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    Clinical Trial Results:
    A randomised control trial to determine whether a 5 day course of antibiotics is more clinically and cost effective than a 24 hour prophylactic course for the prevention of surgical site infection following lower limb amputation surgery

    Summary
    EudraCT number
    		 2012-003146-32
    Trial protocol
    		 GB  
    Global end of trial date
    28 Dec 2016

    Results information
    Results version number
    		 v1(current)
    This version publication date
    07 Oct 2020
    First version publication date
    07 Oct 2020
    Other versions
    Summary report(s)
    		 ASSIT main results and summary report
    ASSIT Choice of Statistical Tests

    Trial information

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    Trial identification
    Sponsor protocol code
    ASSIT
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 -
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    Hull University Teaching Hospital NHS Trust
    Sponsor organisation address
    Anlaby Road, Hull, United Kingdom, HU3 2JZ
    Public contact
    Judith Long, Academic Vascular Surgical Unit, Hull Royal Infirmary, 01482 675784, judith.long@hey.nhs.uk
    Scientific contact
    Panos Souroullas, Academic Vascular Surgical Unit, Hull Royal Infirmary, 01482 675784, sourou@doctors.org.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
    12 Jan 2016
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    12 Jan 2016
    Global end of trial reached?
    Yes
    Global end of trial date
    28 Dec 2016
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    Primary objective: to establish if a 5 day course of antibiotics is more clinically and cost effective than a 24 hour prophylactic course in preventing surgical site infection in patients undergoing lower limb amputation.
    Protection of trial subjects
    Full written informed consent was received from all participants prior to any study procedures. Patients were free to withdraw from the study at any time.
    Background therapy
    		 -
    Evidence for comparator
    		 -
    Actual start date of recruitment
    01 Jan 2013
    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: 161
    Worldwide total number of subjects
    161
    EEA total number of subjects
    161
    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)
    73
    From 65 to 84 years
    77
    85 years and over
    11

    Subject disposition

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    Recruitment
    Recruitment details
    		 A total of 208 patients were screened for eligibility of which 161 patients were recruited and randomised between 17th October 2013 and 12th December 2015.

    Pre-assignment
    Screening details
    		 All patients undergoing either transfemoral, transtibial or transmetatasal amputation were screened: Inclusion Adults ≥18 yrs undergoing MLLA. Exclusion Allergies to chlorhexidine/alcohol/ iodophors Admitted to hospital requiring emergency amputation due to severe sepsis Use of investigational drug/device therapy within preceding 4 weeks

    Period 1
    Period 1 title
    Baseline (overall period)
    Is this the baseline period?
    		 Yes
    Allocation method
    Randomised - controlled
    Blinding used
    		 Single blind
    Roles blinded
    		 Assessor [1]
    Blinding implementation details
    Blinding of treating surgical team and participant was not performed. Blinding of the investigator assessing outcomes was achieved by having outcome assessments performed by a member of the research team who was unaware of treatment allocation.

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 5-day Antibiotic Group
    Arm description
    		 Both treatment groups received 24 hours of intravenous (IV) treatment, consisting of three doses of 1.2g of amoxicillin with clavulanic acid and 500mg of metronidazole eight hours apart starting on induction of anaesthesia. In cases of amputations proximal to the transtibial level, a single weight-adjusted dose of gentamicin (7mg/Kg) was also administered on induction. Those in the five-day treatment arm received further oral antibiotic prophylaxis with 625mg of Co-amoxiclav TDS and 400mg metronidazole administered three times a day for four days.
    Arm type
    		 Active comparator

    Investigational medicinal product name
    Co-amoxiclav
    Investigational medicinal product code
    Other name
    Augmentin
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Augmentin 1.2g IV three times daily for 24 hours. If the patient is randomised to the 5-day duration antibiotic arm then Augmentin 625mg oral tablets three times daily are added to the 24 hour course for a further 4 days.

    Investigational medicinal product name
    Metronidazole
    Investigational medicinal product code
    Other name
    Flagyl
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    500mg IV three times daily for 24 hours. If the patient is randomised to 5-day duration arm, then another 4 days of oral metronidazole at 400mg three times daily is added to the course

    Investigational medicinal product name
    Iodine
    Investigational medicinal product code
    Other name
    Povidone iodine
    Pharmaceutical forms
    Cutaneous solution
    Routes of administration
    Topical use
    Dosage and administration details
    Intra-operative skin preparation prior to incision to skin.

