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    Clinical Trial Results:
    An open label trial of azithromycin in chronic productive cough

    Summary
    EudraCT number
    		 2013-002938-20
    Trial protocol
    		 GB  
    Global end of trial date
    15 Jul 2016

    Results information
    Results version number
    		 v1(current)
    This version publication date
    24 Mar 2019
    First version publication date
    24 Mar 2019
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    13031
    Additional study identifiers
    ISRCTN number
    		 ISRCTN93221282
    US NCT number
    		 -
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    University of Nottingham
    Sponsor organisation address
    Jubilee campus, Nottingham, United Kingdom, NG51PB
    Public contact
    Tim Harrison, University of Nottingham, 44 1158231714, tim.harrison@nottingham.ac.uk
    Scientific contact
    Tim Harrison, University of Nottingham, 44 1158231714, tim.harrison@nottingham.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
    15 Jul 2016
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    15 Jul 2016
    Global end of trial reached?
    Yes
    Global end of trial date
    15 Jul 2016
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    This was a single‐centre study with detailed description of baseline clinicopathological features followed by an open‐label trial of 12 weeks of low‐dose azithromycin (250 mg thrice weekly) in subjects with idiopathic chronic productive cough. The main aims were to describe the baseline clinicopathological features of the patients and identify responders and non‐responders to 12‐week low‐dose azithromycin, using change in Leicester Cough Questionnaire (LCQ) as the primary outcome.
    Protection of trial subjects
    Patients with a productive cough of ≥3 months duration who had not smoked for ≥10 years with a <20 pack‐year smoking history were recruited from respiratory clinic if initial investigations found no cause for their symptoms. Subjects were excluded if they had evidence of immunodeficiency, established bronchiectasis on HRCT, history of inhaled irritant exposure, a contraindication to azithromycin treatment (prolonged QT interval on electrocardiogram (ECG)/significant cardiac pathology or liver function tests >2× the upper normal limit) or documented macrolide hypersensitivity. The study was approved by a local Research Ethics Committee (Ref 13/YH/0245). All participants meeting the inclusion criteria attended a baseline visit where written informed consent was obtained. Investigations were carried out over five study visits
    Background therapy
    		 -
    Evidence for comparator
    		 -
    Actual start date of recruitment
    01 Jan 2014
    Long term follow-up planned
    No
    Independent data monitoring committee (IDMC) involvement?
    No
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    United Kingdom: 30
    Worldwide total number of subjects
    30
    EEA total number of subjects
    30
    Number of subjects enrolled per age group
    In utero
    0
    Preterm newborn - gestational age < 37 wk
    0
    Newborns (0-27 days)
    0
    Infants and toddlers (28 days-23 months)
    0
    Children (2-11 years)
    0
    Adolescents (12-17 years)
    0
    Adults (18-64 years)
    30
    From 65 to 84 years
    0
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 Between January 2014 and January 2016, 102 eligible subjects were identified. Fifty‐seven of these were already taking azithromycin or another long‐term antibiotic and 15 declined the study. Diagnosis of asthma was based on a previous clinical diagnosis.

    Pre-assignment
    Screening details
    		 Selection criteria for patients with chronic productive cough: - Age 18 and over - Male or female - Non-smokers for 10 years and <20 pack year equivalents in total - Persistent productive cough for > 3 months in duration Exclusion criteria for patients with chronic productive cough: - History of obvious inhaled irritant exposure - Evidence

    Pre-assignment period milestones
    Number of subjects started
    		 30
    Number of subjects completed
    		 30

    Period 1
    Period 1 title
    Visit 1
    Is this the baseline period?
    		 Yes
    Allocation method
    Not applicable
    Blinding used
    		 Not blinded

    Arms
    Arm title
    		 All participants
    Arm description
    		 Results are given for all participants whom received Azithromycin treatment per protocol
    Arm type
    		 Experimental

    Investigational medicinal product name
    Azithromycin
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Capsule, hard
    Routes of administration
    Oral use
    Dosage and administration details
    Azithromycin capsules 250mg 3 times a week for 12 weeks.

    Number of subjects in period 1
    		All participants
    Started
    30
    Completed
    30
    Period 2
    Period 2 title
    Visit 2: Bronchoscopy
    Is this the baseline period?
    		 No
    Allocation method
    Not applicable
    Blinding used
    		 Not blinded

    Arms
    Arm title
    		 All particiants
    Arm description
    		 Results are given for all participants whom received Azithromycin treatment per protocol
    Arm type
    		 Experimental

    Investigational medicinal product name
    Azithromycin
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Capsule, hard
    Routes of administration
    Oral use
    Dosage and administration details
    Azithromycin capsules 250mg 3 times a week for 12 weeks.

