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

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

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.

Study Overview

• Status: Completed
• Conditions: Appendicitis Perforated
• Intervention / Treatment: Drug: Combination of fosfomycin, metronidazole and rhGM-CSF (administered together intraperitoneally) and three days of antibiotics p.o.; Drug: Standard antibiotics intravenously

• Study Type: Interventional
• Enrollment (Actual): 13
• Phase: Phase 2

Contacts and Locations

Study Locations

• Denmark
  • Copenhagen, Denmark, 2400
    • Department of Surgery, Bispebjerg Hospital
  • Herlev, Denmark, 2730
    • Department of Surgery, Herlev Hospital

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (ADULT, OLDER_ADULT)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

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

Study Plan

How is the study designed?

Design Details

• Primary Purpose: TREATMENT
• Allocation: NON_RANDOMIZED
• Interventional Model: PARALLEL
• Masking: NONE

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
ACTIVE_COMPARATOR: Control group	Drug: Standard antibiotics intravenously; 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.
EXPERIMENTAL: Intervention group	Drug: Combination of fosfomycin, metronidazole and rhGM-CSF (administered together intraperitoneally) and three days of antibiotics p.o.; 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.

What is the study measuring?

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

Collaborators and Investigators

• Sponsor: Herlev Hospital
• Collaborators: Bispebjerg Hospital

Publications and helpful links

General Publications

• Fonnes S, Roepstorff S, Holzknecht BJ, Olesen CS, Olsen JHH, Schmidt L, Alder R, Gamborg S, Rasmussen T, Arpi M, Jorgensen LN, Rosenberg J. Shorter Total Length of Stay After Intraperitoneal Fosfomycin, Metronidazole, and Molgramostim for Complicated Appendicitis: A Pivotal Quasi-Randomized Controlled Trial. Front Surg. 2020 May 5;7:25. doi: 10.3389/fsurg.2020.00025. eCollection 2020.

Study record dates

Study Major Dates

• Study Start (ACTUAL): February 14, 2018
• Primary Completion (ACTUAL): July 17, 2018
• Study Completion (ACTUAL): July 17, 2018

Study Registration Dates

• First Submitted: February 5, 2018
• First Submitted That Met QC Criteria: February 15, 2018
• First Posted (ACTUAL): February 19, 2018

Study Record Updates

• Last Update Posted (ACTUAL): October 16, 2018
• Last Update Submitted That Met QC Criteria: October 14, 2018
• Last Verified: October 1, 2018

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Digestive System Diseases; Infections; Gastrointestinal Diseases; Gastroenteritis; Intestinal Diseases; Cecal Diseases; Intraabdominal Infections; Appendicitis; Anti-Infective Agents; Antiprotozoal Agents; Antiparasitic Agents; Antitubercular Agents; Metronidazole; Anti-Bacterial Agents; Antibiotics, Antitubercular; Fosfomycin
• Other Study ID Numbers: HEH-SF-02

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: UNDECIDED

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No