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    Clinical Trial Results:
    Multicenter randomized controlled phase 2 trial to evaluate AM-125 in the treatment of acute peripheral vertigo following neurosurgery (TRAVERS)

    Summary
    EudraCT number
    		 2018-002474-52
    Trial protocol
    		 BE   CZ   PL   DE   GB   SK   IT  
    Global end of trial date
    28 Mar 2022

    Results information
    Results version number
    		 v1(current)
    This version publication date
    30 Aug 2023
    First version publication date
    30 Aug 2023
    Other versions

    Trial information

    		 Close Top of page
    Trial identification
    Sponsor protocol code
    AM-125-CL-18-01
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT03908567
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    Auris Medical AG
    Sponsor organisation address
    Peter Merian Street 90, Basel, Switzerland,
    Public contact
    CEO, Auris Medical AG, tm@aurismedical.com
    Scientific contact
    CEO, Auris Medical AG, tm@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
    29 Aug 2022
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    28 Mar 2022
    Global end of trial reached?
    Yes
    Global end of trial date
    28 Mar 2022
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    The study consisted of two parts (Part A and B): Primary objective of Part A was a. to explore and provide an estimate of the dose response curve for AM-125, and b. to evaluate the efficacy of AM-125 compared to placebo in reducing the symptoms of vestibular dysfunction and accelerating vestibular compensation following surgery-induced acute vestibular syndrome (AVS). Part A contained as well an oral open-label arm with 16 mg betahistine dihydrochloride tablets (authorized in the EU). The primary objective of Part B was to evaluate the efficacy of two selected doses of AM-125 versus placebo, as determined based on the results from Part A, in reducing the symptoms of vestibular dysfunction and accelerating vestibular compensation following surgery-induced acute vestibular syndrome compared to placebo. The 10 and 20 mg cohorts were selected for efficacy testing in Part B. All subjects performed twice daily a home-based vestibular rehabilitation therapy exercise program.
    Protection of trial subjects
    The trial was performed in compliance with International Conference on Harmonisation Good Clinical Practice (ICH GCP) Guidelines, and in accordance with the current version of the Declaration of Helsinki.
    Background therapy
    		 -
    Evidence for comparator
    		 -
    Actual start date of recruitment
    18 Jul 2019
    Long term follow-up planned
    No
    Independent data monitoring committee (IDMC) involvement?
    Yes
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    Poland: 7
    Country: Number of subjects enrolled
    Slovakia: 22
    Country: Number of subjects enrolled
    Belgium: 3
    Country: Number of subjects enrolled
    Czechia: 51
    Country: Number of subjects enrolled
    France: 5
    Country: Number of subjects enrolled
    Germany: 21
    Country: Number of subjects enrolled
    Italy: 15
    Worldwide total number of subjects
    124
    EEA total number of subjects
    124
    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)
    109
    From 65 to 84 years
    15
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 The study consisted of a Screening phase which started 28 days prior to Day 0 when the patient underwent surgery. Patients were randomized to treatment on Day 3. The treatment phase continued up to Day 31 with three Follow up visits (FUVs): Day 7 (FUV1), Day 14 (FUV2), and Day 31 (FUV3). Final follow-up phase continued until Day 45 (FUV4).

    Pre-assignment
    Screening details
    		 The study consisted of two parts: In part A, a total of 67 subjects were screened at approximately 20 sites in Europe and Australia, of which 49 were randomized to AM-125 or placebo and 16 to oral betahistine (open label). In part B, a total of 102 subjects were screened of which 75 subjects were randomized at the same sites.

    Period 1
    Period 1 title
    Treatment and follow-up (overall period)
    Is this the baseline period?
    		 Yes
    Allocation method
    Randomised - controlled
    Blinding used
    		 Double blind
    Roles blinded
    		 Subject, Investigator, Monitor
    Blinding implementation details
    There were no differences in the spray pump devices (active vs. placebo) and no discernible difference in the odor or appearance of the spray formulations. The oral arm was an open-label arm for reference.

