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    Clinical Trial Results:
    Efficacy and Safety of AM-101 in the Treatment of Acute Peripheral Tinnitus 2 (TACTT2)

    Summary
    EudraCT number
    		 2013-005587-26
    Trial protocol
    		 CZ  
    Global end of trial date
    22 Jun 2016

    Results information
    Results version number
    		 v2(current)
    This version publication date
    01 Mar 2018
    First version publication date
    21 Dec 2017
    Other versions
    		 v1
    Version creation reason
    • Correction of full data set
    Total numbers of non-serious adverse events needs to be corrected to contain only the number subjects that was affected by AEs equal/above the 2% threshold. Phone number in field sponsor contact needs to be corrected.

    Trial information

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    Trial identification
    Sponsor protocol code
    AM-101-CL-12-01
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT01803646
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    Auris Medical Inc.
    Sponsor organisation address
    500 North Michigan Avenue, Suite 600, Chicago, Illinois, United States, 60611
    Public contact
    Thomas Meyer, Auris Medical Inc, +1 312 396 4150, hear@aurismedical.com
    Scientific contact
    Thomas Meyer, Auris Medical Inc, +1 3123964150, 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
    23 Nov 2016
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    22 Jun 2016
    Global end of trial reached?
    Yes
    Global end of trial date
    22 Jun 2016
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    The primary objective of the study is the evaluation and confirmation of the efficacy of repeated i.t. AM-101 injections in the treatment of acute peripheral tinnitus
    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
    		 -
    Evidence for comparator
    		 -
    Actual start date of recruitment
    24 Feb 2014
    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
    Czech Republic: 64
    Country: Number of subjects enrolled
    Canada: 34
    Country: Number of subjects enrolled
    Israel: 3
    Country: Number of subjects enrolled
    Korea, Republic of: 27
    Country: Number of subjects enrolled
    Turkey: 11
    Country: Number of subjects enrolled
    United States: 204
    Worldwide total number of subjects
    343
    EEA total number of subjects
    64
    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)
    313
    From 65 to 84 years
    30
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 A total of 86 sites were initiated in Canada, the United States, the Czech Republic, Israel, Turkey and Republic of South Korea. In total, 69 sites screened each at least 1 subject and 64 sites randomized subjects for treatment.

    Pre-assignment
    Screening details
    		 The study consisted of a screening period (Day [D] -14 to D0). 478 subjects had been assessed for eligibility, of which 135 have been excluded for the following reasons: - not meeting inclusion criteria (n=98) - declined to participate (n=30) - other reasons (n=7)

    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, Monitor, Data analyst
    Blinding implementation details
    The Sponsor, Investigators as well as the subjects were blinded regarding the dose administered during the study. In particular, the gel formulation was of the same appearance for AM-101 than the Placebo and revealed no differences during or following injection, neither to the Investigator, nor to the subject.

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 AM-101 0.87 mg/mL gel
    Arm description
    		 Three intratympanic administration of AM-101 0.87 mg/mL gel within 5 days (D0-D4)
    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
    Three intratympanic administrations of AM-101 0.87 mg/mL (0.25 mL). In case of eligible bilateral tinnitus subjects, both ears were treated.

    Arm title
    		 Placebo
    Arm description
    		 Three intratympanic administration of placebo gel within 5 days (D0-D4).
    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
    Three intratympanic administrations of AM-101 0 mg/mL (0.25 mL). In case of eligible bilateral tinnitus subjects, both ears were treated.

    Number of subjects in period 1
    		AM-101 0.87 mg/mL gel Placebo
    Started
    204
    139
    Completed
    187
    129
    Not completed
    17
    10
         Randomization error
    1
    2
         Consent withdrawn by subject
    9
    6
         Adverse event, non-fatal
    1
    1
         Lost to follow-up
    5
    1
         Protocol deviation
    1
    -

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    AM-101 0.87 mg/mL gel
    Reporting group description
    		 Three intratympanic administration of AM-101 0.87 mg/mL gel within 5 days (D0-D4)

    Reporting group title
    Placebo
    Reporting group description
    		 Three intratympanic administration of placebo gel within 5 days (D0-D4).

    Reporting group values
    		 AM-101 0.87 mg/mL gel Placebo Total
    Number of subjects
    		 204 139 343
    Age categorical
    Units: Subjects
        Adolescents (12-17 years)
    		 0 0 0
        Adults (18-64 years)
    		 188 125 313
        From 65-84 years
    		 16 14 30
    Age continuous
    Units: years
        arithmetic mean (standard deviation)
    		 43.4 ( 14.6 ) 44.2 ( 15.2 ) -
    Gender categorical
    Units: Subjects
        Female
    		 43 37 80
        Male
    		 161 102 263
    Subject analysis sets

    Subject analysis set title
    Valid for Safety
    Subject analysis set type
    		 Intention-to-treat
    Subject analysis set description
    This analysis set included all subjects who were treated with at least 1 intratympanic injection of either AM-101 or placebo. It was used as a general analysis set for safety and tolerability data. Comprises 336 subjects of 343 enrolled subjects.

