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    Clinical Trial Results:
    What is the clinical and cost effectiveness of benzocaine/phenazone ear drops for reducing antibiotic consumption and ear pain in children aged between 6 months and 10 years presenting to primary care with acute otitis media (AOM)? An individually randomised, placebo controlled three-arm superiority trial with cost-effectiveness analysis, qualitative evaluation and a parallel observational cohort study.

    Summary
    EudraCT number
    		 2014-004016-11
    Trial protocol
    		 GB  
    Global end of trial date
    19 Mar 2019

    Results information
    Results version number
    		 v1(current)
    This version publication date
    26 Oct 2019
    First version publication date
    26 Oct 2019
    Other versions

    Trial information

    		 Close Top of page
    Trial identification
    Sponsor protocol code
    2305
    Additional study identifiers
    ISRCTN number
    		 ISRCTN09599764
    US NCT number
    		 -
    WHO universal trial number (UTN)
    		 -
    Other trial identifiers
    		 NHS Research Ethics Committee: 15/SC/0376
    Sponsors
    Sponsor organisation name
    University of Bristol
    Sponsor organisation address
    One Cathedral Square, Bristol, United Kingdom, BS1 5DD
    Public contact
    CEDAR Trial Manager (H Downing), University of Bristol, School of Social and Community Medicine, +44 01173313906, harriet.downing@bristol.ac.uk
    Scientific contact
    CEDAR Trial Manager (H Downing), University of Bristol, School of Social and Community Medicine, +44 01173313906, harriet.downing@bristol.ac.uk
    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
    01 May 2018
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    16 Nov 2017
    Global end of trial reached?
    Yes
    Global end of trial date
    19 Mar 2019
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    The aim of the CEDAR study is to investigate the clinical and cost effectiveness of benzocaine plus phenazone (active) ear drops compared to usual care (no drops) for reducing antibiotic consumption in children aged between twelve months and ten years presenting to primary care with AOM.
    Protection of trial subjects
    Details of serious adverse events were collected, and the trial team notified immediately, using adverse event forms. Parents were also asked on the last day of their questionnaire whether their child had experienced any new or worsening symptoms during the trial.
    Background therapy
    		 -
    Evidence for comparator
    		 -
    Actual start date of recruitment
    01 Sep 2016
    Long term follow-up planned
    No
    Independent data monitoring committee (IDMC) involvement?
    Yes
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    United Kingdom: 106
    Worldwide total number of subjects
    106
    EEA total number of subjects
    106
    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)
    14
    Children (2-11 years)
    92
    Adolescents (12-17 years)
    0
    Adults (18-64 years)
    0
    From 65 to 84 years
    0
    85 years and over
    0

    Subject disposition

    		 Close Top of page
    Recruitment
    Recruitment details
    		 Due to a delay in the supply of a suitable placebo, recruitment began in October 2016, across 27 GP practices, randomising children to to the active treatment ("active drops") or usual care ("no drops"). When the placebo became available in March 2017 the 3-arm study began recruiting across 35 GP practices and recruitment ended in June 2017.

    Pre-assignment
    Screening details
    		 Combining figures from the 2- and 3-arm trials, 190 children (+ parents) were assessed for suitability. As 60 children were not invited to participate, e.g. clinician didn't have time, this left 130 children that were invited. 10 declined to participate, 10 were found to be ineligible and 4 were not recruited, resulting in 106 randomised children.

    Period 1
    Period 1 title
    Baseline (5-arms)
    Is this the baseline period?
    		 Yes
    Allocation method
    Randomised - controlled
    Blinding used
    		 Not blinded
    Blinding implementation details
    Encompassing the 2-arm and 3-arm trials. The 2-arm trial was unblinded as both the clinician and parent/child were aware if they'd been allocated active drops or no treatment. The 3-arm trial was partially blinded as, if allocated to active or placebo drops, there was no way of distinguishing between the two. The PI and trial team remained blinded throughout the trial, apart from the trial statistician who was reporting to the data monitoring committee.

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 2-arm Active drops
    Arm description
    		 The Investigational Medicinal Product (IMP) for this trial was a benzocaine and phenazone otic solution. This is an oil based, combined local anaesthetic (benzocaine) and analgesic (phenazone, International Nonproprietary Name, also known in the US as antipyrine) ear drop. One millilitre contains 14 mg (1.4%) of benzocaine and 54mg (5.4%) phenazone suspended in a glycerine-based liquid along with a preservative (hydroxyquinolone sulphate). For this trial we intended to test Auralgan©, manufactured by Pfizer Consumer Healthcare (Australia) and sold in 15mL bottles.
    Arm type
    		 Active comparator

    Investigational medicinal product name
    Auralgan
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Ear drops, solution
    Routes of administration
    Auricular use
    Dosage and administration details
    Parents were given instructions on how to administer the drops and asked to use them every 1 to 2 hours (up to a maximum of 12 times in 24 hours).