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Placebo
    Arm description
    		 Recruitment into this arm took place in part A (n=7) and part B (n=25).
    Arm type
    		 Placebo

    Investigational medicinal product name
    Placebo
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Nasal spray, solution
    Routes of administration
    Intranasal use
    Dosage and administration details
    1 actuation in each nostril. Three times daily for 28 days. 100 uL per actuation (0 mg/ml betahistine dihydrochloride).

    Arm title
    		 Intranasal AM-125, 1 mg
    Arm description
    		 Recruitment into this arm happenend solely in part A.
    Arm type
    		 Experimental

    Investigational medicinal product name
    AM-125
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Nasal spray, solution
    Routes of administration
    Intranasal use
    Dosage and administration details
    1 actuation in each nostril. Three times daily for 28 days. 100 uL per actuation (5 mg/ml betahistine dihydrochloride).

    Arm title
    		 Intranasal AM-125, 10 mg
    Arm description
    		 Recruitment into this arm took place in part A (n=9) and part B (n=25).
    Arm type
    		 Experimental

    Investigational medicinal product name
    AM-125
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Nasal spray, solution
    Routes of administration
    Intranasal use
    Dosage and administration details
    1 actuation in each nostril. Three times daily for 28 days. 100 uL per actuation (50 mg/ml betahistine dihydrochloride).

    Arm title
    		 Intranasal AM-125, 20 mg
    Arm description
    		 Recruitment into this arm took place in part A (n=8) and part B (n=25).
    Arm type
    		 Experimental

    Investigational medicinal product name
    AM-125
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Nasal spray, solution
    Routes of administration
    Intranasal use
    Dosage and administration details
    1 actuation in each nostril. Three times daily for 28 days. 100 uL per actuation (100 mg/ml betahistine dihydrochloride).

    Arm title
    		 Oral betahistine
    Arm description
    		 Was added for reference without placebo. Open-label arm.
    Arm type
    		 Active comparator

    Investigational medicinal product name
    Oral betahistine, 16 mg tablets
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Coated tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Three times daily a tablet containing 16 mg betahistine dihydrochloride for 28 days (tablet approved and holding a marketing authorization in the EU).

    Number of subjects in period 1
    		Placebo Intranasal AM-125, 1 mg Intranasal AM-125, 10 mg Intranasal AM-125, 20 mg Oral betahistine
    Started
    32
    9
    34
    33
    16
    Completed
    31
    8
    32
    29
    14
    Not completed
    1
    1
    2
    4
    2
         Consent withdrawn by subject
    -
    -
    2
    -
    1
         Adverse event, non-fatal
    -
    1
    -
    2
    -
         Adverse event related to surgery, but not IMP
    -
    -
    -
    2
    1
         Lost to follow-up
    1
    -
    -
    -
    -

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Placebo
    Reporting group description
    		 Recruitment into this arm took place in part A (n=7) and part B (n=25).

    Reporting group title
    Intranasal AM-125, 1 mg
    Reporting group description
    		 Recruitment into this arm happenend solely in part A.

    Reporting group title
    Intranasal AM-125, 10 mg
    Reporting group description
    		 Recruitment into this arm took place in part A (n=9) and part B (n=25).

    Reporting group title
    Intranasal AM-125, 20 mg
    Reporting group description
    		 Recruitment into this arm took place in part A (n=8) and part B (n=25).

    Reporting group title
    Oral betahistine
    Reporting group description
    		 Was added for reference without placebo. Open-label arm.

