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    Clinical Trial Results:
    A randomized, double-blind, placebo-controlled, parallel group study to determine the efficacy, the duration of action, and safety of latanoprost in patients with Menière’s disease

    Summary
    EudraCT number
    		 2013-002261-18
    Trial protocol
    		 SE  
    Global end of trial date
    28 Apr 2016

    Results information
    Results version number
    		 v1(current)
    This version publication date
    19 May 2017
    First version publication date
    19 May 2017
    Other versions

    Trial information

    		 Close Top of page
    Trial identification
    Sponsor protocol code
    M05-2013
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT01973114
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    Synphora AB
    Sponsor organisation address
    c/o Kajsa Lönroth Brotorpsvägen 11, Sundbyberg, Sweden, 174 41
    Public contact
    Chief Executive Officer, Synphora AB, +46 703253847, fredrik.henell@synphora.com
    Scientific contact
    Chief Executive Officer, Synphora AB, +46 703253847, fredrik.henell@synphora.com
    Paediatric regulatory details
    Is trial part of an agreed paediatric investigation plan (PIP)
    No
    Does article 45 of REGULATION (EC) No 1901/2006 apply to this trial?
    No
    Does article 46 of REGULATION (EC) No 1901/2006 apply to this trial?
    No
    Results analysis stage
    Analysis stage
    Final
    Date of interim/final analysis
    23 Jun 2016
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    28 Apr 2016
    Global end of trial reached?
    Yes
    Global end of trial date
    28 Apr 2016
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    The primary objective is to determine the efficacy and duration of action of latanoprost as treatment of Menière’s disease
    Protection of trial subjects
    Patients were observered in the clinics during the study visits. Physical examination was performed at screening. Vital signs were taken at screening, baseline and end of study. Adverse events were registered from baseline until the last visit. Concomitant medications were collected and reviewed throughout the study.
    Background therapy
    		 -
    Evidence for comparator
    		 -
    Actual start date of recruitment
    19 Aug 2013
    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
    Sweden: 100
    Worldwide total number of subjects
    100
    EEA total number of subjects
    100
    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)
    73
    From 65 to 84 years
    27
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 Patients were recruited at 12 centers across Sweden. Patients with definite unilateral Menière’s disease with an active vertigo component were included in the study. First patient in was 16 October 2013 and last patient last visit was 28 April 2016.

    Pre-assignment
    Screening details
    		 The study population was adults aged 18 or above with definite unilateral Menière’s disease. Patients had to have a reduction in hearing. Furthermore patients had to have experience of vertigo attacks and tinnitus during the last three months. A 4-6 weeks run-in period was used in order to obtain accurate baseline values.

    Pre-assignment period milestones
    Number of subjects started
    		 249 [1]
    Number of subjects completed
    		 100

    Pre-assignment subject non-completion reasons
    Reason: Number of subjects
    		 Patient's non-compliance/ protocol violation: 3
    Reason: Number of subjects
    		 Protocol deviation: 9
    Reason: Number of subjects
    		 Lost to follow-up: 1
    Reason: Number of subjects
    		 Inclusion criteria not met: 136
    Notes
    [1] - The number of subjects reported to have started the pre-assignment period are not the same as the worldwide number enrolled in the trial. It is expected that these numbers will be the same.
    Justification: Denotes the number of patients (249) entering the screening/run-in period. Of these 249 patients 100 were enrolled/randomized to receive treatment.
    Period 1
    Period 1 title
    Outcome of randomization
    Is this the baseline period?
    		 Yes
    Allocation method
    Randomised - controlled
    Blinding used
    		 Double blind
    Roles blinded
    		 Subject, Investigator, Monitor, Data analyst, Carer, Assessor

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Latanoprost 1 injection
    Arm description
    		 In this arm patients were randomized to one injection of latanoprost.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Latanoprost
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for injection
    Routes of administration
    Intratympanic use
    Dosage and administration details
    The study drug contained 0.005% latanoprost (13,14-dihydro-17-phenyl-18,19,20-trinor-PGF2α-isopropyl ester) dissolved in phosphate buffered saline. The dose was 0.4-1.0 ml.

    Arm title
    		 Placebo 1 injection
    Arm description
    		 In this arm patients were randomized to one injection of placebo.
    Arm type
    		 Placebo

    Investigational medicinal product name
    Placebo
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for injection
    Routes of administration
    Intratympanic use
    Dosage and administration details
    The placebo consisted of phosphate buffered saline. The dose was 0.4-1.0 ml.

    Arm title
    		 Latanoprost 3 injections
    Arm description
    		 In this arm patients were randomized to three injections of latanoprost.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Latanoprost
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for injection
    Routes of administration
    Intratympanic use
    Dosage and administration details
    The study drug contained 0.005% latanoprost (13,14-dihydro-17-phenyl-18,19,20-trinor-PGF2α-isopropyl ester) dissolved in phosphate buffered saline. The daily dose was 0.4-1.0 ml.

    Arm title
    		 Placebo 3 injections
    Arm description
    		 In this arm patients were randomized to three injections of placebo.
    Arm type
    		 Placebo

    Investigational medicinal product name
    Placebo
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for injection
    Routes of administration
    Intratympanic use
    Dosage and administration details
    The placebo consisted of phosphate buffered saline. The daily dose was 0.4-1.0 ml.

