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    Clinical Trial Results:
    The safety and pharmacokinetics of intraperitoneal administration of granulocyte-macrophage colony-stimulating factor, fosfomycin, and metronidazole in patients undergoing appendectomy for uncomplicated appendicitis

    Summary
    EudraCT number
    		 2015-005772-16
    Trial protocol
    		 DK  
    Global end of trial date
    07 Dec 2017

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

    Trial information

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    Trial identification
    Sponsor protocol code
    HEH-SF-01
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT03046758
    WHO universal trial number (UTN)
    		 -
    Sponsors
    Sponsor organisation name
    Department of Surgery, 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
    14 Feb 2018
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    07 Dec 2017
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    The safety of intraperitoneal administration is evaluated through the white blood cell counts 4 hours postoperatively. A toxic effect is defined by a drop below the lower reference range.
    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 12 hours 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
    24 Feb 2017
    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: 14
    Worldwide total number of subjects
    14
    EEA total number of subjects
    14
    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)
    13
    From 65 to 84 years
    1
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 Patients planed for an acute surgery were approached by the trial personnel and informed about the trial. Patients, who fulfilled the inclusion criteria and presented none of the exclusion criteria, apart from those criteria that can only be clarified at surgery, were enrolled in the trial after informed consent.

    Pre-assignment
    Screening details
    		 A total of 121 patients were screened. 26 participants were enrolled and 12 of these were excluded prior to or during surgery. The most common reasons for exclusion were a normal or perforated appendix found during surgery.

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

    Arms
    Arm title
    		 Experimental
    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.
    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.

    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 wereadministered intraperitoneally and remained as local installation.

    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.1 g metronidazole

    Number of subjects in period 1
    		Experimental
    Started
    14
    Completed
    14

    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
    		 14 14
    Age categorical
    Units: Subjects
        In utero
    		 0
        Preterm newborn infants (gestational age < 37 wks)
    		 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)
    		 0
        From 65-84 years
    		 0
        85 years and over
    		 0
    Age continuous
    Units: years
        median (full range (min-max))
    		 24 (18 to 67) -
    Gender categorical
    Units: Subjects
        Female
    		 0 0
        Male
    		 14 14
    Height
    Units: cm
        median (full range (min-max))
    		 183 (172 to 198) -
    Weight
    Units: kg
        median (full range (min-max))
    		 88 (65 to 110) -
    BMI
    Units: kg/m^2
        median (full range (min-max))
    		 26 (20 to 32) -

    End points

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    End points reporting groups
    Reporting group title
    Experimental
    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.

    Primary: Primary, postoperative WBC

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    End point title
    		 Primary, postoperative WBC [1]
    End point description
    The safety of intraperitoneal administration was evaluated through the white blood cell counts (WBC) 4 hours postoperatively. A toxic effect was defined by a drop below the lower reference range. Furthermore, postoperative and baseline WBC was compared with Wilcoxon signed-rank test, which found no difference ( p=0.65).
    End point type
    Primary
    End point timeframe
    Preoperatively (baseline) and 4 hours ± 30 minutes postoperatively
    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: The statistical analysis is described. The statistical analyses could not be filled correctly as only one group but two time points are compared and not two groups.
    End point values
    		 Experimental
    Number of subjects analysed
    14
    Units: ×10^9/l
        median (full range (min-max))
    10.6 (7.10 to 20.5)
    No statistical analyses for this end point

    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.
    Assessment type
    		 Systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 ICD
    Dictionary version
    10
    Reporting groups
    Reporting group title
    Overall
    Reporting group description
    		 -

    Serious adverse events
    		 Overall
    Total subjects affected by serious adverse events
         subjects affected / exposed
    0 / 14 (0.00%)
         number of deaths (all causes)
    0
         number of deaths resulting from adverse events
    0
    Frequency threshold for reporting non-serious adverse events: 5%
    Non-serious adverse events
    		 Overall
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    4 / 14 (28.57%)
    Cardiac disorders
    Hypotension
         subjects affected / exposed
    1 / 14 (7.14%)
         occurrences all number
    1
    Gastrointestinal disorders
    Diarrhoea
         subjects affected / exposed
    3 / 14 (21.43%)
         occurrences all number
    3

    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.
    No control group was included and low number of participants was included in this pilot trial. The recorded harms could be directly related to the trial treatment, the anaesthesia, or the surgery itself.

    Online references
    http://www.ncbi.nlm.nih.gov/pubmed/31040341
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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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