    Reporting group values
    		 Placebo Intranasal AM-125, 1 mg Intranasal AM-125, 10 mg Intranasal AM-125, 20 mg Oral betahistine Total
    Number of subjects
    		 32 9 34 33 16 124
    Age categorical
    Randomization was stratified by age at baseline (< 50 years of age, ≥ 50 years of age).
    Units: Subjects
        In utero
    		 0 0 0 0 0 0
        Preterm newborn infants (gestational age < 37 wks)
    		 0 0 0 0 0 0
        Newborns (0-27 days)
    		 0 0 0 0 0 0
        Infants and toddlers (28 days-23 months)
    		 0 0 0 0 0 0
        Children (2-11 years)
    		 0 0 0 0 0 0
        Adolescents (12-17 years)
    		 0 0 0 0 0 0
        Adults (18-64 years)
    		 0 0 0 0 0 0
        From 65-84 years
    		 0 0 0 0 0 0
        85 years and over
    		 0 0 0 0 0 0
        Adults > 50 years
    		 20 4 20 22 12 78
        Adults < 50 years
    		 12 5 14 11 4 46
    Age continuous
    Units: years
        arithmetic mean (standard deviation)
    		 59.2 ( 5.13 ) 58.5 ( 7.23 ) 59.2 ( 6.82 ) 58.8 ( 5.4 ) 58.0 ( 6.15 ) -
    Gender categorical
    Units: Subjects
        Female
    		 22 5 18 14 11 70
        Male
    		 10 4 16 19 5 54

    End points

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    End points reporting groups
    Reporting group title
    Placebo
    Reporting group description
    		 Recruitment into this arm took place in part A (n=7) and part B (n=25).

    Reporting group title
    Intranasal AM-125, 1 mg
    Reporting group description
    		 Recruitment into this arm happenend solely in part A.

    Reporting group title
    Intranasal AM-125, 10 mg
    Reporting group description
    		 Recruitment into this arm took place in part A (n=9) and part B (n=25).

    Reporting group title
    Intranasal AM-125, 20 mg
    Reporting group description
    		 Recruitment into this arm took place in part A (n=8) and part B (n=25).

    Reporting group title
    Oral betahistine
    Reporting group description
    		 Was added for reference without placebo. Open-label arm.

    Subject analysis set title
    Enrolled Set
    Subject analysis set type
    		 Full analysis
    Subject analysis set description
    All subjects who signed informed consent.

    Subject analysis set title
    Intention to Treat Set
    Subject analysis set type
    		 Intention-to-treat
    Subject analysis set description
    Includes all randomized subjects. Subjects are analyzed according to their randomized treatment.

    Subject analysis set title
    Safety Set
    Subject analysis set type
    		 Safety analysis
    Subject analysis set description
    Includes all subjects who received randomized therapy. Subjects are summarized according to the treatment received.

    Subject analysis set title
    Per Protocol Set
    Subject analysis set type
    		 Per protocol
    Subject analysis set description
    Includes all subjects from the ITT Analysis Set who received at least one dose of study drug and are without major protocol deviations which would interfere with the analysis of the primary endpoint. Subjects are analyzed according to the treatment received.

    Primary: Improvement in tandem Romberg test (eyes closed)

