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    Clinical Trial Results:
    Safety of AM-101 in Patients with Acute Inner Ear Tinnitus from Noise Trauma: a Dose-Finding Phase I/II Study

    Summary
    EudraCT number
    		 2006-002692-41
    Trial protocol
    		 DE  
    Global end of trial date
    15 Mar 2008

    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

    		 Close Top of page
    Trial identification
    Sponsor protocol code
    AM-101-AAT-PHA1
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 -
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    Laboratoires Auris SAS
    Sponsor organisation address
    CEEI Cap Alpha/ Avenue de l’Europe/ Clapiers, Montpellier Cedex 09, France, 34940
    Public contact
    see below at Affiliate, see below at Affiliate, 0041 61 2011350, ear@aurismedical.com
    Scientific contact
    see below at Affiliate, see below at Affiliate, 0041 61 2011350, ear@aurismedical.com
    Sponsor organisation name
    Affiliate = 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
    07 Aug 2008
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    15 Mar 2008
    Global end of trial reached?
    Yes
    Global end of trial date
    15 Mar 2008
    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 tolerability of the dose range expected to be needed for later clinical studies and to determine the nature of adverse reactions that could be expected. The secondary objectives of the study were the preliminary evaluation of the potential therapeutic benefit of AM-101 in the treatment of inner ear tinnitus as well as the evaluation of systemic exposure following a single intratympanic injection of AM-101 (pharmacokinetics).
    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), and the ethical principles outlined in the Declaration of Helsinki dated 1989, respectively in their most current version.
    Background therapy
    		 N/A
    Evidence for comparator
    		 N/A
    Actual start date of recruitment
    01 Mar 2007
    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: 24
    Worldwide total number of subjects
    24
    EEA total number of subjects
    24
    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)
    24
    From 65 to 84 years
    0
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 This study was designed as a double-blind, randomised, placebo-controlled, dose escalation, phase I/II study of a single intratympanic administration of AM-101 with a 2 month follow-up period. The study consisted of 4 dose cohorts (30, 90, 270 or 810 μg/ml) with 2 placebo and 4 verum patients per cohort. It involved 4 study sites in Germany.

    Pre-assignment
    Screening details
    		 Main inclusion criteria were: Age 18 - 60 years; permanent, stable, single tinnitus induced by acute acoustic trauma or sudden deafness; tinnitus on-set occurred within the past 3 months. All screened patients had been randomised.

    Period 1
    Period 1 title
    Study period (overall period)
    Is this the baseline period?
    		 Yes
    Allocation method
    Randomised - controlled
    Blinding used
    		 Double blind
    Roles blinded
    		 Subject, Investigator
    Blinding implementation details
    The investigators as well as the subjects were blinded regarding the dose administered during the whole study. In particular, the gel formulation was of the same appearance for all doses and the placebo and revealed no differences during or following injection, neither to the investigator, nor to the patient.

    Arms
    Are arms mutually exclusive
    No

    Arm title
    		 AM-101 30 µg/ml
    Arm description
    		 Each patient received study treatment comprising a single intratympanic injection of 30 µg/ml of AM-101 followed by a 2 month treatment-free follow-up period.
    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 30 µg/ml were injected.

    Arm title
    		 AM-101 90 µg/ml
    Arm description
    		 Each patient received study treatment comprising a single intratympanic injection of 90 µg/ml of AM-101 followed by a 2 month treatment-free follow-up period.
    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 90 µg/ml were injected.

    Arm title
    		 AM-101 270 µg/ml
    Arm description
    		 Each patient received study treatment comprising a single intratympanic injection of 270 µg/ml of AM-101 followed by a 2 month treatment-free follow-up period.
    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 270 µg/ml were injected.

    Arm title
    		 AM-101 810 µg/ml
    Arm description
    		 Each patient received study treatment comprising a single intratympanic injection of 810 µg/ml of AM-101 followed by a 2 month treatment-free follow-up period.
    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 810 µg/ml were injected.

    Arm title
    		 AM-101 pooled set
    Arm description
    		 This is a pooled set of all 4 treatment cohorts receiving AM-101 which was used for the primary analysis.
    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 either 30, 90, 270 or 810 μg/ml were injected.

    Arm title
    		 Placebo
    Arm description
    		 Matching placebo was administered following the same way (see above) with 2 subjects receiving placebo per dose cohort.
    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.

