Clinical trial NCT03289351
Conditions: Perforated Appendicitis Postoperative Infection
Sponsor: Phoenix Children's Hospital
Start date: 2017-05-22; Completion date: 2023-11-07
Enrollment: 162 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
After appendix has been removed for perforated appendicitis, patients will receive postoperative antibiotics. In the last 5 years, the literature has transitioned from a 3 -drug therapy to 2-drug therapy. Now there is a recent literature suggesting a single-drug therapy may be safe and adequate. In fact, using zosyn (piperacillin-tazobactam) as a single-drug therapy, there are additional benefits of simplicity, compliance, and lower infectious complications. Currently surgeons are already using both 2-drug regimen (ceftriaxone/metronidazole) and single-drug regimen (zosyn) interchangeable as both are FDA approved and regulated antibiotics for intra-abdominal infection. There is a clear need to compare outcomes between these two options.

Detailed description:
The diagnosis of perforated appendicitis will be documented intraoperatively with photos of extraluminal fecal contents or visible holes on the appendix. Patients will be randomized to 121 in each arm. Postoperative antibiotic therapy option will be decided based on blinded sequence model. 30 day postoperative follow up visit or calls will be made to assess and collect infectious complications.

Arms: arm 1: ceftriaxone/metronidazole arm 2: piperacillin-tazobactam
Interventions: intervention 1: Piperacillin, Tazobactam Drug Combination
Intervention descriptions: intervention 1: Single drug therapy

Protocol documents:
Prot_SAP_000.pdf: 
Two Different Antibiotics Versus One Antibiotic for Pediatric Perforated Appendicitis
NCT03289351
12/07/2018


12/07/2018: Version 3
STUDY PROTOCOL
PCH IRB# 17-011
Randomized Control Trial:  Two Different Antibiotics versus One Antibiotic for Pediatric Perforated 
Appendicitis
Justin Lee, Erin Garvey, Raphael Parrado, Bethany Sussman, Jodie Greenberg , Lois Sayrs, Daniel Ostlie
Version 2: 6/5/2018
Version 3: 12/7/2018
BACKGROUND AND SIGNIFICANCE
Appendicitis is the most common pediatric surgical emergency. Postoperative antibiotic therapy has 
evolved from a 3-drug regimen to 2-drug regimen to once daily dosing of the 2-drug regimen including 
ceftriaxone and metronidazole (CM).1 A recent retrospective review compared the CM regimen to other 
available antibiotic regimens including single-drug regimen.2 Although statistically not significant, the 
study found a two-fold greater risk of infectious complications in those receiving the CM regimen. No 
patients on piperacillin-tazobactam (P) single-drug regimen had postoperative intraabdominal abscess. 
Despite this potential benefit of decreasing postoperative abscess rate, the literature lacks comparative 
analysis of CM versus P regimen. In addition to lower infectious complication rate, the single-drug 
regimen (P) may have additional benefits of simplicity and compliance in comparison to the 2-drug 
regimen (CM).3-5 
GOALS AND OBJECTIVES
This study is a multisite (Phoenix Children's Hospital and The Children’s Mercy Hospital) prospective 
randomized trial comparing the two-drug regimen with CM versus single-drug regimen with P. 
Primary: 
30 day intraabdominal abscess rate
Secondary:
30 day all complications: see list in “Data Collection” table
MATERIALS AND METHODS
Participants: 


12/07/2018: Version 3
Patients with perforated appendicitis treated at Phoenix Children’s Hospital (PCH) and Children’s Mercy 
Hospital (CMH) with perforated appendicitis will be included in the study.  Inclusion criterion is applied 
using a strict definition of perforation: visible hole in the appendix or extraluminal stool contents. The 
visible hole or extraluminal stool contents must be photographed and stored in the medical records. 
Exclusion criteria include iatrogenic perforation of the appendix, documented allergy to antibiotics in 
the trial, nonoperative management of perforated appendicitis with radiographic evidence of abscess, 
and open appendectomies 
Interventions: 
After perforation is determined in the operating room, postoperative antibiotic regimen is randomized 
to either two-drug regimen (CM) or single-drug regimen (P). 
Sample Size: 
The power calculation was based on the postoperative intra-abdominal abscess rate of 8% with CM 
versus 4% with other antibiotic regimens. 
Prior data indicated that the abscess rate among controls (CM) is 8% and 4% with “other antibiotic“ 
regimens. Included in this “other antibiotic regimens” was single-drug regimen (P) with no postoperative 
abscess. If the true failure rate for experimental group (P) was set as 0.1%, a sample size of 121 control 
subjects (CM) and 121 experimental subjects (P) would yield alpha of 0.05 and a power of 0.80. The 
study will proceed until 121 cases are collected on each arm with an expected 5% retrition rate. 
Each site will contribute 121 participants with approximately half of the subject at each site in each 
treatment group.
Assignment: 
Perforation is clearly defined by the operating surgeon at the time of the operation. Postoperatively, 
consent is obtained from the parents. The randomization sequence is accessed to identify the next 
allotment. Each institution will have a randomization sequence. Randomization sequences will be 
generated by the lead site (PCH) and sent to non-lead sites (CMH). 
Protocol: 
Institutional staff surgeons will perform appendectomies based on the call schedule and practices at 
each institution. Computerized order sets are currently being used for postop operative orders. All 
patients will receive a course of antibiotics. Intravenous antibiotics will transition to oral antibiotics 
when tolerating regular diet. A white blood cell (WBC) count is drawn on the day of discharge if ready 
for discharge before postoperative day 5. Elevated WBC will lead to discharge home with oral antibiotics 
for a cumulative total of 7 day course of antibiotics including IV and PO. For all patients, discharge 
criteria include temperature less than 38.0 for 24 hours, tolerating regular diet, and pain controlled on 
oral medications. 