    Arm title
    		 2-arm No drops
    Arm description
    		 No intervention.
    Arm type
    		 No intervention

    Investigational medicinal product name
    No investigational medicinal product assigned in this arm
    Arm title
    		 3-arm Active drops
    Arm description
    		 The Investigational Medicinal Product (IMP) for this trial was a benzocaine and phenazone otic solution. This is an oil based, combined local anaesthetic (benzocaine) and analgesic (phenazone, International Nonproprietary Name, also known in the US as antipyrine) ear drop. One millilitre contains 14 mg (1.4%) of benzocaine and 54mg (5.4%) phenazone suspended in a glycerine-based liquid along with a preservative (hydroxyquinolone sulphate). For this trial we intended to test Auralgan©, manufactured by Pfizer Consumer Healthcare (Australia) and sold in 15mL bottles.
    Arm type
    		 Active comparator

    Investigational medicinal product name
    Auralgan
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Ear drops, solution
    Routes of administration
    Auricular use
    Dosage and administration details
    Parents were given instructions on how to administer the drops and asked to use them every 1 to 2 hours (up to a maximum of 12 times in 24 hours).

    Arm title
    		 3-arm Placebo drops
    Arm description
    		 The placebo was glycerine, with packaging as close in appearance as possible to that used for the active drops (Albany Molecular Research (Glasgow) Ltd).
    Arm type
    		 Placebo

    Investigational medicinal product name
    Placebo (one off production for the CEDAR trial by Albany Molecular Research (Glasgow) Ltd)
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Ear drops, solution
    Routes of administration
    Auricular use
    Dosage and administration details
    Parents were given instructions on how to administer the drops and asked to use them every 1 to 2 hours (up to a maximum of 12 times in 24 hours).

    Investigational medicinal product name
    Placebo (one off production for the CEDAR trial by Albany Molecular Research (Glasgow) Ltd)
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Ear drops, solution
    Routes of administration
    Auricular use
    Dosage and administration details
    Parents were given instructions on how to administer the drops and asked to use them every 1 to 2 hours (up to a maximum of 12 times in 24 hours).

    Arm title
    		 3-arm No drops
    Arm description
    		 No intervention.
    Arm type
    		 No intervention

    Investigational medicinal product name
    No investigational medicinal product assigned in this arm
    Number of subjects in period 1
    		2-arm Active drops 2-arm No drops 3-arm Active drops 3-arm Placebo drops 3-arm No drops
    Started
    38
    36
    12
    10
    10
    Completed
    38
    36
    12
    10
    10
    Period 2
    Period 2 title
    2-arm trial
    Is this the baseline period?
    		 No
    Allocation method
    Randomised - controlled
    Blinding used
    		 Not blinded

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Active drops
    Arm description
    		 The Investigational Medicinal Product (IMP) for this trial was a benzocaine and phenazone otic solution. This is an oil based, combined local anaesthetic (benzocaine) and analgesic (phenazone, International Nonproprietary Name, also known in the US as antipyrine) ear drop. One millilitre contains 14 mg (1.4%) of benzocaine and 54mg (5.4%) phenazone suspended in a glycerine-based liquid along with a preservative (hydroxyquinolone sulphate). For this trial we intended to test Auralgan©, manufactured by Pfizer Consumer Healthcare (Australia) and sold in 15mL bottles.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Auralgan
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Ear drops, solution
    Routes of administration
    Auricular use
    Dosage and administration details
    Parents were given instructions on how to administer the drops and asked to use them every 1 to 2 hours (up to a maximum of 12 times in 24 hours).

    Arm title
    		 No drops
    Arm description
    		 No intervention.
    Arm type
    		 No intervention

    Investigational medicinal product name
    No investigational medicinal product assigned in this arm
    Number of subjects in period 2 [1]
    		Active drops No drops
    Started
    38
    36
    Completed
    38
    36
    Notes
    [1] - The number of subjects starting the period is not consistent with the number completing the preceding period. It is expected the number of subjects starting the subsequent period will be the same as the number completing the preceding period.
    Justification: Period 1 relates to all baseline data for the 2-arm and 3-arm trials. Period 2 then relates to the 2-arm trial only and period 3 relates to the 3-arm trial only. The number of individuals starting periods 2 and 3, added together, equal the number completing period 1.
    Period 3
    Period 3 title
    3-arm trial
    Is this the baseline period?
    		 No
    Allocation method
    Randomised - controlled
    Blinding used
    		 Double blind
    Roles blinded
    		 Subject, Investigator, Monitor, Carer, Assessor
    Blinding implementation details
    Randomisation was stratified by centre in blocks of 30 packs, each block having the packs arranged in a random and consecutively numbered sequence. Each pack contained either 2 bottles of active medicine, 2 bottles of placebo medicine, or no bottles (a non-medicinal item of comparable weight). Patients were enrolled by their GP/nurse who were unaware of the contents of the next treatment pack in the sequence. When the trial pack was opened, those in the 'no drops' group became unblinded.

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Active drops
    Arm description
    		 The Investigational Medicinal Product (IMP) for this trial was a benzocaine and phenazone otic solution. This is an oil based, combined local anaesthetic (benzocaine) and analgesic (phenazone, International Nonproprietary Name, also known in the US as antipyrine) ear drop. One millilitre contains 14 mg (1.4%) of benzocaine and 54mg (5.4%) phenazone suspended in a glycerine-based liquid along with a preservative (hydroxyquinolone sulphate). For this trial we intended to test Auralgan©, manufactured by Pfizer Consumer Healthcare (Australia) and sold in 15mL bottles.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Auralgan
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Ear drops, solution
    Routes of administration
    Auricular use
    Dosage and administration details
    Parents were given instructions on how to administer the drops and asked to use them every 1 to 2 hours (up to a maximum of 12 times in 24 hours).

