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    Clinical Trial Results:
    What is the clinical and cost effectiveness of oral steroids in the treatment of acute lower respiratory tract infection (LRTI)? A placebo controlled randomised trial

    Summary
    EudraCT number
    2012-000851-15
    Trial protocol
    GB  
    Global end of trial date
    27 Feb 2015

    Results information
    Results version number
    v1(current)
    This version publication date
    10 May 2018
    First version publication date
    10 May 2018
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    UoB1581
    Additional study identifiers
    ISRCTN number
    ISRCTN57309858
    US NCT number
    -
    WHO universal trial number (UTN)
    -
    Other trial identifiers
    NHS REC: 12/SW/0180, EudraCT: 2012-000851-15, NIHR CSP: 102138
    Sponsors
    Sponsor organisation name
    University of Bristol
    Sponsor organisation address
    Senate House, Tyndall Avenue, Bristol, United Kingdom, BS8 1TH
    Public contact
    Birgit Whitman, University of Bristol, +44 01173317130, birgit.whitman@bristol.ac.uk
    Scientific contact
    Birgit Whitman, University of Bristol, +44 01173317130, birgit.whitman@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
    18 Jul 2017
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    21 Jan 2015
    Global end of trial reached?
    Yes
    Global end of trial date
    27 Feb 2015
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    Does the use of oral prednisolone reduce the duration of moderately bad or worse cough and / or the severity of all its associated symptoms on days 2 to 4 by at least 20% when compared to no steroid treatment in adults ≥18 years presenting to primary care with acute LRTI?
    Protection of trial subjects
    All Serious Adverse events were reported to the UH Bristol contact and Centre Principal Investigator by a delegated member of the research team within 24 hours of their knowledge of the event.
    Background therapy
    -
    Evidence for comparator
    -
    Actual start date of recruitment
    01 Oct 2012
    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: 398
    Worldwide total number of subjects
    398
    EEA total number of subjects
    398
    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)
    336
    From 65 to 84 years
    62
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    The study was conducted between July 2013 and October 2014. Family physicians and nurses (recruiting clinicians) were trained in study procedures by 4 centres at the Universities of Bristol, Southampton, Nottingham, and Oxford. Fifty-eight family physicians and 50 practice nurses based in 54 family practices assessed patients for suitability.

    Pre-assignment
    Screening details
    525 patients were assessed for suitability, of whom; 124 were excluded due to ineligibility, 4 declined participation and 401 were randomised.

    Period 1
    Period 1 title
    Overall trial (overall period)
    Is this the baseline period?
    Yes
    Allocation method
    Randomised - controlled
    Blinding used
    Double blind
    Roles blinded
    Investigator, Monitor, Subject, Data analyst, Assessor
    Blinding implementation details
    The treatment allocation schedule was computer generated by a statistician independent of the trial team in a 1:1 ratio, using a variable block size (4, 6, 8 and 10). Allocated medication was added to numbered participant packs by pharmacists independent of the team. All packs were identical, containing either 20mg oral prednisolone tablets (Galen Pharma GmbH) or placebo tablets matched on dimension, appearance and taste (Piramal Healthcare Ltd).

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    Prednisolone
    Arm description
    Participant packs containing ten 20-mg oral prednisolone tablets (Galen Pharma GmbH). Participants were asked to take 2 tablets once daily for 5 days, starting on the day of consultation, if possible before starting any antibiotics (if receiving a "delayed" prescription).
    Arm type
    Active comparator

    Investigational medicinal product name
    Prednisolone
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Participants were asked to take 2 tablets once daily for 5 days, starting on the day of consultation, if possible before starting any antibiotics (if receiving a "delayed" prescription).

    Arm title
    Placebo
    Arm description
    Participant packs containing ten 20-mg placebo tablets matched on dimension, appearance and taste (Piramal Healthcare Ltd) to oral prednisolone tablets. Participants were asked to take 2 tablets once daily for 5 days, starting on the day of consultation, if possible before starting any antibiotics (if receiving a "delayed" prescription).
    Arm type
    Placebo

    Investigational medicinal product name
    Placebo (no active ingredient)
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Participants were asked to take 2 tablets once daily for 5 days, starting on the day of consultation, if possible before stating any antibiotics (if receiving a "delayed" prescription).

    Number of subjects in period 1
    Prednisolone Placebo
    Started
    198
    200
    Completed
    198
    200

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Prednisolone
    Reporting group description
    Participant packs containing ten 20-mg oral prednisolone tablets (Galen Pharma GmbH). Participants were asked to take 2 tablets once daily for 5 days, starting on the day of consultation, if possible before starting any antibiotics (if receiving a "delayed" prescription).

