Clinical trial NCT03159754
Conditions: Appendicitis Perforated Appendicitis Ruptured Appendicitis Complicated Appendicitis
Sponsor: University of Michigan
Start date: 2017-06-29; Completion date: 2020-03-26
Enrollment: 40 participants; Allocation: NON_RANDOMIZED; Intervention model: PARALLEL

Brief summary:
When the appendix becomes infected and inflamed, it is called appendicitis. Sometimes, if the infection and inflammation get worse, the appendix can die or burst, leading to a larger infection or even pus pockets around the appendix. This is called complicated, or perforated, appendicitis. Three common treatments for complicated appendicitis are

* appendectomy (removal of the appendix) right away
* appendectomy several weeks after the diagnosis
* treating the appendicitis without performing an appendectomy

This study seeks to determine which of these three approaches is most cost-effective in children with complicated appendicitis.

Detailed description:
This is a single center, prospective study to compare early appendectomy vs. non-operative management of immunocompetent patients with complicated appendicitis, and then to compare interval appendectomy vs. no interval appendectomy in those managed with the initial non-operative approach. Patients who choose early appendectomy will have surgery within 24 hours of diagnosis and be discharged once they are afebrile for 24 hours, have a normal WBC count, and can tolerate a diet. They will be discharged with 5 days of oral ciprofloxacin and metronidazole and follow-up in clinic 2-4 weeks later. Patients who choose non-operative management will receive piperacillin-tazobactam with or without abscess drainage until they are afebrile 24 hours with a normal WBC count and are tolerating a diet, followed by 5 days of oral ciprofloxacin and metronidazole upon discharge. These patients will then be seen in clinic in 2-4 weeks, at which time they will be given the choice of whether or not to undergo interval appendectomy at least 8 weeks from initial presentation. Those in the interval appendectomy group will follow-up one month post-operatively. Patients in both groups will be contacted 3 months and 2 years following initial presentation.

{{{While 40 participants were enrolled as intended, and some data was collected from them, a combination of staff turnover and subsequent resource constraints did not permit the analysis originally intended. Thus, results data is shown comparing the early appendectomy participants against the other two arms combined.}}}}

Arms: arm 1: None arm 2: None arm 3: None
Interventions: intervention 1: Early Appendectomy intervention 2: Interval Appendectomy intervention 3: Antibiotics
Intervention descriptions: intervention 1: Removal of the appendix within 24 hours of admission intervention 2: Removal of the appendix after initial antibiotic treatment and at least 6 weeks of recovery. intervention 3: Zosyn will be administered unless the patient has a penicillin allergy, in which case patients will receive both ciprofloxacin and metronidazole.

Protocol documents:
Prot_SAP_000.pdf: 
Study Title: Optimal Care of Complicated Appendicitis
Principal Investigator: Steven Bruch, MD, MSc
Institution: University of Michigan
NCT: NCT03159754
Protocol Version approved by IRB on 4/5/2017


Principal Investigator Name: Steven Bruch, MD, MSc 
UM HUM # 00103791 
PROTOCOL VERSION #: 1.0 
 
Page 1 of 17 
 
CLINICAL PROTOCOL 
 
STUDY TITLE 
Optimal Care of Complicated Appendicitis 
 
 
Study Agents: None  
 
HUM #: 00103791 
 
Principal Investigator: Steven Bruch, MD, MSc 
 
Institution: University of Michigan 
 
Version and Date: Version 1.2 February 24, 2017 
 
 


Principal Investigator Name: Steven Bruch, MD, MSc 
UM HUM # 00103791 
PROTOCOL VERSION #: 1.0 
 