    Arm title
    		 No drops
    Arm description
    		 No intervention.
    Arm type
    		 No intervention

    Investigational medicinal product name
    No investigational medicinal product assigned in this arm
    Arm title
    		 Placebo drops
    Arm description
    		 The placebo was glycerine, with packaging as close in appearance as possible to that used for the active drops (Albany Molecular Research (Glasgow) Ltd).
    Arm type
    		 Placebo

    Investigational medicinal product name
    Placebo (one off production for the CEDAR trial by Albany Molecular Research (Glasgow) Ltd)
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Ear drops, solution
    Routes of administration
    Auricular use
    Dosage and administration details
    Parents were given instructions on how to administer the drops and asked to use them every 1 to 2 hours (up to a maximum of 12 times in 24 hours).

    Number of subjects in period 3 [2]
    		Active drops No drops Placebo drops
    Started
    12
    10
    10
    Completed
    12
    10
    10
    Notes
    [2] - The number of subjects starting the period is not consistent with the number completing the preceding period. It is expected the number of subjects starting the subsequent period will be the same as the number completing the preceding period.
    Justification: Period 1 relates to all baseline data for the 2-arm and 3-arm trials. Period 2 then relates to the 2-arm trial only and period 3 relates to the 3-arm trial only. The number of individuals starting periods 2 and 3, added together, equal the number completing period 1.

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    2-arm Active drops
    Reporting group description
    		 The Investigational Medicinal Product (IMP) for this trial was a benzocaine and phenazone otic solution. This is an oil based, combined local anaesthetic (benzocaine) and analgesic (phenazone, International Nonproprietary Name, also known in the US as antipyrine) ear drop. One millilitre contains 14 mg (1.4%) of benzocaine and 54mg (5.4%) phenazone suspended in a glycerine-based liquid along with a preservative (hydroxyquinolone sulphate). For this trial we intended to test Auralgan©, manufactured by Pfizer Consumer Healthcare (Australia) and sold in 15mL bottles.

    Reporting group title
    2-arm No drops
    Reporting group description
    		 No intervention.

    Reporting group title
    3-arm Active drops
    Reporting group description
    		 The Investigational Medicinal Product (IMP) for this trial was a benzocaine and phenazone otic solution. This is an oil based, combined local anaesthetic (benzocaine) and analgesic (phenazone, International Nonproprietary Name, also known in the US as antipyrine) ear drop. One millilitre contains 14 mg (1.4%) of benzocaine and 54mg (5.4%) phenazone suspended in a glycerine-based liquid along with a preservative (hydroxyquinolone sulphate). For this trial we intended to test Auralgan©, manufactured by Pfizer Consumer Healthcare (Australia) and sold in 15mL bottles.

    Reporting group title
    3-arm Placebo drops
    Reporting group description
    		 The placebo was glycerine, with packaging as close in appearance as possible to that used for the active drops (Albany Molecular Research (Glasgow) Ltd).

    Reporting group title
    3-arm No drops
    Reporting group description
    		 No intervention.

