Intraperitoneal Administration of Fosfomycin, Metronidazole and Molgramostim Versus Intravenous Antibiotics for Perforated Appendicitis

Study Overview
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Brief Summary
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The objective of this trial is to evaluate if intraoperative intraperitoneal administration of fosfomycin, metronidazole and recombinant human granulocyte-macrophage colony-stimulating factor (rhGM-CSF) followed by oral antibiotic for three days is as effective as the current intravenous antibiotic treatment given during and three days after appendectomy for perforated appendicitis. The primary outcome is the total length of hospital stay, defined as the number of hours in hospital after end of operation and until 30-day follow-up.

Official Title
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Intraperitoneal Administration of Fosfomycin, Metronidazole and Molgramostim Versus Intravenous Conventional Antibiotics for Perforated Appendicitis - a Pivotal Quasi-randomized Controlled Trial

Conditions
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Appendicitis Perforated

Intervention / Treatment
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* Drug: Combination of fosfomycin, metronidazole and rhGM-CSF (administered together intraperitoneally) and three days of antibiotics p.o.
* Drug: Standard antibiotics intravenously


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Age ≥18 years Suspicion of acute appendicitis and planned for diagnostic laparoscopy and eventual laparoscopic appendectomy Perforated appendicitis (diagnosed during surgery by the surgeon) Negative p-HCG (women) Written informed consent after written and verbal information (preoperatively for the intervention group and postoperatively for the control group) Exclusion Criteria: Cannot understand, read or speak Danish Previous allergic reaction to fosfomycin, metronidazole, rhGM-CSF, or penicillins e.g. piperacillin or amoxicillin Diagnostic laparoscopy revealing normal appendix not requiring an appendectomy or appendicitis without perforation Other intra-abdominal pathology requiring surgical intervention at the same operation Known renal or hepatic disease or biochemical evidence at the time of admission Known hematologic disease in current medical treatment American Society of Anesthesiologists (ASA) physical status ≥4 (a patient with severe systemic disease that is a constant threat to life) Body weight >110 kg Surgery converted to open appendectomy Anticipated compliance problems

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Non-Randomized
Intervention Model: Parallel Assignment
Interventional Model Description: Quasi-randomised controlled trial
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Intervention group<br> | Drug: Combination of fosfomycin, metronidazole and rhGM-CSF (administered together intraperitoneally) and three days of antibiotics p.o.<br>* All drugs will be administered together intraperitoneally at the end of the surgery after the appendix has been removed. Hereafter, the intervention group will receive three days of orally administered antibiotics: 500 mg amoxicillin combined with 125 mg clavulanic acid and 500 mg metronidazole. These doses will be administered three times daily.<br>|
| Active Comparator: Control group<br> | Drug: Standard antibiotics intravenously<br>* 4 g piperacillin/500 mg tazobactam and 1 g metronidazole administered intravenously during surgery followed by 4 g piperacillin/500 mg tazobactam and 500 mg metronidazole administered intravenously three times daily for three days.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Total length of hospital stay | in hours | From end of surgery until 30-days follow-up | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Gastrointestinal Quality of Life Index (GIQLI) | A disease-specific questionnaire validated in Danish is collected at 10 days postoperatively (±2 days) and at 30 days postoperatively (±3 days) | 10 days (±2 days) and 30 days (±3 days) postoperatively | 
| Side effects | Number and description. A questionnaire regarding side effects is collected within the first 24 hours after surgery and at 10 days postoperatively (±2 days) | Within 24 hours after surgery and 10 days (±2 days) postoperatively | 
| Postoperative complications | Number. According to the Clavien-Dindo grading | From end of surgery until 30-days follow-up | 
| Surgical site infections requiring surgical drainage | It is defined as deep incisional surgical site infection according to Centre for Disease Control and Prevention (CDC) | From end of surgery until 30-days follow-up | 
| Intraabdominal abscesses requiring drainage | Number. It is defined as an organ/space surgical site infection according to CDC | From end of surgery until 30-days follow-up | 
| Readmissions | Number. Only readmissions related to the surgery will be registered; e.g. admission and treatment of a non-related condition will not be registered. | From end of surgery until 30-days follow-up | 
| Reoperations | Number. Only reoperations related to the appendectomy will be registered. | From end of surgery until 30-days follow-up | 
| Time to return to normal activities | Time period in days. The date is defined at the time point at which the participant could return to normal daily activities. | From end of surgery until 30-days follow-up | 
| Period of sick leave absence from work | Time periode in days. The parameter is defined as the number of days from the operation to the time point at where the participant returned to work or school. | From end of surgery until 30-days follow-up | 
| Costs | The estimated total costs of admission, surgery, possible complications, reoperations etc. in the two treatment groups. | From end of surgery until 30-days follow-up | 
| Adverse events |  | From end of surgery until 30-days follow-up | 
| Microbiological flora and susceptibility | Number and type of positive specimens. If participants have a postoperative infectious complication. | From end of surgery until 30-days follow-up |