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    Clinical Trial Results:
    A Phase III, Multicenter, Randomized, Double-Blind Clinical Trial to Assess the Efficacy and Safety of Clotrimazole 1% Otic Solution Compared to Placebo for the Treatment of Fungal Otitis Externa (Otomycosis).

    Summary
    EudraCT number
    		 2019-003463-22
    Trial protocol
    		 ES   PT   BG   RO  
    Global end of trial date
    19 Oct 2021

    Results information
    Results version number
    		 v1(current)
    This version publication date
    30 Dec 2022
    First version publication date
    30 Dec 2022
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    CLOTOT3-16IA03
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT03686397
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    Laboratorios Salvat, S.A
    Sponsor organisation address
    Gall 30-36, Barcelona, Spain, 08950
    Public contact
    Enrique Jiménez, Laboratorios Salvat, S.A, 34 933946400, ejimenez@svt.com
    Scientific contact
    Enrique Jiménez, Laboratorios Salvat, S.A, 34 933946400, ejimenez@svt.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
    18 Feb 2022
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    19 Oct 2021
    Global end of trial reached?
    Yes
    Global end of trial date
    19 Oct 2021
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    To demonstrate the superior efficacy of Clotrimazole vs placebo in the treatment of otomycosis, with respect to the therapeutic cure at test of cure in the MITT population.
    Protection of trial subjects
    If patient reported no improvement in otomycosis signs/symptoms, the investigator might treat patient with other medication (rescue medication) at their discretion. For patients who required analgesic medication for otalgia, the recommended medication was paracetamol.
    Background therapy
    		 -
    Evidence for comparator
    		 -
    Actual start date of recruitment
    09 Jun 2020
    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
    Portugal: 15
    Country: Number of subjects enrolled
    Romania: 34
    Country: Number of subjects enrolled
    Spain: 41
    Country: Number of subjects enrolled
    Bulgaria: 103
    Worldwide total number of subjects
    193
    EEA total number of subjects
    193
    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)
    145
    From 65 to 84 years
    48
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 The principal investigator was an otolaryngologist

    Pre-assignment
    Screening details
    		 A fungal cultures was performed at baseline to know if subject had an ear infection due to Apergillus and/or Candida spp. The main efficacy population of the study was the MITT population (evaluable patients): randomized subjects who had a positive baseline culture for Aspergillus spp and/or Candida spp.

    Period 1
    Period 1 title
    Baseline MITT Population (overall period)
    Is this the baseline period?
    		 Yes
    Allocation method
    Randomised - controlled
    Blinding used
    		 Double blind
    Roles blinded
    		 Subject, Investigator, Monitor, Data analyst, Assessor
    Blinding implementation details
    All study medication products had the same packaging and labels

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Clotrimazole
    Arm description
    		 -
    Arm type
    		 Experimental

    Investigational medicinal product name
    Clotrimzole
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Ear drops, solution
    Routes of administration
    Auricular use
    Dosage and administration details
    1 vial in the affected ear(s) twice a day during 14 days

    Arm title
    		 Placebo
    Arm description
    		 -
    Arm type
    		 Placebo

    Investigational medicinal product name
    Saline solution 0.9%
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Ear drops, solution
    Routes of administration
    Auricular use
    Dosage and administration details
    1 vial in the affected ear(s) twice a day during 14 days

    Number of subjects in period 1 [1]
    		Clotrimazole Placebo
    Started
    75
    35
    Completed
    70
    27
    Not completed
    5
    8
         Consent withdrawn by subject
    -
    1
         Adverse event, non-fatal
    -
    1
         covid pandemia, bacterial ear culture
    2
    -
         Lack of efficacy
    3
    5
         Protocol deviation
    -
    1
    Notes
    [1] - The number of subjects reported to be in the baseline period are not the same as the worldwide number enrolled in the trial. It is expected that these numbers will be the same.
    Justification: A fungal culture was performed at baseline to know if subject had an ear infection due to Aspergillus and/or Candida spp. The main efficay population of the study was the MITT population (evaluable patients): randomized subjects who had a positive baseline culture for Aspergillus and/or Candida spp. From the 193 randomized patients, only 110 patients showed positive fungal culture for Aspergillus and/or Candida spp.

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Baseline MITT Population
    Reporting group description
    		 -

    Reporting group values
    		 Baseline MITT Population Total
    Number of subjects
    		 110 110
    Age categorical
    Units: Subjects
        Adults (18-64 years)
    		 78 78
        From 65-84 years
    		 32 32
        85 years and over
    		 0 0
    Age continuous
    Units: years
        median (standard deviation)
    		 52.4 ( 15.53 ) -
    Gender categorical
    Units: Subjects
        Female
    		 50 50
        Male
    		 60 60

    End points

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    End points reporting groups
    Reporting group title
    Clotrimazole
    Reporting group description
    		 -

    Reporting group title
    Placebo
    Reporting group description
    		 -

    Primary: Therapeutic cure (Clinical and Mycological Cure)

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    End point title
    		 Therapeutic cure (Clinical and Mycological Cure)
    End point description
    Proportion of subjects with therapeutic cure
    End point type
    Primary
    End point timeframe
    Test of cure on day 24
    End point values
    		 Clotrimazole Placebo
    Number of subjects analysed
    75 [1]
    35 [2]
    Units: Count of participants
        number (not applicable)
    59
    8
    Notes
    [1] - MITT Population
    [2] - MITT Population
    Statistical analysis title
    		 Therapeutic cure
    Statistical analysis description
    Therapeutic cure is defined as both mycological cure and clinical cure. Mycological cure is defined as eradication (culture does not show growth of any fungal pathogen) or presumed eradication (there is no material to culture and the overall clinical outcome is clinical cure). Subjects who received rescue medication are considered therapeutic failure. Missing endpoints are set to therapeutic failure.
    Comparison groups
    Clotrimazole v Placebo
    Number of subjects included in analysis
    110
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 < 0.05
    Method
    		 Chi-squared
    Confidence interval

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    Overall study period (about 4 weeks)
    Adverse event reporting additional description
    If pre-existing signs and symptoms of otomycosis worsen during the study, this was considered treatment failure instead of an adverse event (AE). The AE were reviewed in the safety population (subjects who received at least 1 dose of study medication)
    Assessment type
    		 Non-systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    23.0
    Reporting groups
    Reporting group title
    Clotrimazole
    Reporting group description
    		 -

    Reporting group title
    Placebo
    Reporting group description
    		 -

    Serious adverse events
    		 Clotrimazole Placebo
    Total subjects affected by serious adverse events
         subjects affected / exposed
    0 / 127 (0.00%)
    1 / 64 (1.56%)
         number of deaths (all causes)
    0
    0
         number of deaths resulting from adverse events
    0
    0
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Cholesteatoma
    alternative assessment type: Systematic
         subjects affected / exposed
    0 / 127 (0.00%)
    1 / 64 (1.56%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Infections and infestations
    Laberinthitis
    alternative assessment type: Systematic
         subjects affected / exposed
    0 / 127 (0.00%)
    1 / 64 (1.56%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 2%
    Non-serious adverse events
    		 Clotrimazole Placebo
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    0 / 127 (0.00%)
    3 / 64 (4.69%)
    Nervous system disorders
    Dizziness
         subjects affected / exposed
    0 / 127 (0.00%)
    3 / 64 (4.69%)
         occurrences all number
    0
    3

    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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    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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