    Reporting group values
    		 2-arm Active drops 2-arm No drops 3-arm Active drops 3-arm Placebo drops 3-arm No drops Total
    Number of subjects
    		 38 36 12 10 10 106
    Age categorical
    Age in years
    Units: Subjects
        In utero
    		 0 0 0 0 0 0
        Preterm newborn infants (gestational age < 37 wks)
    		 0 0 0 0 0 0
        Newborns (0-27 days)
    		 0 0 0 0 0 0
        Infants and toddlers (28 days-23 months)
    		 7 4 2 0 1 14
        Children (2-11 years)
    		 31 32 10 10 9 92
        Adolescents (12-17 years)
    		 0 0 0 0 0 0
        Adults (18-64 years)
    		 0 0 0 0 0 0
        From 65-84 years
    		 0 0 0 0 0 0
        85 years and over
    		 0 0 0 0 0 0
    Age continuous
    Units: years
        arithmetic mean (standard deviation)
    		 4.6 ± 2.5 4.6 ± 2.5 4.9 ± 2.5 5.0 ± 1.9 4.6 ± 2.9 -
    Gender categorical
    Units: Subjects
        Female
    		 20 20 1 7 5 53
        Male
    		 18 16 11 3 5 53
        Missing
    		 0 0 0 0 0 0
    Ethnic group
    Units: Subjects
        White
    		 33 31 9 6 9 88
        Other
    		 1 0 1 1 0 3
        Missing
    		 4 5 2 3 1 15
    Living in an area of deprivation
    Index of Multiple Deprivation based on the children’s home postcode at birth, categorised as those living in the top 20% of deprived areas in the UK (England’s 2015 rank and Wales’ 2014 rank)
    Units: Subjects
        Yes
    		 3 3 2 0 4 12
        No
    		 34 32 9 10 6 91
        Missing
    		 1 1 1 0 0 3
    Smokers in household
    Units: Subjects
        Yes
    		 2 1 1 1 2 7
        No
    		 32 30 9 6 7 84
        Missing
    		 4 5 2 3 1 15
    Additional children in household
    Units: Subjects
        Yes
    		 22 21 8 4 7 62
        No
    		 12 10 2 3 2 29
        Missing
    		 4 5 2 3 1 15
    Breast fed at 3-months
    Units: Subjects
        Yes
    		 14 9 7 4 2 36
        No
    		 20 22 3 3 7 55
        Missing
    		 4 5 2 3 1 15
    Does the child wear a hearing aid
    Units: Subjects
        Yes
    		 0 0 0 0 0 0
        No
    		 34 31 10 7 9 91
        Missing
    		 4 5 2 3 1 15
    Flu vaccination during past 12 months
    Units: Subjects
        Yes
    		 15 16 4 4 4 43
        No
    		 19 15 6 3 5 48
        Missing
    		 4 5 2 3 1 15
    Mother attended with child
    Units: Subjects
        Yes
    		 26 25 9 5 8 73
        No
    		 3 3 0 2 0 8
        Missing
    		 9 8 3 3 2 25
    Accompanying adult employed/full time education/retired
    Units: Subjects
        Yes
    		 25 26 7 6 3 67
        No
    		 9 5 3 1 6 24
        Missing
    		 4 5 2 3 1 15
    Accompanying adult a university graduate
    Units: Subjects
        Yes
    		 11 11 3 3 3 31
        No
    		 18 17 6 4 4 49
        Missing
    		 9 8 3 3 3 26
    Received painkillers today
    Question: Has your child received any painkilling medicine, e.g. paracetamol or ibuprofen, in the last 6 hours before being checked for trial suitability
    Units: Subjects
        Yes
    		 32 25 7 4 7 75
        No
    		 5 9 4 5 3 26
        Missing
    		 1 2 1 1 0 5
    AOM in both ears (bilateral)
    Units: Subjects
        Yes
    		 8 5 2 4 2 21
        No
    		 30 31 9 6 8 84
        Missing
    		 0 0 1 0 0 1
    Given a delayed antibiotic
    Units: Subjects
        Yes
    		 4 11 3 1 3 22
        No
    		 34 25 8 9 7 83
        Missing
    		 0 0 1 0 0 1
    Accompanying adult's age
    Units: Years
        arithmetic mean (standard deviation)
    		 35.0 ± 6.0 36.4 ± 6.7 38.7 ± 6.8 37.6 ± 8.2 31.5 ± 3.1 -
    Child ear pain score (0-10)
    Answered by those aged >=5
    Units: Scale 0-10
        arithmetic mean (standard deviation)
    		 6.0 ± 2.6 6.1 ± 3.1 6.4 ± 2.3 5.5 ± 3.0 7.5 ± 2.5 -
    Parent ear pain score (0-10)
    Units: Scale 0-10
        arithmetic mean (standard deviation)
    		 6.9 ± 1.5 6.3 ± 1.7 6.3 ± 1.8 5.3 ± 1.3 6.2 ± 2.2 -
    Number of days in pain
    Units: Days
        arithmetic mean (standard deviation)
    		 2.7 ± 2.0 2.5 ± 1.4 1.5 ± 0.9 2.7 ± 1.5 2.3 ± 1.8 -
    Episodes of distress/crying (0-6)
    Units: 0-6
        arithmetic mean (standard deviation)
    		 3.8 ± 1.5 3.3 ± 1.3 3.0 ± 1.7 2.4 ± 1.3 4.2 ± 1.7 -
    Disturbed sleep (0-6)
    Units: 0-6
        arithmetic mean (standard deviation)
    		 4.1 ± 1.6 3.7 ± 1.6 2.9 ± 1.5 2.7 ± 1.3 4.2 ± 1.3 -
    Interference with normal activities (0-6)
    Units: 0-6
        arithmetic mean (standard deviation)
    		 3.1 ± 1.5 2.7 ± 1.5 2.5 ± 1.8 2.9 ± 1.5 3.3 ± 1.3 -
    Eating/drinking less than normal (0-6)
    Units: 0-6
        arithmetic mean (standard deviation)
    		 2.7 ± 1.7 2.2 ± 1.6 1.7 ± 1.6 2.4 ± 1.8 2.0 ± 1.7 -
    Fever (0-6)
    Units: 0-6
        arithmetic mean (standard deviation)
    		 1.9 ± 1.7 2.7 ± 1.7 1.2 ± 1.6 2.1 ± 1.5 2.1 ± 1.9 -
    Hearing problems (0-6)
    Units: 0-6
        arithmetic mean (standard deviation)
    		 1.2 ± 1.4 1.4 ± 1.8 1.4 ± 1.6 1.0 ± 1.6 0.7 ± 1.1 -
    Cough (0-6)
    Units: 0-6
        arithmetic mean (standard deviation)
    		 2.5 ± 1.8 1.8 ± 1.7 1.0 ± 1.0 2.2 ± 1.7 1.5 ± 1.6 -
    Blocked/runny nose (0-6)
    Units: 0-6
        arithmetic mean (standard deviation)
    		 2.3 ± 1.8 2.1 ± 1.8 1.8 ± 1.9 1.7 ± 1.1 2.9 ± 1.8 -
    Vomiting (0-6)
    Units: 0-6
        arithmetic mean (standard deviation)
    		 0.5 ± 1.5 0.4 ± 1.0 0.2 ± 0.6 0.4 ± 1.3 0.5 ± 1.1 -
    General health (0-10)
    From 0 (not at all unwell) to 10 (extremely unwell)
    Units: 0-10
        arithmetic mean (standard deviation)
    		 3.6 ± 1.9 3.3 ± 1.8 3.9 ± 1.7 3.3 ± 1.5 3.1 ± 1.2 -
    Temperature
    Units: Degrees celsius
        arithmetic mean (standard deviation)
    		 37.0 ± 0.6 36.9 ± 0.7 37.1 ± 0.8 37.5 ± 1.3 37.1 ± 0.6 -