Page 2 of 17 
Table of Contents 
1 
INTRODUCTION ...................................................................................................... 5 
1.1 
INDICATION ........................................................................................................ 5 
1.2 
BACKGROUND AND RATIONALE ................................................................. 5 
1.3 
HYPOTHESIS ....................................................................................................... 6 
1.4 
PREVIOUS HUMAN EXPERIENCE ................................................................. 6 
2 
STUDY OBJECTIVES AND ENDPOINTS ............................................................ 6 
2.1 
OBJECTIVES ........................................................................................................ 6 
2.2 
OUTCOMES .......................................................................................................... 6 
2.2.1 
PRIMARY OUTCOME .................................................................................. 6 
2.2.2 
SECONDARY OUTCOMES .......................................................................... 6 
3 
STUDY DESIGN ........................................................................................................ 7 
4 
SUBJECT SELECTION ............................................................................................ 8 
4.1 
SUBJECT RECRUITMENT ................................................................................ 8 
4.1.1 
INCLUSION CRITERIA ................................................................................ 8 
4.1.2 
EXCLUSION CRITERIA.......... ERROR! BOOKMARK NOT DEFINED. 
5 
STUDY TREATMENTS............................................................................................ 9 
5.1 
ALLOCATION TO TREATMENT .................................................................... 9 
5.2 
DRUG SUPPLIES ............................ ERROR! BOOKMARK NOT DEFINED. 
5.2.1 
FORMULATION, PREPARATION AND DISPENSING ............ ERROR! 
BOOKMARK NOT DEFINED. 
5.2.2 
DRUG STORAGE AND DRUG ACCOUNTABILITY ................ ERROR! 
BOOKMARK NOT DEFINED. 
6 
STUDY PROCEDURES ............................................................................................ 9 
7 
ASSESSMENTS ....................................................................................................... 11 
7.1 
PRIMARY ENDPOINT ASSESSMENTS ........................................................ 11 
7.2 
SECONDARY ENDPOINT ASSESSMENTS .................................................. 11 
8 
RISK AND RISK MITIGATION ........................................................................... 11 
9 
ADVERSE EVENT REPORTING ......................................................................... 12 
10 DATA ANALYSIS/STATISTICAL METHODS .................................................. 14 
10.1 
SAMPLE SIZE DETERMINATION ................................................................ 14 
10.2 
DATA ANALYSIS ............................................................................................... 14 
10.2.1 
ANALYSIS OF PRIMARY ENDPOINT .................................................... 14 
10.2.2 
ANALYSIS OF SECONDARY ENDPOINTS ............................................ 14 
11 MONITORING ......................................................................................................... 14 
11.1 
DATA SAFETY AND MONITORING BOARD (DSMB) .............................. 14 
12 ETHICS ..................................................................................................................... 14 
12.1 
INSTITUTIONAL REVIEW BOARD (IRB) ................................................... 14 
12.2 
SUBJECT INFORMATION AND CONSENT................................................. 15 
12.3 
STUDY DISCONTINUATION CRITERIA ..................................................... 15 
12.3.1 
STOPPING RULES FOR SAFETY REASONS ........................................ 15 
12.3.2 
RULES FOR DISCONTINUATION OF A SUBJECT ............................. 15 
13 REFERENCES ......................................................................................................... 16 
 
 


Principal Investigator Name: Steven Bruch, MD, MSc 
UM HUM # 00103791 
PROTOCOL VERSION #: 1.0 
 
Page 3 of 17 
 
 
PROTOCOL SYNOPSIS 
 
 
Sponsor: Steven Bruch, MD, MSc 
Name of Product(s):  
Study Title: Optimal Care of Complicated Appendicitis 
Study Phase:  
Objectives:  
• To determine the best management strategy for complicated appendicitis 
Outcomes 
Primary: 
• Cost 
Secondary: 
• Complications 
• Time (days) away from activities/Parents lost work days 
• Days of antibiotics 
• Length of Stay 
• Number of radiographic studies 
• Number of percutaneous drainage procedures 
• Quality of life 
• Recurrent appendicitis 
Hypotheses:  
Primary:  
• Non-operative management of perforated appendicitis without interval 
appendectomy will result in decreased overall cost 
• There will be no significant difference in cost between early and interval 
appendectomy groups 
Secondary:  
• Patients who undergo non-operative management of perforated appendicitis 
without interval appendectomy will have fewer days away from activities and 
shorter lengths of stay 
• Patients who undergo non-operative management of perforated appendicitis will 
require more radiographic studies and/or percutaneous drains 


Principal Investigator Name: Steven Bruch, MD, MSc 
UM HUM # 00103791 
PROTOCOL VERSION #: 1.0 
 
