The Safety and Pharmacokinetics of Intraperitoneal Administration in Patients Undergoing Appendectomy for Uncomplicated Appendicitis

The Safety and Pharmacokinetics of Intraperitoneal Administration of Granulocyte-macrophage Colony-stimulating Factor, Fosfomycin, and Metronidazole in Patients Undergoing Appendectomy for Uncomplicated Appendicitis

The objective of this trial is to evaluate the safety of the intraperitoneal administration of the combination of fosfomycin, metronidazole, and granulocyte-macrophage colony-stimulating factor (GM-CSF) in patients undergoing surgery for uncomplicated appendicitis. Further, in a sub-trial the aim is to investigate the plasma concentrations of fosfomycin and metronidazole after intraperitoneal administration.

Study Overview

• Status: Completed
• Conditions: Appendicitis
• Intervention / Treatment: Drug: A combination of fosfomycin, metronidazole and GM-CSF i.p.

• Study Type: Interventional
• Enrollment (Actual): 14
• Phase: Phase 2

Contacts and Locations

Study Locations

• Denmark
  • Herlev, Denmark, 2730
    • Department of Surgery, Herlev Hospital

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 16 years to 98 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: Male

Description

Inclusion Criteria:

• Men ≥18 years old
• Suspicion of acute appendicitis and planned for diagnostic laparoscopy and eventual appendectomy
• Written informed consent after written and verbal information

Exclusion Criteria:

• Cannot understand, read or speak Danish
• Previous allergic reaction to fosfomycin, metronidazole, or GM-CSF
• Perforated appendicitis (diagnosed either during surgery or at a preoperative computer tomography (CT) scan)
• Diagnostic laparoscopy revealing normal appendix not requiring an appendectomy
• Other intra-abdominal pathology requiring surgical intervention (diagnosed either during surgery or at a preoperative CT-scan)
• Known renal or hepatic disease or biochemical evidence at the time of admission
• Known autoimmune disease or other chronic inflammation
• Known hematologic disease or cancer
• Previous abdominal surgery (either laparoscopic or open surgery)
• Daily use or use of medication one week prior to or during the trial period apart from painkillers such as paracetamol, ibuprofen, tramadol, and morphine as well as drugs needed for anaesthesia, thrombosis prophylaxis, and nausea. Limitations for antibiotics are defined below
• Use of other antimicrobial agents than the trial treatment one month before until 24 hours after the trial treatment
• Participant in another drug trial one month prior to the date of the surgery
• Body mass index ≥35 kg/m2
• Weekly intake of alcohol >14 units, where one unit corresponds to 12 g alcohol

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: N/A
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

1

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Participants	Drug: 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.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Main trial (14 patients): Drop of white blood cell counts	The safety of intraperitoneal administration is evaluated through the white blood cell counts 4 hours (± 30 minutes) postoperatively. A toxic effect is defined by a drop below the lower reference range.	4 hours (± 30 minutes)
Sub-trial (8 patients): The pharmacokinetics of fosfomycin.	The plasma concentrations of fosfomycin over time are measured with high-performance liquid chromatography mass spectrometry (HPLC-MS) until 24 hours after surgery ±4 hours.	Until 24 hours after surgery ±4 hours.

