Clinical trial NCT02991937
Conditions: Appendicitis
Sponsor: NYU Langone Health
Start date: 2016-12-01; Completion date: 2020-12-01
Enrollment: 39 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
Several prior studies have demonstrated that medical management of acute appendicitis in adults is a safe first-line therapy option. This study aims to determine whether non-operative management of uncomplicated acute appendicitis with antibiotics is non-inferior to operative management in a pediatric population. This study will be a randomized controlled trial comparing non-operative management with antibiotics to surgical management of uncomplicated acute appendicitis. The hypothesis is that antibiotics are not worse than surgery for the treatment of uncomplicated appendicitis in children.

Detailed description:

Arms: arm 1: Subjects in the medical therapy arm will be treated with piperacillin/tazobactam for at least 24 hours. Ciprofloxacin/metronidazole will be used in penicillin-allergic patients. Subjects will be maintained on nothing by mouth with intravenous fluids for at least 12 hours. Subjects will be transitioned to oral antibiotics when their WBC is normal, they have a decrease in CRP by ≥ 15%, and they have been afebrile for 24 hours on IV antibiotics. arm 2: Subjects in the surgical treatment arm will receive intravenous antibiotics until the time of operation, and will be maintained on intravenous fluids and no oral intake until they undergo appendectomy as per standard of care. Appendectomy will occur within 24 hours of enrollment. Subjects in the surgical treatment arm will receive post-operative antibiotics as per standard of care.
Interventions: intervention 1: Piperacillin/Tazobactam intervention 2: Surgical Treatment
Intervention descriptions: intervention 1: 24 hours of IV antibiotic administration intervention 2: Appendectomy

Protocol documents:
Prot_SAP_000.pdf: 
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Study Title: Comparison of Medical and Surgical Treatment of Uncomplicated Acute Appendicitis 
in Children 
 
Principal Investigator: Jason Fisher 
 
NYU IRB Study Number: s16-00655 
NCT Number: NCT02991937 
HHC IRB Study Number: STUDY00000621 
 
Purpose of the Study and Background 
Purpose of the Study 
Several prior studies have demonstrated that medical management of acute appendicitis in adults 
is a safe first-line therapy option. This study aims to determine whether non-operative 
management of uncomplicated acute appendicitis with antibiotics is non-inferior to operative 
management in a pediatric population.  
Background 
Appendicitis has traditionally been thought of as a surgical condition. Over the past ten years 
there have been several studies comparing medical and surgical management of acute 
appendicitis in adults which have demonstrated that medical management with antibiotics alone 
is a safe first-line option in adults with acute appendicitis.1-4 Long-term follow-up of patients 
managed without surgery has also demonstrated longer-lasting safety of non-operative 
management of acute appendicitis in adults.4 For pediatric patients, surgery is still the mainstay 
of treatment for uncomplicated appendicitis and perforated appendicitis. Recent prospective 
studies have demonstrated that non-operative management with antibiotics may be a feasible 
option for cases of uncomplicated acute appendicitis in children.5,6 These studies, however, are 
limited by small sample sizes, and/or nonrandom treatment assignment.  
The current standard of care for preoperative antibiotics in uncomplicated appendicitis includes a 
second or third generation cephalosporin with metronidazole if the cephalosporin does not provide 
adequate anaerobic coverage.7 These antibiotics are used to control infection and bridge patients 
to surgery rather than to achieve true eradication of the infection. Additionally, these antibiotics 
prevent post-operative complications such as wound infections and intra-abdominal abscesses. 
Typically, patients receiving pre-operative antibiotics for appendicitis will receive them for at most 
12-24 hours prior to surgery, the equivalent of 1-3 doses. For patients with beta-lactam or 
cephalosporin allergies the standard of care is ciprofloxacin with metronidazole. In patients with 
uncomplicated appendicitis operation adequately treats the infection, and post-operative 
antibiotics are rarely needed.  
In prior studies conducted in children and adults the antibiotics used to treat uncomplicated 
appendicitis non-operatively were intravenous piperacillin/tazobactam or a carbapenem for at 
least 24 hours. For patients with beta-lactam allergies ciprofloxacin/metronidazole was typically 
used for the initial intravenous therapy.2,5,6,8 This is followed by oral amoxicillin/clavulanate or a 
fluoroquinolone/metronidazole 
for 
a 
total 
antibiotic 
course 
of 
7-10 
days.1-3,5,6,8 
Piperacillin/tazobactam and carbapenems are broader in spectrum of coverage than the pre-
operative antibiotics used per standard of care. For uncomplicated appendicitis managed 
operatively there is no difference in outcomes if broad-spectrum or narrow-spectrum pre-operative 
antibiotics are used.9 Broad-spectrum antibiotics are used for non-operative management 
because infection control is dependent on strong therapeutic agents rather than a procedural 


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intervention. Given local E. coli resistance patterns to Augmentin, ciprofloxacin/metronidazole will 
be used as the first-line oral antibiotic combination in this study. These antibiotics will provide 
adequate gram-negative, pseudomonal and anaerobic coverage, as per guidance by a Pediatric 
Infectious Disease Specialist at NYU.  
Study Design 
This study will be a randomized controlled trial comparing non-operative management with 
antibiotics to surgical management of uncomplicated acute appendicitis. The hypothesis is that 
antibiotics are not worse than surgery for the treatment of uncomplicated appendicitis in children. 
The primary outcome will be survey scores on the Pediatric Quality of Life Inventory (PedsQL) 
Generic Core Scale Parent-proxy report. Secondary outcomes will include child scores on the 
PedsQL; length of stay; immediate, 1-week, 2-week, 30-day, and 60-day success of non-
operative management; readmission rates for both groups; and long-term complications over one 
year.  
Characteristics of the Research Population 
Number of Subjects 
A total of 190 subjects will be included in the study. This is based on validating statistics for the 
PedsQL Child Report and Parent-Proxy report.10 Given the potential variability of response for 
subjects on the child report based on maturity of the subject, the Parent-Proxy report will be used 
as the primary outcome. For the Parent-proxy report the standard deviation of scores is 15.9 with 
an of mean clinically important difference (MCID) is 4.5 on the same 100-point scale. To establish 
non-inferiority the MCID will be used as a clinically acceptable margin of difference between the 
two treatment arms. The null hypothesis is that PedsQL scores for the non-operative management 
group will be lower than PedsQL scores for the operative management group by 4.5 points or 
fewer. The alternative hypothesis is that scores for the non-operative management group will be 
lower than scores for the operative management group by more than 4.5 points. Given our 
hypothesis that antibiotics alone are non-inferior to operative management, a significance level of 
α = 0.05 (Z1-α = 1.645) and Power of 0.80 (β = 0.20, Z1-β = 0.84), the expected sample size 
necessary for a non-inferiority trial is 77 per group, based on the formula for a one-tailed test: N 
(per group) = (Z1-α + Z1-β)2 * (SD/MCID)2.  1The total sample necessary for the study would 
therefore be 154 subjects.  
There are few studies in pediatric populations from which to generalize data about consent rates 
for randomization. The prior study conducted in children in the US was a parent-option format, 
and the consent rate for participation was 88%. Of the subjects and parents who agreed to 
participate 39% chose surgery, suggesting a non-operative approach is not significantly less 
favorable for parents. In adults, the more recent studies cite consent rates of participants at 80-
90%. Expecting a 10-20% non-consent rate, a total of 190 patients would need to be enrolled to 
maintain the power of the study.  
Patients will be identified for potential study inclusion upon consultation of the Pediatric Surgery 
team. Subjects will be recruited from all hospital sites covered by the pediatric surgical faculty at 
NYU. These sites include NYU Tisch Hospital, Bellevue Hospital, and Hackensack University 
Medical Center (HUMC) in New Jersey. Additionally, the pediatric surgeons cover consults from 
NYU Brooklyn and the NYU-run free-standing Cobble Hill Emergency Department. Patients under 
the age of 12 from these last two sites are transferred to Tisch Hospital for care, and will be 
 
 


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recruited at Tisch Hospital. Patients aged 13 and above will be recruited at the hospital where 
they initially present (NYU Brooklyn or Cobble Hill). 
In the past year approximately 170 patients who would have been eligible for study enrollment 
presented to these facilities for treatment of acute appendicitis. 50% of subjects were treated at 
NYU Tisch Hospital, 35% at HUMC, and 15% at Bellevue. Using these proportions to estimate 
enrollment, 95 subjects are expected to be recruited from NYU, 67 from HUMC and 28 from 
Bellevue. The protocol has been submitted for independent review by the IRBs of these 
institutions. Approval of the study at HUMC is dependent on approval by the NYU IRB. When the 
study is approved by the IRB at HUMC a modification will be submitted to the NYU IRB, which 
will include the approval letter by the external site.   
Gender of Subjects 
Subjects of both genders are eligible for enrollment in the study. The gender distribution is not 
expected to favor either gender.   
Age of Subjects 
Subjects will be 6-17 years old. Prior studies comparing medical and surgical management of 
appendicitis in children used age criteria of 5-15 or 7-17 years of age. The incidence of 
appendicitis prior to the age of 5 is one to six cases per 10,000 children, making it a rare diagnosis 
in children under the age of 5. Peak incidence of acute appendicitis occurs in the second decade 
of life from 10-19 years of age. Younger children are more likely to present at a later stage of 
disease and are therefore less likely to improve with antibiotics alone. Given that individuals 18 
and older at the time of presentation are treated by adult general surgeons, limiting age eligibility 
to individuals 6-17 years of age will capture the patients most likely to benefit from the intervention 
while simultaneously limiting the variability in surgical intervention.  
Racial and Ethnic Origin  
Participants of all racial and ethnic origins will be eligible for participation. The intended racial and 
ethnic distribution of subjects is not expected to vary significantly from that of the populations at 
the study sites.  
Inclusion Criteria 
Age 6-17, first episode of appendicitis, Pain < 48 hours, White blood cell count < 18,000, 
temperature < 103º F, radiographic evidence of acute appendicitis on ultrasound or CT without 
evidence of perforation, and appendiceal diameter < 11 mm, ability to take oral antibiotics  
Exclusion Criteria 
Prior antibiotic treatment for appendicitis, presence of medical condition prohibiting surgical 
therapy, radiographic or clinical evidence of abscess or perforation, appendiceal mass, positive 
pregnancy test, other diagnosis equally as likely as appendicitis, pain for ≥ 48 hours, white blood 
cell count ≥ 18,000, temperature ≥ 103º F, or appendiceal diameter ≥ 11 mm, inability to take oral 
antibiotics.  
Vulnerable Subjects 
The study population will include the vulnerable population of children. This is necessitated by the 
primary aim of the study, to determine whether medical management of acute appendicitis is 
superior to surgical management in a pediatric population. The study is designed to limit subjects 
to those who are likely to benefit from the treatment offered.  


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Methods & Procedures 
Methods & Procedures  
Patients for whom the Pediatric Surgery team is consulted for abdominal pain suspicious for acute 
appendicitis will be screened for inclusion/exclusion criteria. Eligible participants will have a 
diagnosis of acute appendicitis made by an attending pediatric surgeon on the basis of history 
and physical exam, with confirmatory imaging. The consent process will be conducted by the 
attending pediatric surgeon, all of whom are listed on this study, with the patient and their 
parent/guardian. Assent from the subject will be obtained independently of consent from their 
representative. 
Subjects will be randomized to receive either medical therapy or surgical intervention. 
Randomization will be achieved using a permuted block protocol. Blocks will be determined and 
treatments within a block will be assigned for each block prior to the start of the study. Upon 
enrollment, the treatment arm of each subject will be assigned as per the pre-determined order. 
Subjects in both treatment arms will be maintained with intravenous fluids and no oral intake from 
the time of identification. If it has not already been done by the Pediatric Emergency Department 
team, a CBC with differential and C-reactive protein level (CRP) will be drawn. All potential 
subjects will receive piperacillin/tazobactam as antibiotic therapy at the time of diagnosis. 
Ciprofloxacin/metronidazole will be used in penicillin-allergic subjects. Patients often present with 
acute appendicitis during evening hours, making the time from initial evaluation to surgery 
approximately 12-24 hours. Starting all patients on the same antibiotics after initial evaluation will 
allow all potential subjects to receive identical initial treatment while still allowing potential subjects 
and their representatives ample time to consider participation in the study.  
Subjects in the medical therapy arm will be treated with piperacillin/tazobactam for at least 24 
hours. Ciprofloxacin/metronidazole will be used in penicillin-allergic patients. Subjects will be 
maintained on nothing by mouth with intravenous fluids for at least 12 hours. During this time their 
pain, and vital signs will be monitored every 4 hours as per standard of care. Specific attention 
will be paid to trends in pain levels, temperature and heart rate. If they show improvement in 
abdominal pain, they may be advanced to a diet.  
After 24 hours of IV antibiotic administration a repeat CBC with differential and CRP will be drawn. 
Subjects will be transitioned to oral antibiotics when they have been afebrile for 24 hours on IV 
antibiotics, and they have a normal WBC or decrease in CRP by ≥ 15%. If patients have not 
achieved these clinical milestones after 48 hours of IV antibiotics, they will have an 
appendectomy.  All patients will receive one dose of oral ciprofloxacin/metronidazole and be 
observed to assess tolerance prior to discharge. Subjects tolerating oral antibiotics will be 
discharged on oral antibiotics for a total 10-day course when they have adequate pain control and 
are ambulating. If oral ciprofloxacin is not a feasible option (if prohibitively expensive due to lack 
of coverage by insurance or unavailable due to pharmacy stock or compounding issue), the 
patients will be discharged on a regimen of oral Augmentin. All patients’ insurance coverage will 
be checked for oral ciprofloxacin and metronidazole coverage prior to switching to oral Augmentin 
so as to limit the patients’ exposure to different antibiotics within a short period of time. Augmentin  
offers similar coverage to ciprofloxacin and is readily available, and prior studies have found that 
Augmentin is non-inferior to emergency appendectomy for the treatment of acute appendicitis, in 
both children and adults. 11-14 
Failure of antibiotic therapy will be defined as lack of improvement in pain or vital signs, persistent 
fever, failure to normalize WBC, uptrending or < 15% decrease in CRP, or worsening clinical 


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exam after 48 hours of treatment with intravenous antibiotics. These patients will have an 
appendectomy. 
Subjects in the surgical treatment arm will receive intravenous antibiotics until the time of 
operation, and will be maintained on intravenous fluids and no oral intake until they undergo 
appendectomy as per standard of care. Appendectomy will occur within 24 hours of enrollment. 
Subjects in the surgical treatment arm will receive post-operative antibiotics as per standard of 
care.  
Follow-up will occur on the following schedule:  
24 hours after discharge: Subjects will receive a phone call from the research team to ensure 
they were able to obtain and start outpatient oral antibiotics.  
1 week after discharge: Subjects will receive a phone call from the research team to assess 
recovery, and return to school (subjects) or work (parents). Subjects in the medical treatment arm 
will be asked about whether they have been taking antibiotics appropriately, and whether they 
have developed complications such as recurrence of appendicitis. 
2 weeks after discharge: Subjects will receive a phone call from the research team to evaluate 
whether they recovered from treatment, whether they experienced any complications, and when 
they returned to school/work. For subjects in the surgical treatment arm complications include 
abscess development and wound infections. The primary complication for subjects in the medical 
treatment arm is recurrence of appendicitis. 
30 days after discharge: Subjects and their parents/guardians will present for an office visit. For 
subjects in the surgical arm this is a standard post-operative visit. For subjects in the medical 
treatment arm this will be the equivalent post-treatment evaluation. Subjects and their 
representatives will be given the PedsQL Generic Core Scale to complete at this visit.The PedsQL 
Generic Core Scale is a validated instrument available in multiple languages to assess quality of 
life in pediatric patients, with a parent-proxy report available. The instrument is designed for 
pediatric patients with different version of the form available for self-report and parent-report 
based on subject age. This is considered to be the best quality-of-life assessment tool in the 
pediatric population. A surgery-specific or appendicitis-specific scale is not available, so the 
generic core scale will be used. This instrument assesses daily physical, emotional, social and 
school functioning.  
30-day follow-up will also determine the 30-day success of non-operative management and 30-
day readmissions for participants in both groups.  
30 days provides adequate time for subjects in both groups to recover from treatment and resume 
their pre-treatment level of activity. This will allow the survey to assess the extent to which 
subject/parent life was affected by appendicitis and treatment course. Given that the antibiotic 
treatment regimen for the non-operative arm in this study is expected to last 10 days, follow-up at 
a period shorter than 30 days may not allow enough time after completion of treatment to assess 
for the effect of treatment on patient life and return to pre-treatment functioning, which is part of 
the aim of the PedsQL survey 
60 days after discharge: Subjects will receive a phone call from the research team to assess for 
complications as a result of treatment. For subjects in the medical treatment arm this will include 
recurrence of appendicitis and appendectomy during the 60-day follow-up period.  
1 year following treatment; Subjects will receive a phone call from the research team. Long-
term follow-up will occur via telephone at 1 year to determine whether subjects developed 
complications after the 60-day follow-up period, and whether subjects in the medical treatment 


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arm experienced recurrence of appendicitis, and/or had an appendectomy after the 60-day follow-
up period.   
.  
Data Analysis and Data  Safety Monitoring  
See above for rationale behind sample size determination. An intention-to-treat analysis will be 
performed based on the initial group a subject is randomized to. Survey result data will be 
analyzed using a one-tailed two-sample student’s t-test to assess for non-inferiority of non-
operative management. A chi-squared test will be used to compare readmission rates of the two 
groups. 95% confidence intervals will be established for immediate and 30-day success rates of 
non-operative management and need for interval appendectomy. Finally, the types of 
complications in each treatment group will be analyzed qualitatively. Subgroup analyses will be 
performed to determine whether there are differences in outcomes between patients based on 
the study site at which they are treated.  
Given that surgery is the standard of practice for uncomplicated acute appendicitis in children, 
safety will be evaluated based on outcomes in the medical treatment arm. Data safety monitoring 
of the overall study will be the responsibility of Dr. Fisher. Tracy McTiernan, CPNP will be 
responsible for day-to-day review of study participants. She is a certified pediatric nurse 
practitioner and has been working with the pediatric surgery team at NYU for several years. For 
each patient enrolled records will be reviewed after 48 hours of admission to evaluate for 
complications within the immediate treatment period. These early complications will include 
reactions to antibiotics, and early failure of medical treatment requiring surgery during the initial 
hospital stay.  
Outcomes will be monitored on a 6-month basis, with the start of the 6-month period being the 
first date of initial treatment. Adverse events during this 6-month period will include readmission, 
need for non-surgical invasive procedures such as drain placement by interventional radiology, 
failure of medical therapy requiring surgery, other complications of medical management such as 
allergic reaction, and overall length of stay. The study will be stopped early if greater than 25% of 
patients in the medical treatment arm require an invasive procedure (surgical or non-surgical) 
within this 6-month period. 
Adverse events related to medical or surgical therapy will be reported to the IRB as soon as 
possible within 72 hours of their confirmed diagnosis. Often times children with acute appendicitis 
demonstrate natural variations in symptomatology that may appear to be complications at first, 
but resolve within 24 hours without intervention. Additionally, most complications of medical or 
surgical treatment of appendicitis are associated with low morbidity.  Therefore, to allow proper 
diagnosis of a complication, without shielding the IRB from timely data nor placing the patient at 
unnecessary risk, a 72-hour reporting window after confirmed diagnosis is most appropriate.” 
Reports on decisions made as a result of safety monitoring review will be distributed to study sites 
via email. The email will contain a summary of adverse events and trends in the data to that point. 
The report will be sent to all investigators and support staff (surgical PAs and NPs) at all study 
sites. Information on individual patients will not be included in this email. Reports will be sent to 
all study sites and the IRB every 6 months.   
Da ta Storage and Confidentiality  
Subject data will be deidentified by assigning a unique study-ID to each subject which is linked to 
their medical record number. All data, including PedsQL survey scores will be stored in a REDCap 
database created specifically for this study. Paper surveys will be maintained in the study binder 


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in a locked cabinet in the Pediatric Surgery office. Only study personnel will have access to the 
data. 
The key linking subject medical record numbers with study-IDs will be maintained in a separate 
REDCap registry accessible only by the study PI and Tracy McTiernan, CPNP.  
Risk/Benefit Assessment 
Risk 
Risks of medical therapy for appendicitis include necessarily longer initial hospital stay, 
readmission, treatment failure requiring surgery or another procedure during the initial presenting 
episode, recurrence of appendicitis at a later date, possible appendectomy after the initial 
treatment episode, and potential allergic reaction to antibiotics. 
Risks of antibiotics depend on the specific agent used. Adverse effects of the antibiotics to be 
used in this study are as follows: 
Piperacillin-Tazobactam  
• 
GI reactions: diarrhea, nausea, vomiting, constipation, abdominal pain   
• 
Local infusion reaction: rash and pruritus  
• 
Pharyngitis 
• 
Allergic reaction  
Ciprofloxacin 
• 
Musculoskeletal pain/joint sprains (With oral cipro, resolve within 30 days of end of 
treatment)   
• 
GI reactions: diarrhea, vomiting, dyspepsia, abdominal pain 
• 
Neurological events: dizziness, nervousness, insomnia, somnolence  
• 
Rhinitis  
• 
Rash  
Metronidazole 
• 
GI reaction: nausea, vomiting, diarrhea, abdominal pain, constipation 
• 
Headache 
Skin flushingAugmentin 
• 
GI reaction: diarrhea, abdominal pain, nausea, vomiting 
• 
Rash, urticaria 
• 
Vaginitis 
• 
Candidiasis 
 
Risks of operative treatment include pain, bleeding, infection, and potential damage to 
surrounding structures, which are the standard risks of surgery. Common risks of anesthesia 
include pain, nausea and vomiting. Rare, more serious risks of anesthesia include allergic 
reaction to anesthetic agents, cardiovascular collapse, respiratory depression.  
Protection Against Risks  
Risks of medical therapy will be minimized by careful selection of subjects for enrollment and 
regular monitoring of pain, vital signs, and clinical exam during the period of IV antibiotic treatment 
to detect treatment failure early. Patients who experience an allergic reaction to antibiotics will 
treated for the reaction, switched to a different antibiotic combination and identified as a protocol 
violation.  


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Risks of operative treatment will be minimized by careful selection of subjects for enrollment, and 
having trained pediatric surgeons and pediatric anesthesiologists provide care for patients pre-, 
peri-, and post-operatively. Laparoscopic surgery minimizes the risks of pain, bleeding and 
infection, and is the standard of care for appendectomy. Open operations will only be performed 
if a laparoscopic approach is determined to be unsafe.  
Potential Benefits to the Subjects 
The benefits of medical treatment of appendicitis include avoidance of surgery and risks of 
surgery and anesthesia, quicker return to school and activity, and shorter parental leave.  
Benefits of surgery include shorter initial hospital stay, decreased exposure to antibiotics, prompt 
resolution of the infection and decreased risk of recurrence.  
Subject Identification, Recruitment and Consent/Assent 
Method of Subject Identification and Recruitment  
On an annual basis, the pediatric surgeons at NYU perform 170 appendectomies across 3 
hospital settings (NYU Tisch Hospital, Bellevue Hospital, Hackensack University Medical Center 
in New Jersey) on patients who would be eligible for study inclusion. They also cover pediatric 
surgery consults from NYU Lutheran and the NYU-run Cobble Hill Emergency Department.   
Any patient for whom the Pediatric Surgery service is consulted regarding possible appendicitis 
will be identified as a potential subject. Potential subjects will be screened for inclusion and 
exclusion criteria and will be recruited upon meeting these criteria. Given the urgent nature with 
which subjects present seeking treatment for appendicitis, it is not possible to adopt a more 
targeted recruitment strategy such as letters or phone calls to participants.  
Upon meeting inclusion criteria, subjects and their parents will be informed about the study an its 
purpose, they will undergo the consent process, and will be provided up to 12 hours to consider 
participation prior to committing to a treatment plan, as detailed in the “Process of Consent” 
section below.  
Process of Consent 
Consent will be obtained by the attending physician on call. All of the pediatric surgeons at NYU 
are listed on this protocol. Subjects and their representatives will be taken to a private area for 
the consent process. They will be provided with a written version of the consent/assent document 
or a consent short form in their native language. An authorized interpreter will be used to help 
ensure clear communication and comprehension of the details of study participation whenever 
necessary.  
The informed consent process will include explanation of the diagnosis of acute appendicitis and 
explanation that the purpose of the study is to compare the effectiveness of antibiotics and surgery 
for treating acute appendicitis. The consent process will specify that the treatment arm will be 
determined randomly, that participation in the study is voluntary, and that subjects can withdraw 
at any point in time.  
While acute appendicitis is an urgent diagnosis, it is not an emergent diagnosis requiring an 
immediate trip to the operating room within the first few hours of presentation. There is typically a 
period of 6-12 hours between the time of diagnosis of acute appendicitis and the time that subjects 
must commit to a definitive treatment plan. The initial management will be identical for both 
treatment arms during this time period (fluid resuscitation, no oral intake and IV antibiotics). 
Subjects and parents will be informed about the study at the time of initial diagnosis, but the 
decision to enroll can be delayed up to 12 hours to allow subjects and parents adequate time to 


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consider participation without increasing risk of treatment failure, or progression to complicated 
appendicitis in either group.  
Subjects and their representatives will be informed that participation will last one year from the 
date of enrollment, with follow-up intervals of 30-days, and 1 year after treatment. The details of 
study participation will be explained, including completion of the PedsQL Generic Core Scale at 
the 30-day follow-up point, as well as phone interviews at the 1-year follow-up points. The 
physician will explain the risks and benefits of medical treatment as well as the course of treatment 
should subjects choose not to participate. Finally, subjects and their representatives will be 
informed of how data collected for the purposes of the trial will be stored in order to maintain 
patient privacy.  
Subjects and their representatives will be asked to demonstrate comprehension of the consent 
process prior to signing the consent/assent form for the study. Subjects who are 17 years of age 
at the time of enrollment will be asked to sign a consent form if they turn 18 during the study 
period. Signed forms will be kept in a regulatory binder to be stored in a locked cabinet in the 
Division of Pediatric Surgery office.  
Subjec t/Representative Comprehension  
Subjects and representatives will be asked to verbally describe the purpose of the study and risks 
and benefits of participation as well as alternate therapy options should they choose not to 
participate to confirm comprehension during the consent process. Subjects will be asked to assent 
to participation in addition to representative consent.   
Consent Forms 
Consent/assent forms attached.  
Costs to the Subject 
Subjects will incur the standard cost of treatment for appendicitis including the costs of treatment 
in the emergency room, imaging, and hospital stay as per their insurance company coverage. 
Patient in the non-operative treatment arm will incur the cost of both inpatient and outpatient 
antibiotics. All costs for treatment will be billed to subject insurance. 
Payment for Participation 
Subjects will not be paid for participation in the study.  
Study Monitoring, Auditing, and Inspecting 
Study Monitoring Plan  
Dr. Fisher will be responsible for overall study monitoring. Study monitoring will include site 
assessment review and staff training prior to initiation of the study. Interval visits will review sites 
for maintenance of study-related documents and assessment of study-related facilities. Interim 
monitoring visits will occur every 3-6 months based on the site activity. Other monitoring will occur 
as needed or requested. 
Auditing and Inspecting 
The investigator will permit study-related monitoring, audits, and inspections by the IRB/ECand 
University compliance and quality assurance groups of all study related documents. The 
investigator will also ensure the capability for inspections of applicable study-related facilities. 
Participation as an investigator in this study implies acceptance of potential inspection by 
government regulatory authorities and applicable University compliance and quality assurance 
offices. 


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References 
1. 
Di Saverio S, Sibilio A, Giorgini E, et al. The NOTA Study (Non Operative Treatment for 
Acute Appendicitis): prospective study on the efficacy and safety of antibiotics 
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2. 
Hansson J, Körner U, Khorram-Manesh A, Solberg A, Lundholm K. Randomized clinical 
trial of antibiotic therapy versus appendicectomy as primary treatment of acute 
appendicitis in unselected patients. British Journal of Surgery. 2009;96(5):473-481. 
3. 
Hansson J, Körner U, Ludwigs K, Johnsson E, Jönsson C, Lundholm K. Antibiotics as 
First-line Therapy for Acute Appendicitis: Evidence for a Change in Clinical Practice. 
World journal of surgery. 2012;36(9):2028-2036. 
4. 
McCutcheon BA, Chang DC, Marcus LP, et al. Long-term outcomes of patients with 
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913. 
5. 
Minneci PC, Sulkowski JP, Nacion KM, et al. Feasibility of a Nonoperative Management 
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6. 
Svensson JF, Patkova B, Almstrom M, et al. Nonoperative treatment with antibiotics 
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7. 
Nadler EP, Gaines BA. The Surgical Infection Society guidelines on antimicrobial 
therapy for children with appendicitis. Surgical infections. 2008;9(1):75-83. 
8. 
Salminen P, Paajanen H, Rautio T, et al. Antibiotic therapy vs appendectomy for 
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JAMA. 2015;313(23):2340-2348. 
9. 
Kronman MP, Oron AP, Ross RK, et al. Extended- Versus Narrower-Spectrum 
Antibiotics for Appendicitis. Pediatrics. 2016;138(1). 
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