    Number of subjects in period 1
    		Latanoprost 1 injection Placebo 1 injection Latanoprost 3 injections Placebo 3 injections
    Started
    24
    12
    42
    22
    Completed
    24
    12
    42
    22
    Period 2
    Period 2 title
    Treatment
    Is this the baseline period?
    		 No
    Allocation method
    Randomised - controlled
    Blinding used
    		 Double blind
    Roles blinded
    		 Subject, Investigator, Monitor, Data analyst, Carer, Assessor

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Latanoprost 1 injection
    Arm description
    		 In this arm patients were randomized to one injection of latanoprost.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Latanoprost
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for injection
    Routes of administration
    Intratympanic use
    Dosage and administration details
    The study drug contained 0.005% latanoprost (13,14-dihydro-17-phenyl-18,19,20-trinor-PGF2α-isopropyl ester) dissolved in phosphate buffered saline. The dose was 0.4-1.0 ml.

    Arm title
    		 Placebo 1 injection
    Arm description
    		 In this arm patients were randomized to one injection of placebo.
    Arm type
    		 Placebo

    Investigational medicinal product name
    Placebo
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for injection
    Routes of administration
    Intratympanic use
    Dosage and administration details
    The placebo consisted of phosphate buffered saline. The dose was 0.4-1.0 ml.

    Arm title
    		 Latanoprost 3 injections
    Arm description
    		 In this arm patients were randomized to three injections of latanoprost.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Latanoprost
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for injection
    Routes of administration
    Intratympanic use
    Dosage and administration details
    The study drug contained 0.005% latanoprost (13,14-dihydro-17-phenyl-18,19,20-trinor-PGF2α-isopropyl ester) dissolved in phosphate buffered saline. The daily dose was 0.4-1.0 ml.

    Arm title
    		 Placebo 3 injections
    Arm description
    		 In this arm patients were randomized to three injections of placebo.
    Arm type
    		 Placebo

    Investigational medicinal product name
    Placebo
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Solution for injection
    Routes of administration
    Intratympanic use
    Dosage and administration details
    The placebo consisted of phosphate buffered saline. The daily dose was 0.4-1.0 ml.

    Number of subjects in period 2
    		Latanoprost 1 injection Placebo 1 injection Latanoprost 3 injections Placebo 3 injections
    Started
    24
    12
    42
    22
    Completed
    20
    11
    41
    21
    Not completed
    4
    1
    1
    1
         Consent withdrawn by subject
    2
    -
    -
    -
         Plastic ear tube inserted
    -
    -
    1
    -
         Wrong intervals
    2
    -
    -
    -
         Adverse event, non-fatal
    -
    1
    -
    -
         investigator:s failure
    -
    -
    -
    1

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Latanoprost 1 injection
    Reporting group description
    		 In this arm patients were randomized to one injection of latanoprost.

    Reporting group title
    Placebo 1 injection
    Reporting group description
    		 In this arm patients were randomized to one injection of placebo.

    Reporting group title
    Latanoprost 3 injections
    Reporting group description
    		 In this arm patients were randomized to three injections of latanoprost.

    Reporting group title
    Placebo 3 injections
    Reporting group description
    		 In this arm patients were randomized to three injections of placebo.

    Reporting group values
    		 Latanoprost 1 injection Placebo 1 injection Latanoprost 3 injections Placebo 3 injections Total
    Number of subjects
    		 24 12 42 22 100
    Age categorical
    Units: Subjects
        In utero
    		 0 0 0 0 0
        Preterm newborn infants (gestational age < 37 wks)
    		 0 0 0 0 0
        Newborns (0-27 days)
    		 0 0 0 0 0
        Infants and toddlers (28 days-23 months)
    		 0 0 0 0 0
        Children (2-11 years)
    		 0 0 0 0 0
        Adolescents (12-17 years)
    		 0 0 0 0 0
        Adults (18-64 years)
    		 18 11 27 17 73
        From 65-84 years
    		 6 1 15 5 27
        85 years and over
    		 0 0 0 0 0
    Age continuous
    Units: years
        arithmetic mean (standard deviation)
    		 58.4 ± 7.72 47.9 ± 13.28 59.2 ± 12.61 53.5 ± 13.05 -
    Gender categorical
    Units: Subjects
        Female
    		 9 4 14 11 38
        Male
    		 15 8 28 11 62
    Subject analysis sets

    Subject analysis set title
    Latanoprost 1 or 3 injections
    Subject analysis set type
    		 Full analysis
    Subject analysis set description
    Patients receiving 1 injection of Latanoprost or 3 injections of Latanoprost

    Subject analysis set title
    Placebo 1 or 3 injections
    Subject analysis set type
    		 Full analysis
    Subject analysis set description
    Patients receiving 1 injection of Placebo or 3 injections of Placebo

    Subject analysis sets values
    		 Latanoprost 1 or 3 injections Placebo 1 or 3 injections
    Number of subjects
    66
    34
    Age categorical
    Units: Subjects
        In utero
    0
    0
        Preterm newborn infants (gestational age < 37 wks)
    0
    0
        Newborns (0-27 days)
    0
    0
        Infants and toddlers (28 days-23 months)
    0
    0
        Children (2-11 years)
    0
    0
        Adolescents (12-17 years)
    0
    0
        Adults (18-64 years)
    45
    28
        From 65-84 years
    21
    6
        85 years and over
    0
    0
    Age continuous
    Units: years
        arithmetic mean (standard deviation)
    58.9 ± 11.02
    51.5 ± 13.21
    Gender categorical
    Units: Subjects
        Female
    23
    15
        Male
    43
    19

    End points

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    End points reporting groups
    Reporting group title
    Latanoprost 1 injection
    Reporting group description
    		 In this arm patients were randomized to one injection of latanoprost.