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    End point title
    		 Improvement in tandem Romberg test (eyes closed) [1]
    End point description
    Tandem Romberg Test is a physical assessment used to evaluate disturbance in subject's balance. In the present protocol, subjects were asked to stand straight in tandem stand (the heel of one foot touching the toes of the other foot, shoes removed) with eyes closed. The time for which the subjects were able to hold this position until they either opened their eyes or moved their feet in order to maintain balance for a maximum of 30 seconds, was measured by the examiner. On each occasion the assessment was performed three times. The best performance was used for efficacy analysis. The assessment was performed at SV, TV and at all FUVs.
    End point type
    Primary
    End point timeframe
    From TV (baseline) to FUV4.
    Notes
    [1] - 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: In this entry major endpoints are presented. The final analysis did focus on the 10 mg and 20 mg cohorts. Therefore, the statistic for the 1 mg cohort is not presented here. For more information the reader can refer to the publication of the study or send a request to the sponsor.
    End point values
    		 Placebo Intranasal AM-125, 10 mg Intranasal AM-125, 20 mg
    Number of subjects analysed
    31
    32
    31
    Units: seconds
        least squares mean (standard error)
    10.7 ( 1.38 )
    10.5 ( 1.35 )
    11.2 ( 1.37 )
    Statistical analysis title
    		 Improvement in TRT between Placebo and AM-125
    Statistical analysis description
    In the MMRM model, the dependent variable was the endpoint change in the tandem Romberg test from baseline to FUV4. Randomized treatment, time (i.e. FUV1, 2, 3 and 4) and time by-randomized treatment interaction were fitted as fixed effects with baseline value as a covariate. Subject were included as a random effect. Analysis was stratified by age. The primary estimand of interest was the contrast between AM-125 doses and placebo at FUV4.
    Comparison groups
    Placebo v Intranasal AM-125, 10 mg v Intranasal AM-125, 20 mg
    Number of subjects included in analysis
    94
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 < 0.8 [2]
    Method
    		 Mixed models analysis
    Confidence interval
    Notes
    [2] - AM-125 10 mg vs. Placebo p-value = 0.9 AM-125 20 mg vs. Placebo p-value = 0.8

    Secondary: Improvement in time standing on foam (SOF)

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    End point title
    		 Improvement in time standing on foam (SOF) [3]
    End point description
    Subjects were asked to stand straight on a foam plate with parallel feet (shoes removed) and eyes closed. An examiner measured the time that subjects were able to hold this position until they either open their eyes or move their feet in order to maintain balance for a maximum of 30 seconds.
    End point type
    Secondary
    End point timeframe
    From baseline to FUV2.
    Notes
    [3] - 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: In this entry major endpoints are presented. The final analysis did focus on the 10 mg and 20 mg cohorts. Therefore, the statistic for the 1 mg cohort is not presented here. For more information the reader can refer to the publication of the study or send a request to the sponsor.
    End point values
    		 Placebo Intranasal AM-125, 10 mg Intranasal AM-125, 20 mg
    Number of subjects analysed
    31
    32
    31
    Units: seconds
        least squares mean (standard error)
    14.77 ( 1.83 )
    15.89 ( 1.78 )
    18.46 ( 1.85 )
    Statistical analysis title
    		 Improvement in SOF between Placebo and AM-125
    Statistical analysis description
    Same model as for primary endpoint was used.
    Comparison groups
    Placebo v Intranasal AM-125, 10 mg v Intranasal AM-125, 20 mg
    Number of subjects included in analysis
    94
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 < 0.158 [4]
    Method
    		 Mixed models analysis
    Confidence interval
    Notes
    [4] - AM-125 10 mg vs. Placebo p-value = 0.66 AM-125 20 mg vs. Placebo p-value = 0.16

    Other pre-specified: Change in the Vestibular Rehabilitation Benefit Questionnaire score from