    Subject analysis set title
    Valid for Efficacy
    Subject analysis set type
    		 Intention-to-treat
    Subject analysis set description
    This analysis set was defined based on the Intention to Treat principle. It was used as the primary set for efficacy evaluation. It includes all subjects who: • were treated with at least 1 intratympanic injection of either AM-101 or placebo • had a valid TLQ (NRSLoudest) rating at Baseline and at least 1 valid post-Baseline TLQ (NRSLoudest) rating or had a valid TFI rating at Baseline and at least 1 valid post-Baseline TFI rating.

    Subject analysis sets values
    		 Valid for Safety Valid for Efficacy
    Number of subjects
    336
    326
    Age categorical
    Units: Subjects
        Adolescents (12-17 years)
    0
    0
        Adults (18-64 years)
    306
    297
        From 65-84 years
    30
    29
    Age continuous
    Units: years
        arithmetic mean (standard deviation)
    ( )
    ( )
    Gender categorical
    Units: Subjects
        Female
    78
    78
        Male
    258
    248

    End points

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    End points reporting groups
    Reporting group title
    AM-101 0.87 mg/mL gel
    Reporting group description
    		 Three intratympanic administration of AM-101 0.87 mg/mL gel within 5 days (D0-D4)

    Reporting group title
    Placebo
    Reporting group description
    		 Three intratympanic administration of placebo gel within 5 days (D0-D4).

    Subject analysis set title
    Valid for Safety
    Subject analysis set type
    		 Intention-to-treat
    Subject analysis set description
    This analysis set included all subjects who were treated with at least 1 intratympanic injection of either AM-101 or placebo. It was used as a general analysis set for safety and tolerability data. Comprises 336 subjects of 343 enrolled subjects.

    Subject analysis set title
    Valid for Efficacy
    Subject analysis set type
    		 Intention-to-treat
    Subject analysis set description
    This analysis set was defined based on the Intention to Treat principle. It was used as the primary set for efficacy evaluation. It includes all subjects who: • were treated with at least 1 intratympanic injection of either AM-101 or placebo • had a valid TLQ (NRSLoudest) rating at Baseline and at least 1 valid post-Baseline TLQ (NRSLoudest) rating or had a valid TFI rating at Baseline and at least 1 valid post-Baseline TFI rating.

    Primary: Efficacy: Patient-reported TLQ Improvement from Baseline to FUV3

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    End point title
    		 Efficacy: Patient-reported TLQ Improvement from Baseline to FUV3
    End point description
    Improvement in patient-reported tinnitus loudness TLQ NRSLoudest from baseline to FUV3.
    End point type
    Primary
    End point timeframe
    Baseline (TV1) up to end of study (FUV3)
    End point values
    		 AM-101 0.87 mg/mL gel Placebo
    Number of subjects analysed
    195
    129
    Units: Numerical rating scale (0-10)
        least squares mean (confidence interval 95%)
    0.80 (0.51 to 1.08)
    0.63 (0.38 to 0.87)
    Statistical analysis title
    		 Improvement in tinnitus loudness from baseline
    Comparison groups
    AM-101 0.87 mg/mL gel v Placebo
    Number of subjects included in analysis
    324
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.32
    Method
    		 Mixed models analysis
    Parameter type
    		 Mean difference (final values)
    Point estimate
    -0.17
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.51
         upper limit
    		 0.17

    Primary: Co-Primary Efficacy: Improvement in TFI total score from baseline to FUV3

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    End point title
    		 Co-Primary Efficacy: Improvement in TFI total score from baseline to FUV3
    End point description
    The final TFI is a patient reported outcome questionnaire and contains 25 questions. It includes eight subscales: Intrusive, Sense of Control, Cognitive, Sleep, Auditory, Relaxation, Quality of Life, and Emotional. The TFI total score is considered as valid if there are evaluable answers for at least 19 of the 25 items (76% of items) (Meikle et al. 2012).
    End point type
    Primary
    End point timeframe
    Improvement in TFI total score from baseline to FUV3
    End point values
    		 AM-101 0.87 mg/mL gel Placebo
    Number of subjects analysed
    180
    121
    Units: Total score of 25 questions
        least squares mean (confidence interval 95%)
    10.4 (6.5 to 14.3)
    9.6 (5.9 to 13.3)
    Statistical analysis title
    		 Improvement TFI total score at FUV3
    Comparison groups
    AM-101 0.87 mg/mL gel v Placebo
    Number of subjects included in analysis
    301
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.63
    Method
    		 Mixed models analysis
    Parameter type
    		 Mean difference (final values)
    Point estimate
    -0.79
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -4
         upper limit
    		 2.4