    Reporting group title
    Placebo 1 injection
    Reporting group description
    		 In this arm patients were randomized to one injection of placebo.

    Reporting group title
    Latanoprost 3 injections
    Reporting group description
    		 In this arm patients were randomized to three injections of latanoprost.

    Reporting group title
    Placebo 3 injections
    Reporting group description
    		 In this arm patients were randomized to three injections of placebo.
    Reporting group title
    Latanoprost 1 injection
    Reporting group description
    		 In this arm patients were randomized to one injection of latanoprost.

    Reporting group title
    Placebo 1 injection
    Reporting group description
    		 In this arm patients were randomized to one injection of placebo.

    Reporting group title
    Latanoprost 3 injections
    Reporting group description
    		 In this arm patients were randomized to three injections of latanoprost.

    Reporting group title
    Placebo 3 injections
    Reporting group description
    		 In this arm patients were randomized to three injections of placebo.

    Subject analysis set title
    Latanoprost 1 or 3 injections
    Subject analysis set type
    		 Full analysis
    Subject analysis set description
    Patients receiving 1 injection of Latanoprost or 3 injections of Latanoprost

    Subject analysis set title
    Placebo 1 or 3 injections
    Subject analysis set type
    		 Full analysis
    Subject analysis set description
    Patients receiving 1 injection of Placebo or 3 injections of Placebo

    Primary: Speech discrimination in noise Visit 3

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    End point title
    		 Speech discrimination in noise Visit 3
    End point description
    Change in speech discrimination in noise (ISO 8253-3) from Baseline (Day 1) to Day 14. At Baseline (Visit 2a/Day 1) speech discrimination in noise was measured (50 Swedish PB words) using a speech weighted noise, S/N = 4, where the signal is adjusted to each patient’s most comfortable level. This signal level is to be applied at all subsequent measurements. The endpoint is measured in percentage (%). A positive score in change from baseline means an improvement in hearing.
    End point type
    Primary
    End point timeframe
    Day 14 compared to Baseline (Day 1)
    End point values
    		 Latanoprost 1 or 3 injections Placebo 1 or 3 injections
    Number of subjects analysed
    66
    34
    Units: percentage
        arithmetic mean (standard deviation)
    2.7 ± 13.94
    1.4 ± 12.12
    Statistical analysis title
    		 Change in speech discrimination in noise
    Statistical analysis description
    Change in speech discrimination in noise from baseline (Day 1) to Day 14. A positive score in change from baseline means an improvement in hearing.
    Comparison groups
    Latanoprost 1 or 3 injections v Placebo 1 or 3 injections
    Number of subjects included in analysis
    100
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [1]
    P-value
    		 = 0.8829
    Method
    		 Mixed models analysis
    Parameter type
    		 Mean difference (final values)
    Point estimate
    0.363
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -4.524
         upper limit
    		 5.25
    Notes
    [1] - The analysis performs a weighted comparison of Latanoprost 1 injection and Latanoprost 3 injections compared to Placebo 1 injection and Placebo 3 injections. The weight are proportional to the number patients in the respective group at Day 14.

    Secondary: Speech discrimination in noise Visit 4

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    End point title
    		 Speech discrimination in noise Visit 4
    End point description
    End point type
    Secondary
    End point timeframe
    Day 28 compared to Baseline (Day 1)
    End point values
    		 Latanoprost 1 or 3 injections Placebo 1 or 3 injections
    Number of subjects analysed
    59
    33
    Units: percentage
        arithmetic mean (standard deviation)
    1.8 ± 17.38
    5.21 ± 12.34
    Statistical analysis title
    		 Change in speech discrimination in noise
    Statistical analysis description
    Change in speech discrimination in noise from baseline (Day 1) to Day 28. A positive score in change from baseline means an improvement in hearing.
    Comparison groups
    Latanoprost 1 or 3 injections v Placebo 1 or 3 injections
    Number of subjects included in analysis
    92
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.2652
    Method
    		 Mixed models analysis
    Parameter type
    		 Mean difference (final values)
    Point estimate
    -3.446
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -9.562
         upper limit
    		 2.669

    Secondary: Speech discrimination in noise Visit 5

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    End point title
    		 Speech discrimination in noise Visit 5
    End point description
    A positive score in change from baseline means an improvement in hearing.
    End point type
    Secondary
    End point timeframe
    Day 42 compared to Baseline (Day 1)
    End point values
    		 Latanoprost 1 or 3 injections Placebo 1 or 3 injections
    Number of subjects analysed
    62
    29
    Units: percentage
        arithmetic mean (standard deviation)
    4.21 ± 18.92
    6.48 ± 12.59
    Statistical analysis title
    		 Change in speech discrimination in noise
    Statistical analysis description
    Change in speech discrimination in noise from baseline (Day 1) to Day 42. A positive score in change from baseline means an improvement in hearing.
    Comparison groups
    Latanoprost 1 or 3 injections v Placebo 1 or 3 injections
    Number of subjects included in analysis
    91
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [2]
    P-value
    		 = 0.3547
    Method
    		 Mixed models analysis
    Parameter type
    		 Mean difference (final values)
    Point estimate
    -3.106
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -9.75
         upper limit
    		 3.538
    Notes
    [2] - The analysis performs a weighted comparison of Latanoprost 1 injection and Latanoprost 3 injections compared to Placebo 1 injection and Placebo 3 injections. The weight are proportional to the number patients in the respective group at Day 14

