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    Clinical Trial Results:
    Intraperitoneal administration of fosfomycin, metronidazole and molgramostim versus intravenous conventional antibiotics for perforated appendicitis – a pivotal quasi-randomized controlled trial

    Summary
    EudraCT number
    		 2017-004753-16
    Trial protocol
    		 DK  
    Global end of trial date
    17 Jul 2018

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

    Trial information

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    Trial identification
    Sponsor protocol code
    HEH-SF-02
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT03435900
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    Herlev Hospital
    Sponsor organisation address
    Herlev Ringvej 75, Herlev, Denmark, 2730
    Public contact
    CPO office, Department of Surgery, 0045 38683414, siv.fonnes@regionh.dk
    Scientific contact
    CPO office, Department of Surgery, 0045 38683414, siv.fonnes@regionh.dk
    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
    04 Feb 2019
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    17 Jul 2018
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    The primary outcome is the total length of hospital stay, defined as the number of hours in hospital after end of operation (not before operation) and until 30-day follow-up.
    Protection of trial subjects
    The trial would be stopped if severe adverse effects or severe complications, which were not expected, arose from the trial treatment. This was to be decided by the sponsor. Assessment of harms: The participants were asked if they had experienced any changes both the first day after surgery and 10 days after the surgery in combination with an objective examination. This was documented in the CRF. Further, the patient was asked if they have experienced any adverse events defined as any unfavourable and unintended sign, symptom, or disease associated with the intraperitoneal treatment, whether or not related to that treatment. A follow-up was conducted 30 days after surgery. This was also be documented in the CRF.
    Background therapy
    		 -
    Evidence for comparator
    		 -
    Actual start date of recruitment
    14 Feb 2018
    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
    Denmark: 13
    Worldwide total number of subjects
    13
    EEA total number of subjects
    13
    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)
    10
    From 65 to 84 years
    3
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 The intervention group, who were planed for an acute surgery, and the control group, who had undergone laparoscopy appendectomy for perforated appendix, were approached by the trial personnel and informed about the trial.

    Pre-assignment
    Screening details
    		 A total of 82 patients were screened. 13 participants were quasi-randomised and 12 of these fulfilled the trial. The most common reasons for exclusion were a normal or non-perforated appendix found during surgery.

    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
    Quasi-randomisation makes blinding impossible. However, allocation concealment would be impossible even in a proper randomized setting due to the intraperitoneal formulation in the intervention group.

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Intervention
    Arm description
    		 A combination of fosfomycin, metronidazole and GM-CSF i.p. All drugs will be administered together intraperitoneally at the end of the surgery after the appendix has been removed. Postoperatively, the intervention group will receive orally administered antibiotics: 500 mg amoxicillin/125 mg clavulanic acid and 500 mg metronidazole administered three times daily for three days.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Repomol
    Investigational medicinal product code
    PR1
    Other name
    molgramostim, rhGM-CSF
    Pharmaceutical forms
    Powder for suspension for injection
    Routes of administration
    Intraperitoneal use
    Dosage and administration details
    A dose of 50 microgram Repomol (molgramostim/rhGM-CSF) in 0.2 ml of solution (water for injection) in combination with 4 g of fosfomycin and 1 g metronidazole, which were administered intraperitoneally and will remain as local installation. Postoperatively, orally administered antibiotic were given to the participants.

    Investigational medicinal product name
    Fosfomycin disodium salt
    Investigational medicinal product code
    PR2
    Other name
    fosfomycin
    Pharmaceutical forms
    Powder for injection
    Routes of administration
    Intraperitoneal use
    Dosage and administration details
    A dose of 4 g of fosfomycin diluted in 300 ml of sterile water for injections in combination with 50 microgram Repomol (molgramostim/rhGM-CSF) and 1 g metronidazole, which were administered intraperitoneally and remained as local installation. Postoperatively, orally administered antibiotic were given to the participants.

    Investigational medicinal product name
    Metronidazole
    Investigational medicinal product code
    PR2
    Other name
    Metronidazole
    Pharmaceutical forms
    Infusion
    Routes of administration
    Intraperitoneal use
    Dosage and administration details
    A dose of 1 g metronidazole corresponing to 200 ml in combination with 50 microgram Repomol (molgramostim/rhGM-CSF) and 4 g of fosfomycin and 1 g metronidazole, which were administered intraperitoneally and remained as local installation. Postoperatively, orally administered antibiotic were given to the participants.

