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    Clinical Trial Results:
    A phase II, randomized, double-blind, parallel groups study to assess the efficacy and safety of Nimodipine 20 mg + Betahistine 16 mg versus Placebo + Betahistine 16 mg in the treatment of vertigo

    Summary
    EudraCT number
    2013-005122-33
    Trial protocol
    IT  
    Global end of trial date
    08 Jul 2015

    Results information
    Results version number
    v1(current)
    This version publication date
    20 Dec 2017
    First version publication date
    20 Dec 2017
    Other versions
    Summary report(s)
    Synopsis CSR Nimobet vers. 1 date 16.12.2015

    Trial information

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    Trial identification
    Sponsor protocol code
    NIMOBET-1
    Additional study identifiers
    ISRCTN number
    -
    US NCT number
    -
    WHO universal trial number (UTN)
    -
    Sponsors
    Sponsor organisation name
    MDM S.p.A.
    Sponsor organisation address
    Via Volturno 29/b, Monza, Italy, 20052
    Public contact
    Servizio Segreteria MDM, MDM S.p.A., 0039 039 3909110, mdm@mdmspa.com
    Scientific contact
    Servizio Segreteria MDM, MDM S.p.A., 0039 039 3909110, mdm@mdmspa.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
    16 Dec 2015
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    08 Jul 2015
    Global end of trial reached?
    Yes
    Global end of trial date
    08 Jul 2015
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    To evaluate the efficacy of Nimodipine 20 mg + Betahistine 16 mg (b.i.d) for the treatment of vertigo, compared to Betahistine 16 mg (b.i.d), as assessed by the Dizziness Handicap Inventory (DHI) after 4 weeks of treatment
    Protection of trial subjects
    No specific measure was taken, other than good clinical practice procedures
    Background therapy
    Betahistine dihydrochloride tablet 16 mg, 1 tablet b.i.d.
    Evidence for comparator
    The rationale for using in this study a combination of betahistine and nimodipine in the symptomatic relief of vertigo is derived from their modes of action. A recent retrospective study based on a ten-year experience with two long-term medical protocols prescribed to well defined Menière’s disease patients showed a moderate reduction of the impact of vertigo on quality of life in betahistine-treated patients while a more significant effect was reported in those patients treated with the combination of nimodipine and betahistine. In addition, both protocols (betahistine alone versus betahistine + nimodipine) resulted in a better control of vertigo and postural control, but a greater reduction of frequency of the attacks and larger effects on body sway were obtained with the combination of drugs.
    Actual start date of recruitment
    01 Apr 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
    Italy: 82
    Worldwide total number of subjects
    82
    EEA total number of subjects
    82
    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)
    30
    From 65 to 84 years
    49
    85 years and over
    3

    Subject disposition

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    Recruitment
    Recruitment details
    Prior to performing any trial assessments, the Investigator will ensure that the patient has provided written informed according to the procedure described in the protocol. The first subject signed the informed consent and performed the Visit 1 (Screening Visit) on January 19th, 2015 and the last subject on May 12th, 2015.

    Pre-assignment
    Screening details
    Screening was performed on Visit 1 (Day -7). If eligible, the patients were instructed to discontinue their prestudy vestibular suppressants drugs for a 7 days wash out period. All screened subjects were eligible and entered the study.

    Period 1
    Period 1 title
    Overall trial (overall period)
    Is this the baseline period?
    Yes
    Allocation method
    Randomised - controlled
    Blinding used
    Double blind
    Roles blinded
    Investigator, Subject, Monitor, Data analyst, Carer, Assessor
    Blinding implementation details
    The treatment was provided in kits identified by a random code. The two study treatments (Nimodipine and placebo) were indistiguishable. The Investigator was provided with a set of sealed envelopes to unblind the codes for valid medical or safety reasons.The Investigator had to contact the Sponsor before breaking the blinded code. When the code was unblinded, the reason had to be fully documented on the CRF. The unblinding envelopes were checked for their integrity and returned to the Sponsor.