    Reporting group title
    Placebo
    Reporting group description
    Participant packs containing ten 20-mg placebo tablets matched on dimension, appearance and taste (Piramal Healthcare Ltd) to oral prednisolone tablets. Participants were asked to take 2 tablets once daily for 5 days, starting on the day of consultation, if possible before starting any antibiotics (if receiving a "delayed" prescription).

    Reporting group values
    Prednisolone Placebo Total
    Number of subjects
    198 200 398
    Age categorical
    Greater than or equal to 18 years of age
    Units: Subjects
        Adults (18-64 years)
    162 174 336
        From 65-84 years
    36 26 62
    Age continuous
    Units: years
        arithmetic mean (standard deviation)
    50.0 ± 16.1 44.8 ± 15.5 -
    Gender categorical
    Units: Subjects
        Female
    116 134 250
        Male
    82 66 148
    Centre
    Units: Subjects
        Bristol
    118 113 231
        Oxford
    39 45 84
        Southampton
    24 21 45
        Nottingham
    17 21 38
    Occupation
    Units: Subjects
        Employed
    137 143 280
        Unemployed
    17 21 38
        Retired
    41 30 71
        Full-time education
    3 6 9
    Smoking status
    Units: Subjects
        Current
    31 38 69
        Past
    63 55 118
        Never
    104 106 210
        Missing
    0 1 1
    Ethnicity
    Units: Subjects
        White
    188 193 381
        Other
    10 6 16
        Missing
    0 1 1
    Living with smoker
    Units: Subjects
        Yes
    25 32 57
        No
    158 163 321
        Missing
    15 5 20
    Personal history of hayfever
    Units: Subjects
        Yes
    41 46 87
        No
    147 143 290
        Missing
    10 11 21
    Personal history of eczema
    Units: Subjects
        Yes
    30 26 56
        No
    154 164 318
        Missing
    14 10 24
    Personal history of asthma
    Units: Subjects
        Yes
    10 8 18
        No
    178 185 363
        Missing
    10 7 17
    Family history of asthma, eczema or hayfever
    Units: Subjects
        Yes
    73 76 149
        No
    109 113 222
        Missing
    16 11 27
    Influenza vaccine in last 12 months
    Units: Subjects
        Yes
    63 44 107
        No
    135 156 291
    Recruited in winter (Oct-Mar)
    Units: Subjects
        Yes
    112 114 226
        No
    86 86 172
    Sputum present within last 24hrs
    Units: Subjects
        Yes
    149 156 305
        No
    48 44 92
        Missing
    1 0 1
    Shortness of breath present within last 24hrs
    Units: Subjects
        Yes
    146 133 279
        No
    52 67 119
    Wheeze present within last 24 hrs
    Units: Subjects
        Yes
    88 98 186
        No
    109 102 211
        Missing
    1 0 1
    Abnormal peak flow (<80% of expected)
    Units: Subjects
        Yes
    87 79 166
        No
    110 121 231
        Missing
    1 0 1
    Abnormal respiratory rate (>20/min)
    Units: Subjects
        Yes
    2 1 3
        No
    194 198 392
        Missing
    2 1 3
    Chest retraction or prolonged expiration
    Units: Subjects
        Yes
    0 1 1
        No
    198 199 397
    Wheeze or rhonchi on auscultation
    Units: Subjects
        Yes
    11 11 22
        No
    187 189 376
    Crackles or crepitations on auscultation
    Includes unilateral and bilateral
    Units: Subjects
        Yes
    4 6 10
        No
    194 194 388
    Bronchial breathing
    Units: Subjects
        Yes
    0 2 2
        No
    198 198 396
    Taken prescribed beta-agonist in past 24hrs
    Units: Subjects
        Yes
    9 3 12
        No
    189 197 386
    Over the counter drugs taken for current cough
    Units: Subjects
        Yes
    128 139 267
        No
    70 61 131
    Given delayed antibiotic prescription
    Units: Subjects
        Yes
    22 25 47
        No
    176 175 351
    Chest pain present within last 24 hrs
    Units: Subjects
        Yes
    88 97 185
        No
    110 103 213
    Prior duration of cough
    Number of days the patient has been suffering with a cough
    Units: Days
        median (inter-quartile range (Q1-Q3))
    13.0 (7.0 to 20.0) 10.0 (6.0 to 17.5) -
    Weight
    Units: kg
        median (inter-quartile range (Q1-Q3))
    77.0 (64.5 to 91.0) 76.0 (66.5 to 90.5) -
    Height
    Units: cm
        median (inter-quartile range (Q1-Q3))
    168.0 (161.0 to 175.0) 168.0 (163.0 to 176.0) -
    Deprivation
    English Index of Multiple Deprivation scores (range 0-100), higher scores indicate higher levels of deprivation.
    Units: index score (0-100)
        median (inter-quartile range (Q1-Q3))
    11.0 (5.0 to 23.0) 12.0 (5.0 to 23.0) -
    Patient reported illness severity score
    Units: scale 0-10
        median (inter-quartile range (Q1-Q3))
    6.0 (5.0 to 7.0) 5.0 (4.0 to 7.0) -
    Pulse
    Units: beats per minute
        arithmetic mean (standard deviation)
    77.8 ± 12.3 77.7 ± 11.8 -
    Temperature
    Units: Degrees celsius
        arithmetic mean (standard deviation)
    36.6 ± 0.5 36.6 ± 0.4 -
    Oxygen saturation
    Units: Percentage
        arithmetic mean (standard deviation)
    97.5 ± 1.3 97.8 ± 1.1 -
    Respiratory rate
    Units: per minute
        arithmetic mean (standard deviation)
    15.4 ± 2.5 15.0 ± 2.4 -