    Number of subjects in period 1
    		AM-101 30 µg/ml AM-101 90 µg/ml AM-101 270 µg/ml AM-101 810 µg/ml AM-101 pooled set Placebo
    Started
    4
    4
    4
    4
    16
    8
    Completed
    4
    4
    3
    4
    15
    8
    Not completed
    0
    0
    1
    0
    1
    0
         Consent withdrawn by subject
    -
    -
    1
    -
    1
    -

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    AM-101 30 µg/ml
    Reporting group description
    		 Each patient received study treatment comprising a single intratympanic injection of 30 µg/ml of AM-101 followed by a 2 month treatment-free follow-up period.

    Reporting group title
    AM-101 90 µg/ml
    Reporting group description
    		 Each patient received study treatment comprising a single intratympanic injection of 90 µg/ml of AM-101 followed by a 2 month treatment-free follow-up period.

    Reporting group title
    AM-101 270 µg/ml
    Reporting group description
    		 Each patient received study treatment comprising a single intratympanic injection of 270 µg/ml of AM-101 followed by a 2 month treatment-free follow-up period.

    Reporting group title
    AM-101 810 µg/ml
    Reporting group description
    		 Each patient received study treatment comprising a single intratympanic injection of 810 µg/ml of AM-101 followed by a 2 month treatment-free follow-up period.

    Reporting group title
    AM-101 pooled set
    Reporting group description
    		 This is a pooled set of all 4 treatment cohorts receiving AM-101 which was used for the primary analysis.

    Reporting group title
    Placebo
    Reporting group description
    		 Matching placebo was administered following the same way (see above) with 2 subjects receiving placebo per dose cohort.

    Reporting group values
    		 AM-101 30 µg/ml AM-101 90 µg/ml AM-101 270 µg/ml AM-101 810 µg/ml AM-101 pooled set Placebo Total
    Number of subjects
    		 4 4 4 4 16 8 24
    Age categorical
    Units: Subjects
        In utero
    		 0 0 0 0 0 0 0
        Preterm newborn infants (gestational age < 37 wks)
    		 0 0 0 0 0 0 0
        Newborns (0-27 days)
    		 0 0 0 0 0 0 0
        Infants and toddlers (28 days-23 months)
    		 0 0 0 0 0 0 0
        Children (2-11 years)
    		 0 0 0 0 0 0 0
        Adolescents (12-17 years)
    		 0 0 0 0 0 0 0
        Adults (18-64 years)
    		 4 4 4 4 16 8 24
        From 65-84 years
    		 0 0 0 0 0 0 0
        85 years and over
    		 0 0 0 0 0 0 0
    Age continuous
    Units: years
        arithmetic mean (standard deviation)
    		 20 ( 1.4 ) 25.8 ( 5.5 ) 26.5 ( 8.8 ) 28.5 ( 11.1 ) 25.2 ( 7.6 ) 33 ( 17.3 ) -
    Gender categorical
    Units: Subjects
        Female
    		 0 0 1 1 2 1 3
        Male
    		 4 4 3 3 14 7 21

    End points

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    End points reporting groups
    Reporting group title
    AM-101 30 µg/ml
    Reporting group description
    		 Each patient received study treatment comprising a single intratympanic injection of 30 µg/ml of AM-101 followed by a 2 month treatment-free follow-up period.

    Reporting group title
    AM-101 90 µg/ml
    Reporting group description
    		 Each patient received study treatment comprising a single intratympanic injection of 90 µg/ml of AM-101 followed by a 2 month treatment-free follow-up period.

    Reporting group title
    AM-101 270 µg/ml
    Reporting group description
    		 Each patient received study treatment comprising a single intratympanic injection of 270 µg/ml of AM-101 followed by a 2 month treatment-free follow-up period.

    Reporting group title
    AM-101 810 µg/ml
    Reporting group description
    		 Each patient received study treatment comprising a single intratympanic injection of 810 µg/ml of AM-101 followed by a 2 month treatment-free follow-up period.

    Reporting group title
    AM-101 pooled set
    Reporting group description
    		 This is a pooled set of all 4 treatment cohorts receiving AM-101 which was used for the primary analysis.