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    Treatment group A
    Arm description
    Betahistine dihydrochloride tablet (30 tablets, 16 mg) plus Nimodipine drops (ISKIDROP, 25 ml, 30 mg/0.75 ml)
    Arm type
    Experimental

    Investigational medicinal product name
    Nimodipine drops: Iskidrop, 25 ml, 30 mg/0.75 ml
    Investigational medicinal product code
    C08CA06
    Other name
    Pharmaceutical forms
    Oral drops
    Routes of administration
    Oral use
    Dosage and administration details
    20 drops twice a day

    Investigational medicinal product name
    Betahistine dihydrochloride: Betahistine ratiopharm 30 tablets, 16 mg
    Investigational medicinal product code
    N07CA01
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    1 tablet twice a day

    Arm title
    Treatment group B
    Arm description
    Betahistine dihydrochloride tablet (30 tablets, 16 mg) plus Placebo drops (25 ml, 0 mg/0.75 ml)
    Arm type
    Placebo

    Investigational medicinal product name
    Placebo drops: 25 ml, 0 mg/0.75 ml
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Oral drops
    Routes of administration
    Oral use
    Dosage and administration details
    20 drops twice a day

    Investigational medicinal product name
    Betahistine dihydrochloride: Betahistine ratiopharm 30 tablets, 16 mg
    Investigational medicinal product code
    N07CA01
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    1 tablet twice a day

    Number of subjects in period 1
    Treatment group A Treatment group B
    Started
    43
    39
    Completed
    41
    37
    Not completed
    2
    2
         Protocol deviation
    1
    -
         Adverse event, non-fatal
    1
    2

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Treatment group A
    Reporting group description
    Betahistine dihydrochloride tablet (30 tablets, 16 mg) plus Nimodipine drops (ISKIDROP, 25 ml, 30 mg/0.75 ml)

    Reporting group title
    Treatment group B
    Reporting group description
    Betahistine dihydrochloride tablet (30 tablets, 16 mg) plus Placebo drops (25 ml, 0 mg/0.75 ml)

    Reporting group values
    Treatment group A Treatment group B Total
    Number of subjects
    43 39 82
    Age categorical
    Units: Subjects
        Adults (18-64 years)
    14 16 30
        From 65-84 years
    26 23 49
        85 years and over
    3 0 3
    Age continuous
    Age at baseline
    Units: years
        arithmetic mean (standard deviation)
    66.84 ± 12.70 65.64 ± 11.59 -
    Gender categorical
    Gender
    Units: Subjects
        Female
    30 29 59
        Male
    13 10 23
    Vertigo
    Type of vertigo
    Units: Subjects
        Central
    12 10 22
        Mixed
    10 8 18
        Peripheral
    21 21 42

    End points

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    End points reporting groups
    Reporting group title
    Treatment group A
    Reporting group description
    Betahistine dihydrochloride tablet (30 tablets, 16 mg) plus Nimodipine drops (ISKIDROP, 25 ml, 30 mg/0.75 ml)

    Reporting group title
    Treatment group B
    Reporting group description
    Betahistine dihydrochloride tablet (30 tablets, 16 mg) plus Placebo drops (25 ml, 0 mg/0.75 ml)

    Subject analysis set title
    ITT Central A
    Subject analysis set type
    Sub-group analysis
    Subject analysis set description
    ITT patients with central vertigo at screening visit - Treatment group A

    Subject analysis set title
    ITT Central B
    Subject analysis set type
    Sub-group analysis
    Subject analysis set description
    ITT patients with central vertigo at screening visit - Treatment group B

    Subject analysis set title
    ITT Peripheral A
    Subject analysis set type
    Sub-group analysis
    Subject analysis set description
    ITT patients with peripheral vertigo at screening visit - Treatment group A

    Subject analysis set title
    ITT Peripheral B
    Subject analysis set type
    Sub-group analysis
    Subject analysis set description
    ITT patients with peripheral vertigo at screening visit - Treatment group B

    Subject analysis set title
    ITT Mixed A
    Subject analysis set type
    Sub-group analysis
    Subject analysis set description
    ITT patients with mixed vertigo at screening visit - Treatment group A

    Subject analysis set title
    ITT Mixed B
    Subject analysis set type
    Sub-group analysis
    Subject analysis set description
    ITT patients with mixed vertigo at screening visit - Treatment group B

    Subject analysis set title
    ITT Central/Mixed A
    Subject analysis set type
    Sub-group analysis
    Subject analysis set description
    ITT patients with central/mixed vertigo at screening visit - Treatment group A