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    End point title
    		 Change in the Vestibular Rehabilitation Benefit Questionnaire score from [5]
    End point description
    Subjects were self-assessing their vestibular symptoms and the impact of vestibular dysfunction with the Vestibular Rehabilitation Benefit Questionnaire (Morris et al. 2009) at all visits. The VRBQ as a measure of vestibular deficit was analyzed only in Part B of the study. The score decreased over time in all treatment groups with the largest improvements observed in the AM 125 20 mg group. The improvements (LS Mean change), using MMRM analysis, compared to baseline in VRBQ score did not reach statistical significance for either treatment group when compared to placebo. The trend for better improvement in the AM-125 20 mg group was driven primarily by reduction in subjective dizziness and anxiety among symptoms and lower impact on quality of life. The results presented below correspond to the FUV3.
    End point type
    Other pre-specified
    End point timeframe
    From TV (baseline) to FUV3
    Notes
    [5] - 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: In this entry major endpoints are presented. The final analysis did focus on the 10 mg and 20 mg cohorts. Therefore, the statistic for the 1 mg cohort is not presented here. For more information the reader can refer to the publication of the study or send a request to the sponsor.
    End point values
    		 Placebo Intranasal AM-125, 10 mg Intranasal AM-125, 20 mg
    Number of subjects analysed
    32
    34
    33
    Units: Score
        least squares mean (standard error)
    -27.5 ( 2.9 )
    -22.65 ( 2.9 )
    -28.76 ( 3.1 )
    Statistical analysis title
    		 Improvement in VRBQ between Placebo and AM-125
    Statistical analysis description
    Results are provided for FUV3
    Comparison groups
    Placebo v Intranasal AM-125, 10 mg v Intranasal AM-125, 20 mg
    Number of subjects included in analysis
    99
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.24 [6]
    Method
    		 Mixed models analysis
    Confidence interval
    Notes
    [6] - AM-125 10 mg vs. Placebo p-value = 0.24 AM-125 20 mg vs. Placebo p-value = 0.78

    Post-hoc: Resolution of Spontaneous Nystagmus

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    End point title
    		 Resolution of Spontaneous Nystagmus [7]
    End point description
    Nystagmus is a condition of involuntary eye movement and is commonly seen in many types of balance disorder. The number of subjects with presence of nystagmus and without nystagmus were analyzed at all the FUV visits in treatment groups of AM 125 10 mg, AM 125 20 mg, and placebo. The most significant results were observed at FUV4, which are reported hereby.
    End point type
    Post-hoc
    End point timeframe
    From TV (baseline) to FUV4
    Notes
    [7] - 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: In this entry major endpoints are presented. The final analysis did focus on the 10 mg and 20 mg cohorts. Therefore, the statistic for the 1 mg cohort is not presented here. For more information the reader can refer to the publication of the study.
    End point values
    		 Placebo Intranasal AM-125, 10 mg Intranasal AM-125, 20 mg
    Number of subjects analysed
    32
    34
    33
    Units: number
    8
    10
    14
    Statistical analysis title
    		 Resolution of spontaneous nystagmus
    Comparison groups
    Placebo v Intranasal AM-125, 10 mg v Intranasal AM-125, 20 mg
    Number of subjects included in analysis
    99
    Analysis specification
    Post-hoc
    Analysis type
    		 superiority
    P-value
    		 = 0.47 [8]
    Method
    		 Mixed models analysis
    Confidence interval
    Notes
    [8] - AM-125 10 mg vs. Placebo p-value = 0.27 AM-125 20 mg vs. Placebo p-value = 0.47

    Post-hoc: Change in Tandem Romberg test excluding subjects with substantial vestibular compensation at baseline

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    End point title
    		 Change in Tandem Romberg test excluding subjects with substantial vestibular compensation at baseline [9]
    End point description
    Mapping the change in the Tandem Romberg test against the change in the Standing on Foam test at a subject level revealed several cases that were unable to perform the Tandem Romberg test at baseline, but achieved meaningful or even maximum Standing on Foam scores. This pointed to the presence of substantial vestibular compensation in part of study participants in spite of the attempts to exclude such subjects. For a post hoc sensitivity analysis, subjects were excluded if their time to failure in the Standing on Foam test at baseline was ≥ 10 sec., a level which separated outliers from the bulk of low-performing subjects (7 in the placebo, 2 in each of the active treated groups). Their exclusion had no impact on the overall pattern of recovery in the Tandem Romberg test, but resulted in a larger differential in improvement between the AM-125 20 mg and placebo group at FUV2 and FUV3. Results reported below correspond to FUV3.
    End point type
    Post-hoc
    End point timeframe
    From baseline to FUV3
    Notes
    [9] - 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: In this entry major endpoints are presented. The final analysis did focus on the 10 mg and 20 mg cohorts. Therefore, the statistic for the 1 mg cohort is not presented here. For more information the reader can refer to the publication of the study or send a request to the sponsor.
    End point values
    		 Placebo Intranasal AM-125, 10 mg Intranasal AM-125, 20 mg
    Number of subjects analysed
    24
    32
    30
    Units: seconds
        least squares mean (standard deviation)
    7.9 ( 6.47 )
    9.7 ( 7.92 )
    12.2 ( 10.58 )
    Statistical analysis title
    		 Improvement in TRT between Placebo and AM-125
    Comparison groups
    Placebo v Intranasal AM-125, 20 mg
    Number of subjects included in analysis
    54
    Analysis specification
    Post-hoc
    Analysis type
    		 superiority
    P-value
    		 = 0.059 [10]
    Method
    		 Mixed models analysis
    Confidence interval
    Notes
    [10] - Results are provided for AM-125 20mg vs . Placebo at FUV3