    End points

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    End points reporting groups
    Reporting group title
    2-arm Active drops
    Reporting group description
    		 The Investigational Medicinal Product (IMP) for this trial was a benzocaine and phenazone otic solution. This is an oil based, combined local anaesthetic (benzocaine) and analgesic (phenazone, International Nonproprietary Name, also known in the US as antipyrine) ear drop. One millilitre contains 14 mg (1.4%) of benzocaine and 54mg (5.4%) phenazone suspended in a glycerine-based liquid along with a preservative (hydroxyquinolone sulphate). For this trial we intended to test Auralgan©, manufactured by Pfizer Consumer Healthcare (Australia) and sold in 15mL bottles.

    Reporting group title
    2-arm No drops
    Reporting group description
    		 No intervention.

    Reporting group title
    3-arm Active drops
    Reporting group description
    		 The Investigational Medicinal Product (IMP) for this trial was a benzocaine and phenazone otic solution. This is an oil based, combined local anaesthetic (benzocaine) and analgesic (phenazone, International Nonproprietary Name, also known in the US as antipyrine) ear drop. One millilitre contains 14 mg (1.4%) of benzocaine and 54mg (5.4%) phenazone suspended in a glycerine-based liquid along with a preservative (hydroxyquinolone sulphate). For this trial we intended to test Auralgan©, manufactured by Pfizer Consumer Healthcare (Australia) and sold in 15mL bottles.

    Reporting group title
    3-arm Placebo drops
    Reporting group description
    		 The placebo was glycerine, with packaging as close in appearance as possible to that used for the active drops (Albany Molecular Research (Glasgow) Ltd).

    Reporting group title
    3-arm No drops
    Reporting group description
    		 No intervention.
    Reporting group title
    Active drops
    Reporting group description
    		 The Investigational Medicinal Product (IMP) for this trial was a benzocaine and phenazone otic solution. This is an oil based, combined local anaesthetic (benzocaine) and analgesic (phenazone, International Nonproprietary Name, also known in the US as antipyrine) ear drop. One millilitre contains 14 mg (1.4%) of benzocaine and 54mg (5.4%) phenazone suspended in a glycerine-based liquid along with a preservative (hydroxyquinolone sulphate). For this trial we intended to test Auralgan©, manufactured by Pfizer Consumer Healthcare (Australia) and sold in 15mL bottles.

    Reporting group title
    No drops
    Reporting group description
    		 No intervention.
    Reporting group title
    Active drops
    Reporting group description
    		 The Investigational Medicinal Product (IMP) for this trial was a benzocaine and phenazone otic solution. This is an oil based, combined local anaesthetic (benzocaine) and analgesic (phenazone, International Nonproprietary Name, also known in the US as antipyrine) ear drop. One millilitre contains 14 mg (1.4%) of benzocaine and 54mg (5.4%) phenazone suspended in a glycerine-based liquid along with a preservative (hydroxyquinolone sulphate). For this trial we intended to test Auralgan©, manufactured by Pfizer Consumer Healthcare (Australia) and sold in 15mL bottles.

    Reporting group title
    No drops
    Reporting group description
    		 No intervention.

    Reporting group title
    Placebo drops
    Reporting group description
    		 The placebo was glycerine, with packaging as close in appearance as possible to that used for the active drops (Albany Molecular Research (Glasgow) Ltd).

    Primary: Antibiotic consumption (Active vs. No drops)

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    End point title
    		 Antibiotic consumption (Active vs. No drops)
    End point description
    Question: Did your child consume antibiotics by mouth today? Y/N
    End point type
    Primary
    End point timeframe
    Asked whether or not the child had taken antibiotics every day for 8 days.
    End point values
    		 Active drops No drops Active drops No drops Placebo drops
    Number of subjects analysed
    29
    30
    10
    8
    7
    Units: Yes or No to consumption during the week
        Yes
    1
    9
    0
    2
    3
        No
    28
    21
    10
    6
    4
    Statistical analysis title
    		 Odds Ratio (Active vs. No drops)
    Statistical analysis description
    When comparing active and no drops arms in the 2-arm trial, logistic regression was employed, with and without adjustment. When comparing active and no drops in the 3-arm trial the calculations were made by hand, using a continuity correction of 0.4444 to account for the zero numerator. The results were then combined in a meta-analysis (using the inverse method) to give an overall comparison between arms.
    Comparison groups
    Active drops v No drops v Active drops v No drops
    Number of subjects included in analysis
    77
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.009 [1]
    Method
    		 Regression, Logistic
    Parameter type
    		 Odds ratio (OR)
    Point estimate
    0.09
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.02
         upper limit
    		 0.55
    Variability estimate
    Standard error of the mean
    Notes
    [1] - Unadjusted p value = 0.009 whereas adjustment for delayed antibiotic script was 0.035.