    Secondary: Speech discrimination in noise Visit 6

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    End point title
    		 Speech discrimination in noise Visit 6
    End point description
    A positive score in change from baseline means an improvement in hearing.
    End point type
    Secondary
    End point timeframe
    Day 56 compared to Baseline (Day 1)
    End point values
    		 Latanoprost 1 or 3 injections Placebo 1 or 3 injections
    Number of subjects analysed
    60
    31
    Units: percentage
        arithmetic mean (standard deviation)
    3.02 ± 17.52
    7.45 ± 13.57
    Statistical analysis title
    		 Change in speech discrimination in noise
    Statistical analysis description
    Change in speech discrimination in noise from baseline (Day 1) to Day 56. A positive score in change from baseline means an improvement in hearing.
    Comparison groups
    Latanoprost 1 or 3 injections v Placebo 1 or 3 injections
    Number of subjects included in analysis
    91
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [3]
    P-value
    		 = 0.1423
    Method
    		 Mixed models analysis
    Parameter type
    		 Mean difference (final values)
    Point estimate
    -5.025
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -11.77
         upper limit
    		 1.724
    Notes
    [3] - The analysis performs a weighted comparison of Latanoprost 1 injection and Latanoprost 3 injections compared to Placebo 1 injection and Placebo 3 injections. The weight are proportional to the number patients in the respective group at Day 14

    Secondary: Speech discrimination in noise Visit 7

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    End point title
    		 Speech discrimination in noise Visit 7
    End point description
    A positive score in change from baseline means an improvement in hearing.
    End point type
    Secondary
    End point timeframe
    Day 84 compared to Baseline (Day 1)
    End point values
    		 Latanoprost 1 or 3 injections Placebo 1 or 3 injections
    Number of subjects analysed
    63
    33
    Units: percentage
        arithmetic mean (standard deviation)
    4.84 ± 21.05
    9.67 ± 13.23
    Statistical analysis title
    		 Change in speech discrimination in noise
    Statistical analysis description
    Change in speech discrimination in noise from baseline (Day 1) to Day 84. A positive score in change from baseline means an improvement in hearing.
    Comparison groups
    Latanoprost 1 or 3 injections v Placebo 1 or 3 injections
    Number of subjects included in analysis
    96
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [4]
    P-value
    		 = 0.1369
    Method
    		 Mixed models analysis
    Parameter type
    		 Mean difference (final values)
    Point estimate
    -5.442
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -12.65
         upper limit
    		 1.766
    Notes
    [4] - The analysis performs a weighted comparison of Latanoprost 1 injection and Latanoprost 3 injections compared to Placebo 1 injection and Placebo 3 injections. The weight are proportional to the number patients in the respective group at Day 14

    Secondary: Tinnitus (THI score) Visit 3

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    End point title
    		 Tinnitus (THI score) Visit 3
    End point description
    A negative score in change from baseline means an improvement.
    End point type
    Secondary
    End point timeframe
    Day 14 compared to Baseline (Day 1)
    End point values
    		 Latanoprost 1 or 3 injections Placebo 1 or 3 injections
    Number of subjects analysed
    66
    34
    Units: score
        arithmetic mean (standard deviation)
    -3.67 ± 8.79
    -2.18 ± 9.26
    Statistical analysis title
    		 Change in Tinnitus (THI score)
    Statistical analysis description
    Change in Tinnitus (THI score) Day 14 compared to baseline (Day 1). A negative score in change from baseline means an improvement.
    Comparison groups
    Placebo 1 or 3 injections v Latanoprost 1 or 3 injections
    Number of subjects included in analysis
    100
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [5]
    P-value
    		 = 0.3857
    Method
    		 Mixed models analysis
    Parameter type
    		 Mean difference (final values)
    Point estimate
    -1.646
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -5.399
         upper limit
    		 2.107
    Notes
    [5] - The analysis performs a weighted comparison of Latanoprost 1 injection and Latanoprost 3 injections compared to Placebo 1 injection and Placebo 3 injections. The weight are proportional to the number patients in the respective group at Day 14

    Secondary: Tinnitus (THI score) Visit 4

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    End point title
    		 Tinnitus (THI score) Visit 4
    End point description
    A negative score in change from baseline means an improvement.
    End point type
    Secondary
    End point timeframe
    Day 28 compared to Baseline (Day 1)
    End point values
    		 Latanoprost 1 or 3 injections Placebo 1 or 3 injections
    Number of subjects analysed
    61
    33
    Units: score
        arithmetic mean (standard deviation)
    -4.69 ± 10.78
    -4.61 ± 13.84
    Statistical analysis title
    		 Change in Tinnitus (THI score)
    Statistical analysis description
    Change in Tinnitus (THI score) Day 14 compared to baseline (Day 1). A negative score in change from baseline means an improvement.
    Comparison groups
    Latanoprost 1 or 3 injections v Placebo 1 or 3 injections
    Number of subjects included in analysis
    94
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [6]
    P-value
    		 = 0.9753
    Method
    		 Mixed models analysis
    Parameter type
    		 Mean difference (final values)
    Point estimate
    -0.08
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -5.223
         upper limit
    		 5.063
    Notes
    [6] - The analysis performs a weighted comparison of Latanoprost 1 injection and Latanoprost 3 injections compared to Placebo 1 injection and Placebo 3 injections. The weight are proportional to the number patients in the respective group at Day 14

