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    Clinical Trial Results:
    Targeted retreatment of incompletely recovered COPD exacerbations with ciprofloxacin: a double-blind, randomised, placebo-controlled, multicentre Phase III trial

    Summary
    EudraCT number
    		 2012-002198-72
    Trial protocol
    		 GB  
    Global end of trial date
    22 Jan 2019

    Results information
    Results version number
    		 v1(current)
    This version publication date
    29 Nov 2019
    First version publication date
    29 Nov 2019
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    14IC2031
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT02300220
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    Imperial College London
    Sponsor organisation address
    South Kensingston Campus, London, United Kingdom, SW7 2AZ
    Public contact
    Jadwiga Wedzicha, Imperial College London, j.wedzicha@imperial.ac.uk
    Scientific contact
    Jadwiga Wedzicha, Imperial College London, j.wedzicha@imperial.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
    28 Feb 2019
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    22 Jan 2019
    Global end of trial reached?
    Yes
    Global end of trial date
    22 Jan 2019
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    The principal research question is whether an extra course of antibiotics, given two weeks after an exacerbation (flare up) of chronic obstructive pulmonary disease, can prevent repeat exacerbations in those patients who have not fully recovered from the first exacerbation.
    Protection of trial subjects
    None
    Background therapy
    		 Patients continued on usual therapy as prescribed for the COPD or co-morbidities.
    Evidence for comparator
    		 Ciprofloxacin was the IMP of choice for this study based on the following: - According to the Global Initiative for Chronic Obstructive Lung Disease (GOLD), the European Respiratory Society guidelines for the management of adult lower respiratory tract infections, and the Canadian guidelines for the management of acute exacerbations of chronic bronchitis, ciprofloxacin is the antibiotic of choice for the treatment of patients with severe exacerbations of COPD (1, 2, 3,4). - Based on the findings from WP1, ciprofloxacin, as a second line treatment, was found to be one of 5 most commonly used antibiotics amongst GP practices for the treatment of COPD in the UK - Ciprofloxacin is non-penicillin, therefore patients who meet the eligibility criteria for the trial but are allergic to penicillin, can also be recruited. 1. Rabe K. F., et al. 2007. Global strategy for the diagnosis, management, and prevention of chronic obstructive pulmonary disease: GOLD executive summary. Am. J. Respir. Crit. Care Med. 176:532–555. 2. Woodhead M., et al. 2005. Guidelines for the management of adult lower respiratory tract infections. Eur. Respir. J. 26:1138–1180. 3. Balter M. S., et al. 2003. Canadian guidelines for the management of acute exacerbations of chronic bronchitis. Can. Respir. J. 10(Suppl.):3B–32B. 4. Kontou P, Chatzika K, Pitsiou G, Stanopoulos I, Argyropoulou-Pataka P, Kioumis I. Pharmacokinetics of ciprofloxacin and its penetration into bronchial secretions of mechanically ventilated patients with chronic obstructive pulmonary disease. Antimicrob Agents Chemother. 2011 Sep;55 (9):4149-53. Epub 2011 Jun 13.
    Actual start date of recruitment
    05 May 2014
    Long term follow-up planned
    Yes
    Long term follow-up rationale
    		 Safety, Efficacy, Ethical reason, Regulatory reason, Scientific research
    Long term follow-up duration
    		 13 Months
    Independent data monitoring committee (IDMC) involvement?
    Yes
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    United Kingdom: 144
    Worldwide total number of subjects
    144
    EEA total number of subjects
    144
    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)
    37
    From 65 to 84 years
    107
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 Participants were recruited between May 2014 to January 2019

    Pre-assignment
    Screening details
    		 144 participants were eligible

    Period 1
    Period 1 title
    Overall (overall period)
    Is this the baseline period?
    		 Yes
    Allocation method
    Randomised - controlled
    Blinding used
    		 Double blind
    Roles blinded
    		 Subject, Investigator

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Ciprofloxacin
    Arm description
    		 -
    Arm type
    		 Experimental

