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    Clinical Trial Results:
    A cluster randomised trial of different strategies of antibiotic use to reduce the incidence and consequences of chest infection in acute stroke patients with swallowing problems.

    Summary
    EudraCT number
    2007-004298-24
    Trial protocol
    GB  
    Global end of trial date
    18 Sep 2014

    Results information
    Results version number
    v1(current)
    This version publication date
    06 Dec 2018
    First version publication date
    06 Dec 2018
    Other versions
    Summary report(s)
    FINAL STUDY REPORT

    Trial information

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    Trial identification
    Sponsor protocol code
    KCH-STR-INF
    Additional study identifiers
    ISRCTN number
    ISRCTN37118456
    US NCT number
    -
    WHO universal trial number (UTN)
    -
    Sponsors
    Sponsor organisation name
    King's College Hospital
    Sponsor organisation address
    Denmark Hill, London, United Kingdom, SE59RS
    Public contact
    Professor Lalit Kalra, King's College Hospital NHS Foundation Trust, 0044 0203299 1718, lalit.kalra@kcl.ac.uk
    Scientific contact
    Professor Lalit Kalra, King's College Hospital NHS Foundation Trust, 0044 0203299 1718, lalit.kalra@kcl.ac.uk
    Sponsor organisation name
    King's College London
    Sponsor organisation address
    The Strand, London, United Kingdom, WC2R 2LS
    Public contact
    Professor Lalit Kalra, King's College London, 0044 0203299 1718, lalit.kalra@kcl.ac.uk
    Scientific contact
    Professor Lalit Kalra, King's College London, 0044 0203299 1718, lalit.kalra@kcl.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
    09 Apr 2015
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    18 Sep 2014
    Global end of trial reached?
    Yes
    Global end of trial date
    18 Sep 2014
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    The main hypothesis for the study is that prophylactic use of antibiotics (an "act first" approach) in acute stroke patients with swallowing problems on a bedside clinical assessment will be better than the current practice of monitoring for infection and treatment if necessary (a "wait and watch" approach) in reducing chest infections and their consequences in stroke patients
    Protection of trial subjects
    The study will be undertaken in hospital based stroke units that have a defined policy for acute stroke care and participate in the National Stroke Audit (NSA).
    Background therapy
    not applicable
    Evidence for comparator
    A Pragmatic cluster randomised controlled trial in 50 participating stroke units. Cluster randomisation at the stroke unit level for treatment or no treatment.
    Actual start date of recruitment
    01 Jan 2009
    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: 1224
    Worldwide total number of subjects
    1224
    EEA total number of subjects
    1224
    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)
    160
    From 65 to 84 years
    678
    85 years and over
    386

    Subject disposition

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    Recruitment
    Recruitment details
    Between April 21, 2008, and May 17, 2014, we randomly assigned 48 stroke units (and 1224 patients clustered within the units) to the two treatment groups: 24 to antibiotics and 24 to standard care alone (control).

    Pre-assignment
    Screening details
    The inclusion criteria: 1. Ischaemic or hemorrhagic stroke confirmed on CT imaging 2. Recruited within 48 hours of symptom onset 3. Unable to tolerate normal diet or fluids because of a. impaired consciousness levels. b. failed clinical bedside swallowing assessment performed by a trained assessor c. “nil orally” orders, nasogastric tubes, mo

    Period 1
    Period 1 title
    Overall Trial (overall period)
    Is this the baseline period?
    Yes
    Allocation method
    Randomised - controlled
    Blinding used
    Not blinded
    Blinding implementation details
    Cluster-randomised, open-label controlled trial. Centres were randomised on a 1:1 ratio to either the intervention or the control group using a minimisation algorithm. Randomisation was stratified for number of stroke admissions per year and the proportion of admitted directly to specialist care

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    Antibiotic Intervention
    Arm description
    Patients received prophylactic antibiotics for 7 days plus standard stroke unit care
    Arm type
    Experimental

    Investigational medicinal product name
    Amoxicillin
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Powder and solvent for solution for injection/infusion, Powder and solvent for oral solution
    Routes of administration
    Intravenous use, Oral use
    Dosage and administration details
    Administered according to local practice for 7 days