    Secondary: Tinnitus (THI score) Visit 5

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    End point title
    		 Tinnitus (THI score) Visit 5
    End point description
    A negative score in change from baseline means an improvement.
    End point type
    Secondary
    End point timeframe
    Day 42 compared to Baseline (Day 1)
    End point values
    		 Latanoprost 1 or 3 injections Placebo 1 or 3 injections
    Number of subjects analysed
    61
    30
    Units: score
        arithmetic mean (standard deviation)
    -6.26 ± 11.5
    -5.53 ± 16.19
    Statistical analysis title
    		 Change in Tinnitus (THI score)
    Statistical analysis description
    Change in Tinnitus (THI score) Day 14 compared to baseline (Day 1). A negative score in change from baseline means an improvement.
    Comparison groups
    Latanoprost 1 or 3 injections v Placebo 1 or 3 injections
    Number of subjects included in analysis
    91
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [7]
    P-value
    		 = 0.7121
    Method
    		 Mixed models analysis
    Parameter type
    		 Mean difference (final values)
    Point estimate
    -1.082
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -6.897
         upper limit
    		 4.734
    Notes
    [7] - The analysis performs a weighted comparison of Latanoprost 1 injection and Latanoprost 3 injections compared to Placebo 1 injection and Placebo 3 injections. The weight are proportional to the number patients in the respective group at Day 14

    Secondary: Tinnitus (THI score) Visit 6

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    End point title
    		 Tinnitus (THI score) Visit 6
    End point description
    A negative score in change from baseline means an improvement.
    End point type
    Secondary
    End point timeframe
    Day 56 compared to Baseline (Day 1)
    End point values
    		 Latanoprost 1 or 3 injections Placebo 1 or 3 injections
    Number of subjects analysed
    62
    32
    Units: score
        arithmetic mean (standard deviation)
    -7.03 ± 12.39
    -4.5 ± 15.97
    Statistical analysis title
    		 Change in Tinnitus (THI score)
    Statistical analysis description
    Change in Tinnitus (THI score) Day 14 compared to baseline (Day 1). A negative score in change from baseline means an improvement.
    Comparison groups
    Latanoprost 1 or 3 injections v Placebo 1 or 3 injections
    Number of subjects included in analysis
    94
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [8]
    P-value
    		 = 0.3632
    Method
    		 Mixed models analysis
    Parameter type
    		 Mean difference (final values)
    Point estimate
    -2.67
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -8.48
         upper limit
    		 3.14
    Notes
    [8] - The analysis performs a weighted comparison of Latanoprost 1 injection and Latanoprost 3 injections compared to Placebo 1 injection and Placebo 3 injections. The weight are proportional to the number patients in the respective group at Day 14

    Secondary: Tinnitus (THI score) Visit 7

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    End point title
    		 Tinnitus (THI score) Visit 7
    End point description
    A negative score in change from baseline means an improvement.
    End point type
    Secondary
    End point timeframe
    Day 84 compared to Baseline (Day 1)
    End point values
    		 Latanoprost 1 or 3 injections Placebo 1 or 3 injections
    Number of subjects analysed
    63
    33
    Units: score
        arithmetic mean (standard deviation)
    -6.67 ± 14.89
    -4.67 ± 16.36
    Statistical analysis title
    		 Change in Tinnitus (THI score)
    Statistical analysis description
    Change in Tinnitus (THI score) Day 14 compared to baseline (Day 1). A negative score in change from baseline means an improvement.
    Comparison groups
    Latanoprost 1 or 3 injections v Placebo 1 or 3 injections
    Number of subjects included in analysis
    96
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [9]
    P-value
    		 = 0.5026
    Method
    		 Mixed models analysis
    Parameter type
    		 Mean difference (final values)
    Point estimate
    -2.235
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -8.84
         upper limit
    		 4.37
    Notes
    [9] - The analysis performs a weighted comparison of Latanoprost 1 injection and Latanoprost 3 injections compared to Placebo 1 injection and Placebo 3 injections. The weight are proportional to the number patients in the respective group at Day 14

    Secondary: Proportion of days with vertigo attacks Week 0-4

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    End point title
    		 Proportion of days with vertigo attacks Week 0-4
    End point description
    A negative score means an improvement, i.e. fewer days virtigo.
    End point type
    Secondary
    End point timeframe
    Week 0-4 compared to run-in period (last 4 weeks prior to treatment)
    End point values
    		 Latanoprost 1 or 3 injections Placebo 1 or 3 injections
    Number of subjects analysed
    66
    34
    Units: percentage
        arithmetic mean (standard deviation)
    -1.8 ± 10.37
    -4 ± 14.36
    Statistical analysis title
    		 Change in proportion of days with vertigo attacks
    Statistical analysis description
    Change in proportion of days with vertigo attacks Week 0-4 compared to run-in period (last 4 weeks prior to treatment). A negative score means an improvement, i.e. fewer days virtigo.
    Comparison groups
    Latanoprost 1 or 3 injections v Placebo 1 or 3 injections
    Number of subjects included in analysis
    100
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.3764
    Method
    		 Mixed models analysis
    Parameter type
    		 Mean difference (final values)
    Point estimate
    2.145
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -2.651
         upper limit
    		 6.941