    Investigational medicinal product name
    Ciprofloxacin
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Capsule
    Routes of administration
    Oral use
    Dosage and administration details
    500 mg, twice daily for 1 week

    Arm title
    		 Placebo
    Arm description
    		 -
    Arm type
    		 Placebo

    Investigational medicinal product name
    Placebo
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Capsule
    Routes of administration
    Oral use
    Dosage and administration details
    twice daily for 1 week

    Number of subjects in period 1
    		Ciprofloxacin Placebo
    Started
    72
    72
    Completed
    68
    65
    Not completed
    4
    7
         Consent withdrawn by subject
    -
    2
         death
    1
    1
         Adverse event, non-fatal
    1
    1
         did not tolerate IDP
    -
    1
         Lost to follow-up
    1
    2
         Protocol deviation
    1
    -

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Ciprofloxacin
    Reporting group description
    		 -

    Reporting group title
    Placebo
    Reporting group description
    		 -

    Reporting group values
    		 Ciprofloxacin Placebo Total
    Number of subjects
    		 72 72 144
    Age categorical
    Units: Subjects
        Adults (18-64 years)
    		 17 20 37
        From 65-84 years
    		 55 52 107
    Age continuous
    Units: years
        geometric mean (standard deviation)
    		 69.1 ( 8.8 ) 69.1 ( 7.4 ) -
    Gender categorical
    Units: Subjects
        Female
    		 28 25 53
        Male
    		 44 47 91

    End points

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

    Reporting group title
    Placebo
    Reporting group description
    		 -

    Primary: Time to the Next COPD Exacerbation

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    End point title
    		 Time to the Next COPD Exacerbation
    End point description
    The primary outcome will be the time to the next COPD exacerbation following targeted retreatment with the IMP or placebo, censored at 90 days.
    End point type
    Primary
    End point timeframe
    7 days of treatment
    End point values
    		 Ciprofloxacin Placebo
    Number of subjects analysed
    72
    72
    Units: days
        median (inter-quartile range (Q1-Q3))
    72 (29 to 90)
    58 (24.5 to 90)
    Statistical analysis title
    		 Time to the Next COPD Exacerbation
    Comparison groups
    Ciprofloxacin v Placebo
    Number of subjects included in analysis
    144
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.764
    Method
    		 Regression, Cox
    Parameter type
    		 Cox proportional hazard
    Point estimate
    1.071
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 0.684
         upper limit
    		 1.676

    Secondary: Duration of the Initial Exacerbation

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    End point title
    		 Duration of the Initial Exacerbation
    End point description
    End point type
    Secondary
    End point timeframe
    7 days of treatment
    End point values
    		 Ciprofloxacin Placebo
    Number of subjects analysed
    56 [1]
    57 [2]
    Units: days
        median (inter-quartile range (Q1-Q3))
    3 (0 to 8)
    4 (0 to 9)
    Notes
    [1] - Missing data from 16 participants
    [2] - Missing data from 15 participants
    Statistical analysis title
    		 Duration of the Initial Exacerbation
    Comparison groups
    Placebo v Ciprofloxacin
    Number of subjects included in analysis
    113
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.703
    Method
    		 Wilcoxon (Mann-Whitney)
    Confidence interval

    Secondary: Number of Participants With Serious Non Fatal Adverse Events

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    End point title
    		 Number of Participants With Serious Non Fatal Adverse Events
    End point description
    End point type
    Secondary
    End point timeframe
    7 days of treatment
    End point values
    		 Ciprofloxacin Placebo
    Number of subjects analysed
    72
    72
    Units: number of participants
    1
    9
    No statistical analyses for this end point

    Secondary: Changes in Lung Function

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    End point title
    		 Changes in Lung Function
    End point description
    End point type
    Secondary
    End point timeframe
    90 days of treatment
    End point values
    		 Ciprofloxacin Placebo
    Number of subjects analysed
    63
    63
    Units: litres
        geometric mean (standard deviation)
    0.0229 ( 0.199 )
    0.0041 ( 0.198 )
    Statistical analysis title
    		 Changes in Lung Function
    Comparison groups
    Ciprofloxacin v Placebo
    Number of subjects included in analysis
    126
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.239
    Method
    		 t-test, 2-sided
    Confidence interval

