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    Clinical Trial Results:
    Studies of the effects of a one week course of either azithromycin or metronidazole on plasma concentration of procalcitonin in patients with heart failure and elevated plasma procalcitonin concentrations

    Summary
    EudraCT number
    		 2011-004745-40
    Trial protocol
    		 GB  
    Global end of trial date
    30 Jul 2014

    Results information
    Results version number
    		 v1(current)
    This version publication date
    22 Jun 2019
    First version publication date
    22 Jun 2019
    Other versions
    Summary report(s)
    		 Results presentation

    Trial information

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    Trial identification
    Sponsor protocol code
    n/a
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 -
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    Hull and East Yorkshire Hospitals NHS Trust
    Sponsor organisation address
    Anlaby Road, Hull, United Kingdom, HU3 2JZ
    Public contact
    Prof Andrew Clark, University of Hull, 01482 461775, a.l.clark@hull.ac.uk
    Scientific contact
    Prof Andrew Clark, University of Hull, 01482 461775, a.l.clark@hull.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
    30 Jul 2014
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    30 Jul 2014
    Was the trial ended prematurely?
    Yes
    General information about the trial
    Main objective of the trial
    In patients with heart failure who have an elevated concentration of procalcitonin (a marker of infection) which is not explained by clinical evidence of infection, can treatment for one week with azithromycin or with metronidazole reduce plasma concentrations of procalcitonin compared to a control group who receive no antibiotics. Procalcitonin is associated with a poor prognosis so understanding the mechanism for an elevated concentration in those without infection may provide a therapeutic target.
    Protection of trial subjects
    Patients may stop treatment or withdraw from follow-up at any time without giving a reason. Patients who stop treatment will be asked to have follow-up visits as scheduled. Reasons for withdrawal will be recorded. Patients will be assessed at the end of a one week course of treatment and one and six weeks after completion. The primary endpoint is the change in plasma concentration of procalcitonin. Side effects will be recorded. This will include laboratory safety data including electrolytes, renal and liver function tests and a 12-lead ECG. The most likely adverse events are due to gastro-intestinal side effects from antibiotics and those related to the underlying HF problem rather than study medication. Patients with HF are at risk of recurrent hospitalisation for a range of cardiovascular events. Adverse events will be recorded at each visit and all serious adverse events will be reported. Patients will stop medication if the adverse event is attributed to medication and be treated appropriately. All patients will be followed-up for six weeks.
    Background therapy
    		 None
    Evidence for comparator
    		 Metronidazole and ciprofloxacin are two medications (vs standard care) in this study are licensed in the UK although not for the treatment of heart failure. We will use generic medication as prescribed to other patients under the hospitals care. Illustrative Summary of Product Characteristics are available at the websites provided below. Ciprofloxacin (250mg tablets) is indicated for a wide range of respiratory, soft-tissue, gastro-intestinal and chlamydial infections. Metronidazole (200mg tablets) is an anti-microbial drug with high activity against anaerobic bacteria and protozoa and is indicated for the treatment of such infections including helicobacter pylori and dental infections. The aim of this pilot study is to determine, in patients with HF and an elevated plasma PCT, whether a one-week course of either ciprofloxacin or metronidazole reduces elevated plasma concentration of PCT compared to a similar observation period without antibiotic treatment. The study is un-blinded but the research scientists performing the PCT assay will be blind to treatment. If antibiotics reduce PCT this suggests that PCT should be used as a potential marker of therapeutic benefit with antibiotic therapy and provides the basis for larger, clinically definitive studies. Alternatively, if PCT does not fall with antibiotic therapy this suggests that elevated PCT reflects patho
    Actual start date of recruitment
    01 Mar 2012
    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: 40
    Worldwide total number of subjects
    40
    EEA total number of subjects
    40
    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)
    7
    From 65 to 84 years
    33
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 Patients will be enrolled from patients observational studies of HF to which patients have already consented to provide a blood sample for research purposes, specifically (REC references): SICA-HF (10/H1313/64), BIOSTAT-HF 11/H1304/5 or HeartCycle/LifeLab (03/02/044).

    Pre-assignment
    Screening details
    		 Blood samples as described in the recruitment section will be analysed for procalcitonin levels. Patients with elevated levels (>50pg/ml) will be approached for participation in the study.

    Period 1
    Period 1 title
    Overall trial (overall period)
    Is this the baseline period?
    		 Yes
    Allocation method
    Randomised - controlled
    Blinding used
    		 Not blinded

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 ciprofloxacin
    Arm description
    		 ciprofloxacin 250mg once daily for one week
    Arm type
    		 Experimental

    Investigational medicinal product name
    ciprafloxacin
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Auricular use
    Dosage and administration details
    250mg per day. oral.