    End points

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    End points reporting groups
    Reporting group title
    Prednisolone
    Reporting group description
    Participant packs containing ten 20-mg oral prednisolone tablets (Galen Pharma GmbH). Participants were asked to take 2 tablets once daily for 5 days, starting on the day of consultation, if possible before starting any antibiotics (if receiving a "delayed" prescription).

    Reporting group title
    Placebo
    Reporting group description
    Participant packs containing ten 20-mg placebo tablets matched on dimension, appearance and taste (Piramal Healthcare Ltd) to oral prednisolone tablets. Participants were asked to take 2 tablets once daily for 5 days, starting on the day of consultation, if possible before starting any antibiotics (if receiving a "delayed" prescription).

    Primary: PO: Duration of moderately bad or worse cough (0-28 days)

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    End point title
    PO: Duration of moderately bad or worse cough (0-28 days)
    End point description
    End point type
    Primary
    End point timeframe
    From baseline up to 28 days. If the patient was still suffering from a cough by day 28 then they were censored at this time point.
    End point values
    Prednisolone Placebo
    Number of subjects analysed
    173
    161
    Units: Days
        median (confidence interval 95%)
    5 (4 to 5)
    5 (4 to 6)
    Statistical analysis title
    Duration of MBW cough (censored at 28)
    Statistical analysis description
    Adjusted for centre and prior duration of cough
    Comparison groups
    Prednisolone v Placebo
    Number of subjects included in analysis
    334
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.36
    Method
    Regression, Cox
    Parameter type
    Hazard ratio (HR)
    Point estimate
    1.11
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.89
         upper limit
    1.39

    Primary: PO: Severity of symptoms

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    End point title
    PO: Severity of symptoms
    End point description
    Mean severity score of the 6 main symptoms (cough, phlegm, shortness of breath, sleep disturbance, feeling generally unwell and activity disturbance) on days 2-4; the mean score was calculated across the symptoms for each day and then the overall mean was calculated with a maximum value of 6.
    End point type
    Primary
    End point timeframe
    On days 2-4
    End point values
    Prednisolone Placebo
    Number of subjects analysed
    188
    181
    Units: Severity (0-6)
        arithmetic mean (confidence interval 95%)
    1.99 (1.85 to 2.13)
    2.16 (2.00 to 2.32)
    Statistical analysis title
    Difference in mean symptom severity score
    Statistical analysis description
    Adjusted for centre and baseline severity
    Comparison groups
    Placebo v Prednisolone
    Number of subjects included in analysis
    369
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.05
    Method
    Regression, Linear
    Parameter type
    Mean difference (final values)
    Point estimate
    -0.2
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -0.4
         upper limit
    0

    Secondary: Mean area under the curve for cough symptoms

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    End point title
    Mean area under the curve for cough symptoms
    End point description
    Patients were asked each day to measure the severity score of their cough on a scale of 0 (not affected) - 6 (as bad as it could be). The area under the curve was then calculated for each patient for the total 28 days.
    End point type
    Secondary
    End point timeframe
    0-28 days
    End point values
    Prednisolone Placebo
    Number of subjects analysed
    185
    179
    Units: severity score per day (0-6)
        arithmetic mean (confidence interval 95%)
    40.16 (36.67 to 43.65)
    42.88 (38.88 to 46.87)
    Statistical analysis title
    Cough symptoms - area under the curve
    Statistical analysis description
    Area under the curve adjusted for centre and baseline prior duration of cough
    Comparison groups
    Placebo v Prednisolone
    Number of subjects included in analysis
    364
    Analysis specification
    Pre-specified
    Analysis type
    superiority [1]
    P-value
    = 0.36
    Method
    Regression, Linear
    Parameter type
    Mean difference (final values)
    Point estimate
    -2.43
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -7.66
         upper limit
    2.8
    Notes
    [1] - Although the statistical technique (area under the curve) was not pre-specified the team did say that they would explore the duration and severity of other symptoms in a secondary analysis.