    Investigational medicinal product name
    Clarithromycin
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Powder for concentrate for solution for infusion, Powder for oral solution, Powder for oral solution in sachet, Powder for oral suspension
    Routes of administration
    Intravenous drip use , Oral use
    Dosage and administration details
    Administered according to local policy and care for 7 days

    Investigational medicinal product name
    Metronidazole
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Oral solution, Powder and solvent for solution for injection/infusion, Oral emulsion
    Routes of administration
    Oral use, Intravenous drip use
    Dosage and administration details
    Administered according to local practice and care for 7 days

    Investigational medicinal product name
    Trimethoprim
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Oral liquid, Oral solution, Oral suspension, Powder and solvent for solution for infusion
    Routes of administration
    Intravenous use, Oral use
    Dosage and administration details
    Administered according to local practice and care for 7 days

    Arm title
    Control Arm
    Arm description
    Standard clinical care with no intervention.
    Arm type
    No intervention

    Investigational medicinal product name
    No investigational medicinal product assigned in this arm
    Number of subjects in period 1
    Antibiotic Intervention Control Arm
    Started
    620
    604
    Completed
    413
    428
    Not completed
    207
    176
         Death due to disease (secondary endpoint)
    184
    -
         Death due to disease (secondary endpoi
    -
    158
         Consent withdrawn by subject
    5
    2
         Lost to follow-up
    18
    16

    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
    1224 1224
    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)
    160 160
        From 65-84 years
    678 678
        85 years and over
    386 386
    Gender categorical
    Units: Subjects
        Female
    696 696
        Male
    528 528

    End points

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    End points reporting groups
    Reporting group title
    Antibiotic Intervention
    Reporting group description
    Patients received prophylactic antibiotics for 7 days plus standard stroke unit care

    Reporting group title
    Control Arm
    Reporting group description
    Standard clinical care with no intervention.

    Primary: Clinical Endpoint

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    End point title
    Clinical Endpoint [1]
    End point description
    The clinical primary outcome measure is the incidence of PSP in the first 14 days after stroke onset or prior to discharge home if sooner. This will be defined as temperature >37.5°C on two consecutive measurements or a single measurement of >38.0°C with chest symptoms and one or more of the following: white cell count >11 000/mL, pulmonary infiltrate on chest x-rays, positive microbiology cultures.[2,8-10] The diagnosis of PSP will be adjudicated independently by non-participating clinicians masked to treatment allocation based on anonymised clinical information submitted by centres.
    End point type
    Primary
    End point timeframe
    0 to 90 days post Stroke
    Notes
    [1] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: Please see attached document for results.
    End point values
    Antibiotic Intervention Control Arm
    Number of subjects analysed
    413
    428
    Units: whole
    413
    428
    Attachments
    Results
    SAE LINE LISTING
    No statistical analyses for this end point

    Primary: Primary Economic Endpoint

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    End point title
    Primary Economic Endpoint [2]
    End point description
    The primary cost outcome measure will be the total hospital costs (acute and rehabilitation) for the initial episode of care, calculated as a product of costs per unit of each type of care (standardised NHS tariff) and amount used, using methodology validated previously
    End point type
    Primary
    End point timeframe
    Duration of the trial
    Notes
    [2] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: Please see attached document for results.
    End point values
    Antibiotic Intervention Control Arm
    Number of subjects analysed
    413
    428
    Units: whole
    413
    428
    Attachments
    Results Lancet
    No statistical analyses for this end point

    Secondary: Death

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    End point title
    Death
    End point description
    At 14 days: 1. Death, death or PSP at 14 days of stroke onset 2. National Institute of Health Stroke Scale (NIHSS) at 14 days of stroke onset or at discharge if sooner 3. Change in NIHSS from baseline at 14 days of stroke onset or at discharge if sooner 4. Discontinuation of antibiotic prophylaxis in the intervention group (< 4 days of treatment) 5. Antibiotic use in the control group within 7 days of stroke onset 6. Duration of hospital stay if ≤14 days 7. Participation in programmed assessment or therapy activities, measured as the number and duration of supervised rehabilitation during hospital stay. 8. C. difficile diarrhoea 9. New onset of MRSA infection 10. Per protocol Adverse Event (AE), Adverse Reaction (AR), Serious Adverse Event / Reaction (SAE / SAR), and Suspected Unexpected Serious Adverse Reactions (SUSAR).
    End point type
    Secondary
    End point timeframe
    0 to 14 days
    End point values
    Antibiotic Intervention Control Arm
    Number of subjects analysed
    413
    428
    Units: whole
    413
    428
    No statistical analyses for this end point