Page 4 of 17 
Study Design: Pilot study with N=40; Group placement will be determined by patient 
choice both for early appendectomy vs. non-operative management, and for interval 
appendectomy vs. no interval appendectomy for those initially managed non-operatively.   
This is a single center, prospective study to compare early appendectomy vs. non-
operative management of immunocompetent patients with complicated appendicitis, and 
then to compare interval appendectomy vs. no interval appendectomy in those managed 
with the initial non-operative approach.  Patients who choose early appendectomy will 
have surgery within 24 hours of diagnosis and be discharged once they are afebrile for 24 
hours, have a normal WBC count, and can tolerate a diet.  They will be discharged with 5 
days of oral ciprofloxacin and metronidazole and follow-up in clinic 2-4 weeks later.  
Patients who choose non-operative management will receive piperacillin-tazobactam with 
or without abscess drainage until they are afebrile 24 hours with a normal WBC count and 
are tolerating a diet, followed by 5 days of oral ciprofloxacin and metronidazole upon 
discharge.  These patients will then be seen in clinic in 2-4 weeks, at which time they will 
be given the choice of whether or not to undergo interval appendectomy at least 8 weeks 
from initial presentation.  Those in the interval appendectomy group will follow-up one 
month post-operatively.  Patients in both groups will be contacted 3 months and 2 years 
following initial presentation.  
Study Population: Patients ages 5-17 with the clinical diagnosis of complicated 
appendicitis. 
Inclusion/Exclusion Criteria:  
Inclusion Criteria 
1. Age 5-17 years 
2. CT or MRI read with free intraperitoneal air, RLQ abscess, visible 
hole in the appendix, and/or extruded fecalith, OR 
3. CT or MRI read with phlegmon or diffuse/extensive 
inflammation/free fluid plus 1 of 3 of the following (with CT) or 2 
of 3 of the following (with MRI) *: 
a. WBC > 15 
b. Peritonitis (involuntary RLQ guarding, + Rosving sign, 
percussion tenderness, and/or rebound tenderness) 
c. Temperature > 38.0 C 
*>90% specificity for complicated appendicitis based on unpublished institutional data 
Exclusion Criteria 
1. Immunocompromized 
2. History of major abdominal operation 
3. Previous appendicitis 
4. Major comorbidities that preclude safe operation 
5. Inability to follow-up or appropriately consent 


Principal Investigator Name: Steven Bruch, MD, MSc 
UM HUM # 00103791 
PROTOCOL VERSION #: 1.0 
 
Page 5 of 17 
Test Product; Dose; and Mode of Administration:  
Reference or Placebo Therapy; Dose; and Mode of Administration:  
Duration of Treatment:   
Variables: 
• Duration of IV antibiotic therapy and length of stay in all groups will be 
determined by clinical features including duration of fever, leukocytosis, and 
ability to tolerate a diet 
• Need for percutaneous drainage will be based on imaging findings (ultrasound, 
CT, or MRI) and clinical status 
• Number of radiographic studies will be determined by clinical course 
• Management plan (early appendectomy, interval appendectomy, or no 
appendectomy) will be determined by patient/parent choice.   
Statistical Methods: The direct cost is a continuous variable, which may be assessed by 
univariate analysis (independent t-test).  The secondary endpoints of complications, time 
away from activities/parents from work, days of antibiotics, length of stay, and number of 
percutaneous drainages are continuous variables and will be analyzed in the same manner.  
 
Sample size determination: 
The study is powered to show a $7,000 reduction in cost.  To do this, we will enroll at 
least 68 patients in each arm.  We will begin with a pilot study of 40 total patients to 
better predict our sample size requirement. 
 
1 INTRODUCTION 
1.1 
Indication 
A large prospective study is required to determine the optimal timing of appendectomy in 
complicated appendicitis, as well as the necessity of interval appendectomy in non-operative 
management. 
1.2 
Background and Rationale 
Complicated appendicitis, defined as perforation with or without abscess, is currently treated one 
of two ways: Immediate operation, or IV antibiotics with or without drainage, followed by 
interval appendectomy 6-8 weeks later.  Recent prospective studies have shown conflicting 
evidence as to which of these management strategies is preferred with respect to cost and length 
of hospital stay, and were influenced by lack of power or by earlier than anticipated failure of 
non-operative therapy 1,2.  Furthermore, in those patients initially managed non-operatively, the 


Principal Investigator Name: Steven Bruch, MD, MSc 
UM HUM # 00103791 
PROTOCOL VERSION #: 1.0 
 