    Secondary: Mean area under the curve for phlegm symptoms

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    End point title
    Mean area under the curve for phlegm symptoms
    End point description
    Patients were asked each day to measure the severity score of their phlegm on a scale of 0 (not affected) - 6 (as bad as it could be). The area under the curve was then calculated for each patient for the total 28 days.
    End point type
    Secondary
    End point timeframe
    Day 1-28
    End point values
    Prednisolone Placebo
    Number of subjects analysed
    184
    179
    Units: severity score per day (0-6)
        arithmetic mean (confidence interval 95%)
    25.48 (22.19 to 28.78)
    30.01 (26.40 to 33.61)
    Statistical analysis title
    Difference in mean area under the curve for phlegm
    Statistical analysis description
    Area under the curve adjusted for centre and baseline presence/absence of symptom (previous 24 hours)
    Comparison groups
    Prednisolone v Placebo
    Number of subjects included in analysis
    363
    Analysis specification
    Pre-specified
    Analysis type
    superiority [2]
    P-value
    = 0.09
    Method
    Regression, Linear
    Parameter type
    Mean difference (final values)
    Point estimate
    -4.1
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -8.89
         upper limit
    0.7
    Notes
    [2] - Although the statistical technique (area under the curve) was not pre-specified the team did say that they would explore the duration and severity of other symptoms in a secondary analysis.

    Secondary: Mean area under the curve for shortness of breath

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    End point title
    Mean area under the curve for shortness of breath
    End point description
    End point type
    Secondary
    End point timeframe
    Patients were asked each day to measure the severity score of their shortness of breath on a scale of 0 (not affected) - 6 (as bad as it could be). The area under the curve was then calculated for each patient for the total 28 days.
    End point values
    Prednisolone Placebo
    Number of subjects analysed
    184
    179
    Units: severity score per day (0-6)
        arithmetic mean (confidence interval 95%)
    16.10 (13.25 to 18.95)
    18.39 (15.16 to 21.61)
    Statistical analysis title
    Difference in mean area under the curve for shrtb
    Statistical analysis description
    Area under the curve adjusted for centre and baseline presence/absence of symptom (previous 24 hours)
    Comparison groups
    Prednisolone v Placebo
    Number of subjects included in analysis
    363
    Analysis specification
    Pre-specified
    Analysis type
    superiority [3]
    P-value
    = 0.27
    Method
    Regression, Linear
    Parameter type
    Mean difference (final values)
    Point estimate
    -2.3
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -6.34
         upper limit
    1.75
    Notes
    [3] - Although the statistical technique (area under the curve) was not pre-specified the team did say that they would explore the duration and severity of other symptoms in a secondary analysis.

    Secondary: Mean area under the curve for wheeze

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    End point title
    Mean area under the curve for wheeze
    End point description
    Patients were asked each day to measure the severity score of their wheeze on a scale of 0 (not affected) - 6 (as bad as it could be). The area under the curve was then calculated for each patient for the total 28 days.
    End point type
    Secondary
    End point timeframe
    0-28 days
    End point values
    Prednisolone Placebo
    Number of subjects analysed
    183
    179
    Units: severity scores per day (0-6)
        arithmetic mean (confidence interval 95%)
    12.32 (9.69 to 14.96)
    13.24 (10.37 to 16.11)
    Statistical analysis title
    Difference in mean area under the curve for wheeze
    Statistical analysis description
    Area under the curve adjusted for centre and baseline presence/absence of symptom (previous 24 hours)
    Comparison groups
    Prednisolone v Placebo
    Number of subjects included in analysis
    362
    Analysis specification
    Pre-specified
    Analysis type
    superiority [4]
    P-value
    = 0.92
    Method
    Regression, Linear
    Parameter type
    Mean difference (final values)
    Point estimate
    0.18
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -3.27
         upper limit
    3.64
    Notes
    [4] - Although the statistical technique (area under the curve) was not pre-specified the team did say that they would explore the duration and severity of other symptoms in a secondary analysis.

    Secondary: Mean area under the curve for blocked or runny nose

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    End point title
    Mean area under the curve for blocked or runny nose
    End point description
    Patients were asked each day to measure the severity score of their blocked/runny nose on a scale of 0 (not affected) - 6 (as bad as it could be). The area under the curve was then calculated for each patient for the total 28 days.
    End point type
    Secondary
    End point timeframe
    0-28 days
    End point values
    Prednisolone Placebo
    Number of subjects analysed
    182
    179
    Units: severity score per day (0-6)
        arithmetic mean (confidence interval 95%)
    19.83 (16.38 to 23.28)
    20.06 (17.12 to 23.00)
    Statistical analysis title
    Difference in mean area under the curve for nose
    Statistical analysis description
    Area under the curve adjusted for centre and baseline presence/absence of symptom (previous 24 hours)
    Comparison groups
    Prednisolone v Placebo
    Number of subjects included in analysis
    361
    Analysis specification
    Pre-specified
    Analysis type
    superiority [5]
    P-value
    = 0.76
    Method
    Regression, Linear
    Parameter type
    Mean difference (final values)
    Point estimate
    0.67
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -3.7
         upper limit
    5.05
    Notes
    [5] - Although the statistical technique (area under the curve) was not pre-specified the team did say that they would explore the duration and severity of other symptoms in a secondary analysis.