    Reporting group title
    Placebo
    Reporting group description
    		 Matching placebo was administered following the same way (see above) with 2 subjects receiving placebo per dose cohort.

    Primary: Safety: Incidence of hearing loss grade 2 at two contiguous test frequencies at day 30 compared to baseline by treatment

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    End point title
    		 Safety: Incidence of hearing loss grade 2 at two contiguous test frequencies at day 30 compared to baseline by treatment [1]
    End point description
    The primary variable for the safety assessment was the incidence of a hearing loss ≥ Grade 2 (i.e. a loss of ≥ 25 dB) in any two contiguous kHz levels in the treated ear. The primary endpoint was on D30. Any hearing loss induced by the treatment and/or the procedure was hypothesised to become permanent by this time. As defined in the statistical analysis plan: The total number and percent of primary safety events has been summarised by treatment. No formal statistical tests have been used to compare group differences. The ITT analysis set was used for the primary data analyses and is identical with the safety set in this study. The key study results are presented in the pooled verum data sets as the the primary study outcome.
    End point type
    Primary
    End point timeframe
    Baseline to D30
    Notes
    [1] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: No statistical analysis was performed. Number of events was zero.
    End point values
    		 AM-101 30 µg/ml AM-101 90 µg/ml AM-101 270 µg/ml AM-101 810 µg/ml AM-101 pooled set Placebo
    Number of subjects analysed
    4
    4
    3
    4
    15
    8
    Units: number subjects
    0
    0
    0
    0
    0
    0
    No statistical analyses for this end point

    Primary: Efficacy: Changes in tinnitus severity as measured by the TBF-12

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    End point title
    		 Efficacy: Changes in tinnitus severity as measured by the TBF-12
    End point description
    The primary variable for the efficacy assessment was the measure of tinnitus handicap with the TBF-12 score. The primary endpoint was the change in TBF-12 between D0 and D30.
    End point type
    Primary
    End point timeframe
    Baseline to Day 30
    End point values
    		 AM-101 30 µg/ml AM-101 90 µg/ml AM-101 270 µg/ml AM-101 810 µg/ml AM-101 pooled set Placebo
    Number of subjects analysed
    4
    4
    3
    4
    15
    8
    Units: TBF-12 score
        arithmetic mean (standard deviation)
    0.5 ( 3.32 )
    0.25 ( 5.3 )
    -1.67 ( 5.5 )
    0.5 ( 2.7 )
    0 ( 3.9 )
    -0.13 ( 3 )
    Statistical analysis title
    		 Change in TBF-12 score from Baseline to D30
    Comparison groups
    Placebo v AM-101 pooled set
    Number of subjects included in analysis
    23
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    Method
    		 Mixed models analysis
    Parameter type
    		 Estimate
    Point estimate
    0.6
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -6.48
         upper limit
    		 7.68

    Secondary: Efficacy: Improvement of the score of the tinnitus loudness question (TLQ)

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    End point title
    		 Efficacy: Improvement of the score of the tinnitus loudness question (TLQ)
    End point description
    The tinnitus loudness was documented by the patients via a 10 point visual analogue scale (VAS).
    End point type
    Secondary
    End point timeframe
    Day 0 - Day 30
    End point values
    		 AM-101 30 µg/ml AM-101 90 µg/ml AM-101 270 µg/ml AM-101 810 µg/ml AM-101 pooled set Placebo
    Number of subjects analysed
    4
    4
    3
    4
    15
    8
    Units: 10 point visual analogue scale
        arithmetic mean (standard deviation)
    -1 ( 1.15 )
    -1.5 ( 0.58 )
    -1.33 ( 0.58 )
    -0.5 ( 1 )
    -1.07 ( 0.88 )
    -0.31 ( 1.79 )
    Statistical analysis title
    		 Difference Placebo vs. AM-101 overall
    Statistical analysis description
    D0 to D30
    Comparison groups
    Placebo v AM-101 pooled set
    Number of subjects included in analysis
    23
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    Method
    		 Mixed models analysis
    Parameter type
    		 Estimate
    Point estimate
    -0.56
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -2.92
         upper limit
    		 1.8

    Secondary: Efficacy: Change in minimum masking level (MML)

