Piperacillin/Tazobactam Versus ceftriAxone and Metronidazole for Children With Perforated Appendicitis (ALPACA)

Sponsor

McMaster Children's Hospital (Other)

Overall Status

Not yet recruiting

CT.gov ID

NCT05943223

Collaborator

(none)

Enrollment

Arms

Anticipated Duration (Months)

Study Details

Study Description

Brief Summary

This study is an internal pilot for a multicenter, blinded randomized controlled trial. The purpose of the multicenter trial is to determine whether post-operative piperacillin/tazobactam is more effective than ceftriaxone and metronidazole for children treated with laparoscopic appendectomy for perforated appendicitis. We plan to conduct an internal pilot study to determine whether a blinded multicenter randomized controlled trial is feasible.

Condition or Disease	Intervention/Treatment	Phase
Appendicitis Perforated	Drug: Piperacillin/tazobactam Drug: Normal saline Drug: CefTRIAXone Injection Drug: Metronidazole Injection	Phase 2

Detailed Description

Acute appendicitis is the most common indication for emergency surgery in children. The management of this condition is typically an urgent laparoscopic appendectomy under general anesthesia. If the appendix is found to be perforated at the time of surgery, then patients need to stay in hospital for intravenous antibiotics. Patients who do not respond to antibiotic therapy experience prolonged length of stay, need for additional procedures (such as percutaneous drain insertion), or other complications. This represents significant morbidity for patients and their families.

Children with perforated appendicitis were previously treated with post-operative ampicillin, gentamicin, and metronidazole (also known as "triple therapy"). In 2008, a randomized controlled trial showed that triple therapy is non-inferior to ceftriaxone and metronidazole (CM) in terms of intra-abdominal abscess formation and wound infection. CM is also less expensive and has a simplified dosing regimen. As such, post-operative CM became the standard of care for perforated appendicitis at most children's hospitals.

In 2021, an open-label RCT suggested that piperacillin/tazobactam (PT) is more effective than CM for children with perforated appendicitis. Patients randomized to PT had a reduced rate of intra-abdominal abscess formation compared to those treated with CM (odds ratio (OR) 4.80, p=0.002). This trial was not blinded and there was no allocation concealment. In contrast, a multicenter, observational study reported no difference in the rate of intra-abdominal abscess formation among patients treated with PT compared to CM. The conflicting results of these two studies add further uncertainty regarding the choice of antibiotics for these patients.

Another factor that should be considered regarding the use of PT versus CM in children with perforated appendicitis is antibiotic stewardship. PT is a broad-spectrum antibiotic with increased effectiveness against Pseudomonas aeruginosa and resistant Escherichia coli. As a result, this medication is often reserved for patients with confirmed Pseudomonas infection, oncology patients with febrile neutropenia, or those who are critically ill and admitted to the intensive care unit.

The current study is an internal pilot for a multicenter, blinded randomized controlled trial. The purpose of the multicenter trial is to determine whether post-operative piperacillin/tazobactam is more effective than ceftriaxone and metronidazole for children treated with laparoscopic appendectomy for perforated appendicitis. We plan to conduct an internal pilot study to determine whether a blinded multicenter randomized controlled trial is feasible.

Study Design

Study Type:

Interventional

Anticipated Enrollment :

16 participants

Allocation:

Randomized

Intervention Model:

Parallel Assignment

Intervention Model Description:

Internal pilot studyInternal pilot study

Masking:

Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)

Primary Purpose:

Treatment

Official Title:

Assessing the Longitudinal Outcomes of Piperacillin/Tazobactam Versus ceftriAxone and Metronidazole for Children With Perforated Appendicitis (ALPACA): a Randomized Controlled Trial

Anticipated Study Start Date :

Jan 1, 2024

Anticipated Primary Completion Date :

Sep 1, 2024

Anticipated Study Completion Date :

Dec 1, 2024

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Piperacillin/tazobactam	Drug: Piperacillin/tazobactam Post-operative piperacillin/tazobactam 100 mg/kg IV q8h (to a maximum of 4.5 g IV q8h) Drug: Normal saline Post-operative normal saline 50 mL once daily
Active Comparator: Ceftriaxone and metronidazole	Drug: CefTRIAXone Injection Post-operative ceftriaxone 50 mg/kg IV once daily (to a maximum of 2 g IV once daily) Drug: Metronidazole Injection Post-operative metronidazole 10 mg/kg IV q8h (to a maximum of 500 mg IV q8h)

Arm

Intervention/Treatment

Experimental: Piperacillin/tazobactam

Drug: Piperacillin/tazobactam

Post-operative piperacillin/tazobactam 100 mg/kg IV q8h (to a maximum of 4.5 g IV q8h)

Drug: Normal saline

Post-operative normal saline 50 mL once daily

Active Comparator: Ceftriaxone and metronidazole

Drug: CefTRIAXone Injection

Post-operative ceftriaxone 50 mg/kg IV once daily (to a maximum of 2 g IV once daily)

Drug: Metronidazole Injection

Post-operative metronidazole 10 mg/kg IV q8h (to a maximum of 500 mg IV q8h)

Outcome Measures

Primary Outcome Measures

Length of stay [Index admission]
Length of stay in hospital during index admission

Secondary Outcome Measures

Percutaneous drain insertion [Within 30 days of surgery]
Percutaneous drain insertion by Interventional Radiology
Deep or organ-space surgical site infection [Within 30 days of surgery]
Deep or organ-space surgical site infection
Insertion of Peripherally Inserted Central Catheter (PICC) [Within 30 days of surgery]
Insertion of Peripherally Inserted Central Catheter (PICC)
Parenteral nutrition [Within 30 days of surgery]
Need for parenteral nutrition
Post-operative ultrasound [Within 30 days of surgery]
Need for post-operative ultrasound
Clostridium difficile infection [Within 30 days of surgery]
Clostridium difficile infection (confirmed with stool sample and requiring treatment)
Return to the emergency department [Within 30 days of surgery]
Return to the emergency department within 30 days of surgery
Readmission to hospital [Within 30 days of surgery]
Readmission to hospital within 30 days of surgery
Late complications [Telephone call 3 months after surgery]
Telephone confirmation of no additional complications related to perforated appendicitis requiring assessment in clinic, emergency department visit, or admission to hospital
Exit survey [Telephone call 3 months after surgery]
Parents will complete a descriptive questionnaire about the study by telephone

Other Outcome Measures

Recruitment rate [Through study completion (average of 1 year)]
Number of participants randomized per month
Consent rate [Through study completion (average of 1 year)]
Number of participants who consent to participate divided by those who are approached for consent
Rate of protocol violations [Through study completion (average of 1 year)]
Number of participants who do not receive study treatments within 8 hours of surgery, miss a scheduled study treatment, and/or experience treatment crossover divided by those randomized
Rate of loss to follow-up [Through study completion (average of 1 year)]
Number of participants who cannot be contacted by phone 3 months after discharge from hospital divided by those randomized
Cost of trial [Through study completion (average of 1 year)]
Total cost of internal pilot study in Canadian dollars divided by the number of participants randomized

Eligibility Criteria

Criteria

Ages Eligible for Study:

N/A to 18 Years

Sexes Eligible for Study:

All

Accepts Healthy Volunteers:

Inclusion Criteria:

Laparoscopic appendectomy
Perforated appendicitis confirmed intra-operatively (i.e., visible hole in appendix, fecalith found in peritoneal cavity, intra-abdominal abscess, and/or purulent fluid in peritoneal cavity)