    Secondary: Mean area under the curve for chest pain

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    End point title
    Mean area under the curve for chest pain
    End point description
    Patients were asked each day to measure the severity score of their chest pain on a scale of 0 (not affected) - 6 (as bad as it could be). The area under the curve was then calculated for each patient for the total 28 days.
    End point type
    Secondary
    End point timeframe
    0-28 days
    End point values
    Prednisolone Placebo
    Number of subjects analysed
    182
    179
    Units: severity score per day (0-6)
        arithmetic mean (confidence interval 95%)
    6.64 (4.95 to 8.33)
    9.59 (6.98 to 12.19)
    Statistical analysis title
    Difference in mean area under the curve for chestp
    Statistical analysis description
    Area under the curve adjusted for centre and baseline presence/absence of symptom (previous 24 hours)
    Comparison groups
    Prednisolone v Placebo
    Number of subjects included in analysis
    361
    Analysis specification
    Pre-specified
    Analysis type
    superiority [6]
    P-value
    = 0.05
    Method
    Regression, Linear
    Parameter type
    Mean difference (final values)
    Point estimate
    -2.92
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -5.83
         upper limit
    -0.01
    Notes
    [6] - Although the statistical technique (area under the curve) was not pre-specified the team did say that they would explore the duration and severity of other symptoms in a secondary analysis.

    Secondary: Mean area under the curve for fever

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    End point title
    Mean area under the curve for fever
    End point description
    Patients were asked each day to measure the severity score of their fever on a scale of 0 (not affected) - 6 (as bad as it could be). The area under the curve was then calculated for each patient for the total 28 days.
    End point type
    Secondary
    End point timeframe
    0-28 days
    End point values
    Prednisolone Placebo
    Number of subjects analysed
    182
    179
    Units: severity score per day (0-6)
        arithmetic mean (confidence interval 95%)
    2.98 (2.05 to 3.91)
    3.45 (2.07 to 4.82)
    Statistical analysis title
    Difference in mean area under the curve for fever
    Statistical analysis description
    Area under the curve adjusted for centre and baseline presence/absence of symptom (previous 24 hours)
    Comparison groups
    Prednisolone v Placebo
    Number of subjects included in analysis
    361
    Analysis specification
    Pre-specified
    Analysis type
    superiority [7]
    P-value
    = 0.68
    Method
    Regression, Linear
    Parameter type
    Mean difference (final values)
    Point estimate
    -0.33
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -1.9
         upper limit
    1.24
    Notes
    [7] - Although the statistical technique (area under the curve) was not pre-specified the team did say that they would explore the duration and severity of other symptoms in a secondary analysis.

    Secondary: Mean area under the curve for muscle ache

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    End point title
    Mean area under the curve for muscle ache
    End point description
    Patients were asked each day to measure the severity score of their muscle ache on a scale of 0 (not affected) - 6 (as bad as it could be). The area under the curve was then calculated for each patient for the total 28 days.
    End point type
    Secondary
    End point timeframe
    0-28 days
    End point values
    Prednisolone Placebo
    Number of subjects analysed
    182
    179
    Units: severity score per day (0-6)
        arithmetic mean (confidence interval 95%)
    8.83 (6.71 to 10.96)
    10.29 (7.53 to 13.06)
    Statistical analysis title
    Difference in mean area under the curve for muscle
    Statistical analysis description
    Area under the curve adjusted for centre and baseline presence/absence of symptom (previous 24 hours)
    Comparison groups
    Prednisolone v Placebo
    Number of subjects included in analysis
    361
    Analysis specification
    Pre-specified
    Analysis type
    superiority [8]
    P-value
    = 0.35
    Method
    Regression, Linear
    Parameter type
    Mean difference (final values)
    Point estimate
    -1.61
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -4.99
         upper limit
    1.77
    Notes
    [8] - Although the statistical technique (area under the curve) was not pre-specified the team did say that they would explore the duration and severity of other symptoms in a secondary analysis.