    Number of subjects in period 2
    		All particiants
    Started
    30
    Completed
    30
    Period 3
    Period 3 title
    Visit 3: Safety
    Is this the baseline period?
    		 No
    Allocation method
    Not applicable
    Blinding used
    		 Not blinded

    Arms
    Arm title
    		 All participants
    Arm description
    		 Results are given for all participants whom received Azithromycin treatment per protocol
    Arm type
    		 Experimental

    Investigational medicinal product name
    Azithromycin
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Capsule, hard
    Routes of administration
    Oral use
    Dosage and administration details
    Azithromycin capsules 250mg 3 times a week for 12 weeks.

    Number of subjects in period 3
    		All participants
    Started
    30
    Completed
    29
    Not completed
    1
         Adverse event, non-fatal
    1
    Period 4
    Period 4 title
    Visit 4: Post treatment
    Is this the baseline period?
    		 No
    Allocation method
    Not applicable
    Blinding used
    		 Not blinded

    Arms
    Arm title
    		 All participants
    Arm description
    		 Results are given for all participants whom received Azithromycin treatment per protocol
    Arm type
    		 Experimental

    Investigational medicinal product name
    Azithromycin
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Capsule, hard
    Routes of administration
    Oral use
    Dosage and administration details
    Azithromycin capsules 250mg 3 times a week for 12 weeks.

    Number of subjects in period 4
    		All participants
    Started
    29
    Completed
    29
    Period 5
    Period 5 title
    Visit 5: Follow-up
    Is this the baseline period?
    		 No
    Allocation method
    Not applicable
    Blinding used
    		 Not blinded

    Arms
    Arm title
    		 All participants
    Arm description
    		 Results are given for all participants whom received Azithromycin treatment per protocol
    Arm type
    		 Experimental

    Investigational medicinal product name
    Azithromycin
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Capsule, hard
    Routes of administration
    Oral use
    Dosage and administration details
    Azithromycin capsules 250mg 3 times a week for 12 weeks.

    Number of subjects in period 5
    		All participants
    Started
    29
    Completed
    26
    Not completed
    3
         Lost to follow-up
    3

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Visit 1
    Reporting group description
    		 -

    Reporting group values
    		 Visit 1 Total
    Number of subjects
    		 30 30
    Age categorical
    Units: Subjects
        In utero
    		 0 0
        Preterm newborn infants (gestational age < 37 wks)
    		 0 0
        Newborns (0-27 days)
    		 0 0
        Infants and toddlers (28 days-23 months)
    		 0 0
        Children (2-11 years)
    		 0 0
        Adolescents (12-17 years)
    		 0 0
        Adults (18-64 years)
    		 30 30
        From 65-84 years
    		 0 0
        85 years and over
    		 0 0
    Age continuous
    Age of whole cohort
    Units: years
        arithmetic mean (full range (min-max))
    		 57 (25 to 77) -
    Gender categorical
    Units: Subjects
        Female
    		 17 17
        Male
    		 13 13
    Subject analysis sets

    Subject analysis set title
    Responders versus non-responders
    Subject analysis set type
    		 Full analysis
    Subject analysis set description
    Particoants were split onot those whom responded to the treatment and those who did not for analyses

    Subject analysis sets values
    		 Responders versus non-responders
    Number of subjects
    22
    Age categorical
    Units: Subjects
        In utero
        Preterm newborn infants (gestational age < 37 wks)
        Newborns (0-27 days)
        Infants and toddlers (28 days-23 months)
        Children (2-11 years)
        Adolescents (12-17 years)
        Adults (18-64 years)
        From 65-84 years
        85 years and over
    Age continuous
    Age of whole cohort
    Units: years
        arithmetic mean (full range (min-max))
    56 (25 to 77)
    Gender categorical
    Units: Subjects
        Female
    15
        Male
    7

    End points

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    End points reporting groups
    Reporting group title
    All participants
    Reporting group description
    		 Results are given for all participants whom received Azithromycin treatment per protocol
    Reporting group title
    All particiants
    Reporting group description
    		 Results are given for all participants whom received Azithromycin treatment per protocol
    Reporting group title
    All participants
    Reporting group description
    		 Results are given for all participants whom received Azithromycin treatment per protocol
    Reporting group title
    All participants
    Reporting group description
    		 Results are given for all participants whom received Azithromycin treatment per protocol
    Reporting group title
    All participants
    Reporting group description
    		 Results are given for all participants whom received Azithromycin treatment per protocol

    Subject analysis set title
    Responders versus non-responders
    Subject analysis set type
    		 Full analysis
    Subject analysis set description
    Particoants were split onot those whom responded to the treatment and those who did not for analyses

