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

Phase 2

Completed

• Conditions: Appendicitis
• Interventions: Drug: A combination of fosfomycin, metronidazole and GM-CSF i.p.

• Registration Number: NCT03046758
• Lead Sponsor: Herlev Hospital

Brief Summary

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.

Detailed Description

Not available

Study Timeline

• Study First Submitted: 2017-02-02
• Study First Submitted QC: 2017-02-04
• Study First Posted: 2017-02-08
• Study Start: 2017-02-24
• Primary Completion: 2017-12-07
• Study Completion: 2017-12-07
• Status Verified: 2019-05
• Last Update Submitted: 2019-05-28
• Last Update Posted: 2019-05-29

Recruitment & Eligibility

• Status: COMPLETED
• Sex: Male
• Target Recruitment: 14

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 & Design

• Study Type: INTERVENTIONAL
• Study Design: SINGLE_GROUP

Arm && Interventions

Group	Intervention	Description
Participants	A combination of fosfomycin, metronidazole and GM-CSF i.p.	-

Primary Outcome Measures

Name	Time	Method
Main trial (14 patients): Drop of white blood cell counts	4 hours (± 30 minutes)	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.
Sub-trial (8 patients): The pharmacokinetics of fosfomycin.	Until 24 hours after surgery ±4 hours.	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.

Secondary Outcome Measures

Name	Time	Method
Main trial (14 patients): Blood pressure	Until 12 hours ±30 minutes.	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).
Main trial (14 patients): Frequency of respiration	Until 12 hours ±30 minutes.	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).
Main trial (14 patients): Pulse	Until 12 hours ±30 minutes.	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).
Main trial (14 patients): Side effects	10 days postoperatively ±1 day.	Side effects are evaluated through an objective examination and questions about changes 12 hours ±30 minutes and 10 days postoperatively ±1 day.
Main trial (14 patients): Adverse events	Until 30 days postoperatively.	Adverse events are registered from the surgery until 30 days postoperatively through medical records and contact with the participant by telephone.
Main trial (14 patients): Peripheral saturation	Until 12 hours ±30 minutes.	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).
Main trial (14 patients): Biochemical markers	4 hours ±30 minutes postoperatively.	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.
Main trial (14 patients): Temperature	Until 12 hours ±30 minutes.	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).
Main trial (14 patients): Length of stay.	Until 30 days postoperatively.	Length of stay in hours postoperatively (minimum 12 hours).
Sub-trial (8 patients): The pharmacokinetics of metronidazole.	Until 24 hours after surgery ±4 hours.	The plasma concentrations of metronidazole over time are measured with HPLC-MS until 24 hours after surgery ±4 hours.
Sub-trial (8 patients): Microbiological flora and susceptibility	Until 30 days postoperatively.	The microbiological flora and susceptibility of specimens collected during the surgery from the abdominal excess fluid and/or swab from the appendices are investigated.

Trial Locations

Locations (1)

Department of Surgery, Herlev Hospital; 🇩🇰 Herlev, Denmark