

    Serious adverse events
    		 AM-101 low dose AM-101 high dose Placebo
    Total subjects affected by serious adverse events
         subjects affected / exposed
    2 / 78 (2.56%)
    1 / 84 (1.19%)
    4 / 86 (4.65%)
         number of deaths (all causes)
    0
    0
    1
         number of deaths resulting from adverse events
    0
    0
    0
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Gastric neoplasm
         subjects affected / exposed
    0 / 78 (0.00%)
    0 / 84 (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
    Atrial flutter
         subjects affected / exposed
    1 / 78 (1.28%)
    0 / 84 (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
    Blood and lymphatic system disorders
    Cardiomyopathy
         subjects affected / exposed
    0 / 78 (0.00%)
    0 / 84 (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 / 1
    Thrombocytopenia
         subjects affected / exposed
    0 / 78 (0.00%)
    0 / 84 (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
    General disorders and administration site conditions
    Drug intolerance
    Additional description: Drug intolerance to Propafenone
         subjects affected / exposed
    1 / 78 (1.28%)
    0 / 84 (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
    Ear and labyrinth disorders
    Vertigo
         subjects affected / exposed
    0 / 78 (0.00%)
    0 / 84 (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
    Tinnitus
         subjects affected / exposed
    1 / 78 (1.28%)
    0 / 84 (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
    Hypoacusis
         subjects affected / exposed
    1 / 78 (1.28%)
    0 / 84 (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
    Psychiatric disorders
    Somatoform Disorder
         subjects affected / exposed
    0 / 78 (0.00%)
    0 / 84 (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
    Mental disorder
         subjects affected / exposed
    0 / 78 (0.00%)
    1 / 84 (1.19%)
    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
    Frequency threshold for reporting non-serious adverse events: 2%
    Non-serious adverse events
    		 AM-101 low dose AM-101 high dose Placebo
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    35 / 78 (44.87%)
    42 / 84 (50.00%)
    44 / 86 (51.16%)
    Investigations
    Acoustic Stimulation Tests Abnormal
         subjects affected / exposed
    3 / 78 (3.85%)
    7 / 84 (8.33%)
    9 / 86 (10.47%)
         occurrences all number
    3
    7
    9
    Audiogram Abnormal
         subjects affected / exposed
    0 / 78 (0.00%)
    2 / 84 (2.38%)
    2 / 86 (2.33%)
         occurrences all number
    0
    2
    2
    Vascular disorders
    Hypertension
         subjects affected / exposed
    0 / 78 (0.00%)
    0 / 84 (0.00%)
    2 / 86 (2.33%)
         occurrences all number
    0
    0
    2
    Nervous system disorders
    Dizziness
         subjects affected / exposed
    0 / 78 (0.00%)
    1 / 84 (1.19%)
    2 / 86 (2.33%)
         occurrences all number
    0
    1
    2
    Headache
         subjects affected / exposed
    0 / 78 (0.00%)
    4 / 84 (4.76%)
    1 / 86 (1.16%)
         occurrences all number
    0
    4
    1
    General disorders and administration site conditions
    Injection Site Pain
    Additional description: All events of injection site pain (and injection site warmth; n = 1) were reported from a single site.
         subjects affected / exposed
    1 / 78 (1.28%)
    2 / 84 (2.38%)
    2 / 86 (2.33%)
         occurrences all number
    1
    2
    2
    Ear and labyrinth disorders
    Ear Discomfort
         subjects affected / exposed
    1 / 78 (1.28%)
    0 / 84 (0.00%)
    3 / 86 (3.49%)
         occurrences all number
    1
    0
    3
    Ear Pain
         subjects affected / exposed
    3 / 78 (3.85%)
    3 / 84 (3.57%)
    1 / 86 (1.16%)
         occurrences all number
    3
    3
    1
    Hypoacusis
         subjects affected / exposed
    5 / 78 (6.41%)
    1 / 84 (1.19%)
    1 / 86 (1.16%)
         occurrences all number
    5
    1
    1
    Tinnitus
         subjects affected / exposed
    14 / 78 (17.95%)
    15 / 84 (17.86%)
    13 / 86 (15.12%)
         occurrences all number
    14
    15
    13
    Tympanic membrane hyperaemia
         subjects affected / exposed
    2 / 78 (2.56%)
    2 / 84 (2.38%)
    1 / 86 (1.16%)
         occurrences all number
    2
    2
    1
    Tympanic Membrane Perforation/Impaired Healing/Post procedural haemorrhage
    Additional description: Tympanic membrane perforation, impaired healing (General Disorders and Administration Site Conditions) and post-procedural haemorrhage (Injury, Poisoning and Procedural Complications) have been pooled together.
         subjects affected / exposed
    10 / 78 (12.82%)
    8 / 84 (9.52%)
    9 / 86 (10.47%)
         occurrences all number
    10
    8
    9
    Vertigo
         subjects affected / exposed
    1 / 78 (1.28%)
    0 / 84 (0.00%)
    5 / 86 (5.81%)
         occurrences all number
    1
    0
    5
    Psychiatric disorders
    Depression
         subjects affected / exposed
    0 / 78 (0.00%)
    0 / 84 (0.00%)
    2 / 86 (2.33%)
         occurrences all number
    0
    0
    2
    Sleep Disorders
         subjects affected / exposed
    0 / 78 (0.00%)
    0 / 84 (0.00%)
    2 / 86 (2.33%)
         occurrences all number
    0
    0
    2
    Infections and infestations
    Laryngitis
         subjects affected / exposed
    0 / 78 (0.00%)
    0 / 84 (0.00%)
    2 / 86 (2.33%)
         occurrences all number
    0
    0
    2
    Myringitis
         subjects affected / exposed
    1 / 78 (1.28%)
    2 / 84 (2.38%)
    1 / 86 (1.16%)
         occurrences all number
    1
    2
    1
    Nasopharyngitis
         subjects affected / exposed
    1 / 78 (1.28%)
    2 / 84 (2.38%)
    1 / 86 (1.16%)
         occurrences all number
    1
    2
    1
    Upper Respiratory Tract Infection
         subjects affected / exposed
    1 / 78 (1.28%)
    0 / 84 (0.00%)
    2 / 86 (2.33%)
         occurrences all number
    1
    0
    2