    Secondary: Death & Clinical/ Economic endpoints

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    End point title
    Death & Clinical/ Economic endpoints
    End point description
    At 90 days: 11. Modified Rankin Scale at 90 (± 14) days post-stroke 12. Patients achieving dichotomised modified Rankin Scale score (mRS 0-2) at 90 (± 14) days post-stroke 13. Ordinal regression analysis of mRS at 90 (± 14) days post stroke 14. Mortality, institutionalisation and mortality or institutionalisation at 90 (± 14) days post stroke 15. Duration of hospital stay if >14 days 16. Incident chest infections between 15-90 days 17. Barthel Index at 90 (± 14) days 18. EUROQOL scores at 90 (± 14) days post stroke. 19. Incremental cost-effectiveness ratios (ICERs) if either the intervention or control approach involves an additional cost alongside an improvement in outcome (ICERs will then represent the cost per 1% reduction in incidence of PSP and/or cost per quality-adjusted life-year (QALY) gained).
    End point type
    Secondary
    End point timeframe
    At 90 days post Stroke
    End point values
    Antibiotic Intervention Control Arm
    Number of subjects analysed
    413
    428
    Units: whole
    413
    428
    No statistical analyses for this end point

    Adverse events

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    Adverse events information [1]
    Timeframe for reporting adverse events
    Until 90 day timepoint
    Assessment type
    Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    MedDRA
    Dictionary version
    17.1
    Reporting groups
    Reporting group title
    Antibiotic Intervention
    Reporting group description
    -

    Notes
    [1] - There are no non-serious adverse events recorded for these results. It is expected that there will be at least one non-serious adverse event reported.
    Justification: Please see attached document for adverse event descriptions.
    Serious adverse events
    Antibiotic Intervention
    Total subjects affected by serious adverse events
         subjects affected / exposed
    109 / 620 (17.58%)
         number of deaths (all causes)
    184
         number of deaths resulting from adverse events
    0
    Cardiac disorders
    Cardiac (MI, HF, Pul. oedema)
         subjects affected / exposed
    15 / 620 (2.42%)
         occurrences causally related to treatment / all
    0 / 15
         deaths causally related to treatment / all
    0 / 0
    Nervous system disorders
    CT confirmed stroke extension
         subjects affected / exposed
    23 / 620 (3.71%)
         occurrences causally related to treatment / all
    0 / 23
         deaths causally related to treatment / all
    0 / 0
    Other Neurological including ICH
         subjects affected / exposed
    14 / 620 (2.26%)
         occurrences causally related to treatment / all
    0 / 14
         deaths causally related to treatment / all
    0 / 0
    General disorders and administration site conditions
    Transfer to intensive care
         subjects affected / exposed
    6 / 620 (0.97%)
         occurrences causally related to treatment / all
    0 / 6
         deaths causally related to treatment / all
    0 / 0
    Miscellaneous
         subjects affected / exposed
    6 / 620 (0.97%)
         occurrences causally related to treatment / all
    0 / 6
         deaths causally related to treatment / all
    0 / 0
    Gastrointestinal disorders
    Gatrointestinal Bleed
         subjects affected / exposed
    5 / 620 (0.81%)
         occurrences causally related to treatment / all
    0 / 5
         deaths causally related to treatment / all
    0 / 0
    Hepatobiliary disorders
    Elevated hepatic/renal enzymes
         subjects affected / exposed
    8 / 620 (1.29%)
         occurrences causally related to treatment / all
    0 / 8
         deaths causally related to treatment / all
    0 / 0
    Infections and infestations
    All Infections (excluding PSP)
         subjects affected / exposed
    22 / 620 (3.55%)
         occurrences causally related to treatment / all
    0 / 22
         deaths causally related to treatment / all
    0 / 0
    Diarrhoea (non-CDT)
         subjects affected / exposed
    2 / 620 (0.32%)
         occurrences causally related to treatment / all
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    Diarrhoea (CDT)
         subjects affected / exposed
    2 / 620 (0.32%)
         occurrences causally related to treatment / all
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    MRSA colonisation
         subjects affected / exposed
    11 / 620 (1.77%)
         occurrences causally related to treatment / all
    0 / 11
         deaths causally related to treatment / all
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 0%
    Non-serious adverse events
    Antibiotic Intervention
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    0 / 620 (0.00%)