    Investigational medicinal product name
    Chlorhexidine
    Investigational medicinal product code
    Other name
    Hydrex
    Pharmaceutical forms
    Cutaneous solution
    Routes of administration
    Topical use
    Dosage and administration details
    Alcoholic Chlorhexidine skin pre-op preparation

    Investigational medicinal product name
    Teicoplanin
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Powder and solution for solution for injection
    Routes of administration
    Intravenous use
    Dosage and administration details
    Teicoplanin 400mg on induction. If penicillin allergic and on 5-day antibiotic arm then add clindamycin 300mg 4 times daily for further 4 days

    Investigational medicinal product name
    Clindamycin
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Capsule
    Routes of administration
    Oral use
    Dosage and administration details
    Clindamycin 300mg 4 times daily orally to be used in case of penicillin allergy

    Arm title
    		 24 Hour Antibiotic Group
    Arm description
    		 Both treatment groups received 24 hours of intravenous (IV) treatment, consisting of three doses of 1.2g of amoxicillin with clavulanic acid and 500mg of metronidazole eight hours apart starting on induction of anaesthesia. In cases of amputations proximal to the transtibial level, a single weight-adjusted dose of gentamicin (7mg/Kg) was also administered on induction. Participants in the 24-hour treatment arm received no further antibiotics
    Arm type
    		 Active comparator

    Investigational medicinal product name
    Co-amoxiclav
    Investigational medicinal product code
    Other name
    Augmentin
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    Augmentin 1.2g IV three times daily for 24 hours. If the patient is randomised to the 5-day duration antibiotic arm then Augmentin 625mg oral tablets three times daily are added to the 24 hour course for a further 4 days.

    Investigational medicinal product name
    Iodine
    Investigational medicinal product code
    Other name
    Povidone iodine
    Pharmaceutical forms
    Cutaneous solution
    Routes of administration
    Topical use
    Dosage and administration details
    Intra-operative skin preparation prior to incision to skin.

    Investigational medicinal product name
    Metronidazole
    Investigational medicinal product code
    Other name
    Flagyl
    Pharmaceutical forms
    Tablet
    Routes of administration
    Oral use
    Dosage and administration details
    500mg IV three times daily for 24 hours. If the patient is randomised to 5-day duration arm, then another 4 days of oral metronidazole at 400mg three times daily is added to the course

    Investigational medicinal product name
    Chlorhexidine
    Investigational medicinal product code
    Other name
    Hydrex
    Pharmaceutical forms
    Cutaneous solution
    Routes of administration
    Topical use
    Dosage and administration details
    Alcoholic Chlorhexidine skin pre-op preparation

    Investigational medicinal product name
    Teicoplanin
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Powder and solution for solution for injection
    Routes of administration
    Intravenous use
    Dosage and administration details
    Teicoplanin 400mg on induction. If penicillin allergic and on 5-day antibiotic arm then add clindamycin 300mg 4 times daily for further 4 days

    Notes
    [1] - The roles blinded appear inconsistent with a simple blinded trial.
    Justification: Blinding of treating surgical team and participant was not performed. Blinding of the investigator assessing outcomes was achieved by having outcome assessments performed by a member of the research team who was unaware of treatment allocation.
    Number of subjects in period 1
    		5-day Antibiotic Group 24 Hour Antibiotic Group
    Started
    81
    80
    Completed
    76
    76
    Not completed
    5
    4
         Death
    5
    4

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    5-day Antibiotic Group
    Reporting group description
    		 Both treatment groups received 24 hours of intravenous (IV) treatment, consisting of three doses of 1.2g of amoxicillin with clavulanic acid and 500mg of metronidazole eight hours apart starting on induction of anaesthesia. In cases of amputations proximal to the transtibial level, a single weight-adjusted dose of gentamicin (7mg/Kg) was also administered on induction. Those in the five-day treatment arm received further oral antibiotic prophylaxis with 625mg of Co-amoxiclav TDS and 400mg metronidazole administered three times a day for four days.