Page 6 of 17 
majority of pediatric surgeons perform interval appendectomy 6-8 weeks following initial 
presentation despite a lack of clinical evidence 3.  In fact, retrospective studies in both adults and 
children have indicated that the risk of developing recurrent appendicitis in patients managed 
non-operatively for perforated appendicitis is low, calling into question the practice of interval 
appendectomy 4,5.  Therefore, a larger prospective study is required to determine the optimal 
timing of appendectomy in complicated appendicitis, as well as the necessity of interval 
appendectomy in non-operative management. 
1.3 
Hypothesis 
Based on previous studies, our hypotheses are that 1) early appendectomy results in lower health 
care costs than non-operative management followed by interval appendectomy, and 2) interval 
appendectomy may be a non-essential procedure following non-operative management of 
complicated appendicitis resulting in higher costs. 
1.4 
Previous Human Experience 
 
As mentioned above in 1.2, previous studies have shown conflicting data regarding cost-
effectiveness of early versus interval appendectomy, and have been influenced by small sample 
size and earlier than anticipated failure of non-operative therapy.  Previous studies have also 
suggested that interval appendectomy in both adults in children may not be necessary. 
2 STUDY OBJECTIVES AND ENDPOINTS 
2.1 
Objectives 
• To quantify the cost of care and compare them between the three groups 
• To assess complication rates between the three groups 
• To assess the length of time until return to activity/parents return to work 
• To assess the number of percutaneous drainage procedures and/or radiographic studies 
performed in all groups 
• To monitor the length of stay and compare between the three groups 
• To monitor the duration of antibiotic therapy and compare between the three groups 
• To assess and compare quality of life between the three groups 
2.2 
Outcomes 
2.2.1 
Primary Outcome 
• Overall cost of care 
2.2.2 
Secondary Outcomes 
 
• Complications 
• Time to return to activity/parents to return to work 
• Duration of antibiotic therapy 
• Length of stay 


Principal Investigator Name: Steven Bruch, MD, MSc 
UM HUM # 00103791 
PROTOCOL VERSION #: 1.0 
 
Page 7 of 17 
• Number of percutaneous drainage procedures/radiographic imaging studies 
• Quality of life 
• Recurrent appendicitis 
3 STUDY DESIGN  
This is a single center, prospective study to compare early appendectomy vs. non-operative 
management of immunocompetent patients with complicated appendicitis, as well as interval 
appendectomy vs. no interval appendectomy in those managed with the initial non-operative 
approach.  In our study we will identify patients between the ages of 5 and 17 with the diagnosis 
of complicated appendicitis who are not immunocompromised.  We will present the two options 
to the patient and their parents using a prerecorded video that discusses the two treatments with 
their theoretical advantages and disadvantages.  We will allow the patients and their parents to 
decide which option they would like.  We then will treat each study participant using our present 
algorithm for complicated appendicitis (see diagram below).  Study participants who select 
immediate operation will undergo an appendectomy within 24 hours and be treated using our 
present algorithm.  They will follow up in our clinic in 2-4 weeks and complete a gastrointestinal 
quality of life survey at that time.  Study participants who selected initial non-operative 
management will be treated using our present algorithm.  They will follow up in clinic in 2-4 
weeks after initial hospital discharge and also complete a gastrointestinal quality of life survey at 
this time.  At this point in the treatment of complicated appendicitis, there are two options: 
Interval appendectomy, or no appendectomy or further treatment.  We will again use a 
prerecorded video that discusses these two options and their theoretical advantages and 
disadvantages.  The study participants and their parents will then decide whether or not to have 
an interval appendectomy which will be scheduled at least 8 weeks after initial hospital 
discharge.  The interval appendectomy will be performed (admitted the day of the operation and 
most often discharged the following day), and patients will follow up in the clinic one month 
following the appendectomy and data will be collected.  All participating subjects will be 
contacted by phone or email 3 months and again at 2 years after their initial admission and data 
will be collected.  If the patient has not completed his/her clinical course by 3 months, treatment 
(antibiotics, percutaneous drainage, or operative intervention) and further follow-up will be 
determined by the discretion of the treating surgeon.  A chart review and administration of a 
quality of life survey will also occur along with these follow up phone calls and emails.  The 
primary outcome of our study will be cost.  The secondary outcomes will be number and type of 
complications, time away from activities (school etc.) for patients and away from work for 
parents, number of days of antibiotic therapy required, length of stay, number of imaging tests, 
number of percutaneous drainage procedures required, quality of life, and recurrent appendicitis. 
 