    More information

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    Substantial protocol amendments (globally)

    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    05 Sep 2008
    Addition of co-sponsor.
    04 Jun 2009
    Addition to Participant Exclusion Criteria:-  Expected survival <2 weeks under exclusion criteria
    19 Oct 2009
    Change to IMP storage conditions 1. Old Text – Page 9 “IMPs must be stored in a temperature controlled environment (oC) with restricted access to unauthorized personnel.” 2. New Text – page 8, exclusion criteria “IMPs must be stored in a temperature controlled environment (stored according to manufactures instructions) with restricted access to unauthorized personnel.” Change of PI at one site.
    25 Jan 2010
    Protocol changes to consent and recruitment procedures:- 1. Old Text – Page 8, Recruitment and Consent Procedures “If a patient is unable to give written consent because of stroke related deficits such as arm weakness or dysphasia, assent for inclusion will be obtained from the next of kin or relatives. Written consent to support the assent will be sought as soon as the patient is able to provide this consent.” 2. New Text – page 8, Recruitment and Consent Procedures “In circumstances where the patient can read and understand the information on the patient information sheet but is unable to sign due to stroke related deficits such as arm weakness, a researcher or a witness can attest that any mark they make is their signature to consent. Additionally if the patient is able to understand but is unable make a mark due to stroke deficits, an independent witness can countersign the consent form for patient. This witness can be the researcher. Addition of 8 new clinical sites and change of PI at one existing site.
    16 Sep 2011
    1. The duration of the study has been extended up to June 2013 reflecting the current recruitment rates for the study. 2. References to specific recommended antibiotics have been removed from objectives (1) and replaced with prophylactic antibiotics. 3. Objective (3) stated that we will be measuring functional independence, this is not the case, and therefore the statement has been updated. 4. The original recruitment rates in individual centres of 5.6 patients/centre/ month have not been met because of changes in organistaion of stroke services and limited recruitment over weekends. This has changed to a new recruitment target of 2 patients/ centre/ month over a 24 month period. 5. The 4th exclusion criteria have been updated to include “other antibiotics”. 6. Both the health intervention and IMP section in the protocol have been simplified stating that prophylactic treatment will be initiated in dose, form and route in accordance with local hospital antibiotics and infection control policies. It now also includes the addition of the two IMPs (metronidazole and co-trimoxazole) which have been added as they are the preferred antibiotic regime to be used by Charing Cross Hospital (Imperial College Healthcare NHS Trust). 7. References to chest x-ray have been replaced with a statement to the effect that the treatment for patients with raised temperature will follow normal clinical management, and results will be recorded in the CRF.
    17 Sep 2014
    Chest infections have been replaced by Post Stroke Pneumonia (PSP) throughout the protocol The sample size has been updated to reflect a reduced attrition rate. The primary endpoint has been changed from chest infection to post stroke pneumonia based on TSC adjudication. Statistical analysis section of the protocol now provides details of analytical methods. The following non-substantial changes have also been incorporated into this amendment and these have been included in the submission: Page 1: Short title added Change in CI details Change in trial duration Page 4: The trial flow has been refined to be clearer, no change in design Page 5: 2nd paragraph (background) updated Page 7: Inclusion criteria unchanged but presented more clearly Page 10: Secondary endpoints reformatted for better visualisation, otherwise unchanged. Page 15The names of the Chair and members of the TMG, TSC and DMEC have been added. Page 16 Publication Policy added

    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.
    Selection bias, especially in a cluster-randomised trial, could result from patients at increased risk of post-stroke pneumonia being recruited preferentially to the antibiotic intervention group. But no differences noted in baseline characteristics.

    Online references

    http://www.ncbi.nlm.nih.gov/pubmed/30196790
    http://www.ncbi.nlm.nih.gov/pubmed/26343840
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