    Secondary: Proportion of days with vertigo attacks Week 4-8

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    End point title
    		 Proportion of days with vertigo attacks Week 4-8
    End point description
    A negative score means an improvement, i.e. fewer days virtigo.
    End point type
    Secondary
    End point timeframe
    Week 4-8 compared to run-in period (last 4 weeks prior to treatment)
    End point values
    		 Latanoprost 1 or 3 injections Placebo 1 or 3 injections
    Number of subjects analysed
    66
    34
    Units: percentage
        arithmetic mean (standard deviation)
    -2.56 ± 11.45
    -5.79 ± 16.24
    Statistical analysis title
    		 Change in proportion of days with vertigo attacks
    Statistical analysis description
    Change in proportion of days with vertigo attacks Week 4-8 compared to run-in period (last 4 weeks prior to treatment). A negative score means an improvement, i.e. fewer days virtigo.
    Comparison groups
    Latanoprost 1 or 3 injections v Placebo 1 or 3 injections
    Number of subjects included in analysis
    100
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [10]
    P-value
    		 = 0.2336
    Method
    		 Mixed models analysis
    Parameter type
    		 Mean difference (final values)
    Point estimate
    3.229
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -2.123
         upper limit
    		 8.582
    Notes
    [10] - The analysis performs a weighted comparison of Latanoprost 1 injection and Latanoprost 3 injections compared to Placebo 1 injection and Placebo 3 injections. The weight are proportional to the number patients in the respective group at Day 14

    Secondary: Proportion of days with vertigo attacks Week 8-12

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    End point title
    		 Proportion of days with vertigo attacks Week 8-12
    End point description
    A negative score means an improvement, i.e. fewer days virtigo.
    End point type
    Secondary
    End point timeframe
    Week 8-12 compared to run-in period (last 4 weeks prior to treatment)
    End point values
    		 Latanoprost 1 or 3 injections Placebo 1 or 3 injections
    Number of subjects analysed
    66
    33
    Units: percentage
        arithmetic mean (standard deviation)
    -5.7 ± 13.47
    -7.8 ± 15.71
    Statistical analysis title
    		 Change in proportion of days with vertigo attacks
    Statistical analysis description
    Change in proportion of days with vertigo attacks Week 8-12 compared to run-in period (last 4 weeks prior to treatment). A negative score means an improvement, i.e. fewer days virtigo.
    Comparison groups
    Latanoprost 1 or 3 injections v Placebo 1 or 3 injections
    Number of subjects included in analysis
    99
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority [11]
    P-value
    		 = 0.5328
    Method
    		 Mixed models analysis
    Parameter type
    		 Mean difference (final values)
    Point estimate
    1.807
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -3.932
         upper limit
    		 7.546
    Notes
    [11] - The analysis performs a weighted comparison of Latanoprost 1 injection and Latanoprost 3 injections compared to Placebo 1 injection and Placebo 3 injections. The weight are proportional to the number patients in the respective group at Day 14

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    Adverse events were recorded from baseline (Day 1) until last the last visit for each subject.
    Adverse event reporting additional description
    All adverse events, whether volunteered by the subject, discovered by Investigator questioning, or detected through physical examination, laboratory test or other means was documented.
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    13.0
    Reporting groups
    Reporting group title
    Latanoprost 1 injection
    Reporting group description
    		 In this arm patients were randomized to one injection of latanoprost.

    Reporting group title
    Placebo 1 injection
    Reporting group description
    		 In this arm patients were randomized to one injection of placebo. The placebo consisted of phosphate buffered saline.

    Reporting group title
    Latanoprost 3 injections
    Reporting group description
    		 In this arm patients were randomized to three injections of latanoprost.

    Reporting group title
    Placebo 3 injections
    Reporting group description
    		 In this arm patients were randomized to three injections of placebo. The placebo consisted of phosphate buffered saline.