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    End point title
    		 Efficacy: Change in minimum masking level (MML)
    End point description
    A further secondary efficacy endpoint was the change from baseline to D30 in the minimum tinnitus masking level (MML) measured by the investigators. The binaural MML was assessed with a narrow band of noise.
    End point type
    Secondary
    End point timeframe
    Day 0 - Day 30
    End point values
    		 AM-101 30 µg/ml AM-101 90 µg/ml AM-101 270 µg/ml AM-101 810 µg/ml AM-101 pooled set Placebo
    Number of subjects analysed
    4
    4
    3
    4
    15
    8
    Units: dB
        arithmetic mean (standard deviation)
    -1 ( 6.48 )
    -2 ( 4 )
    1 ( 3.61 )
    -6.25 ( 2.5 )
    -2.29 ( 4.84 )
    -0.5 ( 1.87 )
    Statistical analysis title
    		 Difference Placebo vs. AM-101 overall
    Statistical analysis description
    D0 - D30
    Comparison groups
    AM-101 pooled set v Placebo
    Number of subjects included in analysis
    23
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    Method
    		 Mixed models analysis
    Parameter type
    		 Estimate
    Point estimate
    1.24
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -6.77
         upper limit
    		 9.26

    Secondary: PK: Maximum plasma drug concentration level (Cmax) - Esketamine

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    End point title
    		 PK: Maximum plasma drug concentration level (Cmax) - Esketamine [2]
    End point description
    Plasma samples of the 2 highest dose cohorts (270 and 810 µg/ml) were analysed for PK. Concentrations above lower limit of quantification (LLOQ) could be detected in only 1 of the 4 patients in the 270 g/ml dose group, but in 4 out of 4 in the 810 g/ml group. Therefore the samples of 5 patients could be included in the pharmacokinetic (PK) analysis. Statistics N/A - Standard PK analysis methods were used.
    End point type
    Secondary
    End point timeframe
    Sampling on the day of treatment D0, with samples being drawn prior to treatment administration and 15 min, 30 min, 45 min, 1 hour, 3 hours and 6 hours after treatment.
    Notes
    [2] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: For the PK analysis only patients from the 2 high dose cohorts were included.
    End point values
    		 AM-101 pooled set
    Number of subjects analysed
    5 [3]
    Units: ng/mL
        arithmetic mean (standard deviation)
    0.23 ( 0.06 )
    Notes
    [3] - See description in Cmax - Esketamine
    No statistical analyses for this end point

    Secondary: PK: Time to maximum plasma concentration (Tmax) - Esketamine

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    End point title
    		 PK: Time to maximum plasma concentration (Tmax) - Esketamine [4]
    End point description
    End point type
    Secondary
    End point timeframe
    see Cmax - Esketamine
    Notes
    [4] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: For the PK analysis only patients from the 2 high dose cohorts were included.
    End point values
    		 AM-101 pooled set
    Number of subjects analysed
    5 [5]
    Units: hours
        arithmetic mean (standard deviation)
    0.56 ( 0.31 )
    Notes
    [5] - See description in Cmax - Esketamine
    No statistical analyses for this end point

    Secondary: PK: Area under the plasma concentration-time curve (AUC 0-6) - Esketamine

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    End point title
    		 PK: Area under the plasma concentration-time curve (AUC 0-6) - Esketamine [6]
    End point description
    End point type
    Secondary
    End point timeframe
    see Cmax
    Notes
    [6] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: For the PK analysis only patients from the 2 high dose cohorts were included.
    End point values
    		 AM-101 pooled set
    Number of subjects analysed
    5 [7]
    Units: ng*h/mL
        arithmetic mean (standard deviation)
    0.66 ( 0.12 )
    Notes
    [7] - See description in Cmax - Esketamine
    No statistical analyses for this end point

    Secondary: PK: Maximum plasma drug concentration level (Cmax) - S-Norketamine

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    End point title
    		 PK: Maximum plasma drug concentration level (Cmax) - S-Norketamine [8]
    End point description
    see Cmax - Esketamine
    End point type
    Secondary
    End point timeframe
    Sampling on the day of treatment D0, with samples being drawn prior to treatment administration and 15 min, 30 min, 45 min, 1 hour, 3 hours and 6 hours after treatment.
    Notes
    [8] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: For the PK analysis only patients from the 2 high dose cohorts were included.
    End point values
    		 AM-101 pooled set
    Number of subjects analysed
    5 [9]
    Units: ng/mL
        arithmetic mean (standard deviation)
    0.15 ( 0.02 )
    Notes
    [9] - See description in Cmax - Esketamine
    No statistical analyses for this end point