    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
    Only adverse events related to the IMP AM-125 are reported here. Other adverse events related to the surgery are not reported here.
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    21.1
    Reporting groups
    Reporting group title
    Placebo
    Reporting group description
    		 -

    Reporting group title
    AM-125 1mg
    Reporting group description
    		 -

    Reporting group title
    AM-125 10mg
    Reporting group description
    		 -

    Reporting group title
    AM-125 20mg
    Reporting group description
    		 -

    Reporting group title
    Oral Betahistine 16mg
    Reporting group description
    		 -

    Serious adverse events
    		 Placebo AM-125 1mg AM-125 10mg AM-125 20mg Oral Betahistine 16mg
    Total subjects affected by serious adverse events
         subjects affected / exposed
    0 / 32 (0.00%)
    0 / 9 (0.00%)
    0 / 34 (0.00%)
    0 / 33 (0.00%)
    0 / 16 (0.00%)
         number of deaths (all causes)
    0
    0
    0
    0
    0
         number of deaths resulting from adverse events
    0
    0
    0
    0
    0
    Frequency threshold for reporting non-serious adverse events: 0%
    Non-serious adverse events
    		 Placebo AM-125 1mg AM-125 10mg AM-125 20mg Oral Betahistine 16mg
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    3 / 32 (9.38%)
    2 / 9 (22.22%)
    1 / 34 (2.94%)
    5 / 33 (15.15%)
    3 / 16 (18.75%)
    Investigations
    Alanine aminotransferase increased
         subjects affected / exposed
    0 / 32 (0.00%)
    1 / 9 (11.11%)
    0 / 34 (0.00%)
    0 / 33 (0.00%)
    0 / 16 (0.00%)
         occurrences all number
    0
    1
    0
    0
    0
    Aspartate aminotransferase increased
         subjects affected / exposed
    0 / 32 (0.00%)
    1 / 9 (11.11%)
    0 / 34 (0.00%)
    0 / 33 (0.00%)
    0 / 16 (0.00%)
         occurrences all number
    0
    1
    0
    0
    0
    Blood alkaline phosphatase increased
         subjects affected / exposed
    0 / 32 (0.00%)
    0 / 9 (0.00%)
    0 / 34 (0.00%)
    0 / 33 (0.00%)
    1 / 16 (6.25%)
         occurrences all number
    0
    0
    0
    0
    1
    Transaminases abnormal
         subjects affected / exposed
    0 / 32 (0.00%)
    0 / 9 (0.00%)
    1 / 34 (2.94%)
    0 / 33 (0.00%)
    0 / 16 (0.00%)
         occurrences all number
    0
    0
    1
    0
    0
    Vascular disorders
    Flushing
         subjects affected / exposed
    0 / 32 (0.00%)
    1 / 9 (11.11%)
    0 / 34 (0.00%)
    0 / 33 (0.00%)
    0 / 16 (0.00%)
         occurrences all number
    0
    1
    0
    0
    0
    Hypertension
         subjects affected / exposed
    0 / 32 (0.00%)
    1 / 9 (11.11%)
    0 / 34 (0.00%)
    0 / 33 (0.00%)
    0 / 16 (0.00%)
         occurrences all number
    0
    1
    0
    0
    0
    Nervous system disorders
    Headache
         subjects affected / exposed
    0 / 32 (0.00%)
    2 / 9 (22.22%)
    0 / 34 (0.00%)
    1 / 33 (3.03%)
    0 / 16 (0.00%)
         occurrences all number
    0
    2
    0
    2
    0
    Dysgeusia
         subjects affected / exposed
    0 / 32 (0.00%)
    0 / 9 (0.00%)
    0 / 34 (0.00%)
    1 / 33 (3.03%)
    0 / 16 (0.00%)
