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

Primary Purpose

Appendicitis

Status
Completed
Phase
Phase 2
Locations
Denmark
Study Type
Interventional
Intervention
A combination of fosfomycin, metronidazole and GM-CSF i.p.
Sponsored by
Herlev Hospital
About
Eligibility
Locations
Arms
Outcomes
Full info

About this trial

This is an interventional treatment trial for Appendicitis

Eligibility Criteria

18 Years - 100 Years (Adult, Older Adult)MaleDoes not accept healthy volunteers

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

Sites / Locations

  • Department of Surgery, Herlev Hospital

Arms of the Study

Arm 1

Arm Type

Experimental

Arm Label

Participants

Arm Description

Outcomes

Primary Outcome Measures

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.
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.

Secondary Outcome Measures

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.
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).
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).
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).
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).
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).
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).
Main trial (14 patients): Length of stay.
Length of stay in hours postoperatively (minimum 12 hours).
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.
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.
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.
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.

Full Information

First Posted
February 2, 2017
Last Updated
May 28, 2019
Sponsor
Herlev Hospital
Collaborators
Jacob Rosenberg (Sponsor), Barbara Juliane Holzknecht (Investigator), Magnus Arpi (Investigator), Johan Juhl Weisser (Partner, data analysis)
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1. Study Identification

Unique Protocol Identification Number
NCT03046758
Brief Title
The Safety and Pharmacokinetics of Intraperitoneal Administration in Patients Undergoing Appendectomy for Uncomplicated Appendicitis
Official Title
The Safety and Pharmacokinetics of Intraperitoneal Administration of Granulocyte-macrophage Colony-stimulating Factor, Fosfomycin, and Metronidazole in Patients Undergoing Appendectomy for Uncomplicated Appendicitis
Study Type
Interventional

2. Study Status

Record Verification Date
May 2019
Overall Recruitment Status
Completed
Study Start Date
February 24, 2017 (Actual)
Primary Completion Date
December 7, 2017 (Actual)
Study Completion Date
December 7, 2017 (Actual)

3. Sponsor/Collaborators

Responsible Party, by Official Title
Principal Investigator
Name of the Sponsor
Herlev Hospital
Collaborators
Jacob Rosenberg (Sponsor), Barbara Juliane Holzknecht (Investigator), Magnus Arpi (Investigator), Johan Juhl Weisser (Partner, data analysis)

4. Oversight

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

5. Study Description

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.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Appendicitis

7. Study Design

Primary Purpose
Treatment
Study Phase
Phase 2
Interventional Study Model
Single Group Assignment
Masking
None (Open Label)
Allocation
N/A
Enrollment
14 (Actual)

8. Arms, Groups, and Interventions

Arm Title
Participants
Arm Type
Experimental
Intervention Type
Drug
Intervention Name(s)
A combination of fosfomycin, metronidazole and GM-CSF i.p.
Intervention Description
All drugs will be administered together intraperitoneally at the end of the surgery after the appendix has been removed.
Primary Outcome Measure Information:
Title
Main trial (14 patients): Drop of white blood cell counts
Description
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.
Time Frame
4 hours (± 30 minutes)
Title
Sub-trial (8 patients): The pharmacokinetics of fosfomycin.
Description
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.
Time Frame
Until 24 hours after surgery ±4 hours.
Secondary Outcome Measure Information:
Title
Main trial (14 patients): Biochemical markers
Description
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.
Time Frame
4 hours ±30 minutes postoperatively.
Title
Main trial (14 patients): Blood pressure
Description
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).
Time Frame
Until 12 hours ±30 minutes.
Title
Main trial (14 patients): Pulse
Description
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).
Time Frame
Until 12 hours ±30 minutes.
Title
Main trial (14 patients): Frequency of respiration
Description
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).
Time Frame
Until 12 hours ±30 minutes.
Title
Main trial (14 patients): Peripheral saturation
Description
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).
Time Frame
Until 12 hours ±30 minutes.
Title
Main trial (14 patients): Temperature
Description
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).
Time Frame
Until 12 hours ±30 minutes.
Title
Main trial (14 patients): Length of stay.
Description
Length of stay in hours postoperatively (minimum length of stay: 12 hours but information on length of stay is collected until 30 days postoperatively).
Time Frame
Until 30 days postoperatively.
Title
Main trial (14 patients): Length of stay.
Description
Length of stay in hours postoperatively (minimum 12 hours).
Time Frame
Until 30 days postoperatively.
Title
Main trial (14 patients): Side effects
Description
Side effects are evaluated through an objective examination and questions about changes 12 hours ±30 minutes and 10 days postoperatively ±1 day.
Time Frame
10 days postoperatively ±1 day.
Title
Main trial (14 patients): Adverse events
Description
Adverse events are registered from the surgery until 30 days postoperatively through medical records and contact with the participant by telephone.
Time Frame
Until 30 days postoperatively.
Title
Sub-trial (8 patients): The pharmacokinetics of metronidazole.
Description
The plasma concentrations of metronidazole over time are measured with HPLC-MS until 24 hours after surgery ±4 hours.
Time Frame
Until 24 hours after surgery ±4 hours.
Title
Sub-trial (8 patients): Microbiological flora and susceptibility
Description
The microbiological flora and susceptibility of specimens collected during the surgery from the abdominal excess fluid and/or swab from the appendices are investigated.
Time Frame
Until 30 days postoperatively.

10. Eligibility

Sex
Male
Minimum Age & Unit of Time
18 Years
Maximum Age & Unit of Time
100 Years
Accepts Healthy Volunteers
No
Eligibility Criteria
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
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Siv Fonnes, MD
Organizational Affiliation
Center for Perioperative Optimization, Department of Surgery, Herlev Hospital
Official's Role
Principal Investigator
Facility Information:
Facility Name
Department of Surgery, Herlev Hospital
City
Herlev
ZIP/Postal Code
2730
Country
Denmark

12. IPD Sharing Statement

Plan to Share IPD
Undecided
Citations:
PubMed Identifier
31040341
Citation
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.
Results Reference
result
Links:
URL
https://www.nature.com/articles/s41598-019-43151-4
Description
Link to the article regarding the safety (open access)

Learn more about this trial

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

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