    Subject analysis set title
    ITT Central/Mixed B
    Subject analysis set type
    Sub-group analysis
    Subject analysis set description
    ITT patients with central/mixed vertigo at screening visit - Treatment group B

    Subject analysis set title
    ITT Women A
    Subject analysis set type
    Sub-group analysis
    Subject analysis set description
    ITT female patients - Treatment group A

    Subject analysis set title
    ITT Women B
    Subject analysis set type
    Sub-group analysis
    Subject analysis set description
    ITT female patients - Treatment group B

    Subject analysis set title
    ITT Men A
    Subject analysis set type
    Sub-group analysis
    Subject analysis set description
    ITT male patients - Treatment group A

    Subject analysis set title
    ITT Men B
    Subject analysis set type
    Sub-group analysis
    Subject analysis set description
    ITT male patients - Treatment group B

    Primary: Improvement of DHI score

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    End point title
    Improvement of DHI score
    End point description
    The changes in DHI score between baseline and end of treatment have been compared between treatment groups
    End point type
    Primary
    End point timeframe
    Between baseline and end of treatment
    End point values
    Treatment group A Treatment group B ITT Central A ITT Central B ITT Peripheral A ITT Peripheral B ITT Mixed A ITT Mixed B ITT Central/Mixed A ITT Central/Mixed B ITT Women A ITT Women B ITT Men A ITT Men B
    Number of subjects analysed
    41
    37
    11
    9
    20
    20
    10
    8
    21
    17
    29
    27
    12
    10
    Units: points
        arithmetic mean (standard deviation)
    14.05 ± 10.40
    13.41 ± 9.81
    14.73 ± 10.52
    11.33 ± 6.00
    13.20 ± 10.89
    13.30 ± 12.14
    15.00 ± 10.21
    16.00 ± 6.32
    14.86 ± 10.11
    13.53 ± 6.42
    13.38 ± 10.57
    14.00 ± 10.17
    15.67 ± 10.23
    11.80 ± 9.07
    Statistical analysis title
    ANOVA on DHI improvement (ITT population)
    Statistical analysis description
    ANOVA model with factor for treatment on ITT population
    Comparison groups
    Treatment group B v Treatment group A
    Number of subjects included in analysis
    78
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.78 [1]
    Method
    ANOVA
    Parameter type
    Mean difference (final values)
    Point estimate
    0.64
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -3.93
         upper limit
    5.21
    Notes
    [1] - The difference between treatment groups was not statistically significant
    Statistical analysis title
    ANCOVA on DHI improvement (ITT population)
    Statistical analysis description
    ANCOVA model with factors for treatment and baseline values on ITT population
    Comparison groups
    Treatment group A v Treatment group B
    Number of subjects included in analysis
    78
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.843 [2]
    Method
    ANCOVA
    Parameter type
    Mean difference (final values)
    Point estimate
    0.46
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -4.13
         upper limit
    5.04
    Notes
    [2] - The difference between treatment groups was not statistically significant
    Statistical analysis title
    ANOVA on DHI improvement (Central Vertigo)
    Statistical analysis description
    ANOVA model with factor for treatment on patients with central vertigo
    Comparison groups
    ITT Central A v ITT Central B
    Number of subjects included in analysis
    20
    Analysis specification
    Post-hoc
    Analysis type
    superiority
    P-value
    = 0.402 [3]
    Method
    ANOVA
    Parameter type
    Mean difference (final values)
    Point estimate
    3.39
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -4.92
         upper limit
    11.7
    Notes
    [3] - The difference between treatment groups was not statistically significant
    Statistical analysis title
    ANOVA on DHI improvement (Peripheral Vertigo)
    Statistical analysis description
    ANOVA model with factor for treatment on patients with peripheral vertigo
    Comparison groups
    ITT Peripheral B v ITT Peripheral A
    Number of subjects included in analysis
    40
    Analysis specification
    Post-hoc
    Analysis type
    superiority
    P-value
    = 0.978 [4]
    Method
    ANOVA
    Parameter type
    Mean difference (final values)
    Point estimate
    -0.1
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -7.48
         upper limit
    7.28
    Notes
    [4] - The difference between treatment groups was not statistically significant
    Statistical analysis title
    ANOVA on DHI improvement (Mixed Vertigo)
    Statistical analysis description
    ANOVA model with factor for treatment on patients with mixed vertigo
    Comparison groups
    ITT Mixed A v ITT Mixed B
    Number of subjects included in analysis
    18
    Analysis specification
    Post-hoc
    Analysis type
    superiority
    P-value
    = 0.812 [5]
    Method
    ANOVA
    Parameter type
    Mean difference (final values)
    Point estimate
    -1
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -9.77
         upper limit
    7.77
    Notes
    [5] - The difference between treatment groups was not statistically significant
    Statistical analysis title
    ANOVA on DHI improvement (Central/Mixed Vertigo)
    Statistical analysis description
    ANOVA model with factor for treatment on patients with central or mixed vertigo
    Comparison groups
    ITT Central/Mixed A v ITT Central/Mixed B
    Number of subjects included in analysis
    38
    Analysis specification
    Post-hoc
    Analysis type
    superiority
    P-value
    = 0.642 [6]
    Method
    ANOVA
    Parameter type
    Mean difference (final values)
    Point estimate
    1.33
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -4.41
         upper limit
    7.06
    Notes
    [6] - The difference between treatment groups was not statistically significant
    Statistical analysis title
    ANOVA on DHI improvement (Women)
    Statistical analysis description
    ANOVA model with factor for treatment on female patients
    Comparison groups
    ITT Women B v ITT Women A
    Number of subjects included in analysis
    56
    Analysis specification
    Post-hoc
    Analysis type
    superiority
    P-value
    = 0.824 [7]
    Method
    ANOVA
    Parameter type
    Mean difference (final values)
    Point estimate
    -0.62
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -6.19
         upper limit
    4.94
    Notes
    [7] - The difference between treatment groups was not statistically significant
    Statistical analysis title
    ANOVA on DHI improvement (Men)
    Statistical analysis description
    ANOVA model with factor for treatment on male patients
    Comparison groups
    ITT Men A v ITT Men B
    Number of subjects included in analysis
    22
    Analysis specification
    Post-hoc
    Analysis type
    superiority
    P-value
    = 0.364 [8]
    Method
    ANOVA
    Parameter type
    Mean difference (final values)
    Point estimate
    3.87
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -4.82
         upper limit
    12.55
    Notes
    [8] - The difference between treatment groups was not statistically significant