         occurrences all number
    0
    0
    0
    1
    0
    General disorders and administration site conditions
    Chest pain
         subjects affected / exposed
    0 / 32 (0.00%)
    0 / 9 (0.00%)
    0 / 34 (0.00%)
    0 / 33 (0.00%)
    1 / 16 (6.25%)
         occurrences all number
    0
    0
    0
    0
    1
    Mucosal dryness
         subjects affected / exposed
    1 / 32 (3.13%)
    0 / 9 (0.00%)
    0 / 34 (0.00%)
    0 / 33 (0.00%)
    0 / 16 (0.00%)
         occurrences all number
    1
    0
    0
    0
    0
    Gastrointestinal disorders
    Aphthous ulcer
         subjects affected / exposed
    0 / 32 (0.00%)
    0 / 9 (0.00%)
    0 / 34 (0.00%)
    0 / 33 (0.00%)
    1 / 16 (6.25%)
         occurrences all number
    0
    0
    0
    0
    2
    Respiratory, thoracic and mediastinal disorders
    Nasal discomfort
         subjects affected / exposed
    1 / 32 (3.13%)
    1 / 9 (11.11%)
    0 / 34 (0.00%)
    0 / 33 (0.00%)
    0 / 16 (0.00%)
         occurrences all number
    1
    2
    0
    0
    0
    Cough
         subjects affected / exposed
    0 / 32 (0.00%)
    0 / 9 (0.00%)
    0 / 34 (0.00%)
    1 / 33 (3.03%)
    0 / 16 (0.00%)
         occurrences all number
    0
    0
    0
    1
    0
    Epistaxis
         subjects affected / exposed
    0 / 32 (0.00%)
    0 / 9 (0.00%)
    0 / 34 (0.00%)
    1 / 33 (3.03%)
    0 / 16 (0.00%)
         occurrences all number
    0
    0
    0
    1
    0
    Nasal crusting
         subjects affected / exposed
    1 / 32 (3.13%)
    0 / 9 (0.00%)
    0 / 34 (0.00%)
    0 / 33 (0.00%)
    0 / 16 (0.00%)
         occurrences all number
    1
    0
    0
    0
    0
    Nasal dryness
         subjects affected / exposed
    0 / 32 (0.00%)
    1 / 9 (11.11%)
    0 / 34 (0.00%)
    0 / 33 (0.00%)
    0 / 16 (0.00%)
         occurrences all number
    0
    1
    0
    0
    0
    Nasal mucosal disorder
         subjects affected / exposed
    1 / 32 (3.13%)
    0 / 9 (0.00%)
    0 / 34 (0.00%)
    0 / 33 (0.00%)
    0 / 16 (0.00%)
         occurrences all number
    1
    0
    0
    0
    0
    Nasal pruritus
         subjects affected / exposed
    0 / 32 (0.00%)
    0 / 9 (0.00%)
    0 / 34 (0.00%)
    1 / 33 (3.03%)
    0 / 16 (0.00%)
         occurrences all number
    0
    0
    0
    1
    0
    Nasal ulcer
         subjects affected / exposed
    1 / 32 (3.13%)
    0 / 9 (0.00%)
    0 / 34 (0.00%)
    0 / 33 (0.00%)
    0 / 16 (0.00%)
         occurrences all number
    1
    0
    0
    0
    0
    Skin and subcutaneous tissue disorders
    Dermatitis contact
         subjects affected / exposed
    0 / 32 (0.00%)
    0 / 9 (0.00%)
    0 / 34 (0.00%)
    0 / 33 (0.00%)
    1 / 16 (6.25%)
         occurrences all number
    0
    0
    0
    0
    1
    Rash
         subjects affected / exposed
    0 / 32 (0.00%)
    0 / 9 (0.00%)
    0 / 34 (0.00%)
    1 / 33 (3.03%)
    0 / 16 (0.00%)
         occurrences all number
    0
    0
    0
    1
    0
    Psychiatric disorders
    Insomnia
         subjects affected / exposed
    0 / 32 (0.00%)
    1 / 9 (11.11%)
    0 / 34 (0.00%)
    0 / 33 (0.00%)
    0 / 16 (0.00%)
         occurrences all number
    0
    1
    0
    0
    0