    Arm title
    		 Control
    Arm description
    		 Standard intravenous antibiotic agents during surgery (either 1.5 g cefuroxime or 4 g piperacillin/500 mg tazobactam and 1 g metronidazole). Furthermore, a minimum of 500 ml saline was used for irrigation of the abdominal cavity. Postoperatively, the control group received three days of intravenously administered antibiotic agents: 4 g piperacillin/500 mg tazobactam and 500 g metronidazole, three times daily for a minimum of three days.
    Arm type
    		 Active comparator

    Investigational medicinal product name
    Piperacilliin/Tazobactam
    Investigational medicinal product code
    PR1
    Other name
    Pharmaceutical forms
    Infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    During surgery, the control group received either 1.5 g cefuroxime or 4 g piperacillin/500 mg tazobactam and 1 g metronidazole intravenously. After surgery, the control group received an intravenous course of 4 g piperacillin/500 mg tazobactam and 500 g metronidazole for at least three days.

    Investigational medicinal product name
    Cefuroxime
    Investigational medicinal product code
    PR1
    Other name
    Pharmaceutical forms
    Infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    During surgery, the control group received either 1.5 g cefuroxime or 4 g piperacillin/500 mg tazobactam and 1 g metronidazole intravenously. After surgery, the control group received an intravenous course of 4 g piperacillin/500 mg tazobactam and 500 g metronidazole for at least three days.

    Investigational medicinal product name
    Metronidazole
    Investigational medicinal product code
    PR2
    Other name
    Pharmaceutical forms
    Infusion
    Routes of administration
    Intravenous use
    Dosage and administration details
    During surgery, the control group received either 1.5 g cefuroxime or 4 g piperacillin/500 mg tazobactam and 1 g metronidazole intravenously. After surgery, the control group received an intravenous course of 4 g piperacillin/500 mg tazobactam and 500 g metronidazole for at least three days.

    Number of subjects in period 1
    		Intervention Control
    Started
    7
    6
    Completed
    6
    6
    Not completed
    1
    0
         Consent withdrawn by subject
    1
    -

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Intervention
    Reporting group description
    		 A combination of fosfomycin, metronidazole and GM-CSF i.p. All drugs will be administered together intraperitoneally at the end of the surgery after the appendix has been removed. Postoperatively, the intervention group will receive orally administered antibiotics: 500 mg amoxicillin/125 mg clavulanic acid and 500 mg metronidazole administered three times daily for three days.

    Reporting group title
    Control
    Reporting group description
    		 Standard intravenous antibiotic agents during surgery (either 1.5 g cefuroxime or 4 g piperacillin/500 mg tazobactam and 1 g metronidazole). Furthermore, a minimum of 500 ml saline was used for irrigation of the abdominal cavity. Postoperatively, the control group received three days of intravenously administered antibiotic agents: 4 g piperacillin/500 mg tazobactam and 500 g metronidazole, three times daily for a minimum of three days.

    Reporting group values
    		 Intervention Control Total
    Number of subjects
    		 7 6 13
    Age categorical
    Units: Subjects
        In utero
    		 0 0 0
        Preterm newborn infants (gestational age < 37 wks)
    		 0 0 0
        Newborns (0-27 days)
    		 0 0 0
        Infants and toddlers (28 days-23 months)
    		 0 0 0
        Children (2-11 years)
    		 0 0 0
        Adolescents (12-17 years)
    		 0 0 0
        Adults (18-64 years)
    		 5 6 11
        From 65-84 years
    		 2 0 2
        85 years and over
    		 0 0 0
    Gender categorical
    Units: Subjects
        Female
    		 4 1 5
        Male
    		 3 5 8
    ASA score
    Units: Subjects
        ASA I
    		 4 6 10
        ASA II
    		 3 0 3
    Preoperative antibiotics
    Units: Times administered
        median (full range (min-max))
    		 2 (0 to 8) 2 (0 to 4) -
    BMI
    Units: kilogram(s)/square meter
        median (full range (min-max))
    		 29 (24 to 34 ) 28 (21 to 33 ) -
    Height
    Units: meter
        median (full range (min-max))
    		 1.73 (1.63 to 1.85) 1.85 (1.68 to 1.87) -
    Weight
    Units: kilogram(s)
        median (full range (min-max))
    		 82 (65 to 105) 92 (73 to 107) -

    End points

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    End points reporting groups
    Reporting group title
    Intervention
    Reporting group description
    		 A combination of fosfomycin, metronidazole and GM-CSF i.p. All drugs will be administered together intraperitoneally at the end of the surgery after the appendix has been removed. Postoperatively, the intervention group will receive orally administered antibiotics: 500 mg amoxicillin/125 mg clavulanic acid and 500 mg metronidazole administered three times daily for three days.

    Reporting group title
    Control
    Reporting group description
    		 Standard intravenous antibiotic agents during surgery (either 1.5 g cefuroxime or 4 g piperacillin/500 mg tazobactam and 1 g metronidazole). Furthermore, a minimum of 500 ml saline was used for irrigation of the abdominal cavity. Postoperatively, the control group received three days of intravenously administered antibiotic agents: 4 g piperacillin/500 mg tazobactam and 500 g metronidazole, three times daily for a minimum of three days.