    Secondary: Ear Pain on Day 2 (Active vs. Placebo; No drops vs. Placebo; Active vs. No drops))

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    End point title
    		 Ear Pain on Day 2 (Active vs. Placebo; No drops vs. Placebo; Active vs. No drops))
    End point description
    Question: Please score your overall impression of your child's ear pain over the last 24 hours using the scale and write the score in the boxes below. Scale 0 (no pain) to 10 (worst possible pain).
    End point type
    Secondary
    End point timeframe
    Parents were asked to rate their child's pain on a scale of 0 to 10 every day for 8 days. This measurement was taken on the evening of Day 2.
    End point values
    		 Active drops No drops Active drops No drops Placebo drops
    Number of subjects analysed
    32
    30
    10
    9
    7
    Units: Pain: 0 (no pain) to 10 (worst possible)
        arithmetic mean (standard deviation)
    2.81 ± 2.32
    4.43 ± 2.54
    3.10 ± 2.23
    5.00 ± 1.73
    2.14 ± 1.07
    Statistical analysis title
    		 Difference in means (Active vs. placebo)
    Statistical analysis description
    Difference in mean ear pain between the active drops group and placebo drops group, with additional adjustment for parent reported pain score at consultation.
    Comparison groups
    Active drops v Placebo drops
    Number of subjects included in analysis
    17
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.312 [2]
    Method
    		 Regression, Linear
    Parameter type
    		 Mean difference (final values)
    Point estimate
    0.96
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.99
         upper limit
    		 2.91
    Variability estimate
    Standard error of the mean
    Notes
    [2] - Unadjusted p value = 0.312, Adjusting for parent reported pain score at consultation = 0.506.
    Statistical analysis title
    		 Difference in means (No drops vs. placebo)
    Statistical analysis description
    Difference in mean ear pain between the no drops group and placebo drops group, with additional adjustment for parent reported pain score at consultation.
    Comparison groups
    No drops v Placebo drops
    Number of subjects included in analysis
    16
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.002 [3]
    Method
    		 Regression, Linear
    Parameter type
    		 Mean difference (final values)
    Point estimate
    2.86
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 1.25
         upper limit
    		 4.46
    Variability estimate
    Standard error of the mean
    Notes
    [3] - Unadjusted p value = 0.002. Adjusting for parent reported pain score at consultation = 0.003.
    Statistical analysis title
    		 Difference in means (Active vs. no drops)
    Statistical analysis description
    As an exploratory analysis, the active and no drops groups were compared separately in the 2-arm and 3-arm trials to establish whether there was a difference in ear pain between the two groups. The results were pooled using the inverse variance meta-analysis method.
    Comparison groups
    Active drops v No drops v Active drops v No drops
    Number of subjects included in analysis
    81
    Analysis specification
    Post-hoc
    Analysis type
    		 superiority [4]
    P-value
    		 = 0.001 [5]
    Method
    		 Regression, Linear
    Parameter type
    		 Mean difference (final values)
    Point estimate
    -1.7
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -2.74
         upper limit
    		 -0.66
    Variability estimate
    Standard error of the mean
    Notes
    [4] - Exploratory
    [5] - Unadjusted p=0.001, Adjusting for parent reported pain score at consultation <0.001.

    Secondary: Ear Pain on Day 1 (Active vs. Placebo)

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    End point title
    		 Ear Pain on Day 1 (Active vs. Placebo)
    End point description
    Question: Please score your child's ear pain as close to 1 hour (60 minutes) after giving the ear drops as possible, using the scale and write the score in the boxes below. Scale 0 (no pain) to 10 (worst possible pain).
    End point type
    Secondary
    End point timeframe
    Parents were asked to rate their child's pain on a scale of 0 to 10 every day for 8 days. This measurement was taken approximately one hour after administering the drops in the consultation (Day 1).
    End point values
    		 Active drops Placebo drops
    Number of subjects analysed
    10
    7
    Units: Pain: 0 (no pain) to 10 (worst possible)
        arithmetic mean (standard deviation)
    2.70 ± 1.16
    3.42 ± 1.62
    Statistical analysis title
    		 Difference in means (Active vs. placebo)
    Statistical analysis description
    Difference in mean ear pain on Day 1 between active and placebo groups, presenting unadjusted results as well as after adjusting for parent reported pain score at consultation.
    Comparison groups
    Active drops v Placebo drops
    Number of subjects included in analysis
    17
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.295 [6]
    Method
    		 Regression, Linear
    Parameter type
    		 Mean difference (final values)
    Point estimate
    -0.73
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -2.16
         upper limit
    		 0.7
    Variability estimate
    Standard error of the mean
    Notes
    [6] - Unadjusted p = 0.295. Adjusted for parent reported ear pain at consultation = 0.338.