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2-drug regimen (CM) includes once a day dosing of ceftriaxone (50 mg/kg) and metronidazole (30 
mg/kg). Single drug regimen (P) includes piperacillin-tazobactam (<40 kg: 100 mg/kg Q8HR, >40 kg: 
3000mg Q6HR) 
All patients are followed postoperatively for 30 days. CT scans are obtained if the patient’s clinical 
conditions suggest an abdominal abscess at any time after 7 days post-op (PCH procedure is to wait 7 
days to CT for suspected abscess). Postoperative abscess or wound infection are treated with drainage 
and antibiotics dictated by the individual treating surgeons
Data Collection:  
See attached data collection forms.
Statistical Analysis:
Phoenix Children’s Hospital is responsible for data storage and statistical analysis.
Continuous variables will be compared using t-testsand regression analyses. Discrete variables will be 
analyzed with Chi-square and Fisher’s Exact tests with Yates correction where appropriate. Statistical 
significance was defined as P value <0.05. Descriptive statistics such as mean, median standard 
deviation, percentage, and interquartile range will be calculated. Statistical analyses will be designed to 
address the primary and secondary outcomes.     
RISK ASSESSMENT
There are no additional or unnecessary risks associated with this study. All antibiotic therapy options are 
already utilized and FDA-approved antibiotics for perforated appendicitis. 
Participating in this study poses no additional medical risk to subjects. Both antibiotic courses are 
standard of care. Since patients with known allergies are not included in this study, the rate of 
complications due to the assigned antibiotic are no higher than if a patient declined to participate.
The highest risks of this study are breaches of confidentiality and/or privacy. Care and appropriate 
measures will be taken to minimize this risk.
Subjects will be assigned a study ID that will be maintained and recorded in a key. This key will be 
password protected and stored on drive. Only authorized personnel will have access to the sever 
location and only authorized personnel will have password knowledge for the key.  
Any paper data collection will be de-identified and stored securely in a locked office. Any electronically 
filled data collection forms will be de-identified and stored separately from the subject key. Data will be 
entered into a secure HIPAA-compliant REDCap project hosted by Phoenix Children's Hospital/University 
of Arizona. Only authorized study personnel will have access to study data.


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Data will be collected and entered into a REDCap based application.
The data will be stored, maintained, and protected at Phoenix Children’s Hospital/University of Arizona. 
Research Electronic Data Capture (REDCap) is a secure web-based application which provides an 
intuitive interface for collection of research data. This system offers access via secure authentication 
(user ID and password) by clinical site users through the Internet, has audit trails for data manipulation 
and user activity, and can easily export data into formats for use in major statistical packages. Data 
exported from REDCap will be stored on a server that is HIPAA compliant (Phoenix Children's Hospital K 
Drive). Any dataframes containing PHI will be password protected.
Phoenix Children's Hospital is responsible for creating, designing, and customizing the project in 
REDCap. 
DISSEMINATION
This study will be submitted to both regional and national pediatric surgery meetings after completion 
and full analysis. 
REFERENCE 
1.
St Peter SD, Little DC, Calkins CM, et al. A Simple and more cost-effective antibiotic regimen for 
perforated appendicitis. J Pediatr Surg. 2006;41:1020-1024
2.
Lee JY, Ally S, Kelly B, Kays D, Thames L. Once Daily Dosing of Ceftriaxone and Metronidazole in 
Children with Perforated Appendicitis. J Pediatr Pharmacol Ther. 2016 Mar-Apr, 21(2):140-145
3.
Fishmann SJ, Pelosi L, Klavon SL, et al. Perforated Appendicitis: Prospective Outcome Analysis for 
150 Children. J Pediatr Surg. 2000;35(6):923-926
4.
Nadler EP, Reblock KK, Ford HR, et al. Monotherapy versus Multi-Drug Therapy for the 
Treatment of Perforated Appendicitis in Children. Surg Infect. 2003;4(4):327-333
5.
Goldin AB, Sawin RS, Garrison MM, et al. Aminoglycoside-based Triple-Antibiotic Therapy versus 
Monotherapy for Children with Ruptured Appendicitis. Pediatrcs. 2007;119(5):9059-9111