 


Principal Investigator Name: Steven Bruch, MD, MSc 
UM HUM # 00103791 
PROTOCOL VERSION #: 1.0 
 
Page 8 of 17 
Figure 1: 
 
 
4 SUBJECT SELECTION 
4.1 
Subject Recruitment 
Informed consent will be obtained from the parents or legal guardian.  The consent will be 
obtained in person.  Consent will be obtained preoperatively if inclusion criteria are met. 
4.1.1 
Inclusion Criteria 
1. Patient age 5-17 years 
2. At least 1 of the following CT or MRI findings: 
a. Peri-appendicular abscess 
b. Extruded appendicolith 
c. Visible hole in appendiceal wall 
d. Free peritoneal air 
OR 


Principal Investigator Name: Steven Bruch, MD, MSc 
UM HUM # 00103791 
PROTOCOL VERSION #: 1.0 
 
Page 9 of 17 
3. CT or MRI read with phlegmon or diffuse/extensive inflammation/free 
fluid plus 1 of 3 of the following (with CT) or 2 of 3 of the following 
(with MRI) *: 
a. WBC > 15 
b. Peritonitis (involuntary RLQ guarding, + Rosving sign, percussion 
tenderness, and/or rebound tenderness) 
c. Temperature > 38.0 C 
*>90% specificity for complicated appendicitis based on unpublished institutional data 
4.1.2 
Exclusion Criteria 
1. Immunocompromized state 
2. History of major abdominal operation 
3. Previous appendicitis 
4. Major comorbidities that preclude safe operation 
5. Inability to follow-up or appropriately consent 
6. Pregnant women 
7. Allergy to penicillin plus any one of the following: 
a. Hypersensitivity to ciprofloxacin and/or metronidazole 
b. Pregnant/lactating women 
c. Patients taking theophylline 
d. Patient taking tizanidine  
5 STUDY TREATMENTS 
 
5.1 
Allocation to Treatment 
Treatment group will be determined by patient/parent choice.  All patients and families will be 
shown a pre-recorded video describing the treatment options and their theoretic advantages and 
disadvantages prior to making their decision.  This applies to the decisions of early 
appendectomy vs. non-operative therapy, as well as to interval appendectomy vs. no interval 
appendectomy.   
 
6 STUDY PROCEDURES 
 
 
At Baseline (Presentation to Emergency Department) 
 We will record the following: 
• Demographic information including age, gender, duration of symptoms, medical history 
(including any immunosuppressive medications or medical diagnoses causing 
immunocompromised state), WBC count, and imaging findings. 
• Pregnancy test if past menarche 
 
If the patient undergoes appendectomy: 
We will record the following: 


Principal Investigator Name: Steven Bruch, MD, MSc 
UM HUM # 00103791 
PROTOCOL VERSION #: 1.0 
 
Page 10 of 17 
• Operative approach (laparoscopic, open, or laparoscopic converted to open) 
• Operative time 
• Operative findings 
• Intraoperative complications, if any 
 
During admission (for both immediate appendectomy and non-operative groups): 
 
• See Appendix A (complicated appendicitis clinical pathway) for patient management and 
procedures during initial hospitalization 
 
At Discharge (for both immediate appendectomy and non-operative groups): 
• Record length of stay, duration of IV antibiotics, and post-operative complications 
• Administer PedsQLTM quality of life survey 
 
Remainder of post-discharge procedures per schedule of activities below: 
 
SCHEDULE OF ACTIVITIES 
 
Table 1: 
 
 
Time Post-presentation 
Protocol Activity 
Presentation 2-4 weeks 
8 weeks 
3 months 
2 years 
Informed Consent  
X 
  
  
  
 
Demographic and 
Medical History 
X 
  
  
 
 
Vitals 
X 
  
  
  
 
Patient/Parent 
Choice 
X 
 X (for 
non-op) 
  
  
 
Initial 
appendectomy 
X (within 24 
hours) 
 
 
 
 
Initiate 
complicated 
appendicitis 
clinical pathway 
(see Appendix A) 
X 
 
 
 
 
Clinic follow-up 
 
X 
 
X (for 
interval 
operative) 
 
GI QOL survey 
administration 
 
X 
 
 
 
Interval 
appendectomy 
 
 
X 
 
 
PedsQL 
administration 
X 
(discharge) 
 
 
X 
 
X 
Phone/email 
follow-up 
 
 
 
X 
X 
Chart Review 
 
 
 
X 
X 


Principal Investigator Name: Steven Bruch, MD, MSc 
UM HUM # 00103791 
PROTOCOL VERSION #: 1.0 
 
Page 11 of 17 
 
 
7 ASSESSMENTS  
 
7.1 
Primary Endpoint Assessments 
Cost will be determined by data extraction the cost accounting section of the Health System 
Data Warehouse (HSDW). 
7.2 
Secondary Endpoint Assessments  
Complications will be determined and documented during the initial hospitalization and at 
subsequent clinic appointments and phone follow-ups, as documented above. 
 