    Secondary: Analgesic consumption (Active vs. Placebo)

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    End point title
    		 Analgesic consumption (Active vs. Placebo)
    End point description
    Parents answered Y or N and these answers were compiled to create an overall Y/N binary consumption variable.
    End point type
    Secondary
    End point timeframe
    Parents were asked everyday for 8 days whether their child had consumed ibuprofen, paracetamol or other pain-killing remedies during the day.
    End point values
    		 Active drops Placebo drops
    Number of subjects analysed
    9
    7
    Units: Consumption of analgesics (Y/N)
        Yes
    8
    6
        No
    1
    1
    Statistical analysis title
    		 Odds Ratio (Active vs. placebo)
    Statistical analysis description
    Logistic regression to compare analgesic consumption between active and placebo groups. Unadjusted results were presented, as well as results after adjustment for parent reported pain score at consultation.
    Comparison groups
    Active drops v Placebo drops
    Number of subjects included in analysis
    16
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.849 [7]
    Method
    		 Regression, Logistic
    Parameter type
    		 Odds ratio (OR)
    Point estimate
    1.33
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.07
         upper limit
    		 25.91
    Variability estimate
    Standard error of the mean
    Notes
    [7] - Unadjusted p=0.849. Adjustment for parent reported pain score at consultation = 0.911

    Secondary: Overall Symptom Burden (No drops vs. Active; Placebo vs. Active)

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    End point title
    		 Overall Symptom Burden (No drops vs. Active; Placebo vs. Active)
    End point description
    Thinking about and comparing your child's normal behaviour when well, did he/she have any of the following symptoms over the last 24 hours? Episodes of distress/crying (0-6), Disturbed sleep (0-6), Interference with normal activities (0-6), Eating or drinking less than normal (0-6), High temperature/fever (0-6), Hearing problems (0-6). Where 0 is "normal" and 6 is "extremely bad".
    End point type
    Secondary
    End point timeframe
    Overall symptom burden over 8 days, where each day consisted of 6 questions on a scale of 0 to 6. Therefore the area under the curve could be between 0 (0 for eight days) and 288 (6*6 for 8 days).
    End point values
    		 Active drops No drops Active drops No drops Placebo drops
    Number of subjects analysed
    32
    28
    10
    9
    7
    Units: Area under the curve
        median (inter-quartile range (Q1-Q3))
    11.5 (5.8 to 33.5)
    30.3 (6.3 to 45.0)
    15.8 (8.5 to 21.5)
    28.5 (14.0 to 42.0)
    24.5 (10.5 to 50.5)
    Statistical analysis title
    		 Difference in means (No drops vs. active, 2-arm)
    Statistical analysis description
    Comparison in mean (square root) area under the curves for the active and no drops groups (in the 2-arm trial). Due to the skewed nature we compared the square root AUC.
    Comparison groups
    Active drops v No drops
    Number of subjects included in analysis
    60
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.094
    Method
    		 Regression, Linear
    Parameter type
    		 Mean difference (final values)
    Point estimate
    1.14
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.2
         upper limit
    		 2.49
    Variability estimate
    Standard error of the mean
    Statistical analysis title
    		 Difference in means (No drops vs. active, 3-arm)
    Statistical analysis description
    Comparison in mean (square root) area under the curves for the active and no drops groups (in the 3-arm trial). Due to the skewed nature we compared the square root AUC.
    Comparison groups
    Active drops v No drops
    Number of subjects included in analysis
    19
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.072
    Method
    		 Regression, Linear
    Parameter type
    		 Mean difference (final values)
    Point estimate
    1.35
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.13
         upper limit
    		 2.84
    Variability estimate
    Standard error of the mean
    Statistical analysis title
    		 Difference in means (Placebo vs. active, 3-arm)
    Statistical analysis description
    Comparison in mean (square root) area under the curves for the active and placebo groups (in the 2-arm trial). Due to the skewed nature we compared the square root AUC.
    Comparison groups
    Placebo drops v Active drops
    Number of subjects included in analysis
    17
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.085
    Method
    		 Regression, Linear
    Parameter type
    		 Mean difference (final values)
    Point estimate
    1.81
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -0.28
         upper limit
    		 3.9
    Variability estimate
    Standard error of the mean

    Secondary: Overall illness duration (Placebo vs. Active; No drops vs. Active)

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    End point title
    		 Overall illness duration (Placebo vs. Active; No drops vs. Active)
    End point description
    The number of days until the parent rated score of pain is zero for 2 consecutive days.
    End point type
    Secondary
    End point timeframe
    8 days
    End point values
    		 Active drops No drops Active drops No drops Placebo drops
    Number of subjects analysed
    34
    31
    10
    9
    7
    Units: Pain duration (days)
        median (inter-quartile range (Q1-Q3))
    3 (2 to 5)
    4 (3 to 999)
    3 (3 to 5)
    3 (2 to 6)
    2 (2 to 4)
    Statistical analysis title
    		 Hazard ratio (No drops vs. Active 2-arm)
    Statistical analysis description
    Time to event (Kaplan Meier) where the event is two consecutive days of 0 pain (recovery).
    Comparison groups
    No drops v Active drops
    Number of subjects included in analysis
    65
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.11
    Method
    		 Regression, Cox
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    0.62
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.34
         upper limit
    		 1.11
    Variability estimate
    Standard error of the mean
    Statistical analysis title
    		 Hazard ratio (No drops vs. Active 3-arm)
    Statistical analysis description
    Time to event (Kaplan Meier) where the event is two consecutive days of 0 pain (recovery).
    Comparison groups
    No drops v Active drops
    Number of subjects included in analysis
    19
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.9
    Method
    		 Regression, Cox
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    0.94
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.38
         upper limit
    		 2.61
    Variability estimate
    Standard error of the mean
    Statistical analysis title
    		 Hazard ratio (Placebo vs. Active)
    Statistical analysis description
    Time to event (Kaplan Meier) where the event is two consecutive days of 0 pain (recovery).
    Comparison groups
    Placebo drops v Active drops
    Number of subjects included in analysis
    17
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.31
    Method
    		 Regression, Cox
    Parameter type
    		 Hazard ratio (HR)
    Point estimate
    1.7
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.61
         upper limit
    		 4.75
    Variability estimate
    Standard error of the mean