    Primary: Diff LCQ score v1 to v4

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    End point title
    		 Diff LCQ score v1 to v4
    End point description
    End point type
    Primary
    End point timeframe
    Median difference in LCQ score between visit 1 and visit 4
    End point values
    		 All participants All participants
    Number of subjects analysed
    29
    29
    Units: LCQ score
        median (inter-quartile range (Q1-Q3))
    11.5 (7.8 to 18.2)
    17.8 (14.2 to 20.1)
    Statistical analysis title
    		 Change in LCQ v1 to v4
    Comparison groups
    All participants v All participants
    Number of subjects included in analysis
    58
    Analysis specification
    Pre-specified
    Analysis type
    		 equivalence
    P-value
    		 < 0.00001
    Method
    		 Wilcoxon (Mann-Whitney)
    Parameter type
    		 Median difference (final values)
    Point estimate
    6.3
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 6.3
         upper limit
    		 6.3

    Secondary: Difference in 24h sputum volume ml

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    End point title
    		 Difference in 24h sputum volume ml
    End point description
    End point type
    Secondary
    End point timeframe
    Difference between visit 1 and visit 4
    End point values
    		 All participants All participants
    Number of subjects analysed
    29
    29
    Units: mls
        median (inter-quartile range (Q1-Q3))
    7.9 (6.2 to 11.7)
    2.1 (0 to 7.2)
    Statistical analysis title
    		 Diff sputum volume V1 to V4
    Comparison groups
    All participants v All participants
    Number of subjects included in analysis
    58
    Analysis specification
    Pre-specified
    Analysis type
    		 equivalence
    P-value
    		 = 0.0001
    Method
    		 Wilcoxon (Mann-Whitney)
    Parameter type
    		 Median difference (final values)
    Point estimate
    -5.8
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -5.8
         upper limit
    		 -5.8

    Secondary: FE Nitrous Oxide level ppb

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    End point title
    		 FE Nitrous Oxide level ppb
    End point description
    End point type
    Secondary
    End point timeframe
    Difference between v1 and v4
    End point values
    		 All participants All participants
    Number of subjects analysed
    29
    29
    Units: ppb
    18
    12
    Statistical analysis title
    		 Diff FE no level V1 to V4
    Comparison groups
    All participants v All participants
    Number of subjects included in analysis
    58
    Analysis specification
    Pre-specified
    Analysis type
    		 equivalence
    P-value
    		 = 0.009
    Method
    		 Wilcoxon (Mann-Whitney)
    Parameter type
    		 Median difference (final values)
    Point estimate
    -6.5
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -6.5
         upper limit
    		 -6.5

    Secondary: FEV (L)

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    End point title
    		 FEV (L)
    End point description
    End point type
    Secondary
    End point timeframe
    Difference between visit 1 and visit 4
    End point values
    		 All participants All participants
    Number of subjects analysed
    29
    29
    Units: Litres
        arithmetic mean (standard deviation)
    2.77 ( 0.99 )
    2.75 ( 1 )
    Statistical analysis title
    		 Diff FEV V1 to V4
    Comparison groups
    All participants v All participants
    Number of subjects included in analysis
    58
    Analysis specification
    Pre-specified
    Analysis type
    		 equivalence
    P-value
    		 = 0.78
    Method
    		 Wilcoxon (Mann-Whitney)
    Parameter type
    		 Mean difference (final values)
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -
         upper limit
    		 -

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    Throughout the trial
    Assessment type
    		 Non-systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    1.0
    Reporting groups
    Reporting group title
    All participants
    Reporting group description
    		 Azithromycin 3x weekly for 12 weeks

    Serious adverse events
    		 All participants
    Total subjects affected by serious adverse events
         subjects affected / exposed
    0 / 30 (0.00%)
         number of deaths (all causes)
    0
         number of deaths resulting from adverse events
    0
    Frequency threshold for reporting non-serious adverse events: 1%
    Non-serious adverse events
    		 All participants
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    1 / 30 (3.33%)
    General disorders and administration site conditions
    Periorbital oedema
         subjects affected / exposed
    1 / 30 (3.33%)
         occurrences all number
    1

    More information

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

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

    Limitations and caveats
    Limitations of the trial such as small numbers of subjects analysed or technical problems leading to unreliable data.
    None reported
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    The status and protocol content of GB trials is no longer updated since 1 January 2021. For the UK, as of 31 January 2021, EU Law applies only to the territory of Northern Ireland (NI) to the extent foreseen in the Protocol on Ireland/NI. Legal notice
    As of 31 January 2023, all EU/EEA initial clinical trial applications must be submitted through CTIS . Updated EudraCT trials information and information on PIP/Art 46 trials conducted exclusively in third countries continues to be submitted through EudraCT and published on this website.

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