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

Study Overview
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Brief Summary
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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.

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

Conditions
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Appendicitis

Intervention / Treatment
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* Drug: A combination of fosfomycin, metronidazole and GM-CSF i.p.


Participation Criteria
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Eligibility Criteria
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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

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 100 Years

Sexes Eligible for Study
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Male

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
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Participants<br> | Drug: A combination of fosfomycin, metronidazole and GM-CSF i.p.<br>* All drugs will be administered together intraperitoneally at the end of the surgery after the appendix has been removed.<br>|

What is the study measuring?
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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. |