    Secondary: Parent satisfaction

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    End point title
    		 Parent satisfaction
    End point description
    Valid only for active and placebo drop group children (and respective parents). Parents were asked: Overall how satisfied were you with the trial ear drops your child received for their ear pain? Satisfied; neither satisfied nor disatisfied; not satisfied.
    End point type
    Secondary
    End point timeframe
    At the end of the week, on day 8, parents were asked if they were satisfied with the drops
    End point values
    		 Active drops Active drops Placebo drops
    Number of subjects analysed
    29
    10
    7
    Units: Categorical
        Satisfied
    27
    9
    4
        Neither satisfied nor disatisfied
    2
    1
    2
        Not satisfied
    0
    0
    1
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    At the end of the trial (8 days after randomisation) parents were asked to report any new or worsening symptoms.
    Adverse event reporting additional description
    We were alerted to any serious adverse events by the site principal investigator. All other adverse events were captured within the parental questionnaire. All non-serious adverse events were categorised as mild, moderate or severe.
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 SNOMED CT
    Dictionary version
    1.36.4
    Reporting groups
    Reporting group title
    Active drops
    Reporting group description
    		 -

    Reporting group title
    Placebo drops
    Reporting group description
    		 -

    Reporting group title
    No drops
    Reporting group description
    		 -

    Serious adverse events
    		 Active drops Placebo drops No drops
    Total subjects affected by serious adverse events
         subjects affected / exposed
    0 / 50 (0.00%)
    0 / 10 (0.00%)
    1 / 46 (2.17%)
         number of deaths (all causes)
    0
    0
    0
         number of deaths resulting from adverse events
    0
    0
    0
    Respiratory, thoracic and mediastinal disorders
    Difficulty breathing
    Additional description: Child admitted to hospital due to breathing issues. The child was discharged from the hospital the next day and the parent completed the questionnaire. This child was allocated to the usual care group, and so the event is unrelated to treatment.
         subjects affected / exposed
    0 / 50 (0.00%)
    0 / 10 (0.00%)
    1 / 46 (2.17%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 0.5%
    Non-serious adverse events
    		 Active drops Placebo drops No drops
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    2 / 50 (4.00%)
    0 / 10 (0.00%)
    4 / 46 (8.70%)
    Nervous system disorders
    Problem with balance
    Additional description: Reported as moderate.
         subjects affected / exposed
    0 / 50 (0.00%)
    0 / 10 (0.00%)
    1 / 46 (2.17%)
         occurrences all number
    0
    0
    1
    Ear and labyrinth disorders
    Ringing in ear
    Additional description: Reported as mild.
         subjects affected / exposed
    0 / 50 (0.00%)
    0 / 10 (0.00%)
    1 / 46 (2.17%)
         occurrences all number
    0
    0
    1
    Respiratory, thoracic and mediastinal disorders
    Common cold
    Additional description: Reported as moderate.
         subjects affected / exposed
    1 / 50 (2.00%)
    0 / 10 (0.00%)
    0 / 46 (0.00%)
         occurrences all number
    1
    0
    0
    Bleeding from nose
    Additional description: Reported as moderate.
         subjects affected / exposed
    0 / 50 (0.00%)
    0 / 10 (0.00%)
    1 / 46 (2.17%)
         occurrences all number
    0
    0
    1
    Skin and subcutaneous tissue disorders
    Itching of skin
    Additional description: Reported as moderate. They reported itching around the neck.
         subjects affected / exposed
    0 / 50 (0.00%)
    0 / 10 (0.00%)
    1 / 46 (2.17%)
         occurrences all number
    0
    0
    1
    Infections and infestations
    Chicken pox
    Additional description: Reported as mild.
         subjects affected / exposed
    1 / 50 (2.00%)
    0 / 10 (0.00%)
    0 / 46 (0.00%)
         occurrences all number
    1
    0
    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? Yes
    Date
    Interruption
    Restart date
    01 Sep 2017
    The project start date was 1st January 2015, and the planned study end date was 31st March 2018. Issues were encountered with a lengthy delay to the IMP supply. While the IMP supplier was identified through a competitive procurement process, the supplier failed to deliver the active drops and placebo in line with expected and revised timeframes. The trial team requested a variation to the contract with the funder to allow for the trial to reach its target. On the 1st of September 2017, the funder declined the contract variation and requested for the trial to be closed down. The project closed early, on 31st December 2017, as required by the funders.
    -

    Limitations and caveats
    Limitations of the trial such as small numbers of subjects analysed or technical problems leading to unreliable data.
    The project closed early, on 31st December 2017, as required by the funders. Analyses were based on a limited sample size therefore results should be viewed with caution. Some analyses were not conducted owing to low numbers.

    Online references
    http://www.ncbi.nlm.nih.gov/pubmed/31304912
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