A Randomized Pilot Trial of Dilute Povidone-iodine Irrigation vs No Irrigation for Children With Acute, Perforated Appendicitis
Phase: PHASE2
Conditions: Acute, Perforated Appendicitis
Sponsor: The University of Texas Health Science Center, Houston

Protocol Version 5.0 
7.21.2016 
1 
IRB NUMBER: HSC-MS-15-1000 
IRB APPROVAL DATE: 08/29/2016 
 
 
 
 
 
 
 
 
 
 
 
 
 
A Randomized Pilot Trial of Dilute Povidone-iodine Irrigation vs No Irrigation for 
Children with Acute, Perforated Appendicitis 
 
NCT02664220 
 
Version Date: 08/29/2016 
 
 

Protocol Version 5.0 
7.21.2016 
2 
IRB NUMBER: HSC-MS-15-1000 
IRB APPROVAL DATE: 08/29/2016 
 
 
A Randomized Pilot Trial of Dilute Povidone-iodine Irrigation vs No Irrigation for 
 
Children with Acute, Perforated Appendicitis 
 
 
 
Site(s) involved and PI name(s) for corresponding site: 
 
University of Texas Health Sciences Center at Houston (Children’s Memorial Hermann 
Hospital): KuoJen Tsao, MD |||||||||||||||||||||||||||||||||||||||||| 

Protocol Version 5.0 
7.21.2016 
3 
IRB NUMBER: HSC-MS-15-1000 
IRB APPROVAL DATE: 08/29/2016 
 
 
 
Protocol 
 
 
 
Statement of Compliance 
 
Signature Page 
 
List of Abbreviations 
 
Abstract 
 
 
 
1 
Key Roles.................................................................................................................................. 
2 
Background Information and Scientific Rationale ................................................................... 
2.1 
Background Information ............................................................................................... 
2.2 
Scientific Rationale ....................................................................................................... 
2.3 
Potential Risks and Benefits ......................................................................................... 
2.3.1 Potential Risks .................................................................................................. 
2.3.2 Known Potential Benefits ................................................................................. 
3 
Objectives ................................................................................................................................. 
4 
Study Design ............................................................................................................................. 
5 
Study Population ....................................................................................................................... 
5.1 
Selection of the Study Population................................................................................. 
5.2 
Inclusion/Exclusion Criteria ......................................................................................... 
6 
Study Procedures/Evalations .................................................................................................... 
6.1 
Study Procedures .......................................................................................................... 
7 
Statistical Considerations.......................................................................................................... 
7.1 
Study Outcome Measures ............................................................................................. 
7.2 
Sample Size Considerations.......................................................................................... 
7.3 
Baysian Prior Probability…………………………………………………………….. 
7.4 
Participant Enrollment and Follow-Up ......................................................................... 
7.5 
A Priori Practice Algorithm.......................................................................................... 
7.6 
Analysis Plan ................................................................................................................ 
7.7 
Interim Analysis ............................................................................................................ 
7.8 
Data Safety and Monitoring Board (DSMB) ................................................................ 
8 
Subject Confidentiality ............................................................................................................. 
9 
Informed Consent Process ........................................................................................................ 
10 
Publication Plans…………………………………………………………………………… 
11 
Differences, Costs, and Funding…………………………………………………………… 
12 
Literature References 

Protocol Version 5.0 
7.21.2016 
4 
IRB NUMBER: HSC-MS-15-1000 
IRB APPROVAL DATE: 08/29/2016 
 
 
 
STATEMENT OF COMPLIANCE 
 
 
 
 
This study will be conducted according to US and international standards of Good Clinical 
Practice (45 CFR Part 46, 21 CFR Part 50, 21 CFR Part 56, 21 CFR Part 312, and International 
Conference on Harmonisation guidelines), applicable government regulations, and institutional 
research policies and procedures. 

Protocol Version 5.0 
7.21.2016 
5 
IRB NUMBER: HSC-MS-15-1000 
IRB APPROVAL DATE: 08/29/2016 
 
 
 
Signature Page 
 
 
 
KuoJen Tsao, MD 
  
 
 
Principle Investigator 
 
 
 
|||||||||||||||||||||||||||||||||| 
  
 
 
|||||||||||||||||||||||||||||||| 

Protocol Version 5.0 
7.21.2016 
6 
IRB NUMBER: HSC-MS-15-1000 
IRB APPROVAL DATE: 08/29/2016 
 
 
 
List of Abbreviations 
 
 
 
IAA 
Intra-abdominal abscess 
 
CMHH 
Children’s Memorial Hermann Hospital 
 
PVI 
Povidone-iodine (aka. Betadine®) 
CT 
Computed tomography 

Protocol Version 5.0 
7.21.2016 
7 
IRB NUMBER: HSC-MS-15-1000 
IRB APPROVAL DATE: 08/29/2016 
 
 
 
Significance 
 
Postoperative intra-abdominal abscesses are common occurrences after perforated appendicitis in 
pediatric patients despite utilization of evidence-based practices. Povidone-iodine is a commonly 
used antiseptic in surgical procedures and has been shown to be effective in reducing 
postoperative abscesses in adults with perforated appendicitis. This trial will be the first to 
rigorously test the efficacy of povidone-iodine irrigation in children and to verify its safety 
profile in this patient population. 