    Secondary: Improvement of MVS score

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    End point title
    Improvement of MVS score
    End point description
    The changes in MVS score between baseline and end of treatment have been compared between treatment groups
    End point type
    Secondary
    End point timeframe
    Between baseline and end of treatment
    End point values
    Treatment group A Treatment group B ITT Central A ITT Central B ITT Peripheral A ITT Peripheral B ITT Mixed A ITT Mixed B ITT Central/Mixed A ITT Central/Mixed B
    Number of subjects analysed
    41
    37
    11
    9
    20
    20
    10
    8
    21
    17
    Units: points
        arithmetic mean (standard deviation)
    2.61 ± 1.79
    2.32 ± 1.94
    2.09 ± 1.38
    1.56 ± 1.24
    2.60 ± 1.82
    2.60 ± 2.26
    3.20 ± 2.10
    2.50 ± 1.69
    2.62 ± 1.80
    2.00 ± 1.50
    Statistical analysis title
    ANOVA on MVS improvement (ITT population)
    Statistical analysis description
    ANOVA model with factor for treatment
    Comparison groups
    Treatment group A v Treatment group B
    Number of subjects included in analysis
    78
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.501
    Method
    ANOVA
    Parameter type
    Mean difference (final values)
    Point estimate
    0.29
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -0.56
         upper limit
    1.13
    Statistical analysis title
    ANOVA on MVS improvement (Central Vertigo)
    Statistical analysis description
    ANOVA model with factor for treatment on patients with central vertigo
    Comparison groups
    ITT Central A v ITT Central B
    Number of subjects included in analysis
    20
    Analysis specification
    Post-hoc
    Analysis type
    superiority
    P-value
    = 0.377 [9]
    Method
    ANOVA
    Parameter type
    Mean difference (final values)
    Point estimate
    0.54
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -0.71
         upper limit
    1.78
    Notes
    [9] - The difference between treatment groups was not statistically significant
    Statistical analysis title
    ANOVA on MVS improvement (Peripheral Vertigo)
    Statistical analysis description
    ANOVA model with factor for treatment on patients with peripheral vertigo
    Comparison groups
    ITT Peripheral A v ITT Peripheral B
    Number of subjects included in analysis
    40
    Analysis specification
    Post-hoc
    Analysis type
    superiority
    P-value
    = 1 [10]
    Method
    ANOVA
    Parameter type
    Mean difference (final values)
    Point estimate
    0
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -1.31
         upper limit
    1.31
    Notes
    [10] - The difference between treatment groups was not statistically significant
    Statistical analysis title
    ANOVA on MVS improvement (Mixed Vertigo)
    Statistical analysis description
    ANOVA model with factor for treatment on patients with mixed vertigo
    Comparison groups
    ITT Mixed A v ITT Mixed B
    Number of subjects included in analysis
    18
    Analysis specification
    Post-hoc
    Analysis type
    superiority
    P-value
    = 0.456 [11]
    Method
    ANOVA
    Parameter type
    Mean difference (final values)
    Point estimate
    0.7
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -1.24
         upper limit
    2.64
    Notes
    [11] - The difference between treatment groups was not statistically significant
    Statistical analysis title
    ANOVA on MVS improvement (Central/Mixed Vertigo)
    Statistical analysis description
    ANOVA model with factor for treatment on patients with central or mixed vertigo
    Comparison groups
    ITT Central/Mixed A v ITT Central/Mixed B
    Number of subjects included in analysis
    38
    Analysis specification
    Post-hoc
    Analysis type
    superiority
    P-value
    = 0.265 [12]
    Method
    ANOVA
    Parameter type
    Mean difference (final values)
    Point estimate
    0.62
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -0.49
         upper limit
    1.73
    Notes
    [12] - The difference between treatment groups was not statistically significant