    Primary: Primary, total length of stay within 30 days after surgery

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    End point title
    		 Primary, total length of stay within 30 days after surgery
    End point description
    Total length of in hospital stay (measured in hours): defined as from end of the operation until discharge from the hospital plus length of stay during a possible readmission within 30 days from surgery.
    End point type
    Primary
    End point timeframe
    Postoperatively (baseline) to 30 days postoperatively (+/-3 days)
    End point values
    		 Intervention Control
    Number of subjects analysed
    6 [1]
    6
    Units: hours
        median (full range (min-max))
    13 (2 to 21)
    84 (67 to 169)
    Notes
    [1] - 1 participant withdrew consent and data on the primary outcome could, therefore, not be collected.
    Statistical analysis title
    		 Primary analysis
    Comparison groups
    Intervention v Control
    Number of subjects included in analysis
    12
    Analysis specification
    Pre-specified
    Analysis type
    		 superiority
    P-value
    		 = 0.017
    Method
    		 Wilcoxon (Mann-Whitney)
    Confidence interval

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    From the administration until 30 days postoperatively.
    Adverse event reporting additional description
    Adverse events were collected through interview with participants the first postoperative day, at visit 10 days postoperatively and through medical records and contact with the participant by telephone until 30 days after surgery.
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    10.0
    Reporting groups
    Reporting group title
    Intervention group
    Reporting group description
    		 -

    Reporting group title
    Control group
    Reporting group description
    		 -

    Serious adverse events
    		 Intervention group Control group
    Total subjects affected by serious adverse events
         subjects affected / exposed
    1 / 7 (14.29%)
    3 / 6 (50.00%)
         number of deaths (all causes)
    0
    0
         number of deaths resulting from adverse events
    0
    0
    Gastrointestinal disorders
    Abscess drainage
         subjects affected / exposed
    0 / 7 (0.00%)
    2 / 6 (33.33%)
         occurrences causally related to treatment / all
    0 / 0
    2 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Diverticulitis
         subjects affected / exposed
    0 / 7 (0.00%)
    1 / 6 (16.67%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Infections and infestations
    Influenza
         subjects affected / exposed
    1 / 7 (14.29%)
    0 / 6 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 0.05%
    Non-serious adverse events
    		 Intervention group Control group
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    5 / 7 (71.43%)
    5 / 6 (83.33%)
    Injury, poisoning and procedural complications
    Pain
    Additional description: Pain in lower right quadrant
         subjects affected / exposed [1]
    1 / 6 (16.67%)
    0 / 6 (0.00%)
         occurrences all number
    1
    0
    Haematoma
         subjects affected / exposed [2]
    0 / 6 (0.00%)
    1 / 6 (16.67%)
         occurrences all number
    0
    1
    Gastrointestinal disorders
    Diarrhoea
         subjects affected / exposed [3]
    4 / 6 (66.67%)
    3 / 6 (50.00%)
         occurrences all number
    4
    3
    Nausea
         subjects affected / exposed [4]
    1 / 6 (16.67%)
    1 / 6 (16.67%)
         occurrences all number
    1
    1
    Vomiting
         subjects affected / exposed [5]
    0 / 6 (0.00%)
    2 / 6 (33.33%)
         occurrences all number
    0
    2
    Notes
    [1] - The number of subjects exposed to this adverse event is less than the total number of subjects exposed for the reporting group. These numbers are expected to be equal.
    Justification: As one participant withdrew consent, we cannot know if this adverse event arose in this participant.
    [2] - The number of subjects exposed to this adverse event is less than the total number of subjects exposed for the reporting group. These numbers are expected to be equal.
    Justification: As one participant withdrew consent, we cannot know if this adverse event arose in this participant.
    [3] - The number of subjects exposed to this adverse event is less than the total number of subjects exposed for the reporting group. These numbers are expected to be equal.
    Justification: As one participant withdrew consent, we cannot know if this adverse event arose in this participant.
    [4] - The number of subjects exposed to this adverse event is less than the total number of subjects exposed for the reporting group. These numbers are expected to be equal.
    Justification: As one participant withdrew consent, we cannot know if this adverse event arose in this participant.
    [5] - The number of subjects exposed to this adverse event is less than the total number of subjects exposed for the reporting group. These numbers are expected to be equal.
    Justification: As one participant withdrew consent, we cannot know if this adverse event arose in this participant.

    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.
    Quasi-randomised design: no actual randomisation took place (risk of selection bias).
    For support, Contact us.
    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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