    Primary: Safety: Frequency of subjects with deterioration of hearing at FUV2

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    End point title
    		 Safety: Frequency of subjects with deterioration of hearing at FUV2
    End point description
    Deterioration of hearing (Air and Bone conduction) in the treated ear at FUV2. Deterioration is defined as a deterioration of hearing threshold of at least 15 dB from Baseline at the average of 2 contiguous frequencies.
    End point type
    Primary
    End point timeframe
    From baseline to FUV2
    End point values
    		 AM-101 0.87 mg/mL gel Placebo
    Number of subjects analysed
    193
    130
    Units: number subjects
        Air conduction
    12
    9
        Bone conduction
    3
    4
    Statistical analysis title
    		 Deterioration of hearing for air conduction
    Comparison groups
    AM-101 0.87 mg/mL gel v Placebo
    Number of subjects included in analysis
    323
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.821
    Method
    		 Fisher exact
    Confidence interval
    Statistical analysis title
    		 Deterioration of hearing for bone conduction
    Comparison groups
    AM-101 0.87 mg/mL gel v Placebo
    Number of subjects included in analysis
    323
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 1
    Method
    		 Fisher exact
    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
    Assessed by investigator at all visits.
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    19.0
    Reporting groups
    Reporting group title
    AM-101
    Reporting group description
    		 -

    Reporting group title
    Placebo
    Reporting group description
    		 -

    Serious adverse events
    		 AM-101 Placebo
    Total subjects affected by serious adverse events
         subjects affected / exposed
    5 / 201 (2.49%)
    1 / 135 (0.74%)
         number of deaths (all causes)
    0
    0
         number of deaths resulting from adverse events
    0
    0
    Injury, poisoning and procedural complications
    Lower limb fracture
         subjects affected / exposed
    1 / 201 (0.50%)
    0 / 135 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Tendon rupture
         subjects affected / exposed
    1 / 201 (0.50%)
    0 / 135 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cardiac disorders
    Atrial fibrillation
         subjects affected / exposed
    0 / 201 (0.00%)
    1 / 135 (0.74%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Nervous system disorders
    Generalised tonic-clonic seizure
         subjects affected / exposed
    1 / 201 (0.50%)
    0 / 135 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Psychiatric disorders
    Mental disorder
         subjects affected / exposed
    1 / 201 (0.50%)
    0 / 135 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Infections and infestations
    Urinary tract infection
         subjects affected / exposed
    1 / 201 (0.50%)
    0 / 135 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 2%
    Non-serious adverse events
    		 AM-101 Placebo
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    63 / 201 (31.34%)
    38 / 135 (28.15%)
    Nervous system disorders
    Dizziness
         subjects affected / exposed
    10 / 201 (4.98%)
    1 / 135 (0.74%)
         occurrences all number
    10
    1
    Headache
         subjects affected / exposed
    11 / 201 (5.47%)
    6 / 135 (4.44%)
         occurrences all number
    11
    6
    General disorders and administration site conditions
    Injection site pain
         subjects affected / exposed
    5 / 201 (2.49%)
    1 / 135 (0.74%)
         occurrences all number
    5
    1
    Ear and labyrinth disorders
    Ear discomfort
         subjects affected / exposed
    14 / 201 (6.97%)
    8 / 135 (5.93%)
         occurrences all number
    14
    8
    Ear pain
         subjects affected / exposed
    16 / 201 (7.96%)
    10 / 135 (7.41%)
         occurrences all number
    16
    10
    Hypoacusis
         subjects affected / exposed
    8 / 201 (3.98%)
    4 / 135 (2.96%)
         occurrences all number
    8
    4
    Tinnitus
         subjects affected / exposed
    8 / 201 (3.98%)
    5 / 135 (3.70%)
         occurrences all number
    8
    5
    Tympanic membrane perforation
         subjects affected / exposed
    5 / 201 (2.49%)
    4 / 135 (2.96%)
         occurrences all number
    5
    4
    Vertigo
         subjects affected / exposed
    2 / 201 (1.00%)
    4 / 135 (2.96%)
         occurrences all number
    2
    4
    Gastrointestinal disorders
    Nausea
         subjects affected / exposed
    4 / 201 (1.99%)
    2 / 135 (1.48%)
         occurrences all number
    4
    2
    Psychiatric disorders
    Anxiety
         subjects affected / exposed
    7 / 201 (3.48%)
    1 / 135 (0.74%)
         occurrences all number
    7
    1
    Insomnia
         subjects affected / exposed
    4 / 201 (1.99%)
    0 / 135 (0.00%)
         occurrences all number
    4
    0
    Infections and infestations
    Nasopharyngitis
         subjects affected / exposed
    6 / 201 (2.99%)
    4 / 135 (2.96%)
         occurrences all number
    6
    4
    Sinusitis
         subjects affected / exposed
    4 / 201 (1.99%)
    0 / 135 (0.00%)
         occurrences all number
    4
    0
    Upper respiratory tract infection
         subjects affected / exposed
    5 / 201 (2.49%)
    2 / 135 (1.48%)
         occurrences all number
    5
    2

    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/28608739
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