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Main trial (14 patients): Biochemical markers	A standard panel of blood samples (e.g. white blood cell differential count, inflammation marker C-reactive protein (CRP), kidney function tests, liver function tests, and electrolytes) are analysed at admission (baseline) and 4 hours ±30 minutes postoperatively, these markers are compared.	4 hours ±30 minutes postoperatively.
Main trial (14 patients): Blood pressure	Blood pressure in mmHg is measured perioperatively (baseline, 5 minutes, 10 minutes and 15 minutes after the trial treatment has been administered) and postoperatively (4 and 12 hours ±30 minutes after the trial treatment has been administered).	Until 12 hours ±30 minutes.
Main trial (14 patients): Pulse	Pulse in beats per minute is measured perioperatively (baseline, 5 minutes, 10 minutes and 15 minutes after the trial treatment has been administered) and postoperatively (4 and 12 hours ±30 minutes after the trial treatment has been administered).	Until 12 hours ±30 minutes.
Main trial (14 patients): Frequency of respiration	Frequency of respiration in breaths per minute is measured perioperatively (baseline, 5 minutes, 10 minutes and 15 minutes after the trial treatment has been administered) and postoperatively (4 and 12 hours ±30 minutes after the trial treatment has been administered).	Until 12 hours ±30 minutes.
Main trial (14 patients): Peripheral saturation	Peripheral saturation of oxygen in percent is measured perioperatively (baseline, 5 minutes, 10 minutes and 15 minutes after the trial treatment has been administered) and postoperatively (4 and 12 hours ±30 minutes after the trial treatment has been administered).	Until 12 hours ±30 minutes.
Main trial (14 patients): Temperature	Temperature in degrees Celsius is measured perioperatively (baseline, 5 minutes, 10 minutes and 15 minutes after the trial treatment has been administered) and postoperatively (4 and 12 hours ±30 minutes after the trial treatment has been administered).	Until 12 hours ±30 minutes.
Main trial (14 patients): Length of stay.	Length of stay in hours postoperatively (minimum length of stay: 12 hours but information on length of stay is collected until 30 days postoperatively).	Until 30 days postoperatively.
Main trial (14 patients): Length of stay.	Length of stay in hours postoperatively (minimum 12 hours).	Until 30 days postoperatively.
Main trial (14 patients): Side effects	Side effects are evaluated through an objective examination and questions about changes 12 hours ±30 minutes and 10 days postoperatively ±1 day.	10 days postoperatively ±1 day.
Main trial (14 patients): Adverse events	Adverse events are registered from the surgery until 30 days postoperatively through medical records and contact with the participant by telephone.	Until 30 days postoperatively.
Sub-trial (8 patients): The pharmacokinetics of metronidazole.	The plasma concentrations of metronidazole over time are measured with HPLC-MS until 24 hours after surgery ±4 hours.	Until 24 hours after surgery ±4 hours.
Sub-trial (8 patients): Microbiological flora and susceptibility	The microbiological flora and susceptibility of specimens collected during the surgery from the abdominal excess fluid and/or swab from the appendices are investigated.	Until 30 days postoperatively.

Collaborators and Investigators

• Sponsor: Herlev Hospital
• Collaborators: Jacob Rosenberg (Sponsor); Barbara Juliane Holzknecht (Investigator); Magnus Arpi (Investigator); Johan Juhl Weisser (Partner, data analysis)
• Investigators: Principal Investigator: Siv Fonnes, MD, Center for Perioperative Optimization, Department of Surgery, Herlev Hospital

Publications and helpful links

General Publications

• Fonnes S, Holzknecht BJ, Arpi M, Rosenberg J. Intraperitoneal administration of fosfomycin, metronidazole, and granulocyte-macrophage colony-stimulating factor in patients undergoing appendectomy is safe: a phase II clinical trial. Sci Rep. 2019 Apr 30;9(1):6727. doi: 10.1038/s41598-019-43151-4.

Helpful Links

• Link to the article regarding the safety (open access)

Study record dates

Study Major Dates

• Study Start (Actual): February 24, 2017
• Primary Completion (Actual): December 7, 2017
• Study Completion (Actual): December 7, 2017

Study Registration Dates

• First Submitted: February 2, 2017
• First Submitted That Met QC Criteria: February 4, 2017
• First Posted (Estimate): February 8, 2017

Study Record Updates

• Last Update Posted (Actual): May 29, 2019
• Last Update Submitted That Met QC Criteria: May 28, 2019
• Last Verified: May 1, 2019

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; Anti-Bacterial Agents; Antiprotozoal Agents; Antiparasitic Agents; Metronidazole; Fosfomycin
• Other Study ID Numbers: HEH-SF-01

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
• product manufactured in and exported from the U.S.: No