8 
IRB NUMBER: HSC-MS-15-1000 
IRB APPROVAL DATE: 08/29/2016 
Protocol Version 5.0 
7.21.2016 
1.0 Key Roles 
 
 
 
 
 
KuoJen Tsao, MD: As the Principle Investigator, Dr. Tsao will be responsible for the overall 
study from the surgical and medication administration perspective, compliance with regulations 
and ethical standards, patient safety, accuracy of the study results and reporting. 

9 
IRB NUMBER: HSC-MS-15-1000 
IRB APPROVAL DATE: 08/29/2016 
Protocol Version 5.0 
7.21.2016 
2.0 Background Information and Scientific Rationale 
 
 
 
 
 
2.1 Background 
 
Acute appendicitis is the most common gastrointestinal-related disease requiring surgery in 
children. Nearly 25% of all children with perforated appendicitis develop postoperative surgical 
site infections, specifically intra-abdominal abscesses (IAA), which is likely due to the intra- 
abdominal sepsis that occurs with the perforated viscus [1,2]. These IAA lead to increased 
patient discomfort, extended hospital stays, and increased emergency room visits and 
readmissions [3]. In line with other children’s hospitals in the country, Children’s Memorial 
Hermann Hospital (CMHH) has implemented evidence-based practices such as early and 
culture-directed antibiotic coverage, early operation, and protocol-driven postoperative care [1,2]. 
Specifically for patients with perforated appendicitis, over the course of four years, our dedicated 
team of pediatric surgeons has reviewed patient outcomes on an iterative basis, leading to 
targeted intraoperative and postoperative interventions such as transperitoneal drain placement 
and customized home antibiotic regimens in an attempt to decrease postoperative IAA. Despite 
all these efforts, the IAA rate has remained unchanged. 
 
 
In a 2004 survey of North American pediatric surgeons, over 90% responded that they use intra- 
abdominal irrigation for patients with advanced appendicitis [4]. However, although its use is 
widespread, intraoperative irrigation has not been widely studied. There is strong evidence of no 
difference in IAA rate when no irrigation is compared to normal saline irrigation for children 
with perforated appendicitis [5], and there is even some evidence that suggests that NS irrigation 
may actually increase the rate of postoperative IAA [6]. Another irrigation solution that is widely 
available and commonly used in the operating room is povidone-iodine (PVI). PVI is an 
antiseptic solution consisting of polyvinylpyrrolidone with water, iodide, and 1% available 
iodine. It has bactericidal ability against a large array of pathogens, including those pathogens 
which commonly cause postoperative IAA in children with perforated appendicitis [7,8]. Just a 
few examples of how PVI is used for surgery include: skin and mucosal preoperative 
preparation, intestinal intraluminal irrigation prior to division and anastomosis, mediastinal 
washout following sternal wound infections, and refractory chylothorax in newborns [9–11]. 

10 
IRB NUMBER: HSC-MS-15-1000 
IRB APPROVAL DATE: 08/29/2016 
Protocol Version 5.0 
7.21.2016 
 
 
 
Although PVI is commonly used in pediatric operations, its use as an intra-abdominal irrigant for 
perforated appendicitis has not been rigorously studied. 
 
 
A recent meta-analysis demonstrated that intraoperative irrigation with PVI in abdominal, 
gynecologic, and spinal surgeries significantly decreased postoperative abscesses compared to 
normal saline irrigation or no irrigation at all (pooled relative risk 0.13, 95%CI 0.05-0.37, 
p<0.001) [12]. However, of the trials included in this particular analysis, only two of the four 
focused on treating intra-abdominal sepsis and neither of the studies indicated the number or age 
of pediatric patients who were enrolled [13,14]. A recent survey of European general adult 
surgeons found that nearly 40% of them commonly use PVI irrigation for contaminated or dirty 
abdominal surgeries such as perforated appendicitis [15]. Despite the existing data supporting the 
efficacy of PVI to reduce IAA and its common use in dirty abdominal surgeries, there have been 
no recent, high-quality trials demonstrating its effectiveness in reducing IAA after perforated 
appendicitis in children. 
 