    Secondary: PK: Time to maximum plasma concentration (Tmax) - S-Norketamine

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    End point title
    		 PK: Time to maximum plasma concentration (Tmax) - S-Norketamine [10]
    End point description
    End point type
    Secondary
    End point timeframe
    see Cmax - Esketamine
    Notes
    [10] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: For the PK analysis only patients from the 2 high dose cohorts were included.
    End point values
    		 AM-101 pooled set
    Number of subjects analysed
    5 [11]
    Units: hours
        arithmetic mean (standard deviation)
    2.5 ( 1 )
    Notes
    [11] - See description in Cmax - Esketamine
    No statistical analyses for this end point

    Secondary: PK: Area under the plasma concentration-time curve (AUC 0-6) - S-Norketamine

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    End point title
    		 PK: Area under the plasma concentration-time curve (AUC 0-6) - S-Norketamine [12]
    End point description
    End point type
    Secondary
    End point timeframe
    see Cmax - Esketamine
    Notes
    [12] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: For the PK analysis only patients from the 2 high dose cohorts were included.
    End point values
    		 AM-101 pooled set
    Number of subjects analysed
    5 [13]
    Units: ng*h/mL
        arithmetic mean (standard deviation)
    0.73 ( 0.16 )
    Notes
    [13] - See description in Cmax - Esketamine
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    After single-dose treatment, study subjects were followed for 60 days with 3 follow-up visits at D7, D30 and D60. At each visit, AEs were recorded.
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    9.1
    Reporting groups
    Reporting group title
    AM-101 30 µg/ml
    Reporting group description
    		 -

    Reporting group title
    AM-101 90 µg/ml
    Reporting group description
    		 -

    Reporting group title
    AM-101 270 µg/ml
    Reporting group description
    		 -

    Reporting group title
    AM-101 810 µg/ml
    Reporting group description
    		 -

    Reporting group title
    AM-101 pooled set
    Reporting group description
    		 -