    Secondary: Mean area under the curve for headache

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    End point title
    Mean area under the curve for headache
    End point description
    Patients were asked each day to measure the severity score of their headache on a scale of 0 (not affected) - 6 (as bad as it could be). The area under the curve was then calculated for each patient for the total 28 days.
    End point type
    Secondary
    End point timeframe
    0-28 days
    End point values
    Prednisolone Placebo
    Number of subjects analysed
    182
    179
    Units: severity score per day (0-6)
        arithmetic mean (confidence interval 95%)
    10.77 (8.27 to 13.28)
    11.83 (8.89 to 14.77)
    Statistical analysis title
    Difference in mean area under the curve for headac
    Statistical analysis description
    Area under the curve adjusted for centre and baseline presence/absence of symptom (previous 24 hours)
    Comparison groups
    Prednisolone v Placebo
    Number of subjects included in analysis
    361
    Analysis specification
    Pre-specified
    Analysis type
    superiority [9]
    P-value
    = 0.74
    Method
    Regression, Linear
    Parameter type
    Mean difference (final values)
    Point estimate
    -0.62
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -4.34
         upper limit
    3.09
    Notes
    [9] - Although the statistical technique (area under the curve) was not pre-specified the team did say that they would explore the duration and severity of other symptoms in a secondary analysis.

    Secondary: Mean area under the curve for sleep disturbance

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    End point title
    Mean area under the curve for sleep disturbance
    End point description
    Patients were asked each day to measure the severity score of their sleep disturbance on a scale of 0 (not affected) - 6 (as bad as it could be). The area under the curve was then calculated for each patient for the total 28 days.
    End point type
    Secondary
    End point timeframe
    0-28 days
    End point values
    Prednisolone Placebo
    Number of subjects analysed
    183
    179
    Units: severity score per day (0-6)
        arithmetic mean (confidence interval 95%)
    20.80 (17.66 to 23.94)
    22.11 (18.13 to 26.10)
    Statistical analysis title
    Difference in mean area under the curve for sleep
    Statistical analysis description
    Area under the curve adjusted for centre and baseline presence/absence of symptom (previous 24 hours)
    Comparison groups
    Prednisolone v Placebo
    Number of subjects included in analysis
    362
    Analysis specification
    Pre-specified
    Analysis type
    superiority [10]
    P-value
    = 0.76
    Method
    Regression, Linear
    Parameter type
    Mean difference (final values)
    Point estimate
    -0.75
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -5.6
         upper limit
    4.1
    Notes
    [10] - Although the statistical technique (area under the curve) was not pre-specified the team did say that they would explore the duration and severity of other symptoms in a secondary analysis.

    Secondary: Mean area under the curve for feeling generally unwell

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    End point title
    Mean area under the curve for feeling generally unwell
    End point description
    Patients were asked each day to measure the severity score of how well they felt in generally on a scale of 0 (not affected) - 6 (as bad as it could be). The area under the curve was then calculated for each patient for the total 28 days.
    End point type
    Secondary
    End point timeframe
    0-28 days
    End point values
    Prednisolone Placebo
    Number of subjects analysed
    182
    179
    Units: severity score per day (0-6)
        arithmetic mean (confidence interval 95%)
    19.83 (17.22 to 22.45)
    22.68 (19.17 to 26.19)
    Statistical analysis title
    Difference in mean area under the curve for unwell
    Statistical analysis description
    Area under the curve adjusted for centre and baseline presence/absence of symptom (previous 24 hours)
    Comparison groups
    Prednisolone v Placebo
    Number of subjects included in analysis
    361
    Analysis specification
    Pre-specified
    Analysis type
    superiority [11]
    P-value
    = 0.12
    Method
    Regression, Linear
    Parameter type
    Mean difference (final values)
    Point estimate
    -3.25
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -7.38
         upper limit
    0.89
    Notes
    [11] - Although the statistical technique (area under the curve) was not pre-specified the team did say that they would explore the duration and severity of other symptoms in a secondary analysis.

    Secondary: Mean area under the curve for activity disturbance

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    End point title
    Mean area under the curve for activity disturbance
    End point description
    Patients were asked each day to measure the severity score of their activity disturbance on a scale of 0 (not affected) - 6 (as bad as it could be). The area under the curve was then calculated for each patient for the total 28 days.
    End point type
    Secondary
    End point timeframe
    0-28 days
    End point values
    Prednisolone Placebo
    Number of subjects analysed
    182
    179
    Units: severity score per day (0-6)
        arithmetic mean (confidence interval 95%)
    14.29 (12.01 to 16.57)
    19.07 (15.40 to 22.74)
    Statistical analysis title
    Difference in mean area under the curve for active
    Statistical analysis description
    Area under the curve adjusted for centre and baseline presence/absence of symptom (previous 24 hours)
    Comparison groups
    Prednisolone v Placebo
    Number of subjects included in analysis
    361
    Analysis specification
    Pre-specified
    Analysis type
    superiority [12]
    P-value
    = 0.02
    Method
    Regression, Linear
    Parameter type
    Mean difference (final values)
    Point estimate
    -4.78
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    -8.86
         upper limit
    -0.69
    Notes
    [12] - Although the statistical technique (area under the curve) was not pre-specified the team did say that they would explore the duration and severity of other symptoms in a secondary analysis