    Secondary: Improvement of PCS-12 score

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    End point title
    Improvement of PCS-12 score
    End point description
    The changes in PCS-12 score (SF-12) between baseline and end of treatment have been compared between treatment groups
    End point type
    Secondary
    End point timeframe
    Between baseline and end of treatment
    End point values
    Treatment group A Treatment group B ITT Central A ITT Central B ITT Peripheral A ITT Peripheral B ITT Mixed A ITT Mixed B ITT Central/Mixed A ITT Central/Mixed B
    Number of subjects analysed
    41
    37
    11
    9
    20
    20
    10
    8
    21
    17
    Units: Points
        arithmetic mean (standard deviation)
    2.49 ± 4.61
    1.97 ± 4.76
    2.86 ± 4.59
    2.09 ± 4.29
    2.32 ± 4.02
    1.97 ± 5.18
    2.42 ± 6.04
    1.82 ± 4.75
    2.65 ± 5.19
    1.97 ± 4.37
    Statistical analysis title
    ANOVA on PCS-12 (ITT Population)
    Statistical analysis description
    ANOVA model with factor for treatment on ITT patients
    Comparison groups
    Treatment group B v Treatment group A
    Number of subjects included in analysis
    78
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.625 [13]
    Method
    ANOVA
    Parameter type
    Mean difference (final values)
    Point estimate
    0.52
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -1.59
         upper limit
    2.63
    Notes
    [13] - The difference between treatment groups was not statistically significant
    Statistical analysis title
    ANOVA on PCS-12 (Central Vertigo)
    Statistical analysis description
    ANOVA model with factor for treatment on patients with central vertigo
    Comparison groups
    ITT Central A v ITT Central B
    Number of subjects included in analysis
    20
    Analysis specification
    Post-hoc
    Analysis type
    superiority
    P-value
    = 0.704
    Method
    ANOVA
    Parameter type
    Mean difference (final values)
    Point estimate
    0.77
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -3.44
         upper limit
    4.98
    Statistical analysis title
    ANOVA on PCS-12 (Peripheral Vertigo)
    Statistical analysis description
    ANOVA model with factor for treatment on patients with peripheral vertigo
    Comparison groups
    ITT Peripheral A v ITT Peripheral B
    Number of subjects included in analysis
    40
    Analysis specification
    Post-hoc
    Analysis type
    superiority
    P-value
    = 0.815
    Method
    ANOVA
    Parameter type
    Mean difference (final values)
    Point estimate
    0.35
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -2.62
         upper limit
    3.32
    Statistical analysis title
    ANOVA on PCS-12 (Mixed Vertigo)
    Statistical analysis description
    ANOVA model with factor for treatment on patients with mixed vertigo
    Comparison groups
    ITT Mixed A v ITT Mixed B
    Number of subjects included in analysis
    18
    Analysis specification
    Post-hoc
    Analysis type
    superiority
    P-value
    = 0.822
    Method
    ANOVA
    Parameter type
    Mean difference (final values)
    Point estimate
    0.6
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -4.95
         upper limit
    6.14
    Statistical analysis title
    ANOVA on PCS-12 (Central/Mixed Vertigo)
    Statistical analysis description
    ANOVA model with factor for treatment on patients with central or mixed vertigo
    Comparison groups
    ITT Central/Mixed A v ITT Central/Mixed B
    Number of subjects included in analysis
    38
    Analysis specification
    Post-hoc
    Analysis type
    superiority
    P-value
    = 0.666
    Method
    ANOVA
    Parameter type
    Mean difference (final values)
    Point estimate
    0.69
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -2.52
         upper limit
    3.89