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    02 Feb 2009
    - Inclusion criteria amended to include the definition of ISSNHL, clarification of range of inner ear hearing loss required at onset, and the necessity for subjects to be able to read and understand the relevant study documents. - Baseline assessments amended to include the addition of, and criteria for, Frenzel goggle examination, non-caloric nystagmography; and caloric nystagmography. - Tympanometry assessment added at Day 30. - Addition of secondary safety analyses.
    15 May 2009
    - Inclusion criteria, objectives and subgroup analyses expanded to include subjects suffering from acute inner ear tinnitus following acute otitis media (OM) with acute inner ear hearing loss. - Exclusion criterion added to prohibit subjects taking any drug-based therapy for OM that was ongoing or was performed in the past 2 weeks.
    28 Aug 2009
    - Inclusion criteria updated to remove the necessity for a confirmatory audiogram of hearing loss at the time of diagnosis.
    03 May 2010
    - Clarification that routine measurements (eg, pure tone audiometry, otoscopy) to be done within 48 hours before obtaining informed consent and enrolment of the subject may be used as baseline assessment for the study. Modified procedures for study drug destruction. - Main body updated to include bone conducted measurements on Days 7 and 30. - Addition of baseline Minimum Masking Level value as a covariate in the statistical Analysis (analysis of covariance rather than analysis of variance) following updated Committee for Proprietary Medicinal Products (EMA) guidance.
    21 Apr 2011
    - Changes to planned statistical analyses for efficacy evaluation, notably: optimisation of statistical methodology in particular with regard to comprehensive and efficient hypothesis testing; consideration of subject reported tinnitus loudness and annoyance as co-primary endpoints to be tested in the confirmative sense; consideration of potential efficacy differences between unilateral tinnitus and one side treated bilateral tinnitus in the general concept for evaluation; additional secondary analyses, specifically subgroup analyses for efficacy endpoints.

    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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