    Secondary: Number of Participants Who Have Resistance Bacteria in the Sputum

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    End point title
    		 Number of Participants Who Have Resistance Bacteria in the Sputum
    End point description
    Only participants who had sputum
    End point type
    Secondary
    End point timeframe
    7 days of treatment
    End point values
    		 Ciprofloxacin Placebo
    Number of subjects analysed
    16
    17
    Units: number of participants
    0
    1
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    90 days + 1 month
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    10
    Reporting groups
    Reporting group title
    Ciproflaxacin
    Reporting group description
    		 -

    Reporting group title
    Placebo
    Reporting group description
    		 -

    Serious adverse events
    		 Ciproflaxacin Placebo
    Total subjects affected by serious adverse events
         subjects affected / exposed
    1 / 72 (1.39%)
    9 / 72 (12.50%)
         number of deaths (all causes)
    1
    1
         number of deaths resulting from adverse events
    0
    0
    Neoplasms benign, malignant and unspecified (incl cysts and polyps)
    Oncology
         subjects affected / exposed
    1 / 72 (1.39%)
    1 / 72 (1.39%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Cardiac disorders
    Cardiovascular
         subjects affected / exposed
    0 / 72 (0.00%)
    1 / 72 (1.39%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastrointestinal disorders
    Gastrointestinal
         subjects affected / exposed
    0 / 72 (0.00%)
    2 / 72 (2.78%)
         occurrences causally related to treatment / all
    0 / 0
    2 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    Respiratory
         subjects affected / exposed
    0 / 72 (0.00%)
    4 / 72 (5.56%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 4
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Psychiatric disorders
    Psychological
         subjects affected / exposed
    0 / 72 (0.00%)
    1 / 72 (1.39%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 0%
    Non-serious adverse events
    		 Ciproflaxacin Placebo
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    12 / 72 (16.67%)
    8 / 72 (11.11%)
    Nervous system disorders
    Dry Mouth
         subjects affected / exposed
    1 / 72 (1.39%)
    0 / 72 (0.00%)
         occurrences all number
    1
    0
    Tremor
         subjects affected / exposed
    0 / 72 (0.00%)
    1 / 72 (1.39%)
         occurrences all number
    0
    1
    Gastrointestinal disorders
    Nausea
         subjects affected / exposed
    1 / 72 (1.39%)
    1 / 72 (1.39%)
         occurrences all number
    1
    1
    Vomiting
         subjects affected / exposed
    0 / 72 (0.00%)
    1 / 72 (1.39%)
         occurrences all number
    0
    1
    Diarrhoea
         subjects affected / exposed
    5 / 72 (6.94%)
    1 / 72 (1.39%)
         occurrences all number
    5
    1
    Dyspepsia
         subjects affected / exposed
    1 / 72 (1.39%)
    0 / 72 (0.00%)
         occurrences all number
    1
    0
    Abdominal Colic/Pain
         subjects affected / exposed
    2 / 72 (2.78%)
    2 / 72 (2.78%)
         occurrences all number
    2
    2
    Skin and subcutaneous tissue disorders
    Pruritis/Rash
         subjects affected / exposed
    0 / 72 (0.00%)
    2 / 72 (2.78%)
         occurrences all number
    0
    2
    Musculoskeletal and connective tissue disorders
    Ankle Pain/Tendonitis
         subjects affected / exposed
    2 / 72 (2.78%)
    0 / 72 (0.00%)
         occurrences all number
    2
    0

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    28 Jan 2015
    Addition of St Geroges as site. Minor amendment to PIS/updates to protocol
    30 Mar 2017
    Study extension to Dec 2017
    30 Oct 2017
    A 6-month no cost extension to this study has been approved by NIHR.

    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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