    Secondary: Duration of moderately bad or worse cough (0-56 days)

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    End point title
    Duration of moderately bad or worse cough (0-56 days)
    End point description
    End point type
    Secondary
    End point timeframe
    From baseline up to 56 days. If the patient was still suffering from a cough by day 56 then they were censored at this time point.
    End point values
    Prednisolone Placebo
    Number of subjects analysed
    173
    161
    Units: Days
        median (confidence interval 95%)
    5 (4 to 5)
    5 (4 to 6)
    Statistical analysis title
    Duration of MBW cough (censored at 56)
    Statistical analysis description
    Adjusted for centre and prior duration of cough
    Comparison groups
    Prednisolone v Placebo
    Number of subjects included in analysis
    334
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.36
    Method
    Regression, Cox
    Parameter type
    Hazard ratio (HR)
    Point estimate
    1.11
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.89
         upper limit
    1.39

    Secondary: Duration of cough (0-56 days)

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    End point title
    Duration of cough (0-56 days)
    End point description
    End point type
    Secondary
    End point timeframe
    From baseline up to 28 days. If the patients was still suffering from a cough by day 56 then they were censored at this time point.
    End point values
    Prednisolone Placebo
    Number of subjects analysed
    191
    182
    Units: Days
        median (confidence interval 95%)
    18 (17 to 23)
    20 (17 to 25)
    Statistical analysis title
    Duration of cough (censored at 56)
    Statistical analysis description
    Adjusted for centre and prior duration of cough
    Comparison groups
    Prednisolone v Placebo
    Number of subjects included in analysis
    373
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.29
    Method
    Regression, Cox
    Parameter type
    Hazard ratio (HR)
    Point estimate
    1.13
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.9
         upper limit
    1.42

    Secondary: Duration of abnormal peak flow (0-28 days)

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    End point title
    Duration of abnormal peak flow (0-28 days)
    End point description
    End point type
    Secondary
    End point timeframe
    From baseline up to 28 days. Counted as the number of days the patient had a peak flow rate that was <80% of their expected level.
    End point values
    Prednisolone Placebo
    Number of subjects analysed
    117
    115
    Units: Days
        median (confidence interval 95%)
    10 (7 to 17)
    11 (8 to 17)
    Statistical analysis title
    Duration of abnormal peak flow (censored at 28d)
    Statistical analysis description
    Adjusted for centre and prior duration of cough
    Comparison groups
    Prednisolone v Placebo
    Number of subjects included in analysis
    232
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.58
    Method
    Regression, Cox
    Parameter type
    Hazard ratio (HR)
    Point estimate
    1.1
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.79
         upper limit
    1.52

    Secondary: Antibiotic use (up to 7 days)

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    End point title
    Antibiotic use (up to 7 days)
    End point description
    End point type
    Secondary
    End point timeframe
    From baseline up to 7 days. Patients were counted if they reported consuming antibiotics on any of the 7 days.
    End point values
    Prednisolone Placebo
    Number of subjects analysed
    191
    182
    Units: Patients
        Yes
    15
    15
        No
    176
    167
    Statistical analysis title
    Odds ratio for the antibiotic consumption (0-7)
    Statistical analysis description
    Adjusted for centre and whether the patient was given a delayed antibiotic script at baseline
    Comparison groups
    Prednisolone v Placebo
    Number of subjects included in analysis
    373
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.96
    Method
    Regression, Logistic
    Parameter type
    Odds ratio (OR)
    Point estimate
    0.98
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.42
         upper limit
    2.28

    Secondary: Antibiotic use (up to 28 days)

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    End point title
    Antibiotic use (up to 28 days)
    End point description
    End point type
    Secondary
    End point timeframe
    From baseline up to 28 days. Patients were counted if they reported consuming antibiotics on any of the 28 days.
    End point values
    Prednisolone Placebo
    Number of subjects analysed
    191
    182
    Units: Patients
        Yes
    28
    34
        No
    163
    148
    Statistical analysis title
    Odds ratio for the antibiotic consumption (0-28)
    Statistical analysis description
    Adjusted for centre and whether the patients was given a delayed antibiotic script at baseline
    Comparison groups
    Prednisolone v Placebo
    Number of subjects included in analysis
    373
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.39
    Method
    Regression, Logistic
    Parameter type
    Odds ratio (OR)
    Point estimate
    0.78
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.44
         upper limit
    1.39

    Secondary: Patient satisfaction (feel better)