Time to return to activity/parents to work will be determined and documented at subsequent 
clinic appointments and phone follow-ups, as documented above. 
 
Days of antibiotics will be determined by our current algorithm (depicted in Figure 1), based 
on patient fever and WBC count. 
 
Length of stay will be determined by our current algorithm, documented at the end of the 
initial hospitalization, and accrued at any subsequent readmissions. 
 
Number of percutaneous drainage procedures and imaging procedures will be determined by 
clinical course. 
 
Quality of life will be determined by the PedsQL and gastrointestinal QOL surveys. 
 
Recurrent appendicitis will be determined by chart review and patient phone or email 
follow-up. 
 
8 RISK AND RISK MITIGATION 
 
Studies comparing early appendectomy to interval appendectomy for complicated 
appendicitis have demonstrated conflicting results, and therefore it is unclear if one strategy 
bears more risk than the other 1,2.  Both are considered acceptable in current practice.  The 
same can be said of whether or not to perform interval appendectomy at all.  Interval 
appendectomy has been shown in the literature to be a safe and effective operation 6. 
 
ADVERSE EVENTS  
Adverse events associated with complicated appendicitis include intra-abdominal abscess, small 
bowel obstruction, wound infection, unplanned readmission, and complications related to central 
line placement (if necessary) and percutaneous drain placement (if necessary).  These risks 
pertain to patient who both do and do not undergo appendectomy.  Recurrent appendicitis is also 


Principal Investigator Name: Steven Bruch, MD, MSc 
UM HUM # 00103791 
PROTOCOL VERSION #: 1.0 
 
Page 12 of 17 
a risk of non-operative management of complicated appendicitis, as is the need for additional 
treatment with antibiotics 2.  All patients in this study will receive antibiotics (piperacillin-
tazobactam, ciprofloxacin, metronidazole), and will be subject to the risk of drug reaction or 
allergy.  Metronidazole should be administered with caution to patients with central nervous 
system diseases. Patients with severe hepatic disease metabolize metronidazole slowly, with 
resultant accumulation of metronidazole and its metabolites in the plasma. Accordingly, for such 
patients, doses, below those usually recommended should be administered cautiously 
9 ADVERSE EVENT REPORTING 
 
Adverse Event Definition 
An adverse event (AE) is any untoward medical occurrence in a subject participating in an 
investigational study or protocol regardless of causality assessment.  An adverse event can be an 
unfavorable and unintended sign (including an abnormal laboratory finding), symptom, 
syndrome or disease associated with or occurring during the use of an investigational product 
whether or not considered related to the investigational product. 
 
These events may be: 
 
a. Definitely related: clearly associated with study drug/treatment 
b. Probably related:  likely associated with study drug/treatment 
c. Possibly related:  may be associated with study drug or other treatment 
d. Unlikely to be related, or 
e. Definitely not related to the study drug/treatment 
 
For reporting purposes, an AE should be regarded as definitely or probably related to the 
regimen if the investigator believes that at least one of following criteria are met: 
 
a. There is a clinically plausible time sequence between onset of the AE and the administration 
of the study drug or treatment. 
b. There is a biologically plausible mechanism for the study drug or treatment causing or 
contributing to the AE. 
c. The AE cannot be attributed solely to concurrent/underlying illness, other drugs, or 
procedures.  
d. A potential alternative cause does not exist. 
 
Serious Adverse Events (SAE):  An adverse drug experience occurring at any dose that results 
in any of the following outcomes: 
 
a. 
Death 
b. 
A life-threatening adverse drug experience 
c. 
Inpatient hospitalization or prolongation of existing hospitalization 
d. 
A persistent or significant disability &/or incapacity 
e. 
A congenital anomaly or birth defect 
 


Principal Investigator Name: Steven Bruch, MD, MSc 
UM HUM # 00103791 
PROTOCOL VERSION #: 1.0 
 
Page 13 of 17 
Important medical events that may not result in death, be life-threatening, or require 
hospitalization may be considered a serious adverse drug experience when, based upon 
appropriate medical judgment, they may jeopardize the patient or subject and may require 
medical or surgical intervention to prevent one of the outcomes listed in this definition. A 
serious adverse experience includes any experience that is fatal or immediately life threatening, 
results in a persistent or significant disability/incapacity, requires or prolongs in-patient 
hospitalization, or is a congenital anomaly, cancer, or overdose. 
Other important medical events that may not result in death, not be life-threatening, or not 
require hospitalization may be considered a serious adverse experience when, based upon 
appropriate medical judgment, the event may jeopardize the subject/patient and may require 
medical or surgical intervention to prevent one of the outcomes listed previously. 
 