    Secondary: Improvement of MCS-12 score

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    End point title
    Improvement of MCS-12 score
    End point description
    The changes in MCS-12 score (SF-12) between baseline and end of treatment have been compared between treatment groups
    End point type
    Secondary
    End point timeframe
    Between baseline and end of treatment
    End point values
    Treatment group A Treatment group B ITT Central A ITT Central B ITT Peripheral A ITT Peripheral B ITT Mixed A ITT Mixed B ITT Central/Mixed A ITT Central/Mixed B
    Number of subjects analysed
    41
    37
    11
    9
    20
    20
    10
    8
    21
    17
    Units: POINTS
        arithmetic mean (standard deviation)
    4.52 ± 9.57
    4.00 ± 6.18
    2.70 ± 6.77
    2.91 ± 4.74
    4.96 ± 12.09
    3.00 ± 4.76
    5.64 ± 6.45
    7.71 ± 9.43
    4.10 ± 6.63
    5.17 ± 7.50
    Statistical analysis title
    ANOVA on MCS-12 (ITT Population)
    Statistical analysis description
    ANOVA model with factor for treatment on ITT population
    Comparison groups
    Treatment group A v Treatment group B
    Number of subjects included in analysis
    78
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.778
    Method
    ANOVA
    Parameter type
    Mean difference (final values)
    Point estimate
    0.52
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -3.15
         upper limit
    4.2
    Statistical analysis title
    ANOVA on MCS-12 (Central Vertigo)
    Statistical analysis description
    ANOVA model with factor for treatment on patients with central vertigo
    Comparison groups
    ITT Central A v ITT Central B
    Number of subjects included in analysis
    20
    Analysis specification
    Post-hoc
    Analysis type
    superiority
    P-value
    = 0.937
    Method
    ANOVA
    Parameter type
    Mean difference (final values)
    Point estimate
    -0.21
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -5.84
         upper limit
    5.41
    Statistical analysis title
    ANOVA on MCS-12 (Peripheral Vertigo)
    Statistical analysis description
    ANOVA model with factor for treatment on patients with peripheral vertigo
    Comparison groups
    ITT Peripheral A v ITT Peripheral B
    Number of subjects included in analysis
    40
    Analysis specification
    Post-hoc
    Analysis type
    superiority
    P-value
    = 0.504
    Method
    ANOVA
    Parameter type
    Mean difference (final values)
    Point estimate
    1.96
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -3.92
         upper limit
    7.84
    Statistical analysis title
    ANOVA on MCS-12 (Mixed Vertigo)
    Statistical analysis description
    ANOVA model with factor for treatment on patients with mixed vertigo
    Comparison groups
    ITT Mixed A v ITT Mixed B
    Number of subjects included in analysis
    18
    Analysis specification
    Post-hoc
    Analysis type
    superiority
    P-value
    = 0.589
    Method
    ANOVA
    Parameter type
    Mean difference (final values)
    Point estimate
    -2.07
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -10
         upper limit
    5.87
    Statistical analysis title
    ANOVA on MCS-12 (Central/Mixed Vertigo)
    Statistical analysis description
    ANOVA model with factor for treatment on patients with central or mixed vertigo
    Comparison groups
    ITT Central/Mixed A v ITT Central/Mixed B
    Number of subjects included in analysis
    38
    Analysis specification
    Post-hoc
    Analysis type
    superiority
    P-value
    = 0.644
    Method
    ANOVA
    Parameter type
    Mean difference (final values)
    Point estimate
    -1.07
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -5.72
         upper limit
    3.58

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    The reporting period for AEs is the period starting from the time of the first dose taken and lasting until Visit 6. At the end of this follow-up period, all unresolved AEs will be documented on the CRF as “ongoing”.
    Assessment type
    Non-systematic
    Dictionary used for adverse event reporting
    Dictionary name
    MedDRA
    Dictionary version
    18.0
    Reporting groups
    Reporting group title
    Treatment group A
    Reporting group description
    Betahistine dihydrochloride tablet (30 tablets, 16 mg) plus Nimodipine drops (ISKIDROP, 25 ml, 30 mg/0.75 ml) Posology: 1 tablet plus 20 drops, twice in day.

    Reporting group title
    Treatment group B
    Reporting group description
    Betahistine dihydrochloride tablet (30 tablets, 16 mg) plus Placebo drops (25 ml, 0 mg/0.75 ml). Posology: 1 tablet plus 20 drops, twice in day.

    Serious adverse events
    Treatment group A Treatment group B
    Total subjects affected by serious adverse events
         subjects affected / exposed
    0 / 43 (0.00%)
    0 / 39 (0.00%)
         number of deaths (all causes)
    0
    0
         number of deaths resulting from adverse events
    0
    0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    Treatment group A Treatment group B
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    1 / 43 (2.33%)
    2 / 39 (5.13%)
    Gastrointestinal disorders
    Nausea
         subjects affected / exposed
    1 / 43 (2.33%)
    1 / 39 (2.56%)
         occurrences all number
    1
    1
    Skin and subcutaneous tissue disorders
    Wheals
         subjects affected / exposed
    1 / 43 (2.33%)
    0 / 39 (0.00%)
         occurrences all number
    1
    0

    More information

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    Substantial protocol amendments (globally)

    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    24 Feb 2014
    As a result of requests made by the Ethics Committee during the initial evaluation, some changes to protocol version no. 1 have been introduced. This has resulted in a new version of the protocol (version no. 2) and related documents. The present Amendment is intended to harmonize the documents submitted to AIFA with those requested and approved by the Ethics Committee. The requests for changes / additions made by the Ethics Committee have resulted in a new version of the following documents:1) Study Protocol; 2) Synopsis 3) CTA Form 4) Information sheet and Informed Consent Form. The main changes made to the concerned protocol were as follows: 1) In the eligibility criteria, the differential diagnosis of vertigo was better specified; 2) A new exclusion criterion was introduced: patients with hypertension; 3) In the study design an additional visit during the treatment phase (on day 14) was added, in order to better monitor the patients’ safety. We finally took the opportunity to make some "Errata Corrige” to the initial text.
    30 Sep 2014
    The current exclusion criterion n. 1 provides for patients not be included in the study if affected by cerebellopontine lesions, multiple sclerosis, vascular dementia, migraine associated vertigo, phobic vertigo, motion sickness, acoustic neuroma or other CNS tumor, as documented by CT or MRI performed within 3 months of the screening visit. However, since patients who will be included in the study are already being treated for a long time at the center and their health conditions are well known to the Investigator and are periodically re-checked, it is considered sufficient that the exclusion criterion is verified by the Investigator on the basis of a previous instrumental examination (brain CT or MRI) and of the patient's medical history and any changes in the patient’s health over time, since he/she is being treated at the center. The eligibility of the patient will be assessed by the Investigator, based also on a previous brain CT or MRI, although not necessarily carried out in the 3 months prior to the start of the study. For these reasons it is considered appropriate to remove the time limit of 3 months for the acceptability of cerebral CT or MRI, from the first exclusion criterion. We finally took the opportunity to update the period of the study, as communicated to the Ethical Committee with letter dated 23/07/2014, and to correct the investigator phone number indicated in the Information sheet and Informed Consent Form.

    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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