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    End point title
    Patient satisfaction (feel better)
    End point description
    On day 28, patients were asked if they agreed or disagreed with "my OSAC trial tablets helped me to feel better from my cough". The proportions of participants responding 'agree' (as opposed to 'neither agree or disagree' and 'disagree') were compared between the groups.
    End point type
    Secondary
    End point timeframe
    None. Asked at the end of the symptom diary (day 28).
    End point values
    Prednisolone Placebo
    Number of subjects analysed
    178
    171
    Units: Patients
        Agree
    60
    43
        Disagree/Neither agree or disagree
    118
    128
    Statistical analysis title
    Odds ratio for patient satisfaction (feel better)
    Statistical analysis description
    Adjusted for centre
    Comparison groups
    Prednisolone v Placebo
    Number of subjects included in analysis
    349
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.11
    Method
    Regression, Logistic
    Parameter type
    Odds ratio (OR)
    Point estimate
    1.46
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.92
         upper limit
    2.34

    Secondary: Patient satisfaction (future use)

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    End point title
    Patient satisfaction (future use)
    End point description
    On day 28, patients were asked if they agreed or disagreed with "my OSAC trial tablets helped me to feel better from my cough". The proportions of participants responding 'agree' (as opposed to 'neither agree or disagree' and 'disagree') were compared between the groups.
    End point type
    Secondary
    End point timeframe
    None. Asked at the end of the symptom diary (day 28).
    End point values
    Prednisolone Placebo
    Number of subjects analysed
    178
    171
    Units: Patients
        Agree
    99
    81
        Disagree/Neither agree or disagree
    79
    90
    Statistical analysis title
    Odds ratio for patient satisfaction (future use)
    Statistical analysis description
    Adjusted for centre
    Comparison groups
    Prednisolone v Placebo
    Number of subjects included in analysis
    349
    Analysis specification
    Pre-specified
    Analysis type
    superiority
    P-value
    = 0.16
    Method
    Regression, Logistic
    Parameter type
    Odds ratio (OR)
    Point estimate
    1.36
    Confidence interval
         level
    95%
         sides
    2-sided
         lower limit
    0.89
         upper limit
    2.08

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    Serious adverse events were collected throughout the 28 day follow up period. Non-serious adverse events were collected for the first 7 days only (treatment course=5 days).
    Adverse event reporting additional description
    Adverse events were then categorised as expected, unexpected or related to cough.
    Assessment type
    Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    SPC and/or BNF
    Dictionary version
    Latest
    Reporting groups
    Reporting group title
    Prednisolone
    Reporting group description
    Participant packs containing ten 20-mg oral prednisolone tablets (Galen Pharma GmbH). Participants were asked to take 2 tablets once daily for 5 days, starting on the day of consultation, if possible before starting any antibiotics (if receiving a "delayed" prescription).

    Reporting group title
    Placebo
    Reporting group description
    Participant packs containing ten 20-mg placebo tablets matched on dimension, appearance and taste (Piramal Healthcare Ltd) to oral prednisolone tablets. Participants were asked to take 2 tablets once daily for 5 days, starting on the day of consultation, if possible before starting any antibiotics (if receiving a "delayed" prescription).

    Serious adverse events
    Prednisolone Placebo
    Total subjects affected by serious adverse events
         subjects affected / exposed
    0 / 199 (0.00%)
    0 / 200 (0.00%)
         number of deaths (all causes)
    0
    0
         number of deaths resulting from adverse events
    0
    0
    Frequency threshold for reporting non-serious adverse events: 2%
    Non-serious adverse events
    Prednisolone Placebo
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    45 / 199 (22.61%)
    36 / 200 (18.00%)
    Nervous system disorders
    Dizziness
    Additional description: Dizziness or faintness
         subjects affected / exposed
    7 / 199 (3.52%)
    0 / 200 (0.00%)
         occurrences all number
    7
    0
    General disorders and administration site conditions
    Chest pain
    Additional description: Pain in abdomen or chest
         subjects affected / exposed
    5 / 199 (2.51%)
    1 / 200 (0.50%)
         occurrences all number
    5
    1
    Throat irritation
    Additional description: Reportings of sore throat
         subjects affected / exposed
    3 / 199 (1.51%)
    7 / 200 (3.50%)
         occurrences all number
    3
    7
    Gastrointestinal disorders
    Gastrointestinal disorder
         subjects affected / exposed
    12 / 199 (6.03%)
    10 / 200 (5.00%)
         occurrences all number
    12
    10
    Infections and infestations
    Fever
         subjects affected / exposed
    3 / 199 (1.51%)
    5 / 200 (2.50%)
         occurrences all number
    3
    5

    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

    Online references

    http://www.ncbi.nlm.nih.gov/pubmed/28829884
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