    Serious adverse events
    		 Latanoprost 1 injection Placebo 1 injection Latanoprost 3 injections Placebo 3 injections
    Total subjects affected by serious adverse events
         subjects affected / exposed
    0 / 24 (0.00%)
    0 / 12 (0.00%)
    1 / 42 (2.38%)
    0 / 22 (0.00%)
         number of deaths (all causes)
    0
    0
    0
    0
         number of deaths resulting from adverse events
    0
    0
    0
    0
    General disorders and administration site conditions
    Chest pain
         subjects affected / exposed
    0 / 24 (0.00%)
    0 / 12 (0.00%)
    1 / 42 (2.38%)
    0 / 22 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 0%
    Non-serious adverse events
    		 Latanoprost 1 injection Placebo 1 injection Latanoprost 3 injections Placebo 3 injections
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    6 / 24 (25.00%)
    5 / 12 (41.67%)
    23 / 42 (54.76%)
    9 / 22 (40.91%)
    General disorders and administration site conditions
    Pyrexia
         subjects affected / exposed
    0 / 24 (0.00%)
    1 / 12 (8.33%)
    1 / 42 (2.38%)
    0 / 22 (0.00%)
         occurrences all number
    0
    1
    1
    0
    Fatigue
         subjects affected / exposed
    0 / 24 (0.00%)
    0 / 12 (0.00%)
    2 / 42 (4.76%)
    0 / 22 (0.00%)
         occurrences all number
    0
    0
    2
    0
    Infusion related reaction
         subjects affected / exposed
    0 / 24 (0.00%)
    0 / 12 (0.00%)
    0 / 42 (0.00%)
    1 / 22 (4.55%)
         occurrences all number
    0
    0
    0
    2
    Immune system disorders
    Hypersensitivity
         subjects affected / exposed
    0 / 24 (0.00%)
    1 / 12 (8.33%)
    0 / 42 (0.00%)
    0 / 22 (0.00%)
         occurrences all number
    0
    1
    0
    0
    Reproductive system and breast disorders
    Dysmenorrhoea
         subjects affected / exposed
    0 / 24 (0.00%)
    0 / 12 (0.00%)
    0 / 42 (0.00%)
    1 / 22 (4.55%)
         occurrences all number
    0
    0
    0
    2
    Respiratory, thoracic and mediastinal disorders
    Epistaxis
         subjects affected / exposed
    0 / 24 (0.00%)
    0 / 12 (0.00%)
    1 / 42 (2.38%)
    0 / 22 (0.00%)
         occurrences all number
    0
    0
    1
    0
    Psychiatric disorders
    Insomnia
         subjects affected / exposed
    0 / 24 (0.00%)
    0 / 12 (0.00%)
    0 / 42 (0.00%)
    1 / 22 (4.55%)
         occurrences all number
    0
    0
    0
    1
    Depression
         subjects affected / exposed
    0 / 24 (0.00%)
    0 / 12 (0.00%)
    0 / 42 (0.00%)
    1 / 22 (4.55%)
         occurrences all number
    0
    0
    0
    1
    Injury, poisoning and procedural complications
    Auricular haematoma
         subjects affected / exposed
    0 / 24 (0.00%)
    0 / 12 (0.00%)
    1 / 42 (2.38%)
    0 / 22 (0.00%)
         occurrences all number
    0
    0
    1
    0
    Radius fracture
         subjects affected / exposed
    0 / 24 (0.00%)
    1 / 12 (8.33%)
    0 / 42 (0.00%)
    0 / 22 (0.00%)
         occurrences all number
    0
    1
    0
    0
    Procedural headache
         subjects affected / exposed
    0 / 24 (0.00%)
    0 / 12 (0.00%)
    1 / 42 (2.38%)
    0 / 22 (0.00%)
         occurrences all number
    0
    0
    1
    0
    Cardiac disorders
    Tachycardia
         subjects affected / exposed
    0 / 24 (0.00%)
    0 / 12 (0.00%)
    0 / 42 (0.00%)
    1 / 22 (4.55%)
         occurrences all number
    0
    0
    0
    1
    Nervous system disorders
    Headache
         subjects affected / exposed
    1 / 24 (4.17%)
    3 / 12 (25.00%)
    10 / 42 (23.81%)
    2 / 22 (9.09%)
         occurrences all number
    1
    5
    41
    2
    Dizziness
         subjects affected / exposed
    0 / 24 (0.00%)
    0 / 12 (0.00%)
    2 / 42 (4.76%)
    0 / 22 (0.00%)
         occurrences all number
    0
    0
    4
    0
    Visual field defect
         subjects affected / exposed
    0 / 24 (0.00%)
    1 / 12 (8.33%)
    0 / 42 (0.00%)
    0 / 22 (0.00%)
         occurrences all number
    0
    1
    0
    0
    Tremor
         subjects affected / exposed
    0 / 24 (0.00%)
    0 / 12 (0.00%)
    1 / 42 (2.38%)
    0 / 22 (0.00%)
         occurrences all number
    0
    0
    1
    0
    Ear and labyrinth disorders
    Ear pain
         subjects affected / exposed
    2 / 24 (8.33%)
    0 / 12 (0.00%)
    2 / 42 (4.76%)
    1 / 22 (4.55%)
         occurrences all number
    14
    0
    3
    1
    Hyperacusis
         subjects affected / exposed
    0 / 24 (0.00%)
    0 / 12 (0.00%)
    1 / 42 (2.38%)
    1 / 22 (4.55%)
         occurrences all number
    0
    0
    1
    1
    Vertigo
         subjects affected / exposed
    0 / 24 (0.00%)
    0 / 12 (0.00%)
    1 / 42 (2.38%)
    1 / 22 (4.55%)
         occurrences all number
    0
    0
    1
    1
    Ear discomfort
         subjects affected / exposed
    0 / 24 (0.00%)
    0 / 12 (0.00%)