    Arm title
    		 metronidazole
    Arm description
    		 200mg three times per day for one week
    Arm type
    		 Experimental

    Investigational medicinal product name
    metronidazole
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Tablet
    Routes of administration
    Auricular use
    Dosage and administration details
    200mg three times per day for one week

    Arm title
    		 Control arm
    Arm description
    		 no antibiotic treatment
    Arm type
    		 No intervention

    Investigational medicinal product name
    No investigational medicinal product assigned in this arm
    Number of subjects in period 1
    		ciprofloxacin metronidazole Control arm
    Started
    14
    13
    13
    Completed
    14
    13
    13

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Overall trial
    Reporting group description
    		 -

    Reporting group values
    		 Overall trial Total
    Number of subjects
    		 40 40
    Age categorical
    Units: Subjects
        Adults (18-64 years)
    		 7 7
        From 65-84 years
    		 29 29
        85 years and over
    		 4 4
    Age continuous
    Units: years
        median (inter-quartile range (Q1-Q3))
    		 72 (64 to 78) -
    Gender categorical
    Units: Subjects
        Female
    		 13 13
        Male
    		 27 27

    End points

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    End points reporting groups
    Reporting group title
    ciprofloxacin
    Reporting group description
    		 ciprofloxacin 250mg once daily for one week

    Reporting group title
    metronidazole
    Reporting group description
    		 200mg three times per day for one week

    Reporting group title
    Control arm
    Reporting group description
    		 no antibiotic treatment

    Primary: The primary endpoint is change in PCT from baseline to the evaluation at 7-days in patients who either receive an antibiotic compared to those that do not.

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    End point title
    		 The primary endpoint is change in PCT from baseline to the evaluation at 7-days in patients who either receive an antibiotic compared to those that do not.
    End point description
    End point type
    Primary
    End point timeframe
    7 days
    End point values
    		 ciprofloxacin metronidazole Control arm
    Number of subjects analysed
    14
    13
    13
    Units: pg/ml
        number (not applicable)
    14
    13
    13
    Statistical analysis title
    		 Pilot study
    Statistical analysis description
    This is a pilot study and as such there is no statistical justification for recruitment size. We seek to measure any reduction in PCT levels in order to inform a larger trial. We will analyse the data using multivariate Cox regression.
    Comparison groups
    metronidazole v ciprofloxacin
    Number of subjects included in analysis
    27
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 < 0.05
    Method
    		 ANOVA
    Parameter type
    		 Mean difference (final values)
    Confidence interval
         level
    		 95%
         sides
    2-sided
         lower limit
    		 -
         upper limit
    		 -
    Variability estimate
    Standard error of the mean

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    Up to 7 days post dose.
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    21
    Reporting groups
    Reporting group title
    Control arm
    Reporting group description
    		 -

    Reporting group title
    Ciprofoxacin arm
    Reporting group description
    		 -

    Reporting group title
    Metronidazole
    Reporting group description
    		 -

    Serious adverse events
    		 Control arm Ciprofoxacin arm Metronidazole
    Total subjects affected by serious adverse events
         subjects affected / exposed
    1 / 14 (7.14%)
    1 / 13 (7.69%)
    1 / 13 (7.69%)
         number of deaths (all causes)
    0
    0
    0
         number of deaths resulting from adverse events
    0
    0
    0
    Vascular disorders
    Hypertension
         subjects affected / exposed
    0 / 14 (0.00%)
    1 / 13 (7.69%)
    0 / 13 (0.00%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Cardiac disorders
    Cardiomyopathy
    Additional description: Worsening heart failure
         subjects affected / exposed
    1 / 14 (7.14%)
    1 / 13 (7.69%)
    1 / 13 (7.69%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Gastrointestinal disorders
    Constipation
    Additional description: Required hospitilasation
         subjects affected / exposed
    0 / 14 (0.00%)
    0 / 13 (0.00%)
    1 / 13 (7.69%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 0
    1 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 0.05%
    Non-serious adverse events
    		 Control arm Ciprofoxacin arm Metronidazole
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    1 / 14 (7.14%)
    0 / 13 (0.00%)
    0 / 13 (0.00%)
    Social circumstances
    Late developer
    Additional description: Not true, but inflexibility of the database did not allow non-occurrence of non-serious event to be reported!
         subjects affected / exposed
    1 / 14 (7.14%)
    0 / 13 (0.00%)
    0 / 13 (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? Yes
    Date
    Amendment
    13 Jul 2012
    Submitted to REC
    11 Sep 2012
    Submitted to REC

    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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