    Reporting group title
    Placebo
    Reporting group description
    		 -

    Serious adverse events
    		 AM-101 30 µg/ml AM-101 90 µg/ml AM-101 270 µg/ml AM-101 810 µg/ml AM-101 pooled set Placebo
    Total subjects affected by serious adverse events
         subjects affected / exposed
    0 / 4 (0.00%)
    0 / 4 (0.00%)
    0 / 4 (0.00%)
    0 / 4 (0.00%)
    0 / 16 (0.00%)
    0 / 8 (0.00%)
         number of deaths (all causes)
    0
    0
    0
    0
    0
    0
         number of deaths resulting from adverse events
    0
    0
    0
    0
    0
    0
    Frequency threshold for reporting non-serious adverse events: 0%
    Non-serious adverse events
    		 AM-101 30 µg/ml AM-101 90 µg/ml AM-101 270 µg/ml AM-101 810 µg/ml AM-101 pooled set Placebo
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    2 / 4 (50.00%)
    2 / 4 (50.00%)
    4 / 4 (100.00%)
    3 / 4 (75.00%)
    11 / 16 (68.75%)
    6 / 8 (75.00%)
    Investigations
    Paracentesis ear abnormal
         subjects affected / exposed
    0 / 4 (0.00%)
    2 / 4 (50.00%)
    1 / 4 (25.00%)
    0 / 4 (0.00%)
    3 / 16 (18.75%)
    0 / 8 (0.00%)
         occurrences all number
    0
    2
    1
    0
    3
    0
    Nervous system disorders
    Dizziness
         subjects affected / exposed
    0 / 4 (0.00%)
    0 / 4 (0.00%)
    0 / 4 (0.00%)
    0 / 4 (0.00%)
    0 / 16 (0.00%)
    2 / 8 (25.00%)
         occurrences all number
    0
    0
    0
    0
    0
    2
    Headache
         subjects affected / exposed
    2 / 4 (50.00%)
    0 / 4 (0.00%)
    0 / 4 (0.00%)
    0 / 4 (0.00%)
    2 / 16 (12.50%)
    1 / 8 (12.50%)
         occurrences all number
    2
    0
    0
    0
    2
    1
    Neuromuscular blockade
         subjects affected / exposed
    2 / 4 (50.00%)
    0 / 4 (0.00%)
    0 / 4 (0.00%)
    0 / 4 (0.00%)
    2 / 16 (12.50%)
    0 / 8 (0.00%)
         occurrences all number
    2
    0
    0
    0
    2
    0
    Paresthesia
         subjects affected / exposed
    0 / 4 (0.00%)
    0 / 4 (0.00%)
    1 / 4 (25.00%)
    0 / 4 (0.00%)
    1 / 16 (6.25%)
    0 / 8 (0.00%)
         occurrences all number
    0
    0
    1
    0
    1
    0
    Ear and labyrinth disorders
    Deafness
         subjects affected / exposed
    0 / 4 (0.00%)
    0 / 4 (0.00%)
    0 / 4 (0.00%)
    1 / 4 (25.00%)
    1 / 16 (6.25%)
    0 / 8 (0.00%)
         occurrences all number
    0
    0
    0
    1
    1
    0
    Deafness unilateral
         subjects affected / exposed
    1 / 4 (25.00%)
    0 / 4 (0.00%)
    0 / 4 (0.00%)
    0 / 4 (0.00%)
    1 / 16 (6.25%)
    0 / 8 (0.00%)
         occurrences all number
    1
    0
    0
    0
    1
    0
    Ear pain
         subjects affected / exposed
    0 / 4 (0.00%)
    0 / 4 (0.00%)
    0 / 4 (0.00%)
    1 / 4 (25.00%)
    1 / 16 (6.25%)
    0 / 8 (0.00%)
         occurrences all number
    0
    0
    0
    1
    1
    0
    Middle ear inflammation
         subjects affected / exposed
    0 / 4 (0.00%)
    0 / 4 (0.00%)
    0 / 4 (0.00%)
    0 / 4 (0.00%)
    0 / 16 (0.00%)
    1 / 8 (12.50%)
         occurrences all number
    0
    0
    0
    0
    0
    1
    Tinnitus
         subjects affected / exposed
    0 / 4 (0.00%)
    0 / 4 (0.00%)
    0 / 4 (0.00%)
    1 / 4 (25.00%)
    1 / 16 (6.25%)
    1 / 8 (12.50%)
         occurrences all number
    0
    0
    0
    2
    2
    1
    Vertigo
         subjects affected / exposed
    0 / 4 (0.00%)
    0 / 4 (0.00%)
    0 / 4 (0.00%)
    1 / 4 (25.00%)
    1 / 16 (6.25%)
    0 / 8 (0.00%)
         occurrences all number
    0
    0
    0
    1
    1
    0
    Psychiatric disorders
    Insomnia
         subjects affected / exposed
    0 / 4 (0.00%)
    0 / 4 (0.00%)
    0 / 4 (0.00%)
    0 / 4 (0.00%)
    0 / 16 (0.00%)
    1 / 8 (12.50%)
         occurrences all number
    0
    0
    0
    0
    0
    1
    Infections and infestations
    Nasopharyngitis
         subjects affected / exposed
    1 / 4 (25.00%)
    0 / 4 (0.00%)
    1 / 4 (25.00%)
    2 / 4 (50.00%)
    4 / 16 (25.00%)
    1 / 8 (12.50%)
         occurrences all number
    1
    0
    1
    2
    4
    1
    Upper respiratory tract infection
         subjects affected / exposed
    0 / 4 (0.00%)
    0 / 4 (0.00%)
    1 / 4 (25.00%)
    0 / 4 (0.00%)
    1 / 16 (6.25%)
    1 / 8 (12.50%)
         occurrences all number
    0
    0
    1
    0
    1
    1

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    10 May 2007
    The aim of this amendment was to include an evaluation of the potential systemic exposure following a single intratympanic injection of AM-101. The pharmacokinetic characteristics of Esketamine in plasma were to be characterised at the two higher doses tested (270 μg/mL and 810 μg/mL), including determination of the parent and the principal metabolite (S)-Norketamine.
    07 Jun 2007
    - Patients with severe or disabling permanent inner ear tinnitus which set in with sudden deafness were included.
    17 Sep 2007
    - An interim analysis at the end of the 270 μg/mL dose cohort (after Day 7 of the last patient included in this cohort) was added.

    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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