Expected adverse events are those adverse events that are listed in the protocol, the 
Investigator’s Brochure (current edition) or in the study informed consent document. 
 
Unexpected adverse events are those that are not anticipated in the study informed consent.  
This includes adverse events for which the specificity or severity is not consistent with the 
description in the informed consent. 
 
Unanticipated problem: Per FDA Procedural Guidance for Clinical Investigators, Sponsors, and 
IRBs (January 2009), A serious problem that has implications for the conduct of the study 
(requiring a significant and usually safety-related, change in the protocol such as revising 
inclusion/exclusion criteria or including a new monitoring requirement, informed consent or 
investigator’s brochure). 
 
Unanticipated problem Reporting: Per 21 CFR 312.66, 312.53 (c)(1)(vii), and 56.108(b)(1), 
should an Unanticipated problem occur during the investigation, the investigator will 
promptly report all unanticipated problems involving risks to human subjects or others to 
IRBMED /FDA. 
 
 
 
The severity or grade of an adverse event may be measured using the following definitions: 
 
Mild:  Noticeable to the subject, but does not interfere with subject’s expected daily activities, 
usually does not require additional therapy or intervention, dose reduction, or discontinuation of 
the study. 
 
Moderate:  Interferes with the subject’s expected daily activities, may require some additional 
therapy or intervention but does not require discontinuation of the study. 
 
Severe: Extremely limits the subject’s daily activities and may require discontinuation of study 
therapy, and/or additional treatment or intervention to resolve. 
 
Event reporting:  The study will comply with the IRB & FDA reporting requirements and 
guidelines. 
 


Principal Investigator Name: Steven Bruch, MD, MSc 
UM HUM # 00103791 
PROTOCOL VERSION #: 1.0 
 
Page 14 of 17 
10 DATA ANALYSIS/STATISTICAL METHODS 
 
10.1 Sample Size Determination 
The study is powered to show a $7,000 reduction in overall cost.  To do this, we will need to 
enroll at least 68 patients in each arm.  This study represents a pilot study of 40 total patients 
to better determine our sample size requirement.  
10.2 Data Analysis 
10.2.1 
Analysis of Primary Endpoint 
The primary outcome measure of this study is the cost of care.  This is a continuous variable, 
which may be assessed by univariate analysis (independent t-test).   
 
10.2.2 
Analysis of Secondary Endpoints 
 
The secondary endpoints of this study are complications, time away from activities/parents 
from work, days of antibiotics, length of stay, and number of percutaneous drainage and 
radiographic procedures.  These are also continuous variables and will be analyzed by 
univariate analysis (independent t-test). 
11 MONITORING 
11.1 Data Safety and Monitoring Board (DSMB) 
The first DSMB meeting will occur 6 months after study initiation and every 6 months going 
forward. In addition to reviewing Serious Adverse Events (SAEs), the first DSMB meeting 
will focus on over all safety of the trial and study agent and will make a determination as to 
whether or not the study should proceed.  The DSMB will then meet quarterly throughout 
the remainder of the study and at any time during the study in which an unexpected and 
possibly related Serious Adverse Event occurs.  Interim data will also be discussed at the 
quarterly Midwest Pediatric Surgery Consortium meetings. 
 
12 ETHICS 
12.1 Institutional Review Board (IRB) 
 
Prior to study commencement, the protocol, the proposed informed consent form and other 
information to be provided to subjects, will be reviewed by a properly constituted 
Institutional Review Board (IRB) at the University of Michigan (IRBMED). Any 
amendments to the protocol will be reviewed and approved by IRBMED before 
implementation. 


Principal Investigator Name: Steven Bruch, MD, MSc 
UM HUM # 00103791 
PROTOCOL VERSION #: 1.0 
Page 15 of 17 
12.2 Subject Information and Consent 
The study team member will explain to each subject (in this case the parent) or legally 
authorized representative the nature of the study, its purpose, the procedures involved, the 
expected duration, the potential risks and benefits involved and any discomfort it may entail.  
Each subject will be informed that participation in the study is voluntary and that he/she may 
withdraw from the study at any time and that withdrawal of consent will not affect his/her 
subsequent medical treatment or relationship with the treating physician. 
This informed consent will be given by means of a standard written statement, written in 
non-technical language. The subject should read and consider the statement before signing 
and dating it, and should be given a copy of the signed document. If the subject cannot read 
or sign the documents, oral presentation may be made or signature given by the subject’s 
legally appointed representative, if witnessed by a person not involved in the study, 
mentioning that the patient could not read or sign the documents. No patient can enter the 
study before his/her informed consent has been obtained. 
The informed consent form is considered to be part of the protocol, and will be submitted for 
IRB approval. 
12.3 STUDY DISCONTINUATION CRITERIA 
12.3.1 
Stopping Rules for Safety reasons 
The Data Safety Monitoring Board (DSMB) will review all Serious Adverse Events (SAEs) and 
make recommendations regarding the continuation or discontinuation of the study, as 
appropriate. 
12.3.2 
Rules for Discontinuation of a Subject 
In the event a patient drops out of the study or is discontinued due to protocol violations, 
he/she will continue to receive standard of care, and data collection prior to discontinuation 
will be used in intent to treat analysis. 


Principal Investigator Name: Steven Bruch, MD, MSc 
UM HUM # 00103791 
PROTOCOL VERSION #: 1.0 
 
Page 16 of 17 
13 REFERENCES 
 
1. 
St Peter SD, Aguayo P, Fraser JD, et al. Initial laparoscopic appendectomy versus 
initial nonoperative management and interval appendectomy for perforated appendicitis with 
abscess: a prospective, randomized trial. Journal of pediatric surgery 2010;45:236-40. 
2. 
Blakely ML, Williams R, Dassinger MS, et al. Early vs interval appendectomy for 
children with perforated appendicitis. Archives of surgery (Chicago, Ill : 1960) 
2011;146:660-5. 
3. 
Chen C, Botelho C, Cooper A, Hibberd P, Parsons SK. Current practice patterns in 
the treatment of perforated appendicitis in children. Journal of the American College of 
Surgeons 2003;196:212-21. 
4. 
Kaminski A, Liu IL, Applebaum H, Lee SL, Haigh PI. Routine interval 
appendectomy is not justified after initial nonoperative treatment of acute appendicitis. 
Archives of surgery (Chicago, Ill : 1960) 2005;140:897-901. 
5. 
Puapong D, Lee SL, Haigh PI, Kaminski A, Liu IL, Applebaum H. Routine interval 
appendectomy in children is not indicated. Journal of pediatric surgery 2007;42:1500-3. 
6. 
Whyte C, Tran E, Lopez ME, Harris BH. Outpatient interval appendectomy after 
perforated appendicitis. Journal of pediatric surgery 2008;43:1970-2. 
 
 
 


Principal Investigator Name: Steven Bruch, MD, MSc 
UM HUM # 00103791 
PROTOCOL VERSION #: 1.0 
 
Page 17 of 17 
14 APPENDIX A: COMPLICATED APPENDICITIS CLINICAL 
PATHWAY 
 
On Admission: 
• NPO until nausea/vomiting/distention has resolved 
o Upon resolution start clear liquid diet and advance to regular diet as tolerated 
• IV fluids 
o Saline lock when tolerating PO fluids 
• IV antibiotics 
o Zosyn (ciprofloxacin and metronidazole if penicillin allergy) 
• Pain relief 
o Tylenol 
o Ibuprofen or toradol if appropriately hydrated and no bleeding concerns 
o Oxycodone/morphine prn 
• Have patient out of bed and ambulating 
Once the patient is afebrile for 24 hours, tolerating ¾ nutritional goals PO (determined by 
calorie count with the aid of a registered dietitian), diarrhea (if originally present) has 
resolved, and appears clinically improved, check CBC the next morning 
• If WBC is normal (decreased from admission), change to PO ciprofloxacin and 
metronidazole for 5 days 
o OK to discharge to home 
• If WBC is elevated or fever/symptoms still present Post-op or hospital day 5-7, 
continue IV antibiotics and obtain abdominal ultrasound +/- CT scan 
o If abscess identified, consider IR drainage