    Reporting group title
    24 Hour Antibiotic Group
    Reporting group description
    		 Both treatment groups received 24 hours of intravenous (IV) treatment, consisting of three doses of 1.2g of amoxicillin with clavulanic acid and 500mg of metronidazole eight hours apart starting on induction of anaesthesia. In cases of amputations proximal to the transtibial level, a single weight-adjusted dose of gentamicin (7mg/Kg) was also administered on induction. Participants in the 24-hour treatment arm received no further antibiotics

    Reporting group values
    		 5-day Antibiotic Group 24 Hour Antibiotic Group Total
    Number of subjects
    		 81 80 161
    Age categorical
    Units: Subjects
    Age continuous
    Units: years
        median (full range (min-max))
    		 65 (26 to 93) 66 (30 to 93) -
    Gender categorical
    Units: Subjects
        Female
    		 22 19 41
        Male
    		 59 61 120

    End points

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    End points reporting groups
    Reporting group title
    5-day Antibiotic Group
    Reporting group description
    		 Both treatment groups received 24 hours of intravenous (IV) treatment, consisting of three doses of 1.2g of amoxicillin with clavulanic acid and 500mg of metronidazole eight hours apart starting on induction of anaesthesia. In cases of amputations proximal to the transtibial level, a single weight-adjusted dose of gentamicin (7mg/Kg) was also administered on induction. Those in the five-day treatment arm received further oral antibiotic prophylaxis with 625mg of Co-amoxiclav TDS and 400mg metronidazole administered three times a day for four days.

    Reporting group title
    24 Hour Antibiotic Group
    Reporting group description
    		 Both treatment groups received 24 hours of intravenous (IV) treatment, consisting of three doses of 1.2g of amoxicillin with clavulanic acid and 500mg of metronidazole eight hours apart starting on induction of anaesthesia. In cases of amputations proximal to the transtibial level, a single weight-adjusted dose of gentamicin (7mg/Kg) was also administered on induction. Participants in the 24-hour treatment arm received no further antibiotics

    Primary: Incidence of Surgical Site Infection

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    End point title
    		 Incidence of Surgical Site Infection
    End point description
    Incidence of SSI within 30 days of the procedure using the ASEPSIS score as an objective measure of wound healing. Occurrence of a SSI was defined as positive finding at any of the three follow-ups with an ASEPSIS score of ≥ 21.
    End point type
    Primary
    End point timeframe
    30 days
    End point values
    		 5-day Antibiotic Group 24 Hour Antibiotic Group
    Number of subjects analysed
    76
    76
    Units: score of ≥ 21
        number (not applicable)
    9
    30
    Attachments
    		 ASSIT Choice of Statistical Tests
    Statistical analysis title
    		 Logistic regression analysis
    Statistical analysis description
    Continuous data: If the data appeared normally distributed the Kolmogorov statistic or Shapiro Wilk statistic was utilized to confirm this, with a P value > 0.05 indicating normality. P values are quoted to 3 decimal places with values of less than 0.05 being considered significant Categorical data: The primary test utilized was Pearson’s Chi squared test. If more than 20% of the expected frequencies were <5 or if any were <1 then the Fisher’s exact test was utilized.
    Comparison groups
    5-day Antibiotic Group v 24 Hour Antibiotic Group
    Number of subjects included in analysis
    152
    Analysis specification
    Pre-specified
    Analysis type
    		 other [1]
    P-value
    		 < 0.05 [2]
    Method
    		 Chi-squared
    Confidence interval
    Notes
    [1] - SPSS - see uploaded results for full analysis
    [2] - The use of a 5-day antibiotic course was found to be associated with statistically significant 27.7% absolute risk reduction in the incidence of SSI (P=0.000096-Pearson’s χ2 test)

    Adverse events

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    Adverse events information [1]
    Timeframe for reporting adverse events
    Adverse events will be reported in accordance with the Trust's R&D department’s Safety Reporting standard operating procedure (R&D GCP SOP 07) to ensure compliance with UK Clinical Trial Regulations.
    Adverse event reporting additional description
    The AE reporting period for this trial begins as soon as patients have consented to the trial and ends 30 days after patient’s operation date, which signifies the endpoint for the primary objective of this clinical trial.
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    17.0
    Frequency threshold for reporting non-serious adverse events: 5%
    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: See plot 7 in study main results and findings file to see percentage of complications amongst all groups.

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    02 Aug 2013
    Change of antibiotics for patients with penicillin allergies.
    12 Feb 2014
    Patient sample size changed from 164 to 168 and SAE reporting requirements clarified
    26 Jun 2014
    To add third pre-op skin preparation alcoholic povidone iodine

    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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