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    08 Feb 2019
    The protocol amendment 1 was issued due to a request from the Belgian competent authority concerning the use of contraception and the definition of women of childbearing potential. The contraception methods of diaphragm with spermicide, male or female condoms with spermicide, or cervical cap were deleted. Criteria for excluding women with pregnancy, breast-feeding, child-bearing potential and unable/unwilling to use contraceptive methods also need to be checked at TV in addition to SV.
    17 Oct 2019
    The protocol amendment 2 was issued to facilitate subject recruitment as well as to avoid duplication of safety assessments as relevant new safety information was available. It included: -Extension of the subject population to include subjects who developed symptom following labyrinthectomy or vestibular neurectomy as the pathophysiology is the same (acute damage to vestibular nerve with one-sided loss of afferent neurotransmission from the inner ear to the brain). Modification of inclusion and exclusion criteria based on investigator feedback from sites after recruitment start to facilitate a smooth conduct of the study. Removal of two low/intermediate doses (2.5 and 5 mg) in Part A based on favorable safety outcomes in another study (AM 201 CL 18 01) with escalation of exactly the same IMP doses (1 to 20 mg t.i.d.) and the same treatment duration of 4 weeks.
    07 Sep 2020
    The protocol amendment 3 was based on the pre-planned interim analysis following completion of Part A: 10 mg dose was selected as the low dose and the 20 mg dose was selected as the high dose to be tested in Part B. The interim analysis for Part A confirmed the assumptions of the initial sample size calculation. The sample size was therefore not changed and remained 24 patients per treatment arm, 72 patients in total. The VRBQ was added to evaluate important aspects of dizziness impact.
    23 Dec 2021
    The protocol amendment 4 was issued to incorporate result of additional ad-hoc analyses following the completion of Part A. It was concluded that the Tandem Romberg test tends to be more challenging for patients and has a lower likelihood of being affected by a ceiling effect compared to the Standing on Foam test. Also, an efficacy endpoint at 6 weeks following surgery was considered more indicative of lasting improvement than an endpoint after 2 weeks only. Therefore, it was decided to switch the primary and key-secondary endpoints for the final statistical analysis.

    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.
    Limitations that may have affected the results of the primary efficacy endpoint included the small sample size and high placebo response.

    Online references
    http://www.ncbi.nlm.nih.gov/pubmed/37026797
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    The status and protocol content of GB trials is no longer updated since 1 January 2021. For the UK, as of 31 January 2021, EU Law applies only to the territory of Northern Ireland (NI) to the extent foreseen in the Protocol on Ireland/NI. Legal notice
    As of 31 January 2023, all EU/EEA initial clinical trial applications must be submitted through CTIS . Updated EudraCT trials information and information on PIP/Art 46 trials conducted exclusively in third countries continues to be submitted through EudraCT and published on this website.

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