    1 / 42 (2.38%)
    1 / 22 (4.55%)
         occurrences all number
    0
    0
    1
    1
    Tinnitus
         subjects affected / exposed
    0 / 24 (0.00%)
    0 / 12 (0.00%)
    0 / 42 (0.00%)
    1 / 22 (4.55%)
         occurrences all number
    0
    0
    0
    1
    Eye disorders
    Eye swelling
         subjects affected / exposed
    0 / 24 (0.00%)
    0 / 12 (0.00%)
    0 / 42 (0.00%)
    1 / 22 (4.55%)
         occurrences all number
    0
    0
    0
    1
    Gastrointestinal disorders
    Nausea
         subjects affected / exposed
    0 / 24 (0.00%)
    0 / 12 (0.00%)
    1 / 42 (2.38%)
    0 / 22 (0.00%)
         occurrences all number
    0
    0
    1
    0
    Abdominal pain upper
         subjects affected / exposed
    0 / 24 (0.00%)
    0 / 12 (0.00%)
    0 / 42 (0.00%)
    1 / 22 (4.55%)
         occurrences all number
    0
    0
    0
    2
    Dental discomfort
         subjects affected / exposed
    0 / 24 (0.00%)
    0 / 12 (0.00%)
    1 / 42 (2.38%)
    0 / 22 (0.00%)
         occurrences all number
    0
    0
    1
    0
    Skin and subcutaneous tissue disorders
    Rash
         subjects affected / exposed
    0 / 24 (0.00%)
    0 / 12 (0.00%)
    1 / 42 (2.38%)
    0 / 22 (0.00%)
         occurrences all number
    0
    0
    1
    0
    Musculoskeletal and connective tissue disorders
    Back pain
         subjects affected / exposed
    0 / 24 (0.00%)
    1 / 12 (8.33%)
    1 / 42 (2.38%)
    0 / 22 (0.00%)
         occurrences all number
    0
    1
    2
    0
    Arthralgia
         subjects affected / exposed
    0 / 24 (0.00%)
    0 / 12 (0.00%)
    1 / 42 (2.38%)
    0 / 22 (0.00%)
         occurrences all number
    0
    0
    1
    0
    Neck pain
         subjects affected / exposed
    0 / 24 (0.00%)
    0 / 12 (0.00%)
    1 / 42 (2.38%)
    0 / 22 (0.00%)
         occurrences all number
    0
    0
    1
    0
    Infections and infestations
    Nasopharyngitis
         subjects affected / exposed
    2 / 24 (8.33%)
    1 / 12 (8.33%)
    3 / 42 (7.14%)
    0 / 22 (0.00%)
         occurrences all number
    3
    1
    3
    0
    Ear infection
         subjects affected / exposed
    0 / 24 (0.00%)
    0 / 12 (0.00%)
    3 / 42 (7.14%)
    0 / 22 (0.00%)
         occurrences all number
    0
    0
    3
    0
    Sinusitis
         subjects affected / exposed
    0 / 24 (0.00%)
    1 / 12 (8.33%)
    1 / 42 (2.38%)
    0 / 22 (0.00%)
         occurrences all number
    0
    1
    1
    0
    Otitis externa
         subjects affected / exposed
    1 / 24 (4.17%)
    0 / 12 (0.00%)
    0 / 42 (0.00%)
    0 / 22 (0.00%)
         occurrences all number
    1
    0
    0
    0
    Viral infection
         subjects affected / exposed
    0 / 24 (0.00%)
    0 / 12 (0.00%)
    1 / 42 (2.38%)
    0 / 22 (0.00%)
         occurrences all number
    0
    0
    1
    0
    Oral herpes
         subjects affected / exposed
    1 / 24 (4.17%)
    0 / 12 (0.00%)
    0 / 42 (0.00%)
    0 / 22 (0.00%)
         occurrences all number
    1
    0
    0
    0
    Otitis media
         subjects affected / exposed
    0 / 24 (0.00%)
    0 / 12 (0.00%)
    1 / 42 (2.38%)
    0 / 22 (0.00%)
         occurrences all number
    0
    0
    1
    0
    Gastroenteritis
         subjects affected / exposed
    0 / 24 (0.00%)
    0 / 12 (0.00%)
    1 / 42 (2.38%)
    0 / 22 (0.00%)
         occurrences all number
    0
    0
    1
    0
    Diverticulitis
         subjects affected / exposed
    1 / 24 (4.17%)
    0 / 12 (0.00%)
    0 / 42 (0.00%)
    0 / 22 (0.00%)
         occurrences all number
    1
    0
    0
    0
    Otitis media acute
         subjects affected / exposed
    1 / 24 (4.17%)
    0 / 12 (0.00%)
    0 / 42 (0.00%)
    0 / 22 (0.00%)
         occurrences all number
    1
    0
    0
    0
    Injection site pain
         subjects affected / exposed
    0 / 24 (0.00%)
    0 / 12 (0.00%)
    0 / 42 (0.00%)
    1 / 22 (4.55%)
         occurrences all number
    0
    0
    0
    1
    Thirst
         subjects affected / exposed
    0 / 24 (0.00%)
    0 / 12 (0.00%)
    1 / 42 (2.38%)
    0 / 22 (0.00%)
         occurrences all number
    0
    0
    1
    0
    Application site pain
         subjects affected / exposed
    0 / 24 (0.00%)
    0 / 12 (0.00%)
    1 / 42 (2.38%)
    0 / 22 (0.00%)
         occurrences all number
    0
    0
    1
    0
    Pain
         subjects affected / exposed
    0 / 24 (0.00%)
    0 / 12 (0.00%)
    1 / 42 (2.38%)
    0 / 22 (0.00%)
         occurrences all number
    0
    0
    1
    0

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? No

    Interruptions (globally)
    Were there any global interruptions to the trial? No

    Limitations and caveats
    Limitations of the trial such as small numbers of subjects analysed or technical problems leading to unreliable data.
    None reported
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