 
2.2 Scientific Rationale 
 
Hypothesis: Among pediatric patients presenting to CMHH with perforated appendicitis, intra- 
abdominal irrigation with PVI versus no irrigation will decrease the rate of 30-day postoperative 
IAA. 
Specific Aim 1: To conduct a pilot randomized controlled trial to compare the efficacy of PVI 
irrigation to no irrigation for decreasing postoperative IAA in children with perforated 
appendicitis 
Specific Aim 2: To verify the safety profile of dilute PVI for intra-abdominal irrigation 
Specific Aim 3: To determine the effect of PVI irrigation vs no irrigation on hospital length of 
stay, readmissions, and cost 
 
 
2.3 Potential Risks and Benefits 
 
PVI is commonly used in the surgical treatment of adults with dirty abdominal surgeries such as 
perforated appendicitis [15]. PVI could cause an allergic reaction or iodine toxicity; however, 
this is exceptionally rare, especially at dilute concentrations [16]. Potential benefits include a 
reduction in postoperative IAA, decreased length of stay, and fewer readmissions. The 

11 
IRB NUMBER: HSC-MS-15-1000 
IRB APPROVAL DATE: 08/29/2016 
Protocol Version 5.0 
7.21.2016 
 
 
 
knowledge obtained from this study could help to improve patient outcomes following acute, 
perforated appendicitis as well as provide preliminary data for a larger, pragmatic trial. 
 
 
There is a possiblility of breach of confidentiality. However, all data collected will be put into a 
password protected database with will be kept on a pasword-protected secure server with access 
limited to study personnel assocaited wtiht he study. 
 
 
3.0 Objectives 
 
To determine the effect of PVI irrigation versus no irrigation on the rate of IAA at 30-days post- 
operative following appendectomy for acute, perforated appendicitis 
 
 
4.0 Study Design 
 
This will be a single-center, pilot RCT carried out by the Pediatric Surgery Department at UT 
Houston – CMHH. All UT Houston pediatric surgery attendings will participate. Patients will be 
randomized to PVI irrigation or no irrigation. 
 
 
5.0 Study Population 
 
 
 
5.1 Selection of the Study Population 
 
A team of five pediatric surgery research coordinators will coordinate the enrollment, consent, 
and assent processes. The research coordinator team will be available 24/7 to the pediatric 
surgery service via a dedicated pager. Residents and attendings on the pediatric surgery service 
will page the research coordinators upon diagnosing a patient with suspected appendicitis. All 
patients undergoing appendectomy for acute appendicitis will be eligible for the trial. After 
enrollment, only patients who are diagnosed intraoperatively with perforated appendicitis will be 
randomized. 
 
 
5.2 Inclusion/Exclusion Criteria 
 
Inclusion criteria: Patients aged 2-17 years old who undergo an appendectomy for acute, 
perforated appendicitis at CMHH. Diagnosis of perforated appendicitis is made intraoperatively 

12 
IRB NUMBER: HSC-MS-15-1000 
IRB APPROVAL DATE: 08/29/2016 
Protocol Version 5.0 
7.21.2016 
 
 
 
by the surgeon and is defined as the visualization of a gross defect in the appendiceal wall or the 
presence of intraperitoneal stool or a fecalith at the time of operation. 
 
 
Exclusion criteria: 1) patients presenting with simple or gangrenous appendicitis, 2) patients 
with a history of iodine sensitivity, thyroid disease or renal disease, 3) patients undergoing 
interval or incidental appendectomy, and 4) pregnancy. 
 
 
We do not anticipate pregnancy in our study population. Pregnant subjects and their fetuses may 
be placed at undue risk for the purposes of the study. Therefore, pregnant patients will be 
excluded from participating in the study. 
 
 
Withdrawal: Prior to or after providing informed consent, patients may withdraw from the study 
at any point pre- or postoperatively by informing any of the care providers during the patient’s 
hospital stay. 
 
 
6.0 Study Procedures/Evaluations 
 
 
 
6.1 Study Procedures 
 
Randomization and allocation: 
 
Enrollment will occur prior to the operation either in the emergency room, on the ward, or in the 
preoperative holding area. The randomization schema will be variable block randomization, and 
sequentially numbered, opaque, sealed envelopes will be used to blind allocation. Following 
consent, the sealed, opaque envelope will be attached to the patient’s chart which accompanies 
the patient into the operating room. Only if the patient is found intraoperatively to have 
perforated appendicitis will the envelope be opened by the circulating nurse and the patient 
assigned to the control or intervention group. If a patient is determined to have simple or 
gangrenous appendicitis, the sealed envelope will remain unopened, and a research coordinator 
will retrieve it for re-use. 
 
 
Standard Preoperative, Operative, and Postoperative Protocols 

13 
IRB NUMBER: HSC-MS-15-1000 
IRB APPROVAL DATE: 08/29/2016 
Protocol Version 5.0 
7.21.2016 
 
 
 
Upon patient admission to the hospital, the patient will be started on the preoperative 
appendicitis protocol that has been in place at CMHH since 2011. Briefly, this protocol entails 
immediate initiation of intravenous piperacillin-tazobactam or metronidazole/gentamicin for 
patients allergic to penicillin. The intravenous antibiotics are continued throughout the inpatient 
admission. Additionally, patients are fluid resuscitated and analgesia is provided. 
 
 
A laparoscopic approach will be attempted for all patients; however, conversion from 
laparoscopy to an open technique will not result in exclusion from the trial. After carefully 
examining the peritoneal cavity and upon identifying the appendix, the surgeon will declare 
whether or not the patient has a perforated appendicitis (as defined previously). At that point, the 
circulating nurse will open the sealed envelope and group assignment will occur. Subsequently, 
once the surgeon has removed the appendix from the abdomen and ensured hemostasis, the 
surgeon will proceed to use the battery-powered, suction-irrigator device to irrigate primarily the 
right upper, right lower, and pelvic regions as these are the predominant locations for 
postoperative IAA formation [5]. If the patient is assigned to the intervention group, the nurse 
will create the dilute PVI irrigation by first removing 100ml of saline from a 1000ml bag and 
replacing it with 100ml of stock, 10% PVI (readily available in the operating room), thereby 
creating an irrigation solution with 1% PVI. Dilution of the PVI will occur while the surgeon 
completes the operation (removes the appendix). Once the appendix has been removed and 
hemostasis ensured, the surgeon will perform the irrigation with 10cc/kg (minimum 100ml and 
maximum 1000ml) of dilute PVI. The dose of PVI (10cc/kg) is based on previous studies [13,14] 
as well as consensus from our pediatric surgery team and is felt to be a conservative dose [14]. 
After completing the irrigation, the surgeon will suction out all intra-abdominal fluid into a 
suction canister and the amount will be recorded. Patients allocated to the control group will not 
undergo intra-abdominal irrigation. 
 
 
All postoperative care will follow the standardized perforated appendicitis care pathway which 
includes continued intravenous antibiotics until they are discharged from the hospital. Standard 
discharge criteria for perforated appendicitis patients will comprise the following parameters: 
oral/axillary temperature < 100°F (oral) x 24hr, tolerating regular diet, pain relief with oral 
analgesics, ambulating with minimal assistance as age appropriate, normal white blood cell count 

14 
IRB NUMBER: HSC-MS-15-1000 
IRB APPROVAL DATE: 08/29/2016 
Protocol Version 5.0 
7.21.2016 
 
 
 
without bandemia. Those patients who do not meet discharge criteria within seven days will 
undergo a computed tomography (CT). Patients diagnosed with an IAA on CT scan will receive 
an interventional radiology consultation and will undergo percutaneous drainage when deemed 
feasible by the interventional radiologist. 
 
 
The same discharge criteria will apply for all patients. All patients will be scheduled for follow- 
up with a pediatric surgeon within one week of discharge. Those patients who are not able to 
attend the follow up appointment will be called and rescheduled. In the clinic, a post- 
appendectomy form (Appendix A) will be filled out by a pediatric surgeon who will document 
physical exam findings as well as any additional postoperative complications or visits to an 
emergency room (ER) or other healthcare facility as reported by the patient/parents. All patients 
will be called between 30-32 days postoperatively (in case postoperative day 30 falls on the 
weekend), and a form will be filled out that details any further complications or healthcare 
facility visits. 
 
 
Postoperative Laboratory Testing & 6- and 12-month Follow Up 
 
To verify the safety profile of PVI irrigation, at the time of intraoperative diagnosis of perforated 
appendicitis, the anesthesia provider will send a blood sample to the lab to measure baseline 
glucose, TSH, and T4 levels in 10 patients. Two additional samples will be sent at 24 hours and 
as needed at 72 hours postoperatively by the floor nurse. Pediatric endocrinology will follow 
these first 10 patients during their admissions and will provide therapeutic guidance in the 
unlikely event that symptomatic hypothyroidism occurs. Six and 12-month follow up with 
patients (via chart review and phone call) will take place to determine if any small bowel 
obstructions occur due to abdominal adhesions. Although rare, abdominal adhesions are a known 
entity after appendectomy and theoretically may be exacerbated by either normal saline or PVI 
irrigation. 
 
 
7.0 Statistical Consideration 
 
Providing both frequentist and Bayesian approaches has been shown to provide complementary 
interpretations [17]. Furthermore, while a frequentist analysis may result in a “negative” study, 
posterior probabilities based on a Bayesian approach may still be sufficient for clinicians to 

15 
IRB NUMBER: HSC-MS-15-1000 
IRB APPROVAL DATE: 08/29/2016 
Protocol Version 5.0 
7.21.2016 
 
 
 
implement an intervention despite an insignificant p-value or to recruit additional centers to 
participate in an ongoing study. There are several more reasons why performing a Bayesian 
analysis alongside a frequentist analysis may be beneficial, many of which are listed in a study 
by Wijeysundera and colleagues [17]. Therefore, our study will include both frequentist and 
Bayesian analyses. 
 
 
7.1 Study Outcome Measures 
 
The primary outcome will be 30-day postoperative IAA rate. An IAA will be defined as an 
image-confirmed (ultrasound or CT) fluid collection deemed to be an IAA by a pediatric 
radiologist at CMHH. The imaging studies will be obtained for patients who undergo 
postoperative imaging at outside facilities and will be read by CMHH pediatric radiologists. The 
radiologists will remain blinded to the patient’s intervention. Patients who are determined to 
have an IAA will be referred to interventional radiology for percutaneous drainage and will be 
restarted on intravenous antibiotics based on organism susceptibilities. 
 
 
Secondary outcomes will include total hospital length of stay within 30 postoperative days and 
rates of readmissions and ER visits within 30 postoperative days. Total hospital length of stay 
will be the aggregate of all days in the hospital including any appendicitis-related readmissions 
within 30 postoperative days. Thirty-day ER visits and readmissions will also be determined 
through chart review, clinical encounters, and phone calls. Other adverse events that will be 
recorded will include abnormal thyroid function tests requiring endocrinology intervention 
immediately postoperatively and small bowel obstructions within one year after surgery. 
 
 
A small outcomes adjudication committee will review a random sample of patient charts to 
verify the reported findings. Members of the committee will have no vested interest in the 
outcomes of the proposed study and will be blinded to treatment allocation. 
 
The patient list will be generated when the pediatric surgery team informs the research 
coordinator that a patient with suspected appendicitis is being consented for an appendectomy. 
The patient MRN will be converted to a unique patient ID using a linking log that is accessible to 
the study coordinators. Electronic records from Children’s Memorial Hermann Hospital and UT 

16 
IRB NUMBER: HSC-MS-15-1000 
IRB APPROVAL DATE: 08/29/2016 
Protocol Version 5.0 
7.21.2016 
 
 
 
professional building pediatric surgery clinic will be accessed. The data will be collected by the 
principle investigator and those listed in the IRB application. No patient identifiers will be 
collected. Data points to be abstracted from the electronic medical record or requested from the 
Memorial Hermann Hospital system will include: 
 
1.   Age 
 
2.   Race 
 
3.   Gender 
 
4.   Height 
 
5.   Weight 
 
6.   Admission date(s) 
 
7.   Admission time(s) 
 
8.   Admission location(s) 
 
9.   Discharge date(s) 
 
10. Discharge time(s) 
 
11. OR date(s) 
 
12. Postoperative diagnosis 
 
13. Operative procedures 
 
14. Operative reports 
 
15. Pathologic diagnosis 
 
16. Laboratory results 
 
17. Imaging type(s) 
 
18. Imaging dates(s) 
 
19. Imaging location(s) 
 
20. Imaging results 
 
21. Dates and causes of any readmissions 
 
22. Medications administered, including antibiotics 
 
23. Administration dates of medications 
 
24. Side effects related to antibiotic administration 
 
25. Dates of diet advancement 
 
26. Date(s) of surgical site infections 

17 
IRB NUMBER: HSC-MS-15-1000 
IRB APPROVAL DATE: 08/29/2016 
Protocol Version 5.0 
7.21.2016 
 
 
 
27. Hospital costs (to be requested from the Memorial Hermann Hospital system) 
 
a. Direct and indirect costs associated with hospital stay 
 
 
 
7.2 Sample Size Considerations 
 
Using a frequentist approach, to demonstrate a clinically important decrease in IAA from 24% to 
 
16% with 80% power and a two-tailed significance level of 0.05, a sample size of 784 patients 
(392 patients per group) would be required. Based on current practice (approximately 100 
appendectomies are performed annually for perforated appendicitis) and an estimated consent 
rate of 50%, study enrollment would take approximately 15 years. 
 
 
In anticipation of using a Bayesian approach, the CMHH pediatric surgeons have come to 
consensus that they would change the way they practice if a Bayesian analysis could determine 
with 75% confidence whether or not PVI is beneficial. Based on Monte-Carlo simulations using 
the prior probabilities described below, our pediatric surgeons are confident that a 2-year, pilot 
trial will provide sufficient power to guide future efforts (Appendix B). 
 
 
7.3 Bayesian Prior Probabilities 
 
A Bayesian prior represents the probability distribution that summarizes the beliefs about the 
treatment benefit prior to seeing study results. The prior is determined by taking into account 
existing evidence, expert knowledge and option, and defining clinically important outcomes. 
After thorough review of the current literature concerning intra-abdominal irrigation for 
perforated appendicitis (which are referenced in the Introduction) and discussion, the CMHH 
pediatric surgeons feel the following Bayesian priors are appropriate for analyzing the benefit of 
PVI in this trial (RR=relative risk, CI=confidence interval): 
 
 
Neutral: 
RR 1 (95%CI 0.5-1.6) 
Optimistic: 
RR 0.67 (95%CI 0.3-1.2) 
24% IAA (95%CI 13-37%) 
16% IAA (95%CI 9-34%) 
 
 
To determine the prior probability of treatment benefit for the control group (no irrigation), we 
will use three years of prospectively collected data from CMHH of patients who underwent the 
current protocol which is to not perform irrigation (n=325). Further strengthening this prior 

18 
IRB NUMBER: HSC-MS-15-1000 
IRB APPROVAL DATE: 08/29/2016 
Protocol Version 5.0 
7.21.2016 
 
 
 
probability is the fact that similar results have been published by similar programs across the 
country [1,2]. The following prior will be used when analyzing the benefit of no irrigation 
(control group) during the trial: 24% IAA (95%CI 20-29%) 
 
 
7.4 Participant Enrollment and Follow-Up 
 
A multidisciplinary, post-appendectomy surveillance program developed by the Infection 
Control and Pediatric Surgery departments has been in place since 2011 and is tasked with 
prospective surveillance of all appendicitis patients. Through the joint efforts of both 
departments, all appendicitis patients are closely followed during the 30 days after discharge 
through electronic medical record review, wound culture review, and all SSI reporting among the 
Memorial Hermann Hospital affiliates (11 hospitals in the Houston metropolitan area). Each 
documented SSI is jointly reviewed by members of both departments during a monthly meeting. 
 
 
7.5 A Priori Practice Algorithm 
 
The CMHH pediatric surgeons have devised an a priori algorithm to guide their next 
steps in clinical practice based on the study results at the end of two years. The algorithm uses an 
optimistic prior probability of treatment success and takes into account the results of the Monte- 
Carlo simulations previously performed (Appendix B). 
 
 
 

19 
IRB NUMBER: HSC-MS-15-1000 
IRB APPROVAL DATE: 08/29/2016 
Protocol Version 5.0 
7.21.2016 
 
 
 
 
 
7.5 Analysis Plan 
 
Demographics and baseline characteristics of each group will be clearly displayed in a table. 
Primary and secondary outcomes will be determined and compared for each group, including 
effect sizes and 95% CI. For binary outcomes, absolute and relative effect sizes will be 
determined. Bayesian probability models will also be performed to determine the likelihood and 
degree of treatment benefit. Chi-square, Fisher’s exact, Student’s t-test or Mann-Whitney U tests 
will be performed for categorical and continuous variables, respectively. Generalized linear 
models will be utilized to look at predictors of IAA, ER visits, readmissions, and LOS. The data 
will be analyzed based on their distribution. 
 
 
A CONSORT flow diagram will be provided to clearly demonstrate the number of participants 
who were randomized, received the intended treatment, and were analyzed for the primary and 
secondary outcomes. The reasons for losses to each group will be documented; intention-to-treat 
(primary) and per-protocol (secondary) analyses will be performed. 
 
 
Limitations 
 
(1) Subjectivity of the primary outcome. An outcome such as IAA may be subjective due to 
variable definitions or interpretations. However, we utilized a standardized definition that is 
utilized, endorsed, and has been validated by other pediatric surgeons [18]. In addition, trained 
clinicians blinded to the allocation will make the assessments. 
 
 
(2) Failure to blind the treating clinicians. Clinicians making treatment decisions may not be 
blinded to the intervention if they were present during the operation. However, postoperative 
protocols are in place to help minimize differential treatment based on treatment allocation. 
Additionally, the patients, radiologists, and data analysts will be blinded. Research coordinators 
will keep a separate spreadsheet to keep track of group assignment. 
 
 
(3) Generalizability. This study will be performed on pediatric patients at a tertiary care 
 
academic center. The applicability of these results to other clinical settings may be limited. If this 

20 
IRB NUMBER: HSC-MS-15-1000 
IRB APPROVAL DATE: 08/29/2016 
Protocol Version 5.0 
7.21.2016 
 
 
 
study demonstrates safety and efficacy, other institutions will be recruited for a larger, 
multicenter trial. 
 
 
7.7 Interim Analysis 
 
Six months after the first patient is enrolled, an interim analysis will be conducted by an 
independent Data & Safety Monitoring Board to ensure there are no increased harms of PVI and 
that ongoing study participation is not futile. 
 
 
7.8 Data Safety and Monitoring Board (DSMB) 
 
The DSMB will be composed of a general surgeon, pediatric endocrinologist, infectious disease 
physician, statistician, and an academic surgeon with clinical trial experience. 
 
 
Harms will entail but not be limited to: abnormal thyroid tests requiring endocrinology 
intervention or adhesive small bowel obstruction requiring readmission or surgery. There are no 
other anticipated harms imposed by PVI irrigation; however, any unexpected harms that arise 
will be included in the interim and final analyses. At the time of the interim analysis, if the 
probability of increased harms is >75% or the probability that PVI is beneficial is <10%, the 
study will be stopped and existing data will be reported. 
 
 
8.0 Subject Confidentiality 
 
Patient data will be entered into a secure, UT-Houston REDCap database [19] by the study 
coordinators. Only study investigators approved by the Institutional Review Board to participate 
in the study will have access to the REDCap data. Upon completion of the study, the REDCap 
database will be permanently deleted. 
 
 
9.0 Informed Consent Process 
 
Consent will be obtained from each participant prior to surgery after verification that all 
inclusion and exclusion criteria have been met. Patients will have the consent read to them by 
one of the coordinators and all questions will be answered. Minors will also be assented for the 
study. Subjects who speak languages other than English will be commnicated with using an 
official interpreter via the Hermann translator line. This will allow the research team the 

21 
IRB NUMBER: HSC-MS-15-1000 
IRB APPROVAL DATE: 08/29/2016 
Protocol Version 5.0 
7.21.2016 
 
 
 
opportunity to discuss the consent, answer and questions and discuss the protocol with the 
assistance of a certified interpreter. All patients willing to be enrolled in the study will receive a 
signed copy of the consent form. 
 
 
A Waiver of Consent will be requested for eligible study participants unable to provide assent or 
parents/guardians who refuse to sign an informed consent for the following reasons: 
 Emergent intervention requiring medical sedation, incapacitation, and/or endotracheal 
intubation (i.e. septic shock, cardiopulmonary resuscitation) 
 Auditory, visual, or mental impairment and/or learning disability 
 
 Parent or guardian preference - refusal or declination to permit child to provide assent 
 
(i.e. extreme fatigue, weakness, lethargy) 
 
 
 
10.0 
Differences, Costs, and Funding 
 
Currently, each arm of the study (PVI or no irrigation) has been deemed to be safe and is utilized 
commonly by some surgeons in some settings as the standard of care. The unique portion of the 
intervention is simply randomizing all of the interventions in a systematic fashion rather than in a 
arbitrary fashion (current practice). 
 
We do not feel that any of the interventions or follow-ups represent a cost to the patient or 
healthcare system above current practice. 
 
Currently, we are seeking funding to support this trial. However, without an IRB number and 
approved IRB, many funding sources are not available. We anticipate seeking funding from 
intra- and extra-mural grants. 
 
 
 
Literature References 
 
[1] 
 Blakely ML, Williams R, Dassinger MS, Eubanks JW, Fischer P, Huang EY, et al. Early 
vs interval appendectomy for children with perforated appendicitis. JAMA Surg 
2011;146:660–5. 
 
[2] 
 St Peter SD, Aguayo P, Fraser JD, Keckler SJ, Sharp SW, Leys CM, et al. Initial 
laparoscopic appendectomy versus initial nonoperative management and interval 

22 
IRB NUMBER: HSC-MS-15-1000 
IRB APPROVAL DATE: 08/29/2016 
Protocol Version 5.0 
7.21.2016 
 
 
 
appendectomy for perforated appendicitis with abscess: a prospective, randomized trial. J 
Pediatr Surg 2010;45:236–40. 
[3] 
 Newman K, Ponsky T, Kittle K, Dyk L, Throop C, Gieseker K, et al. Appendicitis 2000: 
variability in practice, outcomes, and resource utilization at thirty pediatric hospitals. J 
Pediatr Surg 2003;38:372–9; discussion 372–9. 
[4] 
 Muehlstedt SG, Pham TQ, Schmeling DJ. The management of pediatric appendicitis: a 
survey of North American Pediatric Surgeons. J Pediatr Surg 2004;39:875–9. 
[5] 
 St Peter SD, Adibe OO, Iqbal CW, Fike FB, Sharp SW, Juang D, et al. Irrigation versus 
suction alone during laparoscopic appendectomy for perforated appendicitis: a prospective 
randomized trial. Ann Surg 2012;256:581–5. 
[6] 
 Moore C, Smith R, Herbertson R, Toevs C. Does Use of Intraoperative Irrigation with 
Open or Laparoscopic Appendectomy Reduce Post-Operative Intra-abdominal Abscess? 
Am Surg 2011;77:78–80. 
[7] 
Zamora JL, York N. Chemical and Microbiologic Characteristics and Toxicity of 
 
Povidone-Iodine Solutions 1956. 
 
[8] 
Fallon SC, Hassan SF, Larimer EL, Rodriguez JR, Brandt ML, Wesson DE, et al. 
 
Modification of an evidence-based protocol for advanced appendicitis in children. J Surg 
 
Res 2013;185:273–7. 
 
[9] 
 Parker M, EC A, MWN N, CH D, JC B. Povidone-iodine colorectal carcinoma. Ann R 
Coll Surg Engl 1985;67:1–2. 
[10]  Kovacikova L, Kunovsky P, Skrak P, Hraska V, Kostalova L, Tomeckova E. Thyroid 
hormone metabolism in pediatric cardiac patients treated by continuous povidone-iodine 
irrigation for deep sternal wound infection. Eur J Cardiothorac Surg 2002;21:1037–41. 
[11]  Scottoni F, Fusaro F, Conforti A, Morini F, Bagolan P. Pleurodesis with povidone–iodine 
for refractory chylothorax in newborns: Personal experience and literature review. J 
Pediatr Surg 2015. 
[12]  Fournel I, Tiv M, Soulias M, Hua C, Astruc K, Glele LSA. Meta-analysis of 
intraoperative povidone-iodine application to prevent surgical-site infection. Br J Surg 
2010;97:1603–13. 
 
[13] 
Sindelar WF MR. Intraperitoneal Irrigation with Povidone-Iodine Solution for the 
 
Prevention of Intra-abdominal Abscesses in the Bacterially Contaminated Abdomen. Surg 

23 
IRB NUMBER: HSC-MS-15-1000 
IRB APPROVAL DATE: 08/29/2016 
Protocol Version 5.0 
7.21.2016 
 
 
 
Gynecol Obstet 1979;148:409–11. 
 
[14]  Sindelar WF, Brower ST, Merkel AB, Takesuet EI. Randomised trial of intraperitoneal 
irrigation with low molecular weight povidone-iodine solution to reduce intra-abdominal 
infectious complications. J Hosp Infect 1985;6:103–14. 
[15]  Whiteside OJH, Tytherleigh MG, Thrush S, Farouk R, Galland RB. Intra-operative 
peritoneal lavage--who does it and why? Ann R Coll Surg Engl 2005;87:255–8. 
[16]  Lachapelle JM. A comparison of the irritant and allergenic properties of antiseptics. Eur J 
Dermatology 2014;24:3–9. 
[17]  Wijeysundera DN, Austin PC, Hux JE, Beattie WS, Laupacis A. Bayesian statistical 
inference enhances the interpretation of contemporary randomized controlled trials. J Clin 
Epidemiol 2009;62:13–21.e5. 
[18]  St Peter SD, Sharp SW, Holcomb GW, Ostlie DJ. An evidence-based definition for 
perforated appendicitis derived from a prospective randomized trial. J Pediatr Surg 
2008;43:2242–5. 
 
[19]  Harris P a, Taylor R, Thielke R, Payne J, Gonzalez N, Conde JG. Research electronic 
data capture (REDCap)--a metadata-driven methodology and workflow process for 
providing translational research informatics support. J Biomed Inform 2009;42:377–81. 

24 
IRB NUMBER: HSC-MS-15-1000 
IRB APPROVAL DATE: 08/29/2016 
Protocol Version 5.0 
7.21.2016 
 
 
 
Appendix A: Pediatric Appendicitis, Standardized Clinical Follow-up Form 
 
 

25 
IRB NUMBER: HSC-MS-15-1000 
IRB APPROVAL DATE: 08/29/2016 
Protocol Version 5.0 
7.21.2016 
 
 
 
Appendix B: Monte-Carlo simulations 
 
 
Scenario 1: 
 
• 
Sample size: n=100 (50/group) 
 
• 
True IAA rate (no irrigation): 24% (20-29%) 
 
• 
True IAA rate (PVI): 16% (95%CI 9-34%), RR 0.67 (95%CI: 0.3-1.2) 
 
• 
75% posterior probability the RR<1 
 
• 
Optimistic prior: RR 0.67 (95% CI: 0.3-1.2) 
 
 89% power 
 
Scenario 2: 
 
• 
Sample size: n=200 (100/group) 
 
• 
True IAA rate (no irrigation): 24% (20-29%) 
 
• 
True IAA rate (PVI): 16% (95%CI 9-34%), RR 0.67 (95%CI: 0.3-1.2) 
 
• 
75% posterior probability the RR<1 
 
• 
Optimistic prior: RR 0.67 (95% CI: 0.3-1.2) 
 
 94% power 
 
Scenario 3: 
 
• 
Sample size: n=100 (50/group) 
 
• 
True IAA rate (no irrigation): 24% (20-29%) 
 
• 
True IAA rate (PVI): 16% (95%CI 9-34%), RR 0.67 (95%CI: 0.3-1.2) 
 
• 
75% posterior probability the RR<1 
 
• 
Neutral prior: RR 1 (95